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Purification method of clevidipine butyrate intermediate

A purification method and carboxylic acid technology, applied in the direction of organic chemistry, etc., can solve the problem of no mention of the removal of by-products, and achieve the effects of easy operation, improving the overall yield and reducing the content of main impurities

Active Publication Date: 2013-05-08
BEIJING JIALIN PHARM INC
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Problems solved by technology

The document also pointed out that the impurity was caused by the by-product 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-3 produced during the synthesis of intermediate II, Produced by the reaction of 5-pyridine-dicarboxylic acid with chloromethyl n-butyrate, and the impurity was synthesized, but the removal of the by-product was not mentioned

Method used

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Embodiment 1

[0033] Example 1: Purification of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid (II)

[0034]In a three-necked flask, add the crude product of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid (according to the Literature Chinese journal of pharmaceuticals2011, 42 (7): 484-486 prepared by the same method, in which dicarboxylic acid impurity 5.4%.) 94g (0.264mol), 1050ml isopropanol, cooled with ice water, dropwise added 37.5g 40% (0.375 mol) sodium hydroxide solution, keep the temperature below 20°C, after the addition, stir overnight at room temperature, filter, dissolve the obtained solid in 3L water, decolorize with activated carbon, filter, neutralize the filtrate with hydrochloric acid to pH 5-6, filter, wash with water, and dry , to obtain 84.5 g light yellow solid, yield 90%. HPLC: (99.3%, dicarboxylic acid impurity 0.41%). 1 H NMR (DMSO-d6, ppm): δ=11.57 (s, 1H), 8.7...

Embodiment 2

[0035] Embodiment 2: the synthesis of clevidipine butyrate (Ⅰ)

[0036] In the three-necked flask, add 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid methyl-5-carboxylate purified in Example 1 Acid 35.6g (0.1mol), potassium bicarbonate 20g (0.2mol), DMF500ml, add 20.5g (0.15mol) of chloromethyl n-butyrate under stirring, then react at 60°C for 12 hours, cool to room temperature, add to 3L in water, with CH 2 Cl 2 (1L×3) extraction, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and refined with isopropanol to obtain 40.5 g of white solid with a yield of 89%.

[0037] m.p.: 136.5°C to 138.2°C. HPLC: 99.7%, the main impurity (ie the largest impurity) 0.18%, see figure 2 .

[0038] 1 H NMR (CDCl 3 , ppm): δ=7.01~7.27(m,3H), 6.29(s,1H), 5.73(d,1H),

[0039] 5.68(d,1H), 5.39(s,1H), 3.48(s,1H), 2.19~2.25(m,8H), 1.55(m,2H), 0.83(t,3H).

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Abstract

The invention discloses a purification method of 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-methyl carboxylate-5-carboxylic acid as an import intermediate for synthesizing clevidipine butyrate. The purification method comprises the following steps of: reacting the 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-methyl carboxylate-5-carboxylic acid with alkali to generate alkali metal salt; separating out the alkali metal salt from a solvent to achieve the impurity removal purpose; acidifying the alkali metal salt, and then reacting with n-butyric acid chloroformate to prepare the clevidipine butyrate. The purification method disclosed by the invention obtains high-purity high-yield monocarboxylic acid by effectively removing dicarboxylic acid impurities contained in the monocarboxylic acid intermediate through operation steps which are easy to operate and can obviously reduce the content of principal impurities contained in the clevidipine butyrate by adopting the prepared high-purity monocarboxylic acid intermediate, simplify the purification procedure of the clevidipine butyrate and increase the total yield.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and more specifically relates to a novel antihypertensive drug clevidipine butyrate (Clevidipine Butyrate)——4-(2,3-dichlorophenyl)-2,6-di Purification method of methyl-1,4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid. Background technique [0002] Hypertensive critical illness and perioperative hypertension are common diseases that are extremely harmful to patients. Treating them with intravenous antihypertensive drugs can quickly control blood pressure, thereby reducing the occurrence of various complications. Clevidipine butyrate is a new type of dihydropyridine calcium channel antagonist for intravenous injection, and it is also the first antihypertensive drug for intravenous injection approved by the US FDA in the past ten years. It has rapid onset, short action time, easy regulation, few side effects, and is metabolized in blood and tissues, so it is an ideal antih...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/90
Inventor 郭景军吴俊帽高传夫郭勇王士辉张晓峰田丽娜田凤鸣
Owner BEIJING JIALIN PHARM INC
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