Preparation method of 17alpha-acetoxy-(8, 13)-ene-11alpha-hydroxyprogesterone

A kind of hydroxyprogesterone, acetoxy technology, applied in the field of compound preparation, can solve the problem of no synthesis method and the like

Active Publication Date: 2018-01-05
ZHEJIANG XIANJU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Through searching the data, it is found that there is no information on the confirmation of the structure of this main impurity, and there is no specific synthesis method about it.

Method used

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  • Preparation method of 17alpha-acetoxy-(8, 13)-ene-11alpha-hydroxyprogesterone
  • Preparation method of 17alpha-acetoxy-(8, 13)-ene-11alpha-hydroxyprogesterone
  • Preparation method of 17alpha-acetoxy-(8, 13)-ene-11alpha-hydroxyprogesterone

Examples

Experimental program
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Effect test

Embodiment 1

[0084] A preparation method of 17α-acetoxy-(8,13)-ene-11α-hydroxyprogesterone, operated according to the following steps:

[0085] (1) Preparation of Compound B

[0086] Add 200ml of THF and compound A (10g, 0.029mol) to the reaction flask, stir and cool down to about -40°C, slowly add phosphorus pentachloride (12g, 0.058mol), complete the addition within 30 minutes, and control the temperature at -30°C ~-35°C, react for 2 hours until the reaction is complete. Slowly add 5 times the amount of water dropwise, then add dropwise a solution of sodium hydroxide (10g, 0.25mol) / 18ml of water to adjust the pH to near neutral, concentrate THF under reduced pressure, and finally add 200ml of ice water. Filtered, washed with water, and dried at 60°C to obtain compound B (9.0g, 0.027mol), the molar yield was 94.9%, and the HPLC content was 98%, and the next step was carried out.

[0087] (2) Preparation of Compound C

[0088] Acetic anhydride (27.97 g, 0.27 mol) was added to the reacti...

Embodiment 2

[0097] A preparation method of 17α-acetoxy-(8,13)-ene-11α-hydroxyprogesterone, operated according to the following steps:

[0098] (1) Preparation of Compound B

[0099]Add 200ml of diethyl ether and compound A (10g, 0.029mol) to the reaction flask, stir and cool down to about -40°C, slowly add phosphorus trichloride (7.96g, 0.058mol), complete the addition within 30 minutes, and control the temperature at -30°C ℃~-35℃, react for 2 hours until the reaction is complete. A solution of sodium hydroxide (10 g, 0.25 mol) / 18 ml of water was added dropwise to adjust the pH to near neutral, and finally 200 ml of ice water was precipitated. Filtered, washed with water, and dried at 60°C to obtain compound B (9.1g, 0.028mol), the molar yield was 95.6%, and the HPLC content was 97.8%, and the next step was carried out.

[0100] (2) Preparation of Compound C

[0101] Add acetic anhydride (27.97g, 0.27mol) to the reaction flask, add compound B (9.0g, 0.027mol), stir and raise the temper...

Embodiment 3

[0110] A preparation method of 17α-acetoxy-(8,13)-ene-11α-hydroxyprogesterone, operated according to the following steps:

[0111] (1) Preparation of Compound B

[0112] Add 200ml of tetrahydrofuran and compound A (10g, 0.029mol) to the reaction flask, stir and cool down to about -40°C, slowly add phosphorus oxychloride (10g, 0.065mol), complete the addition within 30 minutes, and control the temperature at -20°C ~-40°C, react for 1-2 hours until the reaction is complete. Slowly add 5 times the amount of water dropwise, control the temperature ≤ 20°C, then add dropwise a solution of sodium hydroxide (10g, 0.25mol) / 18ml of water, adjust the pH to near neutral, concentrate THF under reduced pressure, and finally precipitate into 200ml ice water. Filter, wash with water, and dry at 60° C. to obtain compound B (9.0 g, 0.027 mol), the molar yield is 94.9%, and the HPLC content is 97%, and proceeds to the next step.

[0113] (2) Preparation of Compound C

[0114] Add acetic anhy...

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Abstract

The invention relates to the field of compound preparation, in particular to a preparation method of 17alpha-acetoxy-(8, 13)-ene-11alpha-hydroxyprogesterone. The method includes: taking 11alpha, 17alpha-dihydroxyprogesterone as the raw material, carrying out elimination reaction, esterification reaction, bromination epoxy reaction and fluorination reaction to synthesize a 17alpha-acetoxy-(8, 13)-ene-11alpha-hydroxyprogesterone crude product; and finally performing column chromatography to obtain the high purity target object 17alpha-acetoxy-(8, 13)-ene-11alpha-hydroxyprogesterone refined product. The invention mainly solves the problem that the existing technology is short of synthesis method of the product, the product can be used as a reference substance for quality control of flurogestone acetate, is more beneficial to control of the flurogestone acetate quality and improvement of the drug safety.

Description

technical field [0001] The invention relates to the field of compound preparation, in particular to a method for preparing 17α-acetoxy-(8,13)-en-11α-hydroxyprogesterone, an important impurity in the production process of fluprogesterone acetate. Background technique [0002] Fluorprogesterone acetate is a kind of progestogen drug, which is mainly used for estrus induction or estrus synchronization in sheep and goats, and is in great demand in veterinary drugs. [0003] According to relevant information and documents, the Chinese invention with the publication number CN104402956A and the publication date of March 11, 2015, applied by Jiangxi Ganliang Pharmaceutical Raw Materials Co., Ltd., discloses a preparation method of fluprogesterone acetate, which is based on 9α- OH-AD is synthesized as a starting material, which requires the use of highly toxic substances such as acetone cyanohydrin, the process is complicated, and there is no description of impurities. There are rela...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J7/00
Inventor 赵俊志
Owner ZHEJIANG XIANJU PHARMA
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