An efficient one-pot process for 10-bromo-8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one, an intermediate to SCH 66336

Organic Process Research and Development

Volumn 7, Issue 5, 2003, Pages 692-695

  Fu, Xiaoyong ^a   McAllister, Timothy L ^a   Shi, Xiongwei ^a   Thiruvengadam, T K ^a   Tann, Chou Hong ^a   Lee, Junning ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

10 BROMO 8 CHLORO 5,6 DIHYDROBENZO[5,6]CYCLOHEPTA[1,2 B]PYRIDIN 11 ONE; 4 [2 [4 (3,10 DIBROMO 8 CHLORO 6,11 DIHYDRO 5H BENZO[5,6]CYCLOHEPTA[1,2 B]PYRIDIN 11 YL) 1 PIPERIDINYL] 2 OXOETHYL] 1 PIPERIDINECARBOXAMIDE; ANTINEOPLASTIC AGENT; BROMINE DERIVATIVE; KETONE DERIVATIVE; TIN DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BROMINATION; DEAMINATION; DRUG STRUCTURE; DRUG SYNTHESIS; REDUCTION; STEREOCHEMISTRY;

EID: 0141924725     PISSN: 10836160     EISSN: None     Source Type: Journal    
DOI: 10.1021/op034054f     Document Type: Article

References (26)

