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Synthetic method of Benazepril key intermediate S-amino substance

A synthesis method and intermediate technology are applied in the field of synthesis of key intermediates of Benazepril, which can solve the problems of poor atom economy and high cost, and achieve the effects of low pollution, high conversion rate and high optical purity.

Active Publication Date: 2009-09-23
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The atomic economy of this patent is not good, a large amount of by-product phthalic acid is produced, and the cost is high

Method used

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  • Synthetic method of Benazepril key intermediate S-amino substance
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  • Synthetic method of Benazepril key intermediate S-amino substance

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Take 250 grams of 3-bromo-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine - 1-tert-butyl acetate, 2.5 grams of copper acetate and 3000ml of ethanol were added to the autoclave, and ammonia gas was introduced until the pressure was 5.0Mpa. After stirring at room temperature for 2 hours, the temperature was raised to 50°C for 2 hours. After the reaction finishes, filter cake and filtrate to obtain filter cake, filter cake reclaims copper acetate, after filtrate evaporates ethanol to dryness, residue is recrystallized with ethyl acetate, obtains 3-amino-2,3 of 176g (S, R) configuration, 4,5-Tetrahydro-2-oxo-1H-1-benzazepine - tert-Butyl 1-acetate. Yield: 85.9%, liquid phase purity 98.1%, optical rotation 0.

Embodiment 2

[0041] Take 75 grams of 3-bromo-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine - 1-tert-butyl acetate, 3.75g of copper sulfate, and 750ml of methanol were added to the autoclave, and ammonia gas was introduced until the pressure was 3.0Mpa. After stirring at room temperature for 1 hour, the temperature was raised to 80°C for 1h. After the reaction, the filter cake and filtrate were obtained by filtration, and copper sulfate was recovered from the filter cake. After the filtrate was evaporated to dryness of ethanol, the residue was recrystallized with ethyl acetate to obtain 50.7 g of 3-amino-2,3 in the (S, R) configuration. , 4,5-Tetrahydro-2-oxo-1H-1-benzazepine - tert-Butyl 1-acetate. Yield: 82.5%, liquid phase purity 99.7%, optical rotation 0.

Embodiment 3

[0043] Take 50 grams of 3-bromo-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine -1-Tert-butyl acetate, 5.0 grams of copper bromide, and 400 ml of isopropanol were added to the high-pressure reactor, and ammonia gas was introduced until the pressure was 2.5 Mpa. After stirring at room temperature for 3 hours, the temperature was raised to 120°C for reaction 3h. After the reaction was finished, the filter cake and filtrate were filtered, and the filter cake reclaimed copper bromide. After the filtrate was evaporated to dryness of ethanol, the residue was recrystallized with ethyl acetate to obtain 32.0g (S, R) configuration of 3-amino-2. 3,4,5-Tetrahydro-2-oxo-1H-1-benzazepine - tert-Butyl 1-acetate. Yield: 78.1%, liquid phase purity 97.9%, optical rotation 0.

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Abstract

The invention discloses a synthetic method of Benazepril key intermediate S-amino substance, comprising the following steps of: (1) amination: in a sealed reaction vessel, introducing ammonia gas to 3-bromine-2, 3, 4, 5-tetrahydrogen-2-oxygen-1H-1-benzoaza-1-tert-butyl acetate shown as formula (II) with the existence of a cupric salt catalyst and an organic solvent until the reaction pressure is 2.0MPa to 5.0MPa, evenly mixing, raising the temperature to 50 to 120 DEG C, reacting for 1 to 5 hours, and after the reaction is finished, obtaining 3-amino group-2, 3, 4, 5-tetrahydrogen-2-oxygen-1H-1-benzoaza-1-tert-butyl acetate with the (S, R) configuration after the post-treatment of the reaction solution; and (2) resolving reaction: stirring the product obtained in step (1) at the reaction temperature of 30-70 DEG C for 0.5 to 8 hours in amino acid resolving agent and resolving solvent, and after the reaction is finished, obtaining optically pure (S)-3-amino group-2, 3, 4, 5-tetrahydrogen-2-oxygen-1H-1-benzoaza-1-tert-butyl acetate by the separation treatment of reaction products. The method takes the cupric salt as the catalyst, and the amination is executed under normal medium pressure, therefore, the conversion rate is high and the pollution is light.

Description

(1) Technical field [0001] The present invention relates to a synthetic method of a key intermediate of benazepril. Further, the present invention relates to a (S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H -1-Benzazepine -The synthetic method of tert-butyl acetate. (2) Technical background [0002] Cardiovascular disease is the most common type of disease in humans. According to the report of the World Health Organization, cardiovascular disease is the number one cause of death of the world's population today. In 1999, 16.97 million people died of cardiovascular diseases worldwide, accounting for 30.3% of the world's total deaths. At present, there are four types of drugs commonly used clinically for the treatment of hypertension: diuretics, calcium antagonists, angiotensin-converting enzyme inhibitors (ACEI), and angiotensin II receptor antagonists. [0003] Benazepril Hydrochloride (Benazepril Hydrochloride) is an oral long-acting, sulfhydryl-free angiotensin converting enz...

Claims

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Application Information

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IPC IPC(8): C07D223/16C07B57/00B01J31/04B01J27/055B01J27/122
Inventor 谢媛媛夏建胜苏为科边高峰倪恩魏王小霞
Owner ZHEJIANG UNIV OF TECH
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