Synthesis method of cardiolipin compound

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to a synthesis method of a cardiolipin compound. The synthesis method comprises the following steps: carrying out selective transesterification on tris (2, 2, 2-trifluoroethyl) phosphate and benzyl alcohol to prepare a compound I; the compound I and the compound II are subjected to a substitution reaction to prepare a compound III; carrying out transesterification on the compound III and R1OH to prepare a compound IV; and carrying out reduction reaction on the compound IV to prepare a compound V. The synthesis method of the cardiolipin compound is based on the principle of selective esterification reaction, four-step synthesis is achieved through route design, the yield is high, aftertreatment is simple, large-scale standardized preparation is facilitated, cost is low, and the method has great market prospects.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceutical chemistry, and particularly relates to a method for synthesizing cardiolipin compounds. Background Art

[0002] Cardiolipin is a phospholipid with important physiological functions in organisms. It is composed of two phosphatidic acid molecules covalently linked by a glycerol molecule, so it is also called diphosphatidylglycerol. Cardiolipin plays a key role in mitochondrial-related energy metabolism and cell activities. It can be used to construct artificial membrane systems to study the energy metabolism process and apoptosis process of mitochondria. Cardiolipin is the main antigen component of serological tests for syphilis. The presence and titer of anti-cardiolipin antibodies in the patient's serum can be detected to assist in the diagnosis of syphilis infection. Cardiolipin has unique structures and properties and can be used to develop novel drug carriers. For example, anti-tumor drugs can be encapsulated in cardiolipin liposomes, enabling them to more effectively target tumor cells, improve the efficacy of the drugs, and at the same time reduce the toxic side effects on normal cells.

[0003] Given the wide applications of cardiolipin in diagnosis, pharmaceuticals, and scientific research, it is highly necessary to develop a large-scale preparation method for cardiolipin. However, currently, commercially available cardiolipin is mainly obtained by extraction from fresh calf heart cells, with high costs and limited yields. There are reported chemical synthesis methods for cardiolipin, mainly divided into two categories: (a) coupling the primary hydroxyl group of 2-O-protected glycerol with 1,2-O-diacyl-sn-glycerol using a phosphorylating agent; (b) condensing the primary hydroxyl group of 2-O-protected glycerol and phosphatidic acid in the presence of 2,4,6-triisopropylbenzenesulfonyl chloride (TPS) and pyridine; these two methods gradually construct phospholipid molecules starting from derivatives of substituted glycerol, with cumbersome steps, long reaction times, and high post-treatment costs.

[0004] Therefore, it is necessary to develop a simpler chemical synthesis method for cardiolipin. Summary of the Invention

[0005] Based on this, one or more embodiments of this application provide a method for synthesizing cardiolipin compounds. This synthesis method determines the construction order of three substituents, greatly simplifies the synthesis route, has high yields for each step without the need to input post-treatment components, and is suitable for large-scale production of cardiolipin compounds.

[0006] The technical solution of this application includes the following content:

[0007] A method for synthesizing cardiolipin compounds, comprising the following steps:

[0008] Compound I is prepared by the selective transesterification reaction of tris(2,2,2-trifluoroethyl) phosphate and benzyl alcohol;

[0009] Compound III is prepared by the substitution reaction of the said Compound I and Compound II;

[0010] Compound IV is prepared by the transesterification reaction of the said Compound III and R1OH;

[0011] Compound V is prepared by the reduction reaction of the said Compound IV;

[0012] (I);

[0013] (II);

[0014] (III);

[0015] (IV);

[0016] (V);

[0017] R1 is ;

[0018] R2 is an alkyl group.

[0019] In some embodiments, the selective transesterification reaction of tris(2,2,2-trifluoroethyl) phosphate and benzyl alcohol to prepare Compound I includes:

[0020] At -5°C to 5°C, tris(2,2,2-trifluoroethyl) phosphate and benzyl alcohol are stirred in a first organic solvent for 20 min to 40 min, and then a first organic base is added and stirred for 50 min to 70 min to obtain a first mixed solution;

[0021] The first mixed solution is stirred at 20°C to 40°C for 2 h to 4 h to obtain the said Compound I.

