New preparation method of key intermediate of clevidipine butyrate

A technology of dichlorophenyl and pyridine carboxylic acid, applied in directions such as organic chemistry, can solve the problems of long reaction steps, high price, complicated operation, etc., and achieve the effects of mild reaction conditions, short reaction steps and simple post-processing

Inactive Publication Date: 2009-12-16
CHINA PHARM UNIV
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Problems solved by technology

The method has the following disadvantages: (1) the preparation of raw material acetoacetate (2-methylthio)ethyl needs to use stench and poisonous 2-methylthioethanol, and the yield is low, not easy to obtain
(2) Use expensive methyl iodide
(3) The reaction steps are long and the operation is cumbersome

Method used

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  • New preparation method of key intermediate of clevidipine butyrate
  • New preparation method of key intermediate of clevidipine butyrate
  • New preparation method of key intermediate of clevidipine butyrate

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Embodiment

[0019] Methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (II)

[0020] 2,3-Dichlorobenzaldehyde (10.0g, 57mmol), methyl acetoacetate (13.3g, 114mmol) and 25% ammonia water (15.5g, 228mmol) were added to methanol (15ml), stirred, refluxed for 10h, and the reaction solution Cool to room temperature, filter with suction, and recrystallize the filter cake with 95% ethanol to obtain pale yellow crystal II (17.5 g, 82.7%) (document: 30.4%), mp 186-188°C. 1 HNMR (CDCl 3 ): 7.29-7.06 (m, 3H, Ar-H), 5.68 (brs, 1H, -NH), 5.47 (s, 1H, C 4 -H), 3.60(s, 6H, 2×-COOCH 3 ), 2.31(s, 6H, 2×-CH 3 ).

[0021] 4-(2,3-Dichlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-3-pyridinecarboxylic acid (I)

[0022] II (12.0g, 32mmol) was dissolved in methanol (173ml), added 40% NaOH solution (35.2ml), stirred, refluxed for 15h, the reaction solution was concentrated under reduced pressure to remove methanol, cooled to room temperature, added water (350ml), pumped ...

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Abstract

The invention relates to a preparation method of 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydro-5-methoxylcarbonyl-3-pyridinecarboxylic acid (I). The method is characterized in that methyl acetoacetate, stronger ammonia water and 2, 3-dichlorobenzaldehyde are used as raw materials for direct cyclic condensation to obtain 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylic acid methyl ester (II); part of the compound II is hydrolyzed under alkaline condition to obtain the product 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydro-5-methoxylcarbonyl-3-pyridinecarboxylic acid (I). The method has the advantages that the starting materials are cheap and easy to obtain, the production cost is lowered, the reaction is easy to operate and industrialization is easy to realize.

Description

technical field [0001] The invention relates to a preparation method of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxycarbonyl-3-pyridinecarboxylic acid. Background technique [0002] Clevidipine butyrate (clevidipine butyrate), the chemical name is 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid methyl Butyl (butyryloxymethyl) ester, with the following structural formula, is a new type of dihydropyridine calcium channel blocker for intravenous injection, which selectively inhibits the influx of calcium ions outside the arterial smooth muscle cells. Developed by the Medicines Company, it was approved for marketing by the US FDA on August 1, 2008. Different from many current intravenous antihypertensive drugs that are metabolized by the kidney and (or) the liver, this product has a fast onset of action, fast elimination, no accumulation in the body, and less toxic and side effects. It is mainly used to treat severe hypertension that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
Inventor 陈国华曹秀芝张明亮
Owner CHINA PHARM UNIV
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