3-(2-Nitroethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate preparation method

A technology of nitrophenyl and dihydropyridine, applied in the field of pharmacy, can solve the problems of unsuitable industrial production, low yield, complicated preparation method, etc., and achieve the effects of shortening production cycle, good appearance and simplifying operation process

Active Publication Date: 2018-10-12
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Purpose of the invention: to solve the prior art-(2-nitrile ethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3, The preparation method of 5-dicarboxylate is complicated, the yield is low, and it is not suitable for industrialized production. A preparation method suitable for industrialized production with high yield and good quality is provided.

Method used

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  • 3-(2-Nitroethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Embodiment 1, the synthesis of cyanoethyl acetoacetate:

[0029] 28.4g of 3-hydroxypropionitrile, 46.4g of methyl acetoacetate, and 14.2g of N-bromosuccinimide (NBS) were added to a 250ml reaction flask, 150ml of toluene was added, and the temperature was raised to 90°C. After reacting for 3 hours, it was cooled to room temperature, filtered, and the filtrate was washed three times with water and then spin-dried to obtain 59 g of a yellow liquid with a yield of 95.2% and a purity of 92% by HPLC.

Embodiment 2

[0030] Embodiment 2, the synthesis of cyanoethyl acetoacetate

[0031] 28.4g of 3-hydroxypropionitrile, 46.4g of methyl acetoacetate, and 7.1g of N-bromosuccinimide (NBS) were added to a 250ml reaction flask, 150ml of toluene was added, and the temperature was raised to 90°C. After reacting for 3 hours, it was cooled to room temperature, filtered, and the filtrate was washed three times with water and then spin-dried to obtain 58.6 g of a yellow liquid with a yield of 94.6% and an HPLC purity of 86%.

Embodiment 3

[0032] Embodiment 3, the synthesis of cyanoethyl acetoacetate

[0033] Add 28.4g of 3-hydroxypropionitrile, 46.4g of methyl acetoacetate, and 10g of N-bromosuccinimide (NBS) into a 250ml reaction flask, add 150ml of toluene, heat up to 90°C, and react After 3 hours, it was cooled to room temperature, filtered, and the filtrate was washed three times with water and then spin-dried to obtain 59.5 g of a yellow liquid with a yield of 95.9% and an HPLC purity of 89%.

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Abstract

The invention relates to a preparation method of a barnidipine intermediate 3-(2-nitrile-ethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. The preparation method is characterized by enabling 3-hydroxylpropionitrile and methyl acetoacetate to be subjected to ester exchange under the catalysis of N-bromosuccinimide (NBS), then, ammoniating with a mixture of ammonium acetate and ammonia water, and then, carrying out catalytic reaction by an organic acid, thereby obtaining a final product. The preparation method provided by the invention is used for overcoming the defects of the existing preparation methods that the yield is relatively low and the like, and is applicable to industrial production.

Description

[0001] Technical field: the present invention relates to a kind of barnidipine intermediate 3-(2-nitrile ethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4 -The preparation method of dihydropyridine-3,5-dicarboxylate belongs to the field of pharmaceutical technology. Background technique [0002] 1,4-Dihydropyridine calcium antagonists are currently the most widely used clinically and the strongest class of calcium antagonists. Barnidipine hydrochloride is a product developed by Japan Yamanouchi Pharmaceutical Co., Ltd. It is favored by patients because of its long-lasting and significant antihypertensive effect. [0003] 3-(2-Nitroethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate It is the key intermediate of barnidipine hydrochloride. [0004] CN101643469 has reported a synthetic route of this intermediate, and this route is with 3-hydroxypropionitrile, diketene, m-nitrobenzaldehyde and 3-aminocrotonate methyl ester as starting material,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90C07D211/02
CPCC07D211/02C07D211/90
Inventor 管西涛赵九洋万刚强苗华明
Owner 迪嘉药业集团股份有限公司
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