Method for preparing steroid drug intermediate with 16-alpha-methyl

A technology of methyl steroids and intermediates, which is applied in the field of preparation of steroidal compounds, can solve problems such as difficult impurities, affecting the quality of final products, and increasing the difficulty of refining and purification in subsequent stages, so as to achieve easy access and high feasibility , strong operational effect

Inactive Publication Date: 2011-02-16
GUANGXI WANDE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are important intermediates of 16-α-methyl steroid drugs. In terms of the preparation of pregna-16α-methyl-3β, 17a-diol-20-one, we have not retrieved relevant patent documents. In the relevant literature In terms of reports, we retrieved [Title] my country's research progress on the use of sisal saponin to synthesize steroidal drugs, [Author] Han Guangdian Ma Zhaoyang, [Institution] Beijing Dongfang Huaya Institute of Chiral Medicine, [Title] Chinese Medicine Industry Journal. 2002, 33(9).-459-464, [Abstract] introduced 5a-pregna-16-en-3-ol-20-ketone-3-acetate as the starting material, through methyl 16-methyl-17-hydroxy compound with the same structure as pregna-16α-methyl-3β, 17a-diol-20-one can be obtained through oxidization, esterification, epoxidation and hydrolysis, but it will produce impurities that are difficult to refine , which increases the difficulty of refining and purifying in subsequent workshops and affects the quality of the final product

Method used

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  • Method for preparing steroid drug intermediate with 16-alpha-methyl
  • Method for preparing steroid drug intermediate with 16-alpha-methyl
  • Method for preparing steroid drug intermediate with 16-alpha-methyl

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Preparation of pregna-16α-methyl-3β, 17a-diol-20-one from 5-a-pregna-16-ene-3β-ol-20-one-3-acetate, the reaction principle is as follows image 3 Shown, the specific reaction steps are as follows:

[0030] Grignard reaction:

[0031] 300ml of tetrahydrofuran was added into the bottom flask, under nitrogen protection, 2.1g of cuprous chloride was added under stirring. Cool to below -20°C (-25°C to -20°C), and add 50g of sisalmonene (5-a-pregna-16-ene-3β-ol-20-keto-3-acetate). Keep below -20°C and add 100ml (2.0M) of Grignard reagent prepared from methyl chloride and magnesium, and keep stirring at -25~-20°C for 0.5~1h. Keep it below -20°C, add 30ml of acetic anhydride in 30 minutes, and keep stirring at -25~-20°C for 0.5~1h after the addition is complete. After rising to normal temperature, 100ml of dichloroethane was added, heated to 65°C to distill off tetrahydrofuran. Add 250ml of dichloroethane, then add about 200ml of 20% ammonium chloride solution and shake to ...

Embodiment 2

[0037] Preparation of pregna-16α-methyl-3β, 17a-diol-20-one from 5-a-pregna-16-ene-3β-ol-20-one-3-acetate, the reaction principle is as follows image 3 Shown, the specific reaction steps are as follows:

[0038] Grignard reaction:

[0039] Add 350ml of ether into the round bottom flask, protect it with argon, and add 2.1g of cuprous chloride under stirring. Cool to below -20°C (-20°C to -10°C), and add 50g of sisalmonene (5-a-pregna-16-ene-3β-ol-20-keto-3-acetate). Keep below -10°C and add 100ml (2.5M) of Grignard reagent prepared from iodomethane and magnesium, and keep stirring at -20°C to -10°C for 1.5h. Keep it below 0°C, add 30ml of acetic anhydride in 30 minutes, and keep stirring at -20°C to -10°C for 1.5h after the addition is complete. After rising to normal temperature, 100ml of toluene was added, heated to 40°C to distill off ether. Add 250ml of toluene, then add about 200ml of 20% ammonium chloride solution and shake to dissolve the magnesium salt converted by...

Embodiment 3

[0045] Preparation of pregna-16α-methyl-3β, 17a-diol-20-one from 5-a-pregna-16-ene-3β-ol-20-one-3-acetate, the reaction principle is as follows image 3 Shown, the specific reaction steps are as follows:

[0046] Grignard reaction:

[0047] Add 350ml of dimethyltetrahydrofuran into a round bottom flask, protect it with argon, and add 2.1g of cuprous chloride under stirring. Cool to below 0°C (-10°C to 0°C), and add 50g of sisalmonene (5-a-pregna-16-ene-3β-ol-20-keto-3-acetate). Keep below -10°C and add 100ml (2.5M) Grignard reagent prepared from methyl chloride and magnesium, and keep stirring at -10°C to 0°C for 2h. Keep it below 0°C, add 30ml of acetic anhydride in 30 minutes, and keep stirring at -10°C to 0°C for 2 hours after the addition is complete. After rising to normal temperature, 100ml of toluene was added, heated to 95°C to distill off dimethyltetrahydrofuran. Add 250ml of toluene, then add about 200ml of 1% hydrochloric acid solution and shake to dissolve the ...

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Abstract

The invention provides a method for preparing a steroid drug intermediate with 16-alpha-methyl. In the method, a steroid compound I is selected as an initiator to take part in Grignard reaction to transform the sixteenth bit thereof so as to obtain a Grignard product; the Grignard product takes part in epoxy reaction to transform the seventeenth bit thereof to obtain a Grignard epoxy product; and the Grignard epoxy product takes part in hydrolysis reaction to transform the third bit thereof and perform open loop on the seventeenth bit and the twentieth bit thereof to obtain a steroid compound II which is the steroid drug intermediate with 16-alpha-methyl. The steroid compound II with 16-alpha-methyl is usually used for preparing common clinical meqoeofrol acefate, such as dexamethasone, dexamethasone sodium phosphate, mometasone furoate, dexamethasone acetate and the like.

Description

technical field [0001] The present invention relates to a kind of preparation method of steroid compound, especially relate to the preparation method of intermediate of steroid medicine with 16-alpha-methyl. Background technique [0002] Glucocorticoids are necessary to maintain life. Glucocorticoids in the human body are synthesized and secreted by the cells of the adrenal cortex zona fascicularis, which have an important impact on protein, sugar, fat, water, electrolytic metabolism and the functions of various tissues and organs. Glucocorticoids in super-physiological amounts have various pharmacological effects such as anti-inflammation, anti-infection, anti-endotoxin, anti-allergy, anti-shock and suppression of immune response, and are often used to treat various stress reactions, immune diseases and inflammatory states . At present, it is mainly used for the treatment of active rheumatism, rheumatoid arthritis, lupus erythematosus, severe bronchial asthma, severe derma...

Claims

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Application Information

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IPC IPC(8): C07J7/00
Inventor王远秋谭桂莉杨冰
OwnerGUANGXI WANDE PHARMA