1. Caponigro, F. Anti-Cancer Drugs 2002, 13, 891. Dancey, J. E. Curr. Pharm. Des. 2002, 8, 2259. Singh, S. B.; Lingham, R. B. Curr. Opin. Drug Discovery Dev. 2002, 5, 225.
2. Caponigro, F. Anti-Cancer Drugs 2002, 13, 891. Dancey, J. E. Curr. Pharm. Des. 2002, 8, 2259. Singh, S. B.; Lingham, R. B. Curr. Opin. Drug Discovery Dev. 2002, 5, 225.
3. Caponigro, F. Anti-Cancer Drugs 2002, 13, 891. Dancey, J. E. Curr. Pharm. Des. 2002, 8, 2259. Singh, S. B.; Lingham, R. B. Curr. Opin. Drug Discovery Dev. 2002, 5, 225.
4. Njoroge, F. G.; Girijavallabhan, V. M. Curr. Med. Chem.: Immunol., Endocr. Metab. Agents 2001, 1, 185-198. Liu, M.; Bryant, M. S.; Chen, J.; Lee, S.; Yaremko, B.; Lipari, P.; Malkowski, M.; Ferrari, E.; Nielsen, L.; Prioli, N.; Dell, J.; Sinha, D.; Syed, J.; Korfmacher, W. A.; Nomeir, A. A.; Lin, C.-C. ; Wang, L.; Taveras, A. G.; Doll, R. J.; Njoroge, F. G.; Mallams, A. K.; Remiszewski, S.; Catino, J. J.; Girijavallabhan, V. M.; Kirschmeier, P.; Bishop, W. R. Cancer Res. 1998, 58, 4947-4956.
5. Njoroge, F. G.; Girijavallabhan, V. M. Curr. Med. Chem.: Immunol., Endocr. Metab. Agents 2001, 1, 185-198. Liu, M.; Bryant, M. S.; Chen, J.; Lee, S.; Yaremko, B.; Lipari, P.; Malkowski, M.; Ferrari, E.; Nielsen, L.; Prioli, N.; Dell, J.; Sinha, D.; Syed, J.; Korfmacher, W. A.; Nomeir, A. A.; Lin, C.-C. ; Wang, L.; Taveras, A. G.; Doll, R. J.; Njoroge, F. G.; Mallams, A. K.; Remiszewski, S.; Catino, J. J.; Girijavallabhan, V. M.; Kirschmeier, P.; Bishop, W. R. Cancer Res. 1998, 58, 4947-4956.
6. Njoroge, F. G.; Taveras, A. G.; Kelly, J.; Remiszewski, S.; Mallams, A. K.; Wolin, R.; Afonso, A.; Cooper, A. B.; Rane, D. F.; Liu, Y.-T.; Wong, J.; Vibulbhan, B.; Pinto, P.; Deskus, J.; Alvarez, C. S.; Del Rosario, J.; Connolly, M.; Wang, J.; Desai, J.; Rossman, R. R.; Bishop, W. R.; Patton, R.; Wang, L.; Kirschmeier, P.; Bryant, M. S.; Nomeir, A. A.; Lin, C.-C.; Liu, M.; McPhail, A. T.; Doll, R. J.; Girijavallabhan, V. M.; Ganguly, A. K. J. Med. Chem. 1998, 41, 4890-4902. Taveras, A. G.; Aki, C.; Chao, J.; Doll, R. J.; Lalwani, T.; Girijavallabhan, V.; Strickland, C. L.; Windsor, W. T.; Weber, P.; Hollinger, F.; Snow, M.; Patton, R.; Kirschmeier, P.; James, L.; Liu, M.; Nomeir, A. J. Med. Chem. 2002, 45, 3854-3864.
7. Njoroge, F. G.; Taveras, A. G.; Kelly, J.; Remiszewski, S.; Mallams, A. K.; Wolin, R.; Afonso, A.; Cooper, A. B.; Rane, D. F.; Liu, Y.-T.; Wong, J.; Vibulbhan, B.; Pinto, P.; Deskus, J.; Alvarez, C. S.; Del Rosario, J.; Connolly, M.; Wang, J.; Desai, J.; Rossman, R. R.; Bishop, W. R.; Patton, R.; Wang, L.; Kirschmeier, P.; Bryant, M. S.; Nomeir, A. A.; Lin, C.-C.; Liu, M.; McPhail, A. T.; Doll, R. J.; Girijavallabhan, V. M.; Ganguly, A. K. J. Med. Chem. 1998, 41, 4890-4902. Taveras, A. G.; Aki, C.; Chao, J.; Doll, R. J.; Lalwani, T.; Girijavallabhan, V.; Strickland, C. L.; Windsor, W. T.; Weber, P.; Hollinger, F.; Snow, M.; Patton, R.; Kirschmeier, P.; James, L.; Liu, M.; Nomeir, A. J. Med. Chem. 2002, 45, 3854-3864.
8. Ganguly, A. K.; Doll, R. J.; Girijavallabhan, V. M. Curr. Med. Chem. 2001, 8, 1419-1436. Morgan, B.; Zaks, A.; Dodds, D. R.; Liu, J.; Jain, R.; Megati, S.; Njoroge, F. G.; Girijavallabhan, V. M. J. Org. Chem. 2000, 65, 5451-5459.
9. Ganguly, A. K.; Doll, R. J.; Girijavallabhan, V. M. Curr. Med. Chem. 2001, 8, 1419-1436. Morgan, B.; Zaks, A.; Dodds, D. R.; Liu, J.; Jain, R.; Megati, S.; Njoroge, F. G.; Girijavallabhan, V. M. J. Org. Chem. 2000, 65, 5451-5459.
10. Njoroge, F. G.; Vibulbhan, B.; Pinto, P.; Chan, T.-M.; Osterman, R.; Remiszewski, S.; Del Rosario, J.; Doll, R.; Girijavallabhan, V.; Ganguly, A. K. J. Org. Chem. 1998, 63, 445-451.
