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Preparation method of hypotensive drug (R)-cilnidipine

A technology of cilnidipine and antihypertensive drugs, applied in the field of chiral drug synthesis, to achieve the effect of easy separation and simple steps

Inactive Publication Date: 2018-04-06
QINGDAO CHENDA BIOLOGICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Due to the unique and interesting biological effects of chiral drugs, the drug molecule of cilnidipine contains a chiral center, but the single chiral compound of cilnidipine has not been extensively studied

Method used

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  • Preparation method of hypotensive drug (R)-cilnidipine
  • Preparation method of hypotensive drug (R)-cilnidipine
  • Preparation method of hypotensive drug (R)-cilnidipine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] In a round bottom flask, add 15.5g (100mmol) of cyanoethyl acetoacetate, 18.1g (120mmol) of m-nitrobenzaldehyde, 20.7g (130mmol) of methoxyethyl 3-amino-2-butenoate and 150ml of isopropanol was heated and refluxed for 8 hours, concentrated under reduced pressure, and recrystallized from n-hexane-dichloromethane (15:1) to obtain racemic 1,4-dihydro-2,6-dimethyl-4-( 3-nitrophenyl)-3,5-pyridinedicarboxylic acid-3-(2-cyanoethyl ester)-5-(2-methoxyethyl ester) 35.9g, yield 83.7%, purity 99.15% .

Embodiment 2

[0032] In a round bottom flask, add 15.5 g (100 mmol) of cyanoethyl acetoacetate, 18.1 g (120 mmol) of m-nitrobenzaldehyde, 23.9 g (150 mmol) of methoxyethyl 3-amino-2-butenoate and 140ml of isopropanol was heated and refluxed for 8 hours, concentrated under reduced pressure, recrystallized from n-hexane-dichloromethane (15:1) to obtain racemic 1,4-dihydro-2,6-dimethyl-4-( 3-nitrophenyl)-3,5-pyridinedicarboxylic acid-3-(2-cyanoethyl ester)-5-(2-methoxyethyl ester) 36.8g, yield 85.7%, purity 99.09% .

Embodiment 3

[0034] In a round bottom flask, add 15.5 g (100 mmol) of cyanoethyl acetoacetate, 16.6 g (110 mmol) of m-nitrobenzaldehyde, 19.1 g (120 mmol) of methoxyethyl 3-amino-2-butenoate and 150ml of isopropanol was heated and refluxed for 6 hours, concentrated under reduced pressure, recrystallized from n-hexane-dichloromethane (15:1) to obtain racemic 1,4-dihydro-2,6-dimethyl-4-( 3-nitrophenyl)-3,5-pyridinedicarboxylic acid-3-(2-cyanoethyl ester)-5-(2-methoxyethyl ester) 35g, yield 81.6%, purity 99.41%.

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Abstract

The invention relates to the preparation field of a single configuration of a hypotensive drug (R)-cilnidipine, in particular to a preparation method of a hypotensive drug (R)-cilnidipine. The preparation method comprises the following steps: 1) adding ethyl cyano acetoacetate, m-nitrobenzaldehyde, 3-amino-2-methoxyethyl butenoate into isopropanol for a reflux reaction to obtain a racemized product; 2) adding the racemized product into an aqueous solution, adding lipase as a catalyst to stir for a catalytic reaction, and after reaction, acidifying and filtering a reaction liquid to obtain (R)-1,4-dihydrogen-2,6-dimethyl-4-(3-nitryl phenyl)-3,5-dipicolinic acid-5-(2-methoxyl ethyl); and 3) carrying out an esterification reaction with cinnamyl alcohol to obtain (R)-cilnidipine. The method provided by the invention obtains (R)-cilnidipine with high selectivity and high yield, and ee% reaches up to 99.7%.

Description

technical field [0001] The invention belongs to the field of chiral drug synthesis, and in particular relates to a preparation method of antihypertensive drug (R)-cilnidipine. Background technique [0002] Hypertension is the most common new cerebrovascular disease in the world. In recent years, surveys on the situation of hypertension in my country have shown that there are more than 100 million hypertensive patients in my country, and 3.5 million new hypertensive patients are added every year. Hypertension not only has a high prevalence rate, but also often causes heart, brain, and kidney complications. It is the main risk factor for stroke and coronary heart disease, and has become the primary factor causing human death. [0003] Cilnidipine was listed as an antihypertensive drug in 1996. It is a long-acting 1,4-dihydropyridine calcium channel antagonist (the specific chemical structure is as follows). The drug was developed by Fujirebio in Japan in the form of racemate ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
CPCC07B2200/07C07D211/90
Inventor 郑伟伟
Owner QINGDAO CHENDA BIOLOGICAL SCI & TECH
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