Lipophilic reagent compounds for liquid phase synthesis of biomolecules

Abstract

The present invention relates to a lipophilic agent for organic synthesis comprising a triazine core and having a lipophilic group. The lipophilic reagent can be dissolved in a solvent system, the lipophilic reagent participates in a chemical reaction, but after the reaction is completed, the solution composition is changed by adding a miscible and poor-solubility solvent, so that the product becomes insoluble. The lipophilic reagent promotes process improvements in which the actual operations only include mixing with reactants in solution, then precipitating the product by changing the solution composition, and obtaining precipitated solids by filtration, thereby simplifying the purification operations by separating the desired solids. The operation has repeatability in the multi-step synthesis process, and pure intermediates and pure products can be easily, definitely and rapidly obtained. Therefore, the invention can accelerate the research and development of drug biomolecules, and represents the great progress of improving the production efficiency and the green chemical industry.

Description

Field of the Invention

[0001] The present invention relates to a lipophilic reagent for organic synthesis and a method for performing an organic synthesis reaction using the lipophilic reagent. More specifically, the present invention relates to a lipophilic reagent for organic synthesis, which comprises a triazine core having a lipophilic group. The compound can be rapidly and repeatedly transformed from a soluble state to a solid state due to changes in solution components, can be provided as a reactant in an organic synthesis reaction, or as a compound combined with an unreacted compound or a by-product in an organic synthesis reaction, and can be easily separated from the reaction system after the reaction. Background of the Invention

[0002] In the traditional organic chemical reaction process, the basic technology is to separate the desired product after the reaction is completed, or to remove excess reagents, by-products, catalysts, etc. from the mixture of the reaction solution. In rare cases, the desired product will solidify (or crystallize) from the reaction mixture to form a pure product. The products of most organic synthesis reactions may be liquid, or appear as oily substances due to their properties, or become solid after purification. Liquid products can be obtained by distillation or high vacuum distillation, which requires the liquid product to have thermal stability. For those compounds that are oily or difficult to solidify, silica gel column chromatography is usually selected for purification. However, according to the fluidity of the desired product on silica gel and the complexity of other unwanted components in the mixture, a large amount of silica gel and a large amount of solvent are required, which leads to an increase in the cost of compound production and the cost of waste solvent treatment. For compounds that become solid after purification, it may take a lot of effort to solidify (or crystallize) from a mixture containing various reactants and by-products. The solidification (or crystallization) conditions of different compounds vary. In many cases, the solidification (or crystallization) conditions are found through experience based on trial and error. Especially in sequential multi-step syntheses, process development becomes very expensive and time-consuming because of the need to consider the solidification (or crystallization) conditions according to the characteristics of the compounds synthesized in each step.

[0003] In order to solve these problems, including the generation of solid compounds in each step of a multi-step synthesis, a method is known in the prior art, that is, using chemical functionalization reagents on a solid phase support, such as polystyrene resins, polyethylene glycol resins, etc. This synthesis method on a solid phase support allows each step of the reaction to be attached to the solid phase support, and unnecessary excess reagents, by-products, catalysts, etc. can be removed by simply washing the solid phase with certain solvents. The advantages of solid phase synthesis include high efficiency and high speed, but it also has many disadvantages: (a) due to the heterogeneity of the solid phase, the reaction activity is low, and an excess of reactants must be used to completely convert the reaction; (b) a large amount of solvent is required for each reaction and washing. These problems are particularly serious for large-scale synthesis because the loading capacity of the functionalization reagents on the solid phase support is limited, and the overall cost is significantly increased.

[0004] In general, in traditional liquid-phase synthesis reactions, isolating the desired compounds requires skill and experience and can be very laborious; whereas in synthesis reactions on solid supports, due to the limited loading capacity of functionalized reagents and the heterogeneity of the solid phase, large amounts of reagents and solvents are required for reactions and cleaning, which limits the implementation of large-scale synthesis.

[0005] The key to overcoming the corresponding disadvantages of the above methods, namely the difficulty in isolating the desired compound in traditional liquid phase synthesis and the cost of using excess reagents and solvents in solid phase synthesis, is to invent a new compound that can combine the advantages of the above two methods, namely the high reactivity of traditional liquid phase synthesis and the effective separation technology of solid phase synthesis. In other words, if the reaction can be carried out in a homogeneous solution and the desired product or unwanted byproducts and compounds can be separated as a solid after the reaction is completed, the above limitations can be avoided. Early research in this field used polystyrene (PS) or polyethylene glycol (PEG) as soluble linkers instead of insoluble resins for peptide synthesis, where the soluble linker provides carboxyl terminal protecting groups for the growing polypeptide. Both coupling and deprotection are carried out on the soluble linker in homogeneous solution, and the unbound reactants are washed away by precipitating the growing polypeptide with the linker. However, due to the polymeric nature of PS or PEG, they are complex mixtures composed of chain units of different lengths, so structure determination and quality assurance become virtually impossible. The use of tri(alkoxy)benzyl alcohol as a soluble linker further improved the linker-assisted liquid phase synthesis. These tri(alkoxy)benzyl alcohol linkers are relatively small molecules with well-defined structures, so each step of the reaction can be monitored by thin layer chromatography (TLC) or other analytical methods, and the growing compound with the linker can be identified by nuclear magnetic resonance (NMR), mass spectrometry (MS) and / or other analytical methods. For example, these lipophilic benzyl alcohols are used as soluble linkers for peptide synthesis. Both coupling and deprotection are performed on the linker in a homogeneous solution using a solvent such as tetrahydrofuran (THF), and after the reaction is completed, the unbound reactants are washed away by precipitating the growing polypeptide with the linker using a different solvent such as acetonitrile. However, due to the structural characteristics of the phenol ether in the alkoxybenzyl linker, the phenol moiety tends to undergo electrophilic aromatic substitution, resulting in unexpected changes in the phenol core structure. In addition, due to the electron donating nature of the multiple alkoxy groups to the phenol core structure, the alkoxybenzyl linker is inherently sensitive under special conditions. For example, 2,4,5-tri(alkoxy)benzyl, 3,4,5-tri(alkoxy)benzyl and 2,4-di(alkoxy)benzyl compounds cannot withstand acidic treatment or oxidant treatment, while 3,5-di(alkoxy)benzyl and 2,5-di(alkoxy)benzyl compounds are sensitive to light, resulting in degradation of the linker or premature cleavage in multi-step synthesis. The sensitivity of the linker to acid, oxidant or light is unfavorable, limiting the applicability of the linker to prepare intermediates in multi-step synthesis involving acid, oxidant or light.

[0006] Therefore, there is a need for a broad and generally stable reagent that can not only be reproducibly converted from a soluble state to a solid state as the solution composition changes, but also has the flexibility to install a variety of linkers to meet specific synthetic needs. Such a reagent is soluble in one solvent system, allowing the reagent to link any suitable compound for a series of synthetic reactions, but is insoluble in another solvent system, so that the product can be "easily" obtained as a pure solid. Therefore, the reagent can be used in multi-step synthetic processes, allowing pure intermediates and pure products to be easily, quickly and reliably obtained as solids routinely. Invention Disclosure

[0007] Unless otherwise specified in a sentence, any technical terms and scientific terms used in this specification have the same meaning as those generally understood by those of ordinary skill in the art to which the present invention belongs. Any similar or equivalent methods and materials described in this specification can be used to implement or test the present invention, and preferred methods and materials will be described in the text. All publications and patents cited in this specification are cited here to describe and disclose the products and methods of making that can be used in connection with the present invention, such as those described in the publications. I. Abbreviations and Definitions

[0008] Before describing the detailed embodiments of the present invention, it is necessary to list the abbreviations and definitions used to describe the present invention. The following definitions apply only to the terms used in this patent. The following descriptions of preferred embodiments and examples are only for explanation and illustration. Therefore, they should not be considered to limit the scope of the invention defined by the claims. In addition, when examples are given, they are only for demonstration and not for limitation. For example, when an example "includes" a particular feature, it means that it may have that feature, but is not limited to examples containing that feature.

