Methods of valorising cashew nut shell liquid (CNSL) and / or a component thereof

Abstract

This disclosure relates to methods of manufacturing cardanols and / or derivatives thereof, cardols and / or derivatives thereof, lipids and / or derivatives thereof, and lipid nanoparticles and / or derivatives thereof. The disclosure extends to the cardanols and / or derivatives thereof, the cardols and / or derivatives thereof, the lipids and / or derivatives thereof, and the lipid nanoparticles and / or derivatives thereof. The disclosure further extends to use of lipids, preferably ionizable lipids, in the manufacture of lipid nanoparticles, wherein said lipid nanoparticles are employed in the manufacture of delivery means for active pharmaceutical ingredients (API).

Description

[0001] METHODS OF VALORISING CASHEW NUT SHELL LIQUID (CNSL) AND / OR A COMPONENT THEREOF

[0002] FIELD OF DISCLOSURE

[0003] Generally, this disclosure relates to methods of manufacturing cardanols and / or derivatives thereof, cardols and / or derivatives thereof, lipids and / or derivatives thereof, and lipid nanoparticles and / or derivatives thereof. The disclosure extends to the cardanols and / or derivatives thereof, the cardols and / or derivatives thereof, the lipids and / or derivatives thereof, and the lipid nanoparticles and / or derivatives thereof. The disclosure further extends to methods of valorising cashew nut shell liquid (CNSL) and / or a chemical component thereof by employing same in the manufacture of cardanols and / or derivatives thereof, cardols and / or derivatives thereof, lipids and / or derivatives thereof, and / or lipid nanoparticles and / or derivatives thereof.

[0004] A first aspect of this disclosure relates to a method of manufacturing a cardanol and / or derivatives thereof including 3 -pentadecylphenol. In certain embodiments, this disclosure relates to use of cashew nut shell liquid (CNSL) and / or chemical components thereof in a method of manufacturing a cardanol and / or derivatives thereof including 3 -pentadecylphenol. The cardanol and / or its derivatives may undergo further downstream processing to provide valorisable chemical compounds and / or compositions including lipids and / or lipid nanoparticles. This aspect relates to a cardanol and / or derivatives thereof including 3- pentadecylphenol manufactured from CNSL, and a method for manufacturing same.

[0005] A second aspect of this disclosure relates to a method of manufacturing an arene, particularly a symmetrical resorcinol including 5 -alkylresorcinols and / or derivatives thereof including cardol (5- heptadecylresorcinol, also known as adipostatin A). The symmetrical resorcinol may be a di -hydroxy resorcinol. In certain embodiments, this disclosure relates to use of cashew nut shell liquid (CNSL) and / or chemical components thereof in a method of manufacturing cardol (5-heptadecylresorcinol) from 3- pentadecylphenol and / or derivatives thereof. The cardol may undergo further downstream processing to provide valorisable chemical compounds and / or compositions including lipids and / or lipid nanoparticles. This disclosure extends to arenes including symmetrical resorcinols themselves.

[0006] A third aspect of this disclosure relates to a method of manufacturing an arene, including a 5 -alkyl - 2 -hydroxybenzaldehyde and / or derivatives thereof from 3 -pentadecylphenol. In certain embodiments, this disclosure relates to use of cashew nut shell liquid (CNSL) and / or chemical components thereof in a method of manufacturing 5 -alkyl -2 -hydroxybenzaldehydes and / or derivatives thereof. The 5 -alkyl -2- hydroxybenzaldehydes may undergo further downstream processing to provide valorisable chemical compounds and / or compositions including but not limited to lipids and / or lipid nanoparticles. This disclosure extends to arenes including 5 -alkyl -2 -hydroxybenzaldehyde and / or derivatives thereof themselves. A fourth aspect of this disclosure relates to a method of manufacturing lipids, preferably ionizable lipids. In certain embodiments, this disclosure relates to use of cashew nut shell liquid (CNSL) in a method of manufacturing lipids, and wherein the lipids, preferably ionizable lipids, may be for use in providing lipid nanoparticles, preferably ionizable lipid nanoparticles. In certain example embodiments, this disclosure relates to the use of a cardanol and / or cardol in the manufacturing of the lipids. In certain further example embodiments, this disclosure relates to the use of a cardanol and / or cardol, at least one of which being derived from CNSL and / or chemical components thereof in the manufacturing of the lipids. This disclosure extends to lipids themselves.

[0007] A fifth aspect of this disclosure relates to a method of manufacturing lipid nanoparticles. In certain embodiments, this disclosure relates to use of cashew nut shell liquid (CNSL) and / or chemical components thereof in a method of manufacturing lipids for use in lipid nanoparticle formulation, and wherein the lipid nanoparticles may be for use in transfection applications and / or for use in biological, medical and / or pharmaceutical applications. In certain example embodiments, this disclosure relates to the use of a cardanol in the manufacturing of lipids for use in lipid nanoparticle formulation. In certain further example embodiments, this disclosure relates to the use of a cardanol derived from CNSL in the manufacturing of lipids for use in lipid nanoparticle formulation. The lipid nanoparticles may further undergo downstream processing for the manufacture of vaccines, including mRNA type vaccines. The fifth aspect extends to the lipid nanoparticles themselves and / or the vaccines themselves.

[0008] BACKGROUND

[0009] Recently, there has been a move away from using petroleum or petroleum-based products as starting reagents in organic synthesis of commercially relevant chemical products. In order to employ sustainable carbon sources as starting reagents for organic synthesis researchers have considered the use of biomass, particularly non-edible biomass that would otherwise be discarded. As such, the valorisation of non-edible biomass and / or waste product biomass has been a much-researched topic.

[0010] One non-edible biomass source that has been a topic of much research is cashew nut shell liquid (CNSL). CNSL is known to have little commercial value on its own, however, CNSL is rich in phenolics and is known as a non-edible biomass-derived chemical feedstock for the production of paints, resins, polymers, and surfactants. Cashew crop is a common high value crop in many developing countries and valorising any waste product produced by its cultivation could provide much needed economic benefits and / or upliftment in such countries.

[0011] Furthermore, consumers have become reluctant to purchase non-sustainably derived products.

[0012] CNSL typically includes a mixture of phenolic compounds. The primary constituents of CNSL include three structurally related anacardic acids and three structurally related cardanols, with trace amounts of three structurally related cardols. The cardols are a very minor constituent of CNSL, but it is a chemical compound that may be utilized as a building block for producing higher value chemicals via appropriate downstream organic syntheses.

[0013] Since the three structurally related cardols are a very minor constituent of CNSL, obtaining sufficient amounts for downstream processing into higher value compounds is arduous and expensive. Alternative synthetic routes for producing cardols are known to be expensive and time consuming. The current market price of purchasing cardol is in the region of US$660 for 10 grams which is often viewed as prohibitively high therein stifling its use and application in the production of downstream higher value compounds.

[0014] The cardanols, in particular, where numerous structurally related compounds are converted by hydrogenation into 3 -pentadecylphenol is also commercially available at about $80 for 100 grams, a cheaper price than cardol.

[0015] There is a need for developing new methods of manufacturing cardanols including 3- pentadecylphenol in a cost effective manner for further downstream processing. There is a need to provide a method of manufacturing cardanols utilizing a non-edible biomass source, wherein such biomass may also be a waste product.

[0016] Based on availability and difficulty in manufacturing processes, there is a need for developing new methods of manufacturing arenes, including a 5 -alkylresorcinol, including cardol in a cost effective manner for further downstream processing. There is a need to provide a method of manufacturing an arene, including a 5-alkylresorcinol, including hydrogenated cardol (5-heptadecylresorcinol) utilizing a non-edible biomass source, wherein such biomass may also be a waste product.

[0017] Research into novel transfection applications in biology remains a topical subject matter. Further, in the field of medicine, nucleic acid and / or protein and / or peptide delivery to a desired target site remains a busy field of endeavour. Still further, in the field of medicine, vaccine development has become topical against the background of the COVID-19 pandemic. Particularly, mRNA technologies have been developed as a category of available treatment agents, including therapeutic and / or prophylactic agents, to at least ameliorate the effects of various diseases, and have been utilized successfully in vaccine development and production on commercial scale.

[0018] In regard to mRNA technologies in medicine, it is well known that in order for the mRNA to provide its prophylactic and / or therapeutic effect in vivo, it requires a targeted delivery means that prevents degradation of the nucleic acid prior to its release at a target site, and concomitantly both facilitates cellular uptake and cytoplasmic mRNA release from the delivery means.

[0019] Lipid nanoparticles are known as effective delivery means for biomolecules, particularly of RNA such as mRNA. mRNA loaded lipid nanoparticles need to overcome multiple extracellular and intracellular hurdles in order to function as desired. The lipid nanoparticle needs to protect the mRNA from extracellular nuclease degradation, and also successfully avoid renal glomerular filtration and / or other post administration biochemical / metabolic pathways that could lead to degradation. The mRNA loaded lipid nanoparticle needs to reach its target site, being a particular cell type, and needs to be internalized into said cell. Inside the cell, the mRNA molecules need to be released from the lipid nanoparticle then escape endosomes before being translated into protein in the cytoplasm.

[0020] The above challenges provide for complex chemical structures of lipids and / or lipid nanoparticles that are often both difficult and / or expensive to synthesise and / or formulate.

[0021] Apart from the complex and / or expensive nature of formulating lipid nanoparticles for mRNA transfection, prophylactic and therapeutic technologies, and transfection of cultured cells in vitro or ex vivo, the procurement of raw materials required for such syntheses / formulation is becoming increasingly topical. The public is ever conscious of ethically and / or sustainably sourced raw materials to provide desired solutions. The ethical and / or sustainable nature of COVID-19 vaccines has been a factor in vaccine hesitancy, and will remain a topical issue in future.

[0022] The synthesis of two commercial ionizable lipids (SMI 02 and ALC-0315) used in the formulations for both the MODERNA® and Pfizer-BioNTech COVID vaccines rely on starting materials from petrochemical resources. In the synthesis of both lipids the intermediates and the final lipids require silica gel chromatography in their purification, which adds to the expenses. In addition steps including the use of the Grignard reaction in the synthesis of SMI 02 and chromium mediated oxidation reactions in the synthesis of ALC-0315 add to the complications of the synthesis and waste disposal. WO 2017 / 049245 discloses lipids for the delivery of therapeutic or prophylactic agents.

[0023] WO 2009 / 086558 and WO 2013 / 016058 disclose amino lipids suitable formethods of drug delivery via nanoparticle compositions, liposomes, and lipoplexes.

[0024] W02020 / 183422 teaches CNSL for use in manufacturing compositions including molecules having excited state intramolecular proton transfer ESIPT character for treating and / or preventing sunburn and / or preventing U.V. damage. The prior art does not motivate employing CNSL and / or derivatives thereof as starting reagents for the manufacturing of ionizable lipids for use in medical and / or pharmaceutical applications.

[0025] There is a need for providing a new and innovative method of manufacturing lipids and lipid nanoparticles in sustainable and a cost-effective manner. There is a need to provide a method of manufacturing lipids and lipid nanoparticles utilizing a non-edible biomass source, wherein such biomass may also be a waste product.

[0026] There is a need to ameliorate at least one of the disadvantages above, or otherwise known in the prior art, for at least one of the first to fifth aspects of this disclosure. SUMMARY

[0027] Generally, this disclosure relates to methods of manufacturing cardanols and / or derivatives thereof, cardols and / or derivatives thereof, lipids and / or derivatives thereof, and lipid nanoparticles and / or derivatives thereof. The disclosure extends to the cardanols and / or derivatives thereof, the cardols and / or derivatives thereof, the lipids and / or derivatives thereof, and the lipid nanoparticles and / or derivatives thereof .

[0028] Broadly, the methods of this disclosure may include at least one of, but not limited to, the following:

[0029] (i) a method of manufacturing a cardanol and / or derivatives thereof, including 3- pentadecylphenol;

[0030] (ii) a method of manufacturing an arene, including a symmetrical resorcinol (or di-hydroxy resorcinol), including 5 -alkylresorcinol and / or derivatives thereof, including hydrogenated cardol (5 -heptadecylresorcinol) from 3-pentadecylphenol;

[0031] (iii) a method of manufacturing an arene, including a 5 -alkyl -2 -hydroxybenzaldehyde and / or derivatives thereof from 3-pentadecylphenol;

[0032] (iv) a method of manufacturing lipids, preferably ionizable lipids; and

[0033] (v) a method of manufacturing lipid nanoparticles, preferably ionizable lipid nanoparticles.

[0034] Broadly, any one or more of the methods herein may in certain embodiments provide methods of valorising cashew nut shell liquid (CNSL) and / or a chemical component thereof.

[0035] Broadly, the methods may in certain embodiments each include use of cashew nut shell liquid (CNSL), and / or a chemical component thereof, as a raw material source. In embodiments where a chemical component of CNSL is utilized it is to be understood that such chemical component may be directly derived from CNSL. Alternatively and / or additionally, it is to be understood that such chemical component may be synthetically derived. Alternatively and / or additionally, it is to be understood that such chemical component may be procured from a source different from CNSL.

[0036] Broadly, the disclosure extends to use of CNSL and / or a chemical component thereof in the manufacture of cardanols and / or derivatives thereof, arenes and / or derivatives thereof, 5 -alkylresorcinol and / or derivatives thereof, 5 -alkyl -2 -hydroxybenzaldehyde and / or derivatives thereof, lipids and / or derivatives thereof, lipid nanoparticles and / or derivatives thereof, and cannabinoids and / or derivatives thereof.

[0037] Broadly, the disclosure further extends to cardanols and / or derivatives thereof, arenes and / or derivatives thereof, 5 -alkylresorcinol and / or derivatives thereof, 5 -alkyl -2 -hydroxybenzaldehyde and / or derivatives thereof, lipids and / or derivatives thereof, lipid nanoparticles and / or derivatives thereof, each produced utilizing the methods of this disclosure. Broadly, the disclosure still further extends to cardanols and / or derivatives thereof, arenes and / or derivatives thereof, 5 -alkylresorcinol and / or derivatives thereof, 5 -alkyl -2 -hydroxybenzaldehyde and / or derivatives thereof, lipids and / or derivatives thereof, and lipid nanoparticles and / or derivatives thereof. In such embodiments the aforementioned need not be manufactured in accordance with the methods herein and extend to chemical compounds, chemical compositions and / or chemical formulations themselves.

[0038] In accordance with a first aspect of this disclosure there is provided a method of manufacturing a cardanol and / or derivatives thereof, including 3 -pentadecylphenol. This aspect extends to a cardanol and / or derivatives thereof including 3 -pentadecylphenol manufactured from CNSL and / or a chemical component thereof, and a method for manufacturing same.

[0039] In accordance with a first sub-aspect of the first aspect of this disclosure there is provided a method of manufacturing a cardanol and / or derivatives thereof, including 3 -pentadecylphenol, said method comprising the following steps:

[0040] (a). isolating anacardic acids, cardanols, and cardols from cashew nut shell liquid (CNSL) to provide isolated anacardic acids, isolated cardanols and isolated cardols; and

[0041] (b). decarboxylation of the isolated anacardic acids to provide synthetic cardanols.

[0042] The method may further comprise Step (c), wherein Step (c) comprises hydrogenation of both isolated cardanol and synthetic cardanol to provide saturated cardanols, including 3 -pentadecylphenol.

[0043] Step (a) may include distillation, including vacuum distillation.

[0044] It is to be understood that Step (a) and Step (b) may occur concomitantly.

[0045] The cardanol and / or derivatives thereof may include embodiments including an alkyl chain being saturated or unsaturated. Alternatively, and / or additionally, the alkyl chain may be branched or unbranched. Alternatively, and / or additionally, the alkyl chain may have a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, C8, C9, C10, Cn, C12, C13, C14, C15, Ci6, C17, Cis, C19, C20, C21 and C22. In a certain example embodiment of the disclosure the alkyl chain length has a length of C15. It is to be understood that there may be more than one alkyl chain.

[0046] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities.

[0047] The method may include one or more steps as described and / or exemplified herein below. A cardanol and / or derivatives thereof, including 3 -pentadecylphenol, produced in accordance with the method of the first sub-aspect of the first aspect of the disclosure.

[0048] In accordance with a second sub-aspect of the first aspect of this disclosure there is provided a method of manufacturing a cardanol and / or derivatives thereof, including 3-pentadecylphenol, said method comprising the following steps:

[0049] (a). decarboxylation of anacardic acids to provide cardanols; and

[0050] (b). hydrogenation of cardanols to provide saturated cardanols, including 3-pentadecylphenol.

[0051] The method wherein the anacardic acids are obtained from cashew nut shell liquid (CNSL).

[0052] The cardanol and / or derivatives thereof may include embodiments including an alkyl chain being saturated or unsaturated. Alternatively and / or additionally, the alkyl chain may be branched or unbranched. Alternatively and / or additionally, the alkyl chain may have a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, C8, C9, C10, Cn, C12, C13, C14, C15, Ci6, C17, Cis, C19, C20, C21 and C22. In a certain example embodiment of the disclosure the alkyl chain length has a length of C15. It is to be understood that there may be more than one alkyl chain.

[0053] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities.

[0054] The method may include one or more steps as described and / or exemplified herein below.

[0055] A cardanol and / or derivatives thereof, including 3-pentadecylphenol, produced in accordance with the method of the second sub-aspect of the first aspect of the disclosure.

[0056] In accordance with a third sub-aspect of the first aspect of this disclosure there is provided a method of manufacturing a cardanol and / or derivatives thereof, including 3-pentadecylphenol, said method comprising the following step:

[0057] (a). hydrogenation of cardanols to provide saturated cardanols, including 3-pentadecylphenol.

[0058] The method wherein the cardanols are obtained from cashew nut shell liquid (CNSL).

[0059] The cardanol and / or derivatives thereof may include embodiments including an alkyl chain being saturated or unsaturated. Alternatively and / or additionally, the alkyl chain may be branched or unbranched. Alternatively and / or additionally, the alkyl chain may have a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, C8, C9, C10, Cn, C12, C13, C14, Cis, Cie, C17, Cis, C19, C20, C21 and C22. In a certain example embodiment of the disclosure the alkyl chain length has a length of C15. It is to be understood that there may be more than one alkyl chain.

[0060] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities.

[0061] The method may include one or more steps as described and / or exemplified herein below.

[0062] A cardanol and / or derivatives thereof, including 3 -pentadecylphenol, produced in accordance with the method of the third sub-aspect of the first aspect of the disclosure.

[0063] There is further provided for any one of the first to third sub-aspects of the first aspect of this disclosure substantially as herein described, illustrated and / or exemplified with reference to any one of the descriptions and / or examples and / or photos and / or images and / or chemical reaction schemes and / or diagrammatic drawings herein.

[0064] In accordance with a second aspect of this disclosure there is provided a method of manufacturing an arene, including a symmetrical alkyl resorcinol (or alkyl di-hydroxy resorcinol), including 5- alkylresorcinol and / or derivatives thereof, including hydrogenated cardol (5 -heptadecylresorcinol) from 3- pentadecylphenol.

[0065] The 3 -pentadecylphenol may be derived from cashew nut shell liquid (CNSL) and / or a chemical component thereof. Derivation of the 3 -pentadecylphenol from cashew nut shell liquid (CNSL) may occur, but is not limited to, methods according to any of the aspects or sub-aspects of the disclosure herein above and below.

[0066] This aspect of the disclosure extends to arenes including symmetrical resorcinols themselves.

[0067] In accordance with a first sub-aspect of the second aspect of this disclosure there is provided a method of manufacturing an arene, including a 5 -alkylresorcinol including derivatives thereof, including cardol, said method comprising the following steps:

[0068] (a). isolating anacardic acids, cardanols, and cardols from cashew nut shell liquid (CNSL) to provide the isolated anacardic acids, isolated cardanols and isolated cardols;

[0069] (b). decarboxylation of the isolated anacardic acids to provide synthetic cardanols;

[0070] (c). hydrogenation of both isolated cardanol and synthetic cardanol to provide saturated cardanols, including 3 -pentadecylphenol; and (d). transforming the saturated cardanols to include a functional group, which functional group may include a hydroxy substituent, in position 5, which position 5 may include position meta, therein providing for a 5 -alkylresorcinol and / or ether containing derivatives.

[0071] The functional groups may include at least one of, but not limited to the following group: saturated cyclical functional groups, unsaturated cyclical functional groups, acetates, mesylates, pivaloates, tosylates, Ar-N, Ar-S, and Ar-CX, wherein Ar refers to aryl, N refers to nitrogen, S refers to sulfur, C refers to carbon and X refers to any halogen. The functional groups may be, in certain embodiments, protecting functional groups.

[0072] Step (a) may include distillation, including vacuum distillation.

[0073] It is to be understood that Step (a) and Step (b) may occur concomitantly.

[0074] Step (d) may be provided via direct meta borylation of the hydrogenated cardanol with employing a protecting functional group. Step (d) may be provided as a one pot step.

[0075] Alternatively, Step (d) may include Sub-step (dl): protecting a phenol functional group of the saturated cardanols with a protectional functional group therein providing a protected cardanol.

[0076] Step (d) may further include [after at least commencing Sub-step (dl)] Sub-step (d2): introducing a phenol functional group in the meta position of the protected cardanol.

[0077] Sub-step (d2) introducing a phenol functional group in the meta position of the protected cardanol may include arene C-H borylation. It is to be understood that other synthetic procedures are envisaged.

[0078] The arene C-H borylation may include use of a catalyst, typically a transitional metal catalyst, further typically a transitional metal catalyst including at least one of, but not limited to, the following group of metals: iridium (Ir), rhodium (Rh), platinum (Pt), palladium (Pd), tungsten (W), titanium (Ti), tin (Sn), ruthenium (Ru), iron (Fe) and lead (Pb). In a preferred embodiment of the disclosure the transition metal catalyst may be at least one of, but not limited to, the following group: Cp*Ir(PMe3)H(Bpin), (Ind)Ir(COD), [Ir(COD)Cl]2, [Ir(COE)Cl]2, [Ir(COD)OH]2and [Ir(COD)OMe]2.

[0079] Step (d) may further include [after at least commencing Sub-step (d2)] Sub-step (d3): removing the protectional functional group. Sub-step (d3) may include oxidation and may employ but is not limited to H2O2, oxone, potassium iodate and sodium iodate.

[0080] It is to be understood that the arenes may be 1,3,5-asymmetrical arenes.

[0081] The 5 -alkylresorcinol and / or derivatives thereof may include embodiments wherein the 5 -alkyl chain may be saturated or unsaturated. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain being branched or unbranched. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain having a carbon chain length of between Ci to C22including both Ci, C22and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, Ci2, Ci3, Ci4, Cis, Ci6, Ci7, Cis, Ci9, C20, C21 and C22. In a certain preferred example embodiment of the disclosure the alkyl chain length has a length of C15.

[0082] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities. It is to be understood that there may be more than one alkyl chain.

[0083] The method may include one or more steps as described and / or exemplified herein below.

[0084] A 5 -alkylresorcinol and / or derivatives thereof, including hydrogenated cardol, produced in accordance with the method of the first sub-aspect of the second aspect of the disclosure.

[0085] In accordance with a second sub-aspect of the second aspect of this disclosure there is provided a method of manufacturing an arene, including a 5 -alkylresorcinol and / or derivatives thereof, including cardol, said method comprising the following steps:

[0086] (a). decarboxylation of anacardic acids to provide cardanols;

[0087] (b). hydrogenation of cardanols to provide saturated / hydrogenated cardanols, including 3- pentadecylphenol; and

[0088] (c). transforming the saturated cardanols to include a functional group, which functional group may include a hydroxy substituent, in position 5, which position 5 may include position meta, therein providing for a 5 -alkylresorcinol and / or ether containing derivatives including cardol.

[0089] The method wherein the anacardic acids are obtained from cashew nut shell liquid (CNSL).

[0090] The functional groups may include at least one of, but not limited to the following group: saturated cyclical functional groups, unsaturated cyclical functional groups, acetates, mesylates, pivloates, tosylates, Ar-N, Ar-S, and Ar-CX, wherein Ar refers to aryl, N refers to nitrogen, S refers to sulphur, C refers to carbon and X refers to any halogen. The functional groups may be, in certain embodiments, protecting functional groups.

[0091] Step (c) may be provided via direct meta borylation of the hydrogenated cardanol with employing a protecting functional group. Step (c) may be provided as a one pot step.

[0092] Alternatively, Step (c) may include Sub-step (cl): protecting a phenol functional group of the saturated cardanols with a protectional functional group therein providing a protected cardanol.

[0093] Step (c) may further include [after at least commencing Sub-step (cl)] Sub-step (c2): introducing a phenol functional group in the meta position of the protected cardanol. Sub-step (c2) introducing a phenol functional group in the meta position of the protected cardanol may include arene C-H borylation. It is to be understood that other synthetic procedures are envisaged.

[0094] There arene C-H borylation may include use of a catalyst, typically a transitional metal catalyst, further typically a transitional metal catalyst including at least one of, but not limited to, the following group of metals: iridium (Ir), rhodium (Rh), platinum (Pt), palladium (Pd), tungsten (W), titanium (Ti), tin (Sn), ruthenium (Ru), iron (Fe) and lead (Pb), . In a preferred embodiment of the disclosure the transition metal catalyst may be at least one of, but not limited to, the following group: Cp*Ir(PMe3)H(Bpin), (Ind)Ir(COD), [Ir(COD)Cl]2, [Ir(COE)Cl]2, [Ir(COD)OH]2and [Ir(COD)OMe]2.

[0095] Step (c) may further include [after at least commencing Sub-step (c2)] Sub-step (c3): removing the protectional functional group. Sub-step (c3) may include oxidation and may employ but is not limited to H2O2, oxone, potassium iodate and sodium iodate.

[0096] It is to be understood that the arenes may be 1,3,5-asymmetrical arenes.

[0097] The 5 -alkylresorcinol and / or derivatives thereof may include embodiments wherein the 5 -alkyl chain may be saturated or unsaturated. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain being branched or unbranched. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain having a carbon chain length of between Ci to C22including both Ci, C22and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, Ci2, Ci3, C14, C15, Ci6, C17, Cis, C19, C20, C2iand C22. In a certain preferred example embodiment of the disclosure the alkyl chain length has a length of C15.

[0098] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities. It is to be understood that there may be more than one alkyl chain.

[0099] The method may include one or more steps as described and / or exemplified herein below.

[0100] An arene including a 5 -alkylresorcinol and / or derivatives thereof, including cardol, produced in accordance with the method of the second sub-aspect of the second aspect of the disclosure.

[0101] In accordance with a third sub-aspect of the second aspect of this disclosure there is provided a method of manufacturing an arene, including a 5 -alkylresorcinol including derivatives thereof, including cardol, said method comprising the following steps:

[0102] (a). hydrogenation of cardanols to provide saturated cardanols, including 3 -pentadecylphenol; and (b). transforming the saturated cardanols to include a functional group, which functional group may include a hydroxy substituent, in position 5, which position 5 may include position meta, therein providing for a 5 -alkylresorcinol and / or ether containing derivatives including cardol.

[0103] The method wherein the cardanols are obtained from cashew nut shell liquid (CNSL) and / or a chemical component thereof.

[0104] Step (b) may be provided via direct meta borylation of the hydrogenated cardanol with employing a protecting functional group. Step (b) may be provided as a one pot step.

[0105] Alternatively, Step (b) may include Sub-step (bl): protecting a phenol functional group of the saturated cardanols with a protectional functional group therein providing a protected cardanol.

[0106] Step (b) may further include [after at least commencing Sub-step (bl)] Sub-step (b2): introducing a phenol functional group in the meta position of the protected cardanol.

[0107] Sub-step (b2) introducing a phenol functional group in the meta position of the protected cardanol may include arene C-H borylation. It is to be understood that other synthetic procedures are envisaged.

[0108] There arene C-H borylation may include use of a catalyst, typically a transitional metal catalyst, further typically a transitional metal catalyst including at least one of, but not limited to, the following group of metals: iridium (Ir), rhodium (Rh), platinum (Pt), palladium (Pd), tungsten (W), titanium (Ti), tin (Sn), ruthenium (Ru), iron (Fe) and lead (Pb). In a preferred embodiment of the disclosure the transition metal catalyst may be at least one of, but not limited to, the following group: Cp*Ir(PMe3)H(Bpin), (Ind)Ir(COD), [Ir(COD)Cl]2, [Ir(COE)Cl]2, [Ir(COD)OH]2and [Ir(COD)OMe]2.

[0109] Step (b) may further include [after at least commencing Sub-step (b2)] Sub-step (b3): removing the protectional functional group. Sub-step (b3) may include oxidation and may employ but is not limited to H2O2, oxone, potassium iodate and sodium iodate.

[0110] It is to be understood that the arenes may be 1,3,5-asymmetrical arenes.

[0111] The 5 -alkylresorcinol and / or derivatives thereof may include embodiments wherein the 5 -alkyl chain may be saturated or unsaturated. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain being branched or unbranched. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain having a carbon chain length of between Ci to C22including both Ci, C22and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, Ci2, Ci3, C14, C15, Ci6, C17, Cis, C19, C20, C2iand C22. In a certain preferred example embodiment of the disclosure the alkyl chain length has a length of C15.

[0112] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities. It is to be understood that there may be more than one alkyl chain.

[0113] The method may include one or more steps as described and / or exemplified herein below.

[0114] An arene, including a 5 -alkylresorcinol and / or derivatives thereof, including cardol, produced in accordance with the method of the third sub-aspect of the second aspect of the disclosure.

[0115] There is further provided for any one of the first to third sub-aspects of the second aspect of this disclosure substantially as herein described, illustrated and / or exemplified with reference to any one of the descriptions and / or examples and / or photos and / or images and / or chemical reaction schemes and / or diagrammatic drawings herein.

[0116] In accordance with a third aspect of this disclosure there is provided a method of manufacturing an arene including a 5 -alkyl-2 -hydroxybenzaldehyde and / or derivatives thereof from 3 -pentadecylphenol.

[0117] The method may include use of cashew nut shell liquid (CNSL) as a raw material source and / or a chemical component thereof.

[0118] The method may include any of the steps as described herein including in the first and second aspects of this disclosure.

[0119] This disclosure extends to arenes including 5 -alkyl -2 -hydroxybenzaldehyde and / or derivatives thereof themselves.

[0120] There is further provided for the third aspect of this disclosure substantially as herein described, illustrated and / or exemplified with reference to any one of the descriptions and / or examples and / or photos and / or images and / or chemical reaction schemes and / or diagrammatic drawings herein.

[0121] In accordance with a fourth aspect of this disclosure there is provided a method of manufacturing lipids, preferably ionizable lipids.

[0122] In certain example embodiments, this disclosure relates to a method of manufacturing lipids including use of a cardanol and / or cardol.

[0123] In certain further example embodiments, this disclosure relates to a method of manufacturing lipids including the use of a cardanol and / or cardol, wherein at least one of which being derived from CNSL.

[0124] The disclosure extends to the lipids themselves.

[0125] The ionizable lipids may be employed in the formulation of lipid nanoparticles. The lipid nanoparticles may be employed in the field of biology, molecular biology, medicine and / or pharmacology. In an example embodiment of the disclosure, the lipid nanoparticles may be employed in the field of mRNA prophylactic and / or therapeutic technologies, including vaccines, further including nucleic acid-based -, protein-based and peptide-based vaccines. The lipid nanoparticles may also be utilised for the transfection of cultured cells in vitro or ex vivo.

[0126] The lipid nanoparticles manufactured from cashew nut shell liquid (CNSL) may provide a delivery means for nucleic acids, proteins, and peptides including but not limited to mRNA at a desired site within the human or animal body for use in the prevention and / or treatment and / or amelioration of a disease and / or medical condition in a human or animal body.

[0127] This disclosure extends to the lipid nanoparticles themselves.

[0128] In accordance with a first sub-aspect of the fourth aspect of this disclosure there is provided a method of manufacturing lipids, preferably ionizable lipids, utilizing a cardanol and / or derivatives thereof, including 3 -pentadecylphenol, and wherein said cardanol is derived from cashew nut shell liquid (CNSL), said method comprising any of the steps as described in the first aspect of this disclosure above, including any one of the sub-aspects of the first aspect of this disclosure.

[0129] The method may include steps of functionalizing the cardanol and / or derivatives thereof to provide a lipid comprising: (i) a nitrogen containing ionizable group, (ii) an aromatic ring or analogue thereof, and (iii) at least one alkyl chain.

[0130] The nitrogen containing ionizable group, or atom may be a nitrogen containing heterocycle, preferably wherein the nitrogen containing heterocycle includes an alkaline nitrogen. The nitrogen containing ionizable group may be selected from, but not limited to, the group comprising: piperidines, pyrolidines, triazines and amino acids and / or derivatives of amino acids. It is to be understood that the nitrogen containing ionizable functional group may extend to other chemical moieties. 1,2-diazinane, 1,3- diazinane and imidazolidine. In a certain embodiment the nitrogen containing ionizable functional group may be piperazine. The nitrogen containing ionizable functional group may further or alternatively include acyclic amines.

[0131] The aromatic ring may be derived from phenolics, which in turn are derived from CNSL. The aromatic ring may include modification The aromatic ring may be a phenol, resorcinol, benzaldehyde, benzyl alcohol or benzoic acid and derivatives and / or analogues of the aforementioned.. It is to be understood that the aromatic ring may be reduced to analogues of same, and may include at least one of, but not limited to, the following group: cyclohexyls and linear aliphatics. The reduction may for example take place via birch reduction and / or ozonolysis.

[0132] The at least one alkyl chain may be saturated or unsaturated. Alternatively and / or additionally, the alkyl chain may be branched or unbranched. Alternatively and / or additionally, the alkyl chain may have a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, Cn, C12, C13, C14, C15, Ci6, C17, Cis, C19, C20, C21 and C22. In a certain preferred example embodiment of the disclosure the alkyl chain length has a length of C15. It is to be understood that there may be more than one alkyl chain. There is provided that in embodiments having more than one alkyl chain, the alkyl chains may be structurally the same and / or structurally different.

[0133] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities. It is to be understood that there may be more than one alkyl chain.

[0134] The method may include providing the ionizable lipid with biodegradable functionality, wherein same may include method steps for introducing at least one of, but not limited to, the following functional groups: ester, amide, acetal, disulfide, carbonate, and carbamate. Particularly, in a certain embodiment, the method may further include a step to provide an ester functional group as part of the ionizable lipid.

[0135] The ionizable lipid may be any one as illustrated and / or exemplified herein with reference to the figures, preferably Figure 2. The ionizable lipid may be derived from CNSL.

[0136] The ionizable lipids according to this disclosure may be any one of, but not limited to, the following group:

[0137] 3-(decyloxy)-5-pentadecylphenyl 4-(dimethylamino) butanoate, 3 -((2 -ethylhexyl) oxy)-5- pentadecylphenyl 4-(dimethylamino) butanoate, 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl 4-(4- (2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(octadecyloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(4-(2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)ethyl) piperazin- 1 -yl)ethan- 1 -ol, 2-(4-(2-(3 -(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 - yl)ethan- 1 -ol, 2-ethylhexyl8-(3 -((2-ethylhexyl) oxy)-5 -(2-((4-(4-(2-hydroxyethyl) piperazin- 1 -yl) butanoyl) oxy) ethoxy) phenyl) octanoate, 2, 2'-((2-(3 -((2-ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl)azanediyl)bis(ethan- 1 -ol), 2-(4-(2-(3 -(octadecyloxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 - yl)ethan-l-ol, 2,2'-((2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2,2'-((2- (3 -(oct-3 -yn-l-yloxy) -5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3 -(oct-3 -yn-1- yloxy)-5-pentadecylphenoxy)ethyl) piperazin- 1-yl) ethan-l-ol, (E)-2,2'-((2-(3-((3,7-dimethylocta-2,6-dien- l-yl)oxy)-5pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), (E)-2-(4-(2-(3-((3,7-dimethylocta-2,6- dien-l-yl)oxy)-5 -pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2,2'-((2-(3-(decyloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl)piperazin-l-yl) ethan-l-ol, 2,2'-((2-(3-(octan-2-yloxy)-5-pentadecylphenoxy) ethyl) azanediyl) diethanol, 2,2'-((3 -(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy )propyl)azanediyl)bis(ethan-l-ol), 2-(4-(3- (3 -((2-ethylhexyl) oxy) -5 -pentadecylphenoxy) propyl) piperazin- 1-yl) ethan-l-ol, 2,2'-((4-(3-((2- ethylhexyl)oxy) -5 -pentadecylphenoxy) butyl) azanediyl) bis (ethan-l-ol), 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) piperazin- 1-yl) ethan-l-ol, 1 l-(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl)-2,5,8-trioxa-l l-azatridecan-13-ol, 2,2'-((2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan- 1 -ol), ((2S)- 1 -(2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)pyrrolidin-2- yl)methanol, octyl 4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-2-(octyloxy)-6-pentadecylbenzoate, (3'-((2- ethylhexyl)oxy)-5'-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl)methyl 4-(4-(2-hydroxyethyl)piperazin- 1 -yl)butanoate, (3 '-(octadecyloxy)-5 '-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl) methyl 4-(4-(2-hydroxyethyl)piperazin- 1 - yl)butanoate, (3'-(decyloxy)-5'-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl)methyl 4-(4-(2-hydroxyethyl) piperazin- 1 - yl)butanoate, 2-(3-((9Z,12Z)-octadeca-9,12-dien-l-yloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl)piperazin- 1 -yl) butanoate, 3 -(3 -(decyloxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4-(2- hydroxyethyl)piperazin- 1 -yl) butanoate, 3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4- (2-hydroxyethyl)piperazin-l-yl) butanoate, 2-(4-(3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l- yl)piperazin- 1 -yl)ethanol, 2-(4-(3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl)piperazin- 1 - yl)ethanol, (l-(3-(decyloxy)-5-pentadecylphenyl)-lH-l,2,3-triazol-4-yl)methanol, 2-(3 -((2 -ethylhexyl) oxy)-5-pentadecylphenoxy)-N,N-dimethylethanamine, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) ethanol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(methyl)amino)ethanol, 2- ((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)propane-l,3-diol, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1-yl) ethanamine, l-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino) propane-1, 3-diol, 5-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) pentan- 1 -ol, 5 -((2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)(2-hydroxyethyl) amino) pentan- l-ol, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino)-2-(hydroxymethyl) propane-1, 3-diol, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-(4-(2-hydroxyethyl)piperazin-l- yl)propan-2-ol, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2 -ol, 2,2'-((3-(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-2-hydroxypropyl)azanediyl)diethanol, 1 -(diethylamino) -3 -(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2-yl dodecanoate, l-(diethylamino)-3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenoxy) propan-2 -yl pentanoate, N,N-diethyl-3 -(3 -((2-ethylhexyl)oxy)-5 - pentadecylphenoxy) propan- 1 -amine, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-((2 -hydroxyethyl) (methyl)amino) propan-2 -ol, 2-((2-(dodecanoyloxy)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propyl) (methyl) amino) ethyl dodecanoate, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) (octadecyl) amino) ethanol, 2-(decyl(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)ethanol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) (octadecyl) amino) propane-1, 3-diol, 2-(3- (henicosan-11-yloxy) -5 -pentadecylphenoxy) ethyl4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-((2- ethylhexyl)oxy)-5-pentadecylphenyl2-((5-(bis(2 -hydroxyethyl) amino) pentyl) oxy)-2-methylpropanoate, 2, 2'-((2-(3-(2-(2-(2 -methoxyethoxy) ethoxy) ethoxy) -5 -pentadecylphenoxy) ethyl) azanediyl) diethanol.

