Synthesis of 3-Aminopyrazinone Mediated by 2-Pyridylthioimidate-ZnCl 2 Complexes. Development of an Efficient Route to a Thrombin Inhibitor

Journal of Organic Chemistry

Volumn 68, Issue 23, 2003, Pages 8838-8846

  Chung, John Y L ^a   Cvetovich, Raymond J ^a   Tsay, Fuh Rong ^a   Dormer, Peter G ^a   DiMichele, Lisa ^a   Mathre, David J ^a   Chilenski, Jennifer R ^a   Mao, Bing ^a   Wenslow, Robert ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHLORINATION; HYDROLYSIS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OXIDATION; SYNTHESIS (CHEMICAL); X RAY CRYSTALLOGRAPHY;

ELECTROPHILES;

AROMATIC COMPOUNDS;

3 AMINOPYRAZINONE; 3 BROMOPYRAZINONE; AMINE; PYRAZINE DERIVATIVE; PYRAZINONE; PYRIDINE DERIVATIVE; PYRIDINE N OXIDE AMINE; PYRIDINYLTHIOIMIDATE; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CHLORINATION; CHROMATOGRAPHY; DRUG PURITY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; HYDROLYSIS; NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS; REPRODUCIBILITY; SOLID STATE; STRUCTURE ANALYSIS; X RAY CRYSTALLOGRAPHY;

ANTITHROMBINS; CHLORIDES; IMIDOESTERS; MAGNETIC RESONANCE SPECTROSCOPY; PYRAZINES; PYRIDINES; ZINC COMPOUNDS;

EID: 0242409155     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo034835e     Document Type: Article

References (38)

