Optimization of synthetic process of prasugrel hydrochloride

DAI Li; JIANG Zhi-hui; CAI Zhan; ZHAO Ming-zhu; LI Yan; NI Ting-jun-hong; TIAN Shu-juan; Zhang Da-zhi

doi:10.3969/j.issn.1006-0111.2013.03.009

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Objective To improve the synthetic process of prasugrel hydrochloride in order to enlarge production and get high purity. Methods 2-fluorine phenylacetic acid was reacted with methyl cyclopropanecarboxylate, followed by bromination with NBS to afford α-cyclopropyl carbonyl-2-fluorobenzyl bromide. The latter was condensed with 2-oxo-2, 4, 5, 6, 7, 7a-hexahydro-thieno[3, 2-c]pyridine hydrochloride, and then acetylated and solified to finally afford prasugrel hydrochloride. Results The cost of this optimized synthetic process of prasugrel hydrochloride was obviously low, with easy operation process and availability of high purity. Conclusion The overall yield of new process was 48%, which ensured a more appropriate process for industrial production.

Optimization of synthetic process of prasugrel hydrochloride

Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China

Received Date: 2012-08-30

Rev Recd Date: 2013-04-25

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Abstract: Objective To improve the synthetic process of prasugrel hydrochloride in order to enlarge production and get high purity. Methods 2-fluorine phenylacetic acid was reacted with methyl cyclopropanecarboxylate, followed by bromination with NBS to afford α-cyclopropyl carbonyl-2-fluorobenzyl bromide. The latter was condensed with 2-oxo-2, 4, 5, 6, 7, 7a-hexahydro-thieno[3, 2-c]pyridine hydrochloride, and then acetylated and solified to finally afford prasugrel hydrochloride. Results The cost of this optimized synthetic process of prasugrel hydrochloride was obviously low, with easy operation process and availability of high purity. Conclusion The overall yield of new process was 48%, which ensured a more appropriate process for industrial production.

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Reference (6)

[1]	宋建虹,杜小莉. 新型口服抗血小板活化和聚集药物——普拉格雷[J].中国药学杂志, 2010,45(17);1357.
[2]	Jakubowski JA,Winters KJ,Naganuma H,et al. Prasugrel:a novel thienopyridine antiplatelet agent.A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile[J].Cardiovascular Drug Rev, 2007, 25(4):357.
[3]	Alain B,Daniel F,Jian-Pierre M,et al. Derivatives of alpha(2-oxo-2,4,5,6,7,7a-hexahy drothieno[3,2-c]-5-pyridyl) phenyl acetic acid,and their use as platelet and thrombotic aggregation inhibitiors[P].US.4740510,1988-04-26.
[4]	Hiroyuki K,Fumitoshi A,Atsuhiro S,et al. Tetra-hydrothienopyridine derivatives, furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation[P].EP 0542411,1993-05-19.
[5]	吴雪松,岑均达,郭珩. 制备普拉格雷的中间体及其制备方法[P].CN101245072A, 2008-08-20.
[6]	程兴栋,童玲, 杨玉雷,等. 普拉格雷的合成工艺研究[J].中国新药杂志, 2010,19(15);1314.

[1]	宋建虹,杜小莉. 新型口服抗血小板活化和聚集药物——普拉格雷[J].中国药学杂志, 2010,45(17);1357.
[2]	Jakubowski JA,Winters KJ,Naganuma H,et al. Prasugrel:a novel thienopyridine antiplatelet agent.A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile[J].Cardiovascular Drug Rev, 2007, 25(4):357.
[3]	Alain B,Daniel F,Jian-Pierre M,et al. Derivatives of alpha(2-oxo-2,4,5,6,7,7a-hexahy drothieno[3,2-c]-5-pyridyl) phenyl acetic acid,and their use as platelet and thrombotic aggregation inhibitiors[P].US.4740510,1988-04-26.
[4]	Hiroyuki K,Fumitoshi A,Atsuhiro S,et al. Tetra-hydrothienopyridine derivatives, furo and pyrrolo analogs thereof and their preparation and uses for inhibiting blood platelet aggregation[P].EP 0542411,1993-05-19.
[5]	吴雪松,岑均达,郭珩. 制备普拉格雷的中间体及其制备方法[P].CN101245072A, 2008-08-20.
[6]	程兴栋,童玲, 杨玉雷,等. 普拉格雷的合成工艺研究[J].中国新药杂志, 2010,19(15);1314.

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Optimization of synthetic process of prasugrel hydrochloride

doi: 10.3969/j.issn.1006-0111.2013.03.009

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通讯作者: 陈斌, [email protected]

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