[0009] In describing and claiming the present invention, the following terminology will be used.

[0010] "Organic synthesis" is a special branch of chemical synthesis that deals with the deliberate production of organic compounds. Organic molecules are often complex, and their synthesis involves successive synthetic steps from simple, commercially available starting materials such as petrochemicals or natural precursors. Organic synthesis proceeds step by step until the molecule is complete; the compounds produced in each step before the last are called synthetic intermediates, and the compounds produced in the last step are called products. Each step of the synthesis involves a chemical reaction, and the reagents and conditions for each reaction must provide an adequate yield of the pure product.

[0011] "Column chromatography" is a chromatographic method in chemistry used to separate a single chemical compound from a mixture. Chromatography allows compounds to be separated based on their differential adsorption on an adsorbent; compounds move through the column at different rates, separating them into their different components. The technique has wide applicability because a variety of different adsorbents (normal phase, reversed phase, or other) and a variety of solvents can be used. The most common adsorbent used in column chromatography is silica gel. Silica gel is an amorphous, porous form of silicon dioxide (silica) consisting of an irregular three-dimensional framework of alternating silicon and oxygen atoms and nanometer-scale voids and pores. There is an important ratio between the weight of the adsorbent and the dry weight of the mixture containing the target compound to be purified. For silica gel column chromatography, this ratio ranges from 20:1 to 100:1, depending on the elution of the target compound. A single solvent or a mixture of solvents is used as the eluent to move the compound through the column. Column chromatography is an extremely time-consuming step in the laboratory and can easily become a bottleneck in any process development due to the large amount of solvents and labor required.

[0012] "Solid phase synthesis" is a method of covalently bonding molecules to functionalized linkers on a solid support material and synthesizing them stepwise in a single reaction vessel using selective protecting group chemistry. Compared with conventional synthesis in solution state, its advantages include high efficiency, high quantity, simplicity and rapidity. By using excess reagents, the reaction can be completed and high yields can be obtained. This method is often used to synthesize biomolecules such as peptides, deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and other molecules that need to be synthesized in a specific arrangement. These biomolecules can be obtained by cutting from the solid support by appropriate methods.

[0013] "Traceless synthesis" represents a smart synthesis strategy using functionalized linkers on soluble or insoluble supports. Compounds synthesized on this support can be released without any trace of linkers, which were used to connect intermediates during the synthesis. Therefore, the target product consists only of components (atoms, functional groups) inherent to the target structure.

[0014] "Biomolecule" refers to a substance with biological activity, including therapeutic compounds or diagnostic agents, as well as lead compounds in the context of research and development. In addition, the term also includes various probes (e.g., oligonucleotides alone or oligonucleotides with imaging agents attached) and substances that can alter biological processes within cells. Biomolecules include small organic molecules, which refer to carbon-containing agents with a molecular weight of less than or equal to 1000 Daltons. Biomolecules also include macromolecules, which refer to macromolecules of biological or synthetic origin with a molecular weight greater than 1000 Daltons, such as, but not limited to, polypeptides, proteins, oligonucleotides, polynucleotides and their analogs, such as peptide nucleic acids (PNA).

[0015] "Therapeutic compound" refers to, but is not limited to, any composition that can be beneficial to a mammal. Many such compounds, when taken up by cells, cause observable changes in the structure, function, or composition of the cells. Observable changes include increased or decreased expression of one or more proteins, phosphorylation of proteins or other cellular components, inhibition or activation of enzymes, inhibition or activation of binding thereof, increased rate of synthesis of metabolites, increased or decreased cell proliferation, etc. Other compounds can exert a therapeutic effect when present in tissues even without entering cells.

[0016] "Diagnostic agent" refers to diagnostic imaging agents and contrast agents. The following are non-limiting examples of diagnostic agents: radiolabeled substances, substances used in magnetic resonance imaging, and molecular sensors.

[0017] "Triazine" refers to 1,3,5-triazine (i.e., s-triazine), which is a class of nitrogen-containing heterocycles. Most triazine derivatives are prepared using cyanuric chloride as a starting material, and their three independent and easily adjustable ring positions are conveniently subjected to continuous nucleophilic substitution reactions with various sulfur-, oxygen-, and nitrogen-containing nucleophiles. After all three chlorine atoms are replaced with sulfur-, oxygen-, and nitrogen-containing nucleophiles, the triazine heterocycle can remain intact under a wide range of reaction conditions as a stable core. Therefore, the triazine core is used as the privileged structure of the lipophilic linker of the present invention.

[0018] "Lipophilic reagent" refers to a lipophilic reagent containing a triazine core having a specific "lipophilic group" in the present invention. The lipophilic reagent containing a lipophilic group in the present invention has the property of being able to repeatedly change from a dissolved state to a solid state according to the change of the solution composition. In the multi-step synthesis of biomolecules, the cycle of each reaction step only involves mixing with the reactants in the solution, then precipitating it by changing the solution composition, and then filtering to obtain the precipitated solid. This cycle can be actually performed over and over again during the progress of the synthesis task. In addition, after completing the multi-step synthesis task of the target molecule, the lipophilic reagent is appropriately recycled to regenerate its initial form and can be used again for subsequent tasks of synthesizing the same or different target molecules. Therefore, these cycles can be technically performed for unlimited tasks, indicating its green practicality (saving resources and protecting the environment) in multi-step synthesis tasks and the importance of multiple tasks in the future. The appropriate linker for biomolecule synthesis is called a "lipophilic linker" after connecting the lipophilic reagent, and the lipophilic reagent that connects the reaction site as part of the target compound is called a "lipophilic reagent". Lipophilic reagents include lipophilic linkers and lipophilic reagents. The lipophilic reagent after reacting with the target compound is called a “lipophilic derivative.” The lipophilic reagent and the lipophilic derivative containing a lipophilic linker are both soluble in one solvent system and become insoluble after changing the solvent system.

[0019] "Lipophilic group" refers to a lipophilic group having a carbon number of 12 to 48, which may have substituents attached to the triazine core to form the lipophilic agent of the present invention. II. Problems to be solved by the invention

[0020] In the process research and development of compounds, especially biomolecules as drugs, the main efforts are focused on the post-reaction treatment and purification methods of each intermediate and the final product in the multi-step organic synthesis. The method of separating a specific compound from a mixed solution as a solid is the best. This is because, by solidifying (or crystallizing) a specific component, the separation and / or purification after the reaction can be simplified. The solidification (or crystallization) of a specific component in a solution in this way is achieved by satisfying special conditions in the relationship between the chemical properties and physical properties of the component and the solvent. In many cases, the solidification (or crystallization) conditions are found based on the experience of repeated trials. Especially recently, in continuous multi-step syntheses such as compound library synthesis used in drug research and development, after each reaction is completed, the desired compound is solidified (or crystallized), making the separation of the solidified (or crystallized) material easy, thereby improving the efficiency of process development. On the contrary, by solidifying (or crystallizing) unwanted compounds, the removal of the solidified (or crystallized) material becomes easy, thereby helping to prevent the process from becoming complicated. Finding solidification (or crystallization) conditions leads to very expensive and time-consuming process development. When all efforts have failed to find a process to isolate the desired compound as a solid, column chromatography becomes the last resort for purification. However, column chromatography is extremely time-consuming and costly due to the labor and large amounts of solvents required.