[0138] The ionizable lipids may be derived at least in part from CNSL.

[0139] The ionizable lipid may be utilized in the manufacture of lipid nanoparticles (LNPs). The LNPs may be an ionizable lipid nanoparticle (iLNP). The ionizable lipid may be derived from CNSL. Consequently, the iLNP may include a lipid derived from CNSL.

[0140] The lipid nanoparticle may be provided as a single or multiple component lipid nanoparticle.

[0141] When provided as a multiple component lipid nanoparticle then additional chemicals and / or molecules are formulated together with the lipid nanoparticle of this disclosure therein providing a multiple component lipid nanoparticle.

[0142] Additional chemicals and / or molecules of the multiple component lipid nanoparticle may include at least one of, but not limited to, the following group: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid (including cholesterol or phytosterols and / or its derivatives), (iii) a polymer conjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), (iv) a phospholipid and / or derivatives thereof.

[0143] When provided as a single component lipid nanoparticle then no additional chemicals and / or molecules are formulated together with the lipid nanoparticle of this disclosure. The lipid nanoparticle (single or multiple component) may be loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-LNP). The API may be a nucleic acid. The nucleic acid may be DNA and / or RNA. The DNA may be plasmid DNA. The RNA may be at least one of, but not limited to, the following group: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and other RNAs that activate the RNA interference (RNAi) pathway. The API may alternatively and / or additionally include at least one of, but not limited to, the following group: peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof. When the LNP is loaded with RNA, the L-LNP may be referred to as an RNA-LNP. Similarly, when the iLNP is loaded with RNA, the L-LNP may be referred to as an RNA-iLNP. When the iLNP is loaded with DNA, the L-LNP may be referred to as an DNA-iLNP.

[0144] There is further provided for use of the lipid nanoparticle in the manufacture of a medicament for treatment, prevention and / or amelioration of a disease and / or medical condition.

[0145] There is further provided for the lipid nanoparticle for use in the manufacture of a medicament for treatment, prevention and / or amelioration of a disease and / or medical condition.

[0146] There is further provided for a method of treatment, prevention and / or amelioration of a disease and / or medical condition utilizing the lipid nanoparticle.

[0147] There is further provided for a lipid nanoparticle produced in accordance with the method of the first sub-aspect of the fourth aspect of the disclosure and / or as described and / or exemplified herein below.

[0148] The method may include one or more steps as described and / or exemplified herein below.

[0149] Non-limiting examples of the lipid nanoparticles and their method of production is provided herein below which is incorporated in this summary by way of reference thereto to avoid repetition.

[0150] In accordance with a second sub-aspect of the fourth aspect of this disclosure there is provided a method of manufacturing an ionizable lipid derived from CNSL phenolics.

[0151] The method may include chemical modification of the CNSL phenolic, wherein at least one additional alkyl containing functional group may be introduced onto a position on the phenolic, and wherein the position is distinct from any natural alkyl chain that may be present on the CNSL phenolic.

[0152] The additional alkyl containing functional group may be ionizable.

[0153] Alternatively, and / or additionally, in accordance with a second sub-aspect of the fourth aspect of this disclosure there is provided a method of manufacturing an ionizable lipid utilizing a 5 -alkylresorcinol and / or a 5-alkyl-2-(hydroxymethyl)phenol including derivatives thereof, including cardol, and wherein said 5 -alkylresorcinol or 5-alkyl-2-(hydroxymethyl)phenol is derived from cashew nut shell liquid (CNSL), the method comprising any of the steps as described in the second aspect of this disclosure above, including any one of the sub-aspects of the second aspect of this disclosure. The method may include steps of functionalizing the cardol and / or derivatives thereof to provide an ionizable lipid comprising: (i) a nitrogen containing ionizable functional group, (ii) an aromatic ring or analogue thereof, and (iii) at least one alkyl chain.

[0154] The nitrogen containing ionizable group may be a nitrogen containing heterocycle, preferably wherein the nitrogen containing heterocycle includes an alkaline nitrogen. The nitrogen containing ionizable group may be selected from, but not limited to, the group comprising: piperidines, pyrolidines and triazines and amino acids and / or derivatives thereof. It is to be understood that the nitrogen containing ionizable group may extend to other chemical moieties. 1,2-diazinane, 1,3-diazinane and imidazolidine. In a certain embodiment the nitrogen containing ionizable group may be piperazine. The nitrogen containing ionizable group may further or alternatively include acyclic amines.

[0155] The aromatic ring may be derived from phenolics, which in turn are derived from CNSL. The aromatic ring may include modification The aromatic ring may be a phenol, resorcinol, benzaldehyde, benzyl alcohol or benzoic acid and derivatives and / or analogues of the aforementioned.. It is to be understood that the aromatic ring may be reduced to analogues of same, and may include at least one of, but not limited to, the following group: cyclohexyls and linear aliphatics. The reduction may for example take place via birch reduction and / or ozonolysis.

[0156] The at least one alkyl chain may be saturated or unsaturated. Alternatively and / or additionally, the alkyl chain may be branched or unbranched. Alternatively and / or additionally, the alkyl chain may have a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, Cn, C12, C13, C14, C15, Ci6, C17, Cis, C19, C20, C21 and C22. In a certain preferred example embodiment of the disclosure the alkyl chain length has a length of C15. It is to be understood that there may be more than one alkyl chain. There is provided that in embodiments having more than one alkyl chain, the alkyl chains may be structurally the same and / or structurally different.

[0157] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities.

[0158] The method may include providing the ionizable lipid with biodegradable functionality, wherein same may include method steps for introducing at least one of, but not limited to, the following functional groups: ester, amide, acetal, disulfide, carbonate, and carbamate. Particularly, in a certain embodiment, the method may further include a step to provide an ester functional group as part of the ionizable lipid.

[0159] The ionizable lipid may be any one as illustrated and / or exemplified herein with reference to the figures, preferably Figure 2. The ionizable lipids according to this disclosure may be any one of, but not limited to, the following group:

[0160] 3-(decyloxy)-5-pentadecylphenyl 4-(dimethylamino) butanoate, 3 -((2 -ethylhexyl) oxy)-5 pentadecylphenyl 4-(dimethylamino) butanoate, 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl 4-(4 (2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(octadecyloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2 hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2 hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2 hydroxyethyl) piperazin- 1-yl) butanoate, 2-(4-(2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)ethyl) piperazin- 1 -yl)ethan- 1 -ol, 2-(4-(2-(3 -(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 - yl)ethan- 1 -ol, 2-ethylhexyl8-(3 -((2-ethylhexyl) oxy)-5 -(2-((4-(4-(2-hydroxyethyl) piperazin- 1 -yl) butanoyl) oxy) ethoxy) phenyl) octanoate, 2, 2'-((2-(3 -((2-ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl)azanediyl)bis(ethan-l-ol), 2-(4-(2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl) piperazin-1- yl)ethan-l-ol, 2,2'-((2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2,2'-((2- (3 -(oct-3 -yn-l-yloxy) -5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3 -(oct-3 -yn-1- yloxy)-5-pentadecylphenoxy)ethyl) piperazin- 1-yl) ethan-l-ol, (E)-2,2'-((2-(3-((3,7-dimethylocta-2,6-dien-

[0161] 1-yl)oxy)-5pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), (E)-2-(4-(2-(3-((3,7-dimethylocta-2,6- dien-l-yl)oxy)-5 -pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2,2'-((2-(3-(decyloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl)piperazin-l-yl) ethan-l-ol, 2,2'-((2-(3-(octan-2-yloxy)-5-pentadecylphenoxy) ethyl) azanediyl) diethanol, 2,2'-((3 -(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy )propyl)azanediyl)bis(ethan-l-ol), 2-(4-(3- (3 -((2-ethylhexyl) oxy) -5 -pentadecylphenoxy) propyl) piperazin- 1-yl) ethan-l-ol, 2,2'-((4-(3-((2- ethylhexyl)oxy) -5 -pentadecylphenoxy) butyl) azanediyl) bis (ethan-l-ol), 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) piperazin- 1-yl) ethan-l-ol, 1 l-(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl)-2,5,8-trioxa-l l-azatridecan-13-ol, 2,2'-((2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan- 1 -ol), ((2S)- 1 -(2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)pyrrolidin-2- yl)methanol, octyl 4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-2-(octyloxy)-6-pentadecylbenzoate, (3'-((2- ethylhexyl)oxy)-5'-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl)methyl 4-(4-(2-hydroxyethyl)piperazin- 1 -yl)butanoate, (3'-(octadecyloxy)-5'-pentadecyl-[l,l'-biphenyl]-4-yl) methyl 4-(4-(2-hydroxyethyl)piperazin-l yl)butanoate, (3'-(decyloxy)-5'-pentadecyl-[l,l'-biphenyl]-4-yl)methyl 4-(4-(2-hydroxyethyl) piperazin-1 yl)butanoate, 2-(3-((9Z,12Z)-octadeca-9,12-dien-l-yloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2 hydroxyethyl)piperazin- 1 -yl) butanoate, 3 -(3 -(decyloxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4-(2 hydroxyethyl)piperazin- 1 -yl) butanoate, 3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4 (2-hydroxyethyl)piperazin-l-yl) butanoate, 2-(4-(3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l yl)piperazin- 1 -yl)ethanol, 2-(4-(3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl)piperazin- 1 yl)ethanol, (l-(3-(decyloxy)-5-pentadecylphenyl)-lH-l,2,3-triazol-4-yl)methanol, 2-(3 -((2-ethylhexyl) oxy)-5-pentadecylphenoxy)-N,N-dimethylethanamine, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) ethanol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(methyl)amino)ethanol, 2- ((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)propane-l,3-diol, 2-(4-(2-(3 -((2-ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1-yl) ethanamine, l-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino) propane-1, 3-diol, 5 -((2-(3-((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino) pentan-l-ol, 5-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(2-hydroxyethyl) amino) pentan-l-ol, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino)-2-(hydroxymethyl) propane-1, 3-diol, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-(4-(2-hydroxyethyl)piperazin-l- yl)propan-2-ol, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2 -ol, 2,2'-((3-(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-2-hydroxypropyl)azanediyl)diethanol, 1 -(diethylamino) -3 -(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2-yl dodecanoate, l-(diethylamino)-3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenoxy) propan-2 -yl pentanoate, N,N-diethyl-3 -(3 -((2-ethylhexyl)oxy)-5 - pentadecylphenoxy) propan- 1 -amine, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-((2 -hydroxyethyl) (methyl)amino) propan-2 -ol, 2-((2-(dodecanoyloxy)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propyl) (methyl) amino) ethyl dodecanoate, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) (octadecyl) amino) ethanol, 2-(decyl(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)ethanol,

[0162] 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) (octadecyl) amino) propane-1, 3-diol, 2-(3- (henicosan-l l-yloxy)-5-pentadecylphenoxy) ethyl4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3 3-((2- ethylhexyl)oxy)-5-pentadecylphenyl2-((5-(bis(2 -hydroxyethyl) amino) pentyl) oxy)-2-methylpropanoate, 2, 2'-((2-(3-(2-(2-(2 -methoxyethoxy) ethoxy) ethoxy) -5 -pentadecylphenoxy) ethyl) azanediyl) diethanol.

[0163] The ionizable lipid may be utilized in the manufacture of lipid nanoparticles (LNPs). The LNPs may be an ionizable lipid nanoparticle (iLNP). Consequently, the iLNP may include a lipid derived from CNSL.

[0164] The lipid nanoparticle may be provided as a single or multiple component lipid nanoparticle.

[0165] When provided as a multiple component lipid nanoparticle then additional chemicals and / or molecules are formulated together with the lipid nanoparticle of this disclosure therein providing a multiple component lipid nanoparticle.

[0166] Additional chemicals and / or molecules of the multiple component lipid nanoparticle may include at least one of, but not limited to, the following group: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid (including cholesterol or phytosterols and / or its derivatives), (iii) a polymer conjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), (iv) a phospholipid and / or derivatives thereof.

[0167] When provided as a single component lipid nanoparticle then no additional chemicals and / or molecules are formulated together with the lipid nanoparticle of this disclosure.

[0168] The lipid nanoparticle (single or multiple component) may be loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-LNP). The API may be a nucleic acid. The nucleic acid may be DNA and / or RNA. The DNA may be plasmid DNA. The RNA may be at least one of, but not limited to, the following group: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and other RNAs that activate the RNA interference (RNAi) pathway. The API may alternatively and / or additionally include at least one of, but not limited to, the following group: peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof. When the LNP is loaded with RNA, the L-LNP may be referred to as an RNA-LNP. Similarly, when the iLNP is loaded with RNA, the L-LNP may be referred to as an RNA-iLNP. When the iLNP is loaded with DNA, the L-LNP may be referred to as an DNA-iLNP.

[0169] There is further provided for use of the lipid nanoparticle in the manufacture of a medicament for treatment, prevention and / or amelioration of a disease and / or medical condition.

[0170] There is further provided for the lipid nanoparticle for use in the manufacture of a medicament for treatment, prevention and / or amelioration of a disease and / or medical condition.

[0171] There is further provided for a method of treatment, prevention and / or amelioration of a disease and / or medical condition utilizing the lipid nanoparticle. There is further provided for a lipid nanoparticle produced in accordance with the method of the second sub-aspect of the third aspect of the disclosure and / or as described and / or exemplified herein below.

[0172] The method may include one or more steps as described and / or exemplified herein below.

[0173] Non-limiting examples of the lipid nanoparticles and their method of production is provided herein below which is incorporated in this summary by way of reference thereto to avoid repetition.

[0174] There is further provided for any one of the first to second sub-aspects of the fourth aspect of this disclosure substantially as herein described, illustrated and / or exemplified with reference to any one of the descriptions and / or examples and / or photos and / or images and / or chemical reaction schemes and / or diagrammatic drawings herein.

[0175] In accordance with a fifth aspect of this disclosure there is provided a method of manufacturing lipid nanoparticles (LNPs), typically ionizable lipid nanoparticles (iLNPs) from the ionizable lipids as disclosed in the fourth aspect of this disclosure above. The method may include use of a cardanol. In certain example embodiments, the method may include the use of a cardanol derived from cashew nut shell liquid (CNSL). This aspect extends to the use of the LNPs themselves, typically ionizable lipid nanoparticles (iLNPs) in transfection and / or medical / pharmaceutical applications.

[0176] The lipid nanoparticle, which may be a LNP and / or an iLNP, may be provided as a single or multiple component lipid nanoparticle.

[0177] When provided as a multiple component lipid nanoparticle then additional chemicals and / or molecules are formulated together with the lipid nanoparticle of this disclosure therein providing a multiple component lipid nanoparticle.

[0178] Additional chemicals and / or molecules of the multiple component lipid nanoparticle may include at least one of, but not limited to, the following group: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid (including cholesterol, phytosterols and / or its derivatives), (iii) a polymer conjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), and (iv) a phospholipid and / or derivatives thereof.

[0179] When provided as a single component lipid nanoparticle then no additional chemicals and / or molecules are formulated together with the lipid nanoparticle of this disclosure.

[0180] The lipid nanoparticle (single or multiple component) may be loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-LNP). The API may be a nucleic acid. The nucleic acid may be DNA and / or RNA. The DNA may be plasmid DNA. The RNA may be at least one of, but not limited to, the following group: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and other RNAs that activate the RNA interference (RNAi) pathway. The API may alternatively and / or additionally include at least one of, but not limited to, the following group: peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof. When the LNP is loaded with RNA, the L-LNP may be referred to as an RNA-LNP. Similarly, when the iLNP is loaded with RNA, the L-LNP may be referred to as an RNA-iLNP. When the iLNP is loaded with DNA, the L-LNP may be referred to as an DNA-iLNP. The Applicant envisages other APIs for loaded the LNPs including proteins, peptides, polypeptides, amino acids, nucleotides, oligonucleotides, antisense oligonucleotides, and / or fragments of the aforementioned.

[0181] There is further provided for use of the lipid nanoparticle in the manufacture of a medicament for treatment, prevention and / or amelioration of a disease and / or medical condition.

[0182] There is further provided for the lipid nanoparticle for use in the manufacture of a medicament for treatment, prevention and / or amelioration of a disease and / or medical condition.

[0183] There is further provided for a method of treatment, prevention and / or amelioration of a disease and / or medical condition utilizing the lipid nanoparticle.

[0184] There is further provided for a lipid nanoparticle produced in accordance with the method of the second sub-aspect of the third aspect of the disclosure and / or as described and / or exemplified herein below.

[0185] The method may include one or more steps as described and / or exemplified herein below.

[0186] The method of manufacturing lipid nanoparticles (LNPs) may include a modified solvent injection method, alternatively and / or additionally, may include a microfluidics formulation.

[0187] The modified solvent injection method may include the following steps: diluting RNA / DNA or other active pharmaceutical ingredient (API) (for example but not limited to a protein) in an acidic aqueous buffer; dissolving lipids in an organic solvent (typically an alcohol); adding the dissolved lipids to the diluted RNA / DNA / other API and vortexing / mixing vigorously. It is to be understood that for in vitro assay purposes, LNPs are ready for use after vortexing / mixing. For animal or human use, purification by buffer exchange using methods such as Tangential Flow Filtration is required.

[0188] The microfluidics formulation may include the following steps: diluting RNA / DNA / other API in an acidic aqueous buffer dissolving lipids in an organic solvent (typically an alcohol); adding the dissolved lipids and diluted RNA / DNA / other API; and mixed using a microfluidics device. The microfluidics device may be at a specific flow rate for each component (diluted RNA / DNA and dissolved lipids), and the flow rate ratio of the RNA / DNA: lipids. It is to be understood that this flow rate ratio influences the initial concentration of the dilutions. The mixing may be performed using a microfluidics mixing system that allows for chaotic advection using either a specific asymmetric geometry such as toroidal and herringbone microfluidics or an impingement system. For animal or human use, purification by buffer exchange using methods such as Tangential Flow Filtration is required.

[0189] It is to be understood that the method typically includes a further characterization step. Characterisation, typically following formulation and purification, includes size and zeta potential measurements using an instrument capable of Dynamic and Electrophoretic Light Scattering. This includes directing a beam of light at the sample and using the scattering of the light to detect size, or zeta potential in the presence of an electric field. Encapsulation Efficiency and effective dose of the DNA / RNA may typically be quantified by RiboGreen Assay. This assay allows quantification of unformulated RNA in the absence of a detergent, and total RNA after lysis of LNPs with a detergent.

[0190] Non-limiting examples of the lipid nanoparticles and their method of production is provided herein below which is incorporated in this summary by way of reference thereto to avoid repetition.

[0191] There is further provided for the fifth aspect of this disclosure substantially as herein described, illustrated and / or exemplified with reference to any one of the descriptions and / or examples and / or photos and / or images and / or chemical reaction schemes and / or diagrammatic drawings herein.

[0192] There is further provided for any of the first to the fifth aspects of this disclosure substantially as herein described, illustrated and / or exemplified with reference to any one of the descriptions and / or examples and / or photos and / or images and / or reaction schemes and / or diagrammatic drawings herein.

[0193] In accordance with preferred non-limiting aspects of this disclosure there is provided the following:

[0194] A method of manufacturing ionizable lipids utilizing a cardanol and / or derivatives thereof, including 3 -pentadecylphenol, and wherein said cardanol is derived from cashew nut shell liquid (CNSL), said method comprising the following steps:

[0195] (A). isolating anacardic acids, cardanols, and cardols from cashew nut shell liquid (CNSL) to provide isolated anacardic acids, isolated cardanols and isolated cardols, preferably wherein Step (A) includes a distillation;

[0196] (B). decarboxylation of the isolated anacardic acids to provide synthetic cardanols; and

[0197] (C). functionalizing the synthetic cardanol and / or derivatives thereof to provide an ionizable lipid comprising: (i) a nitrogen containing ionizable group, (ii) an aromatic ring or analogue thereof, and (iii) at least one alkyl chain.

[0198] The method may further comprise Step (D), wherein Step (D) comprises hydrogenation of both isolated cardanol and synthetic cardanol to provide saturated cardanols, including 3 -pentadecylphenol, and wherein Step (D) takes place before Step (C).

[0199] The method wherein the nitrogen containing ionizable group is a nitrogen containing compound, preferably wherein the nitrogen containing compound includes an alkaline nitrogen, and / or is an acyclic amine, cyclic amine or a heterocyclic nitrogen containing compound.

[0200] The method wherein the nitrogen containing ionizable group is selected from the group consisting of: piperidines, pyrolidines, piperazine, 1,2-diazinane, 1,3-diazinane, imidazolidine triazines, and amino acids and / or derivatives of amino acids. It is to be understood that the nitrogen containing ionizable functional group may extend to other chemical moieties. 1,2-diazinane, 1,3-diazinane and imidazolidine.

[0201] The method wherein the aromatic ring is be derived from phenolics, which phenolics are in turn are derived from CNSL, and wherein the aromatic ring is selected from the group consisting of: a phenol, resorcinol, benzaldehyde, benzyl alcohol, and benzoic acid and / or derivatives and / or analogues of the aforementioned.

[0202] The method wherein the aromatic ring is reduced to analogues of same, including cyclohexyls and linear aliphatics, and wherein the reduction takes place via Birch reduction and / or ozonolysis or other synthetic methods that result in the same nonaromatic products.

[0203] The method wherein the at least one alkyl chain is saturated or unsaturated, alternatively and / or additionally the alkyl chain is branched or unbranched, alternatively and / or additionally the alkyl chain has a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween, including wherein the carbon chain length is any one of the group consisting of: Ci, C2, C3, C4, C5, Ce, C- Cs, C9, C10, Cn, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 and C22.

[0204] The further comprising alkyl chain modification, including chain length shortening and / or extension, and wherein said alkyl chain modification includes introduction of a functional group selected from the group consisting of: esters, ethers and amides.

[0205] The method wherein alkyl chain modification take place via oxidative cleavage and / or chemo- selective modification of alkene functionalities.

[0206] The method further comprising a step of introducing at least one of the following groups consisting of: ester, amide, acetal, disulfide, carbonate, and carbamate.

[0207] The method wherein the ionizable lipid is at least one selected from the following group: 3- (decyloxy)-5-pentadecylphenyl 4-(dimethylamino) butanoate, 3-((2-ethylhexyl) oxy)-5 -pentadecylphenyl 4-(dimethylamino) butanoate, 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl 4-(4-(2 -hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(decyloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl) piperazin-1- yl) butanoate, 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl) piperazin-1- yl) butanoate, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5-pentadecylphenoxy)ethyl) piperazin- l-yl)ethan-l-ol, 2-(4- (2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2-ethylhexyl8-(3-((2- ethylhexyl) oxy)-5-(2-((4-(4-(2-hydroxyethyl) piperazin- 1-yl) butanoyl) oxy) ethoxy) phenyl) octanoate, 2,2'-((2-(3-((2-ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl)azanediyl)bis(ethan-l-ol), 2-(4-(2-(3- (octadecyloxy)-5 -pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2,2'-((2-(3-(octadecyloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2,2'-((2-(3-(oct-3-yn-l-yloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(oct-3-yn-l-yloxy)-5- pentadecylphenoxy)ethyl) piperazin- 1-yl) ethan-l-ol, (E)-2,2'-((2-(3-((3,7-dimethylocta-2,6-dien-l- yl)oxy)-5pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), (E)-2-(4-(2-(3-((3,7-dimethylocta-2,6- dien-l-yl)oxy) -5 -pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2,2'-((2-(3-(decyloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(decyloxy)-5-pentadecylphenoxy) ethyl)piperazin-l-yl) ethan-l-ol, 2,2'-((2-(3-(octan-2-yloxy)-5-pentadecylphenoxy) ethyl) azanediyl) diethanol, 2,2'-((3 -(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy )propyl)azanediyl)bis(ethan-l-ol), 2-(4-(3- (3 -((2 -ethylhexyl) oxy) -5 -pentadecylphenoxy) propyl) piperazin- 1-yl) ethan-l-ol, 2,2'-((4-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy) butyl) azanediyl) bis (ethan-l-ol), 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) piperazin- 1-yl) ethan-l-ol, 11-(2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl)-2,5,8-trioxa-l l-azatridecan-13-ol, 2,2'-((2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan- 1 -ol), ((2S)- 1 -(2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)pyrrolidin-2- yl)methanol, octyl 4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-2-(octyloxy)-6-pentadecylbenzoate, (3'-((2- ethylhexyl)oxy)-5'-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl)methyl 4-(4-(2-hydroxyethyl)piperazin- 1 -yl)butanoate, (3 '-(octadecyloxy)-5 '-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl) methyl 4-(4-(2-hydroxyethyl)piperazin- 1 - yl)butanoate, (3'-(decyloxy)-5'-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl)methyl 4-(4-(2-hydroxyethyl) piperazin- 1 - yl)butanoate, 2-(3-((9Z,12Z)-octadeca-9,12-dien-l-yloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l-yl 4-(4-(2- hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenyl)prop-2-yn-l-yl 4-(4- (2-hydroxyethyl)piperazin-l-yl) butanoate, 2-(4-(3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l- yl)piperazin- 1 -yl)ethanol, 2-(4-(3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl)piperazin- 1 - yl)ethanol, (l-(3-(decyloxy)-5-pentadecylphenyl)-lH-l,2,3-triazol-4-yl)methanol, 2-(3 -((2 -ethylhexyl) oxy)-5-pentadecylphenoxy)-N,N-dimethylethanamine, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) ethanol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(methyl)amino)ethanol, 2- ((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)propane-l,3-diol, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1-yl) ethanamine, l-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino) propane-1, 3-diol, 5 -((2-(3-((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino) pentan-l-ol, 5-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(2-hydroxyethyl) amino) pentan-l-ol, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino)-2-(hydroxymethyl) propane-1, 3-diol, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-(4-(2-hydroxyethyl)piperazin-l- yl)propan-2-ol, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2 -ol, 2,2'-((3-(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-2-hydroxypropyl)azanediyl)diethanol, 1 -(diethylamino) -3 -(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2-yl dodecanoate, l-(diethylamino)-3-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2 -yl pentanoate, N,N-diethyl-3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) propan- 1 -amine, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-((2 -hydroxyethyl) (methyl)amino) propan-2 -ol, 2-((2-(dodecanoyloxy)-3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) propyl) (methyl) amino) ethyl dodecanoate, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) (octadecyl) amino) ethanol, 2-(decyl(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)ethanol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) (octadecyl) amino) propane-1, 3-diol, 2-(3- (henicosan-l l-yloxy)-5-pentadecylphenoxy) ethyl4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, , 3-((2- ethylhexyl)oxy)-5 -pentadecylphenyl2-((5 -(bis(2 -hydroxyethyl) amino) pentyl) oxy)-2-methylpropanoate, 2, 2'-((2-(3-(2-(2-(2 -methoxyethoxy) ethoxy) ethoxy) -5 -pentadecylphenoxy) ethyl) azanediyl) diethanol.

[0208] The method further comprising steps of utilizing at least one the ionizable lipids in the manufacture of lipid nanoparticles (LNPs) to provide an ionizable lipid nanoparticle (iLNP).

[0209] The method wherein the ionizable lipid nanoparticle (iLNP) is provided as a single component lipid nanoparticle (scLNP) and / or a multiple component lipid nanoparticle (mcLNP), and wherein the manufacture of lipid nanoparticles (LNPs) includes a modified solvent injection method and / or a microfluidics method.

[0210] The method further comprising the steps of formulating additional chemicals and / or molecules and / or excipients together with the CNSL-derived ionizable lipid to provide the mcLNP, and wherein said additional chemicals and / or molecules and / or excipients includes at least one selected from the group consisting of: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid and / or sterol (including cholesterol or phytosterols and / or its derivatives), (iii) a polymer conjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), (iv) a phospholipid and / or derivatives thereof, and (v) an unconjugated polymer.

[0211] The method wherein the ionizable lipid nanoparticle (iLNP) is loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-iLNP), wherein the API includes nucleic acids, peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof, preferably wherein the API is a nucleic acid, further preferably wherein the nucleic acid is DNA and / or RNA, most preferably wherein the nucleic acid is RNA being at least one of the group consisting of: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and / or other RNAs that activate the RNA interference (RNAi) pathway.

[0212] Ionizable lipids manufactured in accordance with the methods described herein.

[0213] An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipids manufactured in accordance with the methods described herein.

[0214] Ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method described herein.

[0215] An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method described herein.

[0216] The loaded lipid nanoparticle (L-iLNP) for use as a medicament for treatment, prevention and / or amelioration and / or prophylaxis of a disease and / or medical condition in a human or animal body.

[0217] Use of the loaded lipid nanoparticle (L-iLNP) manufactured in accordance with the method described herein for transfection of cells, wherein said transfection takes place in vivo and / or ex vivo. A method of manufacturing an ionizable lipid utilizing a 5-alkylresorcinol and / or a 5-alkyl-2- (hydroxymethyl)phenol including derivatives thereof, including cardol, and wherein said 5-alkylresorcinol or 5-alkyl-2-(hydroxymethyl)phenol is derived from cashew nut shell liquid (CNSL), said method comprising the following steps:

[0218] (A). isolating anacardic acids, cardanols, and cardols from cashew nut shell liquid (CNSL) to provide the isolated anacardic acids, isolated cardanols and isolated cardols, preferably wherein Step (A) includes a distillation;

[0219] (B). decarboxylation of the isolated anacardic acids to provide synthetic cardanols;

[0220] (C). hydrogenation of both isolated cardanol and synthetic cardanol to provide saturated / hydrogenated cardanols, including 3 -pentadecylphenol;

[0221] (D). transforming the saturated cardanols to include a functional group, which functional group include a hydroxy substituent, in position 5, which position 5 includes position meta, therein providing for a 5- alkylresorcinol and / or ether containing derivatives, wherein the functional group is at least one selected from the group consisting of: saturated cyclical functional groups, unsaturated cyclical functional groups, acetates, mesylates, pivaloates, tosylates, Ar-N, Ar-S, and Ar-CX, wherein Ar refers to aryl, N refers to nitrogen, S refers to sulfur, C refers to carbon and X refers to any halogen; and

[0222] (E). functionalizing the synthetic cardanol and / or derivatives thereof to provide an ionizable lipid comprising: (i) a nitrogen containing ionizable group, (ii) an aromatic ring or analogue thereof, and (iii) at least one alkyl chain.

[0223] The method wherein Step (D) takes place via direct meta borylation of the saturated / hydrogenated cardanol with employing a protecting functional group, preferably Step (d) is provided as a one pot step.

[0224] The method wherein Step (d) includes Sub-step (dl): protecting a phenol functional group of the saturated cardanols with a protectional functional group therein providing a protected cardanol.

[0225] The method wherein Step (d) further includes [after at least commencing Sub-step (dl)] Sub-step (d2): introducing a phenol functional group in the meta position of the protected cardanol.

[0226] The method wherein Sub-step (d2) introducing a phenol functional group in the meta position of the protected cardanol includes arene C-H borylation.

[0227] The method wherein the arene C-H borylation includes use of a catalyst, including a transitional metal -based catalyst wherein the metal is selected from the group consisting of: metals: iridium (Ir), rhodium (Rh), platinum (Pt), palladium (Pd), tungsten (W), titanium (Ti), tin (Sn), ruthenium (Ru), iron (Fe) and lead (Pb). The method wherein the transition metal-based catalyst is selected from the following group consisting of: Cp*Ir(PMe3)H(Bpin), (Ind)Ir(COD), [Ir(COD)Cl]2, [Ir(COE)Cl]2, [Ir(COD)OH]2 and [Ir(COD)OMe]2.

[0228] The method further including [after at least commencing Sub-step (d2)] Sub-step (d3): removing the protectional functional group.

[0229] The method wherein Sub-step (d3) includes oxidation and employs at least one selected from the group consisting of: H2O2, oxone, potassium iodate and sodium iodate.

[0230] The method wherein the at least one alkyl chain is saturated or unsaturated, alternatively and / or additionally the alkyl chain is branched or unbranched, alternatively and / or additionally the alkyl chain has a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween, including wherein the carbon chain length is any one of the group consisting of: Ci, C2, C3, C4, C5, Ce, C- C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 and C22.

[0231] The method further comprising alkyl chain modification, including chain length shortening and / or extension, and wherein said alkyl chain modification includes introduction of a functional group selected from the group consisting of: esters, ethers and amides.

[0232] The method wherein alkyl chain modification take place via oxidative cleavage and / or chemo- selective modification of alkene functionalities.

[0233] The method further comprising a step of introducing at least one of the following groups consisting of: ester, amide, acetal, disulfide, carbonate, and carbamate.

[0234] The method wherein the ionizable lipid is at least one selected from the following group: 3- (decyloxy)-5 -pentadecylphenyl 4-(dimethylamino) butanoate, 3-((2-ethylhexyl) oxy)-5 -pentadecylphenyl 4-(dimethylamino) butanoate, 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(octadecyloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(decyloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(4-(2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)ethyl) piperazin- 1 -yl)ethan- 1 -ol, 2-(4-(2-(3 -(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 - yl)ethan- 1 -ol, 2-ethylhexyl8-(3-((2 -ethylhexyl) oxy)-5-(2-((4-(4-(2-hydroxyethyl) piperazin- 1 -yl) butanoyl) oxy) ethoxy) phenyl) octanoate, 2,2'-((2-(3-((2-ethylhexyl) oxy) -5 -pentadecylphenoxy) ethyl)azanediyl)bis(ethan- 1 -ol), 2-(4-(2-(3 -(octadecyloxy) -5 -pentadecylphenoxy) ethyl) piperazin- 1 - yl)ethan-l-ol, 2,2'-((2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2,2'- ((2-(3 -(oct-3 -yn-l-yloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3 -(oct-3 -yn- l-yloxy)-5-pentadecylphenoxy)ethyl) piperazin- 1-yl) ethan-l-ol, (E)-2,2'-((2-(3-((3,7-dimethylocta-2,6- dien-l-yl)oxy)-5pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), (E)-2-(4-(2-(3-((3,7- dimethylocta-2,6-dien- 1 -yl)oxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 -yl)ethan- 1 -ol, 2,2'-((2-(3 - (decyloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(decyloxy)-5- pentadecylphenoxy) ethyl)piperazin- 1 -yl) ethan- 1 -ol, 2,2'-((2-(3 -(octan-2-yloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) diethanol, 2,2'-((3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy )propyl)azanediyl)bis(ethan- 1 -ol), 2-(4-(3-(3-((2-ethylhexyl) oxy)-5- pentadecylphenoxy) propyl) piperazin- 1-yl) ethan-l-ol, 2,2'-((4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) azanediyl) bis (ethan-l-ol), 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) piperazin- 1-yl) ethan-l-ol, 1 l-(2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl)-2,5,8-trioxa-l l-azatridecan-13-ol, 2,2'-((2-(3-(heptadecan-9-yloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), ((2S)-l-(2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)ethyl)pyrrolidin-2-yl)methanol, octyl 4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-2- (octyloxy)-6-pentadecylbenzoate, (3'-((2-ethylhexyl)oxy)-5'-pentadecyl-[l,r-biphenyl]-4-yl)methyl 4-(4- (2-hydroxyethyl)piperazin- 1 -yl)butanoate, (3 '-(octadecyloxy)-5 '-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl) methyl 4-(4-(2-hydroxyethyl)piperazin-l-yl)butanoate, (3'-(decyloxy)-5'-pentadecyl-[l,l'-biphenyl]-4-yl)methyl 4-(4-(2 -hydroxyethyl) piperazin- l-yl)butanoate, 2-(3-((9Z,12Z)-octadeca-9,12-dien-l-yloxy)-5- pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-(decyloxy)-5- pentadecylphenyl)prop-2-yn-l-yl 4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4-(2-hydroxyethyl)piperazin- 1 -yl) butanoate, 2- (4-(3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l-yl)piperazin-l-yl)ethanol, 2-(4-(3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl)piperazin- 1 -yl)ethanol, ( 1 -(3 -(decyloxy)-5 - pentadecylphenyl)-lH-l,2,3-triazol-4-yl)methanol, 2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)- N,N-dimethylethanamine, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) ethanol, 2- ((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(methyl)amino)ethanol, 2-((2-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)propane-l,3-diol, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5- pentadecylphenoxy) ethyl) piperazin- 1-yl) ethanamine, l-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino) propane-1, 3-diol, 5-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) pentan- 1 -ol, 5 -((2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)(2 -hydroxyethyl) amino) pentan-l-ol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino)-2- (hydroxymethyl) propane-1, 3-diol, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-(4-(2- hydroxyethyl)piperazin-l-yl)propan-2-ol, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) propan-2 -ol, 2,2'-((3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-2- hydroxypropyl)azanediyl)diethanol, 1 -(diethylamino)-3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) propan-2 -yl dodecanoate, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2 -yl pentanoate, N,N-diethyl-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan- 1 -amine, l-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy)-3-((2-hydroxyethyl) (methyl)amino) propan-2 -ol, 2-((2- (dodecanoyloxy)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propyl) (methyl) amino) ethyl dodecanoate, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) (octadecyl) amino) ethanol, 2- (decyl(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)ethanol, 2-((2-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) (octadecyl) amino) propane-1, 3-diol, 2-(3-(henicosan-l 1- yloxy)-5-pentadecylphenoxy) ethyl4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, , 3-((2- ethylhexyl)oxy)-5-pentadecylphenyl2-((5-(bis(2 -hydroxyethyl) amino) pentyl) oxy)-2-methylpropanoate, 2, 2'-((2-(3-(2-(2-(2 -methoxyethoxy) ethoxy) ethoxy) -5 -pentadecylphenoxy) ethyl) azanediyl) diethanol. The method further comprising steps of utilizing at least one the ionizable lipids in the manufacture of lipid nanoparticles (LNPs) to provide an ionizable lipid nanoparticle (iLNP).

[0235] The method wherein the ionizable lipid nanoparticle (iLNP) is provided as a single component lipid nanoparticle (scLNP) and / or a multiple component lipid nanoparticle (mcLNP), and wherein the manufacture of lipid nanoparticles (LNPs) includes a modified solvent injection method and / or a microfluidics method.

[0236] The method further comprising the steps of formulating additional chemicals and / or molecules and / or excipients together with the CNSL-derived lipid to provide the mcLNP, and wherein said additional chemicals and / or molecules and / or excipients includes at least one selected from the group consisting of: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid and / or sterol (including cholesterol or phytosterols and / or its derivatives), (iii) a polymer conjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), (iv) a phospholipid and / or derivatives thereof, and (v) an unconjugated polymer.

