An industrial-scale chemical preparation method for 1,2-difatty acid glycerides

Abstract

This invention discloses an industrial-scale chemical preparation method for 1,2-di fatty acid glycerides, comprising the following steps: (A) acetone glycerol is protected with a silyl ether protecting agent and purified by crystallization to obtain intermediate 1; (B) intermediate 1 undergoes a depropionyl protecting group reaction and crystallization to obtain intermediate 2; (C) intermediate 2 undergoes an esterification reaction and crystallization and adsorption to obtain intermediate 3; (D) intermediate 3 undergoes a desilyl ether protection reaction and recrystallization to obtain 1,2-di fatty acid glycerides. This invention, through crystallization purification under different conditions, avoids the disadvantages of traditional chemical methods for preparing 1,2-di fatty acid glycerides, such as the need for multiple column chromatography purification steps, low yield, and difficulty in industrialization. This method features mild operating conditions, high purity, and is easily scalable for large-scale industrialization.

Description

Technical Field

[0001] This invention relates to the field of oil and fat synthesis technology, specifically to an industrial-scale chemical preparation method for 1,2-difatty acid glycerides. Background Technology

[0002] Diglycerides are lipid compounds in which one carboxylic acid chain of a triglyceride is replaced by a hydroxyl group. They have two isomers: 1,2-diglyceride and 1,3-diglyceride. Diglycerides are emulsifiers and surfactants with wide applications in the food, pharmaceutical, cosmetic, and chemical industries. For example, in the food industry, consuming oils containing diglycerides can inhibit weight gain and lower blood lipids. Furthermore, 1,2-diglycerides are precursors to phospholipids such as distearate phosphatidylcholine (DSPC), a key component of lipid nanoparticles used in mRNA therapy and vaccines. Currently, diglycerides are mainly synthesized using chemical and enzymatic methods. Enzymatic methods are difficult to industrialize due to high enzyme costs and the need for specialized reactors. Chemical methods also involve multiple reaction steps, each producing byproducts, and large-scale column chromatography purification and the formulation of different column chromatography eluents are difficult to achieve in production. Therefore, it is necessary to improve existing chemical diglyceride preparation processes to meet the needs of large-scale industrialization.

[0003] Summary of the Invention

[0004] The purpose of this invention is to provide a chemical method suitable for industrial-scale preparation of 1,2-difatty acid glycerides or their pharmaceutically usable salts, solving the problems of high requirements for reactor equipment, low purity, and the need for repeated column chromatography during the synthesis process.

[0005] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0006] An industrial-scale chemical preparation method for 1,2-difatty acid glycerides includes the following steps:

[0007]

[0008] R1 includes one of tert-butyldiphenylsilyl and tert-butyldimethylsilyl, and R2 includes one of saturated or unsaturated fatty acyl groups.

[0009] The preparation method of this invention mainly involves the following steps: (A) Acetone glycerol is protected by a silyl ether protecting agent and then crystallized to remove impurities to obtain intermediate 1; (B) Intermediate 1 undergoes a depropionyl protecting group reaction and crystallizes to obtain intermediate 2; (C) Intermediate 2 undergoes an esterification reaction and crystallizes and adsorbs to obtain intermediate 3; (D) Intermediate 3 undergoes a desilyl ether protection reaction and recrystallization to obtain 1,2-difatty acid glycerides.

[0010] This invention purifies 1,2-difatty acid glycerides by crystallization under different conditions, avoiding the disadvantages of traditional chemical methods that require multiple column chromatography for purification, have low yields, and are difficult to industrialize. This method has mild operating conditions, high purity, and is easy to industrialize on a large scale.

[0011] Preferably, the steps include:

[0012] a. After completely dissolving acetone glycerol and catalyst a in organic solvent a1, add silane ether protective reagent, stir to react, and after the reaction is completed, add organic solvent a2 and stir evenly. Cool and let stand to crystallize. After crystallization, filter, collect and concentrate the filtrate to obtain intermediate 1.

[0013] b. Dissolve intermediate 1 in organic solvent b1, add deprotecting agent b, carry out deprotection reaction, extract with water after the reaction, neutralize and extract with inorganic alkali solution, wash with water, collect and concentrate the organic layer, redissolve with organic solvent a1, add organic solvent a2 after dissolution, stir evenly, cool and let stand to crystallize, filter after crystallization, collect the filter residue, and obtain intermediate 2.

