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Novel preparation process of prasugrel hydrochloride

A prasugrel hydrochloride and process technology, which is applied in the field of medicine, can solve problems such as harsh reaction conditions, difficult raw material procurement, and cumbersome routes, and achieve the effects of easy-to-obtain raw materials, simple operation, and economical raw materials

Active Publication Date: 2014-04-02
南京恒道医药科技股份有限公司
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AI Technical Summary

Problems solved by technology

[0005] The invention provides a preparation method of prasugrel, which uses a catalytic amount of metal catalyst palladium acetate to synthesize 2-acetoxy-5-benzyl-4,5,6,7 in one step when preparing the intermediate -Tetrahydrothieno[3,2-c]pyridine overcomes the defects of difficult procurement of raw materials, harsh reaction conditions, and cumbersome routes in the traditional process, and adopts this route to synthesize prasugrel with a total yield of 80-90%, which is higher than Existing methods are high

Method used

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  • Novel preparation process of prasugrel hydrochloride
  • Novel preparation process of prasugrel hydrochloride

Examples

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Embodiment 15

[0019] The preparation of embodiment 15-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

[0020] Take a 1000mL flask, place it in an ice bath at 0°C, pour 500mL of dichloromethane into it, and add 55.6g of accurately weighed 4,5,6,7-tetrahydrothieno[3,2-c]pyridine in sequence (0.4mol), benzaldehyde 42.4g (0.4mol), glacial acetic acid 2ml, stirred for 30min. Next, 170.0 g (0.8 mol) of sodium triacetoxyborohydride was added, the temperature was slowly raised to room temperature, and stirring was continued for 5 hours. After the reaction is finished, add sodium hydroxide solution to quench and neutralize to weak alkalinity. Continue to stir for 1 h, separate the organic layer, continue to extract the aqueous phase twice with dichloromethane, combine the organic phases, wash the organic phase with saturated sodium chloride, and concentrate the organic phase to obtain 5-benzyl-4,5,6,7-tetra Hydrothieno[3,2-c]pyridine 174g crude product, yield 95%.

Embodiment 2

[0021] Synthesis of Example 22-bromo-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

[0022] Take a clean 5000mL three-necked flask, add 174g (0.76mol) of the compound 5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine crude product obtained in Example 1, and add 500mL of Acetic acid was dissolved, 40% hydrobromic acid 560ml, methanol 500ml, 30% hydrogen peroxide 247.5ml methanol (500ml) solution was added dropwise under ice water cooling, and stirred at room temperature for 3 hours. Add 1100ml of sodium thiosulfate solution dropwise, then add saturated sodium carbonate solution dropwise until the pH is 9, extract with dichloromethane, combine the organic layers, wash with water, dry, and concentrate to dryness to obtain 222.4g of a light yellow solid crude product, which is obtained by recrystallization 210g of 2-bromo-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, yield 90%.

Embodiment 32

[0023] Example 3 Preparation of 2-acetoxy-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

[0024] Add 30.8g (0.1mol) of 2-bromo-5-benzyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine into 180ml of DMF, stir to dissolve, then add acetic acid in sequence under nitrogen protection Palladium 1.23g (0.005mol), 2-dicyclohexylphosphorus-2', 4', 6'-triisopropylbiphenyl (XPhos) 4.76g (0.01mol), sodium acetate 32.8g (0.4mol), reaction The solution was slowly warmed up to 100°C, then stirred for 24 hours, and after the reaction was completed, 500ml of water was slowly added, a large amount of solids precipitated, stirred for 5 hours in an ice bath, filtered, the filter cake was washed with water, and dried to obtain 2-acetoxy-5-benzyl - 25.8 g of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine as a white solid.

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Abstract

The invention discloses a novel synthesis process of prasugrel. The novel synthesis process comprises the steps: firstly, carrying out benzyl protection by taking 4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine, benzaldehyde and sodium triacetoxyborohydride as starting raw materials to generate 5-benzyl-4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine; then, brominating the 5-benzyl-4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine by using hydrobromic acid to obtain 2-bromo-5-benzyl-4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine; next, catalytically synthesizing 2-acetoxy-5-benzyl-4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine by taking palladium acetate as a catalyst and XPhos as a ligand; and finally, carrying out hydrodebenzylation, and coupling the product with alpha-bromo-o-fluorobenzyl cyclopropyl ketone to obtain a target molecule 2-acetoxy-5-(alpha-cyclopropylcarbonyl-2-fluorobenzyl)-4, 5, 6, 7-tetrahydrothieno[3, 2-c]pyridine hydrochloride, i.e., the prasugrel hydrochloride. The process is simple, convenient and novel in route, easy to obtain raw materials, mild in condition, convenient to operate, high in total yield up to 80-90% and suitable for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of prasugrel hydrochloride. Background technique [0002] Thrombosis can cause ischemia and infarction of major organs, and can also cause edema and venous insufficiency, leading to various dysfunctions. Representative antithrombotic drugs currently in clinical use are aspirin, clopidogrel, and asimumab. The effect of clopidogrel is stronger than that of aspirin and has less side effects. It is clinically used to treat atherosclerosis, acute coronary syndrome, and prevent in-stent restenosis and thrombotic complications after coronary stent implantation. Prasugrel is a tetrahydrothienopyridine compound similar to clopidogrel. It has shown better activity, tolerance and safety than clopidogrel in the third phase of clinical trials, and it is expected to become a good antithrombotic drug. [0003] The chemical name of prasugrel is 2-acetoxy-5-(α-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04
CPCC07D495/04
Inventor 袁宇陶义华陈端腾
Owner 南京恒道医药科技股份有限公司
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