[0237] The method wherein the ionizable lipid nanoparticle (iLNP) is loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-iLNP), wherein the API includes nucleic acids, peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof, preferably wherein the API is a nucleic acid, further preferably wherein the nucleic acid is DNA and / or RNA, most preferably wherein the nucleic acid is RNA being at least one of the group consisting of: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and / or other RNAs that activate the RNA interference (RNAi) pathway.

[0238] Ionizable lipids manufactured in accordance with the methods described herein.

[0239] An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipids manufactured in accordance with the methods described herein.

[0240] Ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method described herein.

[0241] An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method described herein.

[0242] The ionizable lipid nanoparticles (iLNPs) for use as a medicament for treatment, prevention and / or amelioration and / or prophylaxis of a disease and / or medical condition in a human or animal body.

[0243] Use of the loaded lipid nanoparticle (L-iLNP) manufactured in accordance with the method described herein for transfection of cells, wherein said transfection takes place in vivo and / or ex vivo. BRIEF DESCRIPTION OF DRAWINGS

[0244] Embodiments of the disclosure will be described below by way of example only and with reference to the accompanying diagrammatic drawings, photos, and / or chemical reaction schemes and which are not to be construed as limiting the scope of the disclosure or any part thereof.

[0245] Figure 1. Shows a reaction scheme for a method of valorising cashew nut shell liquid (CNSL) in accordance with this disclosure.

[0246] Figure 2. Shows all the lipids made in accordance with the methods of this disclosure.

[0247] Figure 3. Shows sizes of mRNA-single-component LNPs (scLNPs) formulated using a modified solvent mixing method. A) mRNA-scLNPs formulated at a 40: 1 lipid:mRNA w:w ratio at a small scale (0.1 m , 10 pg). B) mRNA-scLNPs formulated at a 40: 1 lipid:mRNA w:w ratio at a larger scale (2 m , 200 pg). Bars indicate size (left y axis), points indicate polydispersity index (PDIright y axis). Dotted line indicates polydispersity index (PDI) cut-off of 0.3.

[0248] Figure 4. Shows representative particle sizing bell curves for data in Figure 3B for scENPs of RK-003 (A, DR-03A), RK-006 (B, DR-06A), AG-002 (C, DA-02A), and AG-003 (D, DA-03 A). N=5 for A, C, and D; n=3 for B.

[0249] Figure 5. A- D. Shows expression of the Firefly luciferase (Flue) reporter, encoded by Flue mRNA, after delivering mRNA to HEK293 cells with scENPs.

[0250] Figure 6. Shows bioluminescence imaging of mice following in vivo application of DR-0612, a Flue mRNA loaded ionizable four-component lipid nanoparticle.

[0251] Figure 7. Shows bioluminescence imaging of mice following in vivo application of DA-0211, a Flue mRNA loaded ionizable single-component lipid nanoparticle.

[0252] Figure 8. Modified solvent injection formulation of mRNA in cashew nutshell (CNSE)-derived single component ENPs. Single component ENPs (scENPs) were formulated with Fluc-mRNA using a modified solvent injection (MSI) method. A) All scLNPs were <150 nm in size with low polydispersity indices (PDIs) of <0.3. B) Encapsulation efficiency (% of total RNA) measured by an established RiboGreen assay. All scLNPs have >80 % RNA encapsulation, with the majority having a >90 % RNA encapsulation. Bars represent LNP size (left y-axis) and symbols represent average PDI (right y-axis) of scLNPs respectively. Size (d.nm) is a measure of the particle diameter in nm.

[0253] Figure 9. Microfluidics formulation of mRNA in CNSL-derived four-component LNPs. Multicomponent LNPs (mcLNPs) comprised of four lipid components (Ionizable lipid, cholesterol, DSPC and DMG- PEG2000, mol ratio 50:38.5: 10: 1.5) were used to formulate Flue mRNA using established microfluidics methodology. Particle sizes and PDIs of four-component mcLNPs comprising “RK” (A), “CS” (B) and “AG” (C) CNSL-derived ionizable lipids were measured after purification. Nanoparticle sizes range from 30.2 - 157 nanometres (nm) in diameter, with the majority (27 / 32) CNSL mcLNPs between 55 and 90 nm. PDIs were <0.3 (29 / 32) indicating a homogeneous size distribution of single LNP population. Bars and symbols represent size (left y-axis) and PDI (right y-axis) of scLNPs respectively. Size (d.nm) is a measure of the particle diameter in nm.

[0254] Figure 10. A-C. Shows RNA encapsulation efficiency of CNSL-derived four-component mRNA-mcLNPs formulated using microfluidics. Encapsulation efficiency (% of total RNA) in mcLNPs was measured using an established RiboGreen assay. The majority (31 / 32) had a minimum encapsulation efficiency above 80%, with the 28 / 32 mcLNPs encapsulating >90 % of the mRNA.

[0255] Figure 11. Apparent pKas of CNSL mcLNPs. The apparent pKa of mcLNPs was determined experimentally using a TNS titration assay, by assessing fluorescence as a result of TNS binding at a range of pHs (pH 4- 9). Representative sigmoidal curve plots for DC-09B, DC-013, DR-081, DR-11A, DR-17 and DR-29 are shown

[0256] Figure 12. Delivery efficiency of RNA formulated in CNSL-based scLNPs in HEK293T cell cultures. Flue mRNA-LNPs were formulated using MSI, diluted in a neutral buffer, and used to transfect HEK293T cells. Delivery efficacy was determined by measuring light produced (light units, LU). A) scLNPs show strong Flue transgene expression and hence delivery efficiency after 24 hours. Delivery efficacy was compared to a commercial transfection reagent control (LMMax; Lipofectamine Messenger Max, Thermo Fisher Scientific), showing comparable levels of RNA delivery. B) Expression of scLNPs compared to their mcLNP counterparts, both of which show efficient cellular transfection as shown by Flue transgene expression.

[0257] Figure 13. Delivery efficiency of RNA formulated in CNSL-based four-component mcLNPs in HEK293T cell cultures. “DR” (A), “DC” (B), and “DA” (C) four-component mcLNPs were used to formulate Fluc- mRNA using the modified solvent injection method and used to transfect HEK293T cells. LNPs were compared to a commercial ionizable lipid in a four-component mcLNP (SM-102) formulated the same way. Delivery efficacy was measured as Flue transgene expression as measured by a luciferase assay. Flue substrate luminescence was measured and plotted as light units (LU) on the y-axis. The LNPs show efficient RNA delivery as shown by strong transgene expression comparable to that of the SM-102 control. A negative control is included. Error bars show SEM.

[0258] Figure 14. Cell culture delivery efficacy of CNSL-derived scLNPs formulating pDNA, protein, and ASOs. A) CNSL-derived scLNPs encapsulating Flue expressing pDNA formulated are able to efficiently deliver into cells, with transgene expression comparable to that of a commercial transfection reagent control (L3000; Lipofectamine 3000, Thermo Fisher Scientific). B and C) scLNPs were used to formulate recombinant eGFP protein, and antisense oligonucleotides (ASOs) and used to transfect HEK293 cells. siRNA and ASOs were labelled with the fluorescent marker 6-FAM on the 3' end of the antisense strand. Transfection efficiency was analysed after 24 hours by fluorescent microscopy. B) Successful transfection of cells with eGFP protein was achieved with CNSL-based LNPs, this is shown by eGFP positive cells (black) indicated by arrows. Delivery of ASO (C) molecules into cells is indicated by small black spots from the fluorescent label. Successful delivery of both ASOs and siRNAs was achieved using CNSL-based LNPs. Clusters of molecules delivered into cells are circled, with arrows pointing to examples of single molecules. w:w indicates the weight ratio of ionizable lipid:DNA. Scale bars indicate 400 pm (10x magnification) or 200 pm (20x magnification). A magnification of 10x was used unless otherwise stated.

[0259] Figure 15. Lack of cellular toxicity after transfection of mammalian cells with CNSL-derived LNPs. Cell culture toxicity was assessed using an MTT assay and compared to a negative (buffer) and positive (DMSO treatment) controls for cell toxicity. LNPs formulated with the ionizable lipid SM-102 was used as a control. None of the CNSL-derived scLNPs (A) or mcLNPs (B) display any cellular toxicity relative to the buffer and DMSO controls. DR- 14, an scLNP comprising RK-014, which is structurally similar to an aromatic lipid synthesised using petroleum -based building blocks, shows toxicity in mammalian cells (19% cell viability).

[0260] Figure 16. Delivery efficacy and toxicity studies of Fluc-mRNA formulated in CNSL-derived scLNPs in vivo after intramuscular and intradermal injection. A) scLNPs show expression at 6-hours post injection, dissipating at 24 hours. DA-03 A shows no detectable expression of Flue at 6 hours but showed detectable Flue expression at 24-hours post-injection. B) Aspartate transaminase (AST) and Alanine aminotransferase (ALT) serum enzyme levels were evaluated 7 days post-injection to assess in vivo toxicity of the formulations. No increase in serum enzyme levels was observed indicating the scLNPs are not toxic. Dotted and dashed lines represent cut off values for ALT and AST serum levels respectively. Values below this cut off are considered normal, values above this cut off indicate toxicity.

[0261] Figure 17. In vivo Flue mRNA delivery efficacy of “RK” CNSL-derived four-component mcLNPs. mRNA- Fluc -mcLNPs incorporating the “RK” ionizable lipids were injected either intramuscularly (IM) or intradermally (ID) into the mouse’s left hindlimb or on the lateral abdominal area respectively. Mice were imaged after intraperitoneal injection of D-luciferin at 6- and 24-hours post-injection. 1, 3, 5-tri-substituted benzene ring ionizable lipids show strong delivery dependant on the hydrophobic chain and ionizable region. Branched (DR-03B, -06B, -081, and -11A) and linear chains (DR-05C, -13) showed strong delivery efficacy as seen by transgene expression up to 24 hours at the site of injection. Combinations of branched and alkene hydrophobic chains show also show strong delivery at the site of injection (DR- 17). Removal of the ester group (DR-081) or modifying the ionizable group from a piperazine to a diethanolamine (DR-11A) did not compromise delivery efficacy. The addition of a proline ionizable group (DR-29) altered biodistribution, resulting in partial liver tropism at 6 hours post-injection of the CNSL mcLNP, with the majority of transgene expression at the site of injection. Modifying the ionizable group from of a piperazine DR-06F to a diethanolamine in DR-28 also altered the biodistribution, with transgene expression at the site of injection and in the liver at 6-hours post-injection. Strong delivery efficacy after intradermal injection was achieved, which was proportional to the delivery efficacy after IM injection. All CNSL LNP formulations were functional. Figure 18. In vivo Flue mRNA delivery efficacy of “CS” and “AG” CNSL-derived four-component mcLNPs. mRNA-Fluc-mcLNPs incorporating the “CS” and “AG” ionizable lipids were injected intramuscularly (IM) into the mouse’s left hindlimb. Mice were imaged after intraperitoneal injection of D- luciferin at 6- and 24-hours post-injection. A) The ionizable region of the “CS” 1, 3, 5-tri-substituted benzene ring ionizable lipids was altered to assess delivery efficiency. Addition of an alkyne between the benzene ring and ionizable piperazine branched chains (DC-07, DC-09B) did not compromise delivery efficacy. Amine groups with multiple branched alcohol groups (DC- 18, DC- 19) or additional methyl groups (DC-13) attached to the ionizable amine performed well. Ionizable groups with branched methyl groups attached to the nitrogen group (CS-21) showed strong local delivery and some hepatotropism. B) 1, 2, 4- trisubstituted benzene ionizable lipids with short hydrophobic chains (DA-04) show strong delivery efficacy at 6-hours post-injection. 1, 2, 4-trisubstituted benzene ionizable lipids comprising piperazine rings with long alkane (DA-03B) hydrophobic chains or a long chain containing an alkene (DA-02B) showed good delivery efficacy after IM injection. All CNSL LNP formulations were functional.

[0262] Figure 19. In vivo toxicity assessment of four-component mcLNPs. ALT and AST serum enzyme levels were evaluated 7 days post-injection to assess in vivo toxicity of the formulations. Four-component LNPs incorporating SM-102 were included as a control. No increase in serum enzyme levels was observed indicating the mcLNPs are not toxic. Dotted and dashed lines represent cut off values for ALT and AST serum levels respectively. Values below this cut off are considered normal, values above this cut off indicate toxicity.

[0263] Figure 20. Formulation of Spike-mRNA vaccines using CNSL-derived mcLNPs. Microfluidics was used in encapsulate COVID-19 Spike-mRNA in four-component LNPs derived from CNSL ionizable lipids. LNPs formulated with the ionizable lipid SM-102 was used as a control. A) Particle sizes and PDIs of formulated vaccines. All mcLNPs were <100 nm with low PDIs <0.3. B) The RNA encapsulation efficiencies were all >80 % with 13 / 14 LNPs >90%. Bars and symbols represent size (left y-axis) and PDI (right y-axis) of mcLNPs respectively. Size (d.nm) is a measure of the particle diameter in nm.

[0264] Figure 21. Assessment of secreted cytokines after splenocyte stimulation. Secreted cytokine profiles in ex vivo-stimulated spleen cells from mice injected intramuscularly with 5 pg of CNSL mcLNP-formulated control mRNA encoding a bioluminescence reporter gene, or CNSL mcLNP-formulated COVID-19 Spike- mRNA. LNPs formulated with the ionizable lipid SM-102 were used as controls. Splenocytes were isolated at day 35, stimulated with a SARS-CoV-2 spike peptide pool (or positive / negative controls). Secreted cytokines were evaluated 24 hours after stimulation using the murine LEGENDplex 5-plex Thl kit. These results confirm antigen-specific T cell activation and immunization with CNSL mcLNPs. Stimulation of spleen cells with COVID- 19 Spike-protein peptide pools showed increased concentrations of IFN-y (A, B, C) and IL-2 (D, E, F) in mice vaccinated with the Spike-mRNA, but not with the Fluc-mRNA, confirming the use of CNSL mcLNPs for the delivery of vaccines. Figure 22. Assessment of binding antibodies after prime and boost vaccination with CNSL-derived SARS- CoV-2 Spike-mRNA-LNPs. Serology was performed on blood collected at day 35 (two weeks post-boost) using a SARS-CoV-2 spike binding enzyme linked immunosorbent assay (ELISA). Titration curves are shown, indicating binding antibodies specific to the Wuhan SARS-CoV-2 spike antigen are detected following vaccination indicating induction of humoral immune responses.

[0265] Figure 23. Assessment of delivery efficacy after inclusion of alternative excipients in CNSL mcLNPs. Two, three and four mcLNPs were used to transfect HEK293T cells to assess delivery efficacy of alternate mcLNPs. Alternative excipients were included in some of the formulations to replace DSPC or cholesterol with DOPE and phytosterols respectively. In this example, CNSL-derived ionizable LNPs incorporating RK-006 (A), RK-008 (B) and RK-011 (C) were examined. Two- and three-component CNSL LNPs and mcLNPs incorporating DOPE and phytosterols (Stigmasterol and P-sitosterol), and omission of a PEGylated lipid were assessed. Two- and three -component LNPs comprising of different combinations of CNSL- derived ionizable lipid, DSPC, cholesterol, and DMG-PEG2000 showed strong delivery efficacy into mammalian cells. Replacement of DSPC with DOPE, cholesterol with phytosterols (e.g. stigmasterol and P-Sitosterol), and removal of either the phospholipid, sterol, or PEGylated lipid or a combination of two from the traditional four-component formulation, did not compromise LNP delivery efficacy.

[0266] GENERAL DETAILED DESCRIPTION

[0267] The general provisions of the Summary are repeated herein by way of reference thereto and are not necessarily repeated in full to avoid repetition. The detailed description and examples herein below will include particular embodiments of this disclosure and should not be considered as limiting in any way. Several alternatives may be envisioned by a person skilled in the art which does not depart from the scope of this disclosure. Cashew nut shell liquid (CNSL) has been identified as a sustainably produced biomass and chemical feedstock.

[0268] Utilising CNSL in the methods of this disclosure and the chemicals and / or compositions produced by exercising the methods is extremely cost effective when compared to the existing state of the art methods providing the same or similar compounds (for example cardol and / or derivatives thereof, cardanol and / or derivatives thereof, lipids, and lipid nanoparticles and derivatives thereof), and provides for simplification of organic synthetic routes reducing inter alia the number of process steps, the solvents utilized, the energy expended, and the time expended. The Applicant believes that the methods according to this disclosure provide a technical solution to the technical problems experienced in the state of the art. Furthermore, there is no hint and / or suggestion in the current state of the art that would prompt the person skilled in the art to consider CNSL as a feedstock or starting reagent required to produce the chemicals and / or compositions of this disclosure.

[0269] The primary phenolic constituents of CNSL include, but are not limited to, anacardic acids, cardanols, and 5-alkenyl resorcinols (including cardols), wherein anacardic acids and cardanols are major phenolic constituents and the 5 -alkenyl resorcinols (including cardols) is a very minor constituent. Typically, cardols and cardanols may be utilized as building blocks in downstream processes to provide for high value chemical compounds.

[0270] The phenolics (anacardic acids, cardanols and cardols) were extracted by known organic separation means from CNSL and isolated for further downstream processing, synthesis, functionalization and / or transformation and / or synthetic procedures as described herein.

[0271] The method of manufacturing hydrogenated cardanol as per the first aspect of this disclosure and described herein is extremely cost effective.

[0272] The method of manufacturing hydrogenated cardol as per the second aspect of this disclosure and described herein is extremely cost effective. The current commercial price for hydrogenated cardol is in the region of US$660 for 10 grams. However, utilizing the method described herein the cost price is reduced to US$ 6 (six) for 10 grams. The disclosure provides for a significant reduction in sourcing hydrogenated cardol, and facilitates utilization of hydrogenated cardol as a cost effective building block for high value downstream compounds.

[0273] In accordance with a third aspect of this disclosure there is provided a method of manufacturing an arene including a 5 -alkyl -2 -hydroxybenzaldehyde and / or derivatives thereof from 3 -pentadecylphenol.

[0274] The method of manufacturing lipids, particularly ionizable lipids, as per the fourth aspect of this disclosure and described herein, is extremely cost effective when compared to the existing state of the art, and provides for simplification of organic synthetic routes reducing inter alia the number of process steps, the solvents utilized, the energy expended, and the time expended.

[0275] The method of manufacturing lipid nanoparticles, particularly ionizable lipid nanoparticles, as per the fifth aspect of this disclosure and described herein, is extremely cost effective when compared to the existing state of the art, and provides for simplification of organic synthetic routes and / or formulation routes reducing inter alia the number of process steps, the solvents utilized, the energy expended, and the time expended.

[0276] PREFERRED NON-LIMITING ASPECTS OF THIS DISCLOSURE PROVIDE THE FOLLOWING:

[0277] A method of manufacturing ionizable lipids utilizing a cardanol and / or derivatives thereof, including 3 -pentadecylphenol, and wherein said cardanol is derived from cashew nut shell liquid (CNSL), said method comprising the following steps:

[0278] (A). isolating anacardic acids, cardanols, and cardols from cashew nut shell liquid (CNSL) to provide isolated anacardic acids, isolated cardanols and isolated cardols, preferably wherein Step (A) includes a distillation; (B). decarboxylation of the isolated anacardic acids to provide synthetic cardanols; and

[0279] (C). functionalizing the synthetic cardanol and / or derivatives thereof to provide an ionizable lipid comprising: (i) a nitrogen containing ionizable group, (ii) an aromatic ring or analogue thereof, and (iii) at least one alkyl chain.

[0280] The method may further comprise Step (D), wherein Step (D) comprises hydrogenation of both isolated cardanol and synthetic cardanol to provide saturated cardanols, including 3 -pentadecylphenol, and wherein Step (D) takes place before Step (C).

[0281] The method wherein the nitrogen containing ionizable group is a nitrogen containing compound, preferably wherein the nitrogen containing compound includes an alkaline nitrogen, and / or is an acyclic amine, cyclic amine or a heterocyclic nitrogen containing compound.

[0282] The method wherein the nitrogen containing ionizable group is selected from the group consisting of: piperidines, pyrolidines, piperazine, 1,2-diazinane, 1,3-diazinane, imidazolidine triazines, and amino acids and / or derivatives of amino acids. It is to be understood that the nitrogen containing ionizable functional group may extend to other chemical moieties. 1,2-diazinane, 1,3-diazinane and imidazolidine.

[0283] The method wherein the aromatic ring is be derived from phenolics, which phenolics are in turn are derived from CNSL, and wherein the aromatic ring is selected from the group consisting of: a phenol, resorcinol, benzaldehyde, benzyl alcohol, and benzoic acid and / or derivatives and / or analogues of the aforementioned.

[0284] The method wherein the aromatic ring is reduced to analogues of same, including cyclohexyls and linear aliphatics, and wherein the reduction takes place via Birch reduction and / or ozonolysis or other synthetic methods that result in the same nonaromatic products.

[0285] The method wherein the at least one alkyl chain is saturated or unsaturated, alternatively and / or additionally the alkyl chain is branched or unbranched, alternatively and / or additionally the alkyl chain has a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween, including wherein the carbon chain length is any one of the group consisting of: Ci, C2, C3, C4, C5, Ce, C- Cs, C9, C10, Cn, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 and C22.

[0286] The further comprising alkyl chain modification, including chain length shortening and / or extension, and wherein said alkyl chain modification includes introduction of a functional group selected from the group consisting of: esters, ethers and amides.

[0287] The method wherein alkyl chain modification take place via oxidative cleavage and / or chemo- selective modification of alkene functionalities.

[0288] The method further comprising a step of introducing at least one of the following groups consisting of: ester, amide, acetal, disulfide, carbonate, and carbamate. The method wherein the ionizable lipid is at least one selected from the following group: 3- (decyloxy)-5-pentadecylphenyl 4-(dimethylamino) butanoate, 3-((2-ethylhexyl) oxy)-5 -pentadecylphenyl 4-(dimethylamino) butanoate, 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl 4-(4-(2 -hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(decyloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl) piperazin-1- yl) butanoate, 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl) piperazin-1- yl) butanoate, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5-pentadecylphenoxy)ethyl) piperazin- l-yl)ethan-l-ol, 2-(4- (2-(3 -(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 -yl)ethan- 1 -ol, 2-ethylhexyl8-(3 -((2- ethylhexyl) oxy)-5-(2-((4-(4-(2-hydroxyethyl) piperazin- 1-yl) butanoyl) oxy) ethoxy) phenyl) octanoate, 2,2'-((2-(3-((2-ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl)azanediyl)bis(ethan-l-ol), 2-(4-(2-(3- (octadecyloxy)-5 -pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2,2'-((2-(3-(octadecyloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2,2'-((2-(3-(oct-3-yn-l-yloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(oct-3-yn-l-yloxy)-5- pentadecylphenoxy)ethyl) piperazin- 1-yl) ethan-l-ol, (E)-2,2'-((2-(3-((3,7-dimethylocta-2,6-dien-l- yl)oxy)-5pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), (E)-2-(4-(2-(3-((3,7-dimethylocta-2,6- dien-l-yl)oxy) -5 -pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2,2'-((2-(3-(decyloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl)piperazin-l-yl) ethan-l-ol, 2,2'-((2-(3-(octan-2-yloxy)-5-pentadecylphenoxy) ethyl) azanediyl) diethanol, 2,2'-((3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)propyl)azanediyl)bis(ethan-l-ol), 2-(4-(3- (3 -((2 -ethylhexyl) oxy) -5 -pentadecylphenoxy) propyl) piperazin- 1-yl) ethan-l-ol, 2,2'-((4-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy) butyl) azanediyl) bis (ethan-l-ol), 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) piperazin- 1-yl) ethan-l-ol, 1 l-(2-(3-((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl)-2,5,8-trioxa-l l-azatridecan-13-ol, 2,2'-((2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan- 1 -ol), ((2S)- 1 -(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)pyrrolidin-2- yl)methanol, octyl 4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-2-(octyloxy)-6-pentadecylbenzoate, (3'-((2- ethylhexyl)oxy)-5'-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl)methyl 4-(4-(2-hydroxyethyl)piperazin- 1 -yl)butanoate, (3 '-(octadecyloxy)-5 '-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl) methyl 4-(4-(2-hydroxyethyl)piperazin- 1 - yl)butanoate, (3'-(decyloxy)-5'-pentadecyl-[l,l'-biphenyl]-4-yl)methyl 4-(4-(2-hydroxyethyl) piperazin-1- yl)butanoate, 2-(3-((9Z,12Z)-octadeca-9,12-dien-l-yloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl)piperazin- 1 -yl) butanoate, 3 -(3 -(decyloxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4-(2- hydroxyethyl)piperazin- 1 -yl) butanoate, 3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4- (2-hydroxyethyl)piperazin-l-yl) butanoate, 2-(4-(3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l- yl)piperazin- 1 -yl)ethanol, 2-(4-(3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl)piperazin- 1 - yl)ethanol, (l-(3-(decyloxy)-5-pentadecylphenyl)-lH-l,2,3-triazol-4-yl)methanol, 2-(3 -((2 -ethylhexyl) oxy)-5-pentadecylphenoxy)-N,N-dimethylethanamine, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) ethanol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(methyl)amino)ethanol, 2- ((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)propane-l,3-diol, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1-yl) ethanamine, l-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino) propane-1, 3-diol, 5-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) pentan- 1 -ol, 5 -((2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)(2-hydroxyethyl) amino) pentan- l-ol, 2-((2-(3-((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino)-2-(hydroxymethyl) propane-1, 3-diol, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-(4-(2-hydroxyethyl)piperazin-l- yl)propan-2-ol, l-(diethylamino)-3 -(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) propan-2 -ol, 2,2'-((3-(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-2-hydroxypropyl)azanediyl)diethanol, 1 -(diethylamino) -3 -(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2-yl dodecanoate, l-(diethylamino)-3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenoxy) propan-2 -yl pentanoate, N,N-diethyl-3 -(3 -((2-ethylhexyl)oxy)-5 - pentadecylphenoxy) propan- 1 -amine, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-((2-hydroxyethyl) (methyl)amino) propan-2 -ol, 2-((2-(dodecanoyloxy)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propyl) (methyl) amino) ethyl dodecanoate, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) (octadecyl) amino) ethanol, 2-(decyl(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)ethanol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) (octadecyl) amino) propane-1, 3-diol, 2-(3- (henicosan-l l-yloxy)-5-pentadecylphenoxy) ethyl4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, , 3-((2- ethylhexyl)oxy)-5 -pentadecylphenyl2-((5 -(bis(2 -hydroxyethyl) amino) pentyl) oxy)-2-methylpropanoate, 2, 2'-((2-(3-(2-(2-(2 -methoxyethoxy) ethoxy) ethoxy) -5 -pentadecylphenoxy) ethyl) azanediyl) diethanol.

[0289] The method further comprising steps of utilizing at least one the ionizable lipids in the manufacture of lipid nanoparticles (LNPs) to provide an ionizable lipid nanoparticle (iLNP).

[0290] The method wherein the ionizable lipid nanoparticle (iLNP) is provided as a single component lipid nanoparticle (scLNP) and / or a multiple component lipid nanoparticle (mcLNP), and wherein the manufacture of lipid nanoparticles (LNPs) includes a modified solvent injection method and / or a microfluidics method.

[0291] The method further comprising the steps of formulating additional chemicals and / or molecules and / or excipients together with the CNSL-derived ionizable lipid to provide the mcLNP, and wherein said additional chemicals and / or molecules and / or excipients includes at least one selected from the group consisting of: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid and / or sterol (including cholesterol or phytosterols and / or its derivatives), (iii) a polymer conjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), (iv) a phospholipid and / or derivatives thereof, and (v) an unconjugated polymer.

[0292] The method wherein the ionizable lipid nanoparticle (iLNP) is loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-iLNP), wherein the API includes nucleic acids, peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof, preferably wherein the API is a nucleic acid, further preferably wherein the nucleic acid is DNA and / or RNA, most preferably wherein the nucleic acid is RNA being at least one of the group consisting of: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and / or other RNAs that activate the RNA interference (RNAi) pathway. Ionizable lipids manufactured in accordance with the methods described herein.

[0293] An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipids manufactured in accordance with the methods described herein.

[0294] Ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method described herein.

[0295] An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method described herein.

[0296] The loaded lipid nanoparticle (L-iLNP) for use as a medicament for treatment, prevention and / or amelioration and / or prophylaxis of a disease and / or medical condition in a human or animal body.

[0297] Use of the loaded lipid nanoparticle (L-iLNP) manufactured in accordance with the method described herein for transfection of cells, wherein said transfection takes place in vivo and / or ex vivo.

[0298] A method of manufacturing an ionizable lipid utilizing a 5-alkylresorcinol and / or a 5-alkyl-2- (hydroxymethyl)phenol including derivatives thereof, including cardol, and wherein said 5-alkylresorcinol or 5-alkyl-2-(hydroxymethyl)phenol is derived from cashew nut shell liquid (CNSL), said method comprising the following steps:

[0299] (A). isolating anacardic acids, cardanols, and cardols from cashew nut shell liquid (CNSL) to provide the isolated anacardic acids, isolated cardanols and isolated cardols, preferably wherein Step (A) includes a distillation;

[0300] (B). decarboxylation of the isolated anacardic acids to provide synthetic cardanols;

[0301] (C). hydrogenation of both isolated cardanol and synthetic cardanol to provide saturated / hydrogenated cardanols, including 3 -pentadecylphenol;

[0302] (D). transforming the saturated cardanols to include a functional group, which functional group include a hydroxy substituent, in position 5, which position 5 includes position meta, therein providing for a 5- alkylresorcinol and / or ether containing derivatives, wherein the functional group is at least one selected from the group consisting of: saturated cyclical functional groups, unsaturated cyclical functional groups, acetates, mesylates, pivaloates, tosylates, Ar-N, Ar-S, and Ar-CX, wherein Ar refers to aryl, N refers to nitrogen, S refers to sulfur, C refers to carbon and X refers to any halogen; and

[0303] (E). functionalizing the synthetic cardanol and / or derivatives thereof to provide an ionizable lipid comprising: (i) a nitrogen containing ionizable group, (ii) an aromatic ring or analogue thereof, and (iii) at least one alkyl chain.

[0304] The method wherein Step (D) takes place via direct meta borylation of the saturated / hydrogenated cardanol with employing a protecting functional group, preferably Step (d) is provided as a one pot step. The method wherein Step (d) includes Sub-step (dl): protecting a phenol functional group of the saturated cardanols with a protectional functional group therein providing a protected cardanol.

[0305] The method wherein Step (d) further includes [after at least commencing Sub-step (dl)] Sub-step (d2): introducing a phenol functional group in the meta position of the protected cardanol.

[0306] The method wherein Sub-step (d2) introducing a phenol functional group in the meta position of the protected cardanol includes arene C-H borylation.

[0307] The method wherein the arene C-H borylation includes use of a catalyst, including a transitional metal -based catalyst wherein the metal is selected from the group consisting of: metals: iridium (Ir), rhodium (Rh), platinum (Pt), palladium (Pd), tungsten (W), titanium (Ti), tin (Sn), ruthenium (Ru), iron (Fe) and lead (Pb).

[0308] The method wherein the transition metal-based catalyst is selected from the following group consisting of: Cp*Ir(PMe3)H(Bpin), (Ind)Ir(COD), [Ir(COD)Cl]2, [Ir(COE)Cl]2, [Ir(C0D)0H]2 and [Ir(COD)OMe]2.

[0309] The method further including [after at least commencing Sub-step (d2)] Sub-step (d3): removing the protectional functional group.

[0310] The method wherein Sub-step (d3) includes oxidation and employs at least one selected from the group consisting of: H2O2, oxone, potassium iodate and sodium iodate.

[0311] The method wherein the at least one alkyl chain is saturated or unsaturated, alternatively and / or additionally the alkyl chain is branched or unbranched, alternatively and / or additionally the alkyl chain has a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween, including wherein the carbon chain length is any one of the group consisting of: Ci, C2, C3, C4, C5, Ce, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 and C22.

[0312] The method further comprising alkyl chain modification, including chain length shortening and / or extension, and wherein said alkyl chain modification includes introduction of a functional group selected from the group consisting of: esters, ethers and amides.

[0313] The method wherein alkyl chain modification take place via oxidative cleavage and / or chemo- selective modification of alkene functionalities.

[0314] The method further comprising a step of introducing at least one of the following groups consisting of: ester, amide, acetal, disulfide, carbonate, and carbamate.

[0315] The method wherein the ionizable lipid is at least one selected from the following group: 3- (decyloxy)-5 -pentadecylphenyl 4-(dimethylamino) butanoate, 3-((2-ethylhexyl) oxy)-5 -pentadecylphenyl 4-(dimethylamino) butanoate, 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(octadecyloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(decyloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(4-(2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)ethyl) piperazin- 1 -yl)ethan- 1 -ol, 2-(4-(2-(3 -(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 - yl)ethan- 1 -ol, 2-ethylhexyl8-(3-((2 -ethylhexyl) oxy)-5-(2-((4-(4-(2 -hydroxyethyl) piperazin- 1 -yl) butanoyl) oxy) ethoxy) phenyl) octanoate, 2, 2'-((2-(3 -((2 -ethylhexyl) oxy) -5 -pentadecylphenoxy) ethyl)azanediyl)bis(ethan-l-ol), 2-(4-(2-(3-(octadecyloxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1- yl)ethan-l-ol, 2,2'-((2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2,2'- ((2-(3-(oct-3-yn-l-yloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3 -(oct-3 -yn- l-yloxy)-5-pentadecylphenoxy)ethyl) piperazin- 1-yl) ethan-l-ol, (E)-2,2'-((2-(3-((3,7-dimethylocta-2,6- dien-l-yl)oxy)-5pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), (E)-2-(4-(2-(3-((3,7- dimethylocta-2,6-dien- 1 -yl)oxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 -yl)ethan- 1 -ol, 2,2'-((2-(3 - (decyloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(decyloxy)-5- pentadecylphenoxy) ethyl)piperazin-l-yl) ethan-l-ol, 2,2'-((2-(3-(octan-2-yloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) diethanol, 2,2'-((3-(3 -((2-ethylhexyl)oxy)-5 - pentadecylphenoxy)propyl)azanediyl)bis(ethan- 1 -ol), 2-(4-(3 -(3 -((2 -ethylhexyl) oxy)-5- pentadecylphenoxy) propyl) piperazin- 1-yl) ethan-l-ol, 2,2'-((4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) azanediyl) bis (ethan-l-ol), 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) piperazin- 1-yl) ethan-l-ol, 1 l-(2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl)-2,5,8-trioxa- 11 -azatridecan- 13-ol, 2,2'-((2-(3-(heptadecan-9-yloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), ((2S)-l-(2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)ethyl)pyrrolidin-2-yl)methanol, octyl 4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-2- (octyloxy)-6-pentadecylbenzoate, (3'-((2-ethylhexyl)oxy)-5'-pentadecyl-[l,r-biphenyl]-4-yl)methyl 4-(4- (2-hydroxyethyl)piperazin- 1 -yl)butanoate, (3 '-(octadecyloxy)-5 '-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl) methyl 4-(4-(2-hydroxyethyl)piperazin-l-yl)butanoate, (3'-(decyloxy)-5'-pentadecyl-[l,l'-biphenyl]-4-yl)methyl 4-(4-(2 -hydroxyethyl) piperazin- l-yl)butanoate, 2-(3-((9Z,12Z)-octadeca-9,12-dien-l-yloxy)-5- pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-(decyloxy)-5- pentadecylphenyl)prop-2-yn-l-yl 4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4-(2-hydroxyethyl)piperazin- 1 -yl) butanoate, 2- (4-(3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l-yl)piperazin-l-yl)ethanol, 2-(4-(3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl)piperazin- 1 -yl)ethanol, ( 1 -(3 -(decyloxy)-5 - pentadecylphenyl)-lH-l,2,3-triazol-4-yl)methanol, 2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)- N,N-dimethylethanamine, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) ethanol, 2- ((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(methyl)amino)ethanol, 2-((2-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)propane-l,3-diol, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5- pentadecylphenoxy) ethyl) piperazin- 1-yl) ethanamine, l-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino) propane-1, 3-diol, 5 -((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino) pentan- 1 -ol, 5 -((2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)(2 -hydroxyethyl) amino) pentan- l-ol, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino)-2- (hydroxymethyl) propane- 1 ,3 -diol, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-(4-(2- hydroxyethyl)piperazin- 1 -yl)propan-2-ol, 1 -(diethylamino)-3 -(3 -((2-ethylhexyl)oxy)-5 - pentadecylphenoxy) propan-2 -ol, 2,2'-((3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-2- hydroxypropyl)azanediyl)diethanol, l-(diethylamino)-3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) propan-2 -yl dodecanoate, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2 -yl pentanoate, N,N-diethyl-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan- 1 -amine, l-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy)-3-((2-hydroxyethyl) (methyl)amino) propan-2-ol, 2-((2- (dodecanoyloxy)-3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) propyl) (methyl) amino) ethyl dodecanoate, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) (octadecyl) amino) ethanol, 2- (decyl(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)ethanol, 2-((2-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) (octadecyl) amino) propane-1, 3-diol, 2-(3-(henicosan-l 1- yloxy)-5 -pentadecylphenoxy) ethyl4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, , 3-((2- ethylhexyl)oxy)-5-pentadecylphenyl2-((5-(bis(2 -hydroxyethyl) amino) pentyl) oxy)-2-methylpropanoate, 2, 2'-((2-(3-(2-(2-(2 -methoxyethoxy) ethoxy) ethoxy)-5 -pentadecylphenoxy) ethyl) azanediyl) diethanol. The method further comprising steps of utilizing at least one the ionizable lipids in the manufacture of lipid nanoparticles (LNPs) to provide an ionizable lipid nanoparticle (iLNP).

[0316] The method wherein the ionizable lipid nanoparticle (iLNP) is provided as a single component lipid nanoparticle (scLNP) and / or a multiple component lipid nanoparticle (mcLNP), and wherein the manufacture of lipid nanoparticles (LNPs) includes a modified solvent injection method and / or a microfluidics method.

[0317] The method further comprising the steps of formulating additional chemicals and / or molecules and / or excipients together with the CNSL-derived lipid to provide the mcLNP, and wherein said additional chemicals and / or molecules and / or excipients includes at least one selected from the group consisting of: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid and / or sterol (including cholesterol or phytosterols and / or its derivatives), (iii) a polymer conjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), (iv) a phospholipid and / or derivatives thereof, and (v) an unconjugated polymer.

[0318] The method wherein the ionizable lipid nanoparticle (iLNP) is loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-iLNP), wherein the API includes nucleic acids, peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof, preferably wherein the API is a nucleic acid, further preferably wherein the nucleic acid is DNA and / or RNA, most preferably wherein the nucleic acid is RNA being at least one of the group consisting of: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and / or other RNAs that activate the RNA interference (RNAi) pathway.

