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Synthesis technology for preparing nitrendipine based on three-step method

A synthesis process, the technology of nitrendipine, which is applied in the field of synthesis process of nitrendipine based on the three-step method, can solve the problems of high cost, troublesome post-processing, affecting product purity, etc.

Inactive Publication Date: 2019-01-18
黄石燕舞药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to solve the disadvantages of more impurities generated in the cyclization process in the prior art, affecting product purity, troublesome post-processing, and relatively high cost, and proposes a three-step method based on the preparation of Nitrin The Synthesis Process of Diping

Method used

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  • Synthesis technology for preparing nitrendipine based on three-step method
  • Synthesis technology for preparing nitrendipine based on three-step method
  • Synthesis technology for preparing nitrendipine based on three-step method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] A kind of synthetic technique that the present invention proposes based on three-step method prepares nitrendipine comprises the following steps:

[0033]S1 Ammonification reaction: Take the prescribed amount of absolute ethanol in a three-necked bottle, add 0.70kg of methyl acetoacetate, stir to cool down to 2°C, pass ammonia gas, control the internal temperature below 20°C, and stop the flow until the smell of ammonia escapes. Ammonia gas, keep warm at 2°C and stir for 2 hours, filter, rinse the filter cake with cold ethanol, add methyl acetoacetate to the filtrate, stir to cool down, control the temperature at 2°C, pass ammonia gas, control the internal temperature below 20°C, until there is ammonia smell Escape, stop the ammonia gas, keep warm at 2°C and stir for 2 hours, filter, filter the cake with cold ethanol, combine the filter cakes, blow dry at 30°C or combine after drying to obtain methyl β-aminocrotonate, melting point : 80°C;

[0034] S2 condensation reac...

Embodiment 2

[0038] A kind of synthetic technique that the present invention proposes based on three-step method prepares nitrendipine comprises the following steps:

[0039] S1 Amination reaction: Take the prescribed amount of absolute ethanol in a three-necked bottle, add 0.70kg of methyl acetoacetate, stir and cool down to 5°C, pass ammonia gas, control the internal temperature below 20°C, stop the flow until the smell of ammonia escapes. Ammonia gas, keep warm at 5°C and stir for 2.5h, filter, rinse the filter cake with cold ethanol, add methyl acetoacetate to the filtrate, stir to cool down, control the temperature at 5°C, pass ammonia gas, control the internal temperature below 20°C, until there is ammonia When the odor escapes, stop the ammonia gas flow, keep warm at 5°C and stir for 2.5 hours, filter, rinse the filter cake with cold ethanol, combine the filter cakes, and dry them with air at 32°C or combine them after drying to obtain methyl β-aminocrotonate , melting point: 82°C; ...

Embodiment 3

[0044] A kind of synthetic technique that the present invention proposes based on three-step method prepares nitrendipine comprises the following steps:

[0045] S1 Ammonification reaction: Take the prescribed amount of absolute ethanol in a three-necked bottle, add 0.70kg of methyl acetoacetate, stir to cool down to 8°C, pass ammonia gas, control the internal temperature below 20°C, and stop the flow until the smell of ammonia escapes. Ammonia gas, keep warm at 8°C and stir for 3 hours, filter, rinse the filter cake with cold ethanol, add methyl acetoacetate to the filtrate, stir to cool down, control the temperature at 8°C, pass ammonia gas, control the internal temperature below 20°C, until there is ammonia smell Escape, stop the ammonia gas flow, keep warm at 8°C and stir for 3 hours, filter, rinse the filter cake with cold ethanol, combine the filter cakes, blow dry at 34°C or combine after drying to obtain methyl β-aminocrotonate, melting point : 84°C;

[0046] S2 Conde...

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Abstract

The invention discloses a synthesis technology for preparing nitrendipine based on a three-step method. The synthesis technology comprises the following steps: S1, carrying out amination reaction: enabling liquid ammonia and methyl acetoacetate to react to generate methyl beta-aminocrotonate; S2, carrying out condensation reaction: carrying out the condensation reaction on m-nitrobenzaldehyde andethyl acetoacetate under the actions of catalysts, i.e., piperidine and glacial acetic acid to prepare pure 2-(3-nitrobenzylidene)-ethyl acetoacetate; S3, carrying out ring closing reaction: carryingout Michael reaction on the methyl beta-aminocrotonate and the 2-(3-nitrobenzylidene)-ethyl acetoacetate under the action of a catalyst diisopropylethylamine / glacial acetic acid, and carrying out intra-molecular cyclization to obtain the nitrendipine; S4, refining. According to the synthesis technology, the m-nitrobenzaldehyde (SM1), ethyl acetoacetate (SM2) and methyl aminocrotonate (SM3) are used as starting raw materials for preparation, and heating and ring closing are carried out; the qualified product nitrendipine is obtained through three steps of reaction, and the synthesis technologydoes not contain special reaction conditions.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a synthesis process for preparing nitrendipine based on a three-step method. Background technique [0002] Nitrendipine (nitrendipine, A) chemical name is 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate ethyl methyl ester, Belonging to dihydropyridine calcium antagonists, it is mainly used clinically for the treatment of primary and secondary hypertension. Its synthetic route, industrial production and literature reports are carried out by "one-pot method", namely: m-nitrobenzaldehyde, ethyl acetoacetate and β-aminocrotonic acid generated by the reaction of liquid ammonia and methyl acetoacetate The methyl ester is heated in the same reaction tank to generate nitrendipine. This method has the characteristics of less equipment and relatively simple process steps. The disadvantage of the "one-pot method" production is that more impurities are gene...

Claims

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Application Information

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IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 甘曙光熊永坚余鲜红余辉民
Owner 黄石燕舞药业有限公司
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