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Preparation method of perindopril arginine

A technology for arginine perindopril and perindopril is applied in the field of drug synthesis, and can solve the problems of difficult industrialized operation, poor stability of perindopril, difficult preparation and purification, unsatisfactory processing properties of arginine perindopril, and the like , to achieve the effect of improving product yield

Active Publication Date: 2019-09-27
NANJING GRITPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the above public documents, it is necessary to use perindopril as a raw material to react with arginine, but perindopril has poor stability and is not easy to prepare and purify, and perindopril arginine has unsatisfactory post-treatment properties according to the above documents and is not easy to be industrialized. Therefore, it is necessary to develop a method for preparing perindopril arginine that is more suitable for technological production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment ( 1

[0023] Add 70.0g of perindopril, 26.2g of L-arginine (0.95eq), 210g of purified water into a 2L reaction bottle, stir until the reaction solution is clear, add 770g of dimethyl sulfoxide, and heat up to 40-50°C React and keep the negative pressure <-0.07Mpa for one hour. After the reaction, add 273g of ethyl acetate, lower the temperature at 5-25°C for crystallization for 4 hours, filter the obtained solid with suction, wash the solid with ethyl acetate and dry it in vacuum , The resulting solid was stirred and washed twice with ethyl acetate, filtered with suction, and finally dried in vacuo for 4 hours. Yield 82.3%, purity 99.96%.

Embodiment ( 2

[0025] Add 100g of perindopril, 39.4g of L-arginine (1eq) and 220g of purified water into a 5L reaction bottle, stir until the reaction solution is clear, add 660g of dimethyl sulfoxide, heat up to 40-50°C and keep React for one hour under negative pressure <-0.07Mpa. After the reaction, add methyl tert-butyl ether, cool down at 0-10°C to crystallize for 6 hours, filter the obtained solid with suction, wash the solid with methyl tert-butyl ether and place it in a vacuum After drying, the resulting solid was stirred twice with methyl tert-butyl ether, filtered with suction, and finally dried in vacuum for 6 hours. The yield was 87.5%, and the purity was 99.94%.

Embodiment ( 3

[0027] Add 50 g of diethylaminoperindopril and 17.8 g (0.9 eq) of L-arginine in a 2L reaction flask, stir until the reaction solution is clear, add 350 g of dimethyl sulfoxide, add isopropyl acetate, and cool down to 0 Crystallize at -10°C for 12 hours, filter the obtained solid with suction, wash the solid with isopropyl acetate and dry it in vacuum, then stir the obtained solid twice with isopropyl acetate and filter it with suction, and finally dry it in vacuum for 6 hours. Yield 83.3%, purity 99.92%.

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PUM

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Abstract

The invention belongs to the field of synthesis of drugs, and relates to a preparation method of perindopril arginine. The preparation method of perindopril arginine is characterized in that an organic amine salt of perindopril reacts with L-arginine to obtain the perindopril arginine. The prepared perindopril arginine is a white powder, has a purity reaching 99.9% or above, and has a yield of 80% or above, and the method has the advantages of easiness in suction filtration in the technologic process, and no agglomeration phenomenon.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of perindopril arginine. Background technique [0002] Perindopril arginine is a drug for the treatment of mild to moderate essential hypertension launched by the French company Servier. Compared with perindopril tert-buthamine, the compound is more stable, and the shelf life can be extended to more than 2 years. Moreover, perindopril arginine can be combined with amlodipine besylate to form a compound preparation, which has outstanding curative effect in the treatment of adult patients with hypertension that cannot be adequately controlled by single drugs. [0003] CN101389603 relates to a preparation method of α crystal form, which uses DMSO, water, and methylcyclohexane as solvents to prepare hydrate; CN101389604 relates to a preparation method of β crystal form, which uses perindopril arginine α crystal form through The anhydrous β-crystal form ...

Claims

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Application Information

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IPC IPC(8): C07C277/08C07C279/14C07K5/062
CPCC07C277/08C07K5/06026C07C279/14
Inventor 李先喆邓书兰耿聪聪魏伟业赵卿霍立茹李战
Owner NANJING GRITPHARMA CO LTD
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