[0319] Ionizable lipids manufactured in accordance with the methods described herein.

[0320] An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipids manufactured in accordance with the methods described herein.

[0321] Ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method described herein. An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method described herein.

[0322] The ionizable lipid nanoparticles (iLNPs) for use as a medicament for treatment, prevention and / or amelioration and / or prophylaxis of a disease and / or medical condition in a human or animal body.

[0323] Use of the loaded lipid nanoparticle (L-iLNP) manufactured in accordance with the method described herein for transfection of cells, wherein said transfection takes place in vivo and / or ex vivo.

[0324] DETAILED EMBODIMENTS OF THE FIRST & SECOND ASPECTS OF THE DISCLOSURE

[0325] Below follows a non-limiting example embodiment of the method described in this disclosure. This example should not be construed as limiting the scope of the disclosure.

[0326] In accordance with a first sub-aspect of the first aspect of this disclosure there is provided a method of manufacturing a cardanol and / or derivatives thereof, including 3 -pentadecylphenol, said method comprising the following steps:

[0327] (a). isolating anacardic acids, cardanols, and cardols from cashew nut shell liquid (CNSL) to provide isolated anacardic acids, isolated cardanols and isolated cardols; and

[0328] (b). decarboxylation of the isolated anacardic acids to provide synthetic cardanols.

[0329] The method typically further comprises Step (c), wherein Step (c) comprises hydrogenation of both isolated cardanol and synthetic cardanol to provide saturated cardanols, including 3 -pentadecylphenol.

[0330] Step (a) may include distillation, including vacuum distillation.

[0331] It is to be understood that Step (a) and Step (b) may occur concomitantly.

[0332] The cardanol and / or derivatives thereof may include embodiments including an alkyl chain being saturated or unsaturated. Alternatively, and / or additionally, the alkyl chain may be branched or unbranched. Alternatively, and / or additionally, the alkyl chain may have a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, C8, C9, C10, Cn, C12, C13, C14, C15, Ci6, C17, Cis, C19, C20, C21 and C22. In a certain example embodiment of the disclosure the alkyl chain length has a length of C15. It is to be understood that there may be more than one alkyl chain.

[0333] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities.

[0334] The method may include one or more steps as described and / or exemplified herein below. A cardanol and / or derivatives thereof, including 3 -pentadecylphenol, produced in accordance with the method of the first sub-aspect of the first aspect of the disclosure.

[0335] In accordance with a second sub-aspect of the first aspect of this disclosure there is provided a method of manufacturing a cardanol and / or derivatives thereof, including 3 -pentadecylphenol, said method comprising the following steps:

[0336] (a). decarboxylation of anacardic acids to provide cardanols; and

[0337] (b). hydrogenation of cardanols to provide saturated cardanols, including 3 -pentadecylphenol.

[0338] The anacardic acids are typically obtained from cashew nut shell liquid (CNSL).

[0339] The cardanol and / or derivatives thereof may include embodiments including an alkyl chain being saturated or unsaturated. Alternatively and / or additionally, the alkyl chain may be branched or unbranched. Alternatively and / or additionally, the alkyl chain may have a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, C8, C9, C10, Cn, C12, C13, C14, C15, Ci6, C17, Cis, C19, C20, C21 and C22. In a certain example embodiment of the disclosure the alkyl chain length has a length of C15. It is to be understood that there may be more than one alkyl chain.

[0340] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities.

[0341] The method may include one or more steps as described and / or exemplified herein below.

[0342] A cardanol and / or derivatives thereof, including 3 -pentadecylphenol, produced in accordance with the method of the second sub-aspect of the first aspect of the disclosure.

[0343] In accordance with a third sub-aspect of the first aspect of this disclosure there is provided a method of manufacturing a cardanol and / or derivatives thereof, including 3 -pentadecylphenol, said method comprising the following step:

[0344] (a). hydrogenation of cardanols to provide saturated cardanols, including 3 -pentadecylphenol.

[0345] The cardanols are typically obtained from cashew nut shell liquid (CNSL).

[0346] The cardanol and / or derivatives thereof may include embodiments including an alkyl chain being saturated or unsaturated. Alternatively and / or additionally, the alkyl chain may be branched or unbranched. Alternatively and / or additionally, the alkyl chain may have a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, C8, C9, C10, Cn, C12, C13, C14, Cis, Cie, C17, Cis, C19, C20, C21 and C22. In a certain example embodiment of the disclosure the alkyl chain length has a length of C15 to C22. It is to be understood that there may be more than one alkyl chain.

[0347] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities.

[0348] The method may include one or more steps as described and / or exemplified herein below.

[0349] A cardanol and / or derivatives thereof, including 3 -pentadecylphenol, produced in accordance with the method of the third sub-aspect of the first aspect of the disclosure. In an example embodiment of the method according to the disclosure, 100 g of crude technical grade cashew nut shell liquid (CNSL) obtained from Soxhlet extraction or by mechanical pressing of the cashew nut shell waste was vacuum distilled (ca. 10 mmHg) (Step (a)) with concomitant decarboxylation (Step (b)) of the anacardic acids at 180-190°C to provide 87 g of CNSL containing cardanols (ca. 92%) and cardols (ca. 8%). The mixture including cardanols and cardols is referred to a Product A.

[0350] In accordance with a second aspect of this disclosure there is provided a method of manufacturing a symmetrical alkyl resorcinol (or alkyl di-hydroxy resorcinol) including 5 -alkylresorcinol and / or derivatives thereof, including hydrogenated cardol (5-heptadecylresorcinol) from 3 -pentadecylphenol.

[0351] The 3 -pentadecylphenol is typically derived from cashew nut shell liquid (CNSL). Derivation of the 3 -pentadecylphenol from cashew nut shell liquid (CNSL) may occur, but is not limited to, methods according to any of the aspects or sub-aspects of the disclosure herein above and below.

[0352] In accordance with a second aspect of this disclosure there is provided a method of manufacturing an arene, including 5 -alkylresorcinol, including hydrogenated cardol.

[0353] In accordance with a first sub-aspect of the second aspect of this disclosure there is provided a method of manufacturing an arene, including a 5 -alkylresorcinol including derivatives thereof, including hydrogenated cardol, said method comprising the following steps:

[0354] (a). isolating anacardic acids, cardanols, and cardols from cashew nut shell liquid (CNSL) to provide the isolated anacardic acids, isolated cardanols and isolated cardols;

[0355] (b). decarboxylation of the isolated anacardic acids to provide synthetic cardanols;

[0356] (c). hydrogenation of both isolated cardanols and synthetic cardanols to provide saturated cardanols, including 3 -pentadecylphenol; and (d). transforming the saturated cardanols to include a functional group, which functional group may include a hydroxy substituent, in position 5, which position 5 may include position meta, therein providing for a 5 -alkylresorcinol and / or ether containing derivatives.

[0357] The functional groups may include at least one of, but not limited to the following group: saturated cyclical functional groups, unsaturated cyclical functional groups, acetates, mesylates, pivaloates, tosylates, Ar-N, Ar-S, and Ar-CX, wherein Ar refers to aryl, N refers to nitrogen, S refers to sulphur, C refers to carbon and X refers to any halogen. The functional groups may be, in certain embodiments, protecting functional groups.

[0358] Step (a) may include distillation, including vacuum distillation.

[0359] It is to be understood that Step (a) and Step (b) may occur concomitantly.

[0360] Step (d) may be provided via direct meta borylation of the hydrogenated cardanol with employing a protecting functional group. Step (d) may be provided as a one pot step.

[0361] Alternatively, Step (d) may include Sub-step (dl): protecting a phenol functional group of the saturated cardanols with a protectional functional group therein providing a protected hydrogenated cardanol.

[0362] Step (d) may further include [after at least commencing Sub-step (dl)] Sub-step (d2): introducing a phenol functional group in the meta position of the protected hydrogenated cardanol.

[0363] Sub-step (d2) introducing a phenol functional group in the meta position of the protected hydrogenated cardanol may include arene C-H borylation. It is to be understood that other synthetic procedures are envisaged.

[0364] The arene C-H borylation may include use of a catalyst, typically a transitional metal catalyst, further typically a transitional metal catalyst including at least one of, but not limited to, the following group of metals: iridium (Ir), rhodium (Rh), platinum (Pt), palladium (Pd), tungsten (W), titanium (Ti), tin (Sn), ruthenium (Ru), iron (Fe) and lead (Pb) . In a preferred embodiment of the disclosure the transition metal catalyst may be at least one of, but not limited to, the following group: Cp*Ir(PMe3)H(Bpin) ,(Ind)Ir(COD), [Ir(COD)Cl]2, [Ir(COE)Cl]2, [Ir(COD)OH]2and [Ir(COD)OMe]2.

[0365] Step (d) may further include [after at least commencing Sub-step (d2)] Sub-step (d3): removing the protectional functional group. Sub-step (d3) may include oxidation and may employ but is not limited to H2O2, oxone, potassium iodate and sodium iodate.

[0366] It is to be understood that the arenes may be 1,3,5-asymmetrical arenes.

[0367] The 5 -alkylresorcinol and / or derivatives thereof may include embodiments wherein the 5 -alkyl chain may be saturated or unsaturated. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain being branched or unbranched. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain having a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, C12, Ci3, C14, C15, Ci6, C17, Cis, C19, C20, C21 and C22. In a certain preferred example embodiment of the disclosure the alkyl chain length has a length of C15.

[0368] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further synthetic method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities. It is also to be understood that there may be more than one alkyl chain.

[0369] The method may include one or more steps as described and / or exemplified herein below.

[0370] A 5 -alkylresorcinol and / or derivatives thereof, including hydrogenated cardol, produced in accordance with the method of the first sub-aspect of the second aspect of the disclosure.

[0371] In accordance with a second sub-aspect of the second aspect of this disclosure there is provided a method of manufacturing an arene, including a 5 -alkylresorcinol and / or derivatives thereof, including hydrogenated cardol, said method comprising the following steps:

[0372] (a). decarboxylation of anacardic acids to provide cardanols;

[0373] (b). hydrogenation of cardanols to provide saturated / hydrogenated cardanols, including 3- pentadecylphenol; and

[0374] (c). transforming the saturated cardanols to include a functional group, which functional group may include a hydroxy substituent, in position 5, which position 5 may include position meta, therein providing for a 5 -alkylresorcinol and / or ether containing derivatives including cardol.

[0375] The method wherein the anacardic acids are obtained from cashew nut shell liquid (CNSL).

[0376] The functional groups may include at least one of, but not limited to the following group: saturated cyclical functional groups, unsaturated cyclical functional groups, acetates, mesylates, pivloates, tosylates, Ar-N, Ar-S, and Ar-CX, wherein Ar refers to aryl, N refers to nitrogen, S refers to sulfur, C refers to carbon and X refers to any halogen. The functional groups may be, in certain embodiments, protecting functional groups.

[0377] Step (c) may be provided via direct meta borylation of the hydrogenated cardanol with employing a protecting functional group. Step (c) may be provided as a one pot step.

[0378] Alternatively, Step (c) may include Sub-step (cl): protecting a phenol functional group of the saturated cardanols with a protectional functional group therein providing a protected cardanol. Step (c) may further include [after at least commencing Sub-step (cl)] Sub-step (c2): introducing a phenol functional group in the meta position of the protected cardanol.

[0379] Sub-step (c2) introducing a phenol functional group in the meta position of the protected cardanol may include arene C-H borylation. It is to be understood that other synthetic procedures are envisaged.

[0380] There arene C-H borylation may include use of a catalyst, typically a transitional metal catalyst, further typically a transitional metal catalyst including at least one of, but not limited to, the following group of metals: iridium (Ir), rhodium (Rh), platinum (Pt), palladium (Pd), tungsten (W), titanium (Ti), tin (Sn), ruthenium (Ru), iron (Fe) and lead (Pb), . In a preferred embodiment of the disclosure the transition metal catalyst may be at least one of, but not limited to, the following group: Cp*Ir(PMe3)H(Bpin) ,(Ind)Ir(COD), [Ir(COD)Cl]2,[Ir(COE)Cl]2, [Ir(COD)OH]2and [Ir(COD)OMe]2.

[0381] Step (c) may further include [after at least commencing Sub-step (c2)] Sub-step (c3): removing the protectional functional group. Sub-step (c3) may include oxidation and may employ but is not limited to H2O2, oxone, potassium iodate and sodium iodate.

[0382] It is to be understood that the arenes may be 1,3,5-asymmetrical arenes.

[0383] The 5 -alkylresorcinol and / or derivatives thereof may include embodiments wherein the 5 -alkyl chain may be saturated or unsaturated. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain being branched or unbranched. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain having a carbon chain length of between Ci to C22including both Ci, C22and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, Ci2, Ci3, C14, C15, Ci6, C17, Cis, C19, C20, C2iand C22. In a certain preferred example embodiment of the disclosure the alkyl chain length has a length of C15. It is also to be understood that there may be more than one alkyl chain.

[0384] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities.

[0385] The method may include one or more steps as described and / or exemplified herein below.

[0386] An arene including a 5 -alkylresorcinol and / or derivatives thereof, including hydrogenated cardol, produced in accordance with the method of the second sub-aspect of the second aspect of the disclosure.

[0387] In accordance with a third sub-aspect of the second aspect of this disclosure there is provided a method of manufacturing an arene, including a 5 -alkylresorcinol including derivatives thereof, including hydrogenated cardol, said method comprising the following steps: (a). hydrogenation of cardanols to provide saturated cardanols, including 3 -pentadecylphenol; and

[0388] (b). transforming the saturated cardanols to include a functional group, which functional group may include a hydroxy substituent, in position 5, which position 5 may include position meta, therein providing for a 5 -alkylresorcinol and / or ether containing derivatives including cardol.

[0389] The method wherein the cardanols are obtained from cashew nut shell liquid (CNSL).

[0390] Step (b) may be provided via direct meta borylation of the hydrogenated cardanol with employing a protecting functional group. Step (b) may be provided as a one pot step.

[0391] Alternatively, Step (b) may include Sub-step (bl): protecting a phenol functional group of the saturated cardanols with a protectional functional group therein providing a protected cardanol.

[0392] Step (b) may further include [after at least commencing Sub-step (bl)] Sub-step (b2): introducing a phenol functional group in the meta position of the protected cardanol.

[0393] Sub-step (b2) introducing a phenol functional group in the meta position of the protected hydrogenated cardanol may include arene C-H borylation. It is to be understood that other synthetic procedures are envisaged.

[0394] There arene C-H borylation may include use of a catalyst, typically a transitional metal catalyst, further typically a transitional metal catalyst including at least one of, but not limited to, the following group of metals: iridium (Ir), rhodium (Rh), platinum (Pt), palladium (Pd), tungsten (W), titanium (Ti), tin (Sn), ruthenium (Ru), iron (Fe) and lead (Pb). In a preferred embodiment of the disclosure the transition metal catalyst may be at least one of, but not limited to, the following group: Cp*Ir(PMe3)H(Bpin) ,(Ind)Ir(COD), [Ir(COD)Cl]2, [Ir(COE)Cl]2, [Ir(COD)OH]2and [Ir(COD)OMe]2.

[0395] Step (b) may further include [after at least commencing Sub-step (b2)] Sub-step (b3): removing the protectional functional group. Sub-step (b3) may include oxidation and may employ but is not limited to H2O2, oxone, potassium iodate and sodium iodate.

[0396] It is to be understood that the arenes may be 1,3,5-asymmetrical arenes.

[0397] The 5 -alkylresorcinol and / or derivatives thereof may include embodiments wherein the 5-alkyl chain may be saturated or unsaturated. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain being branched or unbranched. Alternatively and / or additionally, the 5 -alkylresorcinol may include an alkyl chain having a carbon chain length of between Ci to C22including both Ci, C22and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, Ci2, Ci3, C14, C15, Ci6, C17, Cis, C19, C20, C2iand C22. In a certain preferred example embodiment of the disclosure the alkyl chain length has a length of C15. Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities. It is also to be understood that there may be more than one alkyl chain.

[0398] The method may include one or more steps as described and / or exemplified herein below.

[0399] An arene, including a 5 -alkylresorcinol and / or derivatives thereof, including hydrogenated cardol, produced in accordance with the method of the third sub-aspect of the second aspect of the disclosure.

[0400] Figure 1 shows methods according to this disclosure to valorise cashew nut shell liquid (CNSL).

[0401] In more general terms the synthesis procedure is provided hereunder:

[0402] CNSL including a mixture of at least nine compounds (mainly anacardic acids and cardanols) is heated under vacuum by decarboxylation, converting (three) anacardic acids into the (three) cardanols, therein providing a mixture of six compounds mainly the (three) cardanols and as a minor products the (three) cardols.

[0403] Separation of the (three) cardanols from the (three) cardols was done by adding the mixture to an aqueous methanol / ammonia / hexane mixture. The (three) cardanols go in the hexane layer and the (three) cardols go into the aqueous methanol / ammonia layer. The two layers are separated from each other and the aqueous methanol / ammonia layer was then extracted with a mixture of ethyl acetate and hexane to yield the cardols. (This is described in J. Agric. Food Chem. 2002, 50, 4705-4708 470).

[0404] The (three) separated cardanols are hydrogenated it to provide hydrogenated cardanol as a single compound. Similarly, the (three) cardols are hydrogenated to provide hydrogenated cardol as a single compound.

[0405] The hydrogenated cardanol is reacted using an Ir catalysed reaction and further introduction of an OH group at the meta position, therein providing a single major product of hydrogenated cardol. The hydrogenated cardol is used downstream to manufacture ionizable lipids.

[0406] It should be undetsood that hydrogenated cardol manufactured according to prior art methods is expensive and the method described herein provides a significantly cheaper alternative manufacturing method.

[0407] DETAILED EMBODIMENTS OF THE THIRD ASPECT OF THE DISCLOSURE

[0408] In accordance with a third aspect of this disclosure there is provided a method of manufacturing an arene including a 5 -alkyl-2 -hydroxybenzaldehyde and / or derivatives thereof from 3 -pentadecylphenol.

[0409] The method may include use of cashew nut shell liquid (CNSL) as a raw material source. The method may include any of the steps as described herein including in the first and second aspects of this disclosure.

[0410] There is further provided for the third aspect of this disclosure substantially as herein described, illustrated and / or exemplified with reference to any one of the descriptions and / or examples and / or photos and / or images and / or chemical reaction schemes and / or diagrammatic drawings herein.

[0411] DETAILED EMBODIMENTS OF THE FOURTH ASPECT OF THE DISCLOSURE

[0412] In accordance with a fourth aspect of this disclosure there is provided a method of manufacturing ionizable lipids. In certain embodiments the method includes use of cashew nut shell liquid (CNSL) and / or a chemical component thereof.

[0413] The disclosure extends to the lipids themselves.

[0414] The ionizable lipids may be employed in the formulation of lipid nanoparticles. The lipid nanoparticles may be employed in the field of biology, molecular biology, medicine and / or pharmacology. In an example embodiment of the disclosure, the lipid nanoparticles may be employed in the field of mRNA prophylactic and / or therapeutic technologies, including vaccines, further including nucleic acid-based -, protein-based -, and peptide-based vaccines.

[0415] The lipid nanoparticles manufactured from cashew nut shell liquid (CNSL) and / or a chemical component thereof may provide a delivery means for nucleic acids, proteins, and peptides including but not limited to mRNA at a desired site within the human or animal body for use in the prevention and / or treatment and / or amelioration of a disease and / or medical condition in a human or animal body.

[0416] In accordance with a first sub-aspect of the fourth aspect of this disclosure there is provided a method of manufacturing lipids, preferably ionizable lipids, utilizing a cardanol and / or derivatives thereof, including 3 -pentadecylphenol, and wherein said cardanol is derived from cashew nut shell liquid (CNSL), said method comprising any of the steps as described in the first aspect of this disclosure above, including any one of the sub-aspects of the first aspect of this disclosure.

[0417] The method may include steps of functionalizing the cardanol and / or derivatives thereof to provide a lipid nanoparticle comprising: (i) a nitrogen containing ionizable functional group, (ii) an aromatic ring or analogue thereof, and (iii) at least one alkyl chain.

[0418] The nitrogen containing ionizable functional group may be a nitrogen containing heterocycle, preferably wherein the nitrogen containing heterocycle includes an alkaline nitrogen. The nitrogen containing ionizable group may be selected from, but not limited to, the group comprising: piperidines, pyrolidines triazines and amino acids and / or derivatives thereof. It is to be understood that the nitrogen containing ionizable functional group may extend to other chemical moieties. 1,2-diazinane, 1,3-diazinane and imidazolidine. In a certain embodiment the nitrogen containing ionizable functional group may be piperazine. The nitrogen containing ionizable functional group may further or alternatively include acyclic amines.

[0419] The aromatic ring may be derived from phenolics, which in turn are derived from CNSL. The aromatic ring may include modification The aromatic ring may be a phenol, resorcinol, benzaldehyde, benzyl alcohol or benzoic acid and derivatives and / or analogues of the aforementioned. It is to be understood that the aromatic ring may be reduced to analogues of same, and may include at least one of, but not limited to, the following group: cyclohexyls and linear aliphatics. The reduction may for example take place via birch reduction and / or ozonolysis.

[0420] The at least one alkyl chain may be saturated or unsaturated. Alternatively and / or additionally, the alkyl chain may be branched or unbranched. Alternatively and / or additionally, the alkyl chain may have a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. The carbon chain length may be any one of Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, Cn, C12, C13, C14, C15, Ci6, C17, Cis, C19, C20, C21 and C22. In a certain preferred example embodiment of the disclosure the alkyl chain length has a length of C15. It is to be understood that there may be more than one alkyl chain. There is provided that in embodiments having more than one alkyl chain, the alkyl chains may be structurally the same and / or structurally different.

[0421] Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities. It is to be understood that there may be more than one alkyl chain.

[0422] The method may include providing the ionizable lipid with a biodegradable functionality, wherein same may include method steps for introducing at least one of, but not limited to, the following functional groups: ester, amide, acetal, disulfide, carbonate, and carbamate. Particularly, in a certain embodiment, the method may further include a step to provide an ester functional group as part of the ionizable lipid.

[0423] The ionizable lipid may be any one as illustrated and / or exemplified herein with reference to the figures, preferably Figure 2. The ionizable lipid may be derived from CNSL.

[0424] The ionizable lipids according to this disclosure may be any one of, but not limited to, the following group:

[0425] 3 -(decyloxy)-5 -pentadecylphenyl 4-(dimethylamino) butanoate, 3 -((2 -ethylhexyl) oxy)-5- pentadecylphenyl 4-(dimethylamino) butanoate, 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl 4-(4- (2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(decyloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(4-(2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)ethyl) piperazin- 1 -yl)ethan- 1 -ol, 2-(4-(2-(3 -(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 - yl)ethan- 1 -ol, 2-ethylhexyl8-(3 -((2 -ethylhexyl) oxy)-5 -(2-((4-(4-(2-hydroxyethyl) piperazin- 1 -yl) butanoyl) oxy) ethoxy) phenyl) octanoate, 2,2'-((2-(3-((2-ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl)azanediyl)bis(ethan-l-ol), 2-(4-(2-(3-(octadecyloxy)-5 -pentadecylphenoxy) ethyl) piperazin-1- yl)ethan-l-ol, 2,2'-((2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2,2'-((2- (3 -(oct-3 -yn-l-yloxy) -5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3 -(oct-3 -yn-1- yloxy)-5-pentadecylphenoxy)ethyl) piperazin- 1-yl) ethan-l-ol, (E)-2,2'-((2-(3-((3,7-dimethylocta-2,6-dien-

[0426] 1-yl)oxy)-5pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), (E)-2-(4-(2-(3-((3,7-dimethylocta-2,6- dien-l-yl)oxy)-5 -pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2,2'-((2-(3-(decyloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl)piperazin-l-yl) ethan-l-ol, 2,2'-((2-(3-(octan-2-yloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) diethanol, 2,2'-((3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)propyl)azanediyl)bis(ethan-l-ol), 2-(4-(3- (3-((2-ethylhexyl) oxy) -5 -pentadecylphenoxy) propyl) piperazin- 1-yl) ethan-l-ol, 2,2'-((4-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy) butyl) azanediyl) bis (ethan-l-ol), 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) piperazin- 1-yl) ethan-l-ol, 1 l-(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl)-2,5,8-trioxa-l l-azatridecan-13-ol, 2,2'-((2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), ((2S)-l-(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)pyrrolidin-2- yl)methanol, octyl 4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-2-(octyloxy)-6-pentadecylbenzoate, (3'-((2- ethylhexyl)oxy)-5'-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl)methyl 4-(4-(2-hydroxyethyl)piperazin- 1 -yl)butanoate, (3 '-(octadecyloxy)-5 '-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl) methyl 4-(4-(2-hydroxyethyl)piperazin- 1 - yl)butanoate, (3'-(decyloxy)-5'-pentadecyl-[l,l'-biphenyl]-4-yl)methyl 4-(4-(2-hydroxyethyl) piperazin-1- yl)butanoate, 2-(3-((9Z,12Z)-octadeca-9,12-dien-l-yloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl)piperazin- 1 -yl) butanoate, 3 -(3 -(decyloxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4-(2- hydroxyethyl)piperazin- 1 -yl) butanoate, 3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4- (2-hydroxyethyl)piperazin-l-yl) butanoate, 2-(4-(3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l- yl)piperazin- 1 -yl)ethanol, 2-(4-(3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl)piperazin- 1 - yl)ethanol, (l-(3-(decyloxy)-5-pentadecylphenyl)-lH-l,2,3-triazol-4-yl)methanol, 2-(3 -((2 -ethylhexyl) oxy)-5-pentadecylphenoxy)-N,N-dimethylethanamine, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) ethanol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(methyl)amino)ethanol, 2- ((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)propane-l,3-diol, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1-yl) ethanamine, l-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino) propane-1, 3-diol, 5-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) pentan- 1 -ol, 5 -((2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)(2-hydroxyethyl) amino) pentan- l-ol, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino)-2-(hydroxymethyl) propane-1, 3-diol, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-(4-(2-hydroxyethyl)piperazin-l- yl)propan-2-ol, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2 -ol, 2,2'-((3-(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-2-hydroxypropyl)azanediyl)diethanol, 1 -(diethylamino) -3 -(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2-yl dodecanoate, l-(diethylamino)-3-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2 -yl pentanoate, N,N-diethyl-3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) propan- 1 -amine, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-((2 -hydroxyethyl) (methyl)amino) propan-2 -ol, 2-((2-(dodecanoyloxy)-3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) propyl) (methyl) amino) ethyl dodecanoate, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) (octadecyl) amino) ethanol, 2-(decyl(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)ethanol,

[0427] 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) (octadecyl) amino) propane-1, 3-diol, 2-(3- (henicosan-11-yloxy) -5 -pentadecylphenoxy) ethyl4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-((2- ethylhexyl)oxy)-5-pentadecylphenyl2-((5-(bis(2 -hydroxyethyl) amino) pentyl) oxy)-2-methylpropanoate, 2, 2'-((2-(3-(2-(2-(2 -methoxyethoxy) ethoxy) ethoxy) -5 -pentadecylphenoxy) ethyl) azanediyl) diethanol.

[0428] The ionizable lipids may be derived at least in part from CNSL.

[0429] The ionizable lipid may be utilized in the manufacture of lipid nanoparticles (LNPs). The LNPs may be an ionizable lipid nanoparticle (iLNP). Consequently, the iLNP may include a lipid derived from CNSL. The lipid nanoparticle may be provided as a single or multiple component lipid nanoparticle.

[0430] When provided as a multiple component lipid nanoparticle then additional chemicals and / or molecules are formulated together with the lipid nanoparticle of this disclosure therein providing a multiple component lipid nanoparticle.

[0431] Additional chemicals and / or molecules of the multiple component lipid nanoparticle may include at least one of, but not limited to, the following group: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid (including cholesterol and / or its derivatives), (iii) a polymer conjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), (iv) a phospholipid and / or derivatives thereof.

[0432] When provided as a single component lipid nanoparticle then no additional chemicals and / or molecules are formulated together with the lipid nanoparticle of this disclosure.

[0433] The lipid nanoparticle (single or multiple component) may be loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-LNP). The API may be a nucleic acid. The nucleic acid may be DNA and / or RNA. The DNA may be plasmid DNA. The RNA may be at least one of, but not limited to, the following group: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and other RNAs that activate the RNA interference (RNAi) pathway. The API may alternatively and / or additionally include at least one of, but not limited to, the following group: peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof. When the LNP is loaded with RNA, the L-LNP may be referred to as an RNA-LNP. Similarly, when the iLNP is loaded with RNA, the L-LNP may be referred to as an RNA-iLNP. When the iLNP is loaded with DNA, the L-LNP may be referred to as an DNA-iLNP.

[0434] There is further provided for use of the lipid nanoparticle in the manufacture of a medicament for treatment, prevention and / or amelioration of a disease and / or medical condition.

[0435] There is further provided for the lipid nanoparticle for use in the manufacture of a medicament for treatment, prevention and / or amelioration of a disease and / or medical condition.

[0436] There is further provided for a method of treatment, prevention and / or amelioration of a disease and / or medical condition utilizing the lipid nanoparticle.

[0437] There is further provided for a lipid nanoparticle produced in accordance with the method of the first sub-aspect of the third aspect of the disclosure and / or as described and / or exemplified herein below.

[0438] The method may include one or more steps as described and / or exemplified herein below.

[0439] Non-limiting examples of the lipid nanoparticles and their method of production is provided herein below which is incorporated in this summary by way of reference thereto to avoid repetition. In accordance with a second sub-aspect of the fourth aspect of this disclosure there is provided a method of manufacturing an ionizable lipid derived from CNSL phenolics.

[0440] The method may include chemical modification of the CNSL phenolic, wherein at least one additional alkyl containing functional group may be introduced onto a position on the phenolic, and wherein the position is distinct from any natural alkyl chain that may be present on the CNSL phenolic.

[0441] The additional alkyl containing functional group may be ionizable.

[0442] Alternatively, and / or additionally, in accordance with a second sub-aspect of the fourth aspect of this disclosure there is provided a method of manufacturing an ionizable lipid utilizing a 5 -alkylresorcinol and / or a 5-alkyl-2-(hydroxymethyl)phenol including derivatives thereof, including cardol, and wherein said 5 -alkylresorcinol or 5-alkyl-2-(hydroxymethyl)phenol is derived from cashew nut shell liquid (CNSL), the method comprising any of the steps as described in the second aspect of this disclosure above, including any one of the sub-aspects of the second aspect of this disclosure.

[0443] The method may include steps of functionalizing the cardol and / or derivatives thereof to provide an ionizable lipid comprising: (i) a nitrogen containing ionizable functional group, (ii) an aromatic ring or analogue thereof, and (iii) at least one alkyl chain.

[0444] The nitrogen containing ionizable functional group may be a nitrogen containing heterocycle, preferably wherein the nitrogen containing heterocycle includes an alkaline nitrogen. The nitrogen containing ionizable group may be selected from, but not limited to, the group comprising: piperidines, pyrolidines and triazines. It is to be understood that the nitrogen containing ionizable functional group may extend to other chemical moieties. 1,2-diazinane, 1,3-diazinane and imidazolidine. In a certain embodiment the nitrogen containing ionizable functional group may be piperazine. The nitrogen containing ionizable functional group may further or alternatively include acyclic amines.

[0445] The aromatic ring may be derived from phenolics, which in turn are derived from CNSL. The aromatic ring may include modification The aromatic ring may be a phenol, resorcinol, benzaldehyde, benzyl alcohol or benzoic acid and derivatives and / or analogues of the aforementioned. It is to be understood that the aromatic ring may be reduced to analogues of same, and may include at least one of, but not limited to, the following group: cyclohexyls and linear aliphatics. The reduction may for example take place via birch reduction and / or ozonolysis.

[0446] The at least one alkyl chain may be saturated or unsaturated. Alternatively and / or additionally, the alkyl chain may be branched or unbranched. Alternatively and / or additionally, the alkyl chain may have a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween. In a certain preferred example embodiment of the disclosure the alkyl chain length has a length of C15. It is to be understood that there may be more than one alkyl chain. There is provided that in embodiments having more than one alkyl chain, the alkyl chains may be structurally the same and / or structurally different. Alkyl chain modification, including but not limited to, chain length shortening and / or extension may take place using further method steps. It is to be understood that alkyl chain modification may include introduction of functional groups, which may include, but are not limited to, esters, ethers and amides, which may in part take place via for example oxidative cleavage. It is to be understood that alkyl chain modification, may typically include chemo-selective modification of alkene functionalities. It is also to be understood that there may be more than one alkyl chain.

[0447] The method may include providing the ionizable lipid with biodegradable functionality, wherein same may include method steps for introducing at least one of, but not limited to, the following functional groups: ester, amide, acetal, disulfide, carbonate, and carbamate. Particularly, in a certain embodiment, the method may further include a step to provide an ester functional group as part of the ionizable lipid.

[0448] The ionizable lipid may be any one as illustrated and / or exemplified herein with reference to the figures, preferably Figure 2.

[0449] The ionizable lipids according to this disclosure may be any one of, but not limited to, the following group:

[0450] 3-(decyloxy)-5-pentadecylphenyl 4-(dimethylamino) butanoate, 3 -((2 -ethylhexyl) oxy)-5- pentadecylphenyl 4-(dimethylamino) butanoate, 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl 4-(4- (2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(octadecyloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(4-(2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)ethyl) piperazin- 1 -yl)ethan- 1 -ol, 2-(4-(2-(3 -(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 - yl)ethan- 1 -ol, 2-ethylhexyl8-(3 -((2-ethylhexyl) oxy)-5 -(2-((4-(4-(2-hydroxyethyl) piperazin- 1 -yl) butanoyl) oxy) ethoxy) phenyl) octanoate, 2, 2'-((2-(3 -((2-ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl)azanediyl)bis(ethan- 1 -ol), 2-(4-(2-(3 -(octadecyloxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 - yl)ethan-l-ol, 2,2'-((2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2,2'-((2- (3 -(oct-3 -yn-l-yloxy) -5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3 -(oct-3 -yn-1- yloxy)-5-pentadecylphenoxy)ethyl) piperazin- 1-yl) ethan-l-ol, (E)-2,2'-((2-(3-((3,7-dimethylocta-2,6-dien- I-yl)oxy)-5pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), (E)-2-(4-(2-(3-((3,7-dimethylocta-2,6- dien-l-yl)oxy)-5 -pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2,2'-((2-(3-(decyloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl)piperazin-l-yl) ethan-l-ol, 2,2'-((2-(3-(octan-2-yloxy)-5-pentadecylphenoxy) ethyl) azanediyl) diethanol, 2,2'-((3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)propyl)azanediyl)bis(ethan-l-ol), 2-(4-(3- (3 -((2-ethylhexyl) oxy) -5 -pentadecylphenoxy) propyl) piperazin- 1-yl) ethan-l-ol, 2,2'-((4-(3-((2- ethylhexyl)oxy) -5 -pentadecylphenoxy) butyl) azanediyl) bis (ethan-l-ol), 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) piperazin- 1-yl) ethan-l-ol, 11-(2-(3-( (2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl)-2,5,8-trioxa-l l-azatridecan-13-ol, 2,2'-((2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan- 1 -ol), ((2S)- 1 -(2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)pyrrolidin-2- yl)methanol, octyl 4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-2-(octyloxy)-6-pentadecylbenzoate, (3'-((2- ethylhexyl)oxy)-5'-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl)methyl 4-(4-(2-hydroxyethyl)piperazin- 1 -yl)butanoate, (3'-(octadecyloxy)-5'-pentadecyl-[l,l'-biphenyl]-4-yl) methyl 4-(4-(2-hydroxyethyl)piperazin-l- yl)butanoate, (3'-(decyloxy)-5'-pentadecyl-[I, I '-biphenyl] -4-yl)methyl 4-(4-(2-hydroxyethyl) piperazin-1- yl)butanoate, 2-(3-((9Z,12Z)-octadeca-9,12-dien-l-yloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l-yl 4-(4-(2- hydroxyethyl)piperazin- 1 -yl) butanoate, 3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4- (2-hydroxyethyl)piperazin-l-yl) butanoate, 2-(4-(3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l- yl)piperazin- 1 -yl)ethanol, 2-(4-(3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl)piperazin- 1 - yl)ethanol, (l-(3-(decyloxy)-5-pentadecylphenyl)-lH-l,2,3-triazol-4-yl)methanol, 2-(3 -((2 -ethylhexyl) oxy)-5-pentadecylphenoxy)-N,N-dimethylethanamine, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) ethanol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(methyl)amino)ethanol, 2- ((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)propane-l,3-diol, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1-yl) ethanamine, l-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino) propane-1, 3-diol, 5 -((2-(3-((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino) pentan- 1 -ol, 5 -((2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)(2-hydroxyethyl) amino) pentan- l-ol, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) amino)-2-(hydroxymethyl) propane-1, 3-diol, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-(4-(2-hydroxyethyl)piperazin-l- yl)propan-2-ol, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2 -ol, 2,2'-((3-(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-2-hydroxypropyl)azanediyl)diethanol, 1 -(diethylamino) -3 -(3- ((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2-yl dodecanoate, l-(diethylamino)-3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenoxy) propan-2 -yl pentanoate, N,N-diethyl-3 -(3 -((2-ethylhexyl)oxy)-5 - pentadecylphenoxy) propan- 1 -amine, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-((2 -hydroxyethyl) (methyl)amino) propan-2 -ol, 2-((2-(dodecanoyloxy)-3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) propyl) (methyl) amino) ethyl dodecanoate, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) (octadecyl) amino) ethanol, 2-(decyl(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)ethanol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) (octadecyl) amino) propane-1, 3-diol, 2-(3- (henicosan-11-yloxy) -5 -pentadecylphenoxy) ethyl4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-((2- ethylhexyl)oxy)-5-pentadecylphenyl2-((5-(bis(2 -hydroxyethyl) amino) pentyl) oxy)-2-methylpropanoate, 2, 2'-((2-(3-(2-(2-(2 -methoxyethoxy) ethoxy) ethoxy) -5 -pentadecylphenoxy) ethyl) azanediyl) diethanol.

[0451] The ionizable lipid may be utilized in the manufacture of lipid nanoparticles (LNPs). The LNPs may be an ionizable lipid nanoparticle (iLNP). Consequently, the iLNP may include a lipid derived from CNSL.

[0452] The lipid nanoparticle may be provided as a single or multiple component lipid nanoparticle.

[0453] When provided as a multiple component lipid nanoparticle then additional chemicals and / or molecules are formulated together with the lipid nanoparticle of this disclosure therein providing a multiple component lipid nanoparticle.

[0454] Additional chemicals and / or molecules of the multiple component lipid nanoparticle may include at least one of, but not limited to, the following group: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid (including cholesterol and / or its derivatives), (iii) a polymer conjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), (iv) a phospholipid and / or derivatives thereof.

