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A kind of preparation method for the intermediate of synthetic silodosin

A technology for silodosin and intermediates, which is applied in the synthesis field of pharmaceutical intermediates, can solve the problems of poor reductive amination selectivity, unfavorable enlarged production and high production costs, and achieves the effects of simple operation, loss avoidance and cost reduction.

Active Publication Date: 2019-03-29
江苏宇田医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Based on the above routes, the synthesis of the key intermediate of silodosin needs to undergo asymmetric reductive amination or resolution to obtain high optical purity products, wherein the selectivity of reductive amination is poor, and the resolution process needs to be repeated many times. Both have the characteristics of cumbersome operation and high production cost, which is not conducive to industrialized scale-up production

Method used

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  • A kind of preparation method for the intermediate of synthetic silodosin
  • A kind of preparation method for the intermediate of synthetic silodosin
  • A kind of preparation method for the intermediate of synthetic silodosin

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Example 1: Preparation of compound I, 1-(3-benzoyloxypropyl)indoline.

[0039] Add 40.2g of benzoic acid, 135ml of DMF, 45.9ml of triethylamine and 32.5ml of 1-chloro-3-bromopropane to the reaction flask, stir at 25°C for 12 hours, heat up to 50°C and stir for 3 hours, add 34.9ml of indoline, 45.9 ml of triethylamine, react at 100°C for 6 hours. Cool to room temperature, add 270ml of water, extract twice with ethyl acetate, combine the ethyl acetate layers, wash with saturated sodium bicarbonate and saturated brine in turn, add 3mol / L dilute hydrochloric acid to extract to the water layer, add saturated sodium carbonate solution Adjust the pH=8-9, add dichloromethane to extract twice, wash with saturated brine, dry over anhydrous sodium sulfate, and recover the dry solvent under reduced pressure to obtain 69.7g of 1-(3-phenoxypropyl)indoline; Yield: 78%, purity: 98.66%.

Embodiment 2

[0040] Example 2: Preparation of Compound II.

[0041] Add 600ml of anhydrous dichloromethane, 19.6g of L-lactic acid and 50.8g of triethylamine to the reaction bottle, cool down to -20°C, add 55.8g of methanesulfonyl chloride dropwise, control the temperature not to exceed -10°C, and -10 ℃ for 1 hour. The next reaction can be carried out directly without treatment; the intermediates are not easy to separate, and the yield is inconvenient to calculate.

Embodiment 3

[0042] Example 3: Preparation of compound III, namely (S)-[1-(3-benzoyloxypropyl)indolin-5-yl]-2-methanesulfonyloxypropyl-1-one.

[0043]Add 55.6 g of 1-(3-benzoyloxypropyl)indoline prepared in Example 1 in batches to the reaction solution of Compound II prepared in Example 2, and control the temperature not to exceed 0°C. After the addition, 0 Stir at 0°C for 15 minutes, cool down to -10°C, add 30.2g of anhydrous aluminum trichloride in batches, control the temperature not to exceed 0°C, stir at 0°C for 30 minutes after the addition, raise the temperature to 25°C for reaction, and the raw materials are completely reacted Finally, add the reaction mixture to 2000ml of ice-water mixture, add potassium carbonate solution to adjust ph=7-8, filter, separate the filtrate, extract the water layer with 400ml of dichloromethane, combine the dichloromethane layers, dry, and recover under reduced pressure. solvent, to obtain 64.8g of reddish-brown oily substance, namely (S)-[1-(3-phenox...

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Abstract

The invention provides a preparation method of an intermediate for synthesis of silodosin. The preparation method comprises that indoline as a starting material, benzoic acid and 1-chloro-3-bromopropane undergo a reaction so that a benzoyloxypropyl group is introduced to the 1th site of indoline and a compound I is obtained, the compound I and L-lactic acid undergo a reaction to produce a compound II, the compound II undergoes a Friedel-Crafts acylation reaction so that a chiral center is introduced and a compound III is obtained, a compound V is prepared through carbonyl reduction and inversion of configuration, a cyano group is introduced into the 7th site of the compound V so that a compound VII is obtained, and the nitro group is reduced so that a desired compound with high chiral purity is obtained and is (R)-1-[1-(3-benzoyloxypropyl)-5-(2-aminopropyl)-7-cyano]indoline. The preparation method introduces a chiral center through cheap lactic acid in the early stage of the route, prevents the later resolution, has a reasonable design, can be operated simply, effectively improves a yield, reduces a cost and is suitable for large-scale production.

Description

technical field [0001] The present invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a key intermediate for the synthesis of silodosin: (R)-1-[1-(3-benzoyloxypropyl)-5- The preparation method of (2-aminopropyl)-7-cyano]indoline. Background technique [0002] Benign prostatic hyperplasia (BPH) is one of the common diseases of middle-aged and elderly men. More than 50% of the elderly aged 60 or above suffer from this disease, and more than 90% of the elderly aged 85 and above suffer from the disease. Silodosin (silodosin) belongs to a new generation of highly selective α1A-adrenergic receptor antagonists, which is used to treat dysuria caused by benign prostatic hyperplasia. It was approved for marketing, and was subsequently approved for marketing in the United States and Europe. It has been clinically shown that silodosin has a selective inhibitory effect on urethral smooth muscle, can significantly reduce urethral pres...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/08
CPCC07B2200/07C07D209/08
Inventor 朱万里方子健刘德龙
Owner 江苏宇田医药有限公司
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