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Preparation method of intermediate of steroidal drug with 16-beta-methyl

A technology of methyl steroids and intermediates, which is applied in the field of preparation of 16-β-methyl steroid drug intermediates, which can solve the problems of not finding patent documents, affecting the quality of final products, and increasing the difficulty of purification, etc. , to achieve the effect of easy access, high feasibility and strong operability

Inactive Publication Date: 2011-08-10
GUANGXI WANDE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Pregna-16β-methyl-3β, 17a-diol-20-one is an important intermediate for the preparation of steroids with 16-β-methyl, in the pregna-16β-methyl-3β, 17a- In terms of the preparation of diol-20-one, we did not retrieve relevant patent documents. In terms of relevant literature reports, we retrieved [Title] Research Progress of Steroidal Drug Synthesis Using Sisal Saponin in my country, [Author] Han Guangdian Ma Zhaoyang, [Institution] Beijing Dongfang Huaya Institute of Chiral Drugs, Beijing 100024, [Title] China Pharmaceutical Industry Journal. 2002, 33(9).-459-464, [Abstract] Introduced 5a-pregnant- 16-en-3-ol-20-one-3-acetate as the starting material, through methylation, esterification, epoxidation and hydrolysis to obtain pregna-16β-methyl-3β, 17a-diol 16-methyl-17-hydroxy compound with the same structure as 20-ketone, but it will produce impurities that are difficult to refine, which increases the difficulty of refining and purifying in the subsequent process and affects the quality of the final product

Method used

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  • Preparation method of intermediate of steroidal drug with 16-beta-methyl
  • Preparation method of intermediate of steroidal drug with 16-beta-methyl
  • Preparation method of intermediate of steroidal drug with 16-beta-methyl

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of pregna-16β-methyl-3β, 17a-diol-20-one from pregna-5,16-diene-3β-ol-20-one-3-acetate, the reaction principle is as follows image 3 Shown, the specific reaction steps are as follows:

[0026] Epoxidation reaction:

[0027] Add 50 g of (I) (5,16-pregnadiene-3β-ol-20-one-3-acetate) into 500 ml of methanol solvent, and stir to make it uniform. Add 19ml H at 30-40°C 2 o 2 , and 30 ml of 25% (w / w) NaOH solution. After the addition, stir and keep warm for 5 to 24 hours. After the reaction is complete, add sodium bisulfite solution (10%) under stirring until the starch-potassium iodide test paper is negative. Adjust the pH of the solution to 6-7 with acetic acid (appropriate amount). Add 350ml of water, then distill under reduced pressure until the reaction liquid is about 200ml, and cool to room temperature. The reaction solution was slowly poured into 600ml of cold water and stirred for 60min. Filter and dry the filter cake to obtain 43.2 g of dry produc...

Embodiment 2

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

[0038] Epoxidation reaction:

[0039] Add 25 g of pregna-5,16-dien-3β-ol-20-one into 250 ml of methanol solvent, and stir to make it uniform. Control the temperature below 40°C, add 10ml H2O2, and about 15ml 25% (w / w) NaOH solution, after adding, stir and keep warm for 5-24 hours, after the reaction is complete, add sodium bisulfite solution (10%) under stirring Until the starch-potassium iodide test paper is negative. Adjust the pH of the solution to 6-7 with acetic acid (appropriate amount). Add 150ml of water, then distill under reduced pressure until the reaction liquid is about 100ml, and cool to room temperature. The reaction solution was slowly poured into 300ml of cold water and stirred for 60min. Filter and dry the filter cake to obtain 24.4 g of dry product (5-pregnene-...

Embodiment 3

[0049] Preparation of pregna-16β-methyl-3β, 17a-diol-20-one from pregna-5,16-diene-3β-ol-20-one, the reaction principle is as follows image 3 Shown, the specific reaction steps are as follows:

[0050] Epoxidation reaction:

[0051] Add 25 g of pregna-5,16-dien-3β-ol-20-one into 250 ml of tetrahydrofuran solvent, and stir to make it uniform. Control the temperature below 40°C, add 10ml H2O2, and about 15ml 25% (w / w) NaOH solution, after adding, stir and keep warm for 5-24 hours, after the reaction is complete, add sodium bisulfite solution (10%) under stirring Until the starch-potassium iodide test paper is negative. Adjust the pH of the solution to 6-7 with acetic acid (appropriate amount). Add 150ml of water, then distill under reduced pressure until the reaction liquid is about 100ml, and cool to room temperature. The reaction solution was slowly poured into 300ml of cold water and stirred for 60min. Filter and dry the filter cake to obtain 24.4 g of dry product (5-pr...

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Abstract

The present invention provides a preparation method of an intermediate of a steroidal drug with a 16-beta-methyl. In the method, a steroidal compound I is used as a starting material, and a steroidal compound II of the intermediate of the steroidal drug with the 16-beta-methyl can be prepared through epoxy reaction, ketal reaction, hydrogenation reaction, addition reaction and hydrolysis reaction for transformation of Position 3, Position 5, Position 6, Position 16, Position 17 and Position 20 or Position 5, Position 6, Position 16, Position 17 and Position 20. The steroidal compound II with the 16-beta-methyl is generally applied in preparation of the glucocorticoid drugs commonly used in clinical operation, such as betamethasone, betamethasone sodium phosphate, betamethasone acetate, clobetasolpropionate, beclometasone dipropionate, betamethasone valerate and the like. In the formulas of the steroidal compound I and the steroidal compound II, R represents OH or OCOCH3, R1 represents OH, R2 represents CH3, and R3 represents CH3.

Description

technical field [0001] The invention relates to a preparation method of a steroid compound, in particular to a preparation method of a steroid drug intermediate with 16-beta-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 dermatitis, acute leukemia, etc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J7/00
Inventor 王远秋王远宏罗立泳
Owner GUANGXI WANDE PHARMA
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