title: CRTH2 antagonist MK-7246: a synthetic evolution from discovery through development.
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.
authors.affiliation: Department of Process Chemistry, Merck & Co., 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA. carmela_molinaro@merck.com
authors.forename: Carmela
authors.initials: C
authors.lastname: Molinaro
authors.forename: Paul G
authors.initials: PG
authors.lastname: Bulger
authors.forename: Ernest E
authors.initials: EE
authors.lastname: Lee
authors.forename: Birgit
authors.initials: B
authors.lastname: Kosjek
authors.forename: Stephen
authors.initials: S
authors.lastname: Lau
authors.forename: Danny
authors.initials: D
authors.lastname: Gauvreau
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Howard
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Wallace
authors.forename: Paul D
authors.initials: PD
authors.lastname: O'Shea
mesh_terms: D002243:Carbolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D015394:Molecular Structure; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C554899:((7R)-7-(((4-fluorophenyl)sulfonyl)(methyl)amino)-6,7,8,9-tetrahydropyrido(1,2-a)indol-10-yl)acetic acid; D002243:Carbolines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor