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Method for preparing 17alpha-hydroxyprogesteron

A technology of hydroxyprogesterone and cyano, which is applied in the field of preparation of steroid hormone drug intermediates, can solve the problems of large amount of mixed solvents, poor product quality, and many side reactions, and achieve industrial production, production cost reduction, The effect of improving the purity of the crude product

Active Publication Date: 2014-10-29
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The present invention improves the process described in USP5,132,440, provides a new preparation method of 17a-hydroxyprogesterone, and solves the problems of many side reactions, many impurities, large amount of mixed solvent used in the process route, and poor product quality. , process defects that require multiple refinements to achieve commercial-grade quality

Method used

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  • Method for preparing 17alpha-hydroxyprogesteron
  • Method for preparing 17alpha-hydroxyprogesteron
  • Method for preparing 17alpha-hydroxyprogesteron

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] In a 1000ml three-neck flask, add 50g of intermediate (II) and 200ml of toluene, stir and dissolve at room temperature, then add 1.0g of lithium chloride, slowly raise the temperature to 60-65°C, add dropwise 300ml of 2M methyl zinc toluene solution, After about 1.5~2 hours to drop, after the drop, reflux reaction for 4~5 hours, TLC to detect the reaction end point, after the reaction, add 100ml of 25% ammonium chloride solution, stir for 20~25 minutes to destroy the excess methyl zinc, and then Cool to 5-10°C, separate the water layer, extract the water layer with 200ml of toluene, and send it to the waste water treatment station, combine the organic layer and extract, distill under reduced pressure, recover about 90-95% of toluene, add 400 ml of ethanol, stir and raise the temperature To 55~60°C, add 50ml of 2M hydrochloric acid, continue to heat and stir for 1.5~2 hours, TLC confirms that the reaction is complete, after the reaction, add 10g of sodium bicarbonate to m...

Embodiment 2

[0022] In a 1000ml three-neck flask, add 50g of intermediate (II) and 200ml of toluene, stir and dissolve at room temperature, then add 1.0g of lithium chloride, slowly raise the temperature to 60-65°C, add dropwise 300ml of 2M methyl zinc chloride Toluene solution, about 1.5 to 2 hours to drop, after the drop, reflux reaction for 4 to 5 hours, TLC to detect the reaction end point, after the reaction, add 100ml of 25% ammonium chloride solution, stir for 20-25 minutes to destroy the excess formazan Zinc chloride, then cooled to 5-10°C, separated the water layer, extracted the water layer with 200ml of toluene, then sent to the waste water treatment station, combined the organic layer and extract, distilled under reduced pressure, recovered about 90-95% of toluene, added Add 400 ml of ethanol, stir and heat up to 55-60°C, add 50ml of 2M hydrochloric acid, continue to keep warm and stir for 1.5-2 hours, TLC confirms that the reaction is complete, after the reaction, add 10g of so...

Embodiment 3

[0025] In a 1000ml three-neck flask, add 50g of intermediate (II) and 200ml of tetrahydrofuran, stir and dissolve at room temperature, then add 1.0g of lithium chloride, slowly raise the temperature to 60-65°C, add dropwise 300ml of 2M methyl zinc tetrahydrofuran solution, After about 1.5 to 2 hours of dripping, after the dripping, reflux reaction for 4 to 5 hours, TLC to detect the reaction end point, after the reaction, add 100ml of 25% ammonium chloride solution, stir for 20-25 minutes to destroy the excess methyl zinc, Then distill under reduced pressure to recover about 90-95% of tetrahydrofuran, add 400 ml of ethanol, stir and heat up to 55-60°C, add 75ml of 2M hydrochloric acid, continue to keep warm and stir for 1.5-2 hours, TLC confirms that the reaction is complete, after the reaction , add 12g of sodium bicarbonate to make the pH value 4-4.5, concentrate at normal pressure, recover about 320ml of ethanol, add 400ml of water, continue to distill 100ml of solvent, then...

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Abstract

The invention relates to a method for preparing 17alpha-hydroxyprogesterone. The17alpha-hydroxyprogesterone is prepared by taking 17beta- cyano-5-androstene-17-ol-3,3-diethylene ketal (referred as an intermediate II) as a raw material and dimethylzinc or methylzinc chloride as a reagent; the content of the 17alpha-hydroxyprogesterone by HPLC is above 99.5% and the weight yield is 83-87%. The method comprises the following steps of dissolving the intermediate II in an organic solvent, adding lithium chloride as a catalyst, stirring, raising the temperature to 40-80 DEG C, dropwise adding a toluene solution of dimethylzinc or methylzinc chloride of which the concentration is 2M, and continuing to complete the reaction; and then adding an ammonium chloride solution of which the concentration is 25% to destruct an organic zinc reagent, separating the aqueous layer out and extracting, merging the organic layer and the extract and concentrating the solvent to near dryness, and then adding lower alcohol, stirring, raising the temperature to 40-60 DEG C, adding the acid of which the concentration is 2M, hydrolyzing, adjusting the pH value with a weak base after the reaction is completed, evaporating 90% of the solvent out, adding tap water, cooling and crystallizing to obtain a crude 17alpha-hydroxyprogesterone product; and then carrying out reflux decolorizing on the crude product with activated carbon by virtue of alcohol, and refining to obtain the commercial grade 17alpha-hydroxyprogesterone. The 17alpha-hydroxyprogesterone produced by the method disclosed by the invention has the advantages of good purity and high yield and is economic and environment-friendly, and the solvent can be recycled.

Description

technical field [0001] The invention belongs to the preparation technology of steroid hormone drug intermediates, in particular to a preparation method of 17a-hydroxyprogesterone. Background technique [0002] 17a-Hydroxyprogesterone is a common intermediate for the production of steroid hormone drugs. Using it as a raw material, more than ten kinds of commonly used progesterone drugs, such as medroxyprogesterone, cyproterone and megestrol, can be produced; using it as a raw material, 11β, 17a-dihydroxyprogesterone can be obtained through microbial fermentation, which can be Production of more than ten common corticosteroids such as hydrocortisone and prednisone. According to WHO statistics, in 2012, the global market demand reached 2,500-2,800 tons, with a steady growth rate of about 5% per year, and the market has broad prospects. [0003] The traditional production method of 17a-hydroxyprogesterone is to extract diosgenin from the yam plant, after protection, oxidative ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J7/00
Inventor 胡爱国吴来喜曾权
Owner HUNAN KEREY BIOTECH
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