[0014] c. Dissolve the intermediate 2 in the organic solvent a1, add the esterification reagent and esterification catalyst, stir to react, and after the reaction is completed, add the organic solvent a2 and stir. Cool and let it stand to crystallize. After crystallization, filter, collect the filtrate and add the adsorbent to stir and adsorb. Filter, collect and concentrate the filtrate to obtain intermediate 3.

[0015] d. Dissolve the intermediate 3 in organic solvent d, add deprotecting agent d, carry out deprotection reaction, concentrate the reaction solution, dissolve it in purified organic solvent e, cool and let it stand to crystallize, filter, collect the filter residue, and obtain 1,2-di-fatty acid glycerides; the deprotecting agent d includes one or more of triethylamine trihydrofluoride and tetrabutylammonium fluoride.

[0016] Preferably, the steps include:

[0017] a. Dissolve the acetone glycerol and catalyst a completely in the organic solvent a1 at 0-50°C, then add the silane protective reagent and continue stirring for 0.5-8 hours. After the reaction is completed, add the organic solvent a2 and stir for 1-60 minutes. Then, place the mixture at -20-10°C to allow it to crystallize for 1-24 hours. After crystallization, filter the mixture, collect and concentrate the filtrate to obtain intermediate 1.

[0018] b. Dissolve intermediate 1 in organic solvent b1, add deprotecting reagent b, and carry out depropionylation reaction at 0-90°C for 0.5-1 h. After the reaction, extract once with water, neutralize and extract once with inorganic alkali solution, and finally wash with water 1-3 times. Collect and concentrate the organic layer, redissolve it in organic solvent a1, add organic solvent a2 and stir for 1-60 min. Then, place it at -20-10°C to crystallize for 1-24 h. After crystallization, filter and collect the filter residue to obtain intermediate 2.

[0019] c. Dissolve the intermediate 2 in the organic solvent a1, add the esterification reagent and the esterification catalyst, and stir the reaction at 0-50°C for 0.5-8 hours. After the reaction is completed, add the organic solvent a2 and stir for 1-60 minutes. Then, let it stand at -20-10°C for 1-24 hours to crystallize. After crystallization, filter the solution, collect the filtrate, add an adsorbent, and stir the solution at 0-50°C for 0.5-8 hours to adsorb the solution. Filter the solution, collect and concentrate the filtrate to obtain the intermediate 3.

[0020] d. After dissolving the intermediate 3 in organic solvent d, add the deprotecting agent d and react at 0-30°C for 1-24 hours. Concentrate the reaction solution, dissolve it in purified organic solvent e, and let it stand at -20-10°C for 1-24 hours to crystallize. Filter and collect the filter residue to obtain the 1,2-difatty acid glyceride.

[0021] Preferably, catalyst a comprises one or more of imidazole and 4-dimethylaminopyridine; organic solvent a1 comprises chloroform; organic solvent a2 comprises one or more of n-pentane, isopentane, petroleum ether, n-hexane, cyclohexane, isooctane, cyclopentane, n-heptane, and trimethylpentane; organic solvent b1 comprises organic solvent a1, a ternary combination solvent with water, and a ternary combination solvent with methanol or ethanol; deprotecting agent b comprises concentrated hydrochloric acid (approximately 37% aqueous hydrochloric acid solution); and esterification agent comprises C 10 ~C 24The esterification catalyst comprises one or more of saturated or unsaturated fatty acids and acyl chlorides; the esterification catalyst comprises one or more of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide, N,N'-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and N,N'-diisopropylcarbodiimide; the adsorbent comprises one or more of silica gel, activated clay, and activated carbon; the organic solvent d comprises the organic solvent a1, a ternary combination solvent with tetrahydrofuran, and acetonitrile; the deprotecting agent d comprises one or more of triethylamine trihydrofluoride and tetrabutylammonium fluoride; the purified organic solvent e comprises chloroform, a ternary combination solvent with methanol or ethanol or acetone, and water.

[0022] Preferably, the organic solvent b1 comprises the organic solvent a1, a ternary solvent mixture with water, and methanol or ethanol in a volume ratio of 1-10:0.1-1:1-10; the organic solvent d comprises the organic solvent a1, a ternary solvent mixture with tetrahydrofuran and acetonitrile in a volume ratio of 1-2:1-2:1-2; and the refined organic solvent e comprises chloroform, a ternary solvent mixture with methanol or ethanol or acetone and water in a volume ratio of 1-3:2-4:1-3.

