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Preparation method of Silodosin

A technology of silodosin and disubstitution, which is applied in the field of preparation of silodosin, can solve problems affecting the industrialization process, poor selectivity, and difficult sources, and achieve the effects of promoting economic and technological development, controlling costs, and simple processes

Inactive Publication Date: 2013-11-20
南京联智医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method solves the shortcomings of poor condensation reaction selectivity and low yield in the aforementioned method, but due to the source of raw material 2-[2-(2,2,2-trifluoroethoxy)phenoxy]acetaldehyde (X) Relatively difficult, affecting the industrialization process of the process

Method used

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  • Preparation method of Silodosin
  • Preparation method of Silodosin
  • Preparation method of Silodosin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 1-(3-hydroxypropyl)-7-cyano-5-(2-oxopropyl)indoline (II) (2.58g, 10mmol), 2-[2- (2,2,2-Trifluoroethoxy)phenoxy]ethylamine (III) (2.58g, 11mmol) and 1,2-dichloroethane 35mL, add triacetoxyboron under nitrogen atmosphere at room temperature Sodium hydride (3.0g, 14mmol) and acetic acid (0.9g, 15mmol) were heated to 45-50°C and stirred for 20 hours. TLC detected that the reaction was complete. The reaction was quenched by adding 1N sodium hydroxide, extracted twice with 1,2-dichloroethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2,3-dihydro-1-(3- Hydroxypropyl)-7-cyano-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-1H-indole (IV) 4.1 g, yield 86.0%.

Embodiment 2

[0031] Add 1-(3-hydroxypropyl)-7-carboxamido-5-(2-oxopropyl)indoline(II) (2.76g, 10mmol), 2-[2 -(2,2,2-Trifluoroethoxy)phenoxy]ethylamine (III) (2.58g, 11mmol) and 1,2-dichloroethane 50mL, add triacetoxy group under nitrogen atmosphere at room temperature Sodium borohydride (3.0 g, 14 mmol) and acetic acid (0.9 g, 15 mmol) were heated to 50-55° C., stirred for 24 hours, and TLC detected the completion of the reaction. The reaction was quenched by adding 1N sodium hydroxide, extracted twice with 1,2-dichloroethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2,3-dihydro-1-(3- Hydroxypropyl)-7-carboxamido-5-[2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-1H-indyl Dole (IV) 4.0g, yield 80.8%.

Embodiment 3

[0033] Add 2,3-dihydro-1-(3-hydroxypropyl)-7-carboxamido-5-[2-[2-[2-(2,2,2-trifluoroethoxy) into the reaction flask Yl)phenoxy]ethylamino]propyl]-1H-indole(IV) (2.5g, 5mmol) and methanol 40mL, add S-(+)-mandelic acid (0.8g, 5mmol) under stirring, and Place in an ultrasonic generator and shake for 30 minutes, filter the insoluble matter, wash the filter cake with 10 mL of a mixture of ether and methanol, and dissolve the dried white solid with 40 mL of ethyl acetate and 40 mL of 10% sodium hydroxide, and stir at room temperature for 1 hour. After standing for liquid separation, the organic phase was dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 0.88 g of white solid xerodoxine (I) with a yield of 35.2%.

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Abstract

The invention discloses a preparation method of Silodosin (I). The preparation method comprises the steps of: subjecting 1, 7-disubstituted-5-(2-oxopropyl) indoline (II) and 2-[2-(2, 2, 2-trifluoroethoxy)phenoxy]ethylamine (III) to an amination reduction reaction to obtain 2, 3-dihydro-1, 7-disubstituted-5-[2-[2-[2-(2, 2, 2-trifluoroethoxy)phenoxy]ethylamine]propyl]-1H-indole (IV), and subjecting the intermediate (IV) to splitting and conversion of the 1, 7- functional group, thus obtaining the Silodosin (I). The preparation method has high chemical selectivity, can effectively control the cost, and can improve the quality of the product, thus promoting the economic and technological development of the bulk drug.

Description

Technical field [0001] The invention belongs to the technical field of organic synthesis method design and the preparation of raw materials and intermediates, and particularly relates to a preparation method of xerodoxine. Background technique [0002] Silodosin (Silodosin, also known as silodosin) is an alpha developed by Japan Kisei Pharmaceutical Company 1 -Receptor antagonists, which can be used to treat symptoms related to benign prostatic hyperplasia or hypertrophy. Japan's Kisei Pharmaceutical Co., Ltd. and Daiichi Sankyo Pharmaceutical Co., Ltd. applied for a joint application, and it was approved for the first time in Japan in May 2006, under the trade name Urief. Subsequently, Jusheng and Daiichi Sankyo also authorized xerodoxine to Watson Pharmaceuticals, which was approved by the U.S. Food and Drug Administration (FDA) in August 2008 for listing in the United States. The Serodosin capsule preparation imported by Japan's Daiichi Sankyo Pharmaceutical Company was also ...

Claims

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Application Information

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IPC IPC(8): C07D209/08
Inventor 许学农
Owner 南京联智医药科技有限公司
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