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A kind of improved preparation method of benazepril hydrochloride and pharmaceutical composition containing the benazepril hydrochloride

A technology of benazepril hydrochloride and organic phase, applied in the field of pharmaceutical invention, can solve the problem of low total yield, and achieve the effects of simplified operation, reduced types and dosage, and reduced amount of waste liquid

Active Publication Date: 2017-12-12
HUIZHOU XINLITAI PHARMA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method requires the use of toxic sodium cyanoborohydride, and the overall yield is not high

Method used

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  • A kind of improved preparation method of benazepril hydrochloride and pharmaceutical composition containing the benazepril hydrochloride
  • A kind of improved preparation method of benazepril hydrochloride and pharmaceutical composition containing the benazepril hydrochloride
  • A kind of improved preparation method of benazepril hydrochloride and pharmaceutical composition containing the benazepril hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation of embodiment 1 benazepril hydrochloride

[0032] Add 105g (0.50mol) of ethyl R-α-hydroxyphenylbutyrate (I), 122g (0.55mol) of 4-nitrobenzenesulfonyl chloride and 600ml of ethyl acetate into the reaction flask, stir to dissolve and cool to 0-5 ℃. 71 g (0.70 mol) of triethylamine was added dropwise for about 1 h. After the dropwise addition, the temperature was raised to 25° C. and stirring was continued for 2 h. The crystals of triethylamine hydrochloride were filtered out, washed with an appropriate amount of ethyl acetate and combined with the filtrate. Add 100 ml of water to the filtrate, stir for 0.5 h, and then adjust the pH of the aqueous phase to about 6 with 10% hydrochloric acid. The phases were separated after standing, and the organic phase was washed twice with water. The phases were separated after standing, and the organic phase was dried with 50 g of anhydrous sodium sulfate and then filtered. The filter cake was washed with an appropr...

Embodiment 2

[0035] The preparation of embodiment 2 benazepril hydrochloride

[0036] Add 105g (0.50mol) of R-α-hydroxyphenylbutyrate ethyl ester (I), 122g (0.55mol) of 4-nitrobenzenesulfonyl chloride and 600ml of isopropyl acetate into the reaction flask, stir and dissolve, then cool to 0- 5°C. 71 g (0.70 mol) of triethylamine was added dropwise for about 1 h. After the dropwise addition, the temperature was raised to 25° C. and stirring was continued for 2 h. The triethylamine hydrochloride crystals were filtered out, washed with an appropriate amount of isopropyl acetate and combined with the filtrate. Add 100 ml of water to the filtrate, stir for 0.5 h, and then adjust the pH of the aqueous phase to about 6 with 10% hydrochloric acid. The phases were separated after standing, and the organic phase was washed twice with water. Stand still and separate the phases, the organic phase is dried with 50 g of anhydrous potassium sulfate and filtered, and the filter cake is washed with an a...

Embodiment 3

[0039] Embodiment 3 preparation method improvement comparative experiment

[0040] Under the same feeding scale, compare the consumption of main organic material with US4785089 embodiment 6 and 16, the result is shown in the table below.

[0041]

[0042]

[0043] As can be seen from the comparative data in the above table, the present invention does not use toxic toluene and N-methylmorpholine, and the organic solvent types are reduced from three to one, and the use of a single organic solvent greatly facilitates the recovery of solvents, and the acetic acid used Ethyl ester is significantly reduced, and the amount of waste liquid produced is significantly reduced, which has good clean production value.

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Abstract

The invention discloses an improved preparation method of benazepril hydrochloride and pharmaceutical composition containing the benazepril hydrochloride. With the adoption of the preparation method, the safety is high, the cost is low, the clean production value is high, industrial production is easy to realize, and meanwhile, the pharmaceutical composition is easy to prepare and use.

Description

technical field [0001] The invention belongs to the field of medical inventions, and in particular relates to an improved preparation method of benazepril hydrochloride and a pharmaceutical composition containing the benazepril hydrochloride. Background technique [0002] Benazepril hydrochloride is an antihypertensive drug and a potent angiotensin converting enzyme inhibitor (ACE inhibitor). Its chemical name: (3S)-3-[(1S)-1-ethoxycarbonyl-3-phenylpropyl]amino-2,3,4,5-tetrahydro-2-oxo-1H-1- Benzazepine-1-acetic acid hydrochloride. The chemical structural formula is shown in formula 1. [0003] [0004] Several synthetic routes of benazepril hydrochloride have been reported in the literature. Among them, R-α-hydroxyphenylbutyrate ethyl ester (intermediate I) and (S)-3-amino-2,3,4,5-tetrahydro-2-oxo 1H-1-benzazepine - The synthetic route of 1-tert-butyl acetate (intermediate II) as the key intermediate has been applied industrially. U.S. Patent US4785089, He Xiaoqiang...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D223/16A61K31/55A61P9/12
CPCC07D223/16
Inventor 谭端明李汉坤王海
Owner HUIZHOU XINLITAI PHARMA
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