[0023] Preferably, in step a, the molar ratio of acetone glycerol to catalyst a is 1:0.1 to 2, the mass-volume ratio of acetone glycerol to organic solvent a1 is 1:1 to 10, and the mass-volume ratio of acetone glycerol to organic solvent a2 is 1:1 to 20.

[0024] In step b, the mass-volume ratio of intermediate 1 to organic solvent b1 is 1g:1 to 10ml, the mass-volume ratio of intermediate 1 to deprotecting reagent b is 1:0.1 to 1, and the mass-volume ratio of intermediate 1 to organic solvent a2 is 1:1 to 20.

[0025] In step c, the mass-volume ratio of intermediate 2 to organic solvent a1 and organic solvent a2 is 1g:5-20ml:1-20ml, the molar ratio of intermediate 2 to esterification reagent is 1:1.9-2.5, the molar ratio of intermediate 2 to esterification catalyst is 1:0.1-2.5, and the mass ratio of intermediate 2 to adsorbent is 1:1-10.

[0026] In step d, the mass-volume ratio of intermediate 3 to organic solvent d is 1g:1-10ml, the molar ratio of intermediate 3 to deprotecting reagent d is 1:1-10, and the mass-volume ratio of intermediate 3 to organic solvent e is 1g:1-30ml.

[0027] Preferably, in step a, the molar ratio of acetone glycerol to catalyst a is 1:0.1 to 1, the mass-to-volume ratio of acetone glycerol to organic solvent a1 is 1:1 to 5, and the mass-to-volume ratio of acetone glycerol to organic solvent a2 is 1:1 to 10; in step b, the mass-to-volume ratio of intermediate 1 to organic solvent a2 is 1:1 to 10; in step c, the molar ratio of intermediate 2 to esterification reagent is 1:1.95 to 2.05, the molar ratio of intermediate 2 to esterification catalyst is 1:1.95 to 2.05, and the adsorbent includes silica gel.

[0028] Preferably, in step a, the stirring reaction is carried out at room temperature for 0.5 to 5 hours; in step b, the deprotection reaction is carried out at room temperature for 0.5 hours; in step c, the stirring reaction is carried out at room temperature for 1 to 5 hours; and in step d, the deprotection reaction is carried out at room temperature for 12 hours.

[0029] Preferably, the room temperature is 20–30°C.

[0030] A 1,2-di fatty acid glyceride product obtained by an industrial-scale chemical preparation method of 1,2-di fatty acid glycerides as described above.

[0031] Furthermore, the room temperature is 20–30°C.

[0032] A pharmaceutical composition comprising the above-mentioned 1,2-difatty acid glyceride or a pharmaceutically acceptable salt thereof.

[0033] Compared with the prior art, implementing the present invention has the following beneficial effects:

[0034] (1) The present invention is ingenious. The main solvent chloroform is used throughout the entire preparation route. While combining with other solvents to dissolve the sample, refine and purify it, and avoid multiple column passes, it ensures that the number of solvents is as small as possible and that the product yield and purity are high, which is conducive to large-scale production.

[0035] (2) 4-Dimethylaminopyridine (DMAP) catalyst is a common esterification reagent, but it will remain even in low polarity solvents such as pure hexane. Ordinary crystallization, acid washing and extraction methods cannot completely remove DMAP. Column chromatography is avoided as much as possible in industrialization. This invention innovatively uses silica gel adsorption to remove DMAP residues. The operation is simple and easy to industrialize. That is, this invention also discloses an operation method for removing DMAP.

[0036] (3) The special ratio of organic solvent e ensures that the low polarity, unreacted raw materials will not precipitate, while the high polarity, excess triethylamine trihydrofluoride will not precipitate, and the yield is high, thus avoiding column chromatography of the final product, which only requires purification. Attached Figure Description

[0037] Figure 1 This is a gas-phase comparison diagram of common fatty acid diglycerides;

[0038] Figure 2 This is a gas phase image of sample 1,2-distearate diglyceride obtained by the method of the present invention;

[0039] Figure 3 This is a gas phase image of sample 1,2-distearate diglyceride obtained by the method of the present invention;

[0040] Figure 4 This is a comparison chart showing the effects of removing DMAP in Comparative Example 1. Detailed Implementation

[0041] To make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings.

