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Method for preparing clevidipine butyrate

A technology of clevidipine butyrate and dichlorophenyl, which is applied in the field of preparation of antihypertensive drugs, can solve the problems of inability to refine and insoluble, and achieve the effect of avoiding the use of column chromatography

Active Publication Date: 2012-05-23
GUANGDONG JIABO PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the large difference in properties between dimethyl carboxylate and monocarboxylic acid, it is relatively easy to remove, and compound V cannot be removed by conventional recrystallization because it is very close to compound II in properties and is insoluble or extremely difficult to dissolve in water or organic solvents. refined

Method used

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  • Method for preparing clevidipine butyrate
  • Method for preparing clevidipine butyrate
  • Method for preparing clevidipine butyrate

Examples

Experimental program
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Effect test

Embodiment 2

[0019] Preparation and purification of 1,4-dihydro-2,6-4-(2',3'-dichlorophenyl)-5-carboxymethyl-3-pyridine carboxylic acid sodium

[0020] 2.1. Add 10g of 1,4-dihydro-2,6-4-(2',3'-dichlorophenyl)-5-carboxymethyl-3-pyridinecarboxylic acid prepared in Example 1 into a 200ml beaker , 1.3g of sodium hydroxide and 40ml of water mixture, stirred at room temperature to dissolve, filtered, the filtrate was frozen and recrystallized at 0-5°C, filtered and dried to obtain a light yellow solid 1,4-dihydro-2,6-4-(2 ', 3'-dichlorophenyl)-5-carboxymethyl-3-pyridine carboxylic acid sodium 8.76g, the yield was 82.5%, and the purity was 99.5% by HPLC detection with automatic sample injector high performance liquid chromatography.

[0021] 2.2. Add 10g of 1,4-dihydro-2,6-4-(2',3'-dichlorophenyl)-5-carboxymethyl-3-pyridinecarboxylic acid prepared in Example 1 into a 200ml beaker , 1.3g of sodium hydroxide and 50ml of ethanol mixed solution, stirred at room temperature to dissolve, filtered, the...

Embodiment 3

[0024] Methyl(1-oxobutoxy)methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate [Clevidipine Butyrate] Preparation

[0025] Add 7.56g, 4-dihydro-2,6-4-(2',3'-dichlorophenyl)-5-carboxymethyl-3-pyridine carboxylic acid sodium (purity 99.5%) in 1L round bottom flask, Slowly add 2.5ml of chloromethyl n-butyrate to 25ml of DMF, and keep the temperature at 20-25°C, stir at room temperature for 6h after adding, cool in an ice bath, add 40ml of ethyl acetate and 50ml of 5% sodium carbonate solution and stir for 30 minutes, The organic layer was separated, washed with water until neutral, dried and filtered by adding anhydrous sodium sulfate, and spin-dried to obtain a yellow solid, which was recrystallized with isopropanol, filtered, and dried to obtain 8.2 g of bright yellow solid crystals, with a yield of 90%. Autosampler high performance liquid chromatography HPLC detection, purity 99.9%.

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Abstract

The invention discloses a method for preparing clevidipine butyrate, comprising the following steps of: A, firstly forming salt by using 1,4-dihydro-2,6-4-(2',3'-dichlorophenyl)-5-carboxymethyl-3-pyridine carboxylic acid and alkaline metals or alkaline-earth metal ions, and recrystallizing through water or an organtic solvent to obtain 1,4-dihydro-2,6-4-(2',3'-dichlorophenyl)-5-carboxymethyl-3-pyridine formate; and B, reacting the 1,4-dihydro-2,6-4-(2',3'-dichlorophenyl)-5-carboxymethyl-3-pyridine formate obtained in the step A with chloroformate n-butyrate in a DMF (N,N-dimethylformamide) solution or an acetonitrile solvent to obtain the clevidipine butyrate. The clevidipine butyrate prepared by the method has high purity; in addition, the method prevents complex column chromatography from being used and is suitable for large-scale isndustrialized production.

Description

technical field [0001] The invention relates to a preparation method of antihypertensive medicine, in particular to a preparation method of high-purity clevidipine butyrate. Background technique [0002] Clevidipine butyrate, the chemical name is 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate Base (1-oxobutoxy) methyl ester, clevidipine butyrate is a dihydropyridine derivative, which is an ultra-short-acting calcium channel blocker for intravenous injection, which is developed by British AstraZeneca Company as a perioperative Drugs for short-term control of hypertension in the early stage are developed. Clevidipine has a high degree of vascular and myocardial selectivity, and is rapidly metabolized into inactive substances in the body. Clevidipine has a strong pulse rate-lowering activity and also has a dilating effect on systemic blood vessels and pulmonary blood vessels. In 2002, Medicines licensed the product from AstraZeneca. This product w...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90
Inventor 刘红旗林志广童伟国蔡文坚曾少群
Owner GUANGDONG JIABO PHARM CO LTD