A method for synthesizing estradiol benzoate
By improving the synthesis method of estradiol benzoate, using toluene and acylation catalysts instead of benzoyl chloride, and combining purified water and petroleum ether treatment, the problems of high cost and safety risks in the existing technology have been solved, and efficient and safe industrial production has been achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-20
- Publication Date
- 2026-04-03
AI Technical Summary
In existing methods for synthesizing estradiol benzoate, benzoyl chloride is expensive and diethyl ether is difficult to preserve, resulting in high production costs and safety risks. A safer and lower-cost synthesis method is needed.
The process involves reacting estradiol with an alkaline solution to form a salt, then adding toluene and an acylation catalyst, followed by the dropwise addition of benzoic anhydride. The solution is then crystallized with purified water and purified with ethyl acetate solvent, avoiding the use of benzoyl chloride and diethyl ether. Catalysts such as dimethylaminopyridine are used, and the temperature and stirring time are controlled. Finally, the product is crystallized with petroleum ether to obtain a high-quality product.
The synthesis of high-purity (99.25%) estradiol benzoate was achieved with a yield greater than 95%, meeting pharmacopoeia standards, reducing production costs and safety risks, and making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical pharmaceutical technology, specifically to a method for synthesizing estradiol benzoate. Background Technology
[0002] Estradiol benzoate (methylthiouracil; 3-hydroxyestradiol-1,3,5(10)-trien-17β-ol-3-benzoate), molecular formula: C 25 H 28 O3, with CAS number 50-50-0, molecular weight 376.49 g / mol, has the following structural formula:
[0003]
[0004] Estradiol benzoate is an important estrogen drug with wide applications in the pharmaceutical field. It is primarily used to treat various conditions caused by estrogen deficiency, such as amenorrhea, dysfunctional bleeding, menorrhagia or oligomenorrhea, and uterine hypoplasia. It also has an inhibitory effect on mammary gland secretion. Through long-term research and practice, some existing synthetic routes are relatively mature. Typically, estradiol is used as the starting material, combined with benzoyl chloride and diethyl ether, through salt formation and acylation reactions. This process can stably synthesize estradiol benzoate in the laboratory and in large-scale production. However, benzoyl chloride, the main raw material, is expensive and costly. Diethyl ether, required in the reaction process, has a low boiling point and is difficult to store and transport. Both are also controlled hazardous chemicals, requiring special storage and handling conditions during production. Therefore, a more cost-effective and lower-risk preparation method is needed. Summary of the Invention
[0005] The purpose of this invention is to provide a method for synthesizing estradiol benzoate, which, while ensuring quality, addresses the shortcomings of existing preparation methods, such as high preparation costs and safety risks.
[0006] In view of this, the solution of the present invention is as follows:
[0007] A method for synthesizing estradiol benzoate, comprising the following steps:
[0008] S1. Estradiol is dissolved in an alkaline solution to form a salt, and then toluene and an acylation catalyst are added;
[0009] S2. Control the temperature below 70℃, add benzoic anhydride dropwise to the solution obtained in step S1, and then heat to 80-120℃ and stir for 3-5 hours;
[0010] S3. Add purified water to the reaction product solution, stir to induce crystallization, and purify to obtain estradiol benzoate.
[0011] Further, 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, more preferably dimethylaminopyridine.
[0012] And / or, the molar ratio of estradiol to the acylation catalyst is 1:(0.05-0.1), preferably 1:0.067.
[0013] Further, 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] Further, in step S1, the mass-to-volume ratio of estradiol to toluene is 1 kg: (3-5) L.
[0015] Further, 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 as follows:
[0018] 1) Centrifuge the crystallized product, wash with water until neutral, and dry to obtain crude estradiol benzoate;
[0019] 2) The crude estradiol benzoate was decolorized in ethyl acetate solvent, filtered, concentrated under reduced pressure to a paste, cooled to 5-10℃, petroleum ether was added, stirred to precipitate crystals, centrifuged, dried, washed with petroleum ether, dried, and then dried to obtain the refined estradiol benzoate.
