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Method for synthesizing 17alpha-hydroxyprogesterone

A technology of hydroxyprogesterone and its synthetic method, which is applied in the field of preparation of steroid hormone drug intermediates, can solve the problems such as difficult inhibition of methyltestosterone, and achieve the effects of facilitating industrial production, improving product quality, and making the preparation process economical

Active Publication Date: 2016-07-27
ZHEJIANG XIANJU JUNYE PHARM CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there will always be a small amount of water in the solvent during production, so it is difficult to inhibit the production of methyltestosterone
[0006] In summary, the existing 17α-hydroxyprogesterone preparation process, especially the format process, has many technical shortcomings and is limited by technical bottlenecks. Therefore, the preparation method of 17α-hydroxyprogesterone urgently needs new technological breakthroughs

Method used

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  • Method for synthesizing 17alpha-hydroxyprogesterone
  • Method for synthesizing 17alpha-hydroxyprogesterone
  • Method for synthesizing 17alpha-hydroxyprogesterone

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Dissolve 20g of intermediate II in 80ml of toluene, add 1g of cyclohexanone cyanohydrin and 0.2g of anhydrous lithium chloride, stir and cool down to -20~-15°C, control the temperature at -15~-10°C at 3 Add 140ml of 2M methylmagnesium chloride toluene solution dropwise within ~4 hours, and keep it warm for 3~5 hours after dropping, until TLC shows that the raw materials are completely reacted; after the reaction, control the temperature below 5°C and slowly add 60ml of 20% ammonium chloride solution, Destroy the excess Grignard reagent, then concentrate toluene under reduced pressure, cool down to 0-10°C, filter, wash with water until neutral, add the obtained intermediate product directly to 160ml of methanol, then add 6ml of concentrated hydrochloric acid, and react at 15-35°C After 2 to 3 hours, after TLC confirms that the reaction is complete, slowly add 0.6g of weak base to neutralize until the pH value is 6.0 to 6.5, and evaporate 90% of the solvent; add 60g of tap...

Embodiment 2

[0027] Dissolve 20g of intermediate II in 80ml of toluene, add 1g of cyclohexanone cyanohydrin and 0.2g of chlorinated ketone, stir and cool down to -20~-15°C, and control the temperature at -15~-10°C at 3~ Add 140ml of 2M methylmagnesium chloride toluene solution dropwise within 4 hours, and keep it warm for 3 to 5 hours after dropping, until TLC shows that the raw materials are completely reacted; Excess Grignard reagent, then concentrated toluene under reduced pressure, cooled to 0-10°C, filtered, washed with water until neutral, the obtained intermediate product was directly added to 160ml of methanol, then 6ml of concentrated hydrochloric acid was added, and the reaction was performed at 15-35°C for 2 ~ 3 hours, after TLC confirms that the reaction is complete, slowly add 0.6g of weak base, neutralize until the pH value is 6.0 ~ 6.5, evaporate 90% of the solvent; add 60g of tap water, stir and cool to 5 ~ 10 ° C, and precipitate crystallization for 1 to 2 hours, filtered,...

Embodiment 3

[0030] Dissolve 20g of intermediate II in 80ml of toluene, add 1g of cyclohexanone cyanohydrin and 0.2g of anhydrous magnesium chloride, stir and cool down to -20~-15°C, control the temperature at -15~-10°C at 3~4 Add 140ml of 2M methylmagnesium chloride tetrahydrofuran solution dropwise within 1 hour, and keep it warm for 3 to 5 hours after dropping, until TLC shows that the raw materials are completely reacted; after the reaction, control the temperature below 5°C and slowly add 60ml of 20% ammonium chloride solution to destroy excess Grignard reagent, then concentrated under reduced pressure to get tetrahydrofuran, cooled to 0-10°C, filtered, washed with water until neutral, the obtained intermediate product was directly added to 160ml of methanol, then added 6ml of concentrated hydrochloric acid, and reacted at 15-35°C for 2- After 3 hours, TLC confirms that the reaction is complete, slowly add 0.6g of weak base, neutralize until the pH value is 6.0-6.5, evaporate 90% of th...

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Abstract

The invention provides a method for synthesizing 17alpha-hydroxyprogesterone.17beta-cyano-5-androstene-17-alcohol-3,3-ethylene dihydroxy ketal (an intermediate II for short) is adopted as a raw material, and cheap cyclohexanone cyanohydrin is adopted as an inhibitor of a main impurity methyltestosterone. Due to the fact that a cyclohexanone cyanohydrin structure is similar to a D-loop structure in the molecular structural formula of the intermediate II and can replace a D loop to react with OH<1> in a Grignard reaction system, generated methyltestosterone is greatly reduced. Under the catalytic action of anhydrous lithium chloride or CuCl, the reaction temperature is reduced to -15 DEG C to -10 DEG C, and other generated impurities can be reduced at the low temperature. Therefore, the product quality is improved by controlling Grignard reaction conditions, the content of crude HPLC can reach 98% or above, and the total weight yield ranges from 84% to 88% and is improved by 10% to 14% compared with a traditional process.

Description

technical field [0001] The invention belongs to the preparation technology of steroid hormone drug intermediates, and in particular relates to a synthesis method of 17α-hydroxyprogesterone. Background technique [0002] 17α-Hydroxyprogesterone is an important intermediate in the production of steroid hormones, and it can be used as an intermediate to produce progestins such as megestrol acetate, chlormadinone, prednisolone, and methylprednisolone , prednisone acetate and other corticosteroids, it can be seen that its application in the steroid market is very wide, and the demand is very large. [0003] The starting material of 17α-hydroxyprogesterone has been replaced by 4-androstenedione (abbreviated as 4AD) to the traditional diene, because the diene is based on diosgenin, sisal saponin and saponin. It can be prepared by ring-opening, acetylation, oxidation, hydrolysis, epoxidation, oxidation, addition, catalytic hydrogenation and other reactions. This traditional prepar...

Claims

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Application Information

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IPC IPC(8): C07J7/00
CPCC07J7/0045
Inventor 金建峰张峥斌胡明辉魏真董安邦
Owner ZHEJIANG XIANJU JUNYE PHARM CO LTD
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