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Preparation method of dutasteride

A dutasteride and androstane technology, applied in the field of medicinal chemistry, can solve the problems of low average yield and high cost of operation

Active Publication Date: 2013-04-24
CHENGDU GUOHONG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The technical problem to be solved in the present invention is that the existing technology and operation of dutasteride with 3-keto-4-aza-5α-androstane-1-ene-17β-carboxylic acid as raw material have low yield and low cost. high problem

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0044] Dissolve 3-keto-4-aza-5α-androstane-1-ene-17β-carboxylic acid in dichloromethane at a temperature of 10°C to 30°C, then add thionyl chloride, and wait until the reaction is complete , adding 2,5-bis(trifluoromethyl)aniline and pyridine in the temperature range of 10°C to 30°C, and reacting completely in the range of the reflux temperature of 30°C to dichloromethane;

[0045] Wherein the volume of dichloromethane: the quality of 3-keto-4-aza-5α-androstane-1-ene-17β-carboxylic acid is preferably 18:1~40:1 (mL:g);

[0046] The molar ratio of thionyl chloride to 3-keto-4-aza-5α-androstane-1-ene-17β-carboxylic acid is 1.5:1

[0047] The molar ratio of 2,5-bis(trifluoromethyl)aniline to 3-keto-4-aza-5α-androstane-1-ene-17β-carboxylic acid is 1.3:1~2:1;

[0048] The molar ratio of pyridine to 3-keto-4-aza-5α-androstane-1-ene-17β-carboxylic acid is preferably 10:1 to 12:1.

[0049]

[0050] In order to improve and increase the yield of dutasteride crude product prepared from...

Embodiment 1

[0075]At 10°C, dissolve 31.7g of 3-keto-4-aza-5α-androstane-1-ene-17β-carboxylic acid in 570.6ml of dichloromethane, add 17.85g of thionyl chloride under stirring, and stir to react , TLC detects the reaction end point, after the reaction is complete, add 29.8g of 2,5-bis(trifluoromethyl)aniline dropwise at 10°C, then add dropwise 79g of pyridine, heat to 30°C, stir the reaction, TLC monitors the reaction end point , after the reaction, cooled to room temperature, the reaction solution was washed with hydrochloric acid, filtered, the organic phase was separated, and the solvent was distilled off under reduced pressure to obtain 48.2 g of crude dutasteride, with a purity of 92.4% and a yield of 91.3%.

Embodiment 2

[0077] At 30°C, 31.7g of 3-keto-4-aza-5α-androstane-1-ene-17β-carboxylic acid was dissolved in 1268ml of dichloromethane, and 17.85g of thionyl chloride was added under stirring, and the reaction was stirred. TLC detects the end point of the reaction. After the reaction is complete, add 45.8g of 2,5-bis(trifluoromethyl)aniline dropwise at 30°C, then add 94.8g of pyridine dropwise, and heat to 40°C (the reflux temperature of dichloromethane) , stirred the reaction, TLC monitored the reaction end point, after the reaction was finished, cooled to room temperature, the reaction solution was washed with hydrochloric acid, filtered, the organic phase was separated, and the solvent was evaporated under reduced pressure to obtain 47.8g of dutasteride crude product with a purity of 92.6%. The rate is 90.5%.

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Abstract

The invention discloses a novel feeding sequence for preparing dutasteride by taking 3-ketone-4-aza-5alpha-aetioallocholane-1-olefin-17beta-carboxylic acid, pyridine, thionyl chloride and 2,5-(trifluoromethyl)phenylamine as raw materials, as well as concrete operation steps and embodiments. By using the method, the problems of low yield and high cost of the process and operation for synthesizing a crude product of the dutasteride by using the 3-ketone-4-aza-5alpha-aetioallocholane-1-olefin-17beta-carboxylic acid as a raw material at current are solved, the yield of the crude product of the dutasteride synthesized by using the 3-ketone-4-aza-5alpha-aetioallocholane-1-olefin-17beta-carboxylic acid as the raw material is greatly increased, the industrial cost is reduced, and the process is simple, is simple and convenient to operate and is more suitable for the industrial production of the dutasteride.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a synthesis method of dutasteride. Background technique [0002] Dutasteride (DUTASTERIDE, 17β-N-(2,5-bis(trifluoromethyl))phenylcarbamoyl-4-aza-5α-androst-1-en-3-one) is a A new dual inhibitor of 5α reductase, which can inhibit both 5α reductase 1 and 5α reductase 2, is mainly used for the treatment of benign prostatic hyperplasia in men. A large number of clinical trials have shown that dutasteride can significantly reduce the level of dihydrotestosterone in human blood and prostate in the long-term compared with finasteride, and can continuously and effectively reduce the volume of the prostate. Its structural formula is as follows: [0003] [0004] The original manufacturer of dutasteride is GlaxoSmithKline (GLAXOSMITHKLINE). In November 2002, dutasteride was launched in the United States and Europe under the trade name of AVODART (Shi Niao Tong). On Apr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00
Inventor 阳舒波郭礼新
Owner CHENGDU GUOHONG PHARMA
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