CN113416227A

CN113416227A - Novel method for preparing medroxyprogesterone acetate

Info

Publication number: CN113416227A
Application number: CN202110717925.8A
Authority: CN
Inventors: 王彩霞; 周革
Original assignee: Jiaerke Biotechnology Nantong Co ltd
Current assignee: Jiaerke Biotechnology Nantong Co ltd
Priority date: 2021-06-28
Filing date: 2021-06-28
Publication date: 2021-09-21

Abstract

The invention discloses a novel method for preparing medroxyprogesterone acetate, which is characterized in that medroxyprogesterone acetate is taken as a raw material, acetyl chloride is dissolved in a solvent for acetylation reaction in the presence of an acid-binding agent, and the medroxyprogesterone acetate is prepared. The method takes megestrol acetate as a raw material, and dissolves acetyl chloride in a solvent for acetylation reaction in the presence of an acid-binding agent to prepare medroxyprogesterone acetate with the content of more than 98.5 percent, the yield of more than 95 percent, high yield, low cost and short reaction time; the acetyl chloride in the invention has small dosage and the acid-binding agent can be recycled, thereby further greatly reducing the production cost on the basis of environmental protection.

Description

Novel method for preparing medroxyprogesterone acetate

Technical Field

The invention relates to the technical field of medicines and chemical engineering, in particular to a novel preparation method of medroxyprogesterone acetate.

Background

Medroxyprogesterone acetate (Medrroxyprogesterone 17-acetate) is chemically 6 alpha-methyl-17 alpha-hydroxypregn-4-ene-3, 20-dione acetate, the Chinese name a gonepoprostone, developed by Upjohn, USA, and marketed domestically in 10 months 2010. Medroxyprogesterone acetate is a novel luteal pregnancy hormone medicine, can be widely applied to the treatment of diseases such as dysmenorrheal, irregular menstruation, functional uterine bleeding, threatened abortion, endometriosis and the like in clinic, and the injection can be used as a long-acting contraceptive. In addition, relevant researches show that the medicine can also be used for palliative treatment or adjuvant treatment of inoperable, recurrent or metastatic hormone-dependent tumors, such as breast cancer, endometrial cancer, kidney cancer, prostate cancer and the like.

Medroxyprogesterone acetate is currently prepared essentially by acetylation of medroxyprogesterone acetate. Wutianfei et al, in the article "improvement of medroxyprogesterone acetate synthesis process" introduced the existing process for preparing medroxyprogesterone acetate, and proposed that "17 alpha-hydroxyprogesterone is used as the starting material, 6-methine is introduced through 3 steps of enolization, Mannich reaction and Hoffman elimination, and then medroxyprogesterone acetate is prepared through hydrogenation, isomerization and acetylation; in addition, chinese patent publication No. CN102911233A discloses a method for synthesizing medroxyprogesterone, which adopts a technical scheme that 6 α -methyl-17 α -hydroxyprogesterone is subjected to acetylation reaction with acetic acid and acetic anhydride to obtain medroxyprogesterone.

In the prior art, acetic anhydride is used as an acetylating agent, acetic acid is used as a solvent, a large amount of acetic acid-containing wastewater is generated after reaction, and the treatment is difficult and is not beneficial to environmental protection; meanwhile, the production cost is high due to a large excess of acetic anhydride.

Disclosure of Invention

The invention aims to provide a novel method for preparing medroxyprogesterone acetate, which aims to solve the problems that in the existing method for preparing medroxyprogesterone acetate provided by the background art, when the medroxyprogesterone acetate is prepared by acetylation of the medroxyprogesterone acetate, acetic anhydride is used as an acetylating agent, acetic acid is used as a solvent, a large amount of acetic acid-containing wastewater is generated after reaction, the treatment is difficult, and the environmental protection is not facilitated; meanwhile, the production cost is high due to a large excess of acetic anhydride.

In order to realize the purpose, the invention provides a novel method for preparing medroxyprogesterone acetate, which takes medroxyprogesterone acetate as a raw material, and dissolves acetyl chloride in a solvent for acetylation reaction in the presence of an acid-binding agent to prepare medroxyprogesterone acetate, wherein the content is more than 98.5 percent, and the yield is more than 95 percent; the method adopts acetyl chloride as an acetylating agent instead of acetic anhydride, and the excess of the acetyl chloride is not more than 20 percent; and simultaneously, neutralizing the mother liquor obtained after precipitation of medroxyprogesterone acetate to pH =10-12 with 10% sodium hydroxide, layering to obtain an acid-binding agent, and drying the acid-binding agent for recycling. The novel preparation method of medroxyprogesterone acetate is environment-friendly, simple in process, high in yield and low in cost.

