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Preparation method of methylprednisone

A technology of methylprednisone and epoxyprednisone, which is applied in the direction of steroids and organic chemistry, can solve the problems of complex process operation, difficult sewage treatment, high production cost, etc., and achieve process economy, environmental protection and production cost reduction , The effect of easy production and operation

Active Publication Date: 2017-03-22
HUNAN KEREY BIOTECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The object of the invention is to simplify the methylprednisone production process, provide a kind of preparation method of four-step reaction synthesis methylprednisone, improve synthetic total yield, reduce production cost, solve the problem in the traditional production process of methylprednisone Technical problems such as expensive raw materials, difficult sewage treatment, complicated process operations, and high production costs

Method used

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  • Preparation method of methylprednisone
  • Preparation method of methylprednisone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] A: Preparation of ketals

[0021] In a 1000ml three-necked bottle, add 100g 16(17)a-epoxyprednisone, 150ml ethylene glycol, 80ml triethyl orthoformate, 2g p-toluenesulfonic acid, keep warm at 20-25℃ and stir for 16~ After 18 hours, TLC detects the end point of the reaction. After the reaction, add 2ml of triethylamine to neutralize to a pH of about 7, then concentrate under reduced pressure to recover 90% of the solvent, cool, add 500ml of tap water, stir and crystallize for 60-90 minutes, Centrifuge, wash, filter, and discharge the filtrate and lotion to the wastewater treatment tank. The filter cake is directly recrystallized with 20% ethanol aqueous solution, and dried to obtain the ketal product: 20-ketal-16a(17)-epoxyprednisone 112g, HPLC content 98.0%, weight yield 112%.

[0022] B: Preparation of silicon ethers

[0023] In a 1000ml three-neck flask, add 100g of ketal, 400ml of dichloromethane, 80ml of trimethylchlorosilane, add 30g of ethylenediamine under stir...

Embodiment 2

[0027] A: Preparation of ketals

[0028] In a 1000ml three-necked bottle, add 100g 16(17)a-epoxyprednisone, 400ml dichloromethane, 40ml ethylene glycol, 80ml triethyl orthoformate, 2g p-toluenesulfonic acid, keep warm at 20-25 Stir and react at ℃ for 16-18 hours, TLC detects the end point of the reaction, after the reaction, add 2ml triethylamine to neutralize to pH about 7, then concentrate under reduced pressure to recover 90% of the solvent, cool, add 500ml tap water, stir and crystallize for 60 After -90 minutes, centrifuge, wash, and filter by rejection. The filtrate and washing liquid are discharged to the wastewater treatment tank. The filter cake is directly recrystallized with 20% ethanol aqueous solution, and dried to obtain the ketal product: 20-ketal-16a(17)- Epoxyprednisone 110g, HPLC content 98.5%, weight yield 110%.

[0029] B: Preparation of silicon ethers

[0030] In a 1000ml three-neck flask, add 100g of ketal, 400ml of chloroform, 80ml of trimethylchlorosi...

Embodiment 3

[0034] A: Preparation of ketals

[0035] In a 1000ml three-neck flask, add 100g 16(17)a-epoxyprednisone, 400ml toluene, 40ml ethylene glycol, 80ml triethyl orthoformate, 2g p-toluenesulfonic acid, keep stirring at 20-25°C React for 16-18 hours, TLC detects the end point of the reaction, after the reaction, add 2ml triethylamine to neutralize to pH about 7, then concentrate under reduced pressure to recover 90% of the solvent, cool, add 500ml tap water, stir and crystallize for 60-90 Minutes later, centrifuge, wash, reject and filter, and the filtrate and lotion are discharged to the wastewater treatment tank, and the filter cake is directly recrystallized with 20% ethanol aqueous solution, and dried to obtain the ketal product: 20-ketal-16a(17)-epoxy Prednisone 110.6g, HPLC content 97.5%, weight yield 110.6%.

[0036] B: Preparation of silicon ethers

[0037] In a 1000ml three-neck flask, add 100g of ketal, 400ml of dichloromethane, 80ml of trimethylchlorosilane, add 60g of ...

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Abstract

The invention relates to a preparation method of methylprednisone. The method comprises the following steps: carrying out acid catalyzed reaction on 16(17)a-epoxy prednisone prepared from 4-androstenedione (4AD for short) and ethanediol in an organic solvent at 10-50 DEG C to obtain a ketal substance 20-ketal-16(17)a-epoxy prednisone; carrying out alkali catalyzed reaction on the ketal substance and trimethylchlorosilane in an organic solvent to obtain a silyl ether substance 21-methylsilyl-ether-20-ketal-16(17)a-epoxy prednisone; and carrying out Grignard reaction on the silyl ether substance and a 2M methyl grignard reagent in an organic solvent, hydrolyzing the Grignard substance in strong acid to obtain the methylprednisone. The detection indicates that the HPLC (high performance liquid chromatography) content is 99.0% or above, the melting point is 228-237 DEG C, and the synthetic weight total yield is 80-85%. When being used for producing methylprednisone, the method has the advantages of wide raw material sources, economical and environment-friendly technique, simple production operation, short synthesis route, high synthesis yield and lower production cost (than the traditional method by 30-40%). The method is convenient for industrial production.

Description

technical field [0001] The invention belongs to the preparation process of steroid hormone drugs, in particular to a preparation method of methylprednisone. Background technique [0002] Methylprednisone (molecular formula C22H30O5), chemical name 16b-methyl-17a, 21-dihydroxy-pregna-1,4-diene-3,11,20-trione, is a second-generation steroid In clinical practice, it is mainly used for primary and secondary adrenal cortex hypofunction, cerebral edema, rheumatism, acute bronchitis, skin disease, lupus erythematosus, nausea and vomiting caused by tumor chemotherapy, etc. The treatment has low side effects, good effect and broad market prospect. The traditional production method of methylprednisone is to extract diosgenin from the yam plant, and through six steps of chemical reactions, the important hormone drug intermediate obtained by two steps of microbial fermentation - mold dehydrogenate (abbreviated as mildew) as raw material, The key intermediate P4 was obtained through fo...

Claims

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Application Information

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IPC IPC(8): C07J5/00
CPCC07J5/0076
Inventor 甘红星胡爱国谢来宾吴来喜
Owner HUNAN KEREY BIOTECH
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