Synthesis method of estradiol benzoate

Abstract

According to the synthesis method, methylbenzene is used as a solvent, benzoic anhydride is used as an acylation reagent, and on the premise that the synthesis efficiency and quality are guaranteed, the defects that in the prior art, when a reagent is used, safety risks exist, and the cost is high are effectively overcome. In the production process, special storage and operation conditions are not needed, the product quality is controllable, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of chemical pharmacy, and in particular to a method for synthesizing estradiol benzoate. Background Art

[0002] Estradiol benzoate (methylthiouracil; 3-hydroxyestrone-1,3,5(10)-triene-17B-ol-3-benzoate), molecular formula: C 25 H 28 O3, its CAS number is: 50-50-0, molecular weight: 376.49 g / mol, its structural formula is:

[0003]

[0004] Estradiol benzoate is an important estrogen drug, which is widely used in the medical field. It is mainly used for various diseases caused by estrogen deficiency, such as amenorrhea, functional bleeding, menorrhagia, uterine hypoplasia, etc., and also has the effect of inhibiting mammary gland secretion. After long-term research and practice, some existing synthetic process routes have been relatively mature. Usually, estradiol is used as the starting material, combined with benzoyl chloride, ether, etc., through the process of salt formation, acylation and other reaction steps, estradiol benzoate products can be stably synthesized in the laboratory and a certain scale of production. However, benzoyl chloride as the main raw material is expensive and costly, and the ether required in the reaction process has a low boiling point and is not easy to store and transport, and both belong to controlled hazardous chemicals, and require special storage and operating conditions during the production process. Therefore, it is necessary to provide a more cost-saving and low-risk preparation method. Summary of the invention

[0005] The present invention aims to provide a method for synthesizing estradiol benzoate, which is used to solve the defects of high preparation cost and safety risk of the prior art preparation method under the premise of ensuring quality.

[0006] In view of this, the scheme of the present invention is:

[0007] A method for synthesizing estradiol benzoate, comprising the steps of:

[0008] S1. dissolving estradiol in an alkaline solution to form a salt, and then adding toluene and an acylation catalyst;

[0009] S2. Control the temperature below 70°C, add benzoic anhydride dropwise to the solution obtained in step S1, and then raise the temperature to 80-120°C and stir the reaction for 3-5h;

[0010] S3. Add purified water to the reaction product solution, stir to crystallize, and purify to obtain estradiol benzoate.

[0011] Furthermore, in step S1, the acylation catalyst is selected from at least one of dimethylaminopyridine, p-toluenesulfonic acid, and concentrated sulfuric acid; preferably at least one of dimethylaminopyridine and p-toluenesulfonic acid, and more preferably dimethylaminopyridine.

[0012] And / or, the molar ratio of estradiol to acylation catalyst is 1:(0.05-0.1), preferably 1:0.067.

[0013] Furthermore, in step S1, the alkaline solution is a potassium hydroxide solution, and the mass ratio of estradiol to potassium hydroxide is 1:(0.5-3); preferably 1:2.2.

[0014] Furthermore, in step S1, the mass volume ratio of estradiol to toluene is 1 kg:(3-5) L.

[0015] Furthermore, in step S2, the molar ratio of estradiol to benzoic anhydride is 1:(3.5-4.0).

[0016] Furthermore, in step S3, the amount of purified water added is 5-15 times the mass of estradiol, preferably 10 times.

[0017] Further, in step S3, the purification process is:

[0018] 1) centrifuging the crystallized product, washing with water until neutral, and drying to obtain a crude product of estradiol benzoate;

[0019] 2) Decolorize the crude estradiol benzoate in ethyl acetate solvent, filter, and concentrate under reduced pressure to a paste, reduce the temperature to 5-10° C., add petroleum ether, stir to crystallize, centrifuge, spin dry, then wash with petroleum ether, spin dry, and dry to obtain the refined estradiol benzoate.

