title: The Enantiospecific Synthesis of an Isoxazoline. A RGD Mimic Platelet GPIIb/IIIa Antagonist.
abstract: A convergent, large-scale, chiral synthesis of isoxazoline 1 has been achieved in 37% overall yield and >99.6% optical purity, starting from L-asparagine and 4-cyanobenzaldehyde. Hofmann reaction of N(alpha)-n-Boc-L-asparagine with iodosobenzene diacetate provides optically pure N(alpha)-n-Boc-L-alpha,beta-diaminopropionic acid (8) in 75% yield. A process of lipase resolution-base catalyzed epimerization gives the single enantiomer 5. Reaction of acid 5 with amine 9 in the presence of thionyl chloride forms the framework of 1. A Pinner reaction of intermediate 4 in methyl acetate or anisole, followed by an amidination with ammonium acetate, gives optically pure product 1.
authors.affiliation: Chemical Process R&D, The DuPont Merck Pharmaceutical Company, Deepwater, New Jersey 08023-0999.
authors.forename: Lin-hua
authors.lastname: Zhang Lh
authors.forename: J. C.
authors.initials: JC
authors.lastname: Chung
authors.forename: T. D.
authors.initials: TD
authors.lastname: Costello
authors.forename: I.
authors.initials: I
authors.lastname: Valvis
authors.forename: P.
authors.initials: P
authors.lastname: Ma
authors.forename: S.
authors.initials: S
authors.lastname: Kauffman
authors.forename: R.
authors.initials: R
authors.lastname: Ward