Process for the preparation of a glucocorticoid compound
By optimizing the production process of hydrocortisone propyl acetate and employing cyclization, hydrolysis, and esterification reactions, the problems of low yield and high cost in existing technologies have been solved, achieving efficient and low-cost industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- CHINA AGRI UNIV
- Filing Date
- 2024-10-12
- Publication Date
- 2026-05-12
AI Technical Summary
Existing synthetic routes for hydrocortisone acetate have low yields and high raw material prices, making them unsuitable for industrial production.
A new process route for the production of hydrocortisone acetate was adopted, which includes cyclization, hydrolysis and esterification reactions. Specific catalysts and solvents were used, reaction conditions were optimized, the operation process was simplified, and the generation of waste was reduced.
It achieves high yield and high purity under fine chemical production conditions, reduces production costs, is suitable for industrial production, and is environmentally friendly.
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Figure CN119306782B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of veterinary drug technology, specifically to a method for preparing a glucocorticoid compound. Background Technology
[0002] Hydrocortisone and its derivatives are intermediate-acting corticosteroids widely used in clinical practice. Products include hydrocortisone, hydrocortisone acetate, etc. Its efficacy is comparable to prednisone, with a stronger anti-inflammatory effect, 3 to 5 times that of cortisone. However, its water and electrolyte metabolism is very weak, generally making it less likely to cause side effects such as electrolyte disturbances.
[0003] Synthetic processes for hydrocortisone and its derivatives have existed for a long time. Among existing technologies, the synthetic routes for hydrocortisone propyl acetate include: (Poly)cationicλ3-Iodane-Mediated Oxidative Ring Expansion of Secondary Alcohols (Article) [J]. European Journal of Organic
[0004] Chemistry.2018,Vol.2018(No.12):1460-1464.:
[0005]
[0006] Synthetic route 1 uses hydrocortisone-21-acetate as a starting material and synthesizes hydrocortisone propyl acetate through a four-step reaction involving hydrolysis, triethyl orthopropionate, hydrolysis, and esterification. This synthetic route has a low yield and high raw material costs, making it unsuitable for industrial production. Summary of the Invention
[0007] To address the aforementioned issues, this invention provides a novel production process for hydrocortisone propyl acetate. The method uses hydrocortisone as a starting material, undergoing cyclization, hydrolysis, and esterification reactions to obtain hydrocortisone propyl acetate. Specifically, each stage of the production process is easily implemented, simple to operate, easy to control, and yields high output under current fine chemical production conditions. Furthermore, the production cost is relatively low, saving significant time and costs in actual production, resulting in good economic benefits.
[0008] This invention provides a method for preparing glucocorticoid compounds, comprising the following steps:
[0009]
[0010] 1) Using hydrocortisone and trimethyl orthopropionate as starting materials, after being catalyzed by catalyst 1 p-toluenesulfonic acid, intermediate 1: hydrocortisone cyclic ester is obtained. The molar ratio of hydrocortisone to catalyst 1 p-toluenesulfonic acid is 1:(0.1-0.5).
[0011] 2) Add ammonium chloride, a hydrolysis reagent, to intermediate 1. After hydrolysis, intermediate 2, hydrocortisone-17-propyl ester, should be obtained.
[0012] 3) Intermediate 2 undergoes esterification to yield hydrocortisone acetate propyl ester.
[0013] Further, in step 1), the reaction solvent 1 is selected from 1,4-dioxane, dimethyl sulfoxide, N,N-dimethylformamide, and preferably 1,4-dioxane;
[0014] The washing solvent 1 after the reaction is completed is selected from saturated sodium bicarbonate aqueous solution and saturated sodium carbonate aqueous solution, preferably saturated sodium bicarbonate aqueous solution;
[0015] The extraction following washing uses an extractant selected from halogenated hydrocarbons, dichloromethane, dichloroethane, ethyl acetate, and diethyl ether, preferably dichloromethane.
[0016] Preferably, in step 1), the molar ratio of the starting material hydrocortisone to trimethyl orthopropionate is 1:(1-3);
[0017] The molar ratio of hydrocortisone to the reaction solvent is 1:(30-50);
[0018] The mass ratio of hydrocortisone to washing solvent 1 is 1:(3-10);
[0019] The molar ratio of hydrocortisone to extractant is 1:(30-40).