[0020] Preferably, during the above purification process:

[0021] In step 2), the ratio of the crude estradiol benzoate to ethyl acetate is 1 kg: (11-13) L;

[0022] In step 2), medicinal charcoal is used in the decolorization process; the temperature is raised to 70-80°C during the decolorization process.

[0023] In step 2), the drying condition is oven drying at 80° C. for 4-6 hours.

[0024] In step 2), the ratio of the volume of petroleum ether used each time to the mass of the crude product is 3L:1kg.

[0025] Furthermore, the purity of the estradiol benzoate obtained in step S3 purification process is greater than 98.5%.

[0026] Furthermore, when the synthesis method is applied to industrial scale-up, the yield of estradiol benzoate is greater than 95%, and the purity is greater than 98.5%, which fully meets the efficiency and cost requirements of industrial preparation.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The synthesis method of the present invention uses toluene as a solvent and benzoic anhydride as an acylating agent, and under the premise of ensuring synthesis efficiency and quality, effectively avoids the defects of safety risks and high costs when using reagents in the prior art. In the production process, there is no need to use special storage and operating conditions, and there is no need to consider the restrictions of hazardous chemicals control on production raw materials, and the requirements of normalized industrial production and controllable product quality can be guaranteed.

[0029] The reaction product obtained by the synthesis method of the invention is qualified in external standard, has a specific rotation of +57° to +63°, a melting point and related substances are all qualified, and a purity as high as 99.25%. It meets the pharmacopoeia standard after detection, has a simple refining method, and is suitable for industrial production.

[0030] Description of the drawings

[0031] Figure 1 This is the HPLC detection spectrum of estradiol benzoate prepared in Example 1 of the present invention.

[0032] Figure 2 This is the HPLC detection spectrum of estradiol benzoate prepared in Example 2 of the present invention. DETAILED DESCRIPTION

[0033] The technical solution of the present invention will be clearly and completely described and verified in conjunction with the preferred embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] If the manufacturer of reagents or instruments is not specified in the examples, conventional products can be purchased from the market. If specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer can be used.

[0035] Example 1

[0036] The preparation method of estradiol benzoate comprises the following steps:

[0037] In a clean 100L glass reactor, add 30kg purified water and 6.6kg potassium hydroxide, heat to 60℃ to dissolve, add 3kg estradiol, and stir for 1 hour. Add 12L toluene, 90g dimethylaminopyridine, and start to drop 9kg benzoic anhydride, heat to react, control the temperature at about 95℃, and stir to react for 4 hours. Take samples, control the plate layer, and after the reaction is qualified, add about 30L purified water to fill the tank, stir and crystallize for 2 hours, centrifuge, wash neutrally with water, and dry to obtain 4.04kg crude estradiol benzoate. The crude product was tested by HPLC with a purity of 97.03% and estradiol content of 0.77%.

[0038] The crude product was dissolved in 40L ethyl acetate solvent at 75°C, decolorized with 0.2kg medicinal charcoal for 50 minutes, filtered, and concentrated under reduced pressure to a paste, cooled to room temperature, added with 12L petroleum ether, stirred for crystallization, and centrifuged to obtain 3.69kg of estradiol benzoate. Figure 1 As shown, the purity detected by HPLC is 99.252%, which is qualified according to the pharmacopoeia standards.

[0039] Example 2

[0040] The preparation method of estradiol benzoate comprises the following steps:

[0041] In a clean 100L glass reactor, add 25kg purified water and 5kg potassium hydroxide, heat to 60℃ to dissolve, add 3kg estradiol, and stir for 1.5 hours. Add 12L toluene, 70g dimethylaminopyridine, start to drop 8.7kg benzoic anhydride, heat to react, control the temperature at 120℃, and stir for 3 hours. Take samples, control the plate layer, and after the reaction is qualified, add about 30L purified water to fill the tank, stir and crystallize for 2 hours, centrifuge, wash neutrally, and dry to obtain 4.07kg crude estradiol benzoate. The crude product was tested by HPLC with a purity of 96.63% and estradiol content of 0.84%.

