Stereochemically pure lipids for nucleic acid delivery

Abstract

This application generally relates to stereochemically pure lipids that can be used in combination with other lipid components, such as neutral lipids, e.g., cholesterol and polymer-conjugated lipids, to form lipid nanoparticles bearing oligonucleotides to facilitate intracellular delivery of therapeutic nucleic acids, such as oligonucleotides, messenger RNA, both in vitro and in vivo.

Description

[Technical field]

[0001] This application generally relates to stereochemically pure lipids that can be used in combination with other lipid components, such as neutral lipids, cholesterol, and polymer-conjugated lipids, to facilitate intracellular delivery of therapeutic nucleic acids, e.g., oligonucleotides, messenger RNA, and the like, both in vitro and in vivo, and to form lipid nanoparticles bearing oligonucleotides. [Background technology]

[0002] More specifically, embodiments of the present invention relate generally to the production and characterization of stereochemically pure lipids for use in lipid nanoparticles that facilitate or enable the intracellular delivery of pharma- ceutical active compounds, such as nucleic acids (e.g., oligonucleotides, messenger RNA).

[0003] Nucleic acids (e.g., oligonucleotides, messenger RNA) have great potential as therapeutic agents. However, there are currently two problems with using oligonucleotides for therapy. First, free RNA is susceptible to nuclease digestion in plasma. Second, free RNA has limited ability to access intracellular compartments where the associated translational machinery resides. To address this issue, lipid nanoparticles have been designed and developed to facilitate intracellular delivery of nucleic acid drugs. One of the components of these lipid nanoparticles (LNPs) is a synthetic lipid that contains amines that are protonated and therefore positively charged under physiological conditions. Several lipids of that kind are disclosed in WO2017075531 or WO2018081480 by Acuitas Therapeutics Inc., with Acuitas-5 being an example.

[0004] [ka]

[0005] Another commonly used example is ALC-0315, which has shown remarkable usefulness in delivering mRNA vaccines.

[0006] [ka]

[0007] Surprisingly, one important aspect of this lipid class has not been addressed until now. As a result, synthetic lipids that have been incorporated into LNPs to date have been produced and used as mixtures of stereoisomers. The art has not disclosed the synthesis or description of stereochemically pure synthetic lipids for use in LNPs. Routes to such stereochemically pure lipids have not previously been disclosed.

[0008] As a typical example, ALC-0315 contains two asymmetric centers that are sp3 hybridized carbon atoms surrounded by four different substituents. As a result, ALC-0315 exists in three stereoisomers, two chiral enantiomers (R,R)-ALC-0315 and (S,S)-ALC-0315, and one so-called meso compound (R,S)-ALC-0315 that is achiral. None of these isomers have been previously mentioned, characterized, or synthetically accessed, synthetically or chromatographically, or by any other means.

[0009] [ka]

[0010] Only a mixture of these three different stereoisomers is disclosed in WO2018081480, but the document does not describe only the single stereoisomers or their physical, physiological and biological properties. Since the first emergence of Covid-19, no person skilled in the art has recognized the stereochemical complexity of ALC0315, which consists of three isomers, which indicates that the person skilled in the art does not easily come to this subject or has no motivation to work in that direction. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] WO2018081480 Summary of the Invention [Problem to be solved by the invention]

[0012] It is well known that the human body has a remarkable ability to distinguish between stereoisomers. As a result, the majority of modern pharmaceutical drugs are typically used as single isomers.

[0013] Thus, the inventors expect that the stereoisomers of ALC-0315 and related lipids will similarly differ with respect to (a) their ability to prevent nucleic acid degradation and (b) their ability to deliver nucleic acids locally or systemically intracellularly, and further, (c) that the inventors expect that the stereoisomers will differ significantly with respect to tolerability, therapeutic index, and toxicity.

[0014] Thus, there is a need in the art to provide methods to obtain enantiopure lipids, for example by synthesis or degradation. [Means for solving the problem]

[0015] Thus, this patent application relates to the isolation, preparation and characterization of stereochemically pure forms of LNPs such as ALC-315.

[0016] More specifically, the present invention relates to a lipid compound represented by the following formula (I): [ka] or a pharma- ceutically acceptable salt thereof: where C *1 and C *2 Each represents a CH group; C 1a and C 1b are different from each other, C6-C 24 Alkyl or C6-C 24 independently represents alkenyl; C 2a and C 2b are different from each other, C6-C 24 Alkyl or C6-C 24 independently represents alkenyl; C 1a is C 2a is the same as or different from C 1b is C 2b be the same as or different from; R 1 and R 2 are unsubstituted C1-C 12 Alkylene or C2-C 12 alkenylene, R 1 and R 2 preferably represent the same group; R 3 is C1-C 24 Alkylene, C2-C 24 alkenylene, C3-C8 cycloalkylene or C3-C8 cycloalkenylene; F 1 and F 2 are respectively -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) 1,2 selected from -, -SS-, -C(=O)S-, SC(=O)-, -RC(=O)-, -C(=O)R-, RC(=O)R-, -OC(=O)R-, -RC(=O)O- or a direct bond; Here, R is H or C1-C 12 Alkyl, F1 and F 2 each preferably represents the same group, more preferably each is -O(C=O) or -(C=O)O-; F 3 H, OR 4 , -NR 4 2, -CN, halogen, -C(=O)O-(C1-C 12 Alkyl)-, (C1-C 12 Alkyl)-OC(=O)(C1-C 12 alkyl)- or -R 4 C(=0)-(C1-C 12 alkyl)-, R 4 is H or C1-C6 alkyl, Here, C *1 and C *2 The asymmetric centers (stereogenic centers) in are independently enriched in one stereogenic form selected from the (R)-form or the (S)-form.