[0020] Further, in step 2), the reaction solvent 2 is selected from water, ethanol, and isopropanol, preferably water;
[0021] The hydrolysis reaction catalyst 2 is selected from aluminum trichloride and phosphorus trichloride, preferably aluminum trichloride.
[0022] Preferably, in step 2), the molar ratio of intermediate 1 to hydrolysis reagent is 1:(1-10);
[0023] The molar ratio of intermediate 1 to hydrolysis catalyst 2 is 1:(0.1-3), and the volume fraction of catalyst 2 is 0.2-0.6%.
[0024] The molar ratio of intermediate 1 to reaction solvent 2 is 1:(8-12).
[0025] Preferably, the intermediate 2 hydrocortisone-17-propyl ester prepared after the hydrolysis reaction in step 2) has an optical purity of over 99% and a reaction yield of 85-90%.
[0026] Further, in step 3), the reaction solvent 3 is selected from pyridine, dimethylformamide, and 1,4-dioxane, preferably pyridine;
[0027] The esterification catalyst 3 is selected from acetic anhydride, sulfuric acid, hydrochloric acid, and acetyl chloride, preferably acetic anhydride;
[0028] The extraction solvent after the reaction is completed is selected from halogenated hydrocarbons, dichloromethane, dichloroethane, ethyl acetate, and diethyl ether, with dichloromethane being preferred;
[0029] The washing reagent 3 after extraction was selected from sodium chloride solution with a volume fraction of 8-12%;
[0030] After washing, concentrate under reduced pressure to 15-25% of the extractant volume;
[0031] The precipitating reagent added after concentration is selected from cyclohexane.
[0032] Preferably, in step 3), the molar ratio of intermediate 2 to reaction solvent 3 is 1:(50-100);
[0033] The molar ratio of intermediate 2 to esterification catalyst 3 is 1:(1-3);
[0034] The mass ratio of intermediate 2 to the extraction solvent is 1:(4-10);
[0035] The mass ratio of intermediate 2 to washing reagent 3 is 1:(4-10);
[0036] The mass ratio of intermediate 2 to the precipitating reagent is 1:(10-30).
[0037] Furthermore, its preparation method also includes reaction temperature and reaction time;
[0038] In step 1), the reaction temperature is 20-25℃ and the reaction time is 5-10 hours.
[0039] In step 2), the reaction temperature is 40-50℃ and the reaction time is 10-20 hours.
[0040] In step 3), the reaction temperature is 30-35℃ and the reaction time is 4-12 hours.
[0041] Furthermore, the extraction is performed 2-5 times; the washing is performed 2-4 times.
[0042] Compared with the prior art, the advantages of the present invention are:
[0043] 1. The generated "three wastes" are relatively small and easy to treat, giving it the advantages of being green and environmentally friendly. The three-step reaction produces almost no waste gas. The waste liquid produced is 1,4-dioxane, dichloromethane, and cyclohexane, all of which can be recovered. The sodium bicarbonate aqueous solution, ammonium chloride and aluminum trichloride aqueous solution, and sodium chloride solution produced will not cause environmental pollution through neutralization reactions.
[0044] 2. Each step of the production process is easy to implement, simple to operate, and easy to control under current fine chemical production conditions. It does not involve column chromatography or high-pressure reactions.
[0045] 3. High yield, high product purity, and relatively low production cost. It can save a lot of time and costs in actual production, making it more suitable for industrial production. Attached Figure Description
[0046] Figure 1 Mass spectrum of hydrocortisone acetate propyl ester.
[0047] Specific implementation methods
[0048] To make the objectives, technical solutions, and advantages of this application clearer, a more detailed description is provided below. However, it should be understood that the description herein is merely for explaining this application and is not intended to limit its scope.
[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of this application. All reagents and instruments used herein are commercially available, and the characterization methods involved can be found in relevant descriptions in the prior art, and will not be repeated here.
[0050] To further understand this application, the following detailed description is provided in conjunction with the preferred embodiments.
