A kind of preparation method for the indoline derivative of synthetic silodosin

A technology for 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 cost, achieves improved chiral purity, avoids loss, and is simple to operate Effect
CN106380438BActive Publication Date: 2019-07-30江苏宇田医药有限公司
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
江苏宇田医药有限公司
Publication Date
2019-07-30

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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.
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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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