Method for preparing 3-(S)- amino-2,3,4,5-tetrahydro-2-oxy-1H-1-benzazepin-1-tert-butyl acetate

A technology of tert-butyl acetate and benzonitrogen, applied in the field of antihypertensive drugs, can solve the problems of high cost, unsatisfactory yield, large amount of solvent, etc., and achieve the effects of high cost, avoiding dangerous operation, and less waste

Active Publication Date: 2010-01-20
ZHEJIANG SANHE PHARMACHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route adopts the reaction of phthalimide and bromide to introduce amino groups, the operation is simple, the yield is unsatisfactory, and the cost is high. In addition, due to the large amount of solvent and waste water in the reaction, the pollution of the three wastes is serious.

Method used

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  • Method for preparing 3-(S)- amino-2,3,4,5-tetrahydro-2-oxy-1H-1-benzazepin-1-tert-butyl acetate
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  • Method for preparing 3-(S)- amino-2,3,4,5-tetrahydro-2-oxy-1H-1-benzazepin-1-tert-butyl acetate

Examples

Experimental program
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Effect test

example 1

[0025] first step:

[0026] Put 80g of 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, 40g of benzylamine, 40g of potassium carbonate, and 3g of tetrabutylammonium bromide into a 500ml three-necked bottle , Methanol 200ml, heat up and reflux reaction, TLC control, after the reaction is completed, cool down to 5-8°C, filter with suction, stir and wash the filter cake with 200ml of water for 30 minutes, filter with suction, and vacuum dry the filter cake at 70°C for 10 hours to obtain 82 g of 3-benzylamino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine (92.5% yield).

[0027] Step two:

[0028] Put 80g of 3-benzylamino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine into a 1000ml three-necked bottle, 600ml of benzene, 59g of tert-butyl bromoacetate, tetrabutyl Add 5g of ammonium bromide, add 1.4g of solid sodium hydroxide, heat up and reflux for 1 hour, control by TLC, after the reaction is completed, cool down to about 25°C, filter with suction, discard the filter cake, distill the fi...

example 2

[0038] first step:

[0039] Put 80g of 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, 40g of benzylamine, 40g of potassium carbonate, and 3g of tetrabutylammonium bromide into a 500ml three-necked bottle 1. Isopropanol 200ml, heat up and reflux reaction, TLC control, after the reaction is completed, cool down to 5-8°C, filter with suction, stir and wash the filter cake with 200ml of water for 30 minutes, filter with suction, and vacuum dry the filter cake at 70°C for 10 hours , to obtain 81.3 g of 3-benzylamino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine (yield 92.9%).

[0040] Step two:

[0041] 80g of 3-benzylamino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine, 630ml of toluene, 53g of tert-butyl chloroacetate, 53g of tetrabutyl Add 5g of ammonium bromide, add 1.9g of solid potassium hydroxide, heat up and reflux for 1 hour, control by TLC, after the reaction is completed, cool down to about 25°C, filter with suction, discard the filter cake, and distill the filtrate under re...

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Abstract

The invention discloses a method for preparing 3-(S)- amino-2,3,4,5-tetrahydro-2-oxy-1H-1-benzazepin-1-tert-butyl acetate, which comprises the following steps: using 3-brom-1,3,4,5- tetrahydro-2H-1- benzazepin-2-ketone as raw material; carrying out condensation reaction with benzylamine and chloroacetic acid tert-butyl ester, HCl gas salt-forming reaction and hydrogenation reaction under the existence of Pd/C to obtain racemic 3-(S)-amino-2,3,4,5-tetrahydro-2-oxy-1H-1-benzazepin-1-tert-butyl acetate; separating the racemic body by L-(+)tartaric acid, and neutralizing to obtain the target products. The invention has the advantages of simple operation, mild and safe process condition, few three wastes and high yield. The products have high purity and bright color.

Description

technical field [0001] The invention relates to the key intermediate 3-(S)-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid of the antihypertensive drug benazepril Preparation method of tert-butyl ester. Background technique [0002] The trade name of Benazepril: Lotensin is the first-line drug for the treatment of hypertension. It is a new drug developed and listed by Novartis in Switzerland in the 1990s. It is mainly used for the treatment of patients with hypertension and renal failure. Its mechanism of action is to inhibit angiotensin-converting enzyme (ACE), prevent angiotensin I from being transformed into angiotensin II, and cause peripheral vasodilation throughout the body, reduce vascular resistance, and produce antihypertensive effect. The drug is the third generation of antihypertensive drugs, it has been widely used in clinical practice at home and abroad, but the country still relies on imports, due to the high content of synthetic technology and h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16
Inventor 陈英奇王晓钟黄美云戴立言程杰兵张合良
Owner ZHEJIANG SANHE PHARMACHEM
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