[0020] Preferably, in the above purification process:
[0021] In step 2), the ratio of crude estradiol benzoate to ethyl acetate is 1 kg: (11-13) L;
[0022] In step 2), the decolorization process uses medicinal charcoal; the decolorization process is heated to 70-80℃.
[0023] In step 2), the drying conditions are drying in an 80°C oven for 4-6 hours.
[0024] In step 2), the ratio of the volume of petroleum ether used each time to the mass of crude product is 3L:1kg.
[0025] Furthermore, the purification process in step S3 ultimately yields estradiol benzoate with a purity 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 beneficial effects of the present invention are as follows:
[0028] The synthesis method described in this invention uses toluene as a solvent and benzoic anhydride as an acylation reagent. While ensuring synthesis efficiency and quality, it effectively avoids the safety risks and high costs associated with the use of reagents in existing technologies. The production process does not require special storage and operating conditions, nor does it need to consider the restrictions on raw materials imposed by hazardous chemical control. It can ensure the requirements of normalized industrial production and controllable product quality.
[0029] The reaction product obtained by the synthesis method described in this invention has qualified external standards, a specific rotation of +57° to +63°, and qualified melting point and related substances. The purity can reach up to 99.25%, and it meets the pharmacopoeia standards after testing. The purification method is simple and suitable for industrial production.
[0030] Attached Description
[0031] Figure 1 This is the HPLC chromatogram of estradiol benzoate prepared in Example 1 of the present invention.
[0032] Figure 2 This is the HPLC chromatogram of estradiol benzoate prepared in Example 2 of the present invention. Detailed Implementation
[0033] The technical solution of the present invention will be clearly and completely described and verified below with reference to preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.
[0034] For reagents or instruments whose manufacturers are not specified in the examples, these can be purchased from the market as standard products. For items whose specific conditions are not specified, standard conditions or manufacturer-recommended conditions should be followed.
[0035] Example 1
[0036] The preparation method of estradiol benzoate includes the following steps:
[0037] In a clean 100L glass reactor, 30kg of purified water and 6.6kg of potassium hydroxide were added and heated to 60℃ to dissolve them. 3kg of estradiol was then added and stirred for 1 hour. 12L of toluene and 90g of dimethylaminopyridine were added, followed by the dropwise addition of 9kg of benzoic anhydride. The reaction was heated to approximately 95℃ and stirred for 4 hours. Samples were taken, and the reaction was controlled by chromatography. After the reaction was deemed satisfactory, approximately 30L of purified water was added until the reactor was full. Crystallization was carried out for 2 hours, followed by centrifugation, washing with water until neutral, and drying to obtain 4.04kg of crude estradiol benzoate. HPLC analysis showed the crude product to have a purity of 97.03% and a estradiol content of 0.77%.
[0038] The crude product was dissolved in 40 L of ethyl acetate at 75 °C. 0.2 kg of pharmaceutical charcoal was added for decolorization for 50 minutes. The mixture was filtered, concentrated under reduced pressure to a paste, cooled to room temperature, and 12 L of petroleum ether was added. After stirring and crystallization, centrifugation was performed to obtain 3.69 kg of purified estradiol benzoate. Figure 1 As shown, the purity detected by HPLC was 99.252%, which passed the full inspection according to the pharmacopoeia standard.
[0039] Example 2
[0040] The preparation method of estradiol benzoate includes the following steps:
[0041] In a clean 100L glass reactor, 25kg of purified water and 5kg of potassium hydroxide were added and heated to 60℃ to dissolve them. 3kg of estradiol was then added and stirred for 1.5 hours. 12L of toluene and 70g of dimethylaminopyridine were added, followed by the dropwise addition of 8.7kg of benzoic anhydride. The reaction was heated to 120℃ and stirred for 3 hours. Samples were taken, and the reaction was controlled by chromatography. After the reaction was deemed satisfactory, approximately 30L of purified water was added to fill the reactor. Crystallization was carried out for 2 hours, followed by centrifugation, washing with water until neutral, and drying to obtain 4.07kg of crude estradiol benzoate. HPLC analysis showed the crude product to have a purity of 96.63% and a estradiol content of 0.84%.