[0455] When provided as a single component lipid nanoparticle then no additional chemicals and / or molecules are formulated together with the lipid nanoparticle of this disclosure.

[0456] The lipid nanoparticle (single or multiple component) may be loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-LNP). The API may be a nucleic acid. The nucleic acid may be DNA and / or RNA. The DNA may be plasmid DNA. The RNA may be at least one of, but not limited to, the following group: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and other RNAs that activate the RNA interference (RNAi) pathway. The API may alternatively and / or additionally include at least one of, but not limited to, the following group: peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof. When the LNP is loaded with RNA, the L-LNP may be referred to as an RNA-LNP. Similarly, when the iLNP is loaded with RNA, the L-LNP may be referred to as an RNA-iLNP. When the iLNP is loaded with DNA, the L-LNP may be referred to as an DNA-iLNP.

[0457] There is further provided for use of the lipid nanoparticle in the manufacture of a medicament for treatment, prevention and / or amelioration of a disease and / or medical condition.

[0458] There is further provided for the lipid nanoparticle for use in the manufacture of a medicament for treatment, prevention and / or amelioration of a disease and / or medical condition.

[0459] There is further provided for a lipid nanoparticle produced in accordance with the method of the first sub-aspect of the third aspect of the disclosure and / or as described and / or exemplified herein below.

[0460] The method may include one or more steps as described and / or exemplified herein below.

[0461] Various embodiments of lipids were manufactured including embodiments having a 1, 3, 5 -trisubstituted benzene ring and 1, 2, 4-trisubstitued benzene ring.

[0462] Non-limiting examples showing methods of manufacturing lipids, particularly ionizable lipids, according to this disclosure:

[0463] Cardanol was produced from CNSL as per the above.

[0464] The below methods were employed to provide lipid nanoparticles derived from hydrogenated cardanol. Preferably, the hydrogenated cardanol is derived from CNSL. l-((2-ethylhexyl)oxy)-3-pentadecylbenzene:

[0465] To 3 -pentadecylphenol (10.2 g, 33.5 mmol) was added DMF (50 mL), followed 2-ethylhexyl methanesulfonate (7.30 g, 35.0 mmol) and K2CO3 (13.82 g, 100 mmol). The resultant suspension was then heated to 100°C, for 48h until thin layer chromatography (TLC) showed the reaction to be complete. After cooling, the reaction mixture to room temperature, Water (50 mL) was added, followed by hexane (100 mL). The two phases were separated, and the aqueous phase was re-extracted once with 50 mL hexane. The combined organic extracts were washed twice with water (100 mL), and twice with acetonitrile (2 x 50 mL). The acetonitrile extracts were then re -extracted with hexane (3 x 50 mL), and the combined hexane extracts were then dried over MgSCL, and the volatiles removed to provide l-((2-ethylhexyl)oxy)-3- pentadecylbenzene (13.75 g, 33.0 mmol, 99% yield) as an amber oil which was used without further purification.

[0466] 'H NMR (400 MHz, CDC13) 5 7.16 (t, J = 7.7 Hz, 1H), 6.78 - 6.67 (m, 3H), 3.87 - 3.77 (m, 2H), 2.64 - 2.50 (m, 2H), 1.71 (dt, J= 6.0, 12.2 Hz, 1H), 1.60 (p, J = 7.4 Hz, 2H), 1.54 - 1.36 (m, 4H), 1.36 - 1.19 (m, 29H), 0.97 - 0.82 (m, 9H).

[0467] 13C NMR (101 MHz, CDC13) 5 159.42, 144.54, 129.05, 120.56, 114.82, 111.41, 70.31, 39.47, 36.10, 31.97, 31.46, 30.59, 29.74, 29.72, 29.70, 29.64, 29.57, 29.44, 29.40, 29.13, 23.92, 23.10, 22.73, 14.15, 14.12, 11.15. l-(decyloxy)-3-pentadecylbenzene

[0468] To 3 -pentadecylphenol (10.0 g, 32.8 mmol) was added DMF (50 mb), followed 1-bromodecane (7.76 g, 35.1 mmol) and K2CO3 (13.00 g, 94 mmol). The resultant suspension was then heated to 100°C for 16h, at which time TLC (thin layer chromatography) showed the reaction to be complete. After cooling, the reaction mixture to room temperature, water (50 mL) was added, followed by hexane (100 mL). The two phases were separated, and the aqueous phase was re-extracted once with 50 mL hexane. The combined organic extracts were washed twice with water (100 mL), dried over MgSCL, and the volatiles removed to provide the crude product as an amber oil, which was suspended in methanol (100 mL) and heated with stirring until boiling. Stirring was maintained as the solution was cooled in an ice-bath, which eventually induced the precipitation of the product as an amorphous white solid, which was filtered while still cold, and washed with methanol (2 x 50 mL). After drying under vacuum, this provided the desired product l-(decyloxy)-3- pentadecylbenzene (13.43 g, 30.2 mmol, 92% yield) as a white amorphous solid which was used without further purification.

[0469] 'H NMR (400 MHz, CDCI3) 5 7.17 (t, J= 7.7 Hz, 1H), 6.79 - 6.65 (m, 3H), 3.94 (t, J= 6.6 Hz, 2H), 2.62 - 2.48 (m, 2H), 1.77 (p, J= 6.7 Hz, 2H), 1.65 - 1.52 (m, 2H), 1.45 (p, J= 6.7 Hz, 2H), 1.26 (d, J= 7.2 Hz, 37H), 0.92 - 0.83 (m, 6H).

[0470] 13C NMR (101 MHz, CDCk) 5 159.13, 144.57, 129.07, 120.65, 114.79, 111.36, 67.83, 36.06, 31.94, 31.92, 31.42, 29.72, 29.70, 29.68, 29.61, 29.58, 29.54, 29.44, 29.38, 29.34, 26.10, 22.71, 22.70, 14.14. l-( octadecyloxy)-3-Dentadecylbenzene :

[0471] To 3 -pentadecylphenol (10.0 g, 32.8 mmol) was added DMF (50 mL), followed 1 -bromooctadecane (13.12 g, 39.4 mmol) and K2CO3 (13.00 g, 94 mmol). The resultant suspension was then heated to 100°C for 16h, at which time TLC showed the reaction to be complete. After cooling, the reaction mixture to room temperature, water (50 mL) was added, followed by hexane (100 mL). The two phases were separated, and the aqueous phase was re-extracted once with 50 mL hexane. The combined organic extracts were washed twice with water (100 mL), dried over MgSCL, and the volatiles removed to provide the crude product as a solid, which was suspended in methanol (100 mL) and heated with stirring until boiling. Stirring was maintained as the solution was allowed to reach ambient temperature, and soon the product precipitated as an amorphous white solid, which was filtered, and washed with methanol (2 x 50 mL). After drying under vacuum, this provided the desired product l-(octadecyloxy)-3 -pentadecylbenzene (18.21 g, 32.7 mmol, 99% yield) as a white solid which was used without further purification.

[0472] 'H NMR (400 MHz, CDC13) 5 7.16 (t, J= 7.7 Hz, 1H), 6.72 (td, J= 4.9, 10.9, 12.4 Hz, 3H), 3.93 (t, J = 6.6 Hz, 2H), 2.60 - 2.50 (m, 2H), 1.77 (p, J= 6.7 Hz, 2H), 1.60 (p, J= 7.2 Hz, 2H), 1.50 - 1.40 (m, 2H), 1.38 - 1.21 (m, 53H), 0.88 (t, J = 6.8 Hz, 6H).

[0473] 13C NMR (101 MHz, CDCk) 5 159.15, 144.55, 129.07, 120.65, 114.80, 111.36, 67.83, 36.07, 31.96, 31.42,

[0474] 29.73, 29.71, 29.69, 29.64, 29.62, 29.55, 29.46, 29.39, 26.11, 22.72, 14.14. l-(heptadecan-9-yloxy)-3-pentadecylbenzene:

[0475] To 3 -pentadecylphenol (10.0 g, 32.8 mmol), heptadecan-9-ol (13.52g, 50 mmol) and triphenylphosphine (13.11g, 50 mmol) was added, under an argon atmosphere, anhydrous THF (150 mL). The solution was allowed to stir, and triethylamine (7.0 mL, 5.05g, 50 mmol) was added by syringe. The reaction was cooled to 0 °C in an ice-bath and diisopropyl azodicarboxylate (9.8 mL, 10.11g, 50 mmol) was added drop-wise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then quenched with 5% aqueous HC1 (100 mL) and extracted with dichloromethane (3 x 50 mL). The combined extracts were dried over MgSO4, and concentrated to provide a yellow residue which was suspended in lOOmL hexane and stirred for 10 min. The resultant precipitate was removed by filtration, washed with 50 mL hexane, and the combined hexane extracts were stripped of solvent and chromatographed over a silica column using a 0-20% ethyl -acetate :hexane gradient elution to provide the desired product l-(heptadecan-9-yloxy)-3 -pentadecylbenzene (11.40g, 21 mmol, 64% yield) as a colourless oil.

[0476] 'H NMR (400 MHz, CDC13) 5 7.15 (t, J= 7.7 Hz, 1H), 6.76 - 6.66 (m, 3H), 4.19 (p, J= 5.8 Hz, 1H), 2.60 - 2.48 (m, 2H), 1.74 - 1.51 (m, 6H), 1.48 - 1.15 (m, 50H), 0.91 - 0.81 (m, 9H).

[0477] 13C NMR (101 MHz, CDCk) 5 158.70, 144.55, 129.06, 120.51, 116.27, 112.75, 36.05, 33.99, 31.95, 31.90, 31.37, 29.77, 29.73, 29.71, 29.69, 29.64, 29.57, 29.56, 29.39, 29.29, 25.43, 22.72, 22.69, 14.14, 14.12.

[0478] 2-(3-((2-ethylhexyl)oxy)-5-DentadecylDhenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane:

[0479] To a 50 mL capacity sealed tube was added [Ir(OMe)(l,5-cod)]2 (79.5 mg, 0.12 mmol, 0.5mol%), 4,4'-Di- tert-butyl-2,2'-dipyridyl (64.5 mg, 0.24 mmol, 1 mol%) ,bis(pinacolato)diboron, (6.16 g, 24.2 mmol, 1 eq.). The flask was then flushed with argon for 5 min. as the solids were stirred. Then, l-((2-ethylhexyl)oxy)-3- pentadecylbenzene (10.00 g, 24.0 mmol, 1 eq.) was added and the tube was again flushed with Argon gas for 5 min. Thereafter, 3 mL hexane was added to improve mixing. The tube was then sealed and heated with stirring to 120°C for 4 h, after which time NMR analysis showed the reaction was complete. Then, after cooling to room temperature, the contents were taken cautiously taken up into 50 mL acetone and water was added dropwise until bubbling ceased (quenching residual HBP results in hydrogen gas evolution), Then, methanol (50 mL) was added, which induced the formation of a crystalline precipitate. After standing for 30 minutes, the resultant precipitate was collected by filtration, washed with methanol (2 x 50 mL) and dried to provide 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (11.1 g, 20.45 mmol, 85 % yield). The combined supernatant fluid and methanol washings were then stripped of solvent, providing an amber coloured solid mass, which was subsequently taken up into 30 mL boiling acetone, to which was added methanol, dropwise, until a crystalline precipitate began to form. After standing for a few hours, these crystals were collected by filtration and dried to provide another batch of product 2- (3-((2-ethylhexyl)oxy)-5-pentadecylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.41 g, 2.59 mmol, 10.8 % yield), Combined yield of product 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenyl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (12.51 g, 23.05 mmol, 96 % yield) obtained as a white crystalline solid

[0480] 'H NMR (300 MHz, CDCI3) 5 7.21 (s, 1H), 7.14 (d, J = 2.2 Hz, 1H), 6.86 - 6.80 (m, 1H), 3.93 - 3.79 (m,2H), 2.63 - 2.49 (m, 2H), 1.76 - 1.16 (m, 51H), 0.96 - 0.81 (m, 9H).13C NMR (101 MHz, CDC13) 5 158.99, 144.02, 127.11, 118.44, 116.65, 83.71, 70.19, 39.57, 35.96, 31.95, 31.59, 30.60, 29.72, 29.70, 29.68, 29.63, 29.55, 29.38, 29.15, 24.87, 23.94, 23.08, 22.71, 14.14, 14.12, 11.19.

[0481] 2-(3-(decyloxy)-5-DentadecylDhenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane:

[0482] To a 50 mL capacity sealed tube was added [Ir(OMe)(l,5-cod)]2 (80.0 mg, 0.12 mmol, 0.5mol%), 4,4'-di- tert-butyl-2,2'-dipyridyl (64.5 mg, 0.24 mmol, 1 mol%) , bis(pinacolato)diboron, (6.20 g, 24.3 mmol, 1 eq.), followed by l-(decyloxy)-3-pentadecylbenzene (10.61 g, 24.0 mmol, 1 eq.). The tube was then flushed with argon gas for 5 min. as the solids were stirred. Thereafter, 3 mL hexane was added to improve mixing. The tube was then sealed and heated with stirring to 120°C for 4h, after which time NMR analysis showed the reaction was complete. Then, after cooling to room temperature, the contents were taken cautiously taken up into 50mL acetone and water was added dropwise until bubbling ceased (quenching residual HBP in results in Hydrogen gas evolution), Then, methanol (50 mL) was added, which induced the formation of a white crystalline precipitate. After standing for 30 minutes, the resultant precipitate was collected by filtration, washed with methanol (2 x 50 mL) and dried to provide 2-(3-(decyloxy)-5-pentadecylphenyl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (10.1 g, 17.7 mmol, 73.7 % yield). The combined supernatant fluid and methanol washings were then stripped of solvent, providing an amber coloured solid mass, which was subsequently taken up into 20mL boiling acetone, to which was added methanol, dropwise, until a crystalline precipitate began to form. After standing for a few hours, these crystals were collected by filtration and dried to provide another batch of product 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenyl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (2.30 g, 4.02 mmol, 16.7 % yield), Combined yield of product 2-(3-((2- ethylhexyl)oxy)-5-pentadecylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (12.40 g, 21.7 mmol, 91 % yield) obtained as a white amorphous solid.

[0483] 'H NMR (300 MHz, CDCI3) 5 7.21 (s, 1H), 7.14 (d, J= 2.2 Hz, 1H), 6.84 (s, 1H), 3.97 (t, J= 6.5 Hz, 2H), 2.64 - 2.49 (m, 2H), 1.76 (p, J = 6.6 Hz, 2H), 1 ,59(q, J = 7.3 Hz, 2H), 1.50 - 1.39 (m, 2H), 1.34 (s, 14H), 1.26 (d, J= 5.7 Hz, 34H), 0.88 (t, J= 6.2 Hz, 6H).

[0484] 13C NMR (101 MHz, CDCI3) 5 158.73, 144.03, 127.24, 118.62, 116.52, 83.71, 67.87, 35.91, 31.94, 31.92, 31.55, 29.72, 29.70, 29.68, 29.61, 29.58, 29.55, 29.50, 29.43, 29.38, 29.35, 26.10, 24.86, 22.71, 14.14. 4,4,5,5-tetramethyl-2-(3-(octadecyloxy)-5-DentadecylDhenyl)-l,3,2-dioxaborolane:

[0485] To a 50 mL capacity sealed tube was added [Ir(OMe)(l,5-cod)]2 (72.0 mg, 0.12 mmol, 0.8mol%), 4,4'-di- tert-butyl-2,2'-dipyridyl (58.05 mg, 0.22 mmol, 1.5 mol%) , bis(pinacolato)diboron, (4.84 g, 14.52 mmol, 1 eq.), followed by l-(octadecyloxy)-3 -pentadecylbenzene (8.10 g, 14.52 mmol, 1 eq.). The tube was then flushed with argon gas for 5 min. as the solids were stirred. Thereafter, 3 mL hexane was added to improve mixing. The tube was then sealed and heated with stirring to 120°C for 4h, after which time NMR analysis showed the reaction was complete. Then, after cooling to room temperature, the contents were taken cautiously taken up into 50mL acetone, which induced the precipitation of the product as a white solid. Water was then added dropwise until bubbling ceased (quenching residual HBP results in hydrogen gas evolution. After standing for 30 minutes, the resultant precipitate was collected by filtration, washed with acetone (2 x 20 mL) and dried to provide 4,4,5,5-tetramethyl-2-(3-(octadecyloxy)-5-pentadecylphenyl)- 1,3,2-dioxaborolane (9.00 g, 13.2 mmol, 91 % yield). The combined supernatant fluid and acetone washings were then stripped of solvent, providing an amber coloured solid mass, which was subsequently recrystallized from 30 mL boiling acetone. After standing for a few hours, these crystals were collected by filtration and dried to provide another batch of product 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenyl)-

[0486] 4.4.5.5-tetramethyl-l,3,2-dioxaborolane (0.460 g, 0.68 mmol, 4.6 % yield), Combined yield of product

[0487] 4.4.5.5-tetramethyl-2-(3-(octadecyloxy)-5-pentadecylphenyl)-l,3,2-dioxaborolane (9.46 g, 13.88 mmol, 96 % yield) obtained as a white amorphous solid.

[0488] 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane:

[0489] To a 50 mL capacity sealed tube was added [Ir(OMe)(l,5-cod)]2 (67.2 mg, 0.10 mmol, 0.5mol%), 4,4'-di- tert-butyl-2,2'-dipyridyl (49.0 mg, 0.19 mmol, 1 mol%) , bis(pinacolato)diboron, (5.33 g, 21.0 mmol, ca.l eq.), followed by l-(heptadecan-9-yloxy)-3-pentadecylbenzene (11.00 g, 20.3mmol, 1 eq.). The tube was then flushed with Argon gas for 5 min. as the mixture was slowly stirred. Thereafter, 3 mL hexane was added to improve mixing. The tube was then sealed and heated with stirring to 120°C for 4h, after which time NMR analysis showed the reaction was complete. Then, after cooling to room temperature, the contents were taken cautiously taken up into 50 mL acetone and water was added dropwise until bubbling ceased (quenching residual HBP in results in hydrogen gas evolution). The product began precipitating as an amber oil which did not crystalize after cooling in a freezer overnight. Thus, water (50 mL) was added, which induced further precipitation, and the mixture was extracted using hexane (3 x 50mL). The combined hexane extracts were then washed with water (100 mL), dried over MgSCL, and the solvent removed to provide an oily residue which was chromatographed over a silica column using a 0-10% ethyl-acetate:hexane gradient elution to provide the desired product 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (11.12 g, 16.6 mmol, 82% yield) as a colourless oil.

[0490] 'H NMR (400 MHz, CDC13) 5 7.19 (s, 1H), 7.14 (d, J= 2.1 Hz, 1H), 6.80 (s, 1H), 4.27 (p, J= 5.7 Hz, 1H), 2.62 - 2.49 (m, 2H), 1.70 - 1.53 (m, 6H), 1.47 - 1.15 (m, 66H), 0.93 - 0.81 (m, 9H).

[0491] 13C NMR (101 MHz, CDC13) 5 158.18, 143.99, 126.96, 119.53, 118.67, 83.65, 35.94, 33.90, 31.94, 31.89, 31.53, 29.79, 29.72, 29.68, 29.64, 29.57, 29.50, 29.38, 29.29, 25.30, 24.87, 22.71, 22.68, 14.14, 14.12.

[0492] 3-((2-ethylhexyl)oxy)-5-pentadecylphenol:

[0493] To a stirring suspension of 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (8.12 g, 14.96 mmol) 100 mL ethanol was added a solution of urea hydrogen peroxide (5.63g, 59.84 mmol, 4 eq.) in 100 mL ethanol, slowly, at a rate of approximately 1 drop per second. After the addition (ca. 2 hours) the resultant solution became homogenous, indicating reaction completion. The reaction was then allowed to stir for a further 30 minutes at room temperature, and, once completion was confirmed by TLC, the reaction was poured into 200 mL ice water, with stirring. The phenol product precipitated as an amber oil. An additional lOOmL water was added, and the product was extracted from the solution using Hexane (4 x 50 mL). The combined organic extracts were washed with water (150 mL), dried over MgSCL, filtered, and the volatiles removed in-vacuo to provide the product, 3-((2-ethylhexyl)oxy)-5- pentadecylphenol (6.43g, 14.85 mmol, 99% yield) as an amber oil which was used without further purification.

[0494] 'H NMR (400 MHz, CDCI3) 5 6.32 (t, J= 1.7 Hz, 1H), 6.26 - 6.21 (m, 2H), 5.15 (s, 1H), 3.84 - 3.73 (m, 2H), 2.54 - 2.43 (m, 2H), 1.69 (hept, J= 6.0 Hz, 1H), 1.57 (p, J= 6.0, 6.5 Hz, 2H), 1.52 - 1.35 (m, 4H), 1.33 - 1.18 (m, 32H), 0.96 - 0.84 (m, 9H).13C NMR (101 MHz, CDC13) 5 160.59, 156.46, 145.64, 107.59, 107.37, 99.19, 70.45, 39.38, 36.10, 31.95, 31.21, 30.53, 29.72, 29.71, 29.68, 29.62, 29.55, 29.40, 29.39, 29.09, 24.82, 23.87, 23.07, 22.71, 14.14, 14.10, 11.11.

[0495] 3-( decyloxyl-S-Dentadecylphenol :

[0496] To a stirring suspension of 10 mmol 2-(3-(decyloxy)-5-pentadecylphenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (7.3 g, 12.79 mmol) in 100 mL ethanol was added a solution of urea hydrogen peroxide (4.74 g, 50.4 mmol, ca. 4 eq.) in 100 mL ethanol, slowly, at a rate of approximately 1 drop per second. After the addition (ca. 2 hours) the resultant solution became homogenous, indicating reaction completion. The reaction was then allowed to stir for a further 30 minutes at room temperature, and once completion was confirmed by TLC, the reaction was poured into 150 mL ice water, with stirring. The phenol product precipitated as an amorphous solid, which, after stirring for an additional 20 min, was collected by filtration, washed with water (2 x 50mL) and dried to provide the 3-(decyloxy)-5-pentadecylphenol (5.57g, 12.1 mmol, 95% yield) as a white solid.

[0497] 'H NMR (300 MHz, CDCI3) 5 6.32 (s, 1H), 6.27 - 6.19 (m, 2H), 4.73 (s, 1H), 3.90 (t, J = 6.6 Hz, 2H), 2.50 (t, J = 7.5 Hz, 2H), 1.75 (p, J = 6.7 Hz, 2H), 1.59 - 1.52(m, 2H), 1.50 - 1.36 (m, 2H), 1.35 - 1.21 (m, 39H), 0.88 (t, J = 6.4 Hz, 7H).

[0498] 13C NMR (101 MHz, CDCI3) 5 160.35, 156.36, 145.69, 107.61, 107.42, 99.10, 67.96, 36.06, 31.93, 31.91, 31.17, 29.71, 29.69, 29.67, 29.59, 29.57, 29.53, 29.41, 29.37, 29.33, 29.28, 26.06, 22.70, 22.69, 14.13, 0.00.

[0499] 3-(octadecyloxy)-5-pentadecylphenol:

[0500] To a stirring suspension of 10 mmol 4,4,5,5-tetramethyl-2-(3-(octadecyloxy)-5-pentadecylphenyl)-l,3,2- dioxaborolane (5.22 g, 7.64 mmol) in 100 mL ethanol was added a solution of urea hydrogen peroxide (2.83 g, 30.0 mmol, ca. 4 eq.) in 100 mL ethanol, slowly, at a rate of approximately 1 drop per second. During the addition the suspension approached homogeneity, but after ca, 1 hour the product phenol began precipitating as a fine white solid. After the addition (ca. 2 hours) a thick white suspension had developed, which was stirred for a further 30 minutes at room temperature, and once completion was confirmed by TLC, the reaction was poured into 150 mL ice water, with stirring. After stirring for an additional 20 min, the phenol product was collected by filtration, washed with water (2 x 50mL) and dried to provide the 3- (octadecyloxy)-5-pentadecylphenol (4.38 g, 7.65 mmol ca. 100% yield) as a white solid.

[0501] 'H NMR (400 MHz, CDC13) 5 6.32 (s, 1H), 6.24 (s, 1H), 6.22 (t, J= 2.1 Hz, 1H), 4.69 (s, 1H), 3.90 (t, J = 6.6 Hz, 2H), 2.55 - 2.43 (m, 2H), 1.75 (p, J = 6.7 Hz, 2H), 1.57 (p, J = 7.2 Hz, 2H), 1.43 (p, J = 6.6 Hz, 2H), 1.37 - 1.16 (m, 54H), 0.88 (t, J= 6.8 Hz, 6H).

[0502] 13C NMR (101 MHz, CDC13) 5 160.34, 156.36, 145.69, 107.63, 107.44, 99.12, 67.97, 36.06, 31.94, 31.18, 29.72, 29.70, 29.68, 29.63, 29.61, 29.54, 29.43, 29.38, 29.34, 29.29, 26.07, 22.71, 14.14.

[0503] 3-(heptadecan-9-yloxy)-5-pentadecylphenol:

[0504] To a stirring suspension of 10 mmol 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenyl)-4, 4,5,5 -tetramethyl - 1,3,2-dioxaborolane (10.0 g, 14.94 mmol) in 100 mb ethanol was added a solution of urea hydrogen peroxide (5.66 g, 60.0 mmol, ca. 4 eq.) in 200 mL at a rate of approximately 1 drop per second. After the addition (ca. 3 hours) the resultant solution became homogenous, indicating reaction completion. The reaction was then allowed to stir for a further 30 minutes at room temperature, and, once completion was confirmed by TLC, the reaction was poured into 200 mL ice water, with stirring. The phenol product precipitated as an amber oil, which slowly began solidifying. After stirring overnight (ca. 16 h.) the phenol product was collected by filtration, washed with water (2 x 50mL) and dried to provide 3-(heptadecan-9- yloxy)-5-pentadecylphenol: (7.77 g, 13.9 mmol, 93% yield) as a cream coloured amorphous solid.

[0505] 'H NMR (400 MHz, CDCI3) 5 6.30 (s, 1H), 6.24 - 6.18 (m, 2H), 4.70 (s, 1H), 4.15 (p, J = 5.8 Hz, 1H), 2.53 - 2.43 (m, 2H), 1.71 - 1.49 (m, 6H), 1.45 - 1.17 (m, 52H), 0.94 - 0.82 (m, 9H).

[0506] 13C NMR (101 MHz, CDCk) 5 159.91, 156.36, 145.62, 108.79, 107.50, 100.37, 77.96, 36.05, 33.96, 31.94, 31.89, 31.13, 29.75, 29.72, 29.68, 29.63, 29.57, 29.55, 29.38, 29.36, 29.28, 25.40, 22.71, 22.68, 14.13, 14.12.

[0507] 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethanol: To 3-((2-ethylhexyl)oxy)-5-pentadecylphenol (3.49 g, 11.55 mmol) in anhydrous DMF (5.0 mL) was added ethylene carbonate (2.03g, 23.1mmol, 2 eq.) , followed by and cesium carbonate (376 mg, 1.12 mmol, 0.1 eq.) The resultant suspension was heated to 130-140°C for 3 h, at which point TLC showed reaction was complete. The reaction was then allowed to reach room temperature and water (20 mL) was added, followed by hexane (20 mL). The phases were separated and the aqueous phase was re-extracted with hexane (2 x 20mL). The combined organic extracts were washed with water (2 x 20mL), dried over MgSCL, fdtered, and the solvent removed in-vacuo to provide the crude product 2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)ethanol (5.10 g, 10.70 mmol, 93%) as an amber oil which was used without subsequent purification.

[0508] 'H NMR (400 MHz, CDC13) 5 6.36 (s, 1H), 6.34 (s, 1H), 6.31 (t, J= 2.2 Hz, 1H), 4.10 - 4.00 (m, 2H), 3.94 (q, J= 4.9 Hz, 2H), 3.83 - 3.71 (m, 2H), 2.58 - 2.46 (m, 2H), 2.06 (t, J= 6.0 Hz, 1H), 1.76 - 1.64 (m, 1H), 1.63 - 1.55 (m, 3H), 1.54 - 1.37 (m, 4H), 1.28 (d, J= 18.2 Hz, 34H), 0.97 - 0.83 (m, 10H).

[0509] 13C NMR (101 MHz, CDC13) 5 160.49, 159.59, 145.43, 107.57, 106.82, 98.66, 70.45, 69.09, 61.55, 39.41, 36.32, 31.94, 31.31, 30.54, 29.71, 29.70, 29.67, 29.62, 29.55, 29.41, 29.38, 29.09, 23.88, 23.07, 22.71, 14.14, 14.11, 11.12.

[0510] 2-(3-(decyloxy)-5-pentadecylphenoxy)ethanol:

[0511] To 3 -(decyloxy) -5 -pentadecylphenol (3.26 g, 7.08 mmol) in anhydrous DMF (3.0 mL) was added ethylene carbonate (1.25g, 14.16 mmol, 2 eq.) , followed by cesium carbonate (226 mg, 0.672 mmol, ca. 0.1 eq.) The resultant suspension was heated to 130-140°C for 3 h, at which point TLC showed reaction was complete. The reaction was then allowed to reach room temperature and water (20 mL) was added, followed by hexane (20 mL). The phases were separated and the aqueous phase was re-extracted with hexane (2 x 20mL). The combined organic extracts were washed with water (2 x 20mL), dried over MgSCL, fdtered, and the solvent removed in-vacuo to provide the crude product 2-(3-(decyloxy)-5-pentadecylphenoxy)ethanol (3.36 g, 6.66 mmol, 94% yield) as an amber oil which solidified upon standing for a few days. The material was used without subsequent purification.

[0512] 'H NMR (400 MHz, CDCI3) 5 6.37 - 6.32 (m, 2H), 6.30 (t, J= 2.2 Hz, 1H), 4.08 - 4.00 (m, 2H), 3.96 - 3.86 (m, 4H), 2.56 - 2.47 (m, 2H), 1.76 (p, J= 6.7 Hz, 2H), 1.58 (p, J = 7.2 Hz, 2H), 1.44 (t, J = 7.7 Hz, 2H), 1.36 - 1.20 (m, 38H), 0.92 - 0.82 (m, 6H).13C NMR (101 MHz, CDC13) 5 160.22, 159.59, 145.45, 107.54, 106.93, 98.63, 69.08, 67.98, 61.54, 36.30, 31.94, 31.91, 31.29, 29.71, 29.70, 29.67, 29.61, 29.59, 29.57, 29.54, 29.42, 29.37, 29.34, 29.31, 26.07, 22.70, 22.69, 14.13.

[0513] 2-(3-(octadecyloxy)-5-DentadecylDhenoxy)ethanol:

[0514] To 3 -(octadecyloxy)-5 -pentadecylphenol (4.01 g, 6.99 mmol) in anhydrous DMF (5.0 mL) was added ethylene carbonate (1.21g, 14.0 mmol, 2 eq.) , followed by and cesium carbonate (224 mg, 0.670 mmol, ca. 0.1 eq.) The resultant suspension was heated to 130-140°C for 3 h, at which point TLC showed reaction was complete. The reaction was then allowed to reach room temperature and water (20 mL) was added, followed by hexane (20 mL). The phases were separated and the aqueous phase was re-extracted with hexane (2 x 20mL). The combined organic extracts were washed with water (2 x 20mL), dried over MgSCL, filtered, and the solvent removed in-vacuo to provide the crude product 2-(3-(octadecyloxy)-5- pentadecylphenoxy)ethanol (4.13 g, 6.70 mmol, 96% yield) as an off-white solid, which was used without subsequent purification.

[0515] 'H NMR (400 MHz, CDCI3) 5 6.37 - 6.33 (m, 2H), 6.30 (t, J= 2.1 Hz, 1H), 4.10 - 4.00 (m, 2H), 3.93 (dt, J = 6.3, 13.3 Hz, 4H), 2.59 - 2.45 (m, 2H), 2.00 (t, J = 6.3 Hz, 1H), 1.76 (p, J = 6.7 Hz, 2H), 1.64 - 1.50 (m, 2H), 1.50 - 1.38 (m, 2H), 1.38 - 1.16 (m, 54H), 0.88 (t, J= 6.8 Hz, 6H).

[0516] 13C NMR (101 MHz, CDCI3) 5 160.22, 159.59, 145.46, 107.54, 106.92, 98.63, 69.08, 67.98, 61.55, 36.30, 31.93, 31.28, 29.71, 29.69, 29.67, 29.62, 29.60, 29.54, 29.42, 29.37, 29.31, 26.08, 22.70, 14.13.

[0517] 2-(3-(heDtadecan-9-yloxy)-5-DentadecylDhenoxy)ethanol:

[0518] To 3 -(heptadecan-9-yloxy)-5 -pentadecylphenol (3.50 g, 6.26 mmol) in anhydrous DMF (5.0 mL) was added ethylene carbonate (1.08g, 12.5 mmol, 2 eq.), followed by cesium carbonate (200 mg, 0.60 mmol, ca. 0.1 eq.) The resultant suspension was heated to 130-140°C for 3 h, at which point TLC showed reaction was complete. The reaction was then allowed to reach room temperature and water (20 mL) was added, followed by hexane (20 mL). The phases were separated and the aqueous phase was re-extracted with hexane (2 x 20 mL). The combined organic extracts were washed with water (2 x 20mL), dried over MgSCL, filtered, and the solvent removed in-vacuo to provide the crude product 2-(3-(heptadecan-9-yloxy)-5- pentadecylphenoxy)ethanol (3.66 g, 6.07 mmol, 97% yield) as a colourless oil, which was used without subsequent purification.

[0519] 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl 4-(4-(2-hydroxyethyl)piperazin-l-yl)butanoate

[0520] (also referred to as RK-003):

[0521] To an ice-cooled stirring solution of 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethanol (5.00 g, 10.50 mmol) in dichloromethane (50 mL) was added 4-chloro-butyryl chloride (1.70 mb, 2.14 g, 15 mmol), followed by triethylamine (2.80 mL, 2.01g, 20.0 mmol) . The resultant solution was allowed to warm to room temperature and after 1 hour, TLC confirmed the reaction to be complete and the solution was quenched with a saturated solution of sodium bicarbonate (10 mL). The phases were separated and the aqueous phase was re-extracted with dichloromethane (2 x 10mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product, to which was added hexane (10 mL), followed by acetonitrile (lOmL) and the resultant biphasic mixture was shaken and the phases separated. The organic phase was washed once more with lOmL acetonitrile. The combined acetonitrile extracts were then reextracted with hexane (3 x 10mL), and the combined hexane fractions were dried over MgSCL, filtered, and the solvent removed to provide the product which was taken up into toluene (10 mL), to which was added K2CO3 (2.76 g, 20.0 mmol), followed by 2-(piperazin-l-yl)ethanol (2.60 g, 20 mmol) and Tetrabutylammonium iodide (0.554 g, 1.50 mmol). The resultant suspension was heated in a sealed tube to 120°C for 3 hours, until compete by TLC. The suspension was allowed to reach room temperature and hexane (20 mL) was added, followed by sufficient MgSCL to provide an easily filterable suspension. This suspension was then filtered, washed with hexane (2 x 10 mL) and the obtained organic filtrate was subsequently washed with water (2 x 20mL). The organic phase was then dried over MgSCL, filtered, and the solvent removed to provide the crude product, which was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 25 minutes. Then the obtained product was dissolved in hexane (20 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide the product 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl 4-(4-(2- hydroxyethyl)piperazin-l-yl)butanoate (4.60 g, 6.80 mmol, 65% yield) as a pale yellow oil.

[0522] 'H NMR (300 MHz, CDCI3) 5 6.36 (s, 1H), 6.32 (s, 1H), 6.29 (t, J = 2.0 Hz, 1H), 4.46 - 4.35 (m, 2H), 4. 19 - 4.07 (m,2H), 3.80 (d, J = 5.7 Hz, 2H), 3.59 (t, J = 5.4 Hz, 2H), 2.60 - 2.31 (m, 16H), 1.82 (p, J = 7.3 Hz, 2H), 1.74 - 1.65 (m,lH), 1.63 - 1.55 (m, 2H), 1.54 - 1.19 (m, 36H), 0.99 - 0.82 (m, 9H).13C NMR (75 MHz, CDC13) 5 173.51, 160.47, 159.45, 145.39, 107.59, 106.71, 98.63, 70.43, 65.85, 62.81, 59.19, 57.68, 57.54, 53.15, 52.85, 39.39, 36.32, 34.66, 32.11, 31.93, 31.59, 31.32, 30.53,29.70, 29.67, 29.61, 29.54, 29.41, 29.37, 29.08, 25.28, 23.87, 23.06, 22.70, 22.11, 14.13, 14.10, 11.12.

[0523] 2-(3-(decyloxy)-5-DentadecylDhenoxy)ethyl 4-(4-(2-hydroxyethyl)DiDerazin-l-yl)butanoate (also referred to as RK- :

[0524] To an ice-cooled stirring solution of 2-(3-(decyloxy)-5-pentadecylphenoxy)ethanol (3.11 g, 6.16 mmol) in dichloromethane (50 mL) was added 4-chloro-butyryl chloride (1.0 mL, 1.26 g, 8.82 mmol), followed by triethylamine (1.6 mL, 1.1g , 11.76 mmol) . The resultant solution was allowed to warm to room temperature and after 1 hour, TLC confirmed the reaction to be complete and the solution was quenched with a saturated solution of sodium bicarbonate (10 mL). The phases were separated and the aqueous phase was re-extracted with dichloromethane (2 x 10mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product, to which was added hexane (10 mL), followed by acetonitrile (lOmL) and the resultant biphasic mixture was shaken and the phases separated. The organic phase was washed once more with lOmL acetonitrile. The combined acetonitrile extracts were then re-extracted with hexane (3 x 10mL), and the combined hexane fractions were dried over MgSCL, filtered, and the solvent removed to provide the product which was taken up into toluene (10 mL), to which was added K2CO3 (1.62 g, 11.76 mmol), followed by 2-(piperazin-l-yl)ethanol (1.52 g, 11.76 mmol) and tetrabutylammonium iodide (0.500 g, 1.35 mmol). The resultant suspension was heated in a sealed tube to 120°C for 3 hours, until compete by TLC. The suspension was allowed to reach room temperature and hexane (20 mL) was added, followed by sufficient MgSCL to provide an easily filterable suspension. This suspension was then filtered, washed with hexane (2 x 10 mL) and the obtained organic filtrate was subsequently washed with water (2 x 20mL). The organic phase was then dried over MgSCL, filtered, and the solvent removed to provide the crude product, which was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 25 minutes. Then the obtained product was dissolved in hexane (20 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide the product 2-(3-(decyloxy)-5- pentadecylphenoxy)ethyl 4-(4-(2-hydroxyethyl)piperazin-l-yl)butanoate (2.80 g, 3.98 mmol, 64% yield) as a colourless oil.

