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Preparation method of cilnidipine

A technology of cilnidipine and crotonic acid, which is applied in the field of compound synthesis, can solve the problems of increasing the impurity content, long reaction time, increase reaction cost and the like, and achieve the effects of improving purity and yield, short reaction time and less impurities

Active Publication Date: 2021-02-19
BENGBU BBCA MEDICINE SCI DEV
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0004] In the current technology, the production process of preparing the cinnidipine intermediate amide (cinnamyl 3-amino-2-butenoate) generally adopts cinnamyl acetoacetate dissolved in ethanol to react with ammonia gas at a low temperature of 0-5°C. After the reaction ends, 70°C vacuum distillation; because the reaction generates a molecule of water and the cilnidipine aminate is unstable, it is easy to degrade during vacuum distillation, resulting in more quality impurities in the final cilnidipine product; at the same time, the reaction needs to be controlled less The reaction temperature indirectly increases the reaction cost
[0005] Simultaneously, when aminate reacts with 2-(3-nitrophenylidene) methoxyethyl acetoacetate, the reaction temperature is higher, which easily leads to 2-(3-nitrophenylidene) methoxyethyl acetoacetate Ethyl ester decomposes, which reduces the reaction efficiency and further increases the impurity content, resulting in higher cost of impurity removal in the later stage and longer reaction time

Method used

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  • Preparation method of cilnidipine
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  • Preparation method of cilnidipine

Examples

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Effect test

Embodiment 1

[0044] This example provides a preparation method of cinnamyl 3-amino-2-butenoate.

[0045] Add 100 g of cinnamyl acetoacetate into 200 mL of ethanol and stir to dissolve, add 44.0 g of solid ammonium carbonate, stir at a controlled temperature of 25°C, react for 24 hours, filter and wash the filter residue with a small amount of ethanol, collect 274 g of the filtrate, and obtain 3-amino-2- Reaction solution of cinnamyl crotonate.

[0046] The purity detected by liquid phase HPLC is ≥99.01%, and the content of cinnamyl 3-amino-2-butenoate is 0.348 g / g.

Embodiment 2

[0048] This example provides a preparation method of cinnamyl 3-amino-2-butenoate.

[0049] Add 100 g of cinnamyl acetoacetate into 200 mL of isopropanol and stir to dissolve, add 44.0 g of solid ammonium carbonate, stir at a controlled temperature of 20°C, react for 24 hours, filter and wash the filter residue with a small amount of isopropanol, collect 307 g of the filtrate, and obtain 3- A reaction solution of cinnamyl amino-2-butenoate.

[0050] The purity detected by liquid phase HPLC is ≥98.8%, and the content of cinnamyl 3-amino-2-butenoate is 0.296 g / g.

Embodiment 3

[0052] This embodiment provides a preparation method of cilnidipine.

[0053] Add 118.0 g of methoxyethyl 2-(3-nitrophenylidene) acetoacetate to 200 mL of ethanol and stir to dissolve to obtain solution 2, and then add 300 mL of the reaction solution obtained in Example 1 to the mixer through a high-pressure constant-flow pump Inside (the flow rate ratio of the reaction solution to solution 2 is 1.2:1), enter the microchannel reactor (thickness 2mm, 5 groups of microtubes, net volume 43.5mL) through the mixer at a flow rate of 5mL / min, the microchannel The temperature of the reactor was set at 50°C, and the reaction liquid was collected; the reaction liquid was cooled to -20°C to crystallize under stirring, and the crystallization was completed, filtered, and the solid was dried under reduced pressure at 50°C to obtain 181.1 g of cilnidipine finished product, with a yield of 91.4%. Phase purity 99.64%.

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Abstract

The invention relates to a preparation method of cilnidipine. The invention provides a preparation method of cinnamyl 3-aminobut-2-enoate, which comprises the following step: carrying out amination reaction on cinnamyl acetoacetate and ammonium carbonate to obtain the cinnamyl 3-aminobut-2-enoate. On the basis, the invention further provides a method for preparing cilnidipine by taking the cinnamyl 3-aminobut-2-enoate as a raw material. The method provided by the invention is relatively low in reaction temperature, relatively short in reaction time, relatively high in product yield and purity,and simple in aftertreatment.

Description

technical field [0001] The invention belongs to the technical field of compound synthesis, and relates to a preparation method of cilnidipine. Background technique [0002] Cilnidipine is a lipophilic dihydropyridine calcium antagonist used for the treatment of hypertensive patients, and its structural formula is: [0003] [0004] In the current technology, the production process of preparing the cinnidipine intermediate amide (cinnamyl 3-amino-2-butenoate) generally adopts cinnamyl acetoacetate dissolved in ethanol to react with ammonia gas at a low temperature of 0-5°C. After the reaction ends, 70°C vacuum distillation; because the reaction generates a molecule of water and the cilnidipine aminate is unstable, it is easy to degrade during vacuum distillation, resulting in more quality impurities in the final cilnidipine product; at the same time, the reaction needs to be controlled less The reaction temperature indirectly increases the reaction cost. [0005] Simulta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90C07C227/04C07C229/30
CPCC07D211/90C07C227/04C07C229/30
Inventor 郑爱张杰丁亚梅江惠莲
Owner BENGBU BBCA MEDICINE SCI DEV
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