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Preparation method of indoline derivative for synthesizing silodosin

A technology of silodosin and indoline, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of poor reductive amination selectivity, unfavorable scale-up production, and high production costs, and achieves improved chiral purity, avoiding loss, and simple operation Effect

Active Publication Date: 2017-02-08
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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  • Preparation method of indoline derivative for synthesizing silodosin
  • Preparation method of indoline derivative for synthesizing silodosin
  • Preparation method of indoline derivative for synthesizing silodosin

Examples

Experimental program
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Effect test

Embodiment 1

[0037] Example 1: Compound (1): Preparation of 1-(3-benzoyloxypropyl)indoline;

[0038] Add 26.8g of benzoic acid, 90ml of DMF, 30.6ml of triethylamine and 21.7ml of 1-chloro-3-bromopropane into the reaction flask, stir at 25°C for 12 hours, raise the temperature to 50°C and stir for 3 hours, add 23.6ml of indoline, 30.6 ml of triethylamine, react at 100°C for 6 hours. Cool to room temperature, add 180ml 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 saline, dry over anhydrous sodium sulfate, and recover the dry solvent under reduced pressure to obtain 46.4g of 1-(3-phenoxypropyl)indoline; yield : 78%, purity: 98.66%.

Embodiment 2

[0039] Example 2: Compound (2): Preparation of [1-(3-benzoyloxypropyl)-5-formyl]indoline.

[0040] Slowly add 30.8g of phosphorus oxychloride dropwise to 62.5ml of DMF under ice cooling, continue to stir for 30 minutes under the ice bath, and add 28.1g of 1-(3-benzyl) prepared in Example 1 in batches. Acyloxypropyl) indoline, heated to 25 ° C for 3 hours, slowly poured into 800ml of ice water, crystallized overnight, filtered the next day, and dried to obtain 31g of light yellow solid, namely [1-(3-benzene Formyloxypropyl)-5-formyl]indoline; yield: 92%, purity: 92.43%.

Embodiment 3

[0041] Example 3: Compound (3): Preparation of (1R,2R)-[1-(3-benzoyloxypropyl)-5-(1-hydroxyl-2-nitropropyl)]indoline .

[0042] Under nitrogen protection, add 0.91g copper acetate, 1.9g quinidine, 140ml ethanol to the three-necked reaction flask, stir at 25°C for 4 h, cool the resulting catalyst solution to about -10°C, add 31g of the compound prepared in Example 2 ( 2) Ethanol solution (120ml), keep below -10°C and add 37.5g of nitroethane dropwise after adding, keep warm at -10°C for 12 hours after dropping. Add 150ml of 1mol / L hydrochloric acid to quench the reaction after the reaction, concentrate under reduced pressure at 35~40°C to remove most of the ethanol, add ethyl acetate to extract three times, combine the organic phases, wash once with saturated saline, dry over anhydrous sodium sulfate, and filter Concentration gave 32.6g of oily substance, namely (1R,2R)-[1-(3-benzoyloxypropyl)-5-(1-hydroxy-2-nitropropyl)]indoline; Yield: 92%, purity: 98.73%.

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Abstract

The invention provides a preparation method of an indoline derivative for synthesizing silodosin. Indoline is taken as a starting raw material and reacts with benzoic acid and 1-chloro-3-bromopropane to prepare a compound (1); a reaction is carried out in a Vilsmeier agent, and a formyl group in introduced to the 5th position to prepare a compound (2); the compound (2) and nitroethane undergoes an asymmetric Henry reaction in the catalysis of quinidine-copper acetate to prepare a compound (3); the compound (3) is subjected to acetylation through acetic anhydride to prepare a compound (4); a cyano group is introduced to the 7th position to prepare a compound (6); and two functional groups are reduced through palladium-on-carbon hydrogenation in one step to obtain a high-chiral-purity target compound: (R)-1-[1-(3-benzoyloxypropyl)-5-(2-aminopropyl)-7-cyano]indoline. In the early stage of the method, cheap quinidine is used to perform an asymmetric Henry reaction for introduction of chiral centers, thereby avoiding resolution in the latter stage. The method is reasonable in design, simple to operate, effectively improved in yield and reduced in cost, and therefore is suitable for massive 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 Applications(China)
IPC IPC(8): C07D209/08
CPCC07D209/08
Inventor 朱万里宋忠智刘德龙
Owner 江苏宇田医药有限公司
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