[0017] According to the present invention, it is possible to prepare lipid compounds in which the asymmetric centers are enriched in one stereogenic form selected from the (R)-form or the (S)-form, independently of each other. Enriched in the sense of the present invention generally means that the asymmetric centers present in the (R)-form or the (S)-form predominate in one of the two forms in a ratio of 50:50 or more, preferably 60:40 or more, more preferably 70:30 or more, even more preferably 80:20 or more, or even more preferably 90:10 or more, ideally in a ratio of 100:0.

[0018] It will be apparent to those skilled in the art that, depending on the type of hydrocarbon substituent in formula (I), there may be more than one asymmetric center in one compound of formula (I), and complex mixtures will be obtained, especially when produced according to the state of the art of the art. Therefore, enantiopure (optically pure) In order to obtain pure products and reduce the proportion of racemic mixtures, it is highly desirable to use enantiopure starting materials.

[0019] In one embodiment of the present invention, in formula (I), C 1a and C 2a is C6-C 24 Alkyl or C6-C 24 alkenyl, C 1b and C 2b In formula (I), C6-C 24 Alkyl or CC 24 alkenyl. Thus, this number can be reduced to facilitate the synthesis of enantiopure products.

[0020] All functional groups are -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) 1,2 any functional group selected from -, -SS-, -C(=O)S-, SC(=O)-, -RC(=O)-, -C(=O)R-, RC(=O)R-, -OC(=O)R- or -RC(=O)O-, or a direct bond, where R is H or C1-C 12 Alkyl, preferably -O(C=O)- or -(C=O)O-, respectively, may be present in the lipids of the present invention.

[0021] In a further embodiment of the lipid compound, in formula (I), R 1 and R 2 are identical and are unsubstituted C1-C 12 It is alkylene.

[0022] In another embodiment of the lipid compound, R 3 is C1-C 24 It is alkylene.

[0023] In formula (I), F 3 OR 4 , -NR 4 2, -CN, - or halogen, R 4 The lipid compound according to any one of the preceding claims, wherein is H or C1-C6 alkyl.

[0024] A specific lipid compound is represented by formula (I): C *1 and C *2 each represents a CH group; C 1a and C 2a The same C6-C 24 represents an alkyl group; C 1b and C 2b The same C6-C 24 represents an alkyl group; F 1 and F 2 each represents the same group selected from -O(C=O)- and -(C=O)O-; R 1 and R 2 are C 4-8 is an alkylene; R 3 is C1-C 24 is alkylene; F 3 OR 4 or -NR 4 2. R 4 is H or C1-C6 alkyl, Here, C *1 and C *2 Preferably, the asymmetric centers (stereogenic centers) in are independently enriched in one stereogenic form selected from the (R)-form or the (S)-form and are enantiopure.

[0025] In the lipid compound, in formula (I), C *1 and C *2 each represents a CH group; C 1a and C 2a Each represents a C6 alkyl group; C 1b and C 2b Each represents a C8 alkyl group; F1 and F2 are C* (1,2) represents a -O(C=O) group bonded to R 1 and R 2are unsubstituted C 4-8 alkylene, preferably C6 alkylene; R 3 is a C2-C4 alkylene; F 3 OR 4 or -NR 4 2. R 4 is H or a methyl group, wherein each of the C's is independently enriched in one stereogenic form selected from the (R)-form or the (S)-form. *1 and C *2 The asymmetric centers (stereogenic centers) in are of particular importance in view of the identical hydrocarbon groups and therefore, depending on the optical purity of the starting compound, the lipid compounds are expressed in enantiopure (R,R) or (S,S) form or in meso form (R,S).

[0026] The present invention also relates to a method for producing a lipid compound represented by the following formula (I): [ka] In formula (I), C *1 and C *2 each represents a CH group; C 1a and C 2a The same C6-C 24 represents an alkyl group, C 1b and C 2b The same C6-C 24 represents an alkyl group; F 1 and F 2 each represents the same group selected from -O(C=O)- and -(C=O)O-; R 1 and R 2 are C 4-8 is an alkylene; R 3 is C1-C 24 is alkylene; F 3 OR4 or -NR 4 2. R 4 is H or C1-C6 alkyl, Here, C *1 and C *2 are independently enriched in one stereogenic form selected from the (R)-form or the (S)-form, Here, X-C1-C 24 Alkylene-NH2 (wherein X is -OY or -NR 4 2, Y is a protecting group, and R 4 is Y or C1-C6 alkyl) in a first reaction step with at least an equimolar amount of HO-C 4-8 with an alkylenal, preferably an HO-C6 alkylenal, and in an optional second reaction step, at least an equimolar amount of HO-C 4-8 with an alkylenal, preferably an HO-C6 alkylenal, wherein the HO-C 4-8 The alkylenal may be the same or different HO-C from the previous reaction step. 4-8 to obtain a product represented by formula (II), which is an alkylenal, [ka] The resulting reaction product of formula (II) (wherein R1, R2, R3 and F 3 has the meaning defined above), in the (R)- or (S)-configuration, the asymmetric center C * with at least an equimolar amount of a carboxylic acid of formula (III) having: [ka] Here, the asymmetric center C * Each C above 6-24 The alkyl groups are different and, in any further reaction steps, the asymmetric center C can be converted to either (R)- or (S)-form. * with at least an equimolar amount of a carboxylic acid of formula (III) having an asymmetric center C * Each C above6-24 The alkyl groups are different and this carboxylic acid of formula (III) can be the same or a different carboxylic acid of formula (III) as in the previous reaction step.

[0027] Although the methods of the present invention are exemplified for a limited number of functional groups, one of skill in the art can readily adapt the methods to other functional groups and protecting groups, if necessary, based on their understanding of the methods of the present invention and their chemical skills.

