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Preparation method of 1alpha-hydroxyl dehydroepiandrosterone

A technology of dehydroepiandrosterone and hydroxyl, applied in chemical instruments and methods, ketal steroids, steroids and other directions, can solve the problems of high technical requirements, poor selectivity, difficult separation, etc., and achieves broad industrial application prospects and improved The effect of location selectivity and security risk reduction

Active Publication Date: 2022-01-07
ZHEJIANG XIANJU PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] (1) When 1α-hydroxyl is introduced, the selectivity is poor, resulting in a large proportion of isomers. Usually, column separation and other techniques are required to remove isomers, which requires high technical requirements , difficult to separate, low yield;
[0011] (2) Palladium reagent is usually used for dehydrogenation and oxidation. The post-treatment is complex and the recovery of palladium reagent is difficult and costly. position, the reaction needs to be carried out in liquid ammonia, the conditions are severe, and there are great potential safety hazards in the production process, which puts forward higher requirements for the production process, troublesome post-processing, large environmental pollution, and is not conducive to industrial production

Method used

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  • Preparation method of 1alpha-hydroxyl dehydroepiandrosterone
  • Preparation method of 1alpha-hydroxyl dehydroepiandrosterone
  • Preparation method of 1alpha-hydroxyl dehydroepiandrosterone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1 (transposition reaction, transposition reagent adopts potassium tert-butoxide and DBU)

[0068] Transposition reaction: Add 110g of ketal product II and 330mL of dimethyl sulfoxide into the reactor, stir under nitrogen protection at a controlled temperature of 30-40°C, add 110g of potassium tert-butoxide and 55g of DBU, and keep the reaction for 6 hours. After the reaction is completed, Pour into acid water for water analysis, filter, wash the filter cake with drinking water until neutral, refine the filter cake with methanol to obtain 100.1 g of transposition product III, the weight yield is 91%, and the HPLC purity is 98.6%.

Embodiment 2

[0069] Embodiment 2 (transposition reaction, translocation reagent adopts potassium tert-butoxide and DBN)

[0070] Transposition reaction: Add 110g of ketal product II and 550mL of tert-butanol into the reaction kettle, stir at a temperature of 30-40°C under nitrogen protection, add 165g of potassium tert-butoxide and 110g of DBN, and keep the reaction for 3 hours. After the reaction is completed, pour Put into acid water for water analysis, filter, wash the filter cake with drinking water until neutral, refine the filter cake with methanol to obtain 94.6 g of transposition product III, the weight yield is 86%, and the HPLC purity is 96.6%.

[0071] Compared with the comparative example, when DBU or DBN is added to the transposition reagent, the yield and purity of the transposition product are improved, the post-treatment is simple, and the column separation operation with high environmental pollution and high cost is avoided.

Embodiment 3

[0073] The first step, ketal reaction: put 500g of 1,4-androstenedione, 10g of p-toluenesulfonic acid and 1L of dichloromethane into the reaction kettle, pass N 2 , temperature control 15 ~ 20 ℃, stirring to dissolve. Slowly add 385 mL of triethyl orthoformate and 358.5 mL of ethylene glycol dropwise for 1 hour, and control the temperature at 15-25°C for 6-10 hours. After the heat preservation reaction is completed, add the prepared sodium bicarbonate solution into the reaction system, adjust the pH to 8-9, and stir for 20 minutes. Stand still, separate layers, collect the lower dichloromethane, and extract the aqueous layer twice with dichloromethane (500 mL). Combine the organic phases, control the vacuum degree above 0.08MPa and concentrate under reduced pressure to remove dichloromethane, add 2L of drinking water, stir at 25-35°C for 0.5-1 hour, filter with suction, wash the filter cake with drinking water until neutral, and filter the cake with cyclohexane Beat and dry ...

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Abstract

The invention belongs to the technical field of preparation of steroid hormone drugs, and particularly relates to a preparation method of 1alpha-hydroxyl dehydroepiandrosterone, which comprises the following steps of by taking a compound I (1, 4-androstenedione) as a raw material, sequentially carrying out ketalation reaction, transposition reaction, epoxy reaction and reduction hydrolysis reaction to obtain a target product V (1alpha-hydroxyl dehydroepiandrosterone). The problems of high technical requirements for removing isomers, difficulty in separation, low yield and the like in the prior art can be effectively solved.

Description

technical field [0001] The invention belongs to the technical field of preparation of steroid hormone drugs, in particular to a preparation method of 1α-hydroxy dehydroepiandrosterone. Background technique [0002] 1α-Hydroxydhydroepiandrosterone is a very important steroid drug compound, CAS#: 20998-18-9, its structural formula is as follows: [0003] [0004] 1α-Hydroxydhydroepiandrosterone can be used as a starting material, and has a broad market prospect. It is used to prepare alfacalcidol and other calcidol drugs. The existing preparation methods are mainly divided into chemical synthesis and microbial methods. The chemical synthesis method mainly uses 1,4-androstenedione and dehydroepiandrosterone as starting materials. [0005] In 1973, the document Chemical&Pharmaceutical Bulletin (1974), 22(9), 2101-7 reported the synthesis of 1α-hydroxy dehydroepiandrosterone, which used 1,4-androstenedione as the starting material. The 17-position carbonyl is protected by ke...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J1/00C07J21/00C07J71/00
CPCC07J1/0011C07J21/008C07J71/001Y02P20/55
Inventor 戴静陈德家黄雅文
Owner ZHEJIANG XIANJU PHARMA
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