Method for preparing high-purity isradipine

An isradipine and high-purity technology, which is applied in the field of chemical pharmacy, can solve the problems of cumbersome post-treatment of isopropyl acetoacetate, and achieve the effects of convenient purification, high yield and easy operation

Active Publication Date: 2015-07-08
SICHUAN BAILI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The aftertreatment of isopropyl acetoacetate prepared by this method is comparatively loaded down with trivial details

Method used

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  • Method for preparing high-purity isradipine
  • Method for preparing high-purity isradipine
  • Method for preparing high-purity isradipine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Preparation of 2-acetyl-3-benzofurazan-4-yl-isopropyl acrylate (compound 2)

[0049] Add 22.2g (0.15mol) of isopropyl acetoacetate and 10ml of acetic anhydride into the reaction flask, cool in an ice-salt bath to below 5°C, add 1ml of concentrated sulfuric acid dropwise, and slowly add 2,1,3-benzo Oxadiazole-4-carboxaldehyde 14.8g (0.1mol), after the addition is complete, remove the ice-salt bath, stir and dissolve the solid, continue to keep warm for 3.5 hours, and monitor the reaction to 2,1,3-benzoxadiol Terminate the reaction when the remaining amount of azole-4-carboxaldehyde is less than 1%, add 20ml of isopropanol and stir evenly, cool, stir in an ice bath for 1 hour, filter, wash the filter cake with a small amount of isopropanol, then wash with a large amount of water, and dry to obtain 23.9g yellow crystals, yield 86.6%, HPLC Purity (sum of cis and trans isomer purity) ≥ 99.0%.

Embodiment 2

[0050] Example 2: Preparation of methyl 3-aminocrotonate (compound 3)

[0051] Add 55ml of methyl acetoacetate into a three-necked round-bottomed flask, lower the temperature to below 0°C, keep warm and feed ammonia gas to stir the reaction for 2 hours, monitor by TLC until the reaction is complete, let it stand overnight below -10°C, filter it with suction, and dry it under reduced pressure 53.6g of solid was obtained, melting point: 82-83°C, yield 93.2%.

Embodiment 4

[0055] Embodiment 4: the preparation of isradipine

[0056]Add 11g of methyl 3-aminocrotonate and 60ml of isopropanol into the reaction flask, add 23.9g of 2-acetyl-3-benzofurazan-4-yl-isopropylacrylate under stirring, and stir in the dark for 20 hour, the reaction solution was concentrated to dryness, added ethyl acetate 100ml, water 20ml, separated after stirring, the organic phase was dried with anhydrous sodium sulfate, filtered, and the ethyl acetate was reclaimed to dryness to obtain 31g of isradipine crude product. Add 40ml of isopropanol, heat to dissolve, filter while hot, let the filtrate stand for crystallization below 5°C for 16 hours, filter, wash the filter cake with a small amount of frozen isopropanol and dry it in vacuum at 40°C to obtain yellow isradipine 25.7g, yield 80% (HPLC purity 99.4%, homologue impurity content less than 0.1%).

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Abstract

The invention discloses a method for preparing high-purity isradipine. The method includes dehydrating and condensating 4-formaldehyde benzofuroxan in atent solvent to form 2-acetyl-3-benzofuroxan-4-base-isopropyl acrylate; subjecting methyl acetoacetate to ammonolysis to form 3-amino crotonic acid methyl ester; subjecting 2-acetyl-3-benzofuroxan-4-base-isopropyl acrylate and 3-amino crotonic acid methyl ester to reaction to form isradipine. The method for preparing high-purity isradipine is simple in operation process, convenient to operate, high in yield and capable of preparing high-purity isradipine.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy and relates to a preparation method of high-purity isradipine. Background technique [0002] The structural formula of Isradipine is as follows: [0003] [0004] Isradipine is a dihydropyridine calcium antagonist with high selectivity to blood vessels. It can relax peripheral blood vessels, coronary blood vessels and cerebrovascular vessels. It has little effect on the heart and only inhibits the spontaneous activity of the sinus node. It is used for Hypertension, coronary heart disease and angina pectoris, also can be used for congestive heart failure. [0005] U.S. Patent No. 4,466,972 discloses a synthetic method for isradipine. The method adopts a "one-pot method" to prepare isradipine. This method cannot carry out quality control on intermediates, so the prepared product contains a certain amount of impurities of the following formula homologues, and Homologous impurities are ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/04
Inventor 王一茜肖捷
Owner SICHUAN BAILI PHARM CO LTD
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