[0051] Example 1
[0052] Hydrocortisone acetate propyl ester, chemically named 11β,17α,21-trihydroxypregn-4-ene-3,20-dione-21-acetoxy-17α-propionate, has the molecular formula: C 26 H 36 O7. The structural formula is shown below:
[0053]
[0054] This embodiment provides a method for preparing hydrocortisone acetate, a glucocorticoid compound. The specific steps are as follows:
[0055]
[0056] 1) Synthesis of intermediate 1
[0057]
[0058] Starting with hydrocortisone (CAS No.: 50-23-7) and trimethyl orthopropionate (CAS No. 24823-81-2) in a molar ratio of 1:(1-3), in reaction solvent 1 (1,4-dioxane), the molar ratio of hydrocortisone to reaction solvent 1 is 1:(30-50), the reaction temperature is 20-25℃, and after catalysis by catalyst 1 (p-toluenesulfonic acid), the molar ratio of hydrocortisone to catalyst 1 is 1:(0. 1-0.5), the reaction time is 5-10 hours, and the reaction solution is obtained. After the reaction is completed, washing solvent 1 is added to a saturated sodium bicarbonate aqueous solution. The mass ratio of hydrocortisone to washing solvent 1 is 1:(3-10). Stir for 10-30 minutes, then add dichloromethane as the extraction agent. The molar ratio of hydrocortisone to extraction agent is 1:(30-40). Extract 2-5 times, concentrate to dryness, and obtain intermediate 1: hydrocortisone cyclic ester.
[0059] 2) Synthesis of intermediate 2
[0060]
[0061] Intermediate 1 is reacted in water as reaction solvent 2, with a molar ratio of intermediate 1 to reaction solvent 2 of 1:(8-12). Ammonium chloride hydrolysis reagent and aluminum trichloride catalyst 2 are added, with a molar ratio of intermediate 1 to hydrolysis reagent of 1:(1-10). The reaction temperature is 40-50℃, and the molar ratio of intermediate 1 to catalyst 2 is 1:(0.1-3). The volume fraction of catalyst 2 is 0.2-0.6%, and the reaction time is 10-20 hours. After hydrolysis, intermediate 2, hydrocortisone-17-propyl ester, is obtained with an optical purity of over 99%. The yield of the two-step reaction is 85-90%.
[0062] 3) Synthesis of hydrocortisone acetate propyl ester
[0063]
[0064] Intermediate 2 is reacted in pyridine reaction solvent 3, with a molar ratio of intermediate 2 to reaction solvent 3 of 1:(50-100). Acetic anhydride is used as catalyst 3, with a molar ratio of intermediate 2 to catalyst 3 of 1:(1-3). The reaction temperature is 30-35℃, and the reaction time is 4-12 hours. After esterification, dichloromethane is added as an extractant for extraction, with a mass ratio of intermediate 2 to extractant of 1:(4-10). Extraction is performed 2-5 times, followed by washing 2-4 times with sodium chloride solution as a washing reagent, with a volume fraction of 8-12% and a mass ratio of intermediate 2 to washing reagent 3 of 1:(4-10). The mixture is concentrated under reduced pressure to 20% of the extractant volume, stirred for 10-30 minutes, and precipitated with cyclohexane as a precipitation reagent, with a mass ratio of intermediate 2 to precipitation reagent of 1:(10-30), yielding hydrocortisone propyl acetate with a purity of over 99% and a yield of over 92%.
[0065] Example 2
[0066] The preparation process of the glucocorticoid compound prepared according to Example 1 is described in detail in the following experimental examples.
[0067] Experimental Example 1
[0068] A method for preparing a glucocorticoid compound, the specific steps of which are as follows:
[0069] 1) Synthesis of intermediate 1
[0070]
[0071] Add 100g of hydrocortisone and 1000g of 1,4-dioxane sequentially to a 2000mL three-necked flask equipped with a stir bar, drying tube, and thermometer. Add 150g of trimethyl orthopropionate while stirring at room temperature (25°C) until a white, turbid solution is formed. Purge with nitrogen for 5 minutes to replace the air; then quickly add 4.7g of anhydrous p-toluenesulfonic acid. The solid disappears, and the reaction solution becomes colorless or pale yellow and transparent. Stir the reaction at 25°C for approximately 5 hours, until the starting material spot disappears as detected by TLC.
[0072] Add 500g of saturated sodium bicarbonate aqueous solution to a 5000ml beaker, add the reaction solution, stir for 10min, add 2500g of water, stir for 30min, add 800g of dichloromethane and extract three times, collect the dichloromethane layer, concentrate to dryness, and obtain intermediate 1 viscous solid. Proceed directly to the second step of the reaction.
