Preparation method of silodosin intermediate

A technology of silodosin and intermediates, applied in the field of drug synthesis, can solve the problems of difficult to obtain, expensive and difficult auxiliary materials and the like

Active Publication Date: 2016-10-26
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In summary, the existing synthetic techniques often have difficulties in excipients that are expensive and difficult to obtain, or require chiral resolution to reduce the o

Method used

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  • Preparation method of silodosin intermediate
  • Preparation method of silodosin intermediate
  • Preparation method of silodosin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Embodiment 1: the preparation of compound 4

[0084]

[0085] At -5-0°C, put 435g of zinc trifluoromethanesulfonate, 189g of (S)-2-chloropropionyl chloride, and 1500mL of 1,2-dichloroethane into the reaction vessel, and slowly add 306g of the compound dropwise at this temperature 2 in 200mL of 1,2-dichloroethane solution, keep it warm for 1 hour after dripping, then slowly raise the temperature to reflux reaction (83°C), monitor by liquid chromatography until the reaction is complete (8-24 hours), and cool the reaction solution to At room temperature, add cold 5% hydrochloric acid aqueous solution, wash the organic layer with sodium bicarbonate solution and saturated brine successively, collect the organic layer and dry it with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure. Recrystallization from a mixed solvent of dichloromethane and methanol gave 317 g of light yellow solid 4, yield: 80%, melting point: 115°C.

[...

Embodiment 2

[0089] Example 2: Using (S)-2-bromopropionyl chloride instead of (S)-2-chloropropionyl chloride in Example 1, Compound 4 was prepared according to the method described in Example 1, with a yield of 84%.

[0090] NMR data is the same as in Example 1.

Embodiment 3

[0091] Embodiment 3: the preparation of compound 4

[0092]

[0093] At -5-0°C, put 787g of bismuth trifluoromethanesulfonate, 189g of (S)-2-chloropropionyl chloride, and 1500mL of 1,2-dichloroethane into the reaction vessel, and slowly add 306g of the compound dropwise at this temperature 2 in 200mL of 1,2-dichloroethane solution, keep it warm for 1 hour after dripping, then slowly raise the temperature to reflux reaction (83°C), monitor by liquid chromatography until the reaction is complete (8-24 hours), and cool the reaction solution to Add cold 5% hydrochloric acid aqueous solution at room temperature, wash the organic layer with sodium bicarbonate solution and saturated brine successively, collect the organic layer and dry it with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure. The mixed solvent of methyl chloride and methanol was recrystallized to obtain 277g of light yellow solid 4, yield: 70%.

[0094] Nuclear magn...

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Abstract

The invention discloses a preparation method of a silodosin intermediate. The preparation method comprises the following steps that in an organic solvent, under the action of lewis acid, friedel-crafts acylation reaction occurs between a compound 2 and a compound 3, so as to obtain a compound 4, wherein the lewis acid is one of or more of zinc trifluoromethanesulfonate, bismuth trifluoromethanesulfonate, scandium trifluoromethanesulfonate and aluminum trichloride; under the action of organic acid or boron trifluoride ether complex, the compound 4 reacts with triethyl silicane, so as to obtain a compound 5; the compound 5 reacts with sodium azide, so as to obtain a compound 6; under the action of catalysts, the compound 6 reacts with di-tert-butyl dicarbonate ester and hydrogen, so as to obtain a compound 7; under an acidic condition, the deamination protective reaction of the compound 7 occurs, so as to obtain a compound 8; the compound 8 reacts with L-tartaric acid, so as to obtain a compound 1, namely the silodosin intermediate. The preparation method of the silodosin intermediate has the advantages of simplicity, economy and mild reaction conditions, and chiral resolution is not needed.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a silodosin intermediate. Background technique [0002] Silodosin is an α-adrenergic receptor antagonist invented by Kissei Pharmaceutical Company of Japan, which is clinically used for urinary disorders related to benign prostatic hyperplasia. At present, silodosin is mostly synthesized through several steps via the intermediate described in compound 1 (as shown in Reaction Formula 1). [0003] [0004] There are many reports about the synthetic method of silodosin intermediate 1, and the methods reported in the literature have the following: [0005] Patent document JP2001199956 discloses the preparation of 5-[(2R)-2-aminopropyl[-1-[3-(benzoyloxy)propyl]-7-cyanoindol through multi-step reaction using benzoic acid as raw material The method (reaction formula two) of dodoline L-tartrate, the method passes compound 5-[2-oxopropyl]-1-[3-(benzoyloxy) propyl...

Claims

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Application Information

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IPC IPC(8): C07D209/08
CPCC07B2200/07C07D209/08
Inventor 屠勇军杨会林王臻韩明超黄荣明
Owner ZHEJIANG TIANYU PHARMA
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