[0028] In a more specific embodiment, the present invention provides a compound comprising X-C2-C4 alkylene-NH2, where X is -OY or -NR 4 2, Y is a protecting group, and R 4 is Y or C1-C6 alkyl) in a first reaction step with at least two times the molar amount of HO-C 4-8 with an alkylenal to obtain a product of formula (II), wherein R 3 is C2-C4 alkylene, R 1 and R 2 are identical, and each is C 4-8 alkylene, and the resulting reaction product of formula (II) is converted in a further reaction step to an asymmetric center C * with at least a two-fold equimolar amount of a carboxylic acid of formula (IIIa) having: [ka]

[0029] By using at least two equimolar amounts in the two reaction steps, it is possible to obtain "symmetric" lipid compounds that have only two asymmetric centers.

[0030] As important compounds, starting compounds as represented by formula (IV) can be used in the inventive method for such compounds, and each lipid compound covered by the main claim can be obtained by reacting said starting compound with a suitable reaction partner and subjecting the resulting reaction product to suitable further processing and purification steps: [ka] In the formula, R 1 and R 2 are the same or different, C 4-8 is alkylene; R 3 is C1-C 24 is alkylene; F 1 and F 2 are -(C=O)OH, -C(=O)H, -OH, and -S(O), respectively. 1,2 H, -SSH, -C(=O)SH, -C(=S)OH, -RC(=O)H, -C(=O)R, -OC(=O)R or a direct bond, where R is H or C1-C 12 Alkyl, F 3 -OY or -NR 4 2, Y is a protecting group, and R 4 is Y or C1-C6 alkyl.

[0031] The present invention therefore relates to said compounds of formula (IV) and more particularly also to the more specific starting compounds as represented by formula (II). [ka] In the formula, R 1 and R 2 are the same or different, C 4-8 is alkylene; R 3 is C1-C 24 is alkylene; F 3 -OY or -NR 4 2, Y is a protecting group, and R 4is Y or C1-C6 alkyl.

[0032] In the process of the invention, any reaction partner or reactant having one or more asymmetric centers is used in its enriched, ideally enantiopure, form, when the one or more asymmetric centers exist in either of the two forms (R)- or (S)-form, each of which may be obtained by synthesis or resolution.

[0033] In the method of the present invention, the selection of the organic solvent is not essential as long as it is an aprotic organic solvent selected from THF, acetonitrile, other nitriles, chlorinated hydrocarbons, or other aprotic solvents, or a mixture thereof. The reaction conditions are also not essential, and the reaction is usually carried out under normal pressure, in a non-reactive atmosphere, at -78°C to 50°C, preferably -40°C to 30°C.

[0034] In the context of the present aspects, the following definitions are of more general terms used throughout this application.

[0035] When a range of values ​​is listed, it is intended to include each value and subrange within the range. For example, "C 1-6 ” contains, C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 The intention is to

[0036] As used herein, "alkyl" refers to the radical of a linear, cyclic or branched saturated hydrocarbon group having 1 to 24 carbon atoms ("C 1-24In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, an alkyl group has 4 to 8 carbon atoms ("C 4-8 In another embodiment, the alkyl group has 1 to 6 carbon atoms. 1-6 Examples of alkyl groups are methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10Alkyl (e.g., -CH3). In certain embodiments, the alkyl group is a substituted alkyl.

[0037] "Alkenyl" means an alkyl group having 2 to 24 carbon atoms and one or more carbon-carbon double bonds ("C 2-24 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2-4 Alkenyl groups include, for example, ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of the alkenyl group include the above-mentioned C 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In some embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl. [Brief description of the drawings]

[0038] The invention is further illustrated by the following figures, in which: FIG. 1 shows a conventional synthesis of ALC-315. FIG. 2A shows the inventive synthesis of (S,S)-ALC-0315. FIG. 2B shows the inventive synthesis of (R,R)-ALC-0315. FIG. 2C shows the inventive synthesis of (S,R)-ALC-0315 ((meso)-ALC-0315).

[0039] The synthesis of ALC-315, used in the prior art and shown in Figure 1, starts from the commercially available α-branched acid (rac)-1. Such an acid is substituted at the α-position with two n-alkyl chains differing by an ethylene element (CH2CH2) and is technically produced by the dimerization of two aldehydes with an alcohol, making it abundant and cheap. However, in its technical synthesis, the acid produced is racemic, meaning a mixture of two enantiomers described as (R)- and (S)-enantiomers.

[0040] The first step in the synthesis of ALC-315 involves the esterification of (rac)-1 with 1,6-hexanediol. The resulting alcohol is oxidized to the corresponding aldehyde, which then undergoes a double reductive amination with 4-aminobutan-1-ol to give ALC-315. This process is less favorable due to its limited access to a range of enantiopure compounds.

[0041] Our approach starts from an enantiopure carboxylic acid in (R)- or (S)-form. The enantiopure acid is obtained by separating the racemate by physical or chemical methods or by enantioselective synthesis. With the enantiopure acid 1, (R,R)-ALC-0315 and (S,S)-ALC-0315 can be obtained according to the known synthesis of the ALC-315 isomers or by alternative synthesis methods. The synthesis of the corresponding (meso)-ALC-315 requires an improved synthesis in which the two enantiomers of acid 1 are introduced in two separate steps.

