An efficient synthesis of an alphavbeta3 antagonist.
A practical preparation of an alpha(v)beta(3) antagonist is reported. The antagonist consists of three key components, a tetrahydronaphthyridine moiety, a beta-alanine moiety, and a central imidazolidone moiety. The tetrahydronaphthyridine component was prepared using two different methods, both of which relied on variations of the Friedländer reaction to establish the desired regiochemistry. The beta-alanine component was prepared using Davies' asymmetric 1,4-addition methodology as the key stereo-defining step. The central imidazolidone portion was created from these two components using an effective three-step cyclization protocol. Thus, a highly convergent process for the drug candidate was defined.
Yasuda
Nobuyoshi
N
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. nobuyoshi_yasuda@merck.com
Hsiao
Yi
Y
Jensen
Mark S
MS
Rivera
Nelo R
NR
Yang
Chunhua
C
Wells
Kenneth M
KM
Yau
James
J
Palucki
Michael
M
Tan
Lushi
L
Dormer
Peter G
PG
Volante
Ralph P
RP
Hughes
David L
DL
Reider
Paul J
PJ
D002384:Catalysis; D003500:Cyclization; D007093:Imidazoles / Q000138:chemical synthesis*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis*; D013237:Stereoisomerism; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D007093:Imidazoles; D039302:Integrin alphaVbeta3; D009287:Naphthyridines; D015091:beta-Alanine