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Preparation method of dutasteride

A technology of dutasteride and androsteride, applied in the field of preparation of dutasteride, can solve problems such as increased cost, decreased total yield, increased reaction steps, etc., and achieves the improvement of product quality, controllable production, and promotion of development. Effect

Inactive Publication Date: 2013-08-21
ANHUI OURUIDA ELECTRICAL APPLIANCE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But, because after all functional groups change, just carry out amidation and amine exchange reaction, so for raw material pregnenone acid (II), still need to carry out the protection of carboxyl group and deprotection, thus increased reaction steps, and overall yield reduces, The cost increases, so there are still many places to be improved and perfected in this method

Method used

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  • Preparation method of dutasteride
  • Preparation method of dutasteride
  • Preparation method of dutasteride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add pregnenone acid (II) (3.16g, 10mmol) and 35mL of 20% ammonia water into the reaction flask, slowly raise the temperature to 75°C, and react until the system is uniformly dissolved. Continue to heat up to 85°C, and react until the system becomes cloudy again. Add 50 mL of xylene, raise the temperature to reflux, and separate water under reflux until the system becomes clear again. After finishing the reaction, it was concentrated under reduced pressure, and a solid precipitated out. After filtering, the filter cake was washed with toluene and dried in vacuum to obtain 3.10 g of white solid androst-4-en-3-one-17β-carboxamide (III), with a yield of 98.4%.

Embodiment 2

[0031] Add pregnenone acid (II) (3.16g, 10mmol), 50mL of xylene and 5mL of water into the reaction flask, slowly raise the temperature to 75°C, and at the same time pass ammonia gas, and react until the system is uniformly dissolved. Continue to heat up to 85°C, and react until the system becomes cloudy again. Continue to heat up to reflux, and divide water under reflux until the system becomes clear again. After finishing the reaction, it was concentrated under reduced pressure, and a solid precipitated out. After filtering, the filter cake was washed with toluene and dried in vacuo to obtain 3.08 g of white solid androst-4-en-3-one-17β-carboxamide (III), with a yield of 97.8%.

Embodiment 3

[0033] Add 4-aza-androst-5-en-3-one-17β-carboxamide (IV) (3.16g, 10mmol), 5% palladium carbon (0.16g, 5%w / w) into the hydrogenation reaction kettle , 1mL of acetic acid and 50mL of methanol, according to the hydrogenation reaction operating procedures, feed hydrogen. Add to keep the temperature at 20-35° C. and the pressure at 2-3 kg, continue the reaction for 10 hours, and the reaction ends. Concentrate under reduced pressure, and recrystallize the solid from acetone to obtain 3.02 g of 4-aza-5α-androst-3-one-17β-carboxamide (V), with a yield of 95.0%.

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Abstract

The invention discloses a preparation method of dutasteride (N-(2,5-di(trifluoromethyl)phenyl)-4-aza-5alpha-androstane-1-ene-3-keto-17beta-formamide, I). The preparation method comprises the following steps that: pregnene ketonic acid (II) is taken as a raw material to convert carboxylic acid to amide through amidation to prepare androstane-4-ene-3-keto-17beta-formamide (III); the compound (III) is subjected to oxidative ring opening and ammonolysis cyclization to prepare 4-aza-androstane-5-ene-3-keto-17beta-formamide (IV); the compound (IV) is subjected to reductive hydrogenation reaction to generate 4-aza-5alpha-androstane-3-keto-17beta-formamide (V); the compound (V) is subjected to oxidative dehydrogenation to generate 4-aza-5alpha-androstane-1-ene-3-keto-17beta-formamide (VI); and the compound (VI) and 2,5-di(trifluoromethyl phenylamine) (VII) carry out amine exchange reaction in the presence of a catalyst to prepare dutasteride (I). The preparation method has the advantages of concise process, easiness in obtaining raw materials and controllable quality, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis method design and preparation of raw materials and intermediates, and in particular relates to a preparation method of dutasteride. Background technique [0002] Dutasteride (Dutasteride, chemical name N-(2,5-ditrifluoromethylphenyl)-4-aza-5α-androst-1-en-3-one-17β-carboxamide, I ) is a selective inhibitor of steroidal 5α-reductase in two isoforms, type I and type II, developed by GlaxoSmithKline. Dutasteride was approved for marketing by the U.S. Food and Drug Administration in June 2003, and its trade name is Avodart (Anfuda). The drug is clinically used for the treatment of benign prostatic hyperplasia patients, can improve the symptoms of benign prostatic hyperplasia for a long time, and reduce the incidence of prostate cancer. [0003] [0004] The preparation method of dutasteride has been reported. Patents WO95 / 07926, WO95 / 07927, etc. have reported using pregnenone acid (II) ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J73/00
Inventor 许学农
Owner ANHUI OURUIDA ELECTRICAL APPLIANCE TECH
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