[0042] In this application, the inventors describe the synthesis of all possible stereoisomers of LNPs such as ALC-315 using their insightful approach of first preparing chiral acid 1 in enantiopure form. Following this, the three ALC-315 isomers are prepared separately with improved procedures. In one embodiment, the chiral acid is obtained via a chiral auxiliary approach in which a chiral amide can be diastereoselectively alkylated at the α-position. The amide is hydrolyzed to obtain the desired acid 1. Thus, (+)-pseudoephedrine is first converted to the corresponding amide with caprylic acid chloride. The amide is alkylated with 1-iodooctane and then hydrolyzed to obtain enantioenriched (R)-1 with an enantiomeric ratio (er) of 98:2. The enantiomer of (R)-1, (S)-1, can be obtained similarly by reacting (+)-pseudoephedrine with capric anhydride, alkylating the resulting amide with 1-iodohexane, and then hydrolyzing, in an er ratio of 98.5:1.5 to give (S)-1.

[0043] In another embodiment, the racemic acid 1 is separated by high performance liquid chromatography. Thus, the inventors have found that rac-1 can be separated on a preparative scale using HPLC with a chiral stationary phase (Chiralpak IG-3).

[0044] In a further embodiment, the racemic acid 1 is converted to the corresponding amide and separated by high performance liquid chromatography. Thus, the inventors have found that the amide form of rac-1 can be separated on a preparative scale using HPLC with a chiral stationary phase (Chiralpak IG-3).

[0045] With the enantiopure acids (S)-1 and (R)-1 in hand, we synthesized the corresponding ALC-315 isomers following a newly developed route: 6-hydroxyhexanal is reductively aminated with 4-((tert-butyldimethylsilyl)oxy)butan-1-amine. The resulting diol is doubly esterified with acid (S)-1. Once the silyl groups are removed, the pure product (S,S)-ALC-0315 is obtained. Its enantiomer (R,R)-ALC-0315 has been prepared following the same procedure, but with acid (R)-1 instead of acid (S)-1.

[0046] Finally, (R,S)-ALC-0315 (or (meso)-ALC-0315) was also prepared. Thus, the above silyl-protected diol is then esterified with (S)-1 in a first step and with (R)-1 in a second step. Finally, the silyl groups are removed to give the pure product (meso)-ALC-0315.

[0047] The invention is further illustrated by the following experimental part. EXAMPLES

[0048] Experimental Part Example 1: Synthesis of (R)-2-hexyldecanoic acid [ka]

[0049] Step 1: A flame-dried 250 mL two-neck flask was charged with (+)-pseudoephedrine (4.0 g, 24.2 mmol, 1.0 equiv) and triethylamine (4.8 mL, 27.8 mmol, 1.3 equiv) followed by anhydrous tetrahydrofuran (50 mL). The reaction mixture was stirred and cooled to 0° C. An ice-cold solution of caprylic acid chloride (4.8 mL, 27.8 mmol, 1.15 equiv) in tetrahydrofuran (10 mL) was added via addition funnel over 10 min. After 20 min, the excess acid chloride was quenched by the addition of water (10 mL). The reaction mixture was partitioned between ethyl acetate (100 mL) and brine (80 mL) and the organic layer was separated. The organic layer was extracted with brine (2×80 mL), dried over Na2SO4, and concentrated. The solvent was evaporated under reduced pressure to give N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyloctanamide as an oil (6.0 g, 85% yield).

[0050] Step 2: A flame-dried 250 mL two-neck flask was charged with a magnetic stirrer, lithium chloride (3.2 g, 76.1 mmol, 6.0 equiv), diisopropylamine (4.0 mL, 28.6 mmol, 2.25 equiv), and anhydrous tetrahydrofuran (15 mL). The suspension was cooled to -78 °C. After 10 min, a solution of n-butylitride in hexanes (2.8 M, 9.4 mL, 26.4 mmol, 2.08 equiv) was added. The reaction mixture was warmed to 0 °C for 10 min and then cooled to -78 °C. An ice-cold solution of N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyloctanamide (3.7 g, 12.7 mmol, 1.0 equiv) in tetrahydrofuran (55 mL) was slowly added. The reaction mixture was stirred at -78 °C for 1 h, at 0 °C for 15 min, and at room temperature for 5 min. At 0 °C, 1-iodooctane (17.7 mL, 149 mmol, 1.50 equiv) was added and stirring was continued at 0 °C for another 15 min. It was then quenched by the addition of saturated NH4Cl solution. The mixture was partitioned between saturated NH4Cl solution (80 mL) and ethyl acetate (100 mL). The aqueous layer was separated and extracted with ethyl acetate (3x100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography on silica (eluent: 5% EtOAc in hexanes to 15% (v / v) EtOAc). Evaporation of the solvent under reduced pressure gave (R)-2-hexyl-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyldecanamide as an oil (2.9 g, 56% yield).

[0051] Step 3: A 50 mL single-neck flask was charged with a magnetic stirrer, (R)-2-hexyl-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyldecanamide (1.2 g, 3.0 mmol, 1.0 equiv), and 1,4-dioxane (6 mL). An aqueous 18 M H2SO4 acid solution (6 mL) was added slowly. The reaction mixture was heated at 110° C. for 1 h. After 1 h, the reaction mixture was cooled to 0° C. and basified to pH>10 with 50% (w / w) aqueous sodium hydroxide. The resulting mixture was partitioned between water (10 mL) and dichloromethane (20 mL). The aqueous layer was separated and extracted with dichloromethane (2×10 mL). The aqueous layer was acidified to pH<2 with 6M aqueous H2SO4 acid solution and extracted with dichloromethane (3×20 mL), the latter organic extracts dried over Na2SO4. It was then concentrated and the crude product was purified by flash column chromatography on silica (eluent: 20% ethyl acetate in hexane v / v). Evaporation of the solvent under reduced pressure gave (R)-2-hexyldecanoic acid as an oil (0.23 g, 35% yield). The enantiomeric ratio was determined by HPLC, Chiralpak IG-3, acetonitrile / 0.1% TFA-water = 65:35 (v / v), flow rate = 1.0 mL / min, λ = 220 nm, 298 K, t R = 14.7 minutes (major), t R = 16.1 min (minor). er = 98:2.