[0073] 2) Synthesis of intermediate 2
[0074]
[0075] Take intermediate 1 obtained in step 1) into a reaction flask, add 1000g of water, stir and heat to 45℃, slowly pour in 500ml of saturated ammonium chloride aqueous solution, then add 1200g of 0.4% aluminum trichloride aqueous solution. The solution becomes turbid. React at 45℃ for 10h with stirring. TLC detection shows the starting material spot disappears. Concentrate under reduced pressure to remove some water, leaving about 700ml in the reaction flask. A yellow solid precipitates, is filtered under reduced pressure, and the solid is washed with water. Dry at 50℃ for 10h to obtain 114g of intermediate 2, a white solid with a purity of 99.3%. The yield of the two-step reaction is 87.6%.
[0076] 3) Synthesis of hydrocortisone acetate propyl ester
[0077]
[0078] 63 g of intermediate 2 and 600 g of pyridine were added to a 250 ml three-necked flask equipped with a drying tube, thermometer, and stirrer. 20 g of acetic anhydride was added dropwise with stirring. The reaction was carried out at 30 °C for 8 h. TLC analysis confirmed the reaction was complete. The mixture was then poured into 250 g of water. The solution was extracted twice with 300 g and 100 g of dichloromethane. The combined organic layers were washed three times with 252 g of 10% sodium chloride solution. The solution was concentrated under reduced pressure to approximately 100 ml of dichloromethane and dissolved. 1200 g of cyclohexane was added, and the mixture was stirred at room temperature to precipitate the solid. The solid was filtered under reduced pressure and dried to obtain 64.4 g of hydrocortisone acetate with a purity of 99.5%. The yield was 92.9%.
[0079] Mass spectrum as shown Figure 1 As shown, the liquid chromatography-mass spectrometry (LC-MS) system used was a Waters Acquity UPLC I-Class Pluss-XevoG2 XS QToF (USA). Chromatographic conditions were: Phase A was 0.1% formic acid-water, Phase B was acetonitrile, using a 95% A + 5% B initial gradient analysis, analysis time 5 min, injection volume 0.1 μL, and flow rate 0.40 mL / min. The positive source high-resolution electrospray ionization mass spectrometry (HS-MS) spectrum showed a quasi-molecular ion peak at m / z 461.2534 [M+H]. + The calculated value is 461.2534 (C 26 H 37 O7), its molecular formula is determined to be C 26 H 36 O7 has the same molecular formula as this product.
[0080] Experimental Example 2
[0081] A method for preparing a glucocorticoid compound, the specific steps of which are as follows:
[0082] 1) Synthesis of intermediate 1
[0083] The procedure was roughly the same as step 1) of Experimental Example 1, except that 23.5 g of p-toluenesulfonic acid was added and other experimental conditions were the same.
[0084] 2) Synthesis of intermediate 2
[0085] Similar to step 2) of Example 1, 3000 ml of saturated ammonium chloride aqueous solution was poured in, and other experimental conditions remained the same; 110.88 g of intermediate 2, a white solid, with a purity of 99.4% was obtained. The yield of the two-step reaction was 85.2%.
[0086] 3) Synthesis of hydrocortisone acetate propyl ester
[0087] Similar to step 3) of Example 1, 45 g of acetic anhydride was added dropwise with stirring, and other experimental conditions remained the same; 64.9 g of hydrocortisone acetate was obtained, with a purity of 99.5%. The yield was 93.7%.
[0088] Unlike existing processes, our synthetic route, through multiple trials, has confirmed that the amounts of ammonium chloride and p-toluenesulfonic acid are key factors for achieving high overall yields and product purity in the first and second steps. The synthesized intermediate 1 does not require purification and can directly proceed to the next reaction step.
[0089] Comparative Example 1
[0090] A method for preparing a glucocorticoid compound, the specific steps of which are as follows:
[0091] 1) Synthesis of intermediate 1
[0092] The procedure is roughly the same as step 1) of Experimental Example 1, except that 30g of p-toluenesulfonic acid is added and other experimental conditions are the same.
[0093] 2) Synthesis of intermediate 2
[0094] The procedure was largely the same as step 2) of Experimental Example 1, with all other experimental conditions being identical; intermediate 2, a white solid, was obtained at a purity of 67.3%, and the two-step reaction yield was 48.5%.
