Preparation method of 6a-methyl hydrocortisone

A technology of methyl hydrocortisone and hydrocortisone, which is applied in directions such as organic chemistry, steroids, etc., can solve the problems of increased production cost, long synthesis route, low total synthesis yield, etc., and achieves reduced production cost, The production operation is simple, the process is economical and environmentally friendly

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

AI Technical Summary

Problems solved by technology

Its synthetic route is long, and the total yield of synthesis is low, and the extraction of diosgenin and subsequent multi-step synthetic chemical reactions produce more waste water, which is not easy to handle and easily pollutes the environment
More importantly, with the depletion of wild yam plant resources, and t

Method used

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  • Preparation method of 6a-methyl hydrocortisone
  • Preparation method of 6a-methyl hydrocortisone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] A. Preparation of ether compounds

[0028] In a 1000ml three-neck flask, add 100g hydrocortisone, 200ml ethanol, 80ml triethyl orthoformate, 2g p-toluenesulfonic acid, keep warm at 40-45 degrees and stir for 6-8 hours, TLC detects the end point of the reaction, the reaction is complete Finally, add 3ml of pyridine, stir for 20-25 minutes to neutralize the acid, then recover 90-95% organic solvent under reduced pressure, then add 500ml of 50% ethanol aqueous solution, cool the system to -5-0 degrees, stir and crystallize for 2~ After 3 hours, filter with suction, wash with a small amount of ethanol aqueous solution, combine the lotion and filtrate, recover the solvent, and dry the filter cake below 70°C to obtain 101.6 g of ether compound, the HPLC content is 99.2%, and the weight yield is 101.6%.

[0029] B. Preparation of methine

[0030]In a 1000ml three-necked flask, add 100g of ether compound, 800ml of ethanol, and 50ml of dichloromethane. After dissolving, add a s...

example 2

[0034] A, the preparation of ether compound

[0035] In a 1000ml three-neck flask, add 100g hydrocortisone, 200ml chloroform, 80ml triethyl orthoformate, 2g concentrated sulfuric acid, keep warm at 40-45 degrees and stir for 6-8 hours. TLC detects the end point of the reaction. After the reaction, Add 3ml of pyridine, stir for 20-25 minutes to neutralize the acid, then recover 90-95% organic solvent under reduced pressure, then add 500ml of 50% ethanol aqueous solution, cool the system to -5-0 degrees, stir and crystallize for 2-3 hours , suction filtration, washed with a small amount of ethanol aqueous solution, the washing liquid and the filtrate were combined, the solvent was recovered, and the filter cake was dried below 70 degrees to obtain 101.2 g of ether compound, the HPLC content was 99.0%, and the weight yield was 101.2%.

[0036] B. Preparation of methine

[0037] In a 1000ml three-necked flask, add 100g of ether compound, 800ml of tetrahydrofuran, and 50ml of chlo...

Embodiment 3

[0041] A, the preparation of ether compound

[0042] In a 1000ml three-neck flask, add a mixed solution of 100g hydrocortisone, 200ml toluene, 80ml triethyl orthoformate, 2g HCl and 20ml ethanol, keep warm at 40-45 degrees and stir for 6-8 hours, TLC detects the reaction end point, After the reaction, add 3ml of pyridine, stir for 20-25 minutes to neutralize the acid, then recover 90-95% of the organic solvent under reduced pressure, then add 500ml of 50% ethanol aqueous solution, cool the system to -5-0 degrees, stir and crystallize After 2 to 3 hours, filter with suction, wash with a small amount of ethanol aqueous solution, combine the lotion and filtrate, recover the solvent, and dry the filter cake below 70 degrees to obtain 100.8 g of ether compound, with an HPLC content of 99.5% and a weight yield of 100.8%.

[0043] B. Preparation of methine

[0044] In a 1000ml three-neck flask, add 100g of ether compound, 800ml of toluene, and 50ml of chloroform, and after dissolvin...

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Abstract

The invention provides a preparation method of 6a-methyl hydrocortisone. The preparation method comprises the steps that hydrocortisone prepared from 4-androstene-3,17-dione (called as 4AD for short) is adopted as a raw material to generate an acid catalytic reaction with triethyl orthoformate in an organic solvent, and etherate 3-ether enol hydrocortisone is obtained; the etherate generates a Manlixi reaction with N-methylaniline and formaldehyde in an organic solvent, and a methylene product 6-methylene hydrocortisone is obtained; the methylene product generates a catalytic hydrogenation reaction in an organic solvent, and 6a-methyl hydrocortisone is obtained. Compared with a production method achieved by taking a mold removal product obtained by processing diosgenin as a raw material, the method for producing 6a-methyl hydrocortisone has the advantages that raw material sources are wide, the processes are economical and environmentally friendly, production operation is easy and convenient, the synthetic route is short, and the product yield is high; by producing 6a-methyl hydrocortisone through the method, the production cost is reduced by 40%-50% compared with a traditional method; the solvents used in production can be recycled and cyclically reused, and implementation of industrialized production is promoted.

Description

technical field [0001] The invention belongs to the preparation technology of steroid hormone drugs and intermediates thereof, and in particular relates to a preparation method of 6a-methylhydrocortisone, a key intermediate of methylprednisolone. Background technique [0002] Methylprednisolone (molecular formula C22H32O5), chemical name 6a-methyl-11b, 17a, 21-trihydroxy-pregna-1,4-diene-3,20-dione, is a second Steroidal glucocorticoid drugs. Clinically, it is mainly used for primary and secondary adrenal cortex hypofunction, rheumatism, petechiae, acute bronchial asthma, allergic rhinitis, lupus erythematosus, shock, acute leukemia in children, hypercalcemia caused by tumor, etc. The treatment of many diseases has low side effects, good effect and broad market prospect. 6a-Methylhydrocortisone is a key intermediate in the production of methylprednisolone, which can be dehydrogenated at the 1-position of DDQ or dehydrogenated at the 1-position by other methods to obtain me...

Claims

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Application Information

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IPC IPC(8): C07J5/00
CPCC07J5/0053
Inventor 胡爱国甘红星左前进吴来喜
Owner HUNAN KEREY BIOTECH
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