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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
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  • 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

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  • 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).

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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

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
Inventor 竺伟陈宇
Owner SHANGHAI AOBO PHARMTECH INC LTD
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