The Enantiospecific Synthesis of an Isoxazoline. A RGD Mimic Platelet GPIIb/IIIa Antagonist.
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.
Zhang Lh
Lin-hua
Chemical Process R&D, The DuPont Merck Pharmaceutical Company, Deepwater, New Jersey 08023-0999.
Chung
J. C.
JC
Costello
T. D.
TD
Valvis
I.
I
Ma
P.
P
Kauffman
S.
S
Ward
R.
R