[0021] In the case of reactions using chemical functionalized reagents on solid supports (such as polystyrene resins), the reaction sites are only at the solid-liquid interface, so the reaction activity is generally low. This method of synthesis on a solid support allows each step of the reaction to be carried out attached to the solid support, making it convenient to remove unnecessary excess reagents, by-products, catalysts, etc. by simply washing the solid phase with a specific solvent. Although the advantages of solid phase synthesis include high efficiency and high speed, its disadvantages include: (a) the need to use excess reagents for complete reaction, and (b) a large amount of solvent is required for each reaction and washing. These problems are particularly prominent in large-scale synthesis because the scale of synthesis is limited and the overall cost is significantly increased.

[0022] The present invention is proposed to overcome the above problems and aims to provide a lipophilic reagent for organic synthesis and a method of using the same. The lipophilic reagent is soluble in one solvent system, so any suitable compound can be dissolved together in a homogeneous solution for a synthetic reaction; while it is insoluble in another solvent system, so that the desired compound can be separated as a solid. Alternatively, the unwanted compound can be removed by forming a solid from the solution phase after the reaction is completed, thereby preventing the purification process from becoming complicated. III. Lipophilic Reagents

[0023] The embodiments of the present invention are described in detail as follows. These embodiments do not limit any manner of using a lipophilic reagent to perform an organic synthesis reaction in the present invention, and the manner can be appropriately modified within the scope of the present invention. Lipophilic group

[0024] "Lipophilic group" refers to the lipophilic agent of the present invention, which includes a triazine core having a specific lipophilic group. The lipophilic group in this embodiment is shown in chemical formula (1): Chemical formula (1): In this chemical formula: R 1 , R 2 is the designated position of the lipophilic group, which can be different lipophilic groups. 1 and R 2 may be the same or different and are independently selected from an alkyl group having 12 to 48 carbon atoms (which may have a substituent), an alkoxy group having 12 to 48 carbon atoms (which may have a substituent), an aryl group having 12 to 48 carbon atoms (which may have a substituent), an alkylthio group having 12 to 48 carbon atoms (which may have a substituent), an alkylamino group having 12 to 48 carbon atoms (which may have a substituent), and a dialkylamino group having 12 to 48 carbon atoms (which may have a substituent), and R 1 and R 2It contains at least two lipophilic groups, including an alkyl group with 12 to 48 carbon atoms, an alkoxy group with 12 to 48 carbon atoms, an alkylthio group with 12 to 48 carbon atoms, and an alkylamino group or a dialkylamino group with 12 to 48 carbon atoms (which may have a substituent). In the chemical formula, X represents the active site of the lipophilic reagent, which contains one or more atoms selected from carbon atoms, halogen atoms, nitrogen atoms, oxygen atoms, silicon atoms or sulfur atoms. Through the active site X, the lipophilic group is connected to it to form a lipophilic reagent. A lipophilic reagent containing a suitable linker for biomolecule synthesis is called a "lipophilic linker", a lipophilic reagent containing a reaction site for being a part of a target compound is called a "lipophilic reagent", and the lipophilic reagent after reacting with the target compound is called a "lipophilic derivative".

[0025] Because the above compounds contain at least two lipophilic groups selected from alkyl, alkoxy, alkylthio, alkylamino or dialkylamino (having 12 to 48 carbon atoms and may have substituents), they have sufficient lipophilicity and can be dissolved in a wide range of organic solvents. Therefore, the lipophilic reagent and the lipophilic derivative obtained by the reaction with the target compound have the property of being able to change from a dissolved state to a solid state repeatedly according to the change of the solution composition. In addition, the lipophilic group structure of the lipophilic reagent is stable to acid treatment, alkali treatment, oxidation treatment or light treatment, and is particularly suitable for a wide range of organic synthesis. Active site

[0026] In the above chemical formula (1), X represents an active site containing at least one atom selected from carbon, halogen (including fluorine, chlorine, bromine and iodine), oxygen, sulfur and nitrogen. Here, X may also have a structure represented by the following chemical formula (1P), (1C) or (1H), which respectively represent a secondary amine derived from piperazine, a carboxyl group derived from isonicotinic acid or a hydroxyl group derived from 4-piperidinol.

[0027] In addition, the lipophilic reagent (1P) can react with a suitable reagent to form a corresponding amide bond, thereby installing a functional group to become a lipophilic linker. Common linkers include, but are not limited to, the following. The functionalized linker can have a structure shown in the following chemical formulas (1A), (1B), (1W), (1T), and (1R). A represents a carboxylic acid functional group derived from succinic acid, B represents a benzyl alcohol functional group derived from 4-hydroxymethylbenzoic acid, W represents a hydroxyl functional group containing para-hydroxybenzyl alcohol, T represents a trityl alcohol group that needs to be converted into a chlorinated derivative, and R represents a Rink amide group containing an amino functional group. The nature of the linker determines the chemical method used in organic synthesis, especially the conditions for the cleavage of the product from the lipophilic linker. IV. Solutions to the problem

[0028] The present invention solves the problem of simplifying the purification process in organic synthesis by utilizing a lipophilic reagent containing a triazine core with a defined lipophilic group. This lipophilic reagent has the unique property of being able to change from a dissolved state to a solid state repeatedly as the composition of the solution changes. This property makes the purification of the desired intermediates and final products in solid form simple and cost-effective. Alternatively, it can also separate unnecessary compounds from the solution phase after the reaction is completed, thereby further simplifying the process.

[0029] The composition of the lipophilic agent includes a triazine core having specific lipophilic groups, each of which has a carbon number of 12 to 48 and may have a substituent, and an active site. The triazine core having the lipophilic group functions as a lipophilic group and is referred to as a "lipophilic group", while the lipophilic group having a carbon number of 12 to 48 and may have a substituent is referred to as a "lipophilic group".

[0030] Specifically, the present invention provides the following contents.

[0031] The first aspect of the present invention provides a lipophilic reagent containing a triazine core, which can be used in organic synthesis reactions, as shown in the following chemical formula (1), and has the characteristic of being able to repeatedly change from a dissolved state to a solid state according to changes in solution composition.

[0032] In this chemical formula, the lipophilic group R 1 and R 2 They may be the same or different and are independently selected from the following groups: alkyl groups having 12 to 48 carbon atoms (which may have a substituent), alkoxy groups having 12 to 48 carbon atoms (which may have a substituent), aryl groups having 12 to 48 carbon atoms (which may have a substituent), alkylthio groups having 12 to 48 carbon atoms (which may have a substituent), alkylamino groups having 12 to 48 carbon atoms (which may have a substituent), and dialkylamino groups having 12 to 48 carbon atoms (which may have a substituent). In addition, in the chemical formula, X represents the active site of the lipophilic reagent, comprising one or more atoms selected from carbon atoms, halogen atoms, nitrogen atoms, oxygen atoms, silicon atoms, or sulfur atoms. The lipophilic group connected to the active site is referred to as a "lipophilic reagent". A lipophilic reagent comprising a suitable linker for biomolecule synthesis is referred to as a "lipophilic linker", a lipophilic reagent comprising a reactive site that can be a part of a target compound is referred to as a "lipophilic reagent", and a lipophilic reagent after reacting with a target compound is referred to as a "lipophilic derivative".

[0033] According to the lipophilic reagent of the first aspect, in addition to having an active site composed of carbon, halogen, oxygen, sulfur or nitrogen atoms, the substituents on its triazine ring also include at least two of the following groups: an alkyl group with a carbon number of 12 to 48 (which may have a substituent), an alkoxy group with a carbon number of 12 to 48 (which may have a substituent), an alkylthio group with a carbon number of 12 to 48 (which may have a substituent), an alkylamine group with a carbon number of 12 to 48 (which may have a substituent) or a dialkylamine group with a carbon number of 12 to 48 (which may have a substituent). Because of this, the lipophilic reagent can be uniformly dissolved in a high concentration in a variety of organic solvents, and can react efficiently with the target compound in a variety of organic solvents.