[0052] Example 2: Synthesis of (S)-2-hexyldecanoic acid [ka]

[0053] Step 1: A flame-dried 100 mL two-neck flask was charged with (+)-pseudoephedrine (2.0 g, 12.1 mmol, 1.0 equiv) and triethylamine (2.1 mL, 14.5 mmol, 1.2 equiv), followed by anhydrous dichloromethane (24 mL). At room temperature, capric anhydride (4.8 mL, 13.0 mmol, 1.1 equiv) was added over 10 min. After 3 h, the excess anhydride was quenched by the addition of water (1 mL). The reaction mixture was partitioned between ethyl acetate (50 mL) and brine (40 mL) and the organic layer was separated. The organic layer was extracted with brine (2×20 mL), dried over Na2SO4, and concentrated. Evaporation of the solvent under reduced pressure gave N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyldecanamide as an oil (3.5 g, 95% yield).

[0054] Step 2: A flame-dried 250 mL two-neck flask was charged with a magnetic stirrer, lithium chloride (2.1 g, 69.5 mmol, 6.0 equiv), diisopropylamine (3.7 mL, 26 mmol, 2.25 equiv), and anhydrous tetrahydrofuran (14 mL). The suspension was cooled to -78 °C. After 10 min, a solution of n-butylitride in hexanes (2.8 M, 8.6 mL, 24 mmol, 2.08 equiv) was added. The reaction mixture was warmed to 0 °C for 10 min and then cooled to -78 °C. An ice-cold solution of N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyldecanamide (3.7 g, 11.6 mmol, 1.0 equiv) in THF (50 mL) was slowly added. The reaction mixture was stirred at -78 °C for 1 h, at 0 °C for 15 min, and at room temperature for 5 min. At 0°C, 1-iodohexane (2.6 mL, 17.4 mmol, 1.50 equiv) was added and stirring was continued at 0°C for an additional 15 min. Then, it was quenched by adding saturated NH4Cl solution. The mixture was partitioned between saturated aqueous NH4Cl solution (80 mL) and ethyl acetate (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3x30 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography on silica (eluent: 5% (v / v) EtOAc in hexanes to 15% EtOAc). Evaporation of the solvent under reduced pressure gave (S)-2-hexyl-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyldecanamide as an oil (2.2 g, 47% yield).

[0055] Step 2: A flame-dried 250 mL two-neck flask was charged with a magnetic stirrer, lithium chloride (2.1 g, 69.5 mmol, 6.0 equiv), diisopropylamine (3.7 mL, 26 mmol, 2.25 equiv), and anhydrous tetrahydrofuran (14 mL). The suspension was cooled to -78 °C. After 10 min, a solution of n-butylitride in hexanes (2.8 M, 8.6 mL, 24 mmol, 2.08 equiv) was added. The reaction mixture was warmed to 0 °C for 10 min and then cooled to -78 °C. An ice-cold solution of N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyldecanamide (3.7 g, 11.6 mmol, 1.0 equiv) in THF (50 mL) was slowly added. The reaction mixture was stirred at -78 °C for 1 h, at 0 °C for 15 min, and at room temperature for 5 min. At 0°C, 1-iodohexane (2.6 mL, 17.4 mmol, 1.50 equiv) was added and stirring was continued at 0°C for an additional 15 min. It was then quenched by the addition of saturated NH4Cl solution. The mixture was partitioned between saturated aqueous NH4Cl solution (80 mL) and ethyl acetate (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3x30 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography on silica (eluent: 5% (v / v) EtOAc in hexanes to 15% EtOAc). Evaporation of the solvent under reduced pressure gave (S)-2-hexyl-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyldecanamide as an oil (2.2 g, 47% yield).

[0056] Step 3: A 50 mL single-neck flask was charged with a magnetic stirrer, (S)-2-hexyl-N-(((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyldecanamide (0.94 g, 2.3 mmol, 1.0 equiv.) and 1,4-dioxane (5 mL). An aqueous solution of 18 M H2SO4 (5 mL) was added slowly. The reaction mixture was heated at 110 °C for 1 h. After 1 h, the reaction mixture was cooled to 0 °C and basified to pH > 10 using 50% (w / w) aqueous sodium hydroxide. The resulting mixture was diluted with water (10 mL) and diluted with 10% ethanol. The mixture was partitioned between dichloromethane (20 mL) and 10% hexane (1.0 mL). The aqueous layer was separated and extracted with dichloromethane (2×10 mL). The aqueous layer was acidified to pH<2 with 6M aqueous solution and extracted with dichloromethane (3×20 mL), and the latter organic extract was dried over Na2SO4. It was then concentrated and the crude product was purified by flash column chromatography on silica (eluent: 20% ethyl acetate in hexane v / v). The solvent was evaporated under reduced pressure to give (S)-2-hexyldecanoic acid as an oil (0.25 g, 42% yield). The enantiomeric ratio was determined by HPLC, Chiralpak IG-3, acetonitrile / 0.1% TFA-water=65:35 (v / v), flow rate=1.0 mL / min, λ=220 nm, 298 K, t R = 15.0 min (minor) and t R Measured at 15.4 minutes (major). er=98.5:1.5.

[0057] Example 3: Preparative HPLC separation of rac-2-hexyldecanoic acid [ka]

[0058] rac-2-Hexyldecanoic acid was purchased from Sigma-Aldrich and used as received. rac-2-Hexyldecanoic acid was successfully separated on a preparative scale using HPLC. Conditions: Chiralpak IG-3, acetonitrile / 0.1%TFA-water=65:35(v / v), flow rate=1.0mL / min, λ=220nm, 298K, t R=16.0 min, t R =16.8 minutes.

[0059] Example 4: Preparative HPLC separation of amide derivatives: rac-2-Hexyldecanoic acid was converted to the corresponding acid chloride (ClCOCOCl, cat. DMF, DCM, rt, 2h), which was reacted with several chiral and achiral amines (see diagram below). The corresponding amides were then separated using HPLC (chiral and achiral stationary phases). After hydrolysis (described in step 3), enantiopure 2-hexyldecanoic acid is obtained.

[0060] [ka]

[0061] Example 5: Synthesis of 6,6'-((4-((tert-butyldimethylsilyl)oxy)butyl)azanediyl)bis(hexan-1-ol) [ka]

[0062] A 250 mL single neck flask was charged with a magnetic stirrer, 4-((tert-butyldimethylsilyl)oxy)butan-1-amine chloride (4.8 g, 20.0 mmol, 1.0 equiv.) and 6-hydroxyhexanal (5.8 g, 50 mmol, 2.5 equiv.). Acetic acid (4.8 g, 80 mmol, 4.0 equiv.) and 1,2-dichloroethane (63.0 mL) were added at room temperature. The reaction mixture was then stirred at room temperature for 10 min. Next, NaHB(OAc)3 (17.0 g, 80 mmol, 4.0 equiv.) was added portionwise to the reaction mixture over 1 h at room temperature. After complete addition of NaHB(OAc)3, the reaction mixture was further stirred at room temperature overnight. The reaction mixture was neutralized with saturated aqueous NaHCO3 and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography on silica (eluent: 100% acetone). Evaporation of the solvent under reduced pressure afforded 6,6'-((4-((tert-butyldimethylsilyl)oxy)butyl)azanediyl)bis(hexan-1-ol) as a pale yellow oil (4.1 g, 50% yield).

[0063] Example 6: Synthesis of 6-((4-((tert-butyldimethylsilyl)oxy)butyl)(4-hydroxybutyl)amino)hexan-1-ol [ka]

[0064] A 25 mL single neck flask was charged with a magnetic stirrer, 4-((tert-butyldimethylsilyl)oxy)butan-1-amine chloride (1.1 equiv.) and 6-hydroxyhexanal (1.0 equiv.). Acetic acid (2.0 equiv.) and 1,2-dichloroethane (6.3 mL) were added at rt and the reaction mixture was stirred at room temperature for 10 min. Then, NaHB(OAc)3 (1.5 equiv.) was added portionwise to the reaction mixture over 10 min at room temperature. After complete addition of NaHB(OAc)3, the reaction mixture was further stirred at room temperature overnight. Then, 4-hydroxybutanal (1.1 equiv.), acetic acid (2.0 equiv.) were added at room temperature. The reaction mixture was stirred at room temperature for 10 min. Then, NaHB(OAc)3 (1.5 equiv.) was added portionwise to the reaction mixture over 10 min at room temperature. After complete addition of NaHB(OAc)3, the reaction mixture was further stirred at room temperature for 6 h. The reaction mixture was neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography on silica (eluent: 100% acetone). Evaporation of the solvent under reduced pressure afforded 6-((4-((tert-butyldimethylsilyl)oxy)butyl)(4-hydroxybutyl)amino)hexan-1-ol as a pale yellow oil.

[0065] Example 7: Synthesis of ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)(2R,2'R)-bis(2-hexyldecanoate) [ka]

[0066] To a flame-dried 25 mL Schlenk tube was added 6,6'-((4-((tert-butyldimethylsilyl)oxy)butyl)azanediyl)bis(hexan-1-ol) (39.4 mg, 0.1 mmol, 1.0 equiv), (R)-2-hexyldecanoic acid (50.0 mg, 0.2 mmol, 2.0 equiv, 98:2er) and DMAP (25.6 mg, 0.24 mmol, 2.4 equiv), followed by anhydrous dichloromethane (3 mL). The reaction mixture was cooled to 0 °C and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide chloride (44.9 mg, 0.24 mmol, 2.4 equiv) was added. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (2 mL), brine (5 mL) and extracted with dichloromethane (3x5 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica (eluent: 40% (v / v) ethyl acetate in hexanes). Evaporation of the solvent under reduced pressure afforded ((4-((tert-butyldimethylsilyl)oxy)butyl)azanediyl)bis(hexane-6,1-diyl)(2R,2'R)-bis(2-hexyldecanoate) as an oil (75.0 mg, 87% yield).

[0067] ((4-((tert-butyldimethylsilyl)oxy)butyl)azanediyl)bis(hexane-6,1-diyl)(2R,2'R)-bis(2-hexyldecanoate) was dissolved in tetrahydrofuran (5 mL) and a 1 M solution of TBAF in tetrahydrofuran (0.4 mL, 0.4 mmol, 4.0 equiv.) was added at room temperature. After 2 h, the reaction mixture was quenched with water and extracted with dichloromethane (3x5 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica (eluent: 0%-30% (v / v) acetone in ethyl acetate). Evaporation of the solvent under reduced pressure afforded ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)(2R,2'R)-bis(2-hexyldecanoate) as an oil (51.0 mg, 68% yield over two steps).