[0042] The crude product was dissolved in 40L ethyl acetate solvent at 80°C, decolorized with 0.2kg medicinal charcoal for 50 minutes, filtered, and concentrated under reduced pressure to a paste, cooled to room temperature, added with 12L petroleum ether, stirred for crystallization, and centrifuged to obtain 3.65kg of estradiol benzoate. Figure 2 As shown, the purity detected by HPLC is 98.879%, which is qualified according to the pharmacopoeia standards.

[0043] Example 3

[0044] The preparation method of estradiol benzoate comprises the following steps:

[0045] In a clean 100L glass reactor, add 30kg purified water and 3kg potassium hydroxide, heat to 60℃ to dissolve, add 3kg estradiol, and stir for 1 hour. Add 12L toluene, 130g dimethylaminopyridine, start to drop 10kg benzoic anhydride, heat to react, control the temperature at about 80℃, and stir to react for 5 hours. Take samples, control the plate layer, and after the reaction is qualified, add about 30L purified water to fill the tank, stir and crystallize for 2 hours, centrifuge, wash neutrally with water, and dry to obtain 4.10kg crude estradiol benzoate. The crude product was tested by HPLC with a purity of 96.28%, and estradiol contained 0.87%.

[0046] The crude product was dissolved in 40L of ethyl acetate solvent at 80°C, decolorized with 0.2kg of medicinal charcoal for 50 minutes, filtered, and concentrated under reduced pressure to a paste, cooled to room temperature, added with 12L of petroleum ether, stirred for crystallization, and centrifuged to obtain 3.71kg of estradiol benzoate. The purity detected by HPLC was 98.851%, which was qualified in all tests according to the pharmacopoeia standards.

[0047] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing estradiol benzoate, characterized in that the steps include: S1. dissolving estradiol in an alkaline solution to form a salt, and then adding toluene and an acylation catalyst; S2. Control the temperature below 70°C, add benzoic anhydride dropwise to the solution obtained in step S1, and then raise the temperature to 80-120°C and stir the reaction for 3-5h; S3. Add purified water to the reaction product solution, stir to crystallize, and purify to obtain estradiol benzoate.

2. The synthesis method according to claim 1, characterized in that In step S1, the acylation catalyst is selected from at least one of dimethylaminopyridine, p-toluenesulfonic acid, and concentrated sulfuric acid; And / or, the molar ratio of estradiol to acylation catalyst is 1:(0.05-0.1).

3. The synthesis method according to claim 1, characterized in that In step S1, the alkaline solution is a potassium hydroxide solution, and the mass ratio of estradiol to potassium hydroxide is 1:(0.5-3).

4. The synthesis method according to claim 1, characterized in that In step S2, the molar ratio of estradiol to benzoic anhydride is 1:(3.5-4.0).

5. The synthesis method according to claim 1, characterized in that In step S3, the amount of purified water added is 5-15 times the mass of estradiol.

6. The synthesis method according to claim 1, characterized in that In step S3, the purification process is: 1) centrifuging the crystallized product, washing with water until neutral, and drying to obtain a crude product of estradiol benzoate; 2) Decolorize the crude estradiol benzoate in ethyl acetate solvent, filter, and concentrate under reduced pressure to a paste, reduce the temperature to 5-10° C., add petroleum ether, stir to crystallize, centrifuge, spin dry, then wash with petroleum ether, spin dry, and dry to obtain the refined estradiol benzoate.

7. The synthesis method according to claim 6, characterized in that In step 2), the ratio of the crude estradiol benzoate to ethyl acetate is 1 kg: (11-13) L.

8. The synthesis method according to claim 6, characterized in that In step 2), the decolorization process uses medicinal charcoal; And / or, the decolorization process is heated to 70-80°C.

9. The synthesis method according to claim 6, characterized in that: The purity of the refined estradiol benzoate is greater than 98.5%.

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