title: Practical asymmetric synthesis of a non-peptidic alphavbeta3 antagonist.
abstract: The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite beta-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.
authors.affiliation: Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, United Kingdom. stephen_keen@merck.com
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Keen
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Cowden
authors.forename: Brian C
authors.initials: BC
authors.lastname: Bishop
authors.forename: Karel M J
authors.initials: KM
authors.lastname: Brands
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Davies
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Dolling
authors.forename: David R
authors.initials: DR
authors.lastname: Lieberman
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Stewart
mesh_terms: D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003500:Cyclization; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D039302:Integrin alphaVbeta3; D010421:Pentanoic Acids