[0042] Example 1

[0043] Weigh 10g of acetone glycerol and 7.80g of imidazole into a round-bottom flask, add 50ml of chloroform and stir under ice bath until completely dissolved. Then add 23ml of tert-butyldimethylchlorosilane and continue stirring under ice bath. Monitor the reaction by TLC. The ratio of n-hexane to ethyl acetate is 9:1. Develop the reaction in an iodine tank. After reacting for 2 hours, add 80ml of n-hexane and cool in a refrigerator at 2-8℃ for 4 hours to allow crystals to crystallize. Filter and concentrate the filtrate to obtain 29.50g of intermediate 1, with a yield of 100%, a pale yellow viscous liquid.

[0044] Weigh 10g of intermediate 1 and add 50ml of chloroform, 35ml of methanol, 5ml of water, and 5ml of concentrated hydrochloric acid. Stir and react at room temperature for 0.5h. After extraction with 50ml of water, the organic layer is extracted again with 10ml of 1M sodium carbonate and 40ml of water. Finally, the organic layer is washed with water until neutral and concentrated. After dissolving in 10ml of chloroform and 100ml of n-hexane, the mixture is placed in a refrigerator at 2-8℃ for 2h to crystallize. After crystallization, filter and collect the residue to obtain 8.3g of intermediate 2, with a yield of 93.1%, which is a white, fluffy solid.

[0045] Weigh 7g of intermediate 2, 12.7g of stearic acid, and 5.71g of DMAP and dissolve them in 140ml of chloroform. Then, add 10g of N,N'-dicyclohexylcarbodiimide (DCC) at room temperature and continue stirring. Monitor the reaction by TLC. Develop the reaction with petroleum ether:diethyl ether = 60:40 and perform colorimetric analysis in an iodine tank. After reacting for 2 hours, add 140ml of n-hexane and allow it to crystallize at 2-8℃ for 4 hours. After crystallization, filter the solution and collect the filtrate. Add 10g of silica gel to the filtrate and stir to adsorb the solution at room temperature for 30 minutes. Filter the solution and concentrate it to obtain 17.8g of intermediate 3, with a yield of 97.3%, a colorless and transparent liquid.

[0046] 3g of intermediate 3 was weighed and dissolved in a mixed solvent of 10ml chloroform, 10ml tetrahydrofuran, and 10ml acetonitrile. Then, 6ml of triethylamine trihydrofluoride was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated to remove the solvent. 50ml chloroform, 20ml methanol, and 5ml water were added sequentially, and the mixture was allowed to crystallize at 2–8℃ for 2 hours. The crystals were then filtered, the residue was collected, and dried under vacuum at 40℃ for 4 hours to obtain 2g of 1,2-distearate glyceryl ester, with a yield of 92.1%. The sample was a white solid, and gas chromatography analysis showed a purity of 98.67%. Figure 2 As shown.

[0047] Example 2

[0048] Weigh 50g of acetone glycerol and 28g of imidazole into a round-bottom flask, add 250ml of chloroform and stir at room temperature until completely dissolved. Then add 103ml of tert-butyldiphenylchlorosilane and continue stirring at room temperature. Monitor the reaction by TLC. The ratio of n-hexane to ethyl acetate is 9:1. Develop the reaction in an iodine tank. After 3 hours of reaction, add 500ml of cyclopentane and cool at 2-8℃ for 6 hours to allow crystallization. Filter and concentrate the filtrate to obtain 140.2g of intermediate 1, with a yield of 100%, a pale yellow viscous liquid.

[0049] Weigh 10g of intermediate 1 and add 30ml of chloroform, 25ml of methanol, 5ml of water, and 7ml of concentrated hydrochloric acid. Stir and react at room temperature for 1 hour. After extraction with 50ml of water, the organic layer is extracted again with 10ml of 1M sodium carbonate and 40ml of water. Finally, the organic layer is washed with water until neutral and concentrated. After dissolving in 10ml of chloroform and 100ml of petroleum ether, the mixture is placed in a refrigerator at 2-8℃ for 2 hours to crystallize. After crystallization, filter and collect the residue to obtain 8.1g of intermediate 2, with a yield of 90.8%, which is a white, fluffy solid.

