Development of a second-generation, highly efficient manufacturing route for the HIV integrase inhibitor raltegravir potassium

Organic Process Research and Development

Volumn 15, Issue 1, 2011, Pages 73-83

  Humphrey, Guy R ^a   Pye, Philip J ^a,d   Zhong, Yong Li ^a   Angelaud, Remy ^a,b   Askin, David ^b   Belyk, Kevin M ^a   Maligres, Peter E ^a   Mancheno, Danny E ^c,d   Miller, Ross A ^a   Reamer, Robert A ^a   Weissman, Steven A ^e  

^a MERCK RESEARCH LABORATORIES   (United States)

^b GENENTECH INC   (United States)

^c EMORY UNIVERSITY   (United States)

^d JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

^e Drug Metabolism and Pharmacokinetics   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

A-THERMAL; AMIDOXIME; FUNCTIONALIZED; HIV INTEGRASE INHIBITORS; SECOND-GENERATION SYNTHESIS;

ENVIRONMENTAL IMPACT; MANUFACTURE; PRODUCTIVITY;

POTASSIUM;

EID: 79251517734     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op100257r     Document Type: Article

References (38)

1. Kallings, L. O. J. Intern. Med. 2008, 263 (3) 218-243
2. AIDS epidemic update: December 2007 Joint United Nations Program on HIV/AIDS (UNAIDS) WHO; UNAIDS/07.27E/JC1322E; ISBN: 978 92 9 173621 8, 2007
3. HIV/AIDS Surveillance Report-2006; Centers for Disease Control and Prevention, 2008; Vol. 18.
4. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents.. Panel on Antiretroviral Guidelines for Adults and Adolescents; U.S. Department of Health and Human Services. December 1, 2009; pp 1 - 161. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
5. Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer, M. V.; Rowley, M. J. J. Med. Chem. 2008, 51, 5843-5855
6. Belyk, K. M.; Morrison, H. G.; Jones, P.; Summa, V. Preparation of N -(4-fluorobenzyl)-5-hydroxy-1-methyl-2-(1-methyl-1-{[(5-methyl-1,3, 4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6-oxo-1,6-dihydropyrimidine-4- carboxamide potassium salts as HIV integrase inhibitors. PCT Int. Appl. WO/2006/060712, 2006.
7. Johnson, T. B.; Caldwell, W. T. J. Am. Chem. Soc. 1929, 51, 873-880
8. Budesinsky, I.; Jelinek, V.; Prikryl, J. J. Collect. Czech. Chem. Commun. 1962, 27, 2550-2560
9. Sunderland, C. J.; Botta, M.; Aime, S.; Raymond, K. N. Inorg. Chem. 2001, 40, 6746-6756
10. Dreher, S. D.; Ikemoto, N.; Gresham, V.; Liu, J.; Dormer, P. G.; Balsells, J.; Mathre, D.; Novak, T. J.; Armstrong, J. D., III Tetrahedron Lett. 2004, 45, 6023-6025
11. Employed this three-step sequence, the hydroxypyrimidinones were prepared in 38-42% overall yields from 3 as shown below
12. Culbertson, T. P. J. Heterocycl. Chem. 1979, 16, 1423
13. Summa, V.; Petrocchi, A.; Matassa, V. G.; Taliani, M.; Laufer, R.; Franasco, R. D.; Altamura, S.; Pace, P. J. Med. Chem. 2004, 47, 5336-5339
14. Stansfield, I.; Avolio, S.; Colarusso, S.; Gennari, N.; Narjes, F.; Pacini, B.; Ponzi, S.; Harper, S. Bioorg. Med. Chem. Lett. 2004, 14, 5085-5088
15. Wagner, E.; Becan, L.; Nowakowska, E. Bioorg. Med. Chem. Lett. 2004, 12, 265-272
16. Zhong, Y.-L.; Zhou, H.; Gauthier, D. R., Jr.; Askin, D. Tetrahedron Lett. 2006, 47, 1315
17. Colarusso, S.; