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Method for preparing key intermediate of imidapril and derivative thereof

A technology of intermediates and derivatives, applied in the field of chemical pharmaceuticals, can solve the problems of cumbersome operation, harsh reaction conditions, and unsuitability for industrialized large-scale production, and achieve the effects of fast reaction speed, simple operation, and low pollution

Active Publication Date: 2016-06-29
HUNAN JIUDIAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method needs to be reacted at -50~-45°C, and the two raw materials need to be dissolved in tetrahydrofuran (-50~-45°C) respectively, and then mixed and reacted. The operation is cumbersome and the reaction conditions are harsh, so it is not suitable for industrialization. Production

Method used

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  • Method for preparing key intermediate of imidapril and derivative thereof
  • Method for preparing key intermediate of imidapril and derivative thereof
  • Method for preparing key intermediate of imidapril and derivative thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0023] 16g (4S)-3-benzyloxycarbonyl-1-methyl-2-oxoimidazolidine-4-carboxylic acid tert-butyl ester, 17.5gN-[(S)-1-ethoxycarbonyl-3-benzene Propyl]-L-alanine-N-carboxylic acid anhydride and 4.35g of lithium bromide were added to 100g of toluene, and the temperature was raised to 70-80°C for 3 hours. After the reaction was completed, 15.1 g of colorless syrupy (4S)-1-methyl-3{(2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-phenylpropyl] was obtained after post-treatment Amino]propionyl}-2-oxoimidazolidine-4-carboxy tert-butyl ester. The content detected by HPLC was 99.14%, and the yield was 68.37%.

Embodiment 2

[0025] 16g (4S)-3-benzyloxycarbonyl-1-methyl-2-oxoimidazolidine-4-carboxylic acid tert-butyl ester, 15.3gN-[(S)-1-ethoxycarbonyl-3-benzene Propyl]-L-alanine-N-carboxylic acid anhydride and 5.0g of lithium bromide were added to 100g of toluene, and the temperature was raised to 70-80°C for 3 hours. After the reaction was completed, 14.7 g of colorless slurry (4S)-1-methyl-3{(2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-phenylpropyl] was obtained after post-treatment Amino]propionyl}-2-oxoimidazolidine-4-carboxy tert-butyl ester. The content detected by HPLC was 99.21%, and the yield was 66.56%.

Embodiment 3

[0027] 16g (4S)-3-benzyloxycarbonyl-1-methyl-2-oxoimidazolidine-4-carboxylic acid tert-butyl ester, 17.5gN-[(S)-1-ethoxycarbonyl-3-benzene Propyl]-L-alanine-N-carboxylic acid anhydride and 5.0g of lithium bromide were added to 100g of toluene, and the temperature was raised to 70-80°C for 3 hours. After the reaction was completed, 16.8 g of colorless syrupy (4S)-1-methyl-3{(2S)-2-[N-[(1S)-1-ethoxycarbonyl-3-phenylpropyl] was obtained after post-treatment Amino]propionyl}-2-oxoimidazolidine-4-carboxy tert-butyl ester. The content detected by HPLC was 99.56%, and the yield was 76.07%.

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Abstract

The invention provides a method for preparing a key intermediate of imidapril and a derivative (I) thereof. The method comprises a step of reacting a (4S)-3-substituent-1-methyl-2-oxoimidazolidine-4-carboxylate derivative (II) with N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanine-N-carboxylic acid anhydride (III) or with N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanine (IV) in an aprotic solvent under the catalysis of a lithium salt. The method has the advantages of mild reaction conditions, a fast reaction speed, high yield, small pollution and wide application prospects. In the formula, R<2> is selected from a group consisting of hydrogen atoms, alkali metals, alkaline earth metal atoms, C1-4 alkane groups and a benzyl group; and when the R<2> is a hydrogen atom, an obtained product is imidapril.

Description

technical field [0001] The invention specifically relates to the field of chemical pharmacy. Specifically relates to a method for preparing imidapril key intermediates and derivatives thereof. Background technique [0002] Imidapril is a long-acting oral angiotensin-converting enzyme (ACE) inhibitor that inhibits the activity of angiotensin-converting enzyme. [0003] [0004] The method provided in the Chinese patent CN200710038655.8 is based on formula II (4S)-1-methyl-2-oxoimidazolidine-4-carboxylate (R 1 hydrogen atom) and formula ⅢN-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanine-N-carboxylic acid anhydride as raw materials, reacted in an organic solvent under alkaline conditions Demidapril key intermediate and its derivatives. In the actual operation of this method, the reaction needs to be performed below 0°C, and then the temperature is raised to 20°C to continue the reaction, and there is a strict feeding sequence and feeding time, the operation is complicated...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062
Inventor 朱志宏卜振军肖稳定
Owner HUNAN JIUDIAN PHARMA