[0034] In addition, the lipophilic reagent according to the first aspect can also be mainly used as a nucleophilic scavenger, an electrophilic scavenger, a synthetic building block, a condensing agent or a traceless synthesis. That is, it can be used in a wide range of applications, as a reactant of unnecessary substances such as byproducts, catalysts and unreacted reaction substrates, as a reaction substrate in an organic synthesis reaction, and as a catalyst or reaction accelerator in an organic synthesis reaction. Due to its property of repeatedly changing from a soluble state to a solid state according to the change of the solution composition, it can be easily separated from the reaction system by solidification after the reaction.

[0035] In this way, any added compounds and generated by-products in a reaction involving a lipophilic reagent can be easily separated from the reaction system, or a specific reaction substrate or reaction accelerator involving a lipophilic reagent can be added to the reaction as a compound and can be easily separated from the reaction system after the reaction is completed.

[0036] In addition, when the lipophilic reagent of the first aspect is used for the reaction, the organic synthesis reaction can be carried out at a low cost, because compared with solid phase synthesis, there is no need to use excessive expensive reagents, and the purification process becomes simpler than the effort required to explore the solidification process in traditional organic synthesis, and a large amount of solvents and manpower for purification are saved, including the use of silica gel column chromatography. A green era may emerge, and the laborious silica gel column chromatography used for centuries as the basic method of purification in organic synthesis may become obsolete. Therefore, the present invention may cause a major revolution in the development of traditional synthesis processes.

[0037] Here, the lipophilic reagent means that it can be used to carry out an organic synthesis reaction or a process after the reaction, including a reaction substrate, a reaction accelerator, and a synthesis component, etc. The lipophilic reagent according to the present invention is not particularly limited in terms of the amount used, and can be used in any case, such as for industrial production in large quantities, or for testing, research, etc. in small quantities.

[0038] In addition, the lipophilic group of the present invention is a part of the lipophilic linker. In the present invention, the lipophilic group refers to the lipophilic group position in the compound shown in the chemical formula (1). Specifically, in the chemical formula (1), the lipophilic group refers to R connected to the triazine core. 1 and R 2 , excluding the active site X.

[0039] The second aspect of the present invention provides a lipophilic agent according to the first aspect, characterized in that, in the chemical formula (1), X as an active site is a functional group or a combination of functional groups that can be used for the following applications.

[0040] "Synthetic building block" refers to the organic synthesis reaction assembly provided in the present invention for synthesizing the desired compound, and is a general term for compounds that are introduced into any reaction substrate through a chemical bond to give the reaction substrate a certain reagent activity. Functional groups with derivatization or conversion capabilities can be used as synthetic building blocks. An example of including piperazine (1P) as a secondary amine is shown below.

[0041] "Traceless synthesis" refers to various synthetic strategies for preparing target products in a traceless manner, wherein the target product consists only of components (atoms, functional groups) inherent to the target core structure. However, to date, almost all traceless syntheses have been performed on solid phase materials, which limits their application in large-scale synthesis of various biomolecules. Traceless synthesis can be performed in solution by connecting a suitable linker to a lipophilic group to form a lipophilic linker. Compounds synthesized on lipophilic linkers can be released without leaving traces of linkers used as intermediates in the synthetic process. This application extends the use of lipophilic linkers from traditional biomolecule synthesis (such as peptides and oligonucleotides) to the strategic synthesis of organic compounds of various structural types. The lipophilic reagents of the present invention may significantly revolutionize synthetic chemistry.

[0042] The third aspect of the invention provides a lipophilic agent according to the first or second aspect, wherein R in the chemical formula (1) is 1 and R 2 independently selected from the group consisting of an alkylamino group or a dialkylamino group having 12 to 48 carbon atoms (which may have a substituent) and an alkoxy group having 12 to 48 carbon atoms (which may have a substituent), the group being shown in the following chemical formulas (2, 2' and 2"), wherein R of the chemical formulas 2, 2' and 2" is 3 -NR 4 is R of the chemical formula (1) 1 , and R in Formula 2 5 -NR 6 , R of chemical formula 2' 5-O and R of chemical formula 2" 3 -NR 4 are respectively R of the chemical formula (1) 2 .

[0043] R 3 , R 4 and R 5 may be the same or different and are independently selected from the group consisting of an alkyl group having 12 to 48 carbon atoms (which may have a substituent), R 6 It may include a hydrogen atom, or a short-chain alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, etc. Preferably, R 6 Including short chain alkyl groups such as methyl, ethyl, propyl, isopropyl or butyl. Thus, the lipophilic group does not contain any active protons to prevent possible interference in multi-step synthesis under a wide range of reaction conditions. In addition, in this formula, X represents the active site of the lipophilic agent, which has one or more atoms selected from the group including carbon atoms, halogen atoms, nitrogen atoms, oxygen atoms, silicon atoms or sulfur atoms.

[0044] For the synthesis of a lipophilic reagent as shown in Chemical Formula 2, wherein R 3 , R 4 , R 5 and R 6 First, at a low temperature of 0°C to 20°C, an equivalent of R 3 and R 4 to replace the first chlorine atom of cyanuric chloride in the presence of a base such as N,N-diisopropylethylamine, followed by a reaction of one equivalent of a cyanuric acid containing R at a temperature of 20°C to 50°C. 5 and R 6 The second amine of 2-nitropropylidene amine is subjected to a nucleophilic substitution reaction to replace the second chlorine atom of cyanuric chloride in the presence of a base such as N,N-diisopropylethylamine. The third amine such as piperazine is subjected to a nucleophilic substitution reaction to replace the third chlorine atom of cyanuric chloride at an elevated temperature of 50°C to 100°C to generate compound 2P. P represents the secondary amine from piperazine. The chemical reaction formula is shown below:

[0045] For the synthesis of a lipophilic reagent as shown in Chemical Formula 2', wherein R 3 , R 4 and R 5 The same or different, firstly, at a low temperature of 0°C to 20°C, containing R 5The nucleophilic substitution reaction of one equivalent of an alcohol to replace the first chlorine atom of cyanuric chloride in the presence of a base such as N,N-diisopropylethylamine is then carried out at a temperature of 20°C to 50°C. 3 and R 4 The first amine is subjected to a nucleophilic substitution reaction to replace the second chlorine atom of cyanuric chloride in the presence of a base such as N,N-diisopropylethylamine. Finally, a second amine such as piperazine is subjected to a nucleophilic substitution reaction at a high temperature of 50°C to 100°C to replace the third chlorine atom of cyanuric chloride to generate compound 2'P. P represents a secondary amine from piperazine. The chemical reaction formula is shown below:

[0046] For the synthesis of a lipophilic reagent as shown in Chemical Formula 2, wherein R 3 and R 4 The two equivalents of R 3 and R 4 The first amine of is subjected to a nucleophilic substitution reaction to replace the two chlorine atoms of cyanuric chloride at a high temperature of 20°C to 50°C in the presence of a base such as N,N-diisopropylethylamine. Then a second amine is used to undergo a nucleophilic substitution reaction to replace the third chlorine atom of cyanuric chloride at a high temperature to install the active site X. In the chemical reaction formula shown in the figure below, piperazine is used as an example of the second amine, and the reaction is carried out at a high temperature of 50°C to 100°C to replace the third chlorine atom of cyanuric chloride to generate compound 2"P, in which piperazine serves as an active site. P represents a secondary amine from piperazine.