[0022] In some embodiments, the molar ratio of tris(2,2,2-trifluoroethyl) phosphate, benzyl alcohol and the first organic base is 1:(1 - 1.2):(1 - 1.2).

[0023] In some embodiments, the first organic solvent includes at least one of toluene, tetrahydrofuran and N,N-dimethylformamide; and / or,

[0024] The first organic base includes at least one of 1,8-diazabicyclo[5.4.0]undec-7-ene and lithium tert-butoxide.

[0025] In some embodiments, Compound I and Compound II are prepared into Compound III through a substitution reaction, including:

[0026] At -5°C to 5°C, Compound I and a second organic base are stirred in a second organic solvent for 20 min to 40 min to obtain a second mixed solution;

[0027] At -50°C to -40°C, Compound II is added to the second mixed solution and stirred for 7 h to 9 h to prepare Compound III.

[0028] In some embodiments, the molar ratio of Compound I, the second organic base, and Compound II is 1:(1 - 1.2):(0.5 - 0.6).

[0029] In some embodiments, the second organic solvent includes at least one of toluene, tetrahydrofuran, and N,N-dimethylformamide; and / or,

[0030] The second organic base includes at least one of lithium tert-butoxide and sodium tert-butoxide.

[0031] In some embodiments, Compound III and R1OH are prepared into Compound IV through a transesterification reaction, including:

[0032] At -50°C to -40°C, Compound III and a third organic base are stirred in a third organic solvent for 20 min to 40 min to obtain a third mixed solution;

[0033] At -50°C to -40°C, R1OH is added to the third mixed solution and stirred for 5 h to 7 h to prepare Compound IV.

[0034] In some embodiments, the molar ratio of Compound III, sodium tert-butoxide, and R1OH is 1:(1 - 1.2):(1 - 1.2).

[0035] In some embodiments, the third organic solvent includes at least one of toluene, n-hexane, tetrahydrofuran, and N,N-dimethylformamide; and / or,

[0036] The third organic base includes at least one of sodium tert-butoxide and lithium diisopropylamide

[0037] In some embodiments, Compound IV is prepared into Compound V through a reduction reaction, including:

[0038] Compound IV and palladium on carbon are stirred in a hydrogen environment for 8 h to 12 h to prepare Compound V.

[0039] The synthesis method of the cardiolipin compounds in this application is based on the principle of selective esterification reaction. Through route design, a four-step synthesis is achieved, with high yield, simple post-treatment, which is conducive to large-scale standardized preparation, low cost, and has great market prospects.

[0040] The synthesis method of the cardiolipin compounds in this application can synthesize cardiolipins with different side chains and side chains with special functional groups through stepwise substitution reactions, providing more possibilities for the clinical application of cardiolipin compounds. For example, the cardiolipin can be modified through the side chain group to obtain a drug carrier with higher delivery efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In order to more clearly illustrate the specific embodiments of this application or the technical solutions in the prior art, the following will briefly introduce the drawings required for the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of this application. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0042] Figure 1 The chromatograms obtained by separating and purifying Compound 2 and Compound 3 in Example 1 of this application using high performance liquid chromatography are respectively Figure 1 the corresponding peak eluting at 30.5 min for A in Figure 1 the corresponding peak eluting at 41.5 min for B in

[0043] Figure 2 The high resolution mass spectrum of Compound 4 in Example 1 of this application. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0044] The following further elaborates this application in combination with the embodiments and examples. It should be understood that these examples are only used to illustrate this application and not to limit the scope of this application. In addition, it should be understood that after reading the content taught in this application, those skilled in the art can make various changes or modifications to this application, and these equivalent forms also fall within the protection scope of the appended claims of this application.

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which this application belongs. The terms used in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0046] TERMS

[0047] Unless otherwise stated or there is a contradiction, the terms or phrases used herein have the following meanings:

[0048] As used herein, the term "and / or" includes any one of two or more of the related listed items, as well as any and all combinations of the related listed items. The said any and all combinations include combinations of any two of the related listed items, any more of the related listed items, or all of the related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", "and / or", it should be understood that in this application, this technical solution undoubtedly includes the technical solutions connected by "logical AND", and also undoubtedly includes the technical solutions connected by "logical OR". For example, "A and / or B" includes three parallel solutions: A, B, and A + B. Another example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, it includes combinations of any two or any three of A, B, C, and D, and also includes the four-item combination of A, B, C, and D (that is, the technical solution connected by "logical AND").

