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Preparation method of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxy-carbonyl-3-pyridinecarboxylic acid

A technology of methoxycarbonyl and dichlorophenyl, applied in 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, 4-dihydro-5-methoxycarbonyl - The field of preparation of 3-pyridinecarboxylic acid can solve the problems affecting the purity of the final product clevidipine butyrate, affecting the purity of intermediates, and the dicarboxylic acid dihydrolysis product is difficult to remove. mild effect

Inactive Publication Date: 2012-12-19
上海复奇医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Route three requires selective hydrolysis of dimethyl ester, which is difficult to realize in actual production, so the dicarboxylic acid formed as a dihydrolysis product is difficult to remove, which seriously affects the purity of the intermediate, thereby affecting the purity of the final product clevidipine butyrate

Method used

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  • Preparation method of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxy-carbonyl-3-pyridinecarboxylic acid
  • Preparation method of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxy-carbonyl-3-pyridinecarboxylic acid
  • Preparation method of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxy-carbonyl-3-pyridinecarboxylic acid

Examples

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Embodiment 1

[0032] Example 1: 4-(2,3-Dichlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid tert-butyl, methyl ester (II)

[0033] Ethylene-β-propyl acetate (50g, 0.6mol) was dissolved in tert-butanol (250ml), DMAP (0.8g, 0.006mol) was added and stirred at room temperature for half an hour, and then 2,3-dichlorobenzaldehyde (105g, 0.6 mol) and methyl 3-amino-2-butenoate (69g, 0.6mol), stirred and heated to 90℃ to react for 15 hours, cooled, and removed the solvent under reduced pressure. The residue was diluted with ethyl acetate and passed through diatom Filter with soil, wash with water, wash with saturated brine, separate the organic phase, and concentrate to obtain the crude product (II) directly used in the next step without purification.

Embodiment 2

[0034] Example 2: 4-(2,3-Dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxycarbonyl-3-pyridinecarboxylic acid (I)

[0035] The crude product (II) obtained from the above reaction was dissolved in dichloromethane (1500ml), trifluoroacetic acid (145ml) was added with stirring in an ice bath, stirred at room temperature for 3 hours, concentrated under reduced pressure to dryness, and dichloromethane ( 1000ml), distilled water (800ml), carefully add sodium bicarbonate (60g) under ice bath, stir for 15 minutes, separate and remove the organic phase, wash the aqueous solution with tert-butyl methyl ether, slowly add 1N hydrochloric acid dropwise with vigorous stirring to the pH of the solution 2 , Continue to stir for half an hour, and filter with suction to obtain a yellow solid product (I) (212 g, total yield 75%), with a melting point of 178-180°C.

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Abstract

The invention provides a novel preparation method of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxy-carbonyl-3-pyridinecarboxylic acid (I). According to the method, vinyl acetate-beta propyl ester and tert-butyl alcohol are adopted as raw materials and are subjected to a reaction; after the reaction, no treatment is carried out, and 2,3-dichlorobenzene formaldehyde and 3-amino-2-methyl crotonate are added; a condensation and cyclization reaction is carried out with a one-pot reaction method, such that 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-pyridine tert-butyl methyl dicarboxylic ester (II) is produced. Under an acidic condition, tert-butyl group of II is selectively removed, such that the product 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxy-carbonyl-3-pyridinecarboxylic acid (I) is obtained. The method has the advantage that the product 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxy-carbonyl-3-pyridinecarboxylic acid (I) can be produced with high yield and high purity. The raw materials are easy to obtain. Reaction post-treatment and product purification are simple.

Description

Technical field [0001] The invention relates to a key intermediate of clevidipine butyrate 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxycarbonyl-3- Preparation method of pyridine carboxylic acid. Background technique [0002] Clevidipine butyrate is a fourth-generation dihydropyridine calcium channel blocker, which can selectively inhibit the influx of calcium ions outside the arterial smooth muscle cells, thereby relaxing blood vessels and lowering blood pressure. Developed by the British company Astra Zeneca, it was first listed in the United States in 2008 under the trade name Cleviprex. Its chemical name is 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-3,5-dipyridinecarboxylic acid methyl (butyryloxymethyl) The chemical structure of the ester is shown below. [0003] [0004] The synthesis process of clevidipine butyrate mainly includes patents and literature reports such as WO2000 / 31035, WO1995 / 13066, WO1995 / 12578, CN101759631A, CN101602710A and Chinese Journa...

Claims

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Application Information

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IPC IPC(8): C07D211/90
Inventor 张锐豪常英陆峰
Owner 上海复奇医药科技有限公司
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