Synthesis process for promestriene

A synthesis process, a technology for proestrene, is applied in the field of synthesis of proestrene, can solve problems such as being unsuitable for industrial production, large safety risks, etc., and achieves avoiding the use of highly toxic raw materials, reducing production costs, reducing pollution and safety. hidden effect

Active Publication Date: 2019-09-10
BEIJING JINCHENG TAIER PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method reduces environmental toxicity, but sodium hydride is still used, and flammable hydrogen gas will still be produced during the reaction process, which has a large safety risk and is also not suitable for industrial production.

Method used

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  • Synthesis process for promestriene

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Experimental program
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Effect test

Embodiment 1

[0037] Add 10g of estradiol and 200g of acetone to a 500ml four-necked bottle under the protection of nitrogen at room temperature, stir to dissolve, add 10g of sulfonated carbon-based solid acid catalyst, add 18.97g of 47wt.% hydrobromic acid dropwise at a temperature of 25±5°C, and drop Raise the temperature to 55°C and stir the reaction for 24 hours. After the reaction, filter and recover the solid acid catalyst, add 200g water to the filtrate and stir for 0.5 hour, extract 3 times with 200g ethyl acetate, combine the organic phases and wash 2 times with water, dry over anhydrous magnesium sulfate, and concentrate to After drying, an off-white solid was obtained, which was recrystallized from methanol and dried by filtration to obtain 11.08 g of a white solid. That is, 3-hydroxy-17β-bromoestro-1,3,5,(10)-triene, with a yield of 90% and a purity of 99.2% by HPLC.

[0038] Add 11.08g of 3-hydroxy-17β-bromoestro-1,3,5,(10)-triene to a 500ml four-neck flask under nitrogen prote...

Embodiment 2

[0040] Add 20g of estradiol and 400g of acetone to a 1000ml four-neck bottle under the protection of nitrogen at room temperature, stir and dissolve, add 20g of ZSM-5 molecular sieve catalyst, add 25.29g of 47wt.% hydrobromic acid dropwise at a temperature of 25±5°C, and raise the temperature to Stir and react at 55°C for 24 hours. After the reaction, filter and recover the solid acid catalyst, add 400g water to the filtrate and stir for 0.5 hour, extract 3 times with 400g ethyl acetate, combine the organic phases and wash twice with water, dry over anhydrous magnesium sulfate, and concentrate to dryness. An off-white solid was obtained, which was recrystallized from methanol, filtered and dried to obtain 22.41 g of a white solid. That is, 3-hydroxy-17β-bromoestro-1,3,5,(10)-triene, with a yield of 91% and a purity of 99.4% by HPLC.

[0041]Add 22.41g of 3-hydroxy-17β-bromoestro-1,3,5,(10)-triene to a 1000ml four-neck flask under the protection of nitrogen at room temperature,...

Embodiment 3

[0043] Add 30g of estradiol and 600g of acetone to a 1000ml four-necked flask at room temperature under nitrogen protection, stir to dissolve, add 30g of sulfonated carbon-based solid acid catalyst, add 44.26g of 47wt.% hydrobromic acid dropwise at a temperature of 25±5°C, and drop Raise the temperature to 55°C and stir the reaction for 24 hours. After the reaction, filter and recover the solid acid catalyst, add 600 g of water to the filtrate and stir for 0.5 hours, extract 3 times with 600 g of ethyl acetate, combine the organic phases and wash with water twice, dry over anhydrous magnesium sulfate, and concentrate to After drying, an off-white solid was obtained, which was recrystallized from methanol and dried by filtration to obtain 33.49 g of a white solid. That is, 3-hydroxy-17β-bromoestro-1,3,5,(10)-triene, with a yield of 91% and a purity of 99.6% by HPLC.

[0044] Add 33.49g of 3-hydroxy-17β-bromoestro-1,3,5,(10)-triene to a 1000ml four-neck flask under the protectio...

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Abstract

The invention relates to the technical field of medicine synthesis and in particular to a synthesis process for promestriene. The synthesis process comprises the following steps: by taking estradiol as a raw material, carrying out a halogenation reaction with a halogenation reagent under catalysis of a solid acid catalyst so as to generate 3-hydroxy-17beta-bromo-female steroid-1,3,5,(10)-triene, further carrying out a substitution reaction with a sodium methoxide methanol solution, and finally carrying out a synthesis reaction with 1-bromopropane by using Williamson so as to synthesize 3-hydroxy-17beta-methoxy-female steroid-1,3,5,(10)-triene, wherein the solid acid catalyst is a sulfonated carbon-based solid acid catalyst or a ZSM-5 molecular sieve catalyst. By adopting the synthesis process, hydrobromic acid and sodium methoxide are adopted to substitute sodium hydride of high danger and dimethyl sulphate of large toxicity, no combustible gas can be generated in the reaction, environment pollution and potential safety hazards can be reduced, the yield and the quality of a product can be ensured, the HPLC (high performance liquid) purity is greater than 99.8%, single impurities are less than 0.05%, and the synthesis process is applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a synthesis process of promestriene. Background technique [0002] Promestriene, also known as chlorophenamine, is 3-propoxy-17β-methoxyestro-1,3,5,(10)-triene, and its molecular formula is C 22 h 32 o 2 , with a molecular weight of 328.488, is a local estrogen supplement developed by Dalimei Pharmaceutical Factory in Monaco and launched in France in 1975. Proestrene is the first-line drug for the treatment of vulva, vestibular and vaginal atrophic lesions caused by estrogen deficiency. Clinical trials have shown that it is safe and effective, and well tolerated by patients. [0003] The synthetic technique of promestrine reported at present mainly contains following three kinds: [0004] Method 1: The synthesis route of Monaco Dalimei Pharmaceutical Factory listed in France in 1975: [0005] This route takes estradiol as starting material, utilizes Willi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J1/00
CPCC07J1/0077
Inventor 游亚新张忠政张宾张国斌张治中张彤李宗奇
Owner BEIJING JINCHENG TAIER PHARMA CO LTD
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