The embodiment of the application provides a new preparation method of medroxyprogesterone acetate, which comprises the following steps: dissolving megestrol acetate in a solvent of 8-15 times, adding an acid-binding agent of which the molar ratio is 1.1-1.3 times, adding acetyl chloride of which the molar ratio is 1-1.2 times, and carrying out heat preservation reaction at 0-10 ℃ for 2-9 h; after the HPLC tracking reaction is completed, slowly dripping water into the reactant, filtering and drying to obtain the medroxyprogesterone acetate, wherein the content is more than 98.5 percent, and the yield is more than 95 percent.

The reaction equation is as follows:

。

in the preparation method, the solvent is any one of dichloromethane, chloroform and carbon tetrachloride, and the acid-binding agent is any one of N-methylaniline, N-dimethylaniline and aniline.

One or more technical solutions provided in the embodiments of the present application have at least the following technical effects or advantages:

the new method for preparing medroxyprogesterone acetate provided by the invention is characterized in that medroxyprogesterone acetate is taken as a raw material, acetyl chloride is dissolved in a solvent for acetylation reaction in the presence of an acid-binding agent, and the obtained medroxyprogesterone acetate has the content of more than 98.5%, the yield of more than 95%, high yield, low cost and short reaction time; the acetyl chloride in the invention has small dosage and the acid-binding agent can be recycled, thereby further greatly reducing the production cost on the basis of environmental protection.

Detailed Description

In order to enhance the understanding of the present invention, the present invention will be described in further detail with reference to the following examples.

Example 1

Adding 34g of megestrol acetate and 272g of chloroform into a reaction flask, adding 13g of N-methylaniline, dropwise adding 8.7g of acetyl chloride at about 5 ℃, keeping the temperature for reaction for 9 hours after the addition is finished, slowly dropwise adding 50g of water into a reaction system under cooling after HPLC tracking reaction is completed, filtering, and drying in vacuum to obtain 36.5g of medroxyprogesterone acetate with the content of 98.9% and the yield of 95%; the mother liquor was neutralized with 10% sodium hydroxide to pH =10-12, and the layers were separated, 12.6g of an oil layer was separated and dried over anhydrous sodium sulfate and used.

Example 2

Adding 34g of megestrol acetate and 510g of chloroform into a reaction flask, adding 15.9g of N, N-dimethylaniline, dropwise adding 10.2g of acetyl chloride at about 0 ℃, keeping the temperature for reaction for 2 hours after the addition is finished, slowly dropwise adding 50g of water into a reaction system under cooling after HPLC tracking reaction is completed, filtering, and drying in vacuum to obtain 36.6g of medroxyprogesterone acetate with the content of 98.8 percent and the yield of 95.2 percent; the mother liquor was neutralized with 10% sodium hydroxide to pH =10-12, and the layers were separated, 14.8g of an oil layer was separated, dried over anhydrous sodium sulfate, and used.

Example 3

Adding 34g of megestrol acetate and 374g of chloroform into a reaction flask, adding 14.7g of N-methylaniline, dropwise adding 9.4g of acetyl chloride at about 10 ℃, keeping the temperature for reaction for 5 hours after the addition is finished, after the HPLC tracking reaction is completed, slowly dropwise adding 50g of water into a reaction system under cooling, filtering, and drying in vacuum to obtain 36.8g of medroxyprogesterone acetate with the content of 99.1% and the yield of 95.7%; the mother liquor was neutralized with 10% sodium hydroxide to pH =10-12, and the layers were separated, 12.6g of an oil layer was separated and dried over anhydrous sodium sulfate and used.

Claims

1. A new method for preparing medroxyprogesterone acetate is characterized in that medroxyprogesterone acetate is taken as a raw material, acetyl chloride is dissolved in a solvent for acetylation reaction in the presence of an acid-binding agent, and the medroxyprogesterone acetate is prepared by the specific steps of: dissolving megestrol acetate in a solvent of 8-15 times, adding an acid-binding agent of which the molar ratio is 1.1-1.3 times, adding acetyl chloride of which the molar ratio is 1-1.2 times, and carrying out heat preservation reaction at 0-10 ℃; after the HPLC tracking reaction is completed, slowly dripping water into the reactant, filtering and drying to obtain the medroxyprogesterone acetate.

2. The novel method for preparing medroxyprogesterone acetate according to claim 1, wherein the reaction equation of the novel preparation method is as follows:

。

3. the novel method for preparing medroxyprogesterone acetate according to claim 1, wherein the incubation time is 2-9 h.

4. The method for preparing medroxyprogesterone acetate according to claim 1, wherein the solvent is any one of dichloromethane, chloroform and carbon tetrachloride.

5. The novel method for preparing medroxyprogesterone acetate according to claim 1, wherein the acid-binding agent is any one of N-methylaniline, N-dimethylaniline and aniline.

6. The novel method for preparing medroxyprogesterone acetate according to claim 1, further comprising the following steps: separating out the obtained medroxyprogesterone acetate, neutralizing the residual mother liquor with 10% sodium hydroxide until the pH is =10-12, layering to obtain an acid-binding agent, and drying the acid-binding agent for recycling.