Improved method for synthesis process of manidipine hydrochloride

A manidipine hydrochloride and synthetic process technology, applied in the direction of organic chemistry, can solve the problems of low product purity, complexity and unsuitability for industrial production, and achieve the effects of reducing costs, shortening production cycle, and simple operation

Active Publication Date: 2013-01-16
CHANGZHOU PHARMA FACTORY
View PDF8 Cites 15 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to solve the disadvantages of complex post-treatment not suitable for industrialized production and low product purity in the existing synthesis process, the invention provides an improved method for the synthesis process of manidipine hydrochloride, which optimizes the post-treatment process and improves the purity

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
  • Improved method for synthesis process of manidipine hydrochloride
  • Improved method for synthesis process of manidipine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Step 1: Add 1.22kg (4.12mol) 1-benzhydryl-4-(2-hydroxyethyl)piperazine (IV) into the reaction flask, heat to 70-75°C, add dropwise 0.43kg ( 5.12mol) of diketene, after dropping, keep stirring at 70-80°C for 2h. After the reaction was completed, 6L of ethyl acetate was added for dissolution, and the organic phase was washed with water for 3 times, dried, and concentrated to obtain oily substance 2-(4-benzhydryl-1-piperazinyl) ethyl acetoacetate (III) 1.50 kg (yield: 95.8%).

[0020] Step 2: 1.50kg (3.94mol) of the above-mentioned oil (III) and 0.45kg (3.91mol) of methyl 3-aminocrotonate, 0.59kg (3.90mo) of m-nitrobenzaldehyde, and 4.95kg of isopropanol are dissolved in In a 10L reaction flask, heat and reflux for 7 hours, distill out isopropanol, add 15L ethyl acetate to the residue to dissolve, wash with water, separate liquid, concentrate, add 3L methanol to dissolve, adjust the pH value of the system to between 1-2 with concentrated hydrochloric acid 15L ethyl aceta...

Embodiment 2

[0023] Step 1: Add 1.22kg (4.12mol) 1-benzhydryl-4-(2-hydroxyethyl)piperazine (IV) into the reaction flask, heat to 70-75°C, add dropwise 0.43kg ( 5.12mol) of diketene, after dropping, keep stirring at 70-80°C for 2h. After the reaction was completed, 8 L of methyl acetate was added for dissolution, and the organic phase was washed with water three times, dried, and concentrated to obtain 1.47 kg of oil (III) (yield: 93.9%).

[0024] Step 2: Dissolve 1.1.47kg (3.86mol) of the above-mentioned oil (III) and 0.44kg (3.82mol) of methyl 3-aminocrotonate, 0.58kg (3.84mo) of m-nitrobenzaldehyde, and 4.95kg of isopropanol In a 10L reaction flask, heat and reflux for 7 hours, distill out isopropanol, add 17L methyl acetate to the residue to dissolve, wash with water, separate liquid, concentrate, add 3L methanol to dissolve, adjust the pH value of the system to 1-2 with concentrated hydrochloric acid 17L methyl acetate to dissolve the filter cake, adjust the pH value of the system wit...

Embodiment 3

[0027] Step 1: Add 1.22kg (4.12mol) 1-benzhydryl-4-(2-hydroxyethyl)piperazine (IV) into the reaction flask, heat to 70-75°C, add dropwise 0.43kg ( 5.12mol) of diketene, after dropping, keep stirring at 70-80°C for 2h. After the reaction was completed, 6L of ethyl acetate was added for dissolution, and the organic phase was washed with water for 3 times, dried, and concentrated to obtain oily substance 2-(4-benzhydryl-1-piperazinyl) ethyl acetoacetate (III) 1.52 kg (yield: 97.1%).

[0028] Step 2: 1.50kg (3.94mol) of the above-mentioned oil (III) and 0.45kg (3.91mol) of methyl 3-aminocrotonate, 0.59kg (3.90mo) of m-nitrobenzaldehyde, and 4.95kg of isopropanol are dissolved in In a 10L reaction flask, heat and reflux for 7 hours, distill out isopropanol, add 15L ethyl acetate to the residue to dissolve, wash with water, separate liquid, concentrate, add 3L methanol to dissolve, adjust the pH value of the system to between 1-2 with concentrated hydrochloric acid 15L ethyl aceta...

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

No PUM Login to view more

Abstract

The invention discloses an improved method for a synthesis process of manidipine hydrochloride. The method comprises the following steps: 1-benzhydryl-4-(2-hydroxyethyl)piperazine is taken as a raw material to be acylated with diketene, cyclized with m-nitrobenzaldehyde and methyl 3-aminocrotonate and finally acidized by hydrochloric acid to obtain the manidipine hydrochloride. Due to the optimization of an aftertreatment method, high-vacuum rectification, column chromatography and other purification operation are removed; the maximum single impurity of the product is controlled within 0.1%, and the method has the advantages of simplicity in operation, suitability for industrial production, high product purity and the like.

Description

Technical field: [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to an improved method for manidipine hydrochloride synthesis process. Background technique: [0002] Manidipine Hydrochloride, molecular formula C 35 h 38 N 4 o 6 2HCl, molecular weight: 683.62, CA registration number 89226-75-5, chemical name 1,4-dihydro-2,6-dimethyl-4-(3 nitrophenyl)-3,5-pyridine Dicarboxylic acid 2-[4-(benzhydryl)-1-piperazinyl]ethyl methyl ester dihydrochloride is a calcium antagonist developed by Takeda Pharmaceutical Co., Ltd. in 1990 under the trade name Calslot is listed in Japan and is mainly used to treat mild to moderate essential hypertension. It has a more obvious antihypertensive effect on low renin hypertension and can improve uric acid metabolism. It has a strong effect of relaxing arterial smooth muscle, dilating blood vessels, reducing peripheral vascular resistance and arterial pressure. Its chemical structural formula is...

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
no application Login to view more
IPC IPC(8): C07D211/90
Inventor 金晓峰周付潮殷学治王兵
Owner CHANGZHOU PHARMA FACTORY
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap