Novel environment friendly preparation method for prasugrel

Abstract

The invention relates to the technical field of a preparation method of an antithrombotic medicament Prasugrel. The preparation method condenses and synthesizes 2-cyclopropyl-1-(2-fluorophenyl)-2- carbonyl ethyl ester mesylate and 2-methoxyl-4, 5, 6, 7-tetrahydro-thieno (3, 2-c) pyridine to form 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 andwaste residues) and no corrosion to equipment during the production; simultaneously, the preparation method also has tender reaction conditions, 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...

Examples

Embodiment 1

[0044] Preparation of 1-cyclopropyl-2-(2-fluorophenyl) vinyl acetate (compound of formula 3)

[0045] 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%.

[0046] 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

[0048] Preparation of 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyethanone (compound of formula 4)

[0049] 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%.

[0050] 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

[0052] Preparation of 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyethanone (compound of formula 4)

[0053] Dissolve 5g (0.028mol) 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 4After drying and rotary evaporation, 3.2 g of oily matter can be directly used for the next reaction. Yield 72%.

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...

Examples

Embodiment 1

[0044] Preparation of 1-cyclopropyl-2-(2-fluorophenyl) vinyl acetate (compound of formula 3)

[0045] 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%.

[0046] 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

[0048] Preparation of 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyethanone (compound of formula 4)

[0049] 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%.

[0050] 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

[0052] Preparation of 1-cyclopropyl-2-(2-fluorophenyl)-2-hydroxyethanone (compound of formula 4)

[0053] Dissolve 5g (0.028mol) 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 4After drying and rotary evaporation, 3.2 g of oily matter can be directly used for the next reaction. Yield 72%.

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