Midbody for preparing prasugrel and method of preparing the same

An intermediate and action technology, which is applied in the preparation of sulfonate esters, chemical instruments and methods, catalysts for physical/chemical processes, etc., can solve the problems of large equipment corrosion, low synthesis yield, toxicity, etc. High efficiency and simple operation

Inactive 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-product hydrogen bromide that reaction produces is very big to equipment corrosion; And by A and The yield of B condensation is only 30%, so that the whole synthesis yield is not high
Therefore, this method is not suitable for industrial production

Method used

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  • Midbody for preparing prasugrel and method of preparing the same
  • Midbody for preparing prasugrel and method of preparing the same
  • Midbody for preparing prasugrel and method of preparing the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preparation of 1-cyclopropyl-2-(2-fluorophenyl) vinyl acetate (compound of formula 3)

[0040] Add 17.8g (0.1mol) cyclopropyl-2-fluorobenzyl ketone, 120g (1.2mol) isopropenyl acetate, and 5.7g (0.03mol) toluene-4-sulfonic acid into the reaction flask, and heat to reflux for reaction. The acetone was distilled out continuously, the reaction was complete, cooled to room temperature, the reaction solution was poured into ice water, extracted with dichloromethane, dried with anhydrous sodium sulfate, and revolved to obtain 20.9 g of red-brown oil, yield: 95.0%.

[0041] 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

[0043] Preparation of 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyethanone (compound of formula 4)

[0044] Dissolve 15g (0.068mol) 1-cyclopropyl-2-(2-fluorophenyl) vinyl acetate in 10mL of dichloromethane. After cooling to -10°C, add 16.6g (0.082mol) of m-chlorine in batches Peroxybenzoic acid, stirred 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 matter is obtained, which can be directly used for the next reaction. The yield was 75%.

[0045] 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

[0047] Preparation of 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyethanone

[0048] Dissolve 5g (0.023mol) 1-cyclopropyl-2-(2-fluorophenyl) vinyl acetate in 10mL acetonitrile, add 200mg[((phen) 2 (H 2 O)Fe III ) 2 (μ-O))(ClO 4 ) 4 The catalyst, after cooling to -18°C, add 25mL peroxyacetic acid and stir the reaction 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 and rotary evaporation, 3.2 g oily substance can be directly used for the next reaction. The yield was 72%.

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Abstract

The invention relates to the technical field of an intermediate of antithrombotic drug prasugrel and a preparing method thereof. The intermediate for preparing the prasugrel has a structural format as the right, wherein R stands for alkyl or aryl. Compared with the prior method, the method for preparing the prasugrel by the drug intermediate has the advantages that both raw materials and reagents used by the method are low in cost and toxicity and can be easily obtained, the method generates less 'the three wastes', simultaneously has simple operation and higher yield, and applicability to industrial production.

Description

Technical field [0001] The invention relates to the technical field of an intermediate for the synthesis of an antithrombotic drug prasugrel and a preparation method thereof. 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). It was jointly developed by Sankyo and Eli Lilly in Japan to treat thrombosis. The completed Phase III clinical results show that Prasugrel is compared with the best-selling antiplatelet drug clopidogrel in the market. Its ability to inhibit platelet aggregation is stronger and more effective. [0003] Formula 1) [0004] Document EP542411 discloses a synthetic method of prasugrel, and its synthetic route is as follows: [0005] [0006] This method has the following shortcomings and shortcomings: [0007] The raw material bromine and carbon tetrachloride used for the preparation of compoun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C309/63C07C303/28B01J31/12
Inventor 王国平侯建孙志国邹强于振鹏
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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