[0049] In this application, terms such as "preferred", "better", "even better", etc. are only used to describe embodiments or examples with better effects. It should be understood that they do not constitute a limitation on the protection scope of this application.

[0050] In this application, terms such as "further", "even further", "especially", etc. are used for descriptive purposes, indicating differences in content, but should not be understood as a limitation on the protection scope of this application.

[0051] In this application, in "the first aspect", "the second aspect", "the third aspect", "the fourth aspect", etc., the terms "first", "second", "third", "fourth", etc. are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

[0052] In this application, for the technical features described in an open-ended manner, it includes the closed technical solutions composed of the listed features, as well as the open technical solutions containing the listed features.

[0053] In this application, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the selectable numerical values are considered continuous within the above-mentioned numerical intervals, and include the two numerical endpoints (i.e., the minimum value and the maximum value) of the numerical range, as well as each numerical value between these two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers within the numerical interval, it includes the two endpoint integers of the numerical range, as well as each integer between the two endpoints. In addition, when providing multiple range descriptions of features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0054] For the temperature parameters in this application, unless otherwise specified, both constant temperature treatment and fluctuations within a certain temperature range are allowed. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within ranges such as ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, ±0.1°C are allowed.

[0055] In this application, the weight can be mass units well-known in the chemical industry such as μg, mg, g, kg, etc.

[0056] In this application, unless otherwise specified, when it comes to dimensions, particle sizes, diameters, it generally refers to the average value.

[0057] The method for synthesizing cardiolipin compounds in the examples of this application includes the following steps:

[0058] S100: Tri(2,2,2-trifluoroethyl) phosphate and benzyl alcohol are used to prepare compound I through a selective transesterification reaction;

[0059] S200: Compound I and compound II are used to prepare compound III through a substitution reaction;

[0060] S300: Compound III and R1OH are used to prepare compound IV through a transesterification reaction;

[0061] S400: Compound IV is used to prepare compound V through a reduction reaction;

[0062] (I);

[0063] (II);

[0064] (III);

[0065] (IV);

[0066] (V);

[0067] R1 is ;

[0068] R2 is a carbon chain.

[0069] The carbon chain in this article refers to a linear or branched structure formed by carbon atoms connected to each other. The carbon chain can be a straight chain, that is, carbon atoms are arranged linearly without branches, or a branched structure, that is, one or more carbon atoms on the main chain are connected to other carbon atoms on the main chain to form branches; the carbon atoms in the carbon chain can be connected by single bonds (carbon atoms connected by single bonds are called saturated carbon chains) or double bonds (carbon atoms connected by double bonds are called unsaturated carbon chains); the number of carbon atoms ≥ 6.

[0070] In the cardiolipin compounds of the embodiments of the present application, R2 and the ester group connected thereto together form a fatty acid structure, including medium-chain fatty acids well-known in the art, that is, fatty acids with a carbon chain length of 6 to 12 carbon atoms, and long-chain fatty acids, that is, fatty acids with a carbon chain length of 14 carbon atoms or more.

[0071] The basic structure of the fatty acid in this article is a carbon chain and a carboxyl group located at one end. According to the number of double bonds in the carbon chain, fatty acids can be divided into saturated fatty acids (without double bonds), monounsaturated fatty acids (one double bond), and polyunsaturated fatty acids (two or more double bonds).

[0072] In some embodiments, the structure of R2 is the same as the carbon chain in linoleic acid.

[0073] The structure of linoleic acid is as follows:

[0074] .

[0075] The synthesis method of the cardiolipin compounds of the embodiments of the present application utilizes the principle of selective transesterification of fluoroethyl phosphate to generate asymmetric phosphate esters, provides compound I and substitutes it with compound II to obtain compound III, then performs transesterification of compound III with a side-chain alcohol (R1OH), and then obtains compound V through one-step reduction. The yield of preparing compound III in step S100 can reach more than 95%, so it can be directly put into the next reaction without purification treatment. The whole synthesis route has simple steps, convenient operation, is suitable for large-scale industrial production, has low cost and high efficiency.