[0042] The crude product was dissolved in 40 L of ethyl acetate at 80 °C. 0.2 kg of pharmaceutical charcoal was added for decolorization for 50 minutes. The mixture was filtered, concentrated under reduced pressure to a paste, cooled to room temperature, and 12 L of petroleum ether was added. After stirring and crystallization, centrifugation was performed to obtain 3.65 kg of purified estradiol benzoate. Figure 2 As shown, the purity detected by HPLC was 98.879%, which passed the full inspection according to the pharmacopoeia standard.
[0043] Example 3
[0044] The preparation method of estradiol benzoate includes the following steps:
[0045] In a clean 100L glass reactor, 30kg of purified water and 3kg of potassium hydroxide were added and heated to 60℃ to dissolve them. 3kg of estradiol was then added and stirred for 1 hour. 12L of toluene and 130g of dimethylaminopyridine were added, followed by the dropwise addition of 10kg of benzoic anhydride. The reaction was heated to approximately 80℃ and stirred for 5 hours. Samples were taken, and the reaction was controlled by chromatography. After the reaction was deemed satisfactory, approximately 30L of purified water was added until the reactor was full. Crystallization was carried out for 2 hours, followed by centrifugation, washing with water until neutral, and drying to obtain 4.10kg of crude estradiol benzoate. HPLC analysis showed the crude product to have a purity of 96.28% and a estradiol content of 0.87%.
[0046] The crude product was dissolved in 40L of ethyl acetate at 80℃, decolorized with 0.2kg of pharmaceutical charcoal for 50 minutes, filtered, concentrated under reduced pressure to a paste, cooled to room temperature, and then 12L of petroleum ether was added. After stirring and crystallization, the product was centrifuged and dried to obtain 3.71kg of purified estradiol benzoate. The purity was 98.851% as determined by HPLC, and the product passed all tests according to the pharmacopoeia standards.
[0047] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.
Claims
1. A method for synthesizing estradiol benzoate, characterized in that the step... include: S1. Dissolve estradiol in an aqueous solution of potassium hydroxide to form a salt, then add toluene and dimethylaminopyridine; S2. Control the temperature below 70℃, add benzoic anhydride dropwise to the solution obtained in step S1, and then heat to 80-120℃ and stir for 3-5 hours; S3. Add purified water to the reaction product solution, stir to induce crystallization, and purify to obtain estradiol benzoate; The molar ratio of estradiol to dimethylaminopyridine is 1:(0.05-0.1), the mass ratio of estradiol to potassium hydroxide is 1:(0.5-3), and the molar ratio of estradiol to benzoic anhydride is 1:(3.5-4.0).
2. 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.
3. The synthesis method according to claim 1, characterized in that, In step S3, the purification process is as follows: 1) Centrifuge the crystallized product, wash with water until neutral, and dry to obtain crude estradiol benzoate; 2) The crude estradiol benzoate was decolorized in ethyl acetate solvent, filtered, concentrated under reduced pressure to a paste, cooled to 5-10℃, petroleum ether was added, stirred to precipitate crystals, centrifuged, dried, washed with petroleum ether, dried, and then dried to obtain the refined estradiol benzoate.
4. The synthesis method according to claim 3, characterized in that, In step 2), the ratio of crude estradiol benzoate to ethyl acetate is 1 kg : (11-13) L.
5. The synthesis method according to claim 3, characterized in that, In step 2), the decolorization process uses medicinal charcoal; And / or, the decolorization process is heated to 70-80°C.
6. The synthesis method according to claim 3, characterized in that, The purity of the refined estradiol benzoate is greater than 98.5%.