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Synthetic method of Benazepril key intermediate S-amino substance

A synthesis method and technology of amino compounds, which are applied in organic chemistry methods, chemical instruments and methods, organic compounds/hydrides/coordination complex catalysts, etc., can solve the problems of poor atom economy and high cost, and achieve low pollution. , the effect of high conversion rate and high optical purity

Active Publication Date: 2011-05-25
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-acetic acid tert-butyl ester, 2.5 grams of copper acetate and 3000ml of ethanol, add high pressure reaction Into the kettle, feed ammonia gas until the pressure is 5.0Mpa, stir at room temperature for 2 hours, then start to raise the temperature 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, tert-butyl 4,5-tetrahydro-2-oxo-1H-1-benzazepine-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-acetic acid tert-butyl ester, 3.75 grams of copper sulfate, and 750ml of methanol, add high pressure Into the reactor, feed ammonia gas until the pressure is 3.0Mpa, stir at room temperature for 1 hour, then start to raise the temperature to 80°C for 1 hour. 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. , tert-butyl 4,5-tetrahydro-2-oxo-1H-1-benzazepine-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-acetic acid tert-butyl ester, 5.0 grams of copper bromide, and 400 ml of isopropanol , into a high-pressure reaction kettle, feed ammonia gas until the pressure is 2.5Mpa, stir at room temperature for 3 hours, then start to heat up to 120°C for 3 hours. 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. tert-butyl 3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-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 benazepril intermediate, and further, the present invention relates to a (S)-3-amino-2,3,4,5-tetrahydro-2-oxo-1H- Synthetic method of 1-benzazepine-1-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 enzyme (Ang...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): B01J27/055B01J31/04B01J27/122C07D223/16C07B57/00
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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