[0076] In some embodiments, in the synthesis method of cardiolipin compounds, it is not necessary to use column chromatography to purify intermediate products, which greatly reduces the usage amount of organic solvents, saves costs and reduces pollution.

[0077] The following further explains each step:

[0078] Step S100:

[0079] In step S100, compound I was prepared based on the selective transesterification reaction of tris(2,2,2-trifluoroethyl) phosphate. It has two fluoroethyl groups and one benzyloxy group, and this structure provides the possibility for subsequent selective esterification reactions.

[0080] In some embodiments, tris(2,2,2-trifluoroethyl) phosphate and benzyl alcohol are used to prepare compound I through a selective transesterification reaction, including:

[0081] At -5°C to 5°C, tris(2,2,2-trifluoroethyl) phosphate and benzyl alcohol are stirred in a first organic solvent for 20 min to 40 min, and then a first organic base is added and stirred for 50 min to 70 min to obtain a first mixed solution;

[0082] The first mixed solution is stirred at 20°C to 40°C for 2 h to 4 h to obtain compound I.

[0083] In some embodiments, the molar ratio of tris(2,2,2-trifluoroethyl) phosphate, benzyl alcohol, and the first organic base is 1:(1 to 1.2):(1 to 1.2).

[0084] In some embodiments, the first organic solvent includes at least one of toluene, tetrahydrofuran, and N,N-dimethylformamide; and / or,

[0085] The first organic base includes at least one of 1,8-diazabicyclo[5.4.0]undec-7-ene and lithium tert-butoxide.

[0086] S200: Compound III is prepared by a substitution reaction of compound I prepared in S100 and compound II.

[0087] In some embodiments, compound I and compound II are used to prepare compound III through a substitution reaction, including:

[0088] At -5°C to 5°C, compound I and a second organic base are stirred in a second organic solvent for 20 min to 40 min to obtain a second mixed solution;

[0089] At -50°C to -40°C, compound II is added to the second mixed solution and stirred for 7 h to 9 h to obtain compound III.

[0090] In some embodiments, the molar ratio of compound I, the second organic base, and compound II is 1:(1 to 1.2):(0.5 to 0.6).

[0091] In some embodiments, the second organic solvent includes at least one of toluene, tetrahydrofuran, and N,N-dimethylformamide; and / or,

[0092] The second organic base includes at least one of lithium tert-butoxide and sodium tert-butoxide.

[0093] Step S300:

[0094] In step S300, compound III and R1OH are subjected to transesterification reaction to obtain compound IV. R1 is the key side chain of the cardiolipin compound, which is introduced in this step to replace the fluoroethyl group, complete the connection of the substituents on the phosphate group, and side chains with different substituents can be introduced as needed.

[0095] In some embodiments, the preparation of compound IV by the transesterification reaction of compound III and R1OH includes:

[0096] At -50°C to -40°C, compound III and the third organic base are stirred in a third organic solvent for 20 min to 40 min to obtain a third mixture;

[0097] At -50°C to -40°C, R1OH is added to the third mixture and stirred for 5 h to 7 h to obtain compound IV.

[0098] In some embodiments, the molar ratio of compound III, sodium tert-butoxide and R1OH is 1:(1 to 1.2):(1 to 1.2).

[0099] In some embodiments, the third organic solvent includes at least one of toluene, n-hexane, tetrahydrofuran and N,N-dimethylformamide; and / or,

[0100] The third organic base includes at least one of sodium tert-butoxide and lithium diisopropylamide.

[0101] Step S400:

[0102] In step S400, three benzyloxy groups of compound IV are reductively removed in one step to efficiently prepare the cardiolipin compound.

[0103] In some embodiments, the preparation of compound V by the reduction reaction of compound IV includes:

[0104] Compound IV and palladium on carbon are stirred in a hydrogen environment for 8 h to 12 h to obtain compound V.

[0105] The synthesis method of the cardiolipin compound of the present application is based on the principle of selective esterification reaction, and realizes four-step synthesis through route design, with high yield, simple post-treatment, being conducive to large-scale standardized preparation, low cost, and extremely promising market prospects.

