CRTH2 Antagonist MK-7246: A Synthetic Evolution from Discovery through Development

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• 作者：Carmela Molinaro ; Paul G. Bulger ; Ernest E. Lee ; Birgit Kosjek ; Stephen Lau ; Danny Gauvreau ; Melissa E. Howard ; Debra J. Wallace ; Paul D. O鈥橲hea
• 刊名：The Journal of Organic Chemistry
• 出版年：2012
• 出版时间：March 2, 2012
• 年：2012
• 卷：77
• 期：5
• 页码：2299-2309
• 全文大小：533K
• 年卷期：v.77,no.5(March 2, 2012)
• ISSN：1520-6904

文摘

In this paper, we report the development of different synthetic routes to MK-7246 (1) designed by the Process Chemistry group. The syntheses were initially designed as an enabling tool for Medicinal Chemistry colleagues in order to rapidly explore structure鈥揳ctivity relationships (SAR) and to procure the first milligrams of diverse target molecules for in vitro evaluation. The initial aziridine opening/cyclodehydration strategy was also directly amenable to the first GMP deliveries of MK-7246 (1), streamlining the transition from milligram to kilogram-scale production needed to support early preclinical and clinical evaluation of this compound. Subsequently a more scalable and cost-effective manufacturing route to MK-7246 (1) was engineered. Highlights of the manufacturing route include an Ir-catalyzed intramolecular N鈥揌 insertion of sulfoxonium ylide 41 and conversion of ketone 32 to amine 31 in a single step with excellent enantioselectivity through a transaminase process. Reactions such as these illustrate the enabling impact and efficiency gains that innovative developments in chemo- and biocatalysis can have on the synthesis of pharmaceutically relevant target molecules.