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New preparation method of Prasugrel

A cyclopropylcarbonyl compound technology, applied in the field of medicinal chemistry, can solve the problems of poor selectivity of halogenation reaction, expensive reagents, unfavorable large-scale production, etc., and achieve the effects of increasing the total yield, reducing production costs, and simple operation

Active Publication Date: 2010-07-14
SHANGHAI HAIYAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Not only that, the selectivity of the halogenation reaction at the ortho position of the carbonyl group is poor, the yield is low, and the reagents used are relatively expensive, etc., which are not conducive to large-scale industrial production.

Method used

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  • New preparation method of Prasugrel
  • New preparation method of Prasugrel
  • New preparation method of Prasugrel

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042]At 0°C, add 11.6 g (110 mmol) of sodium tert-butoxide to a THF (1000 mL) solution of 40.0 g (101 mmol) of cyclopropylmethyltriphenylphosphine hydrobromide II, and react at this temperature for 30 min. , then add o-fluorobenzaldehyde I 12.4g (50mmol), react at room temperature for 10h, after TLC detects that the raw material has reacted completely, add saturated NH 4 The reaction was quenched with Cl and extracted with EtOAc (3×1000 mL). The organic phases were combined and washed with saturated brine, MgSO 4 Dry, filter, and concentrate to obtain 13.0 g of the crude product III of the Wittig reaction, with a yield of 80%.

Embodiment 2

[0044] The crude product III 12g (74mmol) obtained in Example 1 was dissolved in 700mLMeOH, then slowly added 2.5mL (10mmol) of 4M NaOH, and then slowly added dropwise 30% H 2 o 2 10.9mL (96mmol), the dropwise addition time is more than 2 hours. After the dropwise addition, stir at this temperature for 5 hours, and use TLC to detect the reaction. After the raw materials have reacted, add saturated Na 2 SO 3 The solution was quenched, the MeOH solvent was concentrated, and then CH 2 Cl 2 Extraction (3×500mL). Combined organic phases were washed with saturated brine, MgSO 4 Dry, filter and concentrate to obtain 12g of compound IV with a yield of 91%.

Embodiment 3

[0046] At room temperature, dissolve 8.7g (56mmol) of compound V in 500mL of dichloromethane, and slowly add K 2 CO 3 15g (112mmol), the feeding time is more than 1 hour, after the dropwise addition, stir at this temperature for 2 hours, slowly add dropwise the epoxy compound IV 10g (56mmol) generated in the embodiment 2 in the reaction system, drop After the addition, the reaction system was heated to reflux for 20 hours, cooled to room temperature, filtered, anhydrous MgSO 4 Dry, concentrate to dryness, and then conduct column chromatography with ethyl acetate:petroleum ether=3:1 to obtain 15.7g of hydroxyl compound VI with a yield of 84%.

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Abstract

The invention discloses a bran-new synthetic route for preparing 2-acetoxyl group-5-(cyclopropyl carbonyl-2-fluorophenyl)-4,5,6,7-tetrahydrothiophene (3,2-c) pyridine (the hydrochloride thereof is Prasugrel). The preparation method comprises the following steps of: constructing the right framework through key Wittig and epoxidation, opening the epoxy by using 5,6,7,7a-tetrahydrothiophene (3,2-c) pyridine-2(4H)-ketone, oxidizing and carrying out enolization to finish the synthesis. The preparation method has the advantages of mild reaction condition, no need of low temperature, high-pressure operation, no need of flammable and combustible reagents and higher yield than that of the traditional preparation method, thereby being an economic and practical synthetic method and being suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a prasugrel, (2-acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothiophene And (3,2-c) pyridine) new preparation method. Background technique [0002] Prasugrel (Prasugrel) is a tetrahydrothienopyridine compound with a structure similar to clopidogrel. It is an oral anti-platelet drug jointly developed by Daiichi Pharmaceutical Sankyo Company and Eli Lilly and Company. Prasugrel works by Blocks the P2Y12 adenosine diphosphate receptor on the surface of platelets and inhibits platelet activation and subsequent aggregation. Antiplatelet drugs are used to prevent platelets from clumping together, or from sticking together, which could lead to blockage of arteries and possible heart attack or stroke. At present, prasugrel has been approved for marketing by the European Medicines Agency (EMEA) and has started sales in the UK. Due to its good tolerance and safety...

Claims

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Application Information

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IPC IPC(8): C07D495/04
Inventor 冯建鹏孙田江张玉斌尹必喜赵锋高中强
Owner SHANGHAI HAIYAN PHARMA TECH