[0047] The fourth aspect of the present invention provides a lipophilic agent according to the third aspect, wherein in the chemical formula (2, 2' and 2"), R 3 , R 4 and R 5 is n-octadecyl, R 6 is a methyl group, which is represented by the following chemical formula (3M, 3G and 3Q) (M represents a melamine core, whose basic structure is 2,4,6-triamino-1,3,5-triazine. G represents a guanamine core, whose structure is very close to melamine, but one substituent is different from the amino group. Q represents a melamine core containing a quadruple n-octadecyl group): X represents the active site of the lipophilic agent, and the active site comprises one or more atoms selected from carbon atoms, halogen atoms, nitrogen atoms, oxygen atoms, silicon atoms or sulfur atoms. According to the fourth aspect, the lipophilic agents (3M) and (3G) each have three n-octadecyl groups, and the lipophilic agent (3Q) has four n-octadecyl groups. They can be uniformly dissolved in high concentrations in many organic solvents, and can react with other compounds in many organic solvents with high reactivity.

[0048] The lipophilic agents represented by chemical formulas (3M), (3G) and (3Q) can be linked to secondary amines such as piperazine to provide active sites containing secondary amines. The corresponding structures (3MP), (3GP) and (3QP) are shown below. P represents a secondary amine derived from piperazine.

[0049] Therefore, taking the synthesis of lipophilic reagent 3QP as an example, two equivalents of dioctadecylamine are used for nucleophilic substitution at a temperature between 20°C and 50°C, and two chlorine atoms of cyanuric chloride are replaced in the presence of a base such as N,N-diisopropylethylamine. Piperazine is used for nucleophilic substitution, and the third chlorine atom of cyanuric chloride is replaced at a high temperature of 50°C to 100°C, to obtain compound 3QP with piperazine installed as an active site.

[0050] Lipophilic agents, as shown in the chemical formula (3M, 3G and 3Q), can be linked to amino acids such as isonicotinic acid to provide an active site containing a carboxylic acid. Its structure (taking 3Q derivative 3C as an example) is shown below: wherein the amino acid is combined with 3Q to form an active site containing a carboxylic acid.

[0051] Lipophilic reagents, as shown in the chemical formula (3M, 3G and 3Q), can be linked to amino alcohols such as 4-piperidinylmethanol to provide an active site containing an alcohol. Its structure (taking 3Q derivative 3H as an example) is shown below: wherein the amino alcohol is combined with 3Q to form an active site containing an alcohol.

[0052] The lipophilic reagent 3H contains a hydroxyl group, for example, and can be used as a linker by forming an ester bond with the carboxyl group of the target compound. After completing the multi-step synthesis task of the target molecule, the linker can be broken by the following methods to obtain the target molecule with a carboxyl group: carboxylate with sodium hydroxide, hydrazine with hydrazine, amide with ammonia, and alcohol with lithium borohydride. At the same time, the linker can be easily restored to its original form and can therefore be reused in subsequent tasks to synthesize the same target molecule or a different target molecule. Therefore, the linker can be reused in virtually unlimited tasks, providing green benefits (saving resources and protecting the environment) for multi-step synthesis tasks and further tasks.

[0053] In addition, the lipophilic reagents (3MP, 3GP, 3QP) of the fourth aspect are very useful for multi-step synthesis of biomolecules such as polypeptides after the lipophilic reagents are derivatized to form corresponding amide bonds with suitable reagents. The nature of the linker determines the chemical reaction used for the synthesis, and in particular determines under what conditions the biomolecule can be cleaved from the lipophilic linker.

[0054] The typical steps of each cycle of organic reactions for the synthesis of biomolecules using lipophilic linkers include the following:

[0055] (a) The lipophilic linker is dissolved in the reaction solvent system.

[0056] (b) reacting the lipophilic linker with the target compound.

[0057] (c) precipitating the derivative of the lipophilic linker and the target compound from the reaction solvent system by repeatedly converting the derivative from a dissolved state to a solid state according to a change in the composition of the solution. The change in the composition of the solution includes adding a poor solvent relative to the lipophilic derivative to the reaction system.

[0058] (d) using a suction filter to perform solid-liquid separation to obtain a derivative.

[0059] Common linkers include but are not limited to the following.

[0060] Lipophilic carboxylic acid linker (3A derived from 3QP as an example): This linker can be formed with succinic anhydride and used to synthesize biomolecules that usually contain hydroxyl groups. The formed ester bond can eventually be cleaved using sodium hydroxide, hydrazine or ammonia to obtain a biomolecule product with a hydroxyl group.

[0061] Lipophilic HMBA linker (taking 3B derived from 3QP as an example): This linker can be formed into hydroxymethylbenzamide (HMBA) for the synthesis of target molecules such as peptides. The hydroxyl group can form an ester bond with the amino acid of a peptide with a specific sequence, and the ester bond can be cut by using sodium hydroxide, hydrazine, ammonia or lithium borohydride to obtain a peptide product in the form of carboxylate, hydrazine, amide or alcohol at the C-terminus of the peptide.

[0062] Lipophilic p-oxybenzyl alcohol linker (3W derived from 3QP as an example): This linker contains a functional group of p-oxybenzyl alcohol and can be used to synthesize target biomolecules such as polypeptides. When the lipophilic linker (3W) is used for peptide synthesis reaction, the hydroxyl group can form an ester bond with the first amino acid as the target compound, thereby obtaining a lipophilic derivative containing the first amino acid. Further amino acids are gradually extended by reacting with the amino acids of the corresponding lipophilic derivatives, that is, an amino acid extension reaction step is performed, in which another amino acid reacts with the amino acid of the lipophilic derivative. After the amino acid extension reaction step with a predetermined sequence is completed, the synthesized polypeptide and the lipophilic linker are separated by adding an acid such as 90-95% trifluoroacetic acid (TFA), thereby obtaining a peptide product in the form of a carboxylic acid at the C-terminus of the polypeptide.

[0063] Lipophilic trityl alcohol linker (3T derived from 3QP as an example): This linker contains a trityl alcohol functional group. The hydroxyl form of trityl alcohol is stable and suitable for storage, but needs to be chlorinated to form trityl chloride before use. This linker can be used to synthesize biomolecules such as peptides. The ester bond formed with the amino acids of the peptide of a given sequence can be finally cleaved and the peptide product with a carboxylic acid at the C-terminus can be separated in a mixture of 1-5% trifluoroacetic acid (TFA) and dichloromethane.

[0064] Lipophilic Rink amide linker (3R derived from 3QP as an example): This lipophilic reagent (3QP) can functionalize amino groups and be used to synthesize biomolecules such as peptides. The amide bond formed by the amino acids of the peptide of the given sequence is finally treated with 50% trifluoroacetic acid (TFA) in dichloromethane for 1 hour to cleave and separate the peptide product with amide at the C-terminus.

[0065] In addition, the lipophilic agent of this embodiment can be a compound represented by the following chemical formula (3QP).

[0066] That is, the compound represented by the chemical formula (3QP) is a lipophilic agent represented by the chemical formula (1), wherein in the chemical formula (1), X is a piperazine group, R 1 and R 2 Alternatively, the compound represented by the chemical formula (3QP) is a lipophilic agent represented by the chemical formula (2"), wherein in the chemical formula (2"), X is a piperazine group, R 3 and R 4 Therefore, the lipophilic agent 3QP is preferably a structure of the chemical formula (1) including a triazine core, which has a lipophilic group R 1 and R 2 , where R 1 and R 2 All are N,N-dioctadecylamine. The amino functional group in piperazine is active and can form a variety of derivatives, which are very useful for further organic synthesis of biomolecules. Method for producing lipophilic reagent

[0067] The method for making the lipophilic reagent shown in the above compound is not particularly limited, but it can be generally synthesized using cyanuric chloride as a starting material. This is because the three independent and easily regulated ring positions of cyanuric chloride can conveniently undergo orderly nucleophilic substitution reactions with a variety of nucleophilic reagents containing sulfur, oxygen and nitrogen. Therefore, the triazine core is used as a privileged structure for assembling the lipophilic reagent of the present invention.

