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Preparation method for synthesizing nicardipine hydrochloride

A nicardipine hydrochloride and hydrochloric acid technology, applied in the field of medicine, can solve the problems of increasing product quality risks and post-processing difficulties, and achieve high yield and high purity effects

Inactive Publication Date: 2015-11-18
SHAANXI CHANGXIANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At the same time, using isopropanol as a solvent, there is a possibility of transesterification between the solvent isopropanol and the two raw materials during the reaction at high temperature for a long time, which virtually increases the quality risk of the product and the difficulty of post-processing

Method used

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  • Preparation method for synthesizing nicardipine hydrochloride
  • Preparation method for synthesizing nicardipine hydrochloride
  • Preparation method for synthesizing nicardipine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment example 1

[0030] Implementation Case 1: Synthesis of α-crystalline nicardipine hydrochloride with acetone as solvent

[0031] Pump 250kg of acetone into the PM-R-C-01 reaction tank, turn on the stirring, open the feeding port, and add 100kg of 3-amino-2-butenoic acid-2'-(N-benzyl-N-methyl)aminoethyl in sequence , 100kg 3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl ester and cover the feeding port. Heat to 50°C, keep it warm for 8 hours, add 1kg of activated carbon for decolorization, filter, and cool the filtrate to 35°C, add 44kg of hydrochloric acid, stir and crystallize at 30-35°C for 12 hours, centrifuge and dry to obtain 148kg of α-crystalline nicardipine hydrochloride, Yellow-green crystalline powder, melting point: 182-184°C, HPLC content: 99.2%, yield 76.68%.

Embodiment example 2

[0032] Implementation Case 2: Synthesis of α-crystalline nicardipine hydrochloride with chloroform as solvent

[0033] Pump 250kg of chloroform into the PM-R-C-01 reaction tank, turn on the stirring, open the feeding port, and add 100kg of 3-amino-2-butenoic acid-2'-(N-benzyl-N-methyl)aminoethyl in sequence , 100kg 3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl ester and cover the feeding port. Heat to 60°C, keep warm for 6 hours, add 1kg of activated carbon for decolorization, filter, and cool the filtrate to 35°C, add 44kg of hydrochloric acid, stir and crystallize at 30-35°C for 12 hours, centrifuge and dry to obtain 158.5kg of α-crystalline nicardipine hydrochloride , yellow-green crystalline powder, melting point: 181-183°C, HPLC content: 99.5%, yield 82.02%.

Embodiment example 3

[0034] Implementation Case 3: Synthesis of α-crystalline nicardipine hydrochloride with methanol as solvent

[0035] Pump 250kg of methanol into the PM-R-C-01 reaction tank, turn on the stirring, open the feeding port, and add 100kg of 3-amino-2-butenoic acid-2'-(N-benzyl-N-methyl)aminoethyl in sequence , 100kg 3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl ester and cover the feeding port. Heat to 70°C, keep warm for 2 hours, add 1kg of activated carbon for decolorization, filter, concentrate the filtrate to viscous, add 250kg of chloroform to dissolve, cool down to 35°C, add 44kg of hydrochloric acid, stir and crystallize at 30-35°C for 12 hours, centrifuge and dry 135.6 kg of nicardipine hydrochloride in α-crystal form was obtained, yellow-green crystalline powder, melting point: 182-183° C., HPLC content: 99.8%, yield 70.02%.

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Abstract

The invention discloses a preparation method for synthesizing nicardipine hydrochloride. 3-amino-2-butenoic acid-2'-(N-benzyl-N-methyl)aminoethyl ester and 3-methyl-4-(3'-nitrophenyl)-3-methyl crotonate are used as raw materials and react in an inert solvent, the reaction is tracked through TLC (thin layer chromatography) or HPLC (high performance liquid chromatography) until being finished, decoloration and filtration are performed, a filtrate is concentrated to be viscous, a crystal solvent is added for dissolution, decoloration is performed by the aid of activated carbon, the temperature is decreased to be proper, hydrochloric acid forms salt crystals, and high-purity alpha-crystal-form nicardipine hydrochloride or beta-crystal-form nicardipine hydrochloride is obtained. The synthesis process of the nicardipine hydrochloride is improved and optimized, with the adoption of the preparation method, the production process is simple to operate, the cost is saved, mass production is facilitated, and the high-purity and high-yield alpha-crystal-form nicardipine hydrochloride and beta-crystal-form nicardipine hydrochloride can be conveniently obtained.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of medicine for treating cardiovascular and cerebrovascular diseases, in particular to the synthesis of nicardipine hydrochloride [2,6-dimethyl-4-m-nitrophenyl-1,4-dihydro A new method of methyl pyridine-3,5-dicarboxylate-2-(N-benzyl-N-methylamino)ethyl ester hydrochloride] involving both α- and β-crystal forms of nicardipine hydrochloride type of preparation method. Background technique [0002] Nicardipine hydrochloride, also known as nifedipine hydrochloride, nicardidine hydrochloride, is a light yellow powder or off-white crystalline powder, chemical name: 2,6-dimethyl-4-m-nitrophenyl -1,4-dihydropyridine-3,5-dicarboxylic acid methyl ester-2-(N-benzyl-N-methylamino)ethyl ester hydrochloride, the structural formula is as follows: [0003] [0004] Nicardipine hydrochloride is a powerful dihydropyridine calcium antagonist, which can inhibit the influx o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60C07D211/02
CPCC07D211/60C07B2200/13C07D211/02
Inventor 畅水平古凤强传雅萍畅通畅快乐
Owner SHAANXI CHANGXIANG PHARMA CO LTD
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