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

Selective synthesis method of diltiazem chiral intermediate

A technology for chiral intermediates and diltiazem, which is applied in the field of selective synthesis of diltiazem chiral intermediates, can solve the problem of high cost and achieve the effects of improving yield, improving utilization rate and reducing cost

Active Publication Date: 2016-05-11
SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
View PDF5 Cites 5 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of these routes are more complicated, and the reaction requires the use of expensive reagents, and the cost is relatively high

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
  • Selective synthesis method of diltiazem chiral intermediate
  • Selective synthesis method of diltiazem chiral intermediate
  • Selective synthesis method of diltiazem chiral intermediate

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0036] The selective synthesis method of diltiazem chiral intermediate of the present invention, such as Figure 1 to Figure 5 As shown, anisaldehyde is used as the main raw material, firstly condensed with the intermediate product 1 formed by the reaction of chloroacetyl chloride and L-menthol, and after purification, it reacts with o-aminothiophenol and undergoes hydrolysis and cyclization steps to obtain the diltiazem chiral intermediate It includes the following steps:

[0037] Step 1. Add L-menthol, 0.01-0.1 equivalents (moles / L-menthol) of DMAP (N,N-dimethyl-4-aminopyridine) and the first solvent into the reactor, and stir After dissolution, add 1.0-2.0 equivalents (moles / L-menthol moles) of acid binding agent, then add 1.0-2.0 equivalents (moles / L-menthol moles) of chloroacetyl chloride dropwise, and stir after the addition After the reaction, the water layer is added after the reaction is completed, and the remaining organic layer after removing the water layer is dried a...

Embodiment 1

[0049] Add 62.5 g of L-menthol to a 1L reaction flask, add 0.5 g of N,N-dimethylaminopyridine (DMAP), 200 mL of dichloromethane, and stir to dissolve. Add 63.0g of sodium carbonate, add 56.5g of chloroacetyl chloride dropwise under controlled temperature 25℃~30℃, and keep the temperature at 25℃~30℃ and stir for 2h. After the reaction was completed, 400 mL of water was added, and the organic layer was stirred and separated by adding 10 g of anhydrous sodium sulfate to dry. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain intermediate product 1, which was directly used in the next reaction without purification.

Embodiment 2

[0051] Add 62.5 g of L-menthol to a 1L reaction flask, add 0.5 g of N,N-dimethylaminopyridine (DMAP), 200 mL of chloroform, and stir to dissolve. Add 63.0g of sodium bicarbonate, add 56.5g of chloroacetyl chloride dropwise under controlled temperature 25℃~30℃, and keep the temperature at 25℃~30℃ and stir for 2h. After the reaction was completed, 400 mL of water was added, and the organic layer was stirred and separated by adding 10 g of anhydrous sodium sulfate to dry. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain intermediate product 1, which was directly used in the next reaction without purification.

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

PropertyMeasurementUnit
boiling pointaaaaaaaaaa
boiling pointaaaaaaaaaa
optical purityaaaaaaaaaa
Login to View More

Abstract

The invention provides a selective synthesis method of diltiazem chiral intermediate. The method is as below: using anisic aldehyde, chloroacetyl chloride and L-menthol as raw materials; first subjecting chloroacetyl chloride and L-menthol to an esterification reaction to obtain an intermediate 1; then subjecting the intermediate 1 with anisic aldehyde to a Darzens condensation reaction to produce diastereomer intermediates 2 and 3; refining to obtain an optically pure intermediate 3; reacting the intermediate 3 with o-aminothiophenol to obtain an intermediate 4; hydrolyzing the intermediate 4 to obtain an intermediate 5; and cyclizing the intermediate 5 to obtain a product. The invention has the advantages that the ester formed by chloroacetyl chloride and L-menthol is selective in the Darzens condensation reaction with anisic aldehyde to generate the more target product, and solubility difference between the target product and the isomer is used to directly obtain optically pure intermediate, without a complicated resolution process, and the yield is greatly improved. The method substantially increases the utilization rate of the main raw material anisic aldehyde and reduces cost.

Description

technical field [0001] The invention relates to a selective synthesis method of a diltiazem chiral intermediate, which belongs to the technical field of chemical pharmacy. Background technique [0002] The chemical name of diltiazem is cis-(+)-5-[(2-dimethylamino)ethyl]-2-(4-methoxyphenyl)-3-acetoxy-2,3- Dihydro-1,5-benzothiazepine-4-(5H)-one hydrochloride is a selective calcium channel blocker. Diltiazem is a benzothiazepine-type calcium antagonist, originally developed by Tanabe Corporation of Japan, and first listed in Japan in the early 1970s, and then successively sold in the United States and Japan under the names of diltiazem, diltiazem, and Xierxin. , France, Spain and other countries listed. At present, the route of synthesizing diltiazem is mainly to first synthesize D-cis-2-(4-methoxyphenyl)-3-hydroxyl-2,3-dihydro-1,5-benzothiazepine-4(5H) -ketone, and then through N-alkylation, O-acetylation two-step reaction to obtain the product. The target product of the p...

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
Patent Type & Authority Applications(China)
IPC IPC(8): C07D281/10C07D303/48C07D301/02
CPCC07D281/10C07D301/02C07D303/48
Inventor 赵飞陈玮吴一尘曾淼徐剑锋
Owner SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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