[0068] Cyanuric chloride has three chlorine atoms and can react sequentially with nucleophiles containing alcohol oxygen, thiol sulfur or amine nitrogen. The first nucleophilic substitution reaction can be carried out at a low temperature of 0°C to 20°C, reacting with nucleophiles containing alcohol oxygen, thiol sulfur or amine nitrogen. The second nucleophilic substitution reaction can be carried out at an elevated temperature of 20°C to 50°C, reacting with nucleophiles containing amine nitrogen. The third nucleophilic substitution reaction can be carried out at a higher temperature of 50°C to 100°C, reacting with nucleophiles containing amine nitrogen. Therefore, a lipophilic reagent having a triazine core with a specific lipophilic group is prepared by nucleophilic substitution reactions with nucleophiles containing alcohol oxygen, thiol sulfur and amine nitrogen, and these nucleophiles have a lipophilic group with a carbon number of 12 to 48 (which may have a substituent). Organic synthesis reaction method

[0069] The lipophilic reagent of the present embodiment can be used by the same method as the reagent without lipophilic group used in common solution phase organic synthesis reaction. That is, in the state that the reaction substance is dissolved or dispersed in the solvent, a lipophilic reagent with a reaction site or functional group is added and reacted. Here, the solvent used in the reaction system can be a general organic solvent, but since the higher the solubility of the lipophilic reagent in the solvent, the higher the reaction activity, it is preferred to select a solvent with high solubility of the lipophilic reagent. Specifically, toluene, xylene (including o-xylene, m-xylene, p-xylene or a mixture thereof), trifluorotoluene, tetrahydrofuran (THF), tert-butyl methyl ether, hexane, heptane, cyclohexane, etc. are preferred, but not limited to these. Although dichloromethane, 1,2-dichloroethane and chloroform are useful, they are not recommended due to their harm to the environment and toxicity to health. In order to confirm the progress of the reaction, a method for general solution phase organic synthesis reaction can be adopted. That is, thin layer silica gel chromatography, high speed liquid chromatography and other methods can be used to track the reaction. React App

[0070] In the reaction step, the desired lipophilic derivative can be obtained by reacting the specified reaction substance and the lipophilic reagent with a reaction site or functional group of the present embodiment. In addition, any chemical reaction can be performed to obtain the desired compound. The residual reaction substances and by-products added to the reaction system can also be reacted with the lipophilic reagent with a reaction site or functional group to remove the residual reaction substances added to the reaction system and the by-products formed in the reaction system. The application of the lipophilic reagent of the present embodiment is not limited to being used as a nucleophilic scavenger and an electrophilic scavenger, and a synthetic component. More importantly, the lipophilic reagent of the present embodiment can be used for the synthesis of biomolecules, particularly the synthesis of macromolecules such as oligonucleotides and polypeptides. Use of lipophilic reagents as synthetic building blocks

[0071] In the case where the lipophilic reagent of the present embodiment is used as a synthetic component, for example, it can be considered that the lipophilic reagent is used as a reaction reagent for nucleophilic addition reaction, nucleophilic substitution reaction, dehydration condensation reaction, etc. As organic synthesis reaction reagents that can be used for such reactions, there are no particular restrictions. For example, in the lipophilic reagent shown in the chemical formula (1), lipophilic reagents (1P), (1C) and (1H) with X as an active site can be mentioned. As a solvent used in the reaction, any solvent commonly used in these reactions can be used. In the present embodiment, from the perspective of the solubility of the lipophilic reagent having a lipophilic group, toluene, xylene (including o-xylene, m-xylene, p-xylene or a mixture thereof), trifluorotoluene, tetrahydrofuran (THF), tert-butyl methyl ether, hexane, heptane, cyclohexane, etc. can be used. Peptide synthesis using lipophilic reagents

[0072] In the lipophilic reagent of this embodiment, X contains a p-oxybenzyl alcohol group as the structure of the chemical formula (1) shown by the functional linker (1W), which is particularly suitable for peptide synthesis. By condensing the carboxyl group of the amino acid with the alcohol group of the lipophilic linker (1W) to form an ester bond, the amino acid is used as a C-terminal carboxyl protecting group to form a lipophilic derivative, and the derivative serves as a lipophilic group for continuous peptide extension. Therefore, in the state where the carboxyl group is bound to the lipophilic linker, the peptide synthesis reaction can be carried out by gradually forming bonds with the activated amino acid. After each step of peptide synthesis, the polypeptide connected to the lipophilic linker can be collected as a solid by changing the solution composition, while the excess residual reaction substrate remains in the reaction solution system and can be removed by filtration. After the peptide synthesis reaction is completed, by adding an acidic reagent such as trifluoroacetic acid (TFA) to the polypeptide containing the lipophilic linker, the polypeptide can be separated from the lipophilic linker to obtain the polypeptide. Therefore, by connecting with the lipophilic linker, the synthesis method provides a simple purification process for each step of peptide extension and eliminates the limitation of large-scale synthesis.

[0073] The application of lipophilic linkers using the reactive site of p-oxybenzyl alcohol (1W) as a functional linker in peptide synthesis is representative. In addition, the hydroxyl functional group formed by derivatization of 4-hydroxymethylbenzoic acid linker (1B), trityl chloride converted from trityl alcohol linker (1T), and Rink amide linker (1R) with lipophilic linkage are also commonly used in peptide synthesis. The nature of the linker determines the chemical reaction used, especially the conditions for cleaving the product from the lipophilic linker. For example, the lipophilic linker (1B) can be cleaved by sodium hydroxide to obtain a peptide product with a carboxylate at the C-terminus; hydrazine to obtain a hydrazine group; ammonia to obtain an amide; and lithium borohydride to obtain an alcohol. The lipophilic linker (1T) can be cleaved by 1-5% TFA (in dichloromethane) within 1 minute to obtain a peptide product with a carboxylic acid at the C-terminus; the lipophilic linker (1R) can be cleaved by 50% TFA (in dichloromethane) within 1 hour to obtain a peptide product with an amide at the C-terminus. Separation by changing the composition of the solution

[0074] The lipophilic agent of the present invention reacts sensitively to changes in solution composition and can crystallize rapidly. Therefore, the lipophilic agent and its derivatives can be solidified (or crystallized) by changing the solution composition.

[0075] As a preferred method for changing the composition of the solution, a poor solvent for lipophilic reagents and their derivatives can be added to the reaction solution. A poor solvent is a solvent that is compatible with the reaction solvent but causes the lipophilic reagent and / or its derivatives to precipitate or solidify. By adding a poor solvent that is highly compatible with the reaction solvent, the solution phase will not separate, so the solution composition can be easily changed. The poor solvent can use the same solvent as the reaction solvent, or use a different solvent. For example, when using toluene, xylene (including o-xylene, m-xylene, p-xylene or a mixture thereof), trifluorotoluene, tetrahydrofuran (THF), tert-butyl methyl ether, hexane, heptane, cyclohexane, etc. as the reaction solvent, methanol, ethanol, isopropanol, 2,2,2-trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, acetic acid, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), etc. can be used as a poor solvent. When a mixed solvent such as THF and DMF is used, methanol, ethanol, isopropanol, 2,2,2-trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, acetic acid, DMSO, etc. can be used as a poor solvent, and DMF can also be used as a poor solvent. By adding a poor solvent to the reaction solution, the polarity of the solution increases, the lipophilic reagent or its derivative can be crystallized and solid-liquid separation can be achieved. Solid-liquid separation can be performed using a suction filter. V. Effects of the Invention

[0076] According to the present invention, the lipophilic reagent can be uniformly dissolved in many organic solvents, so it can react with other compounds with high reactivity to form lipophilic derivatives. In addition, after the reaction, a variety of separation methods can be selected, such as a method for solid-liquid separation by crystallizing the lipophilic derivative, or by adding a separation solvent incompatible with the reaction solvent and separating the lipophilic derivative with a liquid-liquid extraction method. Since the separation conditions of these separation methods can be uniformly determined according to the characteristics of the lipophilic group as a key component of the lipophilic derivative, there is no need to consider the separation conditions according to the characteristics of each organic synthesis reaction or similar characteristics. This not only simplifies process development, but also accelerates the research and development of drugs, etc., by means of compound library synthesis, thereby contributing to technological innovation in the chemical industry.

