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Preparation method of cilnidipine

A technology of cilnidipine and nitrobenzylidene, which is applied in the field of preparation of high-purity cilnidipine compounds, can solve the problems of not being effectively applicable to industrial production, complicated operation, and insufficient yield, and achieves low cost, simple synthesis process, The effect of high yield

Active Publication Date: 2020-04-28
湖南普道医药技术有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Therefore, the synthesis of cilnidipine currently has the problems of insufficient yield, complex operation, and inability to be effectively applied to industrialized production. A simple synthetic process, high yield, low cost, high purity, and suitable for industrialized production has been developed. Nidipine approach makes sense

Method used

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  • Preparation method of cilnidipine

Examples

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Effect test

Embodiment 1

[0063] (1) Synthesis of crude 2-(3-nitrobenzylidene) acetoacetomethoxyethyl ester

[0064] Add 2.4kg of methoxyethyl acetoacetate and 1.6kg of acetic anhydride to a 10L reactor, lower the internal temperature to 0-5°C, add 136g of concentrated sulfuric acid dropwise to control the internal temperature at 0-5°C, and add 2.1kg of room temperature after dropping Nitrobenzaldehyde, the temperature was raised to 25-30°C for 6-7h, and the reaction was terminated. Add 95% ethanol, filter, and vacuum-dry at 45°C for 10 hours to obtain a pale yellow solid.

[0065] (2) Refined 2-(3-nitrobenzylidene)acetoacetomethoxyethyl ester

[0066] Put the crude product of 2-(3-nitrobenzylidene)acetoacetylmethoxyethyl ester in a 30L reaction kettle, add 10kg of dichloromethane to dissolve it, then add saturated sodium bicarbonate solution and stir at room temperature for 30min, let stand and separate , adding pure water to the organic phase and stirring at room temperature for 30 min, standing to...

Embodiment 2

[0074] (1) Synthesis of crude 2-(3-nitrobenzylidene) acetoacetomethoxyethyl ester

[0075] Add 2.2kg of methoxyethyl acetoacetate and 1.3kg of acetic anhydride to a 10L reactor, lower the internal temperature to 0-5°C, add 136g of concentrated sulfuric acid dropwise to control the internal temperature at 0-5°C, and add 2.1kg of room temperature after dropping For nitrobenzaldehyde, heat up to 25-30°C for 2-3 hours to terminate the reaction. Add 95% ethanol, filter, and vacuum-dry at 45°C for 10 hours to obtain a pale yellow solid.

[0076] (2) Refined 2-(3-nitrobenzylidene)acetoacetomethoxyethyl ester

[0077] Put the crude product of 2-(3-nitrobenzylidene)acetoacetylmethoxyethyl ester in a 30L reaction kettle, add 9.9kg of ethyl acetate to dissolve it, then add saturated sodium carbonate solution and stir at room temperature for 30min, let stand and separate , adding pure water to the organic phase and stirring at room temperature for 30 min, standing to separate layers, an...

Embodiment 3

[0085] (1) Synthesis of crude 2-(3-nitrobenzylidene) acetoacetomethoxyethyl ester

[0086] Add 3.3kg of methoxyethyl acetoacetate and 1.68kg of acetic anhydride to a 10L reactor, lower the internal temperature to 0-5°C, add 409g of concentrated sulfuric acid dropwise to control the internal temperature at 0-5°C, and add 2.1kg For nitrobenzaldehyde, the temperature was raised to 25-30°C for 11-12 hours, and the reaction was terminated. Add 95% ethanol, filter, and vacuum-dry at 45°C for 10 hours to obtain a pale yellow solid.

[0087] (2) Refined 2-(3-nitrobenzylidene)acetoacetomethoxyethyl ester

[0088] Put the crude product of 2-(3-nitrobenzylidene)acetoacetylmethoxyethyl ester in a 30L reactor, add 9.6kg of chloroform to dissolve it, then add saturated potassium carbonate solution and stir at room temperature for 30min, let it stand for layers, organic Pure water was added to the mixture and stirred at room temperature for 30 min, and the layers were separated after stand...

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Abstract

The invention discloses a preparation method of high-purity cilnidipine. Methoxyethyl acetoacetate reacts with m-nitrobenzaldehyde to generate 2-(3-nitrobenzylidene) methoxyethyl acetoacetate, and the2-(3-nitrobenzylidene) methoxyethyl acetoacetate reacts with cinnamyl 3-aminocrotonate to generate cilnidipine. According to the method, the refining step of the 2-(3-nitrobenzylidene) methoxyethyl acetoacetate is added; the problem that impurities in the cilnidipine bulk drug are difficult to remove is solved, the subsequent refining process of the cilnidipine is simpler, and the purity of the finished product is high. The method has the advantages of simple synthesis process, complete reaction, high yield and low cost, and is very suitable for industrial production. .

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a preparation method and application of a high-purity cilnidipine compound. Background technique [0002] Cilnidipine (cilnidipine), chemical name: 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyethyl Ester cinnamyl alcohol ester, CAS number: 132203-70-4, molecular formula is C27H28N2O7, molecular weight is 492.52, the structural formula of cilnidipine is as follows: [0003] [0004] Cilnidipine is a dihydropyridine calcium antagonist developed by Fuji Corporation of Japan and first launched in Japan in 1995. Cilnidipine can bind to the dihydropyridine site of the L-type calcium channel on the membrane of vascular smooth muscle cells, inhibiting Ca 2+ Through the transmembrane influx of L-type calcium channels, it relaxes and expands vascular smooth muscle, and plays a role in lowering blood pressure. It can also inhibit Ca 2+...

Claims

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Application Information

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IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 赵子萌宁虎林谭军华肖稳定范朋云郑霞辉
Owner 湖南普道医药技术有限公司
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