[0050] Weigh 7g of intermediate 2, 12.7g of stearic acid, and 2g of DMAP and dissolve them in 140ml of chloroform. Add 10g of N,N'-dicyclohexylcarbodiimide (DCC) under ice bath and continue stirring. Monitor the reaction by TLC. Develop the reaction with petroleum ether:diethyl ether = 60:40 and develop the color in an iodine tank. After reacting for 7 hours, add 140ml of petroleum ether and allow it to crystallize at 2-8℃ for 4 hours. After crystallization, filter and collect the filtrate. Add 20g of silica gel to the filtrate and stir to adsorb at room temperature for 30 minutes. Filter and concentrate the filtrate to obtain 16.5g of intermediate 3, with a yield of 90.2%, a colorless and transparent liquid.

[0051] 10g of intermediate 3 was weighed and dissolved in a mixed solvent of 30ml chloroform, 15ml tetrahydrofuran, and 30ml acetonitrile. Then, 10ml of triethylamine trihydrofluoride was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated to remove the solvent. 30ml chloroform, 40ml acetone, and 30ml water were added sequentially, and the mixture was allowed to crystallize at 2–8℃ for 5 hours. The crystals were then filtered, the residue was collected, and vacuum dried at 40℃ for 4 hours to obtain 6.9g of 1,2-distearate glyceryl ester, with a yield of 95.3%. The sample was a white solid, and gas chromatography analysis showed a purity of 97.73%. Figure 3 As shown.

[0052] Example 3

[0053] Weigh 10g of acetone glycerol and 4.1g of imidazole into a round-bottom flask, add 50ml of chloroform and stir at room temperature until completely dissolved. Then add 21ml of tert-butyldiphenylchlorosilane and continue stirring at room temperature. Monitor the reaction by TLC. The ratio of n-hexane to ethyl acetate is 9:1. Develop the reaction in an iodine tank. After 5 hours of reaction, add 200ml of n-hexane and cool at 2-8℃ for 4 hours to allow crystallization. Filter and concentrate the filtrate to obtain 27.1g of intermediate 1, with a yield of 96.6%, a pale yellow viscous liquid.

[0054] Weigh 20g of intermediate 1 and add 50ml of chloroform, 50ml of methanol, 10ml of water, and 14ml of concentrated hydrochloric acid. Stir and react at room temperature for 1 hour. After extraction with 100ml of water, the organic layer is extracted again with 20ml of 1M sodium carbonate and 100ml of water. Finally, the organic layer is washed with water until neutral and concentrated. After dissolving in 20ml of chloroform and 200ml of n-hexane, the mixture is placed in a refrigerator at 2-8℃ for 3 hours to crystallize. After crystallization, filter and collect the residue to obtain 16.3g of intermediate 2, with a yield of 91.4%, which is a white, fluffy solid.

[0055] Weigh 10g of intermediate 2, 16.30g of palmitic acid, and 7.76g of DMAP and dissolve them in 150ml of chloroform. Then, add 12.30g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) at room temperature and continue stirring. Monitor the reaction by TLC. Develop the reaction with petroleum ether:diethyl ether = 60:40 and develop the color in an iodine tank. After reacting for 3 hours, add 160ml of cyclohexane and allow it to crystallize at 2-8℃ for 5 hours. After crystallization, filter the solution and collect the filtrate. Add 15g of silica gel to the filtrate and stir to adsorb the solution at room temperature for 60 minutes. Filter the solution and concentrate it to obtain 24.10g of intermediate 3, with a yield of 94.8%, a colorless and transparent liquid.

[0056] 10g of intermediate 3 was weighed and dissolved in a mixed solvent of 30ml chloroform, 15ml tetrahydrofuran, and 30ml acetonitrile. Then, 20ml of triethylamine trihydrofluoride was added, and the mixture was stirred at room temperature for 12h. The reaction solvent was then removed by concentration. 30ml of chloroform, 40ml of methanol, and 20ml of water were added sequentially, and the mixture was allowed to crystallize at 2-8℃ for 4h. After filtration, the residue was collected and dried under vacuum at 40℃ for 4h to obtain 6.5g of 1,2-dipalmitoylglycerol, with a yield of 91.9%, as a white solid.

[0057] Comparative Example 1

[0058] Weigh 20g of intermediate 2, 32.6g of palmitic acid, and 15.5g of DMAP and dissolve them in 200ml of chloroform. Then, add 24.5g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) at room temperature and continue stirring. Monitor the reaction by TLC. Develop the reaction with petroleum ether:diethyl ether = 60:40 and perform colorimetric analysis in an iodine tank. After reacting for 3 hours, add 300ml of n-hexane and allow it to crystallize at 2-8℃ for 5 hours. After crystallization is complete, filter the solution and collect the filtrate.

