CRTH2 antagonist MK-7246: a synthetic evolution from discovery through development |
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Authors: | Molinaro Carmela Bulger Paul G Lee Ernest E Kosjek Birgit Lau Stephen Gauvreau Danny Howard Melissa E Wallace Debra J O'Shea Paul D |
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Institution: | Department of Process Chemistry, Merck & Co., 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA. carmela_molinaro@merck.com |
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Abstract: | 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-activity 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-H 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. |
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