[0106] The synthetic method of the cardiolipin compounds in this application can synthesize cardiolipins with different side chains and side chains with special functional groups through stepwise substitution reactions, providing more possibilities for the clinical application of cardiolipin compounds. For example, cardiolipin can be modified through side chain groups to obtain a drug carrier with higher delivery efficiency.

[0107] The following are some specific examples.

[0108] For the experimental parameters not specified in the following specific examples, preferably refer to the guidance given in this application document. You can also refer to the experimental manuals in this field or other experimental methods known in this field, or refer to the experimental conditions recommended by the manufacturers.

[0109] The raw materials and reagents involved in the following specific examples can be obtained commercially, or can be prepared by those skilled in the art according to known means.

[0110] Example 1

[0111] (1) Synthesis of Compound 1: In a 100 ml eggplant-shaped flask, add tris(2,2,2-trifluoroethyl) phosphate (3.44 g, 10 mmol) and benzyl alcohol (1.08 g, 10 mmol). Then add 30 ml of toluene as a solvent, stir the reaction at 0 °C for 30 minutes, add DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 1.52 g, 10 mmol), and continue to stir at 0 °C for 1 h. Resume stirring the reaction at room temperature for 3 h, then add PBS (20 ml) to quench the reaction, extract with ethyl acetate, and then wash the organic layer with saturated brine and dry over anhydrous sodium sulfate. It was found by HPLC detection that the yield was about 95%, and it could be directly used for the next reaction without purification.

[0112] (2) Synthesis of Compound 2: Dissolve Compound 1 (352 mg, 1 mmol) in 5 ml of toluene, add 1.2 ml of a 1.0 mmol n-hexane solution of lithium tert-butoxide, react at 0 °C for 30 min, then cool the solution temperature to -45 °C, and add 2-benzyloxy-1,3-propanediol (90 mg, 0.5 mmol) to the solution and react for 8 h. After the reaction is completed, at -45 °C, add 0.2 ml of acetic acid, stir for 10 minutes, then add 10 ml of PBS solution, extract with ethyl acetate, and then wash the organic layer with saturated brine and dry over anhydrous sodium sulfate. Add the concentrated solution to 2 ml of chromatographically pure acetonitrile, separate and purify it by HPLC (high performance liquid chromatography), and then freeze-dry to obtain the product with a yield of 85%.

[0113] (3) Synthesis of Compound 3: Dissolve Compound 2 (686 mg, 1 mmol) in 5 ml of toluene, add 2 ml of a 1.0 mmol solution of sodium tert-butoxide in n-hexane, then cool the solution to -45 °C, add dilinoleoyl glycerol (1.2 g, 1 mmol) to the solution, and react for 6 hours. After the reaction is completed, at -45 °C, add 0.4 ml of acetic acid, stir for 10 minutes, then add 10 ml of PBS solution, extract with ethyl acetate, and then wash the organic layer with saturated brine and dry over anhydrous sodium sulfate. Add 2 ml of chromatographically pure acetonitrile to the concentrated solution, separate and purify it by HPLC (High Performance Liquid Chromatography), and then lyophilize to obtain the product with a yield of 70%.

[0114] (4) Synthesis of Compound 4: Dissolve Compound 3 (1.7 g, 1 mmol) in 20 ml of anhydrous tetrahydrofuran, add 10% palladium on carbon (900 mg), introduce hydrogen, and carry out a hydrogenation reaction for 10 h. After filtration to remove the palladium on carbon, concentrate the filtrate, extract with water and ethyl acetate, then wash the organic layer with saturated brine and dry over anhydrous sodium sulfate, and rotary evaporate to obtain the final product with a yield of approximately 98%. 1 H NMR δ (CDCl3, 400 MHZ) 0.88 (t, 12H), 1.22 - 1.34 (m, 56H), 1.58 - 1.68 (m, 8H), 2.12 - 2.24 (m, 16H), 2.30 - 2.42 (m, 8H), 2.76 - 2.88 (m, 8H), 3.72 - 3.782 (m, 2H), 3.86 - 3.98 (m, 1H), 4.18 - 4.40 (m, 11H), 5.24 - 5.44 (m, 18H).

