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Synthesis method of dutasteride intermediate

A synthetic method, dutasteride technology, applied in the direction of steroids, organic chemistry, etc., can solve the problems of high price, high cost, unsuitable for large-scale industrial production, etc., to achieve increased yield, improved safety, reduced cost effect

Inactive Publication Date: 2012-10-24
王履诚
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The shortcoming of this method is: this method adopts 10%Pd / C as hydrogenation catalyst, makes 3-oxo-4-aza-5-androstene Catalytic hydrogenation of -17-carboxylic acid in glacial acetic acid at a pressure above 5 MPa is dangerous, and the precious metal 10% Pd / C is expensive and costly, so it is not suitable for large-scale industrial production
[0017] The corresponding 5α-androstane and 5β- Androstane isomers, the properties of the two isomers are relatively similar, difficult to separate, and difficult to purify, so that the yield of synthetic dutasteride is very low, so the study of 3-oxo-4-aza- The synthesis of 5α-androsta-17β-carboxamide and the separation and identification of 5α and 5β isomers have important practical value

Method used

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  • Synthesis method of dutasteride intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Compound Ⅱ (25 g, 47 mmol), methanol (1000 mL), 2 mol / L HCl aqueous solution to adjust pH=2, add NaBH 3 CN (5.9g, 94mmol), stirred at room temperature for 1 h, then adjusted pH=2 with 2 mol / L HCl aqueous solution, added water (100 mL), adjusted pH=8 with 10% NaOH solution, CH 2 Cl 2 Extraction, the organic layer was dried with anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, a small amount of ethyl acetate was added to the crude product and heated to reflux, and ethyl acetate was continuously added to dissolve it completely, cooled at room temperature and left standing to obtain a white crystalline solid compound Ⅰ (18g, 72%), the purity was over 98.0% by HPLC, m.p. 245~247℃.

Embodiment 2

[0040] Compound Ⅱ (25 g, 47 mmol), methanol (1000 mL), 2 mol / L HCl aqueous solution to adjust pH=2, add NaBH 3 CN (12.6 g , 201 mmol), stirred at room temperature for 1 h. Then use 2 mol / L HCl aqueous solution to adjust pH=2, add water (100 mL), adjust pH=8 with 10% NaOH solution, CH 2 Cl 2 Extraction, the organic layer was dried with anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, a small amount of ethyl acetate was added to the crude product and heated to reflux, and ethyl acetate was continuously added to dissolve it completely, cooled at room temperature and left standing to obtain a white crystalline solid compound Ⅰ (23 g, 92%), the purity was over 98.0% by high performance liquid chromatography, m.p. 245~247℃.

Embodiment 3

[0042]Compound Ⅱ (25 g, 47 mmol), methanol (1000 mL), 2 mol / L HCl aqueous solution to adjust pH=2, add NaBH 3 CN (23.6 g, 376 mmol), stirred at room temperature for 1 h. Then use 2 mol / L HCl aqueous solution to adjust pH=2, add water (100 mL), adjust pH=8 with 10% NaOH solution, CH 2 Cl 2 Extraction, the organic layer was dried with anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure, a small amount of ethyl acetate was added to the crude product and heated to reflux, and ethyl acetate was continuously added to dissolve it completely, cooled at room temperature and left standing to obtain a white crystalline solid compound Ⅰ (21g, 84%), the purity was over 98.0% by HPLC, m.p. 245~247℃.

[0043] From the results of Examples 1 to 3, it can be seen that when compound II and reducing agent NaBH 3 When the molar ratio of CN is 1:4, the yield of the synthesis reaction is the highest, which is the best choice.

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Abstract

The invention relates to a synthesis method of a dutasteride intermediate, belonging to the field of medicament. The synthesis method comprises the steps of dissolving 3-oxo-4-aza-androst-5-ene-17beta-carboxamide in organic solvent, adjusting pH value, stirring at room temperature, slowly adding reducing agent NaBH3CN, carrying out hydrogenation reaction for 1h, adjusting pH value with 10% NaOH solution, extracting with CH2Cl2, drying, filtering, evaporating filtrate under reduced-pressure to be dry to obtain crude product and recrystallizing the crude product. The synthesis method has the advantages that the ratio of the obtained alpha-isomer is high, the yield is higher, the production cost is simultaneously reduced, and the experiment safety is improved.

Description

technical field [0001] The invention belongs to the field of medicine and relates to the synthesis of pharmaceutical intermediates, in particular to a synthesis method of a dutasteride intermediate, namely 3-oxo-4-aza-5α-androster-17β-carboxamide. Background technique [0002] Benign prostatic hyperplasia (benign prostate hyperplasia, BPH) is a common chronic disease in middle-aged and elderly men. The main clinical drugs for the treatment of BPH are finasteride and dutasteride. Dutasteride (Avodart) belongs to azasteroid compounds, and is a selective inhibitor of type I and type II 5α reductase. Its curative effect is better than that of finasteride, and its side effects are low. It is a new type of treatment for benign prostate Drugs for proliferation. [0003] Dutasteride, chemical name: (5α, 17β)-N-[2,5-bis(trifluoromethyl)phenyl]-3-oxo-4-aza-androstine-1-ene- 17-carboxamide, the structural formula is (Ⅲ); 3-oxo-4-aza-5α-androst-17β-carboxamide is a key intermediate f...

Claims

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Application Information

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IPC IPC(8): C07J73/00
Inventor 王恩思季丽萍
Owner 王履诚
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