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Preparation method of nitrendipine

A technology of nitrendipine and reaction solution, which is applied in the field of preparation of nitrendipine, and can solve problems such as inability to overcome the impurities of dimethyl ester and diethyl ester, difficult to control, etc.

Active Publication Date: 2020-04-28
北京鑫开元医药科技有限公司
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0003] There are many documents reporting the synthesis of nitrendipine at present. It takes more than 10 hours to reflux directly in ethanol and the impurities of dimethyl and diethyl ester are not easy to control with the increase of batches. Sometimes the single impurity can reach about 1.0%. Although catalysts such as pyridine acetic acid can effectively shorten the time, they still cannot overcome the problem of high impurities in dimethyl ester and diethyl ester

Method used

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  • Preparation method of nitrendipine

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preparation example Construction

[0029] The embodiment of the present invention provides a preparation method of nitrendipine, comprising:

[0030] Step S11, adding (E)-2-(3-nitrobenzylidene)-3-oxobutanoic acid ethyl ester and 3-aminocrotonate methyl ester into the first solvent, at the first temperature, Reflux reaction, obtains the first reaction solution;

[0031] Step S12, at a second temperature, adding acetic anhydride to the first reaction solution to react to obtain a second reaction solution;

[0032] Step S13, at a third temperature, stirring and reacting the second reaction solution, and filtering to obtain the crude nitrendipine;

[0033] Step S14, recrystallizing the crude nitrendipine to obtain nitrendipine.

[0034] Further, in step S11, the molar ratio of (E)-2-(3-nitrobenzylidene)-3-oxobutanoic acid ethyl ester to the 3-aminocrotonate methyl ester is 1 :1~1:1.5, such as 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5, etc., when the molar ratio of (E)-2-(3-n...

Embodiment 1

[0052] Step S201: Add ethyl (E)-2-(3-nitrobenzylidene)-3-oxobutyrate (500.0g, 1.9mol), methyl 3-aminocrotonate (240.3g, 2.1mol ), ethanol (1250ml) was placed in the reaction flask and started to stir, the temperature was raised to 75-80°C, and the reaction was incubated for 1 hour to obtain the first reaction solution;

[0053] Step S202: Add acetic anhydride (9.7 g, 95.0 mmol) to the first reaction solution in step S201, heat it at 75-80°C for 1 hour, and stop heating to obtain a second reaction solution;

[0054] Step S203: the second reaction solution in step S202 was cooled to 15-20°C, stirred at this temperature for 30 minutes, and filtered to obtain crude nitrendipine;

[0055] Step S204: Place the crude nitrendipine in step S203 in ethanol (2000ml), heat up to reflux (about 77°C), dissolve the sample, continue stirring for 30 minutes, filter while hot, and cool the filtrate to 15-20°C with stirring, Filtration, filter cake drying obtains product 575.0g, yield is 84%, H...

Embodiment 2

[0057] Step S301: Add ethyl (E)-2-(3-nitrobenzylidene)-3-oxobutyrate (500.0g, 1.9mol), methyl 3-aminocrotonate (240.3g, 2.1mol ), ethanol (1250ml) was placed in the reaction flask and started to stir, the temperature was raised to 75-80°C, and the reaction was incubated for 1 hour to obtain the first reaction solution;

[0058] Step S302: Add acetic anhydride (19.4 g, 190.0 mmol) to the first reaction solution in step S301, heat at 75-80° C. for 1 hour, and then stop heating to obtain a second reaction solution;

[0059] Step S303: the second reaction solution in step S302 was cooled to 15-20°C, stirred at this temperature for 30 minutes, and filtered to obtain crude nitrendipine;

[0060] Step S304: Place the crude nitrendipine in step S303 in ethanol (2000ml), heat up to reflux (about 77°C), dissolve the sample, continue stirring for 30 minutes, filter while hot, and cool the filtrate to 15-20°C with stirring, Filtration, filter cake drying to obtain product 588.6g, yield 8...

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of nitrendipine, which comprises the following steps: adding (E)-2-(3-nitrobenzylidene)-3-oxobutyrate and methyl 3-aminocrotonate into a first solvent, and carrying out a reflux reaction at a first temperature to obtain a first reaction solution; adding acetic anhydride into the first reaction solution at a second temperature to react to obtain a second reaction solution; carrying out a stirring reaction on the second reaction solution at a third temperature, and filtering to obtain a crude product of nitrendipine; and recrystallizing the crude product of nitrendipine to obtain nitrendipine. The invention provides a preparation method of nitrendipine, and aims to effectively controldimethyl ester impurities and diethyl ester impurities, improve the yield and shorten the reaction time so as to improve the productivity.

Description

technical field [0001] The invention belongs to the technical field of medicines, and in particular relates to a preparation method of nitrendipine. Background technique [0002] Nitrendipine is a dihydropyridine drug, the chemical name is 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate ethyl ester A Ester, with a molecular weight of 360.36, belongs to calcium channel antagonists. Its pharmacological action is similar to that of nifedipine. It has a stronger effect on vascular relaxation than nifedipine, and its antihypertensive effect lasts for a long time. Nitrendipine has a good oral absorption effect, with a bioavailability of 10% to 20%, a half-life of 10 to 22 hours, and a plasma protein binding rate of 98%. In addition, nitrendipine had no effect on the sinoatrial or atrioventricular nodes. [0003] There are many documents reporting the synthesis of nitrendipine at present. It takes more than 10 hours to reflux directly in ethanol and the impur...

Claims

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Application Information

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IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 王永广富佳宋玉杰苏小庭戴信敏
Owner 北京鑫开元医药科技有限公司
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