[0525] 'H NMR (400 MHz, CDCI3) 5 6.35 (s, 1H), 6.32 (s, 1H), 6.29 (t, J= 2.1 Hz, 1H), 4.48 - 4.35 (m, 2H), 4.17 - 4.08 (m, 2H), 3.91 (t, J = 6.6 Hz, 2H), 3.64 - 3.56 (m, 2H), 2.63 - 2.28 (m, 16H), 1.88 - 1.69 (m, 4H), 1.58 (p, J= 7.2 Hz, 2H), 1.49 - 1.39 (m, 2H), 1.39 - 1.17 (m, 38H), 0.92 - 0.82 (m, 6H).13C NMR (101 MHz, CDC13) 5 173.49, 160.21, 159.47, 145.40, 107.58, 106.83, 98.64, 67.96, 65.86, 62.79, 59.21, 57.69, 57.54, 53.16, 52.87, 36.30, 32.11, 31.93, 31.90, 31.29, 29.70, 29.69, 29.66, 29.61, 29.59, 29.57, 29.54, 29.41, 29.37, 29.33, 29.30, 26.07, 22.70, 22.69, 22.12, 14.13.

[0526] 2-(3-(octadecyloxy)-5-DentadecylDhenoxy)ethyl 4-(4-(2-hvdroxyethyl)DiDerazin-l-yl)butanoate (also referred to as RK-004):

[0527] To an ice-cooled stirring solution of 2-(3-(octadecyloxy)-5-pentadecylphenoxy)ethanol (2.03 g, 3.29 mmol) in dichloromethane (50 mL) was added 4-chloro-butyryl chloride (0.5 mL, 0.63 g, 4.41 mmol), followed by triethylamine (0.8 mL, 0.55 g , 5.88 mmol) . The re suitant solution was allowed to warm to room temperature and after 1 hour, TLC confirmed the reaction to be complete and the solution was quenched with a saturated solution of sodium bicarbonate (10 mL). The phases were separated and the aqueous phase was re-extracted with dichloromethane (2 x 10mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product, to which was added hexane (10 mL), followed by acetonitrile (lOmL) and the resultant biphasic mixture was shaken and the phases separated. The hexane phase was washed once more with lOmL acetonitrile. The combined acetonitrile extracts were then re-extracted with hexane (3 x 10mL), and the combined hexane fractions were dried over MgSCL, filtered, and the solvent removed to provide the product which was taken up into toluene (5.0 mL), to which was added K2CO3 (0.81 g, 5.58 mmol), followed by 2- (piperazin-l-yl)ethanol (0.76 g, 5.58 mmol) and tetrabutylammonium iodide (0.250 g, 0.68 mmol). The resultant suspension was heated in a sealed tube to 120°C for 3 hours, until compete by TLC. The suspension was allowed to reach room temperature and hexane (20 mL) was added, followed by sufficient MgSCL to provide an easily filterable suspension. This suspension was then filtered, washed with hexane (2 x 10 mL) and the obtained organic filtrate was subsequently washed with water (2 x 20mL). The organic phase was then dried over MgSCL, filtered, and the solvent removed to provide the crude product, which was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 25 minutes. Then the obtained product was dissolved in hexane (20 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide the product2-(3-(octadecyloxy)-5- pentadecylphenoxy)ethyl 4-(4-(2-hydroxyethyl)piperazin-l-yl)butanoate: (1.57 g, 1.90 mmol, 58% yield) as a colorless oil which slowly solidified over a few weeks of standing. 'H NMR (400 MHz, CDC13) 5 6.28 (s, 1H), 6.25 (s, 1H), 6.22 (t, J= 2.0 Hz, 1H), 4.37 - 4.30 (m, 2H), 4.11 - 4.01 (m, 2H), 3.84 (t, J= 6.6 Hz, 2H), 3.58 - 3.49 (m, 2H), 2.50 - 2.25 (m, 15H), 1.72 (dp, J= 7.0, 26.2 Hz, 4H), 1.50 (q, J = 7.0 Hz, 2H), 1.41 - 1.31 (m, 3H), 1.18 (s, 54H), 0.81 (t, J= 6.8 Hz, 6H).

[0528] 13C NMR (101 MHz, CDCk) 5 172.46, 159.19, 158.44, 144.39, 106.55, 105.81, 97.61, 66.95, 64.84, 61.78, 58.20, 56.65, 56.51, 52.09, 51.83, 35.28, 31.08, 30.91, 30.27, 28.69, 28.67, 28.65, 28.61, 28.58,28.52, 28.41, 28.35, 28.29, 25.06, 21.68, 21.08, 13.11.

[0529] 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy)ethyl 4-(4-(2-hydroxyethyl)piperazin-l- vDbutanoate (also referred to as RK-006):

[0530] To an ice-cooled stirring solution of 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy)ethanol (4.27 g, 7.08 mmol) in dichloromethane (100 mL) was added 4-chloro-butyryl chloride (1.0 mL, 1.26 g, 8.82 mmol), followed by triethylamine (1.6 mL, 1.10 g , 11.76 mmol) . The resultant solution was allowed to warm to room temperature and after 1 hour, TLC confirmed the reaction to be complete and the solution was quenched with a saturated solution of sodium bicarbonate (20 mL). The phases were separated and the aqueous phase was re-extracted with dichloromethane (2 x 20 mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product, to which was added hexane (50 mL), followed by acetonitrile (50 mL) and the resultant biphasic mixture was shaken and the phases separated. The hexane phase was washed once more with lOmL acetonitrile. The combined acetonitrile extracts were then reextracted with hexane (3 x 10mL), and the combined hexane fractions were dried over MgSCL, filtered, and the solvent removed to provide the product which was taken up into toluene (10.0 mL), to which was added K2CO3 (1.62 g, 11.16 mmol), followed by 2-(piperazin-l-yl)ethanol (1.52 g, 11.16 mmol) and tetrabutylammonium iodide (0.500 g, 1.36 mmol). The resultant suspension was heated in a sealed tube to 120°C for 3 hours, until compete by TLC. The suspension was allowed to reach room temperature and hexane (20 mL) was added, followed by sufficient MgSCL to provide an easily filterable suspension. This suspension was then filtered, washed with hexane (2 x 20 mL) and the obtained organic filtrate was subsequently washed with water (2 x 20mL). The organic phase was then dried over MgSO4, filtered, and the solvent removed to provide the crude product, which was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 25 minutes. Then the obtained product was dissolved in hexane (20 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSO4, filtered and dried to provide the product 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy)ethyl 4-(4-(2- hydroxyethyl)piperazin-l-yl)butanoate: (4.51 g, 5.60 mmol, 79% yield) as a colorless oil. 'H NMR (300 MHz, CDC13) 5 6.33 (s, 1H), 6.30 (s, 1H), 6.27 (s, 1H), 4.46 - 4.38 (m, 2H), 4.22 - 4.09 (m, 3H), 3.60 (t, J= 5.4 Hz, 2H), 2.75 - 2.32 (m, 18H), 1.82 (p, J= 7.4 Hz, 2H), 1.70 - 1.51 (m, 6H), 1.26 (s, 51H), 0.87 (t, J= 6.6 Hz, 9H).

[0531] 2-Hydroxy-4-Dentadecylbenzaldehyde:

[0532] Adapted from literature. In a 2-neck round-bottom flask, equipped with a magnetic stirrer bar and reflux condenser, 3 -pentadecylphenol (commercially available, 90% grade, 5.35 g, 15.8 mmol, 1.0 equiv) was dissolved in freshly distilled THF (80 mL) under an inert atmosphere of N2 gas. After complete solubilisation, MgCb (anhydrous powder, 2.26 g, 23.7 mmol, 1.5 equiv) was added and the solution was allowed to stir for 30 min. Thereafter, paraformaldehyde (4. 14 g, 138 mmol, 8.75 equiv) was added and the solution was stirred for another 30 min. NEP, (8.25 mL, 59.3 mmol, 3.75 equiv) was added last and the solution was heated under reflux for 16 h. Upon completion, the reaction mixture was cooled to rt. A 2 M aqueous HC1 solution (40 mL) was added until a pH between 0 to 1 was obtained. EtOAc (4 x 50 mL) was used to extract the organic material. The combined organic extracts were washed with brine, dried over anhydrous Na2SC>4 and filtered through celite. The solvent was removed under reduced pressure to afford the crude product as an orange solid. The crude product was purified by column chromatography on silica gel (2-3% EtOAc / hexane) to afford the pure product as a white solid (4.73 g, 90%).

[0533] 'H NMR (400 MHz, CDCI3) 5 11.05 (s, 1H), 9.83 (s, 1H), 7.44 (d, J= 7.9 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.80 (s, 1H), 2.61 (t, J= 7.7 Hz, 2H), 1.61 (m, 2H), 1.30 (m, 24H), 0.88 (t, J= 6.7 Hz, 3H).

[0534] 13C NMR (75 MHz, CDCI3) 5 195.9, 161.9, 154.0, 133.7, 120.6, 119.0, 117.2, 36.6, 32.1, 30.8, 29.8, 29.7, 29.6, 29.5, 29.4, 22.8, 14.3.

[0535] 2-(Octadecyloxy)-4-Dentadecylbenzaldehyde:

[0536] In a 2-neck round-bottom flask, equipped with a magnetic stirrer bar and reflux condenser, 2-hydroxy-4- pentadecylbenzaldehyde (3.05 g, 9.17 mmol, 1.0 equiv) was dissolved in anhydrous DMF (40 mL) under an inert atmosphere of N2 gas. Potassium carbonate (2.53 g, 18.3 mmol, 2 equiv) was added and the solution was stirred for 10 minutes. Thereafter, 1 -bromooctadecane was added (4.60 g, 13.8 mmol, 1.5 equiv). The solution was heated at 100 °C for 18 h. Hexane (60 mL) was added to dilute the solution. Followed by the addition of water (50 mL). The layers were separated and the aqueous layer was extracted twice more using hexane (2 x 60 mL). The combined organic layers were washed with water (500 mL), then brine (500 mL) to remove all DMF. The organic layer was then dried over anhydrous MgSCL and filtered through celite. The solvent was evaporated under reduced pressure to afford the crude product. The product obtained as an off-white solid was used without further purification (85%).

[0537] 'H NMR (300 MHz, CDC13) 5 10.44 (s, 1H), 7.74 (d, J= 7.9 Hz, 1H), 6.82 (d, J= 7.9 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 4.06 (t, J = 6.4 Hz, 2H), 2.61 (dd, J= 8.8, 6.7 Hz, 2H), 1.89 - 1.78 (m, 2H), 1.69 - 1.57 (m, 3H), 1.48 (m, 3H), 1.25 (m, 72H), 0.91 - 0.83 (m, 8H).

[0538] 13C NMR (101 MHz, CDCh) 6 189.7, 161.9, 152.5, 128.3, 123.0, 120.9, 112.5, 77.5, 77.2, 76.8, 68.6, 36.8, 32.1, 31.2, 29.9, 29.8, 29.8, 29.7, 29.6, 29.5, 29.5, 29.3, 29.3, 26.2, 22.8, 14.3.

[0539] (2-(Octadecyloxy)-4-pentadecylphenyl)methanol :

[0540] 2-(Octadecyloxy)-4-pentadecylbenzaldehyde (0.96 g, 1.64 mmol, 1.0 equiv) was dissolved in a 2-neck round bottom flask, under an inert atmosphere of N2 gas, using freshly-distilled THF (15 mL). To the stirred solution at room temperature, NaBffi (0.062 g, 1.64 mmol, 1 equiv) was added carefully, followed by the addition of ammonium oxalate monohydrate (0.233 g, 1.64 mmol, 1 equiv). The reaction was stirred for 12 h at room temperature. The reaction flask was cooled in an ice-water bath, then water was added dropwise. Ethyl acetate was used to extract the aqueous layer (3 x 50 mL). The combined organic layers were dried over anhydrous MgSCfl and filtered through Celite. The solvent was evaporated under reduced pressure to afford the crude product as an off-white solid (90% yield). The product was used without further purification.

[0541] 2-(Octadecyloxy)-4-pentadecylbenzyl 4-chlorobutanoate:

[0542] In a 2-neck round bottom flask, (2-(octadecyloxy)-4-pentadecylphenyl)methanol (0.229 g, 0.39 mmol, 1.0 equiv) was dissolved in freshly-distilled CH2CI2 (10 mL) under an inert atmosphere ofN2 gas. The reaction flask was cooled in ice and the 4-chlorobutanoyl chloride (0.06 mL, 0.54 mmol, 1.4 equiv), followed by triethylamine (0.08 mL, 0.58 mmol, 1.5 equiv) was added carefully. The reaction as allowed to reach room temperature and was stirred at room temperature for 3.5 h. Completion of the reaction was confirmed using TLC analysis (5% EtOAc / hexane). A saturated aqueous solution of NaHCCf (25 mL) was added carefully to the reaction mixture. The material was transferred to a separating funnel and extracted using CH2CI2 (40 mL), followed by two more extractions using hexane (2 x 50 mL). The combined organic extracts were washed with acetonitrile (2 x 30 mL). The organic hexane layer was collected, dried over anhydrous MgSCfi. filtered through celite and evaporated to dryness under reduced pressure. The product was purified using silica gel column chromatography (2% EtOAc / hexane). The product was obtained in a 95% yield.

[0543] 'H NMR (300 MHz, CDC13) 5 7.20 (d, J= 7.6 Hz, 1H), 6.75 (dd, J= 7.6, 1.5 Hz, 1H), 6.70 (d, J= 1.5 Hz, 1H), 5.16 (s, 2H), 3.98 (t, J= 6.4 Hz, 2H), 3.60 (td, J= 6.4, 1.6 Hz, 2H), 2.64 - 2.47 (m, 4H), 2.18 - 2.06 (m, 2H), 1.85 - 1.73 (m, 2H), 1.62 (dt, J= 11.7, 6.8 Hz, 2H), 1.46 (t, J = 7.7 Hz, 2H), 1.27 (m, 52H), 0.95 - 0.83 (m, 6H).

[0544] 13C NMR (75 MHz, CDC13) 5 172.8, 157.3, 145.2, 130.0, 121.5, 120.3, 111.8, 77.6, 77.2, 76.7, 68.2, 62.3, 44.2, 36.3, 32.1, 31.6, 31.5, 29.9, 29.7, 29.5, 26.2, 22.8, 14.3.

[0545] 2-(Octadecyloxy)-4-pentadecylbenzyl 4-(4-(2-hydroxyethyl)piperazin-l-yl)butanoate (also referred to as AG-003):

[0546] 2-(Octadecyloxy)-4-pentadecylbenzyl 4-chlorobutanoate (0.203 g, 0.29 mmol, 1.0 equiv), potassium carbonate (0.121 g, 0.88 mmol, 3 equiv), tetrabutylammonium iodide (0.027 g, 0.07 mmol, 0.25 equiv) and 2 -hydroxyethylpiperazine (0.11 mL, 0.88 mmol, 3 equiv) were placed in a microwave vessel, equipped with a magnetic stirrer bar. Freshly distilled toluene (5 mL) was added last. The vessel was sealed and the reaction mixture was irradiated for 2 h at 140 °C (180 W). Ethyl acetate (30 mL) and water (30 mL) were used to transfer the material from a microwave vessel to a separating funnel. The organic and aqueous layers were separated. The aqueous layer was then extracted twice more using ethyl acetate (2 x 40 mL). The combined organic extracts were dried over anhydrous MgSCfi and filtered through celite. The solvent was removed under reduced pressure to afford the crude product as a colourless oil. Purification was carried out using automated flash silica column chromatography (12 g column, 0-5% MeOH / CTLCL, gradient elution, over 25 minutes). The pure product was obtained as a colourless oil that solidified to an off-white solid (27% yield).

[0547] 'H NMR (400 MHz, CDC13) 5 7.19 (d, J= 7.6 Hz, 1H), 6.73 (dd, J= 7.6, 1.5 Hz, 1H), 6.68 (d, J= 1.5 Hz, 1H), 5.13 (s, 2H), 3.96 (t, J= 6.5 Hz, 2H), 3.76 - 3.71 (m, 2H), 2.74 (td, J= 21.2, 8.7 Hz, 9H), 2.56 (dd, J = 8.8, 6.7 Hz, 2H), 2.47 (t, J= 7.3 Hz, 2H), 2.38 (t, J= 7.2 Hz, 2H), 1.86 (p, J= 7.3 Hz, 2H), 1.75 (q, J = 7.0 Hz, 2H), 1.58 (p, J= 7.3 Hz, 2H), 1.43 (t, J= 7.8 Hz, 2H), 1.25 (m, 54H), 0.87 (t, J= 6.8 Hz, 6H).

[0548] 13C NMR (101 MHz, CDCL) 5 173.4, 157.2, 145.1, 129.8, 121.6, 120.3, 111.8, 77.5, 77.2, 76.8, 68.2, 62.0, 59.9, 57.3, 57.3, 52.8, 51.9, 36.3, 32.2, 32.1, 31.6, 29.8, 29.8, 29.8, 29.8, 29.7, 29.7, 29.5, 29.5, 29.5, 29.4, 26.2, 22.8, 21.8, 14.3. (.Z)-2-(Octadec-9-en-l-yloxy)-4-pentadecylbenzaldehvde:

[0549] In a 2-neck round-botom flask, equipped with a magnetic stirrer bar and reflux condenser, 2-hydroxy-4- pentadecylbenzaldehyde (2.57 g, 7.73 mmol, 1.0 equiv) was dissolved in anhydrous DMF (40 mL) under an inert atmosphere of N2 gas. Potassium carbonate (1.38 g, 10.0 mmol, 1.3 equiv) was added and the solution was stirred for 10 minutes. Thereafter, (Z)-l-bromooctadec-9-ene was added (3.31 g, 10.0 mmol, 1.3 equiv). The solution was heated at 96 °C for 18 h. Hexane (60 mL) was added to dilute the solution. Followed by the addition of water (50 mL). The layers were separated and the aqueous layer was extracted twice more using hexane (2 x 60 mL). The combined organic layers were washed with water (500 mL), then brine (500 mL) to remove all DMF. The organic layer was then dried over anhydrous MgSCL and filtered through Celite. The solvent was evaporated under reduced pressure to afford the crude product. Purification was carried out using silica gel column chromatography (2% EtOAc / hexane). The product with 84% purity was obtained as an off white solid (79% yield) and was used without further purification.

[0550] 'H NMR (300 MHz, CDCI3) 5 10.44 (s, 1H), 7.74 (d, J= 7.9 Hz, 1H), 6.82 (d, J= 7.9 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 5.43 - 5.28 (m, 2H), 4.06 (t, J= 6.4 Hz, 2H), 2.62 (t, J= 6.8 Hz, 3H), 2.07 - 1.93 (m, 4H), 1.91 - 1.76 (m, 3H), 1.62 (dd, J= 9.9, 4.9 Hz, 3H), 1.48 (t, J= 7.5 Hz, 5H), 1.40 - 1.22 (m, 64H), 0.88 (t, J= 6.7 Hz, 9H).

[0551] 13C NMR (75 MHz, CDCI3) 5 189.7, 161.9, 152.5, 130.1, 129.9, 128.3, 123.0, 120.9, 112.5, 77.6, 77.2, 76.7, 68.5, 36.8, 32.7, 32.1, 32.0, 31.2, 29.9, 29.9, 29.8, 29.8, 29.7, 29.7, 29.6, 29.5, 29.5, 29.4, 29.3, 28.6, 27.4, 27.3, 26.2, 22.8, 22.8, 14.3, 1.2.

[0552] (Z)-(2-(Octadec-9-en-l-yloxy)-4-pentadecylphenyl)methanol:

[0553] (Z)-2-(Octadec-9-en-l-yloxy)-4-pentadecylbenzaldehyde (0.84 g, 1.44 mmol, 1.0 equiv) was dissolved in a 2-neck round botom flask, under an inert atmosphere of N2 gas, using freshly-distilled THF (15 mL). To the stirred solution at room temperature, NaBH (0. 109 g, 2.88 mmol, 2 equiv) was added carefully, followed by the addition of ammonium oxalate monohydrate (0.409 g, 2.88 mmol, 2 equiv). The reaction was stirred 18 h at room temperature. The reaction flask was cooled in an ice -water bath, then water (30 mL) was added carefully. Ethyl acetate was used to extract the aqueous layer (3 x 60 mL). The combined organic layers were dried over anhydrous MgSCL and filtered through celite. The solvent was evaporated under reduced pressure to afford the crude product which was purified using silica gel flash chromatography. The pure product was obtained in a 78% yield.

[0554] 'H NMR (300 MHz, CDC13) 5 7.14 (d, J= 7.5 Hz, 1H), 6.78 - 6.66 (m, 2H), 5.42 - 5.30 (m, 2H), 4.65 (d, J= 6.2 Hz, 2H), 4.01 (t, J= 6.5 Hz, 2H), 2.58 (dd, J= 8.8, 6.7 Hz, 2H), 2.38 (dd, J= 7.4, 5.7 Hz, 1H), 2.00 (dt, J= 15.2, 5.3 Hz, 4H), 1.87 - 1.74 (m, 2H), 1.58 (d, J= 7.2 Hz, 2H), 1.47 (t, J= 7.9 Hz, 2H), 1.40 - 1.23 (m, 48H), 0.92 - 0.83 (m, 7H).

[0555] 13C NMR (75 MHz, CDCI3) 5 157.2, 144.3, 130.6, 130.1, 129.9, 128.8, 126.5, 120.5, 111.5, 77.6, 77.2, 76.7, 68.0, 62.5, 36.3, 32.8, 32.1, 32.1, 31.7, 29.9, 29.9, 29.8, 29.8, 29.7, 29.7, 29.6, 29.5, 29.5, 29.4, 27.4, 27.3, 26.3, 22.8, 22.8, 14.3, 1.2.

[0556] (Z)-2-(octadec-9-en-l-yloxy)-4-pentadecylbenzyl 4-chlorobutanoate:

[0557] In a 2-neck round bottom flask, (Z)-(2-(octadec-9-en-l-yloxy)-4-pentadecylphenyl)methanol (0.200 g, 0.34 mmol, 1.0 equiv) was dissolved in freshly-distilled CH2CI2 (7 mb) under an inert atmosphere of N2 gas. The reaction flask was cooled in ice and the 4-chlorobutanoyl chloride (0.05 mb, 0.44 mmol, 1.3 equiv), followed by triethylamine (0.07 mb, 0.51 mmol, 1.5 equiv) was added carefully. The reaction as allowed to reach room temperature and was stirred at room temperature for 2 h. Completion of the reaction was confirmed using TLC analysis (5% EtOAc / hexane). A saturated aqueous solution of NaHCCf (25 mb) was added carefully to the reaction mixture. The material was transferred to a separating funnel and extracted using CH2CI2 (40 mb), followed by two more extractions using hexane (2 x 50 mb). The combined organic extracts were washed with acetonitrile (2 x 20 mb). The organic hexane layer was collected, dried over anhydrous MgSCE, filtered through Celite and evaporated to dryness under reduced pressure. The product was purified using silica gel column chromatography (2% EtOAc / hexane). The pure product was obtained as a colourless oil (87% yield).

[0558] 'H NMR (300 MHz, CDCI3) 5 7.20 (d, J= 7.6 Hz, 1H), 6.75 (dd, J= 7.6, 1.5 Hz, 1H), 6.69 (d, J= 1.5 Hz, 1H), 5.37 (dt, J= 10.0, 4.3 Hz, 2H), 5.15 (s, 2H), 3.97 (t, J= 6.4 Hz, 2H), 3.60 (t, J= 6.4 Hz, 2H), 2.56 (dt, J= 14.2, 7.3 Hz, 4H), 2.11 (p, J = 6.8 Hz, 2H), 2.06 - 1.94 (m, 4H), 1.84 - 1.72 (m, 2H), 1.61 (d, J= 7.3 Hz, 2H), 1.51 - 1.41 (m, 2H), 1.29 (d, J= 16.2 Hz, 47H), 0.93 - 0.84 (m, 7H).

[0559] 13C NMR (75 MHz, CDCI3) 5 172.8, 157.3, 145.2, 130.6, 130.1, 130.0, 121.5, 120.3, 111.8, 77.6, 77.2, 76.7, 68.2, 62.3, 44.2, 36.3, 32.8, 32.1, 32.1, 31.6, 31.5, 29.9, 29.9, 29.8, 29.8, 29.8, 29.7, 29.6, 29.5, 29.5, 29.3, 27.9, 27.4, 26.2, 22.8, 14.3, 1.2. (Z)-2-(octadec-9-en-l-yloxy)-4-Dentadecylbenzyl 4-(4-(2-hvdroxyethyl)DiDerazin-l-yl)butanoate (also

[0560] AG-002):

[0561] (Z)-2-(octadec-9-en-l-yloxy)-4-pentadecylbenzyl 4-chlorobutanoate (0.185 g, 0.27 mmol, 1.0 equiv), potassium carbonate (0.111 g, 0.80 mmol, 3 equiv), tetrabutylammonium iodide (0.093 g, 0.25 mmol, 0.9 equiv) and 2-hydroxyethylpiperazine (0.1 mL, 0.80 mmol, 3 equiv) were placed in a microwave vessel, equipped with a magnetic stirrer bar. Freshly distilled toluene (5 mL) was added last. The vessel was sealed and the reaction mixture was irradiated for 2 h at 140 °C (180 W). Hexane (50 mL) and water (50 mL) were used to transfer the material from a microwave vessel to a separating funnel. The organic and aqueous layers were separated. The aqueous layer was then extracted twice more using hexane (2 x 50 mL). The combined organic extracts were dried over anhydrous MgSCL and filtered through Celite and evaporated to dryness. The crude product was a colourless oil. Purification was carried out using automated flash silica column chromatography (12 g column, 0-5% MeOH / C LCL, gradient elution, over 25 minutes). The pure product was obtained as a colourless oil (15% yield).

[0562] 'H NMR (400 MHz, CDC13) 5 7.19 (d, J= 7.6 Hz, 1H), 6.73 (dd, J= 7.6, 1.5 Hz, 1H), 6.67 (d, J= 1.5 Hz, 1H), 5.41 - 5.30 (m, 2H), 5.13 (s, 2H), 3.95 (t, J= 6.5 Hz, 2H), 3.65 (t, J= 5.3 Hz, 2H), 3.29 (s, 2H), 2.57 (dq, J= 20.6, 12.8, 9.0 Hz, 11H), 2.38 (q, J= 7.5 Hz, 4H), 1.98 (dq, J= 16.6, 5.2, 4.5 Hz, 3H), 1.84 (p, J= 7.4 Hz, 2H), 1.76 (p, J = 6.6 Hz, 2H), 1.58 (p, J= 7.1 Hz, 2H), 1.43 (q, J = 7.2 Hz, 3H), 1.28 (m, 48H), 0.87 (t, J= 6.8 Hz, 7H).

[0563] 13C NMR (101 MHz, CDCh) 5 173.5, 157.2, 145.0, 130.6, 130.4, 130.1, 129.9, 129.7, 121.7, 120.2, 111.7, 77.5, 77.2, 76.8, 68.1, 61.9, 59.5, 57.6, 57.5, 52.9, 52.7, 36.3, 32.7, 32.3, 32.0, 32.0, 31.9, 31.9, 31.6, 29.9, 29.8, 29.8, 29.8, 29.7, 29.6, 29.6, 29.5, 29.5, 29.5, 29.4, 29.4, 29.4, 29.3, 29.3, 29.1, 29.0, 27.3, 26.2, 22.8, 22.1, 14.2.

[0564] 2-ethylhexyl 8-(3-((2-ethylhexyl)oxy)phenyl)octanoate:

[0565] To a stirring solution of 8-(3-hydroxyphenyl)octanoic acid (1.31 g, 5.54 mmol), in anhydrous DMF (50mL) was added 2-ethylhexyl bromide (2.50 g, 12.95 mmol, 2.3eq.), followed by K2CO3 (3.0 g, 21.7 mmol) and the resultant suspension was heated to 90°C for 16 hours. After cooling to room temperature, water (lOOmL) was added, and the resiude was extracted into hexane (2 x 50mL). The combined organic extracts were then washed with water (2 x lOOmL), brine (lOOmL), dried over MgSCh. and the solvent removed in vacuo to provide the crude product which was purified by column chromatography (SiO2) with EtOAc / Hexane (0- 5% gradient elution) over 15 minutes to afford the pure product 2-ethylhexyl 8-(3-((2- ethylhexyl)oxy)phenyl)octanoate (1.98g, 4.30 mmol, 78%) as a colorless oil.

[0566] 'H NMR (300 MHz, CDC13) 5 7.21 - 7.11 (m, 1H), 6.78 - 6.66 (m, 3H), 3.98 (d, J= 5.8 Hz, 2H), 3.82 (d, J = 5.7 Hz, 2H), 2.56 (t, J = 7.7 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 1.77 - 1.21 (m, 31H), 0.96 - 0.82 (m, 13H).

[0567] 8-(3-((2-ethylhexyl)oxy)-5-hvdroxyDhenyl)octanoate:

[0568] To a 50 mL capacity sealed tube was added [Ir(OMe)(l,5-cod)]2(10.0 mg, 0.016 mmol), 4,4'-Bis(tert-butyl)- 2,2'-bipyridine (21 mg, 0.08 mmol) ,bis(pinacolato)diboron, (811 mg, 3.19 mmol). The flask was then flushed with argon for 5 minutes, as the solids were stirred. Then, 2-ethylhexyl 8-(3-((2- ethylhexyl)oxy)phenyl)octanoate (1.20 g, 2.60 mmol) was added and the tube was again flushed with Argon gas for 5 min. Thereafter, 3 m hexane was added to improve mixing. The tube was then sealed and heated with stirring to 90°C for 16 h, after which time NMR analysis showed the reaction was complete. Then, after cooling to 0 °C, ethanol (20mL) was added dropwise with stirring, and the solution was subsequently allowed to warm to room temperature. Hydrogen peroxide urea (3.31g, 35. Immol) was then added portionwise over a period of 15 minutes. The resultant suspension was then stirred at room temperature for one hour, at which point NMR analysis of the crude mixture confirmed reaction completion. The reaction was poured into 200 m ice water, with stirring, and the product was extracted using Hexane (3 x 100 mb). The combined organic extracts were washed with brine (150 mb), dried over MgSO4, filtered, and the volatiles removed in-vacuo to provide the crude product, which was purified by column chromatography ( Si O2) with EtOAc / Hexane (0-5% gradient elution) over 15 minutes to 2-ethylhexyl 8-(3-((2-ethylhexyl)oxy)-5- hydroxyphenyl)octanoate (1.14 g, 2.39 mmol, 92%) as an amber oil.

[0569] 'H NMR (400 MHz, CDC13) 5 6.31 (t, J= 1.8 Hz, 1H), 6.26 - 6.23 (m, 2H), 5.35 (s, 1H), 3.99 (dd, J= 5.8, 1.5 Hz, 2H), 3.78 (dd, J= 5.8, 1.4 Hz, 2H), 2.49 (t, J= 7.7 Hz, 2H), 2.31 (t, J= 7.5 Hz, 2H), 1.73 - 1.23 (m, 31H), 0.95 - 0.85 (m, 12H). 2-ethylhexyl 8-(3-((2-ethylhexyl)oxy)-5-(2-hvdroxyethoxy)Dhenyl)octanoate:

[0570] To 2-ethylhexyl 8-(3-((2-ethylhexyl)oxy)-5-hydroxyphenyl)octanoate (1.00 g, 2.10 mmol) in anhydrous DMF (5.0 mL) was added ethylene carbonate (0.203g, 2.30 mmol) , followed by K2CO3 (0.30 g, 2.17 mmol). The resultant suspension was heated to 130-140°C for 1 h, at which point TLC confirmed reaction was complete. The reaction was then allowed to reach room temperature and hexane (20 mL) was added, followed by water (20 mL). The phases were separated and the aqueous phase was re-extracted with hexane (2 x 20mL). The combined organic extracts were washed with water (2 x 20mL), dried over MgSCL, filtered, and the solvent removed in-vacuo to provide the crude product 2-ethylhexyl 8-(3-((2-ethylhexyl)oxy)-5-(2- hydroxyethoxy)phenyl)octanoate (1.06 g, 2.04 mmol, 97%) as an amber oil which was used without subsequent purification.

[0571] 'H NMR (400 MHz, CDCI3) 5 6.36 (s, 1H), 6.33 (s, 1H), 6.31 (t, J= 2.3 Hz, 1H), 4.09 - 4.03 (m, 2H), 3.98 (dd, J= 5.8, 1.8 Hz, 2H), 3.96 - 3.91 (m, 2H), 3.80 (dd, J= 5.7, 1.7 Hz, 2H), 2.52 (t, J= 7.8 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 2.03 (s, 1H), 1.74 - 1.25 (m, 31H), 0.94 - 0.85 (m, 12H).

[0572] To a stirring solution of 2-hydroxy-6-pentadecylbenzoic acid (1.41 g, 4.04 mmol), in anhydrous DMF (50mL) was added 1-bromooctane (2.43 g, 12.60 mmol), followed by K2CO3 (3.0 g, 21.7 mmol) and the resultant suspension was heated to 100°C for 16 hours. After cooling to room temperature, water (lOOmL) was added, and the residue was extracted into hexane (2 x 50mL). The combined organic extracts were then washed with water (2 x 100mL), brine (lOOmL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product which was taken up into boiling acetone, to which was added ethanol, until the solution became turbid. The solution was then left in a freezer overnight, after which time a dense crystalline precipitate had formed. The suspension was filtered while cold, and washed with freezer-cooled methanol (2 x 20mL). The resultant solid soon melted once it reached room temperature, and the filtration funnel was rinsed with chloroform to obtain a solution of the collected product. After removal of the solvent, this provided octyl 2-(octyloxy)-6-pentadecylbenzoate (1.78 g, 3.10 mmol, 77%) as a colorless oil. 'H NMR (300 MHz, CDC13) 5 7.22 (t, J= 8.0 Hz, 1H), 6.78 (d, J= 7.4 Hz, 1H), 6.72 (d, J= 8.2 Hz, 1H), 4.30 (t, J= 6.7 Hz, 2H), 3.95 (t, J= 6.5 Hz, 2H), 2.60 - 2.47 (m, 2H), 1.74 (p, J= 6.5 Hz, 4H), 1.63 - 1.52 (m, 2H), 1.47 - 1.37 (m, 4H), 1.37 - 1.21 (m, 40H), 0.92 - 0.83 (m, 9H). octyl 4-hvdroxy-2-(octyloxy)-6-Dentadecylbenzoate:

[0573] To a 50 mL capacity sealed tube was added [Ir(OMe)(l,5-cod)]2(10.0 mg, 0.016 mmol), 4,4'-Bis(tert-butyl)- 2,2'-bipyridine (21 mg, 0.08 mmol), bis(pinacolato)diboron, (820 mg, 3.26 mmol). The flask was then flushed with argon for 5 min. as the solids were agitated. Then octyl 2-(octyloxy)-6-pentadecylbenzoate (1.56 g, 2.71 mmol) was added as a solution in hexane (5mL), and the tube was again flushed with argon gas for 5 min. The tube was then sealed and heated with stirring to 90°C for 3 h, after which time NMR analysis showed the reaction was complete . Then, after cooling to 0 °C, Ethanol (20mL) was added dropwise with stirring. Then, the solution was allowed to warm to room temperature and Hydrogen peroxide urea (3.50 g, 37.2mmol) was added portion-wise over a period of 15 minutes. The resultant suspension was then stirred at room temperature for one hour, at which point NMR analysis of the crude mixture confirmed reaction completion. The reaction was poured into 200 mL ice water, with stirring, and the product was extracted using hexane (3 x 100 mL). The combined organic extracts were washed with brine (150 mL), dried over MgSCL, filtered, and the volatiles removed in-vacuo to provide the crude product, which was purified by column chromatography (SiCL) with EtOAc / Hexane (0-5% gradient elution) over 15 minutes to octyl 4-hydroxy-2-(octyloxy)-6-pentadecylbenzoate (1.37 g, 2.32 mmol, 86%) as a colorless oil.

[0574] 'H NMR (300 MHz, CDCI3) 5 6.21 (s, 2H), 5.50 (s, 1H), 4.27 (t, J= 6.7 Hz, 2H), 3.85 (t, J= 6.5 Hz, 2H), 2.52 - 2.44 (m, 2H), 1.70 (tq, J= 6.4, 3.2 Hz, 4H), 1.53 (p, J = 7.3 Hz, 2H), 1.44 - 1.21 (m, 44H), 0.92 - 0.83 (m, 9H). octyl 4-(2-bromoethoxy)-2-(octyloxy)-6-Dentadecylbenzoate:

[0575] To 4-hydroxy-2-(octyloxy)-6-pentadecylbenzoate (1.29 g, 2.19 mmol) (1.00 g, 2.10 mmol, 92%) in anhydrous DME (5.0 mL) was added 1,2-dibromoethane (2.0 mL, ca. 4.36g, 23.2 mmol) , followed by K2CO3 (0.420 g, 3.03 mmol). The resultant suspension was heated to 90°C for 16 h, after which time the reaction was allowed to reach room temperature and hexane (20 mL) was added, followed by water (20 mL). The phases were separated and the aqueous phase was re-extracted with hexane (2 x 20mL). The combined organic extracts were washed with water (2 x 20mL), acetonitrile (2 x 20mL), and once more with water (20 mL), and subsequently dried over MgSCL, fdtered, and the solvent removed in-vacuo to provide a crude residue still contaminated with residual 1,2-dibromoethane. This was removed by azeotropic co-distillation using hexane (3 x 100mL) to afford octyl 4-(2-bromoethoxy)-2-(octyloxy)-6- pentadecylbenzoate (1.24 g, 1.96 mmol, 90%) as a pale yellow oil, which was used without subsequent purification.

[0576] 'H NMR (400 MHz, CDC13) 5 6.33 - 6.28 (m, 2H), 4.30 - 4.23 (m, 4H), 3.92 (t, J= 6.5 Hz, 2H), 3.62 (t, J = 6.3 Hz, 2H), 2.53 (t, J = 7.9 Hz, 2H), 1.77 - 1.67 (m, 4H), 1.60 - 1.50 (m, 2H), 1.45 - 1.36 (m, 4H), 1.34 - 1.20 (m, 40H), 0.91 - 0.85 (m, 9H).

[0577] 3-pentadecylphenyl pivalate:

[0578] To a stirring solution of 3 -pentadecylphenol (21.0 g, 68.9 mmol) in triethylamine (10.12g, 100 mmol) held at 0°C, under an atmosphere of argon gas was added pivalic anhydride (13.00 g, 69.8 mmol), followed by 4-(dimethylamino)pyridine (0.053 mg, 0.43 mmol). The solution was stirred for 10 minutes at room temperature, and subsequently heated to reflux (external temperature of ca. 100°C) for 4 hours, until NMR analysis showed the reaction to be complete. The solution was then allowed to cool to room temperature, and was subsequently quenched with water (200 mL) and stirred for a further 10 minutes. The biphasic mixture was then extracted into Hexane (200 mL), and washed with aqueouslM HC1 (2 x lOOmL), water (lOOmL), followed by a saturated aqueous solution of NaHCO, (200mL), and brine (lOOmL). The organic phase was then dried over MgSCL, and the volatiles removed to provide the crude product as an amber semisolid. This residue was then recrystalized using boiling acetonitrile, with overnight cooling in a freezer. The solid suspension was subsequently fdtered while cold, and washed with cold acetonitrile (2 x 50mL). After drying, this provided the desired product 3-pentadecylphenyl pivalate (23.22 g, 59.75 mmol, 87% yield) as a white solid. Drying of the supernatant liquid and subsequent recrystallization from a minimum oof acetonitrile provided an additional batch of the product (3.10 g, 7.98 mmol, 11% yield).