[0068] Enantiomeric ratio determination: The enantiomeric ratio was determined by HPLC after derivatization of the lipids to carboxylic acids according to the following reaction sequence: [ka] er≧95.5:4.5, calculation dr→20:1

[0069] Example 8: Synthesis of ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)(2S,2'S)-bis(2-hexyldecanoate) [ka]

[0070] Following the procedure of Example 4, using (S)-2-hexyldecanoic acid, ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)(2S,2'S)-bis(2-hexyldecanoate) was obtained as an oil (61.0 mg, 77% yield over two steps). er≧98:2, calculation dr→20:1

[0071] Example 9: Synthesis of 6-((6-(((R)-2-hexyldecanoyl)oxy)hexyl)(4-hydroxybutyl)amino)hexyl (S)-2-hexyldecanoate [ka]

[0072] A flame dried 25 mL Schlenk tube was charged with 6,6'-((4-((tert-butyldimethylsilyl)oxy)butyl)azanediyl)bis(hexan-1-ol) (75.6 mg, 0.19 mmol, 2.0 equiv), (S)-2-hexyldecanoic acid (25.0 mg, 0.1 mmol, 1.0 equiv, 98:2er) and DMAP (13.7 mg, 0.11 mmol, 1.2 equiv) followed by the addition of anhydrous dichloromethane (3 mL). The reaction mixture was cooled to 0° C. and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide chloride (21.5 mg, 0.11 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (2 mL), brine (5 mL) and extracted with dichloromethane (3×5 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica (eluent: 50% (v / v) acetone in diethyl ether). The solvent was evaporated under reduced pressure to give 6-((4-((tert-butyldimethylsilyl)oxy)butyl)(6-hydroxyhexyl)amino)hexyl (S)-2-hexyldecanoate as an oil.

[0073] The isolated 6-((4-((tert-butyldimethylsilyl)oxy)butyl)(6-hydroxyhexyl)amino)hexyl (S)-2-hexyldecanoate was then transferred to a flame-dried 25 mL Schlenk tube. (R)-2-Hexyldecanoic acid (25.0 mg, 0.1 mmol, 1.0 equiv, 98:2er) and DMAP (13.7 mg, 0.11 mmol, 1.2 equiv) were added followed by anhydrous dichloromethane (3 mL). The reaction mixture was cooled to 0° C. and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide chloride (21.5 mg, 0.11 mmol, 1.2 equiv) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (2 mL), brine (5 mL) and extracted with dichloromethane (3×5 mL). The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica (eluent: 40% (v / v) ethyl acetate in hexanes). Evaporation of the solvent under reduced pressure afforded 6-((4-((tert-butyldimethylsilyl)oxy)butyl)(6-(((R)-2-hexyldecanoyl)oxy)hexyl)amino)hexyl (S)-2-hexyldecanoate as an oil (66 mg, 80% yield over two steps).

[0074] 6-((4-((tert-butyldimethylsilyl)oxy)butyl)(6-(((R)-2-hexyldecanoyl)oxy)hexyl)amino)hexyl-(S)-2-hexyldecanoate was dissolved in tetrahydrofuran (5 mL) and a 1 M solution of TBAF in tetrahydrofuran (0.4 mL, 0.4 mmol, 4.0 equiv.) was added at room temperature. After 2 h, the reaction mixture was quenched with water and extracted with dichloromethane (3x5 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica (eluent: 0%-30% (v / v) acetone in EtOAc). Evaporation of the solvent under reduced pressure afforded 6-((6-(((R)-2-hexyldecanoyl)oxy)hexyl)(4-hydroxybutyl)amino)hexyl (S)-2-hexyldecanoate as an oil (51.0 mg, 71% yield over three steps). Calculation dr→20:1

Claims

1. A lipid compound represented by the following formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof: During the ceremony, C ＊１ and C ＊２ each represents a CH group; C １ａ and C １ｂ are different from each other, and C ６ -C ２４ Alkyl or C ６ -C ２４ independently represent alkenyl; C ２ａ and C ２ｂ are different from each other, and C ６ -C ２４ Alkyl or C ６ -C ２４ independently represent alkenyl; C １ａ is C ２ａ is the same as or different from C １ｂ is C ２ｂ is the same as or different from; R １ and R ２ are unsubstituted C １ -C １２ Alkylene or C ２ -C １２ alkenylene, and R １ and R ２ preferably represent the same group; R ３ is C １ -C ２４ Alkylene, C ２ -C ２４ Alkenylene, C ３ -C ８ Cycloalkylene or C ３ -C ８ is cycloalkenylene; F １ and F ２ are respectively -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) １，２ -, -S-S-, -C(=O)S-, -SC(=O)-, -RC(=O)-, -C(=O)R-, -RC(=O)R-, -OC(=O)R-, -RC(=O)O- or a direct bond, wherein R is H or C １ -C １２ alkyl, and F １ and F ２ preferably represent the same group, more preferably -O(C=O) or -(C=O)O-, respectively; F ３ is H, OR ４ , -NR ４ ２ , —CN, halogen, —C(═O)O—(C １ -C １２ alkyl)-, (C １ -C １２ alkyl)-OC(=O)-(C １ -C １２ alkyl)- or -R ４ C(=0)-(C １ -C １２ alkyl)-, and R ４ is H or C １ -C ６ is alkyl, Here, C ＊１ and C ＊２ The lipid compound, wherein the asymmetric centers (stereogenic centers) in the formula (I) are independently enriched in one stereogenic form selected from the (R)-form and the (S)-form.

2. In formula (I), C １ａ and C ２ａ But C ６ -C ２４ Alkyl or C ６ -C ２４ alkenyl, C １ｂ and C ２ｂ But C ６ -C ２４ Alkyl or C ６ -C ２４ 2. The lipid compound according to claim 1, wherein each of the groups represents an identical group selected from the group consisting of: alkenyl

3. In formula (I), F １ and F ２ is -O(C=O)-, -(C=O)O-, -C(=O)-, -O-, -S(O) １，２ represents the same group selected from -, -S-S-, -C(=O)S-, -SC(=O)-, -RC(=O)-, -C(=O)R-, -RC(=O)R-, -OC(=O)R- or -RC(=O)O-, or represents a direct bond, wherein R is H or C １ -C １２ 3. The lipid compound according to claim 1 or 2, wherein the alkyl is preferably -O(C=O)- or -(C=O)O-, respectively.

