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Method for preparing key intermediate of dihydropyridines calcium channel antagonist and for synthesizing clevidipine butyrate

A kind of technology of clevidipine butyrate and methyl butyrate, applied in the direction of organic chemistry and the like, can solve problems such as unfavorable industrial production, increase the difficulty of synthesis process and operation steps, increase the operation route of synthesizing "dipine" compounds, etc. Avoid acidic chemical raw materials, reduce post-processing operations, and facilitate separation and purification.

Inactive Publication Date: 2012-09-19
CHENGDU AIQUN TECH
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Problems solved by technology

The disadvantage of this type of method is that Hantzsch reaction substrates with different substituent groups need to be prepared in advance, which undoubtedly increases the operational process route for the synthesis of "dipine" compounds, which is not conducive to the implementation of industrial production
[0017] (1) carry out the reaction substrate of Hantzsch reaction need to prepare in advance, do not have ready-made commercialized product, increase the difficulty and operation steps of synthetic technique like this

Method used

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  • Method for preparing key intermediate of dihydropyridines calcium channel antagonist and for synthesizing clevidipine butyrate
  • Method for preparing key intermediate of dihydropyridines calcium channel antagonist and for synthesizing clevidipine butyrate
  • Method for preparing key intermediate of dihydropyridines calcium channel antagonist and for synthesizing clevidipine butyrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Preparation of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxycarbonyl-3-pyridinecarboxylic acid:

[0037] In a 20L reactor, add 2,3-dichlorobenzaldehyde (1.75kg, 10mol), tert-butyl acetoacetate (1.74kg, 11mol) and 3-amino-2-butenoic acid methyl ester (1.15kg, 10mol) , ethanol as the reaction solvent, reacted at 70°C for 18 hours, concentrated under reduced pressure to remove the reaction solvent, and obtained the crude product of Hantsch cyclization. The crude product was recrystallized from 95% ethanol to give 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxycarbonyl-3-pyridine as a light yellow solid Pure tert-butyl carboxylate (3.2kg, yield 78%). 1 H NMR (600MHz, CDCl 3 ): δ7.29~7.24(m, 2H), 7.08~7.05(m, 1H), 5.56(s, 1H), 5.41(s, 1H), 3.60(s, 3H), 2.27(s, 3H), 2.24(s, 3H), 1.37(s, 9H); 13 C NMR (150MHz, CDCl 3 ): δ168.0, 166.9, 147.3, 144.3, 142.2, 132.9, 131.0, 130.1, 128.2, 126.7, 105.2, 102.5, 80.3, 50.8, 39.6, 28.3, 19.5, 19.4. ...

Embodiment 2

[0039] Example 2: Preparation of 4-(2-nitrophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxycarbonyl-3-pyridinecarboxylic acid:

[0040] In 20L reactor, add 2-nitrobenzaldehyde (1.51kg, 10mol), tert-butyl acetoacetate (1.74kg, 11mol) and 3-amino-2-butenoic acid methyl ester (1.15kg, 10mol), ethanol As a reaction solvent, react at 70° C. for 24 hours, and concentrate under reduced pressure to remove the reaction solvent to obtain a crude product of Hantsch cyclization. The crude product was recrystallized from 95% ethanol to give 4-(2-nitrophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxycarbonyl-3-pyridinecarboxylic acid as a pale yellow solid Pure tert-butyl ester (3.182kg, yield 82%).

[0041] The above product (3.182kg) was dissolved in tetrahydrofuran, and trifluoroacetic acid (600ml, 8.2mol) was added dropwise at 0°C, slowly raised to room temperature and reacted for 2 hours, then a large amount of ice water was added, and a large amount of solid precipitated out. The crude product o...

Embodiment 3

[0042] Example 3: Preparation of 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxycarbonyl-3-pyridinecarboxylic acid:

[0043] In 20L reactor, add 3-nitrobenzaldehyde (1.51kg, 10mol), tert-butyl acetoacetate (1.74kg, 11mol) and 3-amino-2-butenoic acid methyl ester (1.15kg, 10mol), ethanol As a reaction solvent, react at 70° C. for 24 hours, and concentrate under reduced pressure to remove the reaction solvent to obtain a crude product of Hantsch cyclization. The crude product was recrystallized from 95% ethanol to give 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydro-5-methoxycarbonyl-3-pyridinecarboxylic acid as a pale yellow solid Pure tert-butyl ester (2.9kg, yield 75%).

[0044] The above product (2.9kg) was dissolved in tetrahydrofuran, and concentrated sulfuric acid (400ml, 7.5mol) was added dropwise at 0°C, slowly raised to room temperature and reacted for 2 hours, then a large amount of ice water was added, and a large amount of solid precipitated out, filtered The crud...

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Abstract

The invention relates to a method for preparing 4-aryl-2, 6-dimethyl-1, 4-dihydro-5-methoxy carbonyl-3-pyridine carboxylic acid (I) which is the key intermediate of the dihydropyridines calcium channel antagonist. Chemical raw materials (3-amino-2-methyl butyrate, tert-butyl acetoacetate and substituted benzaldehyde) which are low in cost, easy to obtain and commercially available are subjected to Hantzsch reaction to synthesize 4-aryl-2,6-dimethyl-1,4-dihydro-5-methoxy carbonyl-3-pyridine carboxylic acid tert-butyl ester (II), the formula II removes the protection of tert-butyl groups selectively, then the filteration is performed directly, and the product 4-aryl-2,6-dimethyl-1,4-dihydro-5-methoxy carbonyl-3-pyridine carboxylic acid (I) is obtained. The invention also discloses the method for preparing the clevidipine butyrate. The method for preparing the formula (I) and the clevidipine butyrate has the advantages that raw materials have low cost and are easy to obtain, reaction conditions are mild, operation is easy and controllable, products are easy to purify and the method is suitable for industrial production.

Description

Technical field: [0001] The invention relates to a method for synthesizing and preparing a key intermediate of a dihydropyridine calcium channel antagonist, and a process route for synthesizing clevidipine butyrate using the method. Background technique: [0002] The study of dihydropyridine calcium channel antagonists - "dipine" drugs began in the 1960s and developed into a new class of drugs in the 1970s. It was originally used for cardiovascular diseases, but now, its treatment scope has been expanded to include cerebrovascular diseases, peripheral vascular diseases, hypertension, migraine, allergic diseases, endocrine and nervous system diseases and so on. E.g: [0003] [0004] The synthesis of such drugs is mainly based on the principle of Hantzsch reaction, and different dihydropyridine compounds are obtained by using different Hantzsch reaction substrates. The disadvantage of this type of method is that Hantzsch reaction substrates with different substituent gro...

Claims

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Application Information

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IPC IPC(8): C07D211/90
Inventor 张明
Owner CHENGDU AIQUN TECH
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