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New crystal form of benazepril hydrochloride and preparation method thereof

A kind of technology of bena hydrochloride and ethyl homophenylalanine carboxylate, applied in the field of medicine

Inactive Publication Date: 2015-07-22
WISDOM PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Benazeprilat reduces peripheral vascular resistance and lowers blood pressure, but does not cause compensatory fluid retention, and can also reduce ventricular afterload without increasing heart rate

Method used

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  • New crystal form of benazepril hydrochloride and preparation method thereof
  • New crystal form of benazepril hydrochloride and preparation method thereof
  • New crystal form of benazepril hydrochloride and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] THF (2300mL) was used as a solvent, and NaOH (33g) was used as a base, and (S,S)-homophenylalanine carboxylate ethyl ester-benzazepine (ethyl (S)-2-(((S)- 2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-

[0031] yl)amino)-4-phenylbutanoate), see patent CN101830850B) (150g) and tetrabutylammonium halide (12g) for specific structure, add tert-butyl chloroacetate (95g) dropwise, stir until the reaction is complete, then filter, and the filtrate is precipitated Then add toluene (400mL), heat and stir to dissolve, and then pass in hydrogen chloride gas until the reaction of removing the tert-butyl protecting group is complete and a solid is produced. After the solid is filtered and dried, acetonitrile is directly added and heated, and the solid obtained after hot filtration is dried to obtain a white crystalline powder, which is the new crystal form of benazepril hydrochloride. Its X-ray diffraction diagram, infrared absorption spectrum diagram and differential thermal analys...

Embodiment 2

[0033] THF (3000mL) was used as solvent, KOH (50g) was used as base, (S,S)-homophenylalanine carboxylate ethyl ester-benzazepine (see patent CN101830850B for specific structure) (150g) and tetrabutyl ammonium halide (5g), dropwise added tert-butyl chloroacetate (95g), stirred until the reaction was complete, then filtered, added toluene (360mL) after the filtrate was desolvated, heated and stirred to dissolve, and then introduced hydrogen chloride gas to remove the tert-butyl protection The base reaction is complete and a solid is produced. After the solid is filtered and dried, acetonitrile is directly added and heated, and the solid obtained after hot filtration is dried to obtain a white crystalline powder, which is the new crystal form of benazepril hydrochloride of the present invention.

Embodiment 3

[0035] Dioxane (2000mL) as solvent, KOH (50g) as base, add (S,S)-homophenylalanine carboxylate ethyl ester-benzazepine (see patent CN101830850B for specific structure) (150g) and tetrabutylammonium halide (15g), add tert-butyl bromoacetate (125g) dropwise, stir until the reaction is complete, then filter, add toluene (450mL) after the filtrate is desolvated, heat and stir until dissolved, then pass in hydrogen chloride gas to remove The tert-butyl protecting group reacted completely and a solid was produced. After the solid is filtered and dried, acetonitrile is directly added and heated, and the solid obtained after hot filtration is dried to obtain a white crystalline powder, which is the new crystal form of benazepril hydrochloride of the present invention.

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Abstract

The invention relates to a new crystal form of benazepril hydrochloride and a preparation method and a drug application thereof. According to the crystal form, a sharp heat melting peak begins to appear at 225.6 DEG C. The invention is beneficial to researches on drug bioactivity and bioavailability, etc.

Description

technical field [0001] The invention belongs to the field of medicine and relates to a new crystal form of benazepril hydrochloride and a preparation method thereof. Background technique [0002] Benazepril hydrochloride (English alias: benazepril hydrochloride) is an angiotensin converting enzyme inhibitor, its chemical name is 3-[(1-ethoxycarbonyl-3-phenyl-(1S)-propyl) Amino] 2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)benzazepine-1-acetic acid hydrochloride, the molecular structure is as follows: [0003] [0004] Benazepril hydrochloride is hydrolyzed to form highly active benazeprilat, which inhibits hemotensin-converting enzyme and reduces various effects mediated by angiotensin II. Benazeprilat reduces peripheral vascular resistance and lowers blood pressure, but does not cause compensatory fluid retention, and can also reduce ventricular afterload without increasing heart rate. In addition, benazeprilat can also improve left ventricular hypertrophy and improve glucose tol...

Claims

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Application Information

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IPC IPC(8): C07D223/16
CPCY02P20/55C07D223/16C07B2200/13
Inventor 邱小龙邹平胡林胡衍毅秦海燕孙艳吴忠平邓贤明江中兴顾惠慧
Owner WISDOM PHARM CO LTD
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