The preparation method of cilnidipine

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

Active Publication Date: 2021-06-04
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

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  • The preparation method of cilnidipine
  • The preparation method of cilnidipine
  • The preparation method of cilnidipine

Examples

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Effect test

Embodiment 1

[0064] (1) Synthesis of crude product of 2-(3-nitrobenzylidene) methoxyethyl acetoacetate

[0065] 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, add 2.1kg of 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 h to obtain a pale yellow solid.

[0066] (2) Refining of 2-(3-nitrobenzylidene) methoxyethyl acetoacetate

[0067] Put the crude product of methoxyethyl 2-(3-nitrobenzylidene)acetoacetate 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 separate layers, and dichlorometh...

Embodiment 2

[0075] (1) Synthesis of crude product of 2-(3-nitrobenzylidene) methoxyethyl acetoacetate

[0076] 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 under control of the internal temperature at 0-5°C, add 2.1kg of 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 h to obtain a pale yellow solid.

[0077] (2) Refining of 2-(3-nitrobenzylidene) methoxyethyl acetoacetate

[0078] Put the crude product of methoxyethyl 2-(3-nitrobenzylidene)acetoacetate in a 30L reaction vessel, 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, and distilling off the ethyl a...

Embodiment 3

[0086] (1) Synthesis of crude product of 2-(3-nitrobenzylidene) methoxyethyl acetoacetate

[0087] 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 h to obtain a pale yellow solid.

[0088] (2) Refining of 2-(3-nitrobenzylidene) methoxyethyl acetoacetate

[0089] Put the crude product of methoxyethyl 2-(3-nitrobenzylidene)acetoacetate in a 30L reactor, add 9.6kg of chloroform to dissolve it, then add a saturated solution of potassium carbonate 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 afte...

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Abstract

The application discloses a preparation method of high-purity cilnidipine, methoxyethyl acetoacetate reacts with m-nitrobenzaldehyde to generate 2-(3-nitrobenzylidene) methoxyethyl acetoacetate, 2 ‑(3‑nitrobenzylidene) methoxyethyl acetoacetate reacts with 3‑amino cinnamyl crotonate to generate cilnidipine, and the present invention adds 2‑(3‑nitrobenzylidene) methoxyethyl acetoacetate The ethyl ethyl ester refining step solves the problem of difficult removal of impurities in the cilnidipine bulk drug, and the subsequent refining process of cilnidipine is simpler and the purity of the finished product is high. Moreover, the synthesis process of the invention is simple, the reaction is complete, the yield is high, and the cost is low, which 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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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 肖稳定宁虎林谭军华赵子萌范朋云郑霞辉向波
Owner 湖南普道医药技术有限公司
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