1. (a) Burgey, C. S.; Robinson, K. A.; Lyle, T. A.; Nantermet, P. G.; Selnick, H. G.; Isaacs, R. C. A.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Singh, R.; Miller-Stein, C.; White, R. B.; Wong, B.; Lyle, E. A.; Stranieri, M. T.; Cook, J. J.; McMasters, D. R.; Pellicore, J. M.; Pal, S.; Wallace, A. A.; Clayton, F. C.; Bohn, D.; Welsh, D. C.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P. Bioorg. Med. Chem. Lett. 2003, 13, 1353-1357.
2. (b) Burgey, C. S.; Robinson, K. A.; Lyle, T. A.; Sanderson, P. E. J.; Lewis, S. D.; Lucas, B. J.; Krueger, J. A.; Singh, R.; Miller-Stein, C.; White, R. B.; Wong, B.; Lyle, E. A.; Williams, P. D.; Coburn, C. A.; Dorsey, B. D.; Barrow, J. C.; Stranieri, M. T.; Holahan, M. A.; Sitko, G. R.; Cook, J. J.; McMasters, D. R.; McDonough, C. M.; Sanders, W. M.; Wallace, A. A.; Clayton, F. C.; Bohn, D.; Leonard, Y. M.; Detwiler, T. J., Jr.; Lynch, J. J., Jr.; Yan, Y.; Chen, Z.; Kuo, L.; Gardell, S. J.; Shafer, J. A.; Vacca, J. P. J. Med. Chem. 2003, 46, 461-473.
3. (c) Dolling, U. H.; Alabaster, R. J.; Ashwood, M. S.; Cottrell, I. F.; Cowden, C. J.; Davies, A. J. PCT Int. Appl. WO 0246160, 2002.
4. (d) Cowden, C.; Cooper, V. B.; Rush, D. J.; Frech, P. PCT Int. Appl. WO 0192234, 2001.
5. (e) Burgey, C.; Isaacs, R. C.; Dorsey, B. D.; Robinson, K. A.; Staas, D. ; Sanderson, P. E.; Barrow, J. PCT Int. Appl. WO 0138323, 2001.
6. (f) Burgey, C. S.; Robinson, K. A.; Williams, P. D.; Coburn, C. A.; Lyle, T. A.; Sanderson, P. E. PCT Int. Appl. WO 0075134, 2000.
7. (a) Taguchi, T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.; Uehara, H.; Endo, H.; Kobayashi, Y. Tetrahedron Lett. 1986, 27, 6103-6106.
8. (b) Kitagawa, O.; Taguchi, T.; Kobayashi, Y. Chem. Lett. 1989, 389-392.
9. Ashwood, M. S.; Cottrell, I. F.; Cowden, C. J.; Wallace, D. J.; Davies, A. J.; Kennedy, D. J.; Dolling, U. H. Tetrahedron Lett. 2002, 43, 9271-9273.
10. Caron, S.; Do, N. M.; Sieser, J. E. Tetrahedron Lett. 2000, 41, 2299-2302.
11. Early oxidation efforts with TFPAA, produced by the addition of TFAA to UHP under acidic conditions in the presence of 1.2 equiv of TFA or BSA to protect the primary amine, gave a selective oxidaton of the pyridine ring in good yields, but the reaction mixture contained about 30% of the trifluoroamide 15. Although an aqueous NaOH workup cleaved the trifluoroacetamide, isolation via extraction of very water soluble pyridine N-oxide 4 proved to be difficult.
12. CAUTION! Solid bromopyrazinone 16 is thermally unstable with an exothermic initiation at ∼50 °C, potentially shock sensitive (1 out of 6 positive drop weight tests), and gradually decomposes at room temperature.
13. Fleitz, F. J.; Lyle, T. A.; Zheng, N.; Armstrong, J. D., III; Volante, R. P. Synth. Commun. 2000, 30, 7171-3180.
14. (a) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127-3129 and references therein.
15. (b) Pyridine N-oxide addition to imidoyl chloride: Tachikawa, R.; Wachi, K.; Sato, S.; Terada, A. Chem. Pharm. Bull. 1981, 29, 3529-3535.
16. (a) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158-1174.
17. (b) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144-57.
18. (c) Chakraborty, M.; McConville, D. B.; Niu, Y.; Tessier, C. A.; Youngs, W. J. J. Org. Chem. 1998, 63, 7563-7567.
19. Ashton, R. P.; Calcagno, P.; Spencer, N.; Harris, K. D. M.; Philp, D. Org. Lett. 2000, 2, 1365-1368 and references therein.
20. Holan, G.; Virgona, C. T.; Watson, K. G. Bioorg. Med. Chem. Lett. 1996, 6, 77-80.
21. Sekine M. J. Org. Chem. 1989, 54, 2321-6. Kamimura, T.; Masegi, T.; Sekine, M.; Hata, T. Tetrahedron Lett. 1984, 25, 4241-4.
22. Sekine M. J. Org. Chem. 1989, 54, 2321-6. Kamimura, T.; Masegi, T.; Sekine, M.; Hata, T. Tetrahedron Lett. 1984, 25, 4241-4.
23. (a) Charette, A. B.; Grenon, M. Tetrahedron Lett. 2000, 41, 1677-1680.
24. (b) Charett, A. B.; Chua, P. J. Org. Chem. 1998, 63, 908-909.
25. (c) Sforza, S.; Dossena, A.; Corradini, R.; Virgili, E.; Marchelli, R. Tetrahedron Lett. 1998, 39, 7110714,
26. (d) Thomas, E. W. Synthesis 1993, 767-768.
27. (e) Sisti, N. J.; Zeller, E.; Grierson, D. S.; Fowler, F. W. J. Org. Chem. 1997, 62, 2093-2097.
28. (a) Schmidt, U.; Gleich, P. Angew. Chem. 1985, 97, 606-607.
29. (b) Lloyd, K.; Young, G. T. J. Chem. Soc. (C) 1971, 2890-6.
30. For a 2-mercaptopyrdine review, see: Schmidt, B.; Kühn, C. J. Prakt. Chem. 1999, 341, 114-120.
31. Zhou, X.-X.; Welch, C. J.; Chattopadhyaya, J. Acta Chem. Scand. 1986, B40, 806-816.
32. 3 for the preparation of 16 gave a slower reaction and lower yield, and coprecipitation of inorganic phosphate salts with isolated product 27 after workup.
33. (a) Moran, D.; Sukcharoenphon K.; Puchta, R.; Schaefer, H. F.; Schleyer, P. v. R.; Hoff, C. D. J. Org. Chem. 2002, 67, 9061-9069.
34. (b) Stoyanov, S.; Petkov, I.; Antonov, L.; Stoyanove, T. Can. J. Chem. 1990, 68, 1482-1489.
35. (c) Shunmugam, R.; Sathyanarayana, D. N. J. Coord. Chem. 1986, 14, 27-30.
36. (d) Kennedy, B. P.; Lever, A. B. P. Can. J. Chem. 1972, 50, 3488-3507.
37. (e) Penfold, B. R. Acta Crystallogr. 1953, 6, 707-713.
38. Ko, M.; Sato, T.; Otsu, T. J. Macromol. Sci., Chem. 1975, A9, 199-210.