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Preparation method of clevidipine butyrate intermediate

A kind of technology of clevidipine butyrate and intermediate, applied in the direction of organic chemistry and the like, can solve the problems of long reaction steps, complicated operation, low yield and the like, and achieves the effects of mild reaction conditions, good hydrolysis selectivity and simple post-processing

Inactive Publication Date: 2012-03-28
SHANDONG INST OF PHARMA IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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) Using expensive methyl iodide, the production cost is high, and it is not suitable for industrialized production
This method has the following disadvantages: (1) the use of expensive butyllithium, tetrakis (triphenylphosphine) palladium price is higher, there is a certain danger, and it is not easy to preserve
(2) Silica gel column separation and purification are used, the reaction steps are long, the operation is cumbersome, the production cost is high, and it is not conducive to industrialized production

Method used

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  • Preparation method of clevidipine butyrate intermediate
  • Preparation method of clevidipine butyrate intermediate
  • Preparation method of clevidipine butyrate intermediate

Examples

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Embodiment 1

[0023] Methyl(1-cyanomethyl)methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (II) Preparation of 3-(2,3-dichlorophenyl)-2-acetylbenzoic acid methyl ester (27.3 g, 0.1 mol), 3-amino-2-butenoic acid (2-cyano) ethyl ester (15.4 g, 0.1mol) was dissolved in methanol (340ml), stirred and refluxed for 7 hours, added activated carbon (8g) for decolorization for 1 hour, hot filtered, crystallized, filtered to obtain off-white or light yellow solid II (37.4g, 88.3%) , 1 HNMR (CDCH 3 ): 8.75 (brs, 1H, -NH), 7.05-7.60 (m, 3H, Ar-H), 4.78 (s, 1H, C 4 -H), 4.52(t, 2H, -OCH 2 -), 3.77(s, 3H, -COOCH 3 ), 2.69(t, 2H, -CH 2 CN) 2.26(s, 6H, 2×-CH 3 ).

Embodiment 2

[0025] Methyl(1-cyanomethyl)methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (II) Preparation of 3-(2,3-dichlorophenyl)-2-acetylbenzoic acid methyl ester (27.3 g, 0.1 mol), 3-amino-2-butenoic acid (2-cyano) ethyl ester (15.4 g, 0.1mol) was dissolved in acetone (280ml), stirred and refluxed for 8 hours, added activated carbon (8g) for decolorization for 1 hour, heated, filtered, crystallized, and filtered to obtain off-white or light yellow solid II (29.1g, 68.6%)

Embodiment 3

[0027] Methyl(1-cyanomethyl)methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (II) Preparation of 3-(2,3-dichlorophenyl)-2-acetylbenzoic acid methyl ester (27.3 g, 0.1 mol), 3-amino-2-butenoic acid (2-cyano) ethyl ester (15.4 g, 0.1mol) was dissolved in dichloromethane (520ml), stirred and refluxed for 7.5 hours, added activated carbon (8g) for decolorization for 1 hour, filtered hot, crystallized, and filtered to obtain off-white or light yellow solid II (22.3g, 52.7 %)

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Abstract

The invention relates to a preparation method of a clevidipine butyrate intermediate, namely 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3 ,5- dipicolinic acid monomethyl ester (I). The preparation method is characterized by taking 3-(2,3-dichlorophenyl)-2-acetyl benzene gadoleic acid methyl ester and 3-amino-2-butenoic acid (2-cyano) ethyl ester as materials, cyclizing the materials to obtain 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl (2-cyano) ethyl ester (II), and hydrolyzing the II under alkaline conndition, thus obtaining the product 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3 ,5- dipicolinic acid monomethyl ester (I). The preparation method has the advantages as follows: the starting material is cheap and easy to obtain, the production cost is reduced, the reaction operation is simple, industrialization is easy, the purity of the obtained material is high and byproducts are few; the byproducts in the preparation method are fewer than that in the preparation of the clevidipine butyrate by butyl chloride methyl ester; the purity is high and the crude product can achieve 99.5%; and medicinal standard requirements can be met.

Description

technical field [0001] The invention relates to a preparation method of 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid monomethyl ester, which belongs to medicine field of chemical technology. Background technique [0002] Clevidipine butyrate (clevidipine butyrate) 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. It was developed by Medicines Company and was released in 2008. On August 1, it was approved by the US FDA for marketing, and the dosage form is injection emulsion. Its chemical name is 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl (1-butyryloxy) methyl Esters, whose structural formula is shown in (III), are different from many antihypertensive drugs that are metabolized by the kidney and (or) liver through intravenous injection at present. It has the characteristi...

Claims

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Application Information

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IPC IPC(8): C07D211/90
Inventor 段崇刚任业明张雯
Owner SHANDONG INST OF PHARMA IND
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