4. In formula (I), R １ and R ２ are identical, and each is an unsubstituted C １ -C １２ 3. The lipid compound of claim 1 or 2, which is alkylene.

5. In formula (I), R ３ is C １ -C ２４ 3. The lipid compound of claim 1 or 2, which is alkylene.

6. In formula (I), F ３ is OR ４ , -NR ４ ２ , —CN, or halogen; R ４ is H or C １ -C ６ 3. The lipid compound of claim 1 or 2, which is alkyl.

7. In formula (I), C ＊１ and C ＊２ each represents a CH group; C １ａ and C ２ａ But the same C ６ -C ２４ represents an alkyl group; C １ｂ and C ２ｂ But the same C ６ -C ２４ represents an alkyl group; F １ and F ２ represent the same group selected from —O(C═O)— and —(C═O)O—; R １ and R ２ are C ４－８ alkylene; R ３ is C １ -C ２４ alkylene; and F ３ is OR ４ or -NR ４ ２ and R ４ is H or C １ -C ６ is alkyl, Here, C ＊１ and C ＊２ The lipid compound according to claim 1, wherein the asymmetric centers (stereogenic centers) in the formula (I) are independently enriched in one stereogenic form selected from the (R)-form or the (S)-form.

8. In formula (I), C ＊１ and C ＊２ each represents a CH group; C １ａ and C ２ａ are C ６ represents an alkyl group; C １ｂ and C ２ｂ are C ８ represents an alkyl group; F1 and F2 are each C ＊（１，２） represents an —O(C═O) group bonded to R １ and R ２ are unsubstituted C ４－８ Alkylene, preferably C ６ alkylene; R ３ is C ２ -C ４ alkylene; and F ３ But OR ４ or -NR ４ ２ and R ４ is H or a methyl group, Here, C ＊１ and C ＊２ The lipid compound according to claim 1, wherein the asymmetric centers (stereogenic centers) in the formula (I) are independently enriched in one stereogenic form selected from the (R)-form or the (S)-form.

9. The following formula (I) 【Chemistry 2】 [In formula (I), C ＊１ and C ＊２ each represents a CH group; C １ａ and C ２ａ is C ６ -C ２４ alkyl, C １ｂ and C ２ｂ is C ６ -C ２４ alkyl; F １ and F ２ represent the same group selected from —O(C═O)— and —(C═O)O—; R １ and R ２ are C ４－８ alkylene; R ３ is C １ -C ２４ alkylene; and F ３ is OR ４ or -NR ４ ２ and R ４ is H or C １ -C ６ is alkyl, Here, C ＊１ and C ＊２ are independently enriched in one stereogenic form selected from the (R)-form or the (S)-form. A method for producing a lipid compound represented by the formula: X-C １ -C ２４ Alkylene-NH ２ (Wherein, X is —OY or NR ４ ２ Y is a protecting group, and R ４ is Y or C １ -C ６ alkyl) in a first reaction step with at least an equimolar amount of HO—C ４－８ Alkylenal, preferably HO—C ６ and, in an optional second reaction step, reacting with at least an equimolar amount of HO—C ４－８ Alkylenals, preferably HO—C ６ and reacting the HO—C alkylenal with the alkylenal. ４－８ The alkylenal may be the same or different HO—C from the previous reaction step. ４－８ to obtain a product represented by formula (II), which is an alkylenal, 【Chemistry 3】 The resulting reaction product of formula (II), where R １ , R ２ , R ３ and F ３ has the meaning defined above in this claim), in the (R)- or (S)-configuration, ＊ with at least an equimolar amount of a carboxylic acid of formula (III) having: 【Chemistry 4】 Here, the asymmetric center C ＊ Each C above ６－２４ The alkyl groups are different and, in any further reaction step, the asymmetric center C ＊ with at least an equimolar amount of a carboxylic acid of formula (III) having the asymmetric center C ＊ Each C above ６－２４ The alkyl groups are different and this carboxylic acid of formula (III) is the same or a different carboxylic acid of formula (III) as in the previous reaction step.

10. X-C ２ -C ４ Alkylene-NH ２ (Wherein, X is —OY or —NR ４ ２ Y is a protecting group, and R ４ is Y or C １ -C ６ In a first reaction step, a hydroxy group (which is an alkyl group) is reacted with at least two times the molar amount of HO—C ４－８ with an alkylenal to give a product of formula (II), wherein R ３ is C ２ -C ４ alkylene, and R １ and R ２ are identical, and each is C ４－８ alkylene, and the resulting reaction product of formula (II) can be converted in a further reaction step to the asymmetric center C ＊ 10. The method for producing a lipid compound of formula (I) according to claim 9, wherein the compound is reacted with at least two equimolar amounts of a carboxylic acid of formula (IIIa): 【Chemistry 5】

11. A starting compound of formula (IV) 【Chemistry 6】 In the formula, R １ and R ２ are the same or different, and each C ４－８ alkylene; R ３ is C １ -C ２４ alkylene; F １ and F ２ are -(C=O)OH, -C(=O)H, -OH, and -S(O), respectively. １，２ H, —S—S—H, —C(═O)SH, —C(═S)OH, —RC(═O)H, —C(═O)R, —O—C(═O)R or a direct bond, where R is H or C １ -C １２ alkyl, and F ３ is -OY or -NR ４ ２ Y is a protecting group, and R ４ is Y or C １ -C ６ The starting compound is alkyl.

12. A starting compound of formula (II) 【Chemistry 7】 In the formula, R １ and R ２ are the same or different, and each C ４－８ alkylene; R ３ is C １ -C ２４ alkylene; and F ３ is -OY or -NR ４ ２ Y is a protecting group, and R ４ is Y or C １ -C ６ The starting compound is alkyl.

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