[0579] 'H NMR (300 MHz, CDC13) 5 7.30 - 7.22 (m, 1H), 7.02 (d, J= 7.7 Hz, 1H), 6.90 - 6.82 (m, 2H), 2.59 (t, J= 7.8 Hz, 2H), 1.67 - 1.53 (m, 2H), 1.35 (s, 9H), 1.32 - 1.20 (m, 24H), 0.92 - 0.83 (m, 3H). 3-Dentadecyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)Dhenyl pivalate:

[0580] To a 50 mL capacity sealed tube was added [Ir(OMe)(l,5-COD)]2 (104.0 mg, 0.157 mmol, 0.8 mol%), 3,4,7,8-Tetramethyl-l,10-phenanthroline (150 mg, 0.64 mmol), bis(pinacolato)diboron, (8.00 g, 31.5 mmol). The flask was then flushed with argon for 5 min. as the solids were stirred. Then, 3 -pentadecylphenyl pivalate (8.05 g, 20.71 mmol) was added and the tube was again flushed with argon gas for 5 min. Thereafter, 3 mL hexane was added to improve mixing. The tube was then sealed and heated with stirring to 110°C for 1 h, after which time NMR analysis showed the reaction was complete. Then, after cooling to 0 °C, acetone (lOmL) was added, followed by the dropwise addition of ethanol until bubbling ceased and a white solid precipitate had formed, (quenching residual HBP in results in hydrogen gas evolution), Then, methanol (50 mL) was added, which induced the further precipitation. After standing for 30 minutes, the resultant precipitate was collected by filtration, washed with cold methanol (2 x 50 mL) and dried to provide 3- pentadecyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl pivalate (8.91 g, 17.31 mmol, 84 % yield) as a white crystalline solid.

[0581] 'H NMR (300 MHz, CDC13) 5 7.47 (s, 1H), 7.28 (d, J= 2.4 Hz, 1H), 6.99 - 6.93 (m, 1H), 2.60 (t, J= 7.9 Hz, 2H), 1.66 - 1.54 (m, 2H), 1.37 - 1.23 (m, 46H), 0.88 (t, J= 6.7 Hz, 3H).

[0582] 3-hydroxy-5-pentadecylphenyl pivalate:

[0583] To a stirring suspension of 3-pentadecyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl pivalate (7.55 g, 14.70 mmol) 100 mL ethanol was added urea hydrogen peroxide (5.60g, 59.80 mmol), portion wise. The resultant suspension was then stirred at room temperature for two hours, at which point NMR analysis of the crude mixture confirmed reaction completion. The reaction was poured into 200 mL ice water, with stirring, and the product was extracted using chloroform (3 x 100 mL). The combined organic extracts were washed with brine (150 mL), dried over MgSCL, filtered, and the volatiles removed in-vacuo to provide the product, 3 -hydroxy-5 -pentadecylphenyl pivalate (5.93 g, 14.69 mmol, quant.) as a colorless oil which solidified overnight to form an amorphous white solid. The material thus obtained was used without further purification, though it can be recrystallized from boiling hexane subsequently stored in the freezer overnight. 'H NMR (400 MHz, CDC13) 5 6.50 - 6.46 (m, 1H), 6.45 - 6.41 (m, 1H), 6.34 (t, J= 2.3 Hz, 1H), 5.40 (s, 1H), 2.51 (t, J= 7.8 Hz, 2H), 1.56 (p, J= 7.3 Hz, 2H), 1.34 (s, 9H), 1.31 - 1.21 (m, 24H), 0.88 (t, J= 6.8 Hz, 3H). l-(octan-2-yloxy)-3-Dentadecylbenzene:

[0584] A stirring solution 3 -pentadecylphenol (1.44 g, 4.73 mmol), octan-2ol (0.930 g, 7.14 mmol) and triphenylphosphine (1.89 g, 7.2 mmol) in anhydrous THF (50 mL) was stirred at 0 °C in an ice-bath, under an argon atmosphere. A solution of diisopropyl azodicarboxylate (1.2 mL, 1.24 g, 6.12 mmol) in anhydrous THF (10 mL) was then added drop-wise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was then removed in-vacuo and the residue which was suspended in lOOmL hexane and stirred for 10 minutes. The resultant precipitate was removed by filtration, washed with 50 mL hexane, and the combined hexane extracts were stripped of solvent and the residue was purified by column chromatography (SiCL) with EtOAc / Hexane (0-5% gradient elution) over 15 minutes to afford the product l-(octan-2-yloxy)-3-pentadecylbenzene (1.15 g, 2.76 mmol, 58%) as a colorless oil.

[0585] 'H NMR (300 MHz, CDCI3) 5 7.21 - 7.11 (m, 1H), 6.78 - 6.65 (m, 3H), 4.33 (h, J= 6.0 Hz, 1H), 2.61 - 2.49 (m, 2H), 1.78 - 1.66 (m, 1H), 1.66 - 1.51 (m, 3H), 1.51 - 1.14 (m, 38H), 0.95 - 0.80 (m, 6H).

[0586] 3-(octan-2-yloxy)-5-DentadecylDhenol:

[0587] To a 50 mL capacity sealed tube was added [Ir(OMe)(l,5-COD)]2 (10.0 mg, 0.016 mmol), 4,4'-Bis(tert- butyl)-2,2'-bipyridine (21 mg, 0.08 mmol) ,bis(pinacolato)diboron, (810 mg, 3.19 mmol). The flask was then flushed with argon for 5 min. as the solids were agitated. Then, l-(octan-2-yloxy)-3 -pentadecylbenzene (1.05 g, 2.52 mmol) was added as a concentrated solution in hexane (2 mL, followed by a 2 mL rinse of the storage flask) and the tube was again flushed with argon gas for 5 min. The tube was then sealed and heated with stirring to 90°C for 16 h, after which time NMR analysis showed the reaction was complete. Then, after cooling to 0 °C, ethanol (20 mL) was added dropwise with stirring and the solution was allowed to warm to room temperature. Hydrogen peroxide urea (3.03 g, 32.2 mmol) was then added portion-wise over a period of 15 minutes. The resultant suspension was then stirred at room temperature for one hour, at which point NMR analysis of the crude mixture confirmed reaction completion. The reaction was poured into 200 mL ice water, with stirring, and the product was extracted using Hexane (3 x 100 mL). The combined organic extracts were washed with brine (150 mL), dried over MgSCL, fdtered, and the volatiles removed in-vacuo to provide the crude product, which was purified by column chromatography (SiCL) with EtOAc / Hexane (0-10% gradient elution) over 15 minutes to 3 -(octan-2-yloxy)-5 -pentadecylphenol (1.02 g, 2.35 mmol, 93%) as an amber oil.

[0588] 'H NMR (400 MHz, CDC13) 5 6.31 (s, 1H), 6.24 - 6.19 (m, 2H), 4.62 (s, 1H), 4.29 (h, J= 6.1 Hz, 1H), 2.49 (t, J= 7.8 Hz, 2H), 1.76 - 1.66 (m, 1H), 1.61 - 1.51 (m, 4H), 1.34 - 1.22 (m, 36H), 0.91 - 0.85 (m, 6H).

[0589] 2-(3-(octan-2-yloxy)-5-pentadecylphenoxy)ethanol:

[0590] To 3 -(octan-2-yloxy)-5 -pentadecylphenol (0.880 g, 2.03 mmol) in anhydrous DMF (5.0 mL) was added ethylene carbonate (0.221, 2.51 mmol) , followed by K2CO3 (0.30 g, 2.17 mmol). The resultant suspension was heated to 130-140°C for 3 h, at which point TLC showed reaction was complete. The reaction was then allowed to reach room temperature and water (20 mL) was added, followed by hexane (20 mL). The phases were separated and the aqueous phase was re-extracted with hexane (2 x 20mL). The combined organic extracts were washed with water (2 x 20mL), dried over MgSCL. fdtered, and the solvent removed in-vacuo to provide the crude product 2-(3-(octan-2-yloxy)-5-pentadecylphenoxy)ethanol (1.00 g, 2.10 mmol, ca. quant.) as an amber oil which was used without subsequent purification.

[0591] 'H NMR (300 MHz, CDCI3) 5 6.34 (dd, J= 3.5, 2.2 Hz, 2H), 6.29 (t, J= 2.3 Hz, 1H), 4.31 (h, J= 6.1 Hz, 1H), 4.09 - 4.00 (m, 2H), 3.99 - 3.89 (m, 2H), 2.56 - 2.47 (m, 2H), 1.99 (t, J= 6.2 Hz, 1H), 1.78 - 1.66 (m, 1H), 1.64 - 1.20 (m, 39H), 0.91 - 0.84 (m, 6H).

[0592] 3-(oct-3-vn-l-yloxy)-5-pentadecylphenyl pivalate:

[0593] A stirring solution of 3 -hydroxy-5 -pentadecylphenyl pivalate (1.03 g, 2.55 mmol), oct-3-yn-l-ol (0. 442g, 3.50 mmol) and triphenylphosphine (0.918 g, 3.50 mmol) in anhydrous THF (50 mL) was stirred at 0 °C in an ice-bath, under an argon atmosphere. A solution of diisopropyl azodicarboxylate (1.0 mL, 1.03 g, 5.10 mmol) in anhydrous THF (10 mL) was then added drop-wise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was then removed in-vacuo and the residue which was suspended in 100 mL hexane and stirred for 10 min. The resultant precipitate was removed by filtration, washed with 50 mL hexane, and the combined hexane extracts were stripped of solvent to provide the crude product 3-(oct-3-yn-l-yloxy)-5-pentadecylphenyl pivalate (1.23g, ca. 2.41mmol) which was used without subsequent purification.

[0594] 'H NMR (300 MHz, CDC13) 5 6.60 (s, 1H), 6.48 (s, 1H), 6.43 (t, J= 2.2 Hz, 1H), 4.01 (t, J= 7.3 Hz, 2H), 2.66 - 2.58 (m, 2H), 2.55 (t, J= 7.8 Hz, 2H), 2.19 - 2.12 (m, 2H), 1.64 - 1.52 (m, 2H), 1.52 - 1.37 (m, 4H), 1.37 - 1.31 (m, 12H), 1.31 - 1.19 (m, 26H), 0.95 - 0.83 (m, 6H).

[0595] 3-(oct-3-vn-l-yloxy)-5-pentadecylphenol:

[0596] To a stirring suspension of 3 -(oct-3 -yn-l-yloxy) -5 -pentadecylphenyl pivalate (1.03g, 2.00mmol) in ethanol (lOOmL) was added a 10% Wt. aqueous solution of potassium hydroxide (50mL). The resultant suspension was stirred for 4 hours, at which point the solution had become homogenous. Then, most of the ethanol was removed in-vacno. and the residue was made acidic with IM aqueous HC1 (200mL), and extracted into ethyl acetate (3 x 50mL). The combined organic extracts were washed with water (lOOmL), brine (lOOmL), dried over MgSCfi, filtered, and the volatiles removed in-vacuo to provide an oily residue which was recrystallized from hexane to afford the pure product 3 -(oct-3 -yn-l-yloxy) -5 -pentadecylphenol (0.620g, 1.45mmol, 73% yield) as a white solid.

[0597] 'H NMR (400 MHz, CDC13) 5 6.35 - 6.32 (m, 1H), 6.26 (t, J= 1.8 Hz, 1H), 6.23 (t, J= 2.3 Hz, 1H), 4.69 (s, 1H), 4.00 (t, J = 7.3 Hz, 2H), 2.62 (tt, J= 7.3, 2.4 Hz, 2H), 2.50 (t, J= 7.7 Hz, 2H), 2.16 (ddt, J= 7.1, 4.8, 2.4 Hz, 2H), 1.57 (p, J= 7.2 Hz, 2H), 1.51 - 1.35 (m, 4H), 1.34 - 1.18 (m, 25H), 0.94 - 0.83 (m, 6H).

[0598] 2-(3-(oct-3-vn-l-yloxy)-5-pentadecylphenoxy)ethan-l-ol:

[0599] To 3-(oct-3-yn-l-yloxy)-5-pentadecylphenol (0.580 g, 1.36 mmol) in anhydrous DMF (5.0 mL) was added ethylene carbonate (0.203, 2.30 mmol) , followed by K2CO3 (0.30 g, 2.17 mmol). The resultant suspension was heated to 130-140°C for 3 h, at which point TLC showed reaction was complete. The reaction was then allowed to reach room temperature and water (20 mL) was added, followed by hexane (20 mL). The phases were separated and the aqueous phase was re-extracted with hexane (2 x 20mL). The combined organic extracts were washed with water (2 x 20mL), dried over MgSCfi. filtered, and the solvent removed in-vacuo to provide the crude product 2-(3 -(oct-3 -yn-l-yloxy)-5-pentadecylphenoxy)ethan-l-ol (0.615g, 1.30 mmol, 96%) as an amber oil which was used without subsequent purification. 'H NMR (300 MHz, CDC13) 5 6.36 (d, J= 2.3 Hz, 2H), 6.32 (t, J= 2.3 Hz, 1H), 4.09 - 3.97 (m, 4H), 3.94 (q, J= 4.8 Hz, 2H), 2.62 (tt, J= 1.3, 2.4 Hz, 2H), 2.53 (t, J= 7.7 Hz, 2H), 2.16 (ddt, J = 6.9, 4.7, 2.4 Hz, 2H), 2.05 (t, J = 6.0 Hz, 1H), 1.58 (p, J = 7.5 Hz, 2H), 1.52 - 1.35 (m, 4H), 1.35 - 1.19 (m, 25H), 0.96 - 0.83 (m, 6H).

[0600] 2-(3-(oct-3-vn-l-yloxy)-5-DentadecylDhenoxy)ethyl methanesulfonate:

[0601] To an ice-cooled stirring solution of 2-(3-(oct-3-yn-l-yloxy)-5-pentadecylphenoxy)ethan-l-ol (0.598 g, 1.26 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.30 mL, 0.44 g, 3.87 mmol), followed by triethylamine (0.8 mL, 0.550 g , 5.88 mmol) . The resultant solution was allowed to warm to room temperature and after 1 hour, TLC confirmed the reaction to be complete and the solution was quenched with water (10 mL). The dichloromethane was removed in-vacuo and the aqueous suspension was subsequently extracted into hexane (2 x 50mL). The combined organic extracts were then washed with an aqueous IM HC1 solution (50mL), followed by water (50mL) and then a saturated solution of sodium bicarbonate (2 x 50 mL) and over MgSCL. After filtration, the solvent removed in vacuo to provide the crude product 2-(3-(oct-3-yn-l-yloxy)-5-pentadecylphenoxy)ethyl methane sulfonate (0.667g, 1.21mmol, 96%), which was used without further purification.

[0602] 'H NMR (400 MHz, CDCI3) 5 6.39 (s, 1H), 6.33 (s, 1H), 6.29 (s, 1H), 4.60 - 4.50 (m, 2H), 4.25 - 4.17 (m, 2H), 4.01 (t, J= 6.5 Hz, 2H), 3.09 (s, 3H), 2.62 (t, J= 7.4 Hz, 2H), 2.52 (t, J= 8.0 Hz, 2H), 2.17 (t, J= 7.0 Hz, 2H), 1.64 - 1.53 (m, 2H), 1.53 - 1.37 (m, 5H), 1.37 - 1.20 (m, 24H), 0.96 - 0.84 (m, 6H). i-3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-

[0603] To a stirring solution of 3 -hydroxy-5 -pentadecylphenyl pivalate (1.00 g, 2.50 mmol), (£)-l-bromo-3,7- dimethylocta-2,6-diene (0.607g, 2.80 mmol) in anhydrous DMF (50mL) was added K2CO3 (3.0 g, 21.7 mmol) and the resultant suspension was heated to 90°C for 16 hours. After cooling to room temperature, water (lOOmL) was added, and the residue was extracted into hexane (2 x 50mL). The combined organic extracts were then washed with water (2 x lOOmL), brine (lOOmL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product which was purified by column chromatography ( Si O2) with EtOAc / Hexane (0-5% gradient elution) over 15 minutes to afford the pure product (£)-3-((3,7-dimethylocta- 2,6-dien-l-yl)oxy)-5 -pentadecylphenyl pivalate (1.01g, 1.86 mmol, 74%) as a colorless oil. 'H NMR (300 MHz, CDC13) 5 6.63 - 6.58 (m, 1H), 6.47 (t, J= 1.8 Hz, 1H), 6.43 (t, J= 2.2 Hz, 1H), 5.48 (t, J= 6.6 Hz, 1H), 5.15 - 5.04 (m, 1H), 4.49 (d, J= 6.7 Hz, 2H), 2.55 (t, J= 7.8 Hz, 2H), 2.20 - 2.02 (m, 4H), 1.72 (s, 3H), 1.68 (s, 3H), 1.63 - 1.52 (m, 5H), 1.36 - 1.32 (m, 12H), 1.25 (s, 30H), 0.90 - 0.84 (m, 3H).

[0604] (E)-3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-DentadecylDhenol:

[0605] To a stirring suspension of (E)-3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-pentadecylphenyl pivalate (0.775 g, 1.44 mmol) in ethanol (lOOmL) was added a 10% Wt. aqueous solution of potassium hydroxide (50mL). The resultant suspension was stirred for 4h, at which point the solution had become homogenous. Then, most of the ethanol was removed in-vacno. and the residue was made acidic with aqueous IM HC1 (200mL), and extracted into ethyl acetate (3 x 50mL). The combined organic extracts were washed with water (100 mL), brine (100 mL), dried over MgSCh. filtered, and the volatiles removed in-vacuo to afford the product (£)-3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-pentadecylphenol (0.660 g, 1.45 mmol, quant.) as an amber oil which slowly solidified upon storage.

[0606] 'H NMR (300 MHz, CDCI3) 5 6.37 (t, J= 1.8 Hz, 1H), 6.27 (d, J= 1.8 Hz, 2H), 5.50 (td, J= 6.6, 1.3 Hz, 1H), 5.17 - 5.07 (m, 1H), 4.85 (s, 1H), 4.51 (d, J= 6.6 Hz, 2H), 2.56 - 2.48 (m, 2H), 2.22 - 2.04 (m, 4H), 1.75 (s, 3H), 1.70 (s, 3H), 1.63 (s, 5H), 1.39 - 1.23 (m, 26H), 0.94 - 0.88 (m, 3H).

[0607] (E)-2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-DentadecylDhenoxy)ethan-l-ol:

[0608] To (E)-3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-pentadecylphenol (0.650 g, 1.43 mmol) in anhydrous DMF (5.0 mL) was added ethylene carbonate (0.205, 2.33 mmol) , followed by K2CO3 (0.30 g, 2.17 mmol). The resultant suspension was heated to 130-140°C for 3 h, at which point TLC showed reaction was complete. The reaction was then allowed to reach room temperature and water (20 mL) was added, followed by hexane (20 mL). The phases were separated and the aqueous phase was re-extracted with hexane (2 x 20mL). The combined organic extracts were washed with water (2 x 20mL), dried over MgSCL, filtered, and the solvent removed in-vacuo to provide the crude product (£)-2-(3-((3,7-dimethylocta-2,6-dien-l- yl)oxy)-5-pentadecylphenoxy)ethan-l-ol (0.670 g, 1.34 mmol, 94%) as an amber oil which was used without subsequent purification. 'H NMR (300 MHz, CDC13) 5 6.38 (d, J= 1.9 Hz, 1H), 6.35 (d, J= 1.4 Hz, 1H), 6.33 (t, J = 2.3 Hz, 1H),

[0609] 5.53 - 5.45 (m, 1H), 5.15 - 5.03 (m, 1H), 4.50 (d, J= 6.6 Hz, 2H), 4.08 - 4.03 (m, 2H), 3.96 - 3.91 (m, 2H),

[0610] 2.53 (t, J= 7.7 Hz, 2H), 2.20 - 2.01 (m, 5H), 1.73 (s, 3H), 1.68 (s, 3H), 1.62 - 1.54 (m, 5H), 1.35 - 1.22 (m, 34H), 0.91 - 0.85 (m, 3H).

[0611] (E)-2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-DentadecylDhenoxy)ethyl methanesulfonate:

[0612] To an ice-cooled stirring solution of (£)-2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5- pentadecylphenoxy)ethan-l-ol (0.641 g, 1.28 mmol) in dichloromethane (20 mL) was added Methanesulfonyl chloride (0.30 mL, 0.44 g, 3.87 mmol), followed by triethylamine (0.8 mL, 0.550 g , 5.88 mmol) . The resultant solution was allowed to warm to room temperature and after 1 hour, TLC confirmed the reaction to be complete and the solution was quenched with water (10 mL). The dichloromethane was removed in-vacuo and the aqueous suspension was subsequently extracted into hexane (2 x 50mL). The combined organic extracts were then washed with a IM aqueous HC1 solution (50 mL), followed by water (50 mL) and then a saturated aqueous solution of sodium bicarbonate (2 x 50 mL) and over MgSCL. After filtration, the solvent removed in vacuo to provide the crude product (£)-2-(3-((3,7-dimethylocta-2,6-dien- l-yl)oxy)-5-pentadecylphenoxy)ethyl methanesulfonate (0.671g, 1.16 mmol, 91%), which was used without further purification.

[0613] 'H NMR (300 MHz, CDCI3) 5 6.42 - 6.38 (m, 1H), 6.32 (t, J= 1.9 Hz, 1H), 6.30 (t, J= 2.3 Hz, 1H), 5.52 - 5.43 (m, 1H), 5.15 - 5.03 (m, 1H), 4.56 (dd, J= 5.5, 3.6 Hz, 2H), 4.50 (d, J= 6.7 Hz, 2H), 4.24 - 4.17 (m, 2H), 3.09 (s, 3H), 2.53 (t, J= 7.7 Hz, 2H), 2.17 - 2.02 (m, 4H), 1.73 (s, 3H), 1.68 (s, 3H), 1.63 - 1.51 (m, 6H), 1.36 - 1.20 (m, 29H), 0.91 - 0.84 (m, 3H).

[0614] 2,2l-((2-(3-((2-ethylhexyl)oxy)-5-DentadecylDhenoxy)ethyl)azanediyl)bis(ethan-l-ol (also called RK- 011):

[0615] To a stirring solution of 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl methanesulfonate (2.79 g, 5.03 mmol) and 2,2'-azanediylbis(ethan-l-ol) (1.12 g, 10.7mmol) in DMF (5 mL) was added K2CO3 (3.0 g, 21.7 mmol), followed by potassium iodide (1.0 g, 6.02mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (100 mL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x lOOmL), and brine (lOOmL), dried over MgSCL. and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCfi. filtered and dried to provide 2,2'-((2-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)azanediyl)bis(ethan-l-ol) (2.10g, 3.83 mmol, 76% yield) as a colorless oil.

[0616] 'H NMR (300 MHz, CDC13) 5 6.39 - 6.36 (m, 1H), 6.34 (t, J= 1.8 Hz, 1H), 6.30 (t, J= 2.3 Hz, 1H), 4.03 (t, J= 5.3 Hz, 2H), 3.81 (d, J= 5.8 Hz, 2H), 3.67 (t, J= 5.3 Hz, 4H), 2.99 (t, J= 5.3 Hz, 2H), 2.96 - 2.68 (m, 5H), 2.53 (t, J = 7.8 Hz, 2H), 1.71 (p, J = 5.9 Hz, 1H), 1.66 - 1.54 (m, 2H), 1.54 - 1.37 (m, 4H), 1.37 - 1.22 (m, 30H), 0.97 - 0.87 (m, 9H).

[0617] 2-(4-(2-(3-((2-ethylhexyl)oxy)-5-DentadecylDhenoxy)ethyl)DiDerazin-l-yl)ethan-l-ol (also called RK- 008):

[0618] To a stirring solution of 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl methane sulfonate (0.805 g, 1.45 mmol) and 2-(piperazin-l-yl)ethan-l-ol (0.418 g, 3.21 mmol) in DMF (5 mL) was added K2CO3 (1.0 g, 6.51 mmol), followed by Potassium Iodide (0.5 g, 3.01mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (100mL) was added, and the residue was extracted into hexane (2 x 100mL). the combined organic phases were subsequently washed with water (2 x 100mL), and brine (lOOmL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSO4, filtered and dried to provide 2-(4-(2-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)piperazin-l-yl)ethan-l-ol (0.670 g, 1.14 mmol, 79% yield) as a colorless oil.

[0619] 'H NMR (400 MHz, CDC13) 5 6.34 (s, 1H), 6.32 (s, 1H), 6.30 (t, J= 2.1 Hz, 1H), 4.08 (t, J= 5.8 Hz, 2H), 3.79 (dd, J= 1.4, 5.7 Hz, 2H), 3.61 (t, J= 5.4 Hz, 2H), 2.80 (t, J= 5.8 Hz, 2H), 2.75 - 2.39 (m, 13H), 1.69 (h, J= 6.1 Hz, 1H), 1.58 (p, J= 6.9, 7.6 Hz, 2H), 1.53 - 1.17 (m, 33H), 0.90 (dt, J= 7.2, 15.8 Hz, 9H). 2,2l-((2-(3-(decyloxy)-5-DentadecylDhenoxy)ethyl)azanediyl)bis(ethan-l-ol) (also called RK-019):

[0620] To a stirring solution of 2-(3-(decyloxy)-5-pentadecylphenoxy)ethyl methanesulfonate (1.10 g, 1.89 mmol) and 2,2'-azanediylbis(ethan-l-ol) (0.500 g, 4.76mmol) in DMF (5 mL) was added K2CO3 (3.0 g, 21.7 mmol), followed by Potassium Iodide (1.0 g, 6.02mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (100 mL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x lOOmL), and brine (lOOmL), dried over MgSO4, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiO2) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x lOmL) and the combined hexane extracts were dried over anhydrous MgSO4, filtered and dried to provide 2,2'-((2-(3-(decyloxy)-5- pentadecylphenoxy)ethyl)azanediyl)bis(ethan-l-ol) (0.990 g, 1.67 mmol, 88% yield) as a colorless oil.

[0621] 'H NMR (300 MHz, CDCI3) 5 6.35 (s, 1H), 6.32 (s, 1H), 6.28 (t, J= 2.3 Hz, 1H), 4.01 (t, J= 5.3 Hz, 2H), 3.91 (t, J = 6.6 Hz, 2H), 3.65 (t, J= 5.2 Hz, 4H), 2.98 (t, J= 5.3 Hz, 2H), 2.79 (t, J= 5.3 Hz, 4H), 2.51 (t, J = 7.8 Hz, 2H), 1.75 (p, J= 6.6 Hz, 2H), 1.65 - 1.50 (m, 2H), 1.50 - 1.38 (m, 2H), 1.26 (d, J= 5.0 Hz, 37H), 0.93 - 0.83 (m, 6H).

[0622] 2-(4-(2-(3-(decyloxy)-5-DentadecylDhenoxy)ethyl)DiDerazin-l-yl)ethan-l-ol (also called RK-020):

[0623] To a stirring solution of 2-(3-(decyloxy)-5-pentadecylphenoxy)ethyl methanesulfonate (0.362 g, 0.622 mmol) and 2-(piperazin-l-yl)ethan-l-ol (0.169 g, 1.30 mmol) in DMF (5 mL) was added K2CO3 (3.0 g, 21.7 mmol), followed by potassium iodide (1.0 g, 6.02 mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (lOOmL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x 100mL), and brine (100mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiCF) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide 2,2'-((2-(3-(decyloxy)-5- pentadecylphenoxy)ethyl)azanediyl)bis(ethan-l-ol) (0.990 g, 1.67 mmol, 88% yield) as a colorless oil. 'H NMR (300 MHz, CDC13) 5 6.33 (t, J= 1.9 Hz, 2H), 6.29 (t, J= 2.3 Hz, 1H), 4.07 (t, J= 5.8 Hz, 2H), 3.91 (t, J= 6.6 Hz, 2H), 3.61 (t, J= 5.4 Hz, 2H), 2.86 - 2.41 (m, 17H), 1.75 (p, J = 6.5 Hz, 2H), 1.58 (p, J = 6.8 Hz, 2H), 1.49 - 1.37 (m, 3H), 1.36 - 1.19 (m, 38H), 0.93 - 0.83 (m, 6H).

[0624] To a stirring solution of 2-(3-(octadecyloxy)-5-pentadecylphenoxy)ethyl methanesulfonate (1.03 g, 1.48 mmol) and 2,2'-azanediylbis(ethan-l-ol) (0.500 g, 4.76mmol) in DMF (5 mL) was added K2CO3 (3.0 g, 21.7 mmol), followed by Potassium Iodide (1.0 g, 6.02mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (lOOmL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x lOOmL), and brine (lOOmL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (Si O2) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x lOmL) and the combined hexane extracts were dried over anhydrous MgSO4, filtered and dried to provide 2,2'-((2-(3-(octadecyloxy)-5- pentadecylphenoxy)ethyl)azanediyl)bis(ethan-l-ol) (0.933 g, 1.33 mmol, 90% yield) as acolorless oil which slowly solidified after multiple days of storage at room temperature.

[0625] 'H NMR (300 MHz, CDCI3) 5 6.25 (s, 1H), 6.22 (s, 1H), 6.18 (t, J= 2.0 Hz, 1H), 3.92 (t, J= 5.3 Hz, 2H), 3.81 (t, J = 6.5 Hz, 2H), 3.55 (t, J= 5.2 Hz, 4H), 2.87 (t, J = 5.3 Hz, 2H), 2.68 (t, J= 5.2 Hz, 4H), 2.59 - 2.29 (m, 4H), 1.66 (p, J= 6.6 Hz, 2H), 1.48 (p, J= 5.5 Hz, 2H), 1.40 - 1.29 (m, 2H), 1.16 (m, 53H), 0.78 (t, J= 6.7 Hz, 6H).

[0626] 2-(4-(2-(3-(octadecyloxy)-5-pentadecylphenoxy)ethyl)piperazin-l-yl)ethan-l-ol (also called RK-012):

[0627] To a stirring solution of 2-(3-(octadecyloxy)-5-pentadecylphenoxy)ethyl methanesulfonate (0.720 g, 1.04 mmol) and 2-(piperazin-l-yl)ethan-l-ol (0.171 g, 1.32 mmol) in DMF (5 mL) was added K2CO3 (3.0 g, 21.7 mmol), followed by Potassium Iodide (1.0 g, 6.02mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (lOOmL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x 100mL), and brine (100mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20 mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide 2-(4-(2-(3- (octadecyloxy)-5-pentadecylphenoxy)ethyl)piperazin-l-yl)ethan-l-ol (0.426 g, 0.58 mmol, 56% yield) as a colorless oil which slowly solidified after multiple days of storage at room temperature.

[0628] 'H NMR (300 MHz, CDC13) 5 6.24 (s, 2H), 6.19 (s, 1H), 3.98 (t, J= 5.8 Hz, 2H), 3.81 (t, J = 6.6 Hz, 2H), 3.52 (t, J = 5.4 Hz, 2H), 2.70 (t, J= 5.8 Hz, 2H), 2.59 - 2.36 (m, 12H), 1.73 - 1.59 (m, 2H), 1.55 - 1.41 (m, 2H), 1.40 - 1.30 (m, 2H), 1.16 (s, 55H), 0.78 (t, J= 6.7 Hz, 6H).

[0629] 2,2l-((2-(3-(heDtadecan-9-yloxy)-5-DentadecylDhenoxy)ethyl)azanediyl)bis(ethan-l-ol) (also called RK-028):

[0630] To a stirring solution of 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy)ethyl methanesulfonate (0.320 g, 0.47 mmol) and 2,2'-azanediylbis(ethan-l-ol) (0.103 g, 0.98mmol) in DMF (5 mL) was added K2CO3 (1.0 g, 7.2 mmol), followed by potassium iodide (0.50 g, 3.0 mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (lOOmL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x 100mL), and brine (lOOmL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20 mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide 2,2'-((2-(3- (heptadecan-9-yloxy)-5-pentadecylphenoxy)ethyl)azanediyl)bis(ethan-l-ol) (0.190 g, 0.275 mmol, 59% yield) as a colorless oil.

[0631] 'H NMR (300 MHz, CDC13) 5 6.34 - 6.29 (m, 2H), 6.26 (t, J= 2.3 Hz, 1H), 4. 17 (p, J= 5.7 Hz, 1H), 4.00 (t, J= 5.3 Hz, 2H), 3.65 (t, J= 5.3 Hz, 4H), 2.98 (t, J= 5.3 Hz, 2H), 2.79 (t, J= 5.3 Hz, 4H), 2.51 (t, J= 7.7 Hz, 2H), 1.69 - 1.51 (m, 6H), 1.45 - 1.19 (m, 52H), 0.91 - 0.84 (m, 9H). 2-(4-(2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy)ethyl)piperazin-l-yl)ethan-l-ol (also called

[0632] RK-009):

[0633] To a stirring solution of 2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy)ethyl methanesulfonate (0.299 g, 0.44 mmol) and 2-(piperazin-l-yl)ethan-l-ol (0.170 g, 1.31mmol) in DMF (5 mL) was added K2CO3 (1.0 g, 7.2 mmol), followed by potassium iodide (0.50 g, 3.0 mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (lOOmL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x 100mL), and brine (100 mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20 mL). The acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide 2-(4-(2-(3- (heptadecan-9-yloxy)-5-pentadecylphenoxy)ethyl)piperazin-l-yl)ethan-l-ol (0.237 g, 0.331 mmol, 75% yield) as a colorless oil.

[0634] 'H NMR (300 MHz, CDC13) 5 6.34 - 6.29 (m, 2H), 6.27 (t, J= 2.2 Hz, 1H), 4. 16 (p, J= 5.7 Hz, 1H), 4.07 (t, J= 5.8 Hz, 2H), 3.62 (t, J= 5.4 Hz, 2H), 2.80 (t, J= 5.8 Hz, 2H), 2.71 - 2.45 (m, 13H), 1.59 (dq, J= 7.3, 8.3, 13.7 Hz, 6H), 1.47 - 1.14 (m, 50H), 0.94 - 0.79 (m, 9H).

[0635] 2,2l-((3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)propyl)azanediyl)bis(ethan-l-ol) (also called RK-022):

[0636] To a stirring solution of l-(3-bromopropoxy)-3-((2-ethylhexyl)oxy)-5-pentadecylbenzene (0.71 g, 1.28 mmol) and 2,2'-azanediylbis(ethan-l-ol) (0.220 g, 2.10 mmol) in DMF (5 mL) was added K2CO3 (1.0 g, 7.23 mmol), followed by potassium iodide (0.05 g, 2.99 mmol). The resultant suspension was left to stir at room temperature for 16 hours. After which time water (100 mL) was added, and the residue was extracted into hexane (2 x 100mL). the combined organic phases were subsequently washed with water (2 x 100mL), and brine (lOOmL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (Si O2) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCfi. filtered and dried to provide 2,2'-((3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)propyl)azanediyl)bis(ethan-l-ol) (0.637g, 1.10 mmol, 86% yield) as a colorless oil.

[0637] 'H NMR (300 MHz, CDC13) 5 6.36 - 6.30 (m, 2H), 6.28 (t, J= 2.2 Hz, 1H), 4.02 (t, J= 5.9 Hz, 2H), 3.80 (d, J= 5.8 Hz, 2H), 3.63 (t, J= 5.3 Hz, 4H), 2.80 - 2.63 (m, 6H), 2.63 - 2.34 (m, 4H), 1.93 (p, J= 6.1 Hz, 2H), 1.70 (p, J = 6.0 Hz, 1H), 1.64 - 1.53 (m, 2H), 1.52 - 1.19 (m, 35H), 0.94 - 0.84 (m, 9H).

[0638] 2-(4-(3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)propyl)piperazin-l-yl)ethan-l-ol (also called

[0639] RK-023):

[0640] To a stirring solution of l-(3-bromopropoxy)-3-((2-ethylhexyl)oxy)-5-pentadecylbenzene (0.69g, 1.24 mmol) and 2-(piperazin-l-yl)ethan-l-ol (0.301g, 2.31 mmol) in DMF (5 mL) was added K2CO3 (1.0 g, 7.23 mmol), followed by Potassium Iodide (0.05 g, 2.99 mmol). The resultant suspension was left to stir at room temperature for 16 hours. After which time water (100 mL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x lOOmL), and brine (100 mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (Si O2) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20 mL).the acetonitrile extract was then re-extracted with hexane (2 x 10 mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide 2-(4-(3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)propyl)piperazin-l-yl)ethan-l-ol (0.511g, 0.85 mmol, 69% yield) as a colorless oil.

[0641] 'H NMR (300 MHz, CDCI3) 5 6.35 - 6.30 (m, 2H), 6.28 (t, J= 2.3 Hz, 1H), 3.98 (t, J= 6.4 Hz, 2H), 3.80 (d, J= 5.6 Hz, 2H), 3.61 (t, J= 5.4 Hz, 2H), 2.81 - 2.24 (m, 15H), 1.95 (p, J= 6.4 Hz, 2H), 1.70 (p, J= 6.1 Hz, 1H), 1.64 - 1.52 (m, 2H), 1.52 - 1.20 (m, 35H), 0.96 - 0.83 (m, 9H).

[0642] 2,2l-((4-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)butyl)azanediyl)bis(ethan-l-ol) (also called RK- 024): To a stirring solution of l-(4-bromobutoxy)-3-((2-ethylhexyl)oxy)-5-pentadecylbenzene (0.56 g, 0.986 mmol) and 2,2'-azanediylbis(ethan-l-ol) (0.220 g, 2.10 mmol) in DMF (5 mb) was added K2CO3 (1.0 g, 7.23 mmol), followed by potassium iodide (0.05 g, 2.99 mmol). The resultant suspension was left to stir at room temperature for 16 hours. After which time water (100 mL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x 100 mL), and brine (100 mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography ( Si O2 ) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide 2,2'-((4-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenoxy )butyl)azanediyl)bis(ethan-l-ol) (0.510g, 0.861 mmol, 87% yield) as a colorless oil.

[0643] 'H NMR (300 MHz, CDCI3) 5 6.33 (s, 1H), 6.31 (s, 1H), 6.28 (t, J= 2.3 Hz, 1H), 3.94 (t, J= 6.1 Hz, 2H), 3.80 (d, J= 5.6 Hz, 2H), 3.65 (t, J= 5.3 Hz, 4H), 3.13 (s, 2H), 2.77 - 2.60 (m, 6H), 2.52 (t, J= 7.8 Hz, 2H), 1.83 - 1.54 (m, 7H), 1.54 - 1.18 (m, 34H), 0.97 - 0.83 (m, 9H).

