New compound 1-cyclopropyl-2-(2-fluorine phenyl)-2-hydroxyl ethanone, preparation method and application thereof

A technology of hydroxyethyl ketone and compound is applied in the field of synthesizing the intermediate of antithrombotic drug prasugrel, which can solve the problems of large corrosion of equipment, low synthesis yield, toxicity and the like, and achieves less three wastes, 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 used for preparing compound A all have very big toxicity, 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 2 The yield of 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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  • New compound 1-cyclopropyl-2-(2-fluorine phenyl)-2-hydroxyl ethanone, preparation method and application thereof
  • New compound 1-cyclopropyl-2-(2-fluorine phenyl)-2-hydroxyl ethanone, preparation method and application thereof
  • New compound 1-cyclopropyl-2-(2-fluorine phenyl)-2-hydroxyl ethanone, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of 1-cyclopropyl-2-(2-fluorophenyl) vinyl acetate (compound of formula 3)

[0032] 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%.

[0033] 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

[0035] Preparation of 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyethanone (compound of formula 4)

[0036] 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%.

[0037] 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

[0039] Preparation of 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyethanone

[0040] 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 of peracetic acid and stir for 5 minutes; 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 of oily matter can be directly used for the next reaction. Yield 72%.

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Abstract

The invention relates to the technical field of an intermediate of an antithrombotic Prasugrel and a preparation method thereof. The intermediate is a compound of 1-cyclopropyl-2-(2- fluobenzene radical)-2-hydroxy butanone. Compared with the prior art, the method for preparing the Prasugrel by the intermediate has the advantages that the method adopts raw materials and agents which are easily obtained with low toxicity and price, and generates less three wastes; moreover, the operation is simple and the yield is higher. The method is suitable for industrialized production.

Description

technical field [0001] The invention relates to the technical field of synthesizing an intermediate 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), 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 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/573C07C45/64C07D495/04B01J31/22
Inventor 王国平侯建孙志国邹强于振鹏
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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