Unlock instant, AI-driven research and patent intelligence for your innovation.
Purification method of clevidipine butyrate intermediate
What is Al technical title?
Al technical title is built by PatSnap Al team. It summarizes the technical point description of the patent document.
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
View PDF7 Cites 6 Cited by
Summary
Abstract
Description
Claims
Application Information
AI Technical Summary
This helps you quickly interpret patents by identifying the three key elements:
Problems solved by technology
Method used
Benefits of technology
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
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more
Image
Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
Click on the blue label to locate the original text in one second.
Reading with bidirectional positioning of images and text.
Smart Image
Examples
Experimental program
Comparison scheme
Effect test
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) sodiumhydroxide 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), potassiumbicarbonate 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 anhydroussodiumsulfate, 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 .
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More
PUM
Login to View More
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 clevidipinebutyrate. 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 acidchloroformate to prepare the clevidipinebutyrate. 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 clevidipinebutyrate 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 (ClevidipineButyrate)——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
the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More
Application Information
Patent Timeline
Application Date:The date an application was filed.
Publication Date:The date a patent or application was officially published.
First Publication Date:The earliest publication date of a patent with the same application number.
Issue Date:Publication date of the patent grant document.
PCT Entry Date:The Entry date of PCT National Phase.
Estimated Expiry Date:The statutory expiry date of a patent right according to the Patent Law, and it is the longest term of protection that the patent right can achieve without the termination of the patent right due to other reasons(Term extension factor has been taken into account ).
Invalid Date:Actual expiry date is based on effective date or publication date of legal transaction data of invalid patent.
Login to View More 
Login to View More