[0644] 2-(4-(4-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)butyl)piperazin-l-yl)ethan-l-ol (also called RK- 025):

[0645] To a stirring solution of l-(4-bromobutoxy)-3-((2-ethylhexyl)oxy)-5-pentadecylbenzene (0.51 g, 0.874 mmol) 2-(piperazin-l-yl)ethan-l-ol (0.170 g, 1.31 mmol) in DMF (5 mL) was added K2CO3 (1.0 g, 7.23 mmol), followed by Potassium Iodide (0.05 g, 2.99 mmol). The resultant suspension was left to stir at room temperature for 16 hours. After which time water (100 mL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x lOOmL), and brine (100mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (Si O2) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSO4, filtered and dried to provide 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)butyl)piperazin-l-yl)ethan-l-ol (0.398 g, 0.645 mmol, 74% yield) as a colorless oil.

[0646] 'H NMR (300 MHz, CDCI3) 5 6.31 (d, J= 7.1 Hz, 2H), 6.27 (t, J= 2.3 Hz, 1H), 3.94 (t, J= 6.3 Hz, 2H), 3.80 (d, J= 5.7 Hz, 2H), 3.61 (t, J = 5.4 Hz, 2H), 2.76 (s, 1H), 2.69 - 2.27 (m, 14H), 1.79 (p, J = 6.9 Hz, 2H), 1.73 - 1.54 (m, 5H), 1.54 - 1.17 (m, 35H), 0.97 - 0.82 (m, 9H). ( -l-(2-(3-((2-ethylhexyl)oxy)-5-DentadecylDhenoxy)ethyl)Dyrrolidin-2-yl)methanol (also called

[0647] RK-029):

[0648] To a stirring solution of 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl methane sulfonate (0.681 g, 1.23 mmol) (S)-pyrrolidin-2-ylmethanol (0.250g, 2.47 mmol) in DMF (5 mL) was added K2CO3 (0.90 g, 6.51 mmol), followed by potassium iodide (0.30 g, 1.81 mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (100 mL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x 100 mL), and brine (100 mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 15 minutes to provide ((25)-l-(2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)ethyl)pyrrolidin-2-yl)methanol (0.566g, 1.01 mmol, 82% yield) as a colorless oil.

[0649] 'H NMR (300 MHz, CDC13) 5 6.36 - 6.31 (m, 2H), 6.29 (t, J= 2.3 Hz, 1H), 4.03 (h, J= 4.6 Hz, 2H), 3.80 (d, J= 5.7 Hz, 2H), 3.65 (dd, J = 10.8, 3.6 Hz, 1H), 3.40 (dd, J= 10.9, 3.2 Hz, 1H), 3.32 - 3.22 (m, 1H), 3.15 (ddd, J= 12.9, 7.4, 5.4 Hz, 1H), 3.00 - 2.66 (m, 3H), 2.56 - 2.37 (m, 3H), 1.97 - 1.83 (m, 1H), 1.83 - 1.65 (m, 4H), 1.65 - 1.18 (m, 36H), 0.98 - 0.82 (m, 9H). ll-(2-(3-((2-ethylhexyl)oxy)-5-DentadecylDhenoxy)ethyl)-2,5,8-trioxa-ll-azatridecan-13-ol (also called RK-026):

[0650] To a stirring solution of 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)ethan-l-ol (0.566 g, 1.09 mmol) and 2-(2-(2-methoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (0.451g, 1.417 mmol) in DMF (10 mL) was added K2CO3 (0.448 g, 3.23 mmol). The resultant suspension was then heated to 50°C for 16 hours. After cooling to room temperature, water (100 mL) was added, and the residue was extracted into a 50% solution of EtO Ac: Hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x 1 OOrnL), and brine ( 1 OOmL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiCL) with MeOH / DCM (0-15% gradient elution) over 15 minutes to provide 1 l-(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)- 2,5,8-trioxa-l 1 -azatridecan- 13 -ol (0.328g, 0.49 mmol, 45% yield) as a colorless oil.

[0651] 'H NMR (400 MHz, CDC13) 5 6.34 (s, 1H), 6.31 (s, 1H), 6.27 (t, J= 2.3 Hz, 1H), 4.01 (t, J= 5.7 Hz, 2H), 3.80 (dd, J= 5.7, 1.9 Hz, 2H), 3.66 - 3.61 (m, 6H), 3.61 - 3.55 (m, 4H), 3.54 (dd, J= 5.7, 3.6 Hz, 2H), 3.37 (s, 3H), 3.01 (t, J= 5.7 Hz, 2H), 2.86 (t, J= 5.6 Hz, 2H), 2.80 (t, J= 5.2 Hz, 2H), 2.51 (t, J= 7.8 Hz, 2H), 1.69 (p, J = 6.1 Hz, 1H), 1.64 - 1.54 (m, 2H), 1.54 - 1.20 (m, 34H), 0.95 - 0.84 (m, 9H).

[0652] 2,2l-((2-(3-(oct-3-vn-l-yloxy)-5-pentadecylphenoxy)ethyl)azanediyl)bis(ethan-l-ol) (also called RK- 015):

[0653] To a stirring solution of 2-(3-(oct-3-yn-l-yloxy)-5-pentadecylphenoxy)ethyl methane sulfonate 0.607 g, 1.10 mmol) and 2,2'-azanediylbis(ethan-l-ol) (0.28 g, 2.68mmol) in DMF (5 mL) was added K2CO3 (0.79 g, 5.71 mmol), followed by Potassium Iodide (1.0 g, 6.02mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (100 mL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x 100mL), and brine (lOOmL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20 mL).the acetonitrile extract was then re-extracted with hexane (2 x 10 mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide 2,2'-((2-(3-(oct-3-yn-l-yloxy)-5- pentadecylphenoxy)ethyl)azanediyl)bis(ethan-l-ol) (0.560 g, 1.00 mmol, 91% yield) as an amber oil.

[0654] 'H NMR (300 MHz, CDCI3) 5 6.39 - 6.35 (m, 2H), 6.31 (t, J= 2.3 Hz, 1H), 4.06 - 3.99 (m, 4H), 3.67 (t, J= 5.3 Hz, 4H), 3.00 (t, J= 5.3 Hz, 2H), 2.81 (t, J= 5.3 Hz, 4H), 2.64 (tt, J= 7.3, 2.4 Hz, 2H), 2.53 (t, J= 7.8 Hz, 2H), 2.18 (ddt, J = 7.0, 4.7, 2.4 Hz, 2H), 1.64 - 1.56 (m, 2H), 1.54 - 1.39 (m, 4H), 1.36 - 1.19 (m, 28H), 0.96 - 0.85 (m, 6H).

[0655] 2-(4-(2-(3-(oct-3-vn-l-yloxy)-5-pentadecylphenoxy)ethyl)piperazin-l-yl)ethan-l-ol (also called RK- 016):

[0656] To a stirring solution of 2-(3-(oct-3-yn-l-yloxy)-5-pentadecylphenoxy)ethyl methane sulfonate 0.599 g, 1.09 mmol) and 2-(piperazin-l-yl)ethan-l-ol (0.170 g, 1.31 mmol) in DMF (5 mL) was added K2CO3 (0.80 g, 5.7 mmol), followed by potassium iodide (1.0 g, 6.02mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (100 mL) was added, and the residue was extracted into hexane (2 x lOOmL). the combined organic phases were subsequently washed with water (2 x lOOmL), and brine (lOOmL), dried over MgSCfi. and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiCL) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20 mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide 2-(4-(2-(3-(oct- 3-yn-l-yloxy)-5-pentadecylphenoxy)ethyl)piperazin-l-yl)ethan-l-ol (0.490 g, 0.84 mmol, 77% yield) as an amber oil.

[0657] 'H NMR (300 MHz, CDC13) 5 6.36 (d, J= 2.3 Hz, 2H), 6.32 (t, J= 2.3 Hz, 1H), 4.12 - 3.97 (m, 4H), 3.63 (t, J= 5.4 Hz, 2H), 2.82 (t, J= 5.8 Hz, 2H), 2.71 - 2.48 (m, 14H), 2.18 (tt, J = 6.9, 2.4 Hz, 2H), 1.60 (p, J= 7.0 Hz, 2H), 1.52 - 1.38 (m, 4H), 1.35 - 1.23 (m, 26H), 0.95 - 0.85 (m, 6H).

[0658] (E)-2,2l-((2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5DentadecylDhenoxy)ethyl)azanediyl) bis(ethan- l-ol) (also called RK-017):

[0659] To a stirring solution of (E)-2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-pentadecylphenoxy)ethyl methanesulfonate (0.461 g, 0.797 mmol) and 2,2'-azanediylbis(ethan-l-ol) (0.25 g, 2.39mmol) in DMF (5 mL) was added K2CO3 (0.60 g, 4.33 mmol), followed by potassium iodide (0.5 g, 3.01 mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (100 mL) was added, and the residue was extracted into hexane (2 x 100mL). the combined organic phases were subsequently washed with water (2 x 100mL), and brine (100 mL), dried over MgSCfi, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography ( Si O 2) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20 mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSO4, filtered and dried to provide (£)-2,2'-((2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5- pentadecylphenoxy)ethyl)azanediyl)bis(ethan-l-ol) (0.440 g, 0.760 mmol, 95% yield) as an amber oil.

[0660] JH NMR (300 MHz, CDCh) 5 6.39 - 6.35 (m, 1H), 6.33 (d, J = 2.3 Hz, 1H), 6.31 (t, J= 2.3 Hz, 1H), 5.48 (td, J= 6.6, 1.3 Hz, 1H), 5.15 - 5.04 (m, 1H), 4.49 (d, J= 6.6 Hz, 2H), 4.01 (t, J= 5.3 Hz, 2H), 3.64 (t, J= 5.2 Hz, 4H), 2.98 (t, J = 5.3 Hz, 2H), 2.79 (t, J = 5.3 Hz, 4H), 2.62 - 2.27 (m, 4H), 2.19 - 2.01 (m, 4H), 1.73 (s, 3H), 1.68 (s, 3H), 1.61 (s, 5H), 1.37 - 1.19 (m, 25H), 0.92 - 0.83 (m, 3H). (E)-2-(4-(2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-DentadecylDhenoxy)ethyl)DiDerazin-l- yl)ethan-l-ol (also called RK-018):

[0661] To a stirring solution of (£)-2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-pentadecylphenoxy)ethyl methanesulfonate (0.501 g, 0.866 mmol) and 2-(piperazin-l-yl)ethan-l-ol (0.170 g, 1.31 mmol) in DMF (5 mL) was added K2CO3 (0.60 g, 4.33 mmol), followed by potassium iodide (0.5 g, 3.01 mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (100 mL) was added, and the residue was extracted into hexane (2 x 100 mL). The combined organic phases were subsequently washed with water (2 x lOOmL), and brine (100 mL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography ( Si O 2) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mL), which was washed with acetonitrile (20 mL).the acetonitrile extract was then re-extracted with hexane (2 x 10 mL) and the combined hexane extracts were dried over anhydrous MgSCL, filtered and dried to provide (E)-2-(4-(2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5- pentadecylphenoxy)ethyl)piperazin-l-yl)ethan-l-ol (0.436 g, 0.711 mmol, 82% yield) as an amber oil.

[0662] 'H NMR (300 MHz, CDCI3) 5 6.40 - 6.28 (m, 3H), 5.48 (td, J = 6.6, 1.3 Hz, 1H), 5.15 - 5.04 (m, 1H), 4.49 (d, J= 6.6 Hz, 2H), 4.07 (t, J= 5.8 Hz, 2H), 3.61 (t, J = 5.4 Hz, 2H), 2.80 (t, J= 5.8 Hz, 2H), 2.67 - 2.48 (m, 12H), 2.18 - 2.01 (m, 4H), 1.73 (s, 3H), 1.68 (s, 3H), 1.64 - 1.51 (m, 5H), 1.37 - 1.19 (m, 27H), 0.91 - 0.85 (m, 3H).

[0663] 2-ethylhexyl8-(3-((2-ethylhexyl)oxy)-5-(2-((4-(4-(2-hvdroxyethyl)DiDerazin-l- yl)butanoyl)oxy)ethoxy)Dhenyl)octanoate (also called RK-010):

[0664] To a stirring solution of 2-ethylhexyl 8-(3-(2-((4-chlorobutanoyl)oxy)ethoxy)-5-((2- ethylhexyl)oxy)phenyl)octanoate (0.856 g, 1.37 mmol) and 2-(piperazin-l-yl)ethan-l-ol (0.340 g, 2.62 mmol) in DMF (5 mL) was added K2CO3 (1.20 g, 8.66 mmol), followed by potassium iodide (1.0 g, 6.02 mmol). The resultant suspension was then heated to 90°C for 16 hours. After cooling to room temperature, water (100 mL) was added, and the residue was extracted into hexane (2 x 100 mL). the combined organic phases were subsequently washed with water (2 x 100 mL), and brine (lOOmL), dried over MgSCL, and the solvent removed in vacuo to provide the crude product. The residue was purified by column chromatography (SiO2) with MeOH / DCM (0-5% gradient elution) over 15 minutes. Then, the obtained product was dissolved in hexane (50 mb), which was washed with acetonitrile (20 mL).the acetonitrile extract was then re-extracted with hexane (2 x 10mL) and the combined hexane extracts were dried over anhydrous MgSCfi. filtered and dried to provide (£)-2-(4-(2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5- pentadecylphenoxy)ethyl)piperazin-l-yl)ethan-l-ol (0.391 g, 0.544 mmol, 40% yield) as an amber oil.

[0665] 'H NMR (400 MHz, CDC13) 5 6.35 (s, 1H), 6.31 (s, 1H), 6.29 (t, J= 2.1 Hz, 1H), 4.44 - 4.37 (m, 2H), 4.18 - 4.10 (m, 2H), 4.03 - 3.93 (m, 2H), 3.83 - 3.74 (m, 2H), 3.60 (t, J = 5.4 Hz, 2H), 2.59 - 2.25 (m, 18H), 1.82 (p, J = 7.4 Hz, 2H), 1.74 - 1.66 (m, 2H), 1.58 (dq, J = 6.3, 6.8, 18.9 Hz, 6H), 1.53 - 1.24 (m, 24H), 0.95 - 0.83 (m, 12H). octyl 4-(2-(bis(2-hvdroxyethyl)amino)ethoxy)-2-(octyloxy)-6-Dentadecylbenzoate (also called RK-

[0666] 031):

[0667] To a stirring solution of octyl 4-(2-bromoethoxy)-2-(octyloxy)-6-pentadecylbenzoate (0.420 g, 0.603 mmol) and 2,2'-azanediylbis(ethan-l-ol) (0.1...

Claims

CLAIMS:

1. A method of manufacturing ionizable lipids utilizing a cardanol and / or derivatives thereof, including 3 -pentadecylphenol, and wherein said cardanol is derived from cashew nut shell liquid (CNSL), said method comprising the following steps:(A). isolating anacardic acids, cardanols, and cardols from cashew nut shell liquid (CNSL) to provide isolated anacardic acids, isolated cardanols and isolated cardols, preferably wherein Step (A) includes a distillation;(B). decarboxylation of the isolated anacardic acids to provide synthetic cardanols; and(C). functionalizing the synthetic cardanol and / or derivatives thereof to provide an ionizable lipid comprising: (i) a nitrogen containing ionizable group, (ii) an aromatic ring or analogue thereof, and (iii) at least one alkyl chain.

2. The method of Claim 1 further comprising Step (D), wherein Step (D) comprises hydrogenation of both isolated cardanol and synthetic cardanol to provide saturated cardanols, including 3 -pentadecylphenol, and wherein Step (D) takes place before Step (C).

3. The method of Claim 2, wherein the nitrogen containing ionizable group is a nitrogen containing compound, preferably wherein the nitrogen containing compound includes an alkaline nitrogen, and / or is an acyclic amine, cyclic amine or a heterocyclic nitrogen containing compound.

4. The method of Claim 3, wherein the nitrogen containing ionizable group is selected from the group consisting of: piperidines, pyrolidines, piperazine, 1,2-diazinane, 1,3-diazinane, imidazolidine triazines, and amino acids and / or derivatives of amino acids. It is to be understood that the nitrogen containing ionizable functional group may extend to other chemical moieties. 1,2-diazinane, 1,3- diazinane and imidazolidine.

5. The method of any one of Claims 1 to 4, wherein the aromatic ring is be derived from phenolics, which phenolics are in turn are derived from CNSL, and wherein the aromatic ring is selected from the group consisting of: a phenol, resorcinol, benzaldehyde, benzyl alcohol, and benzoic acid and / or derivatives and / or analogues of the aforementioned.

6. The method of any one of Claims 1 to 5, wherein the aromatic ring is reduced to analogues of same, including cyclohexyls and linear aliphatics, and wherein the reduction takes place via Birch reduction and / or ozonolysis or other synthetic methods that result in the same nonaromatic products.

7. The method of any one of Claims 1 to 6, wherein the at least one alkyl chain is saturated or unsaturated, alternatively and / or additionally the alkyl chain is branched or unbranched, alternatively and / or additionally the alkyl chain has a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween, including wherein the carbon chain length is any one of the group consisting of: Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, Cn, C12, Ci3, Ci4, C15, Ci6, C17, Ci8, C19, C20, C21 and C22.

8. The method of any one of Claims 1 to 7, further comprising alkyl chain modification, including chain length shortening and / or extension, and wherein said alkyl chain modification includes introduction of a functional group selected from the group consisting of: esters, ethers and amides.

9. The method of Claim 8, wherein alkyl chain modification take place via oxidative cleavage and / or chemo-selective modification of alkene functionalities.

10. The method of any one of Claims 1 to 9, further comprising a step of introducing at least one of the following groups consisting of: ester, amide, acetal, disulfide, carbonate, and carbamate.

11. The method of any one of Claims 1 to 10, wherein the ionizable lipid is at least one selected from the following group: 3-(decyloxy)-5-pentadecylphenyl 4-(dimethylamino) butanoate, 3 -((2 -ethylhexyl) oxy)-5 -pentadecylphenyl 4-(dimethylamino) butanoate, 2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)ethyl 4-(4-(2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(octadecyloxy)-5- pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(decyloxy)-5- pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(heptadecan-9-yloxy)- 5 -pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5-pentadecylphenoxy)ethyl) piperazin- l-yl)ethan-l-ol, 2-(4-(2-(3-(heptadecan-9-yloxy)-5- pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2-ethylhexyl8-(3-((2-ethylhexyl) oxy)-5-(2-((4-(4- (2 -hydroxyethyl) piperazin- 1-yl) butanoyl) oxy) ethoxy) phenyl) octanoate, 2, 2'-((2-(3 -((2 -ethylhexyl) oxy)-5 -pentadecylphenoxy) ethyl)azanediyl)bis(ethan-l-ol), 2-(4-(2-(3-(octadecyloxy)-5- pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2,2'-((2-(3-(octadecyloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2,2'-((2-(3-(oct-3-yn-l-yloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(oct-3-yn-l-yloxy)-5-pentadecylphenoxy)ethyl) piperazin- 1-yl) ethan-l-ol, (E)-2,2'-((2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), (E)-2-(4-(2-(3-((3,7-dimethylocta-2,6-dien-l-yl)oxy)-5-pentadecylphenoxy) ethyl) piperazin- l-yl)ethan-l-ol, 2,2'-((2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl)piperazin-l-yl) ethan-l-ol, 2,2'-((2-(3- (octan-2-yloxy)-5-pentadecylphenoxy) ethyl) azanediyl) diethanol, 2,2'-((3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)propyl)azanediyl)bis(ethan- 1 -ol), 2-(4-(3 -(3 -((2 -ethylhexyl) oxy)-5- pentadecylphenoxy) propyl) piperazin-l-yl) ethan-l-ol, 2,2'-((4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) azanediyl) bis (ethan-l-ol), 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) piperazin- 1-yl) ethan-l-ol, 1 l-(2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) -2,5,8 -trioxa- 11 -azatridecan- 13 -ol, 2,2'-((2-(3-(heptadecan-9-yloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), ((2S)-l-(2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)ethyl)pyrrolidin-2-yl)methanol, octyl 4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-2- (octyloxy)-6-pentadecylbenzoate, (3'-((2-ethylhexyl)oxy)-5'-pentadecyl-[l,l'-biphenyl]-4-yl)methyl 4- (4-(2-hydroxyethyl)piperazin-l-yl)butanoate, (3'-(octadecyloxy)-5'-pentadecyl-[l,l'-biphenyl]-4-yl) methyl 4-(4-(2-hydroxyethyl)piperazin-l-yl)butanoate, (3'-(decyloxy)-5'-pentadecyl-[l,l'-biphenyl]-4- yl)methyl 4-(4-(2-hydroxyethyl) piperazin- l-yl)butanoate, 2-(3-((9Z,12Z)-octadeca-9,12-dien-l-yloxy)- 5 -pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l-yl 4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4-(2-hydroxyethyl)piperazin- 1 -yl) butanoate, 2- (4-(3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l-yl)piperazin-l-yl)ethanol, 2-(4-(3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl)piperazin- 1 -yl)ethanol, ( 1 -(3 -(decyloxy)-5 - pentadecylphenyl)-lH-l,2,3-triazol-4-yl)methanol, 2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)- N,N-dimethylethanamine, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) ethanol, 2- ((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(methyl)amino)ethanol, 2-((2-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)amino)propane- 1 ,3 -diol, 2-(4-(2-(3-((2-ethylhexyl) oxy)- 5 -pentadecylphenoxy) ethyl) piperazin- 1-yl) ethanamine, 1-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino) propane-1, 3-diol, 5 -((2-(3 -((2-ethylhexyl)oxy)-5 - pentadecylphenoxy) ethyl) amino) pentan- l-ol, 5 -((2-(3 -((2-ethylhexyl)oxy)-5 - pentadecylphenoxy)ethyl)(2 -hydroxyethyl) amino) pentan- l-ol, 2-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino)-2-(hydroxymethyl) propane-1, 3-diol, l-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)-3-(4-(2-hydroxyethyl)piperazin-l-yl)propan-2-ol, l-(diethylamino)-3-(3-((2- ethylhexyl)oxy) -5 -pentadecylphenoxy) propan-2 -ol, 2,2'-((3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)-2-hydroxypropyl)azanediyl)diethanol, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)- 5 -pentadecylphenoxy) propan-2 -yl dodecanoate, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) propan-2-yl pentanoate, N,N-diethyl-3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) propan-1 -amine, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-((2- hydroxyethyl) (methyl)amino) propan-2-ol, 2-((2-(dodecanoyloxy)-3 -(3 -((2-ethylhexyl)oxy)-5 - pentadecylphenoxy) propyl) (methyl) amino) ethyl dodecanoate, 2-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) (octadecyl) amino) ethanol, 2-(decyl(2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)ethyl)amino)ethanol, 2-((2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) (octadecyl) amino) propane-1, 3-diol, 2-(3-(henicosan-l l-yloxy)-5-pentadecylphenoxy) ethyl4-(4-(2- hydroxyethyl)piperazin-l-yl) butanoate, , 3-((2-ethylhexyl)oxy)-5-pentadecylphenyl2-((5-(bis(2- hydroxyethyl) amino) pentyl) oxy)-2-methylpropanoate, 2,2'-((2-(3-(2-(2-(2-methoxyethoxy) ethoxy) ethoxy)-5 -pentadecylphenoxy) ethyl) azanediyl) diethanol.

12. The method of any one of Claims 1 to 11, further comprising steps of utilizing at least one the ionizable lipids in the manufacture of lipid nanoparticles (LNPs) to provide an ionizable lipid nanoparticle (iLNP).

13. The method of Claim 12, wherein the ionizable lipid nanoparticle (iLNP) is provided as a single component lipid nanoparticle (scLNP) and / or a multiple component lipid nanoparticle (mcLNP), and wherein the manufacture of lipid nanoparticles (LNPs) includes a modified solvent injection method and / or a microfluidics method.

14. The method of Claim 13, comprising the steps of formulating additional chemicals and / or molecules and / or excipients together with the CNSL-derived ionizable lipid to provide the mcLNP, and wherein said additional chemicals and / or molecules and / or excipients includes at least one selected from the group consisting of: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid and / or sterol (including cholesterol or phytosterols and / or its derivatives), (iii) a polymerconjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), (iv) a phospholipid and / or derivatives thereof, and (v) an unconjugated polymer.

15. The method of any one of Claims 12 to 14, wherein the ionizable lipid nanoparticle (iLNP) is loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-iLNP), wherein the API includes nucleic acids, peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof, preferably wherein the API is a nucleic acid, further preferably wherein the nucleic acid is DNA and / or RNA, most preferably wherein the nucleic acid is RNA being at least one of the group consisting of: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and / or other RNAs that activate the RNA interference (RNAi) pathway.

16. Ionizable lipids manufactured in accordance with the methods of any one of Claims 1 to 11.

17. An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipids manufactured in accordance with the methods of any one of Claims 1 to 11.

18. Ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method of any one of Claims 12 to 15.

19. An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method of any one of Claims 12 to 15.

20. The loaded lipid nanoparticle (L-iLNP)of Claim 15 for use as a medicament for treatment, prevention and / or amelioration and / or prophylaxis of a disease and / or medical condition in a human or animal body.

21. Use of the loaded lipid nanoparticle (L-iLNP) manufactured in accordance with the method of Claim 15 for transfection of cells, wherein said transfection takes place in vivo and / or ex vivo.

22. A method of manufacturing an ionizable lipid utilizing a 5 -alkylresorcinol and / or a 5 -alkyl -2- (hydroxymethyl)phenol including derivatives thereof, including cardol, and wherein said 5 -alkylresorcinol or 5-alkyl-2-(hydroxymethyl)phenol is derived from cashew nut shell liquid (CNSL), said method comprising the following steps: (A). isolating anacardic acids, cardanols, and cardols from cashew nut shell liquid (CNSL) to provide the isolated anacardic acids, isolated cardanols and isolated cardols, preferably wherein Step (A) includes a distillation;(B). decarboxylation of the isolated anacardic acids to provide synthetic cardanols;(C). hydrogenation of both isolated cardanol and synthetic cardanol to provide saturated / hydrogenated cardanols, including 3 -pentadecylphenol;(D). transforming the saturated cardanols to include a functional group, which functional group include a hydroxy substituent, in position 5, which position 5 includes position meta, therein providing for a 5- alkylresorcinol and / or ether containing derivatives, wherein the functional group is at least one selected from the group consisting of: saturated cyclical functional groups, unsaturated cyclical functional groups, acetates, mesylates, pivaloates, tosylates, Ar-N, Ar-S, and Ar-CX, wherein Ar refers to aryl, N refers to nitrogen, S refers to sulfur, C refers to carbon and X refers to any halogen; and(E). functionalizing the synthetic cardanol and / or derivatives thereof to provide an ionizable lipid comprising: (i) a nitrogen containing ionizable group, (ii) an aromatic ring or analogue thereof, and (iii) at least one alkyl chain.

23. The method of Claim 22 wherein Step (D) takes place via direct meta borylation of the saturated / hydrogenated cardanol with employing a protecting functional group, preferably Step (d) is provided as a one pot step.

24. The method of Claim 23, wherein Step (d) includes Sub-step (dl): protecting a phenol functional group of the saturated cardanols with a protectional functional group therein providing a protected cardanol.

25. The method of Claim 24, wherein Step (d) further includes [after at least commencing Sub-step (dl)] Substep (d2): introducing a phenol functional group in the meta position of the protected cardanol.

26. The method of Claim 25, wherein Sub-step (d2) introducing a phenol functional group in the meta position of the protected cardanol includes arene C-H borylation.

27. The method of Claim 26, wherein the arene C-H borylation includes use of a catalyst, including a transitional metal -based catalyst wherein the metal is selected from the group consisting of: metals: iridium (Ir), rhodium (Rh), platinum (Pt), palladium (Pd), tungsten (W), titanium (Ti), tin (Sn), ruthenium (Ru), iron (Fe) and lead (Pb).

28. The method of Claim 27, wherein the transition metal -based catalyst is selected from the following group consisting of: Cp*Ir(PMe3)H(Bpin), (Ind)Ir(COD), [Ir(COD)Cl]2, [Ir(COE)Cl]2, [Ir(COD)OH]2and [Ir(COD)OMe]2.

29. The method of any one of Claims 25 to 28, further including [after at least commencing Sub-step (d2)] Sub-step (d3): removing the protectional functional group.

30. The method of Claim 29, wherein Sub-step (d3) includes oxidation and employs at least one selected from the group consisting of: H2O2, oxone, potassium iodate and sodium iodate.

31. The method of any one of Claims 22 to 30, wherein the at least one alkyl chain is saturated or unsaturated, alternatively and / or additionally the alkyl chain is branched or unbranched, alternatively and / or additionally the alkyl chain has a carbon chain length of between Ci to C22 including both Ci, C22 and any value therebetween, including wherein the carbon chain length is any one of the group consisting of: Ci, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21 and C22.

32. The method of any one of Claims 22 to 31, further comprising alkyl chain modification, including chain length shortening and / or extension, and wherein said alkyl chain modification includes introduction of a functional group selected from the group consisting of: esters, ethers and amides.

33. The method of Claim 32, wherein alkyl chain modification take place via oxidative cleavage and / or chemo-selective modification of alkene functionalities.

34. The method of any one of Claims 22 to 33, further comprising a step of introducing at least one of the following groups consisting of: ester, amide, acetal, disulfide, carbonate, and carbamate.

35. The method of any one of Claims 22 to 34, wherein the ionizable lipid is at least one selected from the following group: 3 -(decyloxy)-5 -pentadecylphenyl 4-(dimethylamino) butanoate, 3-((2 -ethylhexyl) oxy)- 5 -pentadecylphenyl 4-(dimethylamino) butanoate, 2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl4-(4-(2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(octadecyloxy)-5 -pentadecylphenoxy) ethyl 4-(4- (2-hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(decyloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(3-(heptadecan-9-yloxy)-5 -pentadecylphenoxy) ethyl 4-(4-(2- hydroxyethyl) piperazin- 1-yl) butanoate, 2-(4-(2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)ethyl) piperazin- l-yl)ethan-l-ol, 2-(4-(2-(3-(heptadecan-9-yloxy)-5-pentadecylphenoxy) ethyl) piperazin-1- yl)ethan- 1 -ol, 2-ethylhexyl8-(3-((2 -ethylhexyl) oxy)-5-(2-((4-(4-(2-hydroxyethyl) piperazin- 1 -yl) butanoyl) oxy) ethoxy) phenyl) octanoate, 2, 2'-((2-(3 -((2 -ethylhexyl) oxy) -5 -pentadecylphenoxy) ethyl)azanediyl)bis(ethan- 1 -ol), 2-(4-(2-(3 -(octadecyloxy) -5 -pentadecylphenoxy) ethyl) piperazin- 1 - yl)ethan-l-ol, 2,2'-((2-(3-(octadecyloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2,2'- ((2-(3 -(oct-3 -yn-l-yloxy)-5 -pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3 -(oct-3 -yn- l-yloxy)-5-pentadecylphenoxy)ethyl) piperazin- 1-yl) ethan-l-ol, (E)-2,2'-((2-(3-((3,7-dimethylocta-2,6- dien-l-yl)oxy)-5pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), (E)-2-(4-(2-(3-((3,7- dimethylocta-2,6-dien- 1 -yl)oxy)-5 -pentadecylphenoxy) ethyl) piperazin- 1 -yl)ethan- 1 -ol, 2,2'-((2-(3 - (decyloxy)-5-pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), 2-(4-(2-(3-(decyloxy)-5- pentadecylphenoxy) ethyl)piperazin- 1 -yl) ethan- 1 -ol, 2,2'-((2-(3-(octan-2-yloxy)-5-pentadecylphenoxy) ethyl) azanediyl) diethanol, 2,2'-((3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)propyl)azanediyl)bis(ethan- 1 -ol), 2-(4-(3-(3-((2-ethylhexyl) oxy)-5- pentadecylphenoxy) propyl) piperazin-l-yl) ethan-l-ol, 2,2'-((4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) azanediyl) bis (ethan-l-ol), 2-(4-(4-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) butyl) piperazin- 1-yl) ethan-l-ol, 1 l-(2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl)-2,5,8-trioxa- 11 -azatridecan- 13-ol, 2,2'-((2-(3-(heptadecan-9-yloxy)-5- pentadecylphenoxy) ethyl) azanediyl) bis (ethan-l-ol), ((2S)-l-(2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy)ethyl)pyrrolidin-2-yl)methanol, octyl 4-(2-(bis(2-hydroxyethyl)amino)ethoxy)-2- (octyloxy)-6-pentadecylbenzoate, (3'-((2-ethylhexyl)oxy)-5'-pentadecyl-[l,r-biphenyl]-4-yl)methyl 4-(4- (2-hydroxyethyl)piperazin- 1 -yl)butanoate, (3 '-(octadecyloxy)-5 '-pentadecyl-[ 1 , 1 '-biphenyl] -4-yl) methyl 4-(4-(2-hydroxyethyl)piperazin-l-yl)butanoate, (3'-(decyloxy)-5'-pentadecyl-[l,l'-biphenyl]-4-yl)methyl 4-(4-(2 -hydroxyethyl) piperazin- l-yl)butanoate, 2-(3-((9Z,12Z)-octadeca-9,12-dien-l-yloxy)-5- pentadecylphenoxy) ethyl 4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-(decyloxy)-5- pentadecylphenyl)prop-2-yn-l-yl 4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, 3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl 4-(4-(2-hydroxyethyl)piperazin- 1 -yl) butanoate, 2- (4-(3-(3-(decyloxy)-5-pentadecylphenyl)prop-2-yn-l-yl)piperazin-l-yl)ethanol, 2-(4-(3-(3-((2- ethylhexyl)oxy)-5 -pentadecylphenyl)prop-2-yn- 1 -yl)piperazin- 1 -yl)ethanol, ( 1 -(3 -(decyloxy)-5 - pentadecylphenyl)-lH-l,2,3-triazol-4-yl)methanol, 2-(3-((2-ethylhexyl) oxy)-5-pentadecylphenoxy)- N,N-dimethylethanamine, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino) ethanol, 2- ((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)(methyl)amino)ethanol, 2-((2-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)propane-l,3-diol, 2-(4-(2-(3 -((2 -ethylhexyl) oxy)-5- pentadecylphenoxy) ethyl) piperazin- 1-yl) ethanamine, l-((2-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) ethyl) amino) propane-1, 3-diol, 5 -((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl) amino) pentan- 1 -ol, 5 -((2-(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy)ethyl)(2 -hydroxyethyl) amino) pentan-l-ol, 2-((2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) amino)-2- (hydroxymethyl) propane-l,3-diol, l-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-3-(4-(2- hydroxyethyl)piperazin-l-yl)propan-2-ol, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5- pentadecylphenoxy) propan-2 -ol, 2,2'-((3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)-2- hydroxypropyl)azanediyl)diethanol, 1 -(diethylamino)-3 -(3 -((2-ethylhexyl)oxy)-5 -pentadecylphenoxy) propan-2 -yl dodecanoate, l-(diethylamino)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan-2 -yl pentanoate, N,N-diethyl-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propan- 1 -amine, l-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy)-3-((2-hydroxyethyl) (methyl)amino) propan-2-ol, 2-((2- (dodecanoyloxy)-3-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy) propyl) (methyl) amino) ethyl dodecanoate, 2-((2-(3 -((2 -ethylhexyl)oxy)-5 -pentadecylphenoxy) ethyl) (octadecyl) amino) ethanol, 2- (decyl(2-(3-((2-ethylhexyl)oxy)-5-pentadecylphenoxy)ethyl)amino)ethanol, 2-((2-(3-((2- ethylhexyl)oxy)-5-pentadecylphenoxy) ethyl) (octadecyl) amino) propane-1, 3-diol, 2-(3-(henicosan-l 1- yloxy)-5 -pentadecylphenoxy) ethyl4-(4-(2-hydroxyethyl)piperazin-l-yl) butanoate, , 3-((2- ethylhexyl)oxy)-5-pentadecylphenyl2-((5-(bis(2 -hydroxyethyl) amino) pentyl) oxy)-2-methylpropanoate, 2, 2'-((2-(3-(2-(2-(2 -methoxyethoxy) ethoxy) ethoxy) -5 -pentadecylphenoxy) ethyl) azanediyl) diethanol.

36. The method of any one of Claims 22 to 35, further comprising steps of utilizing at least one the ionizable lipids in the manufacture of lipid nanoparticles (LNPs) to provide an ionizable lipid nanoparticle (iLNP).

37. The method of Claim 36, wherein the ionizable lipid nanoparticle (iLNP) is provided as a single component lipid nanoparticle (scLNP) and / or a multiple component lipid nanoparticle (mcLNP), and wherein the manufacture of lipid nanoparticles (LNPs) includes a modified solvent injection method and / or a microfluidics method.

38. The method of Claim 37, comprising the steps of formulating additional chemicals and / or molecules and / or excipients together with the CNSL-derived lipid to provide the mcLNP, and wherein said additional chemicals and / or molecules and / or excipients includes at least one selected from the group consisting of: (i) a second lipid (for example a neutral, anionic, cationic or zwitterionic lipid), (ii) a steroid and / or sterol (including cholesterol or phytosterols and / or its derivatives), (iii) a polymer conjugated lipid (including a polyethylene glycol (PEG) conjugated lipid), (iv) a phospholipid and / or derivatives thereof, and (v) an unconjugated polymer.

39. The method of any one of Claims 36 to 38, wherein the ionizable lipid nanoparticle (iLNP) is loaded with an active pharmaceutical ingredient (API) to provide a loaded lipid nanoparticle (L-iLNP), wherein the API includes nucleic acids, peptides, proteins, nucleosides, nucleotides, polynucleotides and derivatives thereof, preferably wherein the API is a nucleic acid, further preferably wherein the nucleic acid is DNA and / or RNA, most preferably wherein the nucleic acid is RNA being at least one of the group consisting of: messenger RNA (mRNA), self-amplifying RNA (saRNA), circular RNA (cRNA), small interfering RNA (siRNA) and / or other RNAs that activate the RNA interference (RNAi) pathway.

40. Ionizable lipids manufactured in accordance with the methods of any one of Claims 22 to 35.

41. An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipids manufactured in accordance with the methods of any one of Claims 22 to 35.

42. Ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method of any one of Claims 36 to 39.

43. An active pharmaceutical ingredient (API) delivery means comprising the ionizable lipid nanoparticles (iLNPs) manufactured in accordance with the method of any one of Claims 36 to 39.

44. The ionizable lipid nanoparticles (iLNPs) of Claim 39 for use as a medicament for treatment, prevention and / or amelioration and / or prophylaxis of a disease and / or medical condition in a human or animal body.

45. Use of the loaded lipid nanoparticle (L-iLNP) manufactured in accordance with the method of Claim 39 for transfection of cells, wherein said transfection takes place in vivo and / or ex vivo.