[0077] In addition, after completing the task of synthesizing the target molecule in multiple steps, the lipophilic reagent can be reused for the task of synthesizing the same target molecule or a different target molecule by appropriately recycling and regenerating it into its original form. Therefore, the lipophilic reagent can be recycled. The synthesis of the lipophilic reagent of the present invention does not use particularly expensive compounds, and the synthesis using the lipophilic reagent does not require a large amount of excess reactants. Pure solid lipophilic derivatives can be obtained by only precipitating and filtering by changing the composition of the solution, thereby obtaining the required materials with minimal solvent consumption and labor input, and the lipophilic reagent can be regenerated after completing the multi-step synthesis. This shows that the use of lipophilic reagents for organic synthesis is not only economical and efficient, but also represents a major step forward in the greening of chemical processes in terms of promoting productivity, saving resources and protecting the environment. VI. Industrial Applications

[0078] According to the production method of organic synthesis using a lipophilic reagent, the reactant is soluble in a solvent system. Appropriate compounds combined with lipophilic reagents can react in homogeneous solutions, but are insoluble in other solvent systems, so that the desired compound can be separated as a pure solid. This method simplifies the process of separating pure products from reaction mixtures, avoiding the time-consuming and wasteful traditional column chromatography. More importantly, for the synthesis of biomolecules such as peptides and oligonucleotides, by adding a poor solvent after peptide extension or oligonucleotide extension to change the solvent composition for precipitation and solid-liquid separation, this method simplifies the process of separating pure intermediates and final products from reaction mixtures, avoiding the traditional solid phase synthesis method that limits large-scale production. Therefore, a convenient and efficient method for producing drugs such as peptides or oligonucleotides can be provided, which can scale up the production scale and is suitable for industrial production. Example

[0079] The present invention is explained below by the following examples, but the present invention is not limited to these examples. Unless otherwise stated, the practice of the present invention will use techniques such as synthetic organic chemistry, biochemistry, etc., which are well known in the art. These techniques are explained in detail in the literature. See, for example, Kirk-Othmer "Encyclopedia of Chemical Technology" and House's "Modern Synthetic Reactions".

[0080] The following examples are intended to provide a person of ordinary skill in the art with a complete disclosure and description of how to make and use the compositions / compounds / methods of the present invention. Every effort has been made to ensure accuracy in numbers (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should of course be allowed for. Unless otherwise noted, all raw materials were obtained from commercial sources. Example 1

[0081] Synthesis of 2-(4'-piperazinyl)-4-(N-methyl-N-octadecyl)amino-6-[N,N-di(n-octadecyl)amino]-1,3,5-triazine (3MP).

[0082] Cyanuric chloride (5 g, 27.1 mmol) was dissolved in toluene (200 mL) and mixed with N,N-diisopropylethylamine (DIPEA) (18.5 mL, 108.8 mmol). N-methyl-N-octadecylamine (7.68 g, 27.1 mmol) was added to the mixture cooled in an ice bath. Stir for 4 hours, and then the mixture was allowed to warm to room temperature. Di(n-octadecyl)amine (14.15 g, 27.1 mmol) was added to the mixture. Stir for 16 hours at room temperature. After the reaction was completed, ethanol (400 mL) was added, and the precipitation was filtered to obtain a solid product 2-chloro-4-(N-methyl-N-octadecyl)amino-6-[N,N-di(n-octadecyl)amino]-1,3,5-triazine (23.6 g, 95%).

[0083] 2-Chloro-4-(N-methyl-N-octadecyl)amino-6-[N,N-di(octadecyl)amino]-1,3,5-triazine (20 g, 21.8 mmol) was dissolved in toluene (300 mL). Piperazine (10 g, 116 mmol) dissolved in isopropanol (100 mL) was added to the mixture. Stir at 80°C for 16 hours. After the reaction was completed, most of the solvent was removed by evaporation. Ethanol was added to the residue, and after precipitation, suction filtration was performed to obtain a solid product 2-(4'-piperazinyl)-4-(N-methyl-N-octadecyl)amino-6-[N,N-di(octadecyl)amino]-1,3,5-triazine (20.4 g, 97%). Example 2

[0084] Synthesis of 2-(4'-piperazinyl)-4-n-octadecyloxy-6-[N,N-di(n-octadecyl)amino]-1,3,5-triazine (3GP).

[0085] Dissolve cyanuric chloride (25 g, 135.6 mmol) in toluene (1 L) and mix with DIPEA (92.23 mL, 542.32 mmol). Add n-octadecyl alcohol (37.4 g, 138.26 mmol) to the mixture cooled in an ice bath. Stir for 4 hours, then allow the mixture to warm to room temperature and continue stirring for 12 hours. Add di(n-octadecyl)amine (78.63 g, 150.64 mmol) to the mixture. Stir at room temperature for 16 hours. After the reaction is complete, add ethanol (1 L), precipitate and filter to obtain a solid product, 2-chloro-4-n-octadecyloxy-6-[N,N-di(n-octadecyl)amino]-1,3,5-triazine (121.6 g, 99%).

[0086] 2-Chloro-4-octadecyloxy-6-[N,N-di(octadecyl)amino]-1,3,5-triazine (40 g, 44 mmol) was dissolved in toluene (500 mL). Piperazine (20 g, 232 mmol) dissolved in isopropanol (200 mL) was added to the mixture. Stir at 50°C for 16 hours. After the reaction was completed, most of the solvent was removed by evaporation. Ethanol was added to the residue, and after precipitation, suction filtration was performed to obtain a solid product 2-(4'-piperazinyl)-4-octadecyloxy-6-[N,N-di(octadecyl)amino]-1,3,5-triazine (29.6 g, 71%). Example 3

[0087] Synthesis of 2-(4'-piperazinyl)-4,6-di[N,N-di(n-octadecyl)amino]-1,3,5-triazine (3QP).

[0088] Dissolve cyanuric chloride (10 g, 54.2 mmol) in toluene (400 mL) and mix with DIPEA (37 mL, 217.6 mmol). Add di(n-octadecyl)amine (56.6 g, 108.4 mmol) to the mixture cooled in an ice bath. After addition, remove the ice bath. Stir at room temperature for 16 hours. After the reaction is complete, add ethanol (800 mL), precipitate, and filter to obtain a solid product, 2-chloro-4,6-di[N,N-di(n-octadecyl)amino]-1,3,5-triazine (55.7 g, 89%).

[0089] Dissolve 2-chloro-4,6-di[N,N-di(n-octadecyl)amino]-1,3,5-triazine (25 g, 21.6 mmol) in toluene (375 mL). Add piperazine (10 g, 116 mmol) dissolved in isopropanol (100 mL) to the mixture. Stir at 80°C for 16 hours. After the reaction is complete, add ethanol, precipitate, and filter to obtain a solid product 2-(4'-piperazinyl)-4,6-di[N,N-di(n-octadecyl)amino]-1,3,5-triazine (25.1 g, 96%). Example 4

[0090] Synthesis of a lipophilic linker (3W) containing p-oxybenzyl alcohol.

