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Preparation method of imidapril hydrochloride

A technology of imidapril hydrochloride and alanine is applied in the field of preparation of imidapril hydrochloride, which can solve the problems of a large number of impurities and low purity, and achieve the effects of small impurities, control of product purity and high yield

Active Publication Date: 2021-06-25
山东中健康桥制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the existing methods for synthesizing imidapril hydrochloride all contain a large amount of impurities and the purity is not high, so it is necessary to provide a new synthetic method for imidapril hydrochloride

Method used

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  • Preparation method of imidapril hydrochloride
  • Preparation method of imidapril hydrochloride
  • Preparation method of imidapril hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] A preparation method for imidapril hydrochloride, comprising the following steps:

[0107] (1) Synthesis of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine-N-carboxy anhydride:

[0108] Mix and dissolve 3.5kg water and 1.02kg disodium hydrogen phosphate, mix with 2.62kg dichloromethane, 1kg N-[(S)-(+)-1-(ethoxycarbonyl)-3-phenylpropyl]-L propane Amino acid (C181101171-S1), 2kg of dichloromethane, triphosgene / dichloromethane: 0.37kg: 2.64kg of mixed liquid 1 was added to a 200L reaction kettle with stirring in turn, the temperature was controlled at 20°C and stirred for 0.5h, and samples were taken in HPLC Control, stop the reaction when N-[(S)-(+)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine≤5.0%, let it stand for liquid separation for 30 minutes, add 2.06 to the organic phase kg of 2mol / L hydrochloric acid solution and 2.24kg of 23.5% sodium chloride were washed separately, and left to separate for 30 minutes, then added 0.5kg of anhydrous sodium sulfate and stirred...

Embodiment 2

[0115] A preparation method for imidapril hydrochloride, comprising the following steps:

[0116](1) Synthesis of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine-N-carboxy anhydride:

[0117] Mix and dissolve 35kg of water and 10.2kg of disodium hydrogen phosphate, and 26.2kg of dichloromethane, 10kg of N-[(S)-(+)-1-(ethoxycarbonyl)-3-phenylpropyl]-L alanine Acid (C181101171-S1), 20kg of dichloromethane, triphosgene / dichloromethane: 3.7kg: 26.4kg of mixed solution 1 was added to a 200L reaction kettle with stirring in turn, temperature controlled and stirred at 25°C for 0.8h, sampling was performed in the HPLC control , N-[(S)-(+)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine ≤5.0% stop the reaction, let stand for liquid separation for 60 minutes, add 20.6kg organic phase 2mol / L hydrochloric acid solution and 22.4kg of 23.5% sodium chloride were washed separately and left to separate liquids for 60 minutes, added 5kg of anhydrous sodium sulfate and stirred for dehydration fo...

Embodiment 3

[0125] A preparation method for imidapril hydrochloride, comprising the following steps:

[0126] (1) Synthesis of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine-N-carboxy anhydride:

[0127] Mix and dissolve 70kg of water and 20.4kg of disodium hydrogen phosphate, and 52.4kg of dichloromethane, 20kg of N-[(S)-(+)-1-(ethoxycarbonyl)-3-phenylpropyl]-L alanine Acid (C181101171-S1), 40kg of dichloromethane, triphosgene / dichloromethane: 7.4kg: 52.8kg of mixed liquid 1 was added to a 200L reaction kettle with stirring in turn, the temperature was controlled at 30°C and stirred for 1.0h, and the sample was sampled by HPLC. , N-[(S)-(+)-1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine ≤5.0% stop the reaction, let stand for liquid separation for 90 minutes, add 41.2kg organic phase 2mol / L hydrochloric acid solution and 44.8kg of 23.5% sodium chloride were washed separately and left to separate liquids for 90 minutes, adding 10kg of anhydrous sodium sulfate and stirring for dehydration...

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Abstract

The invention relates to the technical field of medicines, and particularly provides a preparation method of imidapril hydrochloride. The preparation method of the imidapril hydrochloride provided by the invention comprises the following steps of firstly, carrying out an N-intramolecular cyclization reaction on a raw material C181101171-S1, then carrying out condensation and maleate forming reaction on the raw material C181101171-S1 and a raw material C181101171-S2, and then carrying out four steps of desalting hydrolysis, hydrochloride forming, refining and the like to obtain a finished product of imidapril hydrochloride. The imidapril hydrochloride product obtained by adopting the preparation method is high in yield, high in purity and small in impurity, the purity of the product can be well controlled, and the method is suitable for industrial production.

Description

Technical field: [0001] The invention relates to the technical field of medicine, in particular to a preparation method of imidapril hydrochloride. Background technique: [0002] Hypertension is a major risk factor for cardiovascular and cerebrovascular diseases. Hypertension is the most common cardiovascular disease, divided into primary hypertension and secondary hypertension, of which primary hypertension accounts for more than 95%. The syndrome with hypertension as the first clinical manifestation is essential hypertension. At present, there are more than 200 million hypertensive patients in my country, and the prevalence of hypertension among Chinese residents continues to increase, and the number of patients is increasing year by year. Hypertension is a common disease that seriously threatens the life and health of people, especially middle-aged and elderly people, and it is also developing towards younger age. trend, has seriously threatened human health. [0003] T...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K1/02C07K1/34
CPCC07K5/06026Y02P20/55
Inventor 刘宗杰
Owner 山东中健康桥制药有限公司
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