[0095] Comparative Example 1 demonstrates that increasing the proportion of p-toluenesulfonic acid (the molar ratio of hydrocortisone to p-toluenesulfonic acid reactants is 1:0.63) not only fails to increase the yield but also leads to more side reactions, affecting the yield of the two-step reaction and resulting in more impurities, which in turn affects the subsequent synthesis preparation.
[0096] Comparative Example 2
[0097] A method for preparing a glucocorticoid compound, the specific steps of which are as follows:
[0098] 1) Synthesis of intermediate 1
[0099] The steps are largely the same as in Example 1, and all other experimental conditions are the same.
[0100] 2) Synthesis of intermediate 2
[0101] Intermediate 1 was transferred to a reaction flask, 1000g of water was added, and the mixture was stirred and heated to 45°C. 100ml of a saturated ammonium chloride aqueous solution was slowly poured in, followed by 1200g of a 0.4% aluminum trichloride aqueous solution. The solution became cloudy. The reaction was continued at 45°C for 20 hours with stirring. TLC analysis showed that the starting material spot did not disappear. Some water was removed by vacuum concentration until approximately 500-600ml remained in the reaction flask. A white solid precipitated, which was filtered under reduced pressure and washed with water. The solid was dried at 50°C for 10 hours to obtain 58.8g of intermediate 2, a white solid. The yield of the two-step reaction was 45.2%, with a purity of 87%.
[0102] Comparative Example 3
[0103] A method for preparing a glucocorticoid compound, the specific steps of which are as follows:
[0104] 1) Synthesis of intermediate 1
[0105] The steps are largely the same as in Example 1, and all other experimental conditions are the same.
[0106] 2) Synthesis of intermediate 2
[0107] Take intermediate 1 into a reaction flask, add 1000g of water, stir and heat to 45℃, then add 1200g of 0.4% aluminum trichloride aqueous solution. The solution becomes turbid. React at 45℃ with stirring for 5-10 hours. TLC detection shows that the starting material spot remains. Concentrate under reduced pressure to remove some water, leaving about 700-800ml in the reaction flask. Filter under reduced pressure and wash with water. Obtain 23g of intermediate 2, a yellow viscous substance with many impurities.
[0108] Comparative Examples 2 and 3 demonstrate that using ammonium chloride in a proportion not covered by this application, or omitting ammonium chloride altogether, will severely affect the reaction progress, the yield of the two-step reaction, and generate more impurities, thus affecting subsequent synthesis and preparation.
[0109] Comparative Example 4
[0110] A method for preparing a glucocorticoid compound, the specific steps of which are as follows:
[0111] 1) Synthesis of intermediate 1
[0112] The steps are largely the same as in Example 1, and all other experimental conditions are the same.
[0113] 2) Synthesis of intermediate 2
[0114] Intermediate 1 was added to a reaction flask along with 1000g of water. The mixture was stirred and heated to 45°C. 45g of acetic acid was slowly poured in, followed by 1200g of a 0.4% aluminum trichloride aqueous solution. The solution became cloudy. The reaction was continued at 45°C with stirring for 5-10 hours. TLC analysis showed that the starting material spot remained. The mixture was concentrated under reduced pressure to remove some water, leaving approximately 80ml in the reaction flask. The solution was then filtered under reduced pressure and washed with water. 56.3g of intermediate 2 (a viscous substance) was obtained. The yield of the two-step reaction was 48.8%, with a purity of 88.6%.
[0115] Comparative Example 4 demonstrates that using an acidic substance with properties similar to ammonium chloride as a hydrolysis reagent also severely affects the reaction progress, the yield of the two-step reaction, and generates more impurities, which affects subsequent synthesis and preparation.
[0116] Compared with the existing methods for preparing hydrocortisone acetate, the product synthesized in this invention does not require purification, and the yield and purity are already very high, reducing costs and losses.
[0117] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of this application should be included within the protection scope of this application.