[0091] 2-(4'-piperazinyl)-4,6-di[N,N-di(n-octadecyl)amino]-1,3,5-triazine (3QP) (2.41 g, 2.00 mmol) was dissolved in toluene (20 mL). Then 4-(hydroxymethyl)phenoxyacetic acid (373 mg, 2.05 mmol) and N,N'-diisopropylcarbodiimide (DIC) (265 mg, 2.10 mmol) were added to the solution for condensation reaction. The reaction mixture was stirred at room temperature until the reaction was completed (30 minutes). After the reaction was completed, acetonitrile was added to the reaction mixture to obtain a solid product, lipophilic linker (3W) (2.73 g) as a precipitate. The precipitate was filtered and washed with acetonitrile. Example 5

[0092] Peptide synthesis using lipophilic linker-3W.

[0093] Acetyl tetrapeptide-2 was synthesized using the lipophilic linker-3W. This tetrapeptide is able to mimic the youth hormone known as thymosin. By compensating for the loss of thymic factors with age, this peptide can stimulate the skin's immune defenses and help skin regeneration. The structure of the peptide is as follows: N2-acetyl-L-lysine-L-α-aspartic acid-L-valine-L-tyrosine. The synthesis process was carried out according to the following general procedure, using Fmoc-O-tert-butyl-L-tyrosine, Fmoc-L-valine, Fmoc-L-aspartic acid 4-tert-butyl ester, Na-Fmoc-Ne-Boc-L-lysine and acetic acid in that order.

[0094] General steps for adding the first amino acid

[0095] Lipophilic linker-3W was dissolved in toluene (1 mmol / 10 ml). Fmoc-amino acid (1.5 eq.), N,N′-diisopropylcarbodiimide (DIC) (1.5 eq.) and 4-(N,N-dimethylamino)pyridine (DMAP) (0.2 eq.) were then added to the solution. The reaction mixture was stirred at room temperature until the reaction was complete (30 min). After the reaction was complete, acetonitrile was added to the reaction mixture to precipitate the product quantitatively. The precipitate was filtered and washed with acetonitrile.

[0096] General procedure for coupling Fmoc amino acids

[0097] To a solution (0.10 M) of the peptides attached to the lipophilic linker-3W in THF were added the corresponding Fmoc-amino acid (1.2 mol equiv), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylaminophosphonate (HBTU) (1.2 mol equiv), 1-hydroxybenzotriazole (HOBt) (1.2 mol equiv) and DIPEA (2.4 mol equiv). The reaction mixture was stirred at room temperature until the reaction was complete (determined by thin layer chromatography). It was then diluted with acetonitrile to give the product as a precipitate.

[0098] General procedure for basic deprotection of peptides attached to lipophilic linker-3W

[0099] The peptide connected to the lipophilic linker-3W was dissolved in a solution of 1% piperidine and 1% 1,8-diazabicyclo[5.4.0]undecene (DBU) in THF (0.10 M). The resulting reaction mixture was stirred at room temperature until the reaction was complete (determined by thin layer chromatography). Acetonitrile was then added to precipitate the product.

[0100] General procedure for final cleavage of peptides from lipophilic linker-3W

[0101] The peptide connected to the lipophilic linker-3W was dissolved in 2.5% triisopropylsilane (TIS) and 2.5% water in trifluoroacetic acid (TFA). The reaction mixture was stirred at room temperature until the reaction was complete. After the reaction was complete, the solution was diluted with ethanol, filtered to remove the precipitate, and then tert-butyl methyl ether was added to the filtrate to precipitate the peptide quantitatively.

Claims

1. A compound of a lipophilic agent, comprising a lipophilic group having a triazine core represented by the following chemical formula (1) in an organic synthesis reaction: in, R 1 to R 2 may be the same or different and independently selected from any one of the following groups: an alkyl group having 12 to 48 carbon atoms, which may have a substituent; an alkoxy group having 12 to 48 carbon atoms, which may have a substituent; an aryl group having 12 to 48 carbon atoms, which may have a substituent; an alkylthio group having 12 to 48 carbon atoms, which may have a substituent; an alkylamino group having 12 to 48 carbon atoms, which may have a substituent; and a dialkylamino group having 12 to 48 carbon atoms, which may have a substituent. X represents the active site of the lipophilic agent, comprising one or more atoms, including a carbon atom, a halogen atom, a nitrogen atom, an oxygen atom, a silicon atom or a sulfur atom.

2. The compound of claim 1, wherein X represents an active site comprising the following structural formulas 1P, 1C, 1H, 1A, 1B, 1W, 1T, 1R:

3. The compound as claimed in claim 1, wherein R 1 and R 2 Independently selected from the following chemical formulas 2, 2' and 2" comprising an alkylamine group having a carbon number of 12 to 48 (which may have a substituent) and an alkoxy group having a carbon number of 12 to 48 (which may have a substituent): in, R 3 , R 4 and R 5 may be the same or different and are independently selected from an alkyl group having a carbon number of 12 to 48 (which may have a substituent), and R 6 It may include hydrogen atoms, methyl, ethyl, propyl, isopropyl or butyl groups, X represents the active site of the lipophilic agent, and has one or more atoms selected from carbon atoms, halogen atoms, nitrogen atoms, oxygen atoms, silicon atoms or sulfur atoms.

4. A compound as claimed in claim 3, wherein in the chemical formula (2, 2' and 2"), R 3 , R 4 and R 5 is n-octadecyl, R 6 is a methyl group, as shown in the following chemical formulas (3M, 3G and 3Q), X represents the active site of the lipophilic agent, and has one or more atoms selected from carbon atoms, halogen atoms, nitrogen atoms, oxygen atoms, silicon atoms or sulfur atoms:

5. A compound as claimed in claim 4, wherein X represents an active site comprising the following chemical formula 3QP, 3C, 3H, 3A, 3B, 3W, 3T, 3R:

6. The compound of claim 1, wherein the lipophilic reagent is useful in the multi-step synthesis of biomolecules.

7. A compound as claimed in claim 6, wherein the biomolecule is a polypeptide.

8. A method for synthesizing a compound containing a lipophilic agent, wherein the lipophilic agent comprises a triazine core and has the following chemical formula: in, R 3 and R 4 may be the same or different, independently selected from an alkyl group containing 12 to 48 carbon atoms (which may be substituted); X represents the active site of the lipophilic agent, which contains one or more atoms selected from the following: a carbon atom, a halogen atom, a nitrogen atom, an oxygen atom, a silicon atom or a sulfur atom. The method comprises: (i) using two equivalents of the first amine (including R 3 and R 4 ) replaces two chlorine atoms of cyanuric chloride by nucleophilic substitution reaction under alkaline conditions at elevated temperature; (ii) A second amine is used to replace the third chlorine atom of cyanuric chloride by a nucleophilic substitution reaction at high temperature, thereby introducing an active site X.

9. The method of claim 8, wherein the elevated temperature is between 20°C and 50°C.

10. The method of claim 8, wherein the elevated temperature is between 50°C and 100°C.

11. The method of claim 8, wherein the base is N,N-diisopropylethylamine.

12. The method of claim 8, wherein R 3 and R 4 It is n-octadecyl, and its chemical formula for lipophilic reagent is as follows:

13. The method of claim 12, wherein the active site X comprises piperazine, which has the following chemical formula for the lipophilic agent:

14. The method of claim 12, wherein the active site X comprises a functional linker.

15. The method of claim 14, wherein the functional linker comprises the following formula:

16. The method of claim 13, wherein a lipophilic agent is used to introduce the functional linker.

17. The method of claim 16, wherein the functional linker comprises the following formula:

18. The method of claim 17, wherein the lipophilic linker can be used for multi-step synthesis of biomolecules.

19. The method of claim 18, wherein the biomolecule is a polypeptide.

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