Kilogram scale synthesis of the pyrazinone acetic acid core of an orally efficacious thrombin inhibitor

Synthetic Communications

Volumn 30, Issue 17, 2000, Pages 3171-3180

  Fleitz, Fred J ^a   Lyle, Terry A ^a   Zheng, Nan ^a   Armstrong III, Joseph D ^a   Volante, R P ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETIC ACID DERIVATIVE; DIAMIDE; PYRAZINE DERIVATIVE; RUTHENIUM; THROMBIN INHIBITOR;

ARTICLE; CATALYSIS; DRUG STRUCTURE; DRUG SYNTHESIS; OXIDATION; REACTION ANALYSIS; STOICHIOMETRY;

EID: 0033868166     PISSN: 00397911     EISSN: None     Source Type: Journal    
DOI: 10.1080/00397910008086927     Document Type: Article

References (23)

1. (a) Patent Application WO 97/40024
2. (b) Sanderson, P. E. J. et. al. J. Med. Chem. 1998, 41, 4466.
3. (a) Palamidessi, G.; Bonanomi, M. Il Farmaco Ed. Sci. 1966, 21, 799.
4. (b) Adachi, J.; Sato, N. J. Org. Chem. 1972, 37, 221.
5. (c) Cheeseman, G. W. H.; Freestone, A. J.;.Godwin, R. A.; Hough, T. L. J. C. S Perkin I 1975, 1888.
6. Hicks, J. L.; Huang, C. C.; Goel, O.P.; Butler, D. E. J. Labelled Compd 1984, 21, 937.
7. Krapcho, A. P.; Maresch, M. J.; Gallagher, C. E.; Hacker, M. P.; Menta, E.; Oliva, A.; DiDomenico, R.; Da Re, G.; Spinelli, S.J. Het. Chem. 1995, 32, 1693.
8. Sugimura, T.; Paquette, L. A. J. Am. Chem. Soc. 1987, 109, 3017.
9. (a) Giddings, S.; Mills, A. J. Org. Chem. 1988, 53, 1103.
10. (b) Kanemoto, S.; Tomioka, H.; Ohsima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1986, 59, 105.
11. (c) Wolfe, S.; Hasan, S. K.; Campbell, J. R. J. C. S. Chem. Comm. 1970, 1420.
12. (d) Carlsen, H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936.
13. For bulk drug production no more than 10 ppm of any heavy metal may be present in the final product.
14. 3 gave lower yields, presumably due to product decomposition.
15. Subsequent crystallization of later intermediates further reduced the residual ruthenium to less than 1 ppm.
16. The reaction proceeded in the absence of TFAA, but complete conversion required longer reaction times.
17. 13C NMR (R. A. Reamer) the amide tautomer depicted predominates which may explain this result.
18. Campiani, G.; Nacci, V.; Correlli, F.; Anzini, M. Synth. Commun. 1991, 21, 1567.
19. Dobeneck, H. V.; Messerschmitt, T. Justus Liebigs Ann. Chem. 1971, 751.
20. (a) Cannizzo, S.; Guerrera, F.; Siracusa, M. A.; Corsaro, A. J. Het. Chem. 1990, 27, 2175.
21. (b) Fujisawa, T.; Mori, T.; Sato, T. Tetrahedron Lett. 1982, 23, 5059.
22. 5 were also examined but failed to give the desired bromide.
23. Attempted hydrolysis of the bisamide 11 to the desired acid was not successful.