[0115] All documents mentioned in this application are cited herein as references as if each document were cited individually as a reference. Unless it conflicts with the purpose of this application and / or the technical solution, the cited documents related to this application are cited in their entirety for all purposes. When this application involves citing documents, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When this application involves citing documents, the examples and preferred methods of the relevant technical features cited can also be incorporated as references into this application, provided that this application can be implemented. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or be amended adaptively according to the description in this application.

[0116] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity of description, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered to be within the scope described in this specification.

[0117] The above-described embodiments merely represent several implementation manners of the present application, but should not be construed as limiting the scope of the patent application. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, and these all belong to the protection scope of the present application. In addition, it should be understood that after reading the above teachings of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the protection scope of the present application. It should also be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments based on the technical solutions provided in the present application are all within the protection scope of the appended claims of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. A method for synthesizing a cardiolipin compound, characterized in that, It includes the following steps: Tris(2,2,2-trifluoroethyl) phosphate and benzyl alcohol are used to prepare Compound I through a selective transesterification reaction; Compound I and Compound II are used to prepare Compound III through a substitution reaction; Compound III and R1OH are used to prepare Compound IV through an transesterification reaction; Compound IV is used to prepare Compound V through a reduction reaction; （I）； (II); (III); (IV); （V）； R1 is ; R2 is an alkyl group.

2. The synthesis method according to claim 1, characterized in that, The preparation of Compound I from tris(2,2,2-trifluoroethyl) phosphate and benzyl alcohol through a selective transesterification reaction includes: At -5°C to 5°C, tris(2,2,2-trifluoroethyl) phosphate and benzyl alcohol are stirred in a first organic solvent for 20 min to 40 min, and then a first organic base is added and stirred for 50 min to 70 min to obtain a first mixture; The first mixture is stirred at 20°C to 40°C for 2 h to 4 h to obtain Compound I.

3. The synthesis method according to claim 2, characterized in that, The molar ratio of tris(2,2,2-trifluoroethyl) phosphate, benzyl alcohol, and the first organic base is 1:(1 - 1.2):(1 - 1.2).

4. The synthesis method according to claim 2 or 3, characterized in that, The first organic solvent includes at least one of toluene, tetrahydrofuran, and N,N-dimethylformamide; and / or, The first organic base includes at least one of 1,8-diazabicyclo[5.4.0]undec-7-ene and lithium tert-butoxide.

5. The synthesis method according to claim 1, wherein, The preparation of Compound III from Compound I and Compound II through a substitution reaction includes: At -5°C to 5°C, Compound I and a second organic base are stirred in a second organic solvent for 20 min to 40 min to obtain a second mixture; At -50°C to -40°C, Compound II is added to the second mixture and stirred for 7 h to 9 h to obtain Compound III.

6. The synthesis method according to claim 5, characterized in that, The molar ratio of Compound I, the second organic base, and Compound II is 1:(1 - 1.2):(0.5 - 0.6).

7. The synthesis method according to claim 5 or 6, characterized in that The second organic solvent includes at least one of toluene, tetrahydrofuran, and N,N-dimethylformamide; and / or, The second organic base includes at least one of lithium tert-butoxide and sodium tert-butoxide.

8. The method for synthesizing cardiolipin according to claim 1, characterized in that, The preparation of Compound IV from Compound III and R1OH through an transesterification reaction includes: At -50°C to -40°C, Compound III and a third organic base are stirred in a third organic solvent for 20 min to 40 min to obtain a third mixture; At -50°C to -40°C, R1OH is added to the third mixture and stirred for 5 h to 7 h to obtain Compound IV.

9. The synthesis method according to claim 8, characterized in that, The molar ratio of Compound III, sodium tert-butoxide, and R1OH is 1:(1 - 1.2):(1 - 1.2).

10. The synthesis method according to claim 8 or 9, characterized in that, The third organic solvent includes at least one of toluene, n-hexane, tetrahydrofuran, and N,N-dimethylformamide; and / or, The third organic base includes at least one of sodium tert-butoxide and lithium diisopropylamide.

11. According to the synthesis method described in claim 1, characterized in that, The preparation of Compound V from Compound IV through a reduction reaction includes: Compound IV and palladium on carbon are stirred in a hydrogen environment for 8 h to 12 h to obtain Compound V.

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