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Preparation method of methylprednisolone hemisuccinate impurity

A technology of methylprednisolone succinate and succinate, which is applied in the field of chemical synthesis to achieve the effects of improving quality standards, clear synthesis paths and high product purity

Active Publication Date: 2019-04-26
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In order to better control the quality of methylprednisolone succinate and ensure the drug safety of methylprednisolone succinate, it is necessary to verify the method for the impurities of methylprednisolone succinate, but there are no relevant reports about 11β, 17α, 21- The preparation method of trihydroxy-6β-methylpregna-1,4-diene-3,20-dione-21-succinate, therefore, it is necessary to conduct in-depth research on the synthesis process of this impurity

Method used

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  • Preparation method of methylprednisolone hemisuccinate impurity
  • Preparation method of methylprednisolone hemisuccinate impurity
  • Preparation method of methylprednisolone hemisuccinate impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0042] Step 1: Preparation of 11β, 17α, 21-trihydroxy-6β-methylpregna-4-ene-3,20-dione (Formula III)

[0043] to N 2 Add 10.0g 11β, 17α, 21-trihydroxy-6-methylenepregn-4-ene-3,20-dione, 250ml absolute ethanol and 50ml cyclohexene into the protected reaction flask, stir, then add 0.68g of triethylamine and 4.0g of 10% Pd / C, heated up to 65-70°C. Insulate and react at 65-70°C for 3h. The reaction solution was filtered to remove the catalyst Pd / C, and the filtrate was evaporated to dryness under reduced pressure to obtain 9.4 g of off-white solid with a yield of 93.5% and a 6β-isomer content of 94.7%.

[0044] Step 2: Preparation of 11β, 17α-dihydroxy-6β-methylpregna-4-ene-3,20-dione-21-acetate (Formula IV)

[0045] to N 2 Add 9.0g11β, 17α, 21-trihydroxy-6β-methylpregn-4-ene-3,20-dione (formula III) and 135ml dichloromethane into the protected reaction flask, stir, then add 3.6g three Ethylamine and 2.93g of acetic anhydride were added and kept warm at 25°C until the end of ...

Embodiment 2

[0056] Preparation of 11β, 17a, 21-trihydroxy-6β-methylpregn-4-ene-3,20-dione (Formula III)

[0057] to N 2 Add 10.0g 11β, 17a, 21-trihydroxy-6-methylenepregn-4-ene-3,20-dione, 250ml absolute ethanol and 50ml cyclohexene into the protected reaction flask, stir, then add 0.68g of triethylamine and 4.0g of 10% Pd / C, heated up to 65-70°C. Insulate and react at 65-70°C for 3h. The reaction solution was filtered to remove the catalyst Pd / C, and the filtrate was evaporated to dryness under reduced pressure to obtain 9.4 g of off-white solid with a yield of 93.5% and a 6β-isomer content of 94.7%.

Embodiment 3

[0059] Preparation of 11β, 17α-dihydroxy-6β-methylpregna-4-ene-3,20-dione-21-acetate (Formula IV)

[0060] to N 2 Add 9.0g11β, 17α, 21-trihydroxy-6β-methylpregn-4-ene-3,20-dione (formula III) and 135ml dichloromethane into the protected reaction flask, stir, then add 3.6g three Ethylamine and 2.93g of acetic anhydride were added and kept warm at 25°C until the end of the reaction. The reaction system was poured into 180ml of ice water, stirred, left to stand for liquid separation, the water phase was extracted twice with 200ml of dichloromethane, and the organic phase was combined. Washed three times with 200 ml of saturated brine; the organic phase was evaporated to dryness under reduced pressure to obtain 9.8 g of light yellow solid with a yield of 98.0%.

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Abstract

The invention belongs to the technical field of chemical synthesis, and relates to a preparation method of a methylprednisolone hemisuccinate impurity, in particular to a preparation method of 11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-1,4-diene-3,20-diketone-21-succinic acid ester. According to the method, 11 beta, 17 alpha, 21- trihydroxy-6 beta-methylenepregna-4-alkene-3, 20-diketoneis taken as a raw material, and is subjected to a series of reduction reaction, esterification reaction, oxidation reaction and hydrolysis reaction, so that the 11 beta, 17 alpha, 21-trihydroxy-6 beta-methylpregna-1,4-diene-3,20-diketone-21-succinic acid ester is obtained. The invention firstly discloses the preparation method of the impurity, and has the advantages of clear synthetic route, simple operation, relatively high purity of a prepared product and the like.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to a preparation method of 11β, 17α, 21-trihydroxy-6β-methylpregna-1,4-diene-3,20-diketone-21-succinate. Background technique [0002] 11β, 17α, 21-trihydroxy-6β-methylpregna-1,4-diene-3,20-dione-21-succinate, is an impurity of methylprednisolone succinate, according to European Pharmacopoeia Record, the structural formula is as follows: [0003] [0004] Methylprednisolone succinate has the following structural formula: [0005] [0006] Methylprednisolone succinate is a synthetic glucocorticoid. Glucocorticoids diffuse through the cell membrane and bind to specific receptors in the cytoplasm. It has anti-inflammatory, immune and anti-allergic activities, used for symptomatic treatment of rheumatic diseases, collagen diseases, skin diseases, allergic symptoms, eye diseases, gastrointestinal diseases, respiratory diseases, edema, etc., as an immunosupp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00
CPCC07J5/0053
Inventor 王县慧邓青均
Owner CHONGQING HUABANGSHENGKAI PHARM
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