Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method for ivabradine and intermediate thereof

An ivabradine and dehydrogenation technology, applied in chemical instruments and methods, organic compound/hydride/coordination complex catalysts, catalytic reactions, etc., can solve the problem of large amount of organic solvent, long reaction time and high process cost The problem is to improve the yield and purity, avoid the column chromatography process, and have a good industrialization prospect.

Active Publication Date: 2015-03-25
GUANGDONG ZHONGSHENG PHARMA
View PDF7 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This method is currently the mainstream route for preparing ivabradine, but it has the following disadvantages: the reaction time is longer and the reaction temperature is higher, wherein the nucleophilic substitution reaction time is more than 15.0h, and the reaction temperature is 90-100°C. Both the two-step reaction of substitution reaction to prepare dehydroivabradine and catalytic hydrogenation to prepare ivabradine require post-processing of column chromatography, the amount of organic solvent is large, and the yield is low (about 17.0%), and there are heavy metal residues, The problem of high process cost makes it difficult to realize industrial production
[0008] In recent years, with the development of science and technology, some new methods for preparing ivabradine have been proposed, but these methods have problems such as difficult access to raw materials or intermediates

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
  • Preparation method for ivabradine and intermediate thereof
  • Preparation method for ivabradine and intermediate thereof
  • Preparation method for ivabradine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 Research on Phase Transfer Catalysts

[0056] The inventors conducted research on commonly used phase transfer catalysts (as shown in Table 1). The end point of the nucleophilic substitution reaction is monitored by HPLC (high performance liquid chromatography), and the reaction is considered complete when the remaining amount of the compound shown in formula II (wherein the substituent X is Br) is less than 0.5%. The experimental results are shown in Table 1. It can be seen from Table 1 that when no phase transfer catalyst is used, the nucleophilic substitution reaction takes up to 15.5 hours; When the quaternary ammonium salt phase transfer catalyst is used as a single phase transfer catalyst, it has played a certain catalytic effect, and the reaction time is shortened to 9.5~13.0h, but the catalytic effect is still not ideal; use catalytic amount (2% of the compound quality shown in formula III %~10%) polyether phase transfer catalyst as a single phase t...

Embodiment 2

[0068] Example 2 Preparation of dehydroivabradine

[0069] In a 500mL three-neck reaction flask, dissolve 20.0g of the compound of formula III in 200mL of DMF, add 30.0g of anhydrous K 2 CO 3 , stirred for 30 minutes, then added 39.1g of formula II compound (wherein substituent X is Br), 0.8g composite phase transfer catalyst (mixed by benzalkonium bromide and polyethylene glycol-800 in a mass ratio of 5:1 ), the temperature of the reaction system was raised to 85° C., and the end point of the reaction was monitored by HPLC, and the reaction was complete after 3.0 h. After the reaction is completed, cool, collect the filtrate by filtration, add the filtrate to 500mL saturated sodium chloride solution, extract twice with 250mL and 200ml ethyl acetate respectively, combine the organic phases, add 20g of anhydrous NaCl 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure at 50° C. to obtain 37.9 g of dehydroivabradine oily substance with a ...

Embodiment 3

[0073] Example 3 Preparation of dehydroivabradine

[0074] In a 500mL three-necked reaction flask, 20.0g of the compound of formula III was dissolved in 200mL of DMF, and 23.0g of anhydrous Na 2 CO 3, stirred for 30 minutes, then added 27g of formula II compound (wherein substituent X is C1), 0.6g composite phase transfer catalyst (mixed by benzalkonium bromide and polyethylene glycol-200 at a mass ratio of 7: 1) , the temperature of the reaction system was raised to 80° C., and the end point of the reaction was monitored by HPLC, and the reaction was complete after 4.5 hours of reaction. After the reaction is complete, cool, collect the filtrate by filtration, add the filtrate to 500mL saturated sodium chloride solution, extract twice with 250mL and 200ml ethyl acetate respectively, combine the organic phases, add 20g of anhydrous NaCl 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure at 50° C. to obtain 37.7 g of dehydroivabradine o...

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 provides a preparation method for ivabradine and an intermediate thereof dehydrogenated ivabradine. The preparation method of the dehydrogenated ivabradine comprises: step a1, enabling a compound shown as a formula II and a compound shown as a formula III to have a nucleophilic substitution reaction in a polar aprotic solvent in the presence of an acid binding agent and a composite phase-transfer catalyst to generate dehydrogenated ivabradine; and step b1, performing separation and purification on dehydrogenated ivabradine obtained in the step a1. The composite phase-transfer catalyst is composed of a quaternary ammonium salt phase-transfer catalyst and a polyether phase-transfer catalyst with the mass ratio of 1-10:1, and X in the formula II is selected from Cl, Br, I, sulfonyloxy, methane sulfonyloxy, benzene sulfonyloxy, p-methylbenzene sulfonyloxy, o-methylbenzene sulfonyloxy or m-methylbenzene sulfonyloxy. The method is capable of substantially shortening the time of nucleophilic substitution reaction, improving product purity, avoiding a column chromatography process and reducing production cost.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of ivabradine and its intermediate dehydroivabradine. Background technique [0002] Ivabradine and its addition salts with pharmaceutically acceptable acids have very high pharmacological and therapeutic value and can be widely used in the treatment or prevention of various clinical conditions of myocardial ischemia, such as angina pectoris, myocardial infarction and concomitant It can also be used for the treatment of heart failure, and it is a new generation of cardiovascular drugs with very broad treatment prospects. [0003] Ivabradine hydrochloride, chemical name: 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutan-1-yl)methyl ]-methylamino]propyl)-1,3,4,5-tetrahydro-2H-benzazepin-2-one hydrochloride, the structure of which is shown below: [0004] [0005] The preparation and therapeutic use of ivabradine hydrochloride 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): C07D223/16B01J31/06
CPCC07D223/16B01J31/0239B01J31/068B01J2231/4283B01J35/19
Inventor 谭珍友龙超峰邓军谢称石黄爱君
Owner GUANGDONG ZHONGSHENG PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com