Eureka AIR delivers breakthrough ideas for toughest innovation challenges, trusted by R&D personnel around the world.

Method for preparing prasugrel

A technology of Grignard reagent and fluorobenzyl, which is applied in the field of antiplatelet drugs, can solve the problems of large amount of acetic anhydride and low coupling reaction yield, and achieve the goal of improving yield and product quality, short steps, and increasing yield Effect

Inactive Publication Date: 2012-09-12
SHANGHAI AOBO PHARMTECH INC LTD
View PDF2 Cites 8 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The coupling reaction yield of this method is very low (32%), and will use the bigger solvent-carbon tetrachloride of toxicity when carrying out bromination; —Sodium hydride, which is unfavorable for unstable target products; and the amount of acetic anhydride is relatively large

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
  • Method for preparing prasugrel
  • Method for preparing prasugrel
  • Method for preparing prasugrel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add magnesium (9.6g, 0.4mol) and methyl tert-butyl ether (40mL) to a 1L three-necked flask, and at room temperature, dropwise add methyl Solution in tert-butyl ether (300 mL). After the dropwise addition, a solution of cyclopropanenitrile (26.8 g, 0.4 mol) in methyl tert-butyl ether (300 mL) was added dropwise to the reaction system. After the dropwise addition was completed, it was heated to reflux for 2 hours. Add saturated aqueous ammonium chloride solution (300mL) to the system, separate the organic layer, extract the aqueous layer with ethyl acetate (300mL), combine the organic layers, dry over anhydrous sodium sulfate, and distill under reduced pressure to obtain oily substance 3 (49.9g , 70%). 1 H NMR (CDCl 3 )δ: 0.88 ~ 0.93 (m, 2H, CH 2 ), 1.07~1.11 (m, 2H, CH 2 ), 2.00~2.04(m, 1H, CH), 3.90(s, 2H, CH 2 ), 7.07-7.29 (m, 4H, ArH).

Embodiment 2

[0032] Add 3 (131g, 0.74mol) and dichloromethane (500mL) into a 5L three-necked flask, add a solution of sulfonyl chloride (99.4g, 0.74mol) in dichloromethane (1000mL) dropwise at room temperature, and continue stirring for 1 hour after dropping . Add saturated aqueous sodium bicarbonate (1500mL), separate the organic layer, extract the aqueous layer with dichloromethane (1500mL), combine the organic layers, dry over anhydrous sodium sulfate, filter, and distill under reduced pressure to obtain oil 4 (125g, 82 %). 1 H NMR (CDCl 3 )δ: 0.94 ~ 1.20 (m, 4H, CH 2 CH 2 ), 2.09-2.13 (m, 1H, CH), 5.91 (s, 1H, CH), 7.12-7.48 (m, 4H, ArH).

Embodiment 3

[0034] 4 (106g, 0.5mol), 5,6,7,7α-tetrahydrothieno[3,2-c]pyridin-2(4H)-one p-toluenesulfonate (163g, 0.5 mol), potassium carbonate (138g, 1mol), sodium iodide (75g, 0.5mol), dimethyl sulfoxide (2500mL), heated at 60°C and stirred for 14 hours. Water was added and extracted with ethyl acetate (2 L). The organic layers were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from isopropyl ether (1 L) to obtain 5 (116 g, 70%) as a pale yellow solid. 1 H NMR (CDCl 3)δ: 0.70~1.08(m, 4H, CH 2 CH 2 ), 1.86~2.02(m, 1H, CH), 2.07~2.14(m, 1H, CH), 2.29~2.43, 2.52~2.58(m, 2H, CH 2 ), 2.85~2.88, 3.08~3.15 ​​(m, 2H, CH 2 ), 3.93~4.00, 4.10~4.14 (m, 2H, CH 2 ), 4.87, 4.90 (s, s, 1H), 6.06, 6.08 (s, s, 1H), 7.15-7.38 (m, 4H, ArH).

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 a method for preparing prasugrel (I). The method comprises the following steps: performing addition reaction of a Grignard reagent prepared from fluorobenzyl bromide and cyclopropanecarbonitrile to obtain cyclopropyl-2-fluorobenzyl ketone; performing chlorination to obtain a main intermediate, namely alpha-cyclopropyl carbonyl-2-fluorobenzyl chloride (II); performing condensation reaction of (II) and 2-oxo-2,4,5,6,7,7alpha-hexahydrothieno[3,2-c]pyridine 4-methylbenzenesulfonate to obtain an intermediate, namely 5-(alpha-cyclopropyl carbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7alpha-hexahydrothieno[3,2-c]pyridine (IV); and performing acetic anhydride esterification on the (IV) to obtain the prasugrel (I).

Description

technical field [0001] The present invention relates to antiplatelet drug prasugrel (2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2- c] Process for the preparation of pyridine) (I). Background technique [0002] Hydrogenated pyridine derivatives, such as ticlopidine and clopidogrel, have been widely used in the treatment of thrombosis and related disorders. Prasugrel (I) is a next-generation hydrogenated pyridine derivative, and studies have shown that it has a good inhibitory effect on platelet aggregation. Its acid addition salt (especially hydrochloric acid or maleate) has good oral absorption, metabolic activity and low toxicity, so it is a promising anticoagulant. [0003] [0004] U.S. Patent US5874581 reports a method for preparing prasugrel: through 2-silyloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine p-toluenesulfonate and cyclopropyl Coupling of -(α-chloro-2-fluorobenzyl)ketone affords 5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-...

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): C07D495/04
Inventor 竺伟陈宇
Owner SHANGHAI AOBO PHARMTECH INC LTD
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
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