[0059] Take 7 filtrates, 20 ml each, and extract them separately with 20 ml of low-polarity (n-heptane) solvent, 10 ml of 1M dilute hydrochloric acid solution, and different adsorbents (5 g each) to remove DMAP. Develop the treated samples using TLC (petroleum ether: diethyl ether = 60:40) and develop the color in an iodine bath. The results are as follows: Figure 4 As shown.

[0060] from Figure 4 It can be seen that adding a low-polarity solvent to the filtrate after crystallization does not change much, and the effect of removing DMAP is limited; 1M dilute hydrochloric acid has a better effect, but it is difficult to remove DMAP completely; among the adsorbents, diatomaceous earth is the worst at removing DMAP, alumina, activated clay and activated carbon have a certain effect on removing DMAP, but silica gel has the best adsorption effect.

[0061] from Figure 1 and Figure 2 , Figure 3The comparison shows that the peak times of the final product obtained by this invention are basically the same as those of common fatty acid diglycerides, indicating that they are the same substance. Furthermore, the impurity peaks of the final product obtained by this invention are significantly smaller than those of common fatty acid diglycerides, meaning it should be considered to have fewer impurities and better quality.

[0062] The above description only discloses preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. Therefore, equivalent variations made in accordance with the claims of the present invention are still within the scope of the present invention.

Claims

1. An industrial-scale chemical preparation method for 1,2-difatty acid glycerides, characterized in that, Includes the following steps: Wherein, R1 is one of tert-butyldiphenylsilyl or tert-butyldimethylsilyl, and R2 is one of saturated or unsaturated fatty acyl groups; Includes the following steps: a. After completely dissolving acetone glycerol and catalyst a in organic solvent a1, add silane ether protective reagent, stir to react, and after the reaction is completed, add organic solvent a2 and stir evenly. Cool and let stand to crystallize. After crystallization, filter, collect and concentrate the filtrate to obtain intermediate 1. b. Dissolve intermediate 1 in organic solvent b1, add deprotecting agent b, carry out deprotection reaction, extract with water after the reaction, neutralize and extract with inorganic alkali solution, wash with water, collect and concentrate the organic layer, redissolve with organic solvent a1, add organic solvent a2 after dissolution, stir evenly, cool and let stand to crystallize, filter after crystallization, collect the filter residue, and obtain intermediate 2. c. Dissolve the intermediate 2 in the organic solvent a1, add the esterification reagent and esterification catalyst, stir to react, and after the reaction is completed, add the organic solvent a2 and stir. Cool and let it stand to crystallize. After crystallization, filter, collect the filtrate and add the adsorbent to stir and adsorb. Filter, collect and concentrate the filtrate to obtain intermediate 3. d. Dissolve the intermediate 3 in organic solvent d, add deprotecting agent d, carry out deprotection reaction, concentrate the reaction solution, dissolve it in purified organic solvent e, cool and allow it to stand to crystallize, filter, collect the filter residue, and obtain 1,2-difatty acid glyceride; the deprotecting agent d is one or more of triethylamine trihydrofluoride and tetrabutylammonium fluoride. The catalyst a is imidazole; the organic solvent a1 is chloroform; the organic solvent a2 is one or more of n-pentane, isopentane, petroleum ether, n-hexane, cyclohexane, isooctane, cyclopentane, n-heptane, and trimethylpentane; the organic solvent b1 is a ternary solvent mixture of the organic solvent a1, water, methanol, or ethanol at a volume ratio of 1~10:0.1~1:1~10; the deprotecting agent b is concentrated hydrochloric acid; and the esterification agent is C 10 ~C 24 The esterification catalyst is one or more of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide, N,N'-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and N,N'-diisopropylcarbodiimide; the adsorbent is silica gel; the organic solvent d is a ternary solvent mixture of the organic solvent a1, tetrahydrofuran, and acetonitrile in a volume ratio of 1~2:1~2:1~2; the purified organic solvent e is a ternary solvent mixture of chloroform, methanol or ethanol or acetone, and water in a volume ratio of 1~3:2~4:1~3.