11. Buck, J. S.; Ide, W. S. Org. Synth. 1933, 13, 28-30. Stipanovic, R. D.; Steidl, J. Synth. Commun. 1986, 16, 1809-13. Dixon, R. P.; Snyder, J. S.; Bradley, L.; Linnenbrink, J. Org. Prep. Proced. Int. 2000, 32, 573-577. Sakowski, J.; Boehm, M.; Sattler, I.; Dahse, H.-M.; Schlitzer, M. J. Med. Chem. 2001, 44, 2886-2899. Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839-42. Satoh, T.; Mitsuo, N.; Nishiki, M.; Inoue, Y.; Ooi, Y. Chem. Pharma. Bull. 1981, 29, 1443-5.
12. Buck, J. S.; Ide, W. S. Org. Synth. 1933, 13, 28-30. Stipanovic, R. D.; Steidl, J. Synth. Commun. 1986, 16, 1809-13. Dixon, R. P.; Snyder, J. S.; Bradley, L.; Linnenbrink, J. Org. Prep. Proced. Int. 2000, 32, 573-577. Sakowski, J.; Boehm, M.; Sattler, I.; Dahse, H.-M.; Schlitzer, M. J. Med. Chem. 2001, 44, 2886-2899. Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839-42. Satoh, T.; Mitsuo, N.; Nishiki, M.; Inoue, Y.; Ooi, Y. Chem. Pharma. Bull. 1981, 29, 1443-5.
13. Buck, J. S.; Ide, W. S. Org. Synth. 1933, 13, 28-30. Stipanovic, R. D.; Steidl, J. Synth. Commun. 1986, 16, 1809-13. Dixon, R. P.; Snyder, J. S.; Bradley, L.; Linnenbrink, J. Org. Prep. Proced. Int. 2000, 32, 573-577. Sakowski, J.; Boehm, M.; Sattler, I.; Dahse, H.-M.; Schlitzer, M. J. Med. Chem. 2001, 44, 2886-2899. Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839-42. Satoh, T.; Mitsuo, N.; Nishiki, M.; Inoue, Y.; Ooi, Y. Chem. Pharma. Bull. 1981, 29, 1443-5.
14. Buck, J. S.; Ide, W. S. Org. Synth. 1933, 13, 28-30. Stipanovic, R. D.; Steidl, J. Synth. Commun. 1986, 16, 1809-13. Dixon, R. P.; Snyder, J. S.; Bradley, L.; Linnenbrink, J. Org. Prep. Proced. Int. 2000, 32, 573-577. Sakowski, J.; Boehm, M.; Sattler, I.; Dahse, H.-M.; Schlitzer, M. J. Med. Chem. 2001, 44, 2886-2899. Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839-42. Satoh, T.; Mitsuo, N.; Nishiki, M.; Inoue, Y.; Ooi, Y. Chem. Pharma. Bull. 1981, 29, 1443-5.
15. Buck, J. S.; Ide, W. S. Org. Synth. 1933, 13, 28-30. Stipanovic, R. D.; Steidl, J. Synth. Commun. 1986, 16, 1809-13. Dixon, R. P.; Snyder, J. S.; Bradley, L.; Linnenbrink, J. Org. Prep. Proced. Int. 2000, 32, 573-577. Sakowski, J.; Boehm, M.; Sattler, I.; Dahse, H.-M.; Schlitzer, M. J. Med. Chem. 2001, 44, 2886-2899. Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839-42. Satoh, T.; Mitsuo, N.; Nishiki, M.; Inoue, Y.; Ooi, Y. Chem. Pharma. Bull. 1981, 29, 1443-5.
16. Buck, J. S.; Ide, W. S. Org. Synth. 1933, 13, 28-30. Stipanovic, R. D.; Steidl, J. Synth. Commun. 1986, 16, 1809-13. Dixon, R. P.; Snyder, J. S.; Bradley, L.; Linnenbrink, J. Org. Prep. Proced. Int. 2000, 32, 573-577. Sakowski, J.; Boehm, M.; Sattler, I.; Dahse, H.-M.; Schlitzer, M. J. Med. Chem. 2001, 44, 2886-2899. Bellamy, F. D.; Ou, K. Tetrahedron Lett. 1984, 25, 839-42. Satoh, T.; Mitsuo, N.; Nishiki, M.; Inoue, Y.; Ooi, Y. Chem. Pharma. Bull. 1981, 29, 1443-5.
17. 2 addition.
18. The structure of impurity 9 was proposed by HPLC-MS analysis of the 8-chloro-10-bromoketone 7.
19. Borchardt, R. T.; Huber, J. H.; Houston, M. J. Med. Chem. 1982, 25, 258-63. Kasai, T.; Nakamori, T.; Furugaki, K. Nippon Kagaku Kaishi 1981, (4), 536-43.
20. Borchardt, R. T.; Huber, J. H.; Houston, M. J. Med. Chem. 1982, 25, 258-63. Kasai, T.; Nakamori, T.; Furugaki, K. Nippon Kagaku Kaishi 1981, (4), 536-43.
21. Aldrich (2003-2004): tin(II) bromide $72.20/50 g, tin(II) chloride $74.10/500 g, and tin(II) sulfate $73.30/500 g.
22. Tin(II) oxide was also effective for this reduction in the presence of 48% HBr.
23. The structure of impurity 10 was proposed by HPLC-MS analysis of the 8-chloro-10-bromoketone 7. The other potential dibromo impurity resulting from the minor C-7 dianzonium intermediate was not identified.
24. The residual Sn analysis was performed by QTI (Quantitative Technologies Inc.).
25. 2Cl: 259.0638, observed: 259.0634; mp 195-197°C.
26. 2ClBr: 336.9743, observed: 336.9737; mp 155-158°C.