Claims
1. A method for preparing a glucocorticoid compound, characterized in that, Includes the following steps: ； 1) Using hydrocortisone and trimethyl orthopropionate as starting materials, after catalysis by catalyst 1 p-toluenesulfonic acid, intermediate 1: hydrocortisone cyclic ester is obtained. The molar ratio of hydrocortisone to catalyst 1 p-toluenesulfonic acid is 1: (0.1-0.5); the reaction temperature is 20-25℃ and the reaction time is 5-10 hours. 2) Add ammonium chloride as a hydrolysis reagent and aluminum trichloride as a hydrolysis catalyst 2 to intermediate 1. After hydrolysis, intermediate 2 is obtained: hydrocortisone-17-propyl ester. The molar ratio of intermediate 1 to hydrolysis reagent is 1:(1-10); the molar ratio of intermediate 1 to hydrolysis catalyst 2 is 1:(0.1-3); the mass fraction of catalyst 2 is 0.2-0.6%; the reaction temperature is 40-50℃; and the reaction time is 10-20 hours. 3) Intermediate 2 undergoes esterification to yield hydrocortisone acetate propyl ester.
2. The preparation method according to claim 1, characterized in that, Step 1) also includes reaction solvent 1, wherein reaction solvent 1 is selected from 1,4-dioxane, dimethyl sulfoxide, and N,N-dimethylformamide; After the reaction is complete, the mixture is washed with washing solvent 1, which is selected from saturated sodium bicarbonate aqueous solution and saturated sodium carbonate aqueous solution. The washing process includes extraction, in which the extractant is selected from halogenated hydrocarbons, dichloromethane, dichloroethane, ethyl acetate, and diethyl ether.
3. The preparation method according to claim 2, characterized in that, In step 1), the reaction solvent 1 is 1,4-dioxane; The washing solvent 1 is a saturated sodium bicarbonate aqueous solution; The extractant is dichloromethane.
4. The preparation method according to claim 2, characterized in that, In step 1), the molar ratio of the starting material hydrocortisone to trimethyl orthopropionate is 1:(1-3); The molar ratio of hydrocortisone to the reaction solvent is 1:(30-50); The mass ratio of hydrocortisone to washing solvent 1 is 1 : (3-10); The molar ratio of hydrocortisone to extractant is 1:(30-40).
5. The preparation method according to claim 1, characterized in that, Step 2) also includes reaction solvent 2, which is selected from water, ethanol, and isopropanol.
6. The preparation method according to claim 5, characterized in that, In step 2), the reaction solvent 2 is water.
7. The preparation method according to claim 5, characterized in that, In step 2), The molar ratio of intermediate 1 to reaction solvent 2 is 1:(8-12).
8. The preparation method according to claim 1, characterized in that, In step 2), the intermediate product 2, hydrocortisone-17-propyl ester, prepared after the hydrolysis reaction, has an optical purity of over 99% and a reaction yield of 85-90%.
9. The preparation method according to claim 1, characterized in that, Step 3) also includes reaction solvent 3, wherein reaction solvent 3 is selected from pyridine, N,N-dimethylformamide, and 1,4-dioxane; It also includes an esterification reaction catalyst 3, which is selected from acetic anhydride, sulfuric acid, hydrochloric acid and acetyl chloride; After the reaction is complete, extraction is performed, and the extractant used in the extraction is selected from haloalkanes, dichloromethane, dichloroethane ethyl acetate and diethyl ether; After extraction, the sample was washed with washing reagent 3, which was selected from sodium chloride solution with a mass fraction of 8-12%. After washing, concentrate under reduced pressure to 15-25% of the extractant volume; After concentration, a precipitation reagent is added to precipitate the product, and the precipitation reagent is selected from cyclohexane.
10. The preparation method according to claim 9, characterized in that, In step 3), the reaction solvent 3 is pyridine; The esterification reaction catalyst 3 is acetic anhydride; The extractant is dichloromethane.
11. The preparation method according to claim 9, characterized in that, In step 3), the molar ratio of intermediate 2 to reaction solvent 3 is 1 : (50-100); The molar ratio of intermediate 2 to esterification catalyst 3 is 1: (1-3); The mass ratio of intermediate 2 to the extraction solvent is 1:(4-10); The mass ratio of intermediate 2 to washing reagent 3 is 1 : (4-10); The mass ratio of intermediate 2 to the precipitating reagent is 1:(10-30).
12. The preparation method according to claim 1, characterized in that, Step 3) also includes a reaction temperature of 30-35℃ and a reaction time of 4-12 hours.
13. The preparation method according to claim 2 or 9, characterized in that, The extraction is performed 2-5 times; the washing is performed 2-4 times.