134 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001
Chang and Chen
Diagram 2
Key Words
Sibrafiban; Lamifiban; Integrin; Fibrinogen;
DHP HM resin; Phase III; GPIIb/IIIa.
ODHP-resin
OH
1) Fm oc-OSu,rt,1h
dioxane:H 2O=10:1(97%)
stepwise elongation
2) p-TsOH,DC M,rt,16h
and final deprotection
C O2 But
N
N
H
O
Fmoc
O
REFERENCES
OH
O
1. Thomp son, L. A.; Ellman, J. A. TetrahedronLett.1994,
35, 9333-9336.
2. Kick, E. K.; Ellman, J. A. J. Med. Chem. 1995, 38, 1427-
1430.
1) NH 2OH-HCl,MeON a
MeOH,rt,48h
2) HC O2 H,rt,10h
1) N aH,THF,BrCH2 CO2But,
r.t.,1h,reflux,3h
N
N
O
R
R
O
O
2) isobutylene (for 2)
N H
NH
O
3. Wang, G. T.; Li, S.; Wideburg, N.; Krafft, G. A.; Kempf,
D. J. J. Med. Chem. 1995, 38, 2995-3002.
4. Wess, G.; Bock, K.; Kleine, H.; Kurz, M.; Guba, W.;
Hemmerle, H.; Lopez-Calle, E.; Baringhaus, K. H.;
Glombik, H.; Enhsen, A.; Kramer, W. Angew. Chem. Int.
Ed. Engl. 1996, 35, 2222-2224.
1a R=Me
2a R=
1b R=Me (36%)
2b R=
(30%)
OBut
OH
CN
O
CN
CO2H
(1) EtOH,H2SO4,20h
N
(for 1 three steps 40%)
sibrafiban (1)
lamifiban (2)
R
5. Koh, J. S.; Ellman, J. A. J. Org. Chem. 1996, 61, 4494-
4495.
O
O
(2) H2,10% Pd/C,Ac2 O,AcOH
(for 2 three steps 43%)
NH
6. Wallace, O. B. TetrahedronLett.1997, 38, 4939-4942.
7. Pearson, W. H.; Clark, R. B. TetrahedronLett. 1997, 38,
7669-7672.
1c R=Me
2c R=
OH
H2
N
NOH
8. Hsieh, H.-P.; Wu, Y.-T.; Chen, S.-T.; Wang, K.-T. Chem.
Commun. 1998, 649-650.
9. Ramaseshan, M,; Ellingboe, J. W.; Dory, Y. L.;
Deslongchamps, P. TetrahedronLett. 2000, 41, 4743-
4749.
10. Weller, T.; Alig, L.; Beresini, M.; Blackburn, B.; Bunting,
S.; Hadvary, P.; Mul ler, M. H.; Knopp, D.; Levet-Trafit,
B.; Lipari, M. T.; Mo di, N. B.; Mul ler, M.; Refino, C. J.;
Schmitt, M.; Schonholzer, P.; Weiss, S.; Steiner, B. J.
Med. Chem. 1996, 39, 3139-3147.
11. Hoekstra, W. J.; Maryanoff, B. E.; Damiano, B. P.;
Andrade-Gordon, P.; Cohen, J. H.; Costanzo, M. J.;
Haertlein, B. J.; Hecker, L. R.; Hulshizer, B. L.;
Kauffman, J. A.; Keane, P.; McComsey, D. F.; Mitch ell, J.
A.; Scott, L.; Shah, R. D.; Yabut, S. C. J. Med. Chem.
1999, 42, 5254-5265.
hydroxylammoniumchloride(NH2OH-HCl, 1.5 eq) and so-
diummethoxide(MeONa, 1.4eq)inmethanol. Withoutpuri-
fication,theresiduewasdeprotectedbyformicacid(5mL)to
af ford amidoxime 1c and 2c. Finally, the amidoxime, 1c, was
reactedwithethanol(5mL)andacatalyticamountofsulfuric
acid to give sibrafiban (1) in 40% yield, while the amido-
xime, 2c, was con verted to lamifiban (2) by hydrogenolysis
using10%palladiumonactivatedcarbon(Pd/C,100mg)and
ace tic an hy dride (2 eq) in 43% yield. The de scribed solid-
phase syn the sis can be used to gen er ate sibrafiban (1) and
lamifiban (2) for use in hu man antithrombotic ther apy stud-
ies.25
ACKNOWLEDGMENTS
12. Alig, L.; Edenhofer, E.; Hadvary, P.; Huzeler, M.; Knopp,
D.; Mul ler, M.; Steiner, B.; Trzeciak, A.; Weller, T. J.
Med. Chem. 1992, 35, 4393-4407.
This re search was sup ported by the Na tional Sci ence
Council,Taiwan,CoreSubjectResearchProgram,Academia
Sinica, Tai wan, and Alps Biotech Grant 11T-890601-1C. We
also thank Mr. Lin Kuo-Ging for HPLC and mass spec tros-
copysupport.
13. Basso, A.; Pegg, N.; Ev ans, B.; Bradley, M. Eur. J. Org.
Chem. 2000, 3887-3891.
14. Zablocki, J. A.; Miyiano, M.; Rao, S. N.; Pan zer-Knodle,
S.; Nichol son, N.; Feigen, L. J. Med. Chem. 1992, 35,
4914-4917.
15. Eldred, C. D.; Ev ans, B.; Hindley, S.; Judkins, B. D.;
Kelly, H. A.; Kitchin, J.; Lumley, P.; Por ter, B.; Ross, B.
Received December 28, 2000.