2. The industrial-scale chemical preparation method of 1,2-difatty acid glycerides as described in claim 1, characterized in that, Includes the following steps: a. Dissolve the acetone glycerol and catalyst a completely in the organic solvent a1 at 0~50℃, then add the silane protective reagent and continue stirring for 0.5~8h. After the reaction is completed, add the organic solvent a2 and stir for 1~60min. Then place it at -20~10℃ to crystallize for 1~24h. After crystallization, filter, collect and concentrate the filtrate to obtain intermediate 1. b. Dissolve intermediate 1 in organic solvent b1, add deprotecting reagent b, and carry out depropionation reaction at 0~90℃ for 0.5~1h. After the reaction, extract once with water, neutralize and extract once with inorganic alkali solution, and finally wash with water 1~3 times. Collect and concentrate the organic layer, redissolve it in organic solvent a1, add organic solvent a2 after dissolution, stir for 1~60min, and place it at -20~10℃ for crystallization for 1~24h. After crystallization, filter and collect the filter residue to obtain intermediate 2. c. Dissolve the intermediate 2 in the organic solvent a1, add the esterification reagent and the esterification catalyst, and stir the reaction at 0~50℃ for 0.5~8h. After the reaction is completed, add the organic solvent a2 and stir for 1~60min. Then, place the mixture at -20~10℃ for 1~24h to crystallize. After crystallization, filter the mixture, collect the filtrate, add the adsorbent, and stir the mixture at 0~50℃ for 0.5~8h to adsorb the filtrate. Filter the mixture, collect and concentrate the filtrate to obtain the intermediate 3. d. After dissolving the intermediate 3 in organic solvent d, add the deprotecting agent d and react at 0~30℃ for 1~24h. Concentrate the reaction solution, dissolve it in purified organic solvent e, and let it stand at -20~10℃ for 1~24h to crystallize. Filter and collect the filter residue to obtain the 1,2-difatty acid glyceride.

3. The industrial-scale chemical preparation method of 1,2-difatty acid glycerides as described in claim 1, characterized in that, In step a, the molar ratio of acetone glycerol to catalyst a is 1:0.1~2, the mass-volume ratio of acetone glycerol to organic solvent a1 is 1:1~10, and the mass-volume ratio of acetone glycerol to organic solvent a2 is 1:1~20. In step b, the mass-volume ratio of intermediate 1 to organic solvent b1 is 1g:1~10ml, the mass-volume ratio of intermediate 1 to deprotecting reagent b is 1:0.1~1, and the mass-volume ratio of intermediate 1 to organic solvent a2 is 1:1~20. In step c, the mass-volume ratio of intermediate 2 to organic solvent a1 and organic solvent a2 is 1g:5~20ml:1~20ml, the molar ratio of intermediate 2 to esterification reagent is 1:1.9~2.5, the molar ratio of intermediate 2 to esterification catalyst is 1:0.1~2.5, and the mass ratio of intermediate 2 to adsorbent is 1:1~10. In step d, the mass-volume ratio of intermediate 3 to organic solvent d is 1g:1~10ml, the molar ratio of intermediate 3 to deprotecting reagent d is 1:1~10, and the mass-volume ratio of intermediate 3 to organic solvent e is 1g:1~30ml.

4. The industrial-scale chemical preparation method of 1,2-difatty acid glycerides as described in claim 3, characterized in that, In step a, the molar ratio of acetone glycerol to catalyst a is 1:0.1~1, the mass-volume ratio of acetone glycerol to organic solvent a1 is 1:1~5, and the mass-volume ratio of acetone glycerol to organic solvent a2 is 1:1~10; in step b, the mass-volume ratio of intermediate 1 to organic solvent a2 is 1:1~10; in step c, the molar ratio of intermediate 2 to esterification reagent is 1:1.95~2.05, and the molar ratio of intermediate 2 to esterification catalyst is 1:1.95~2.

05.

5. The industrial-scale chemical preparation method of 1,2-difatty acid glycerides as described in claim 1, characterized in that, In step a, the stirring reaction is carried out at room temperature for 0.5 to 5 hours; in step b, the deprotection reaction is carried out at room temperature for 0.5 hours; in step c, the stirring reaction is carried out at room temperature for 1 to 5 hours; in step d, the deprotection reaction is carried out at room temperature for 12 hours.

6. The industrial-scale chemical preparation method of 1,2-difatty acid glycerides as described in claim 5, characterized in that, The room temperature is 20~30℃.

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