Industrial production method for prasugrel

A technology based on compounds and alkaline conditions, which is applied in the field of preparation of antithrombotic drug prasugrel, can solve problems such as high labor protection requirements, toxicity, and large equipment corrosion, and achieve low labor protection requirements, high yield, and simple operation Effect

Active Publication Date: 2009-04-08
SHANGHAI SHYNDEC PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The raw material liquid bromine and carbon tetrachloride that prepare compound A are used all have very big toxicity, and environmental pollution is very big, and labor protection requirement is high; The strongly acidic by-produ...

Method used

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  • Industrial production method for prasugrel
  • Industrial production method for prasugrel
  • Industrial production method for prasugrel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Preparation of 1-cyclopropyl-2-(2-fluorophenyl) vinyl acetate (compound of formula 3)

[0038] Add 17.8g (0.1mol) of cyclopropyl-2-fluorobenzyl ketone, 120g (1.2mol) of isopropenyl acetate, and 5.7g (0.03mol) of toluene-4-sulfonic acid into the reaction flask, and heat to reflux for reaction. Acetone was continuously distilled off, the reaction was complete, cooled to room temperature, the reaction solution was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, and rotary evaporated to obtain 20.9 g of reddish-brown oil, yield: 95.0%.

[0039] 1 HNMR (CDCl 3 )δ: 7.00-7.59 (m, 4H), 6.28 (s, 1H), 2.05-2.23 (m, 3H), 1.90-94 (m, 1H), 0.73-0.79 (m, 2H), 0.62-0.72 ( m, 2H). MS-ESI (m / z): 243.0 (M+Na).

Embodiment 2

[0041] Preparation of 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyethanone (compound of formula 4)

[0042] Dissolve 15g (0.068mol) of 1-cyclopropyl-2-(2-fluorophenyl) vinyl acetate in 10mL of dichloromethane, and after cooling to -10°C, add 16.6g (0.082mol) of m-chloro Peroxybenzoic acid, stirred and reacted for 5h, the reaction was complete, extracted with ethyl acetate (80mL*3), the organic phase was washed with saturated brine (50mL*4), anhydrous NaSO 4 After drying and rotary evaporation, 9.8 g of oily substance was obtained, which can be directly used for the next reaction. Yield 75%.

[0043] 1 HNMR (CDCl 3 )δ: 7.10-7.35 (m, 4H), 5.60 (s, 1H), 4.33 (s, 1H), 1.89-1.94 (m, 1H), 0.73-0.79 (m, 2H), 0.62-0.72 (m, 2H). MS-ESI (m / z): 217.0 (M+Na).

Embodiment 3

[0045] Preparation of 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyethanone (compound of formula 4)

[0046] Dissolve 5g (0.023mol) of 1-cyclopropyl-2-(2-fluorophenyl) vinyl acetate in 10mL of acetonitrile, add 200mg [((phen) 2 (H 2 O)Fe III ) 2 (μ-O)](ClO 4 ) 4 Catalyst, after cooling to -18°C, add 25mL peroxyacetic acid, stir for 5min; after the reaction is complete, extract with ethyl acetate (10mL*3), wash the organic phase with saturated brine (20mL*4), anhydrous NaSO 4 After drying, the oily substance obtained by rotary evaporation can be directly used for the next reaction. The 3.2g oily substance obtained by rotary evaporation can be directly used for the next reaction. Yield 72%.

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Abstract

The invention relates to the technical field of a preparation method of an antithrombotic drug Prasugrel. The preparation method utilizes the existing cyclopropyl-2- fluoro-benzylone which is treated with enol esterification, oxidization, sulfonylation, condensation and synthesis to obtain the Prasugrel. Compared with the prior art, the preparation method provided by the invention has low toxicity in raw materials and reagents used, low requirements in labor protection, low prices of and easy access to raw materials and reagents, less emission of three wastes (waste gas, waste water and waste residues), less pollution to the environment and no corrosion to equipment during the production; simultaneously, the preparation method also has simple operation and greater yield compared with the prior art and is applicable to industrial mass production.

Description

technical field [0001] The invention relates to the technical field of preparation methods of antithrombotic drug prasugrel. Background technique [0002] The chemical name of prasugrel is 2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, The structural formula is shown in the following formula (1), jointly developed by Japan Sankyo and Eli Lilly, for the treatment of thrombus, the completed Phase III clinical results show that compared with clopidogrel, the best-selling anti-platelet drug in the market, prasugrel, Its ability to inhibit platelet aggregation is stronger and more effective. [0003] Formula 1) [0004] The document EP542411 discloses a synthetic method of prasugrel, and its synthetic route is as follows: [0005] [0006] There are following shortcomings and deficiencies in this method: [0007] The raw material liquid bromine and carbon tetrachloride that prepare compound A are used all have very big toxicit...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61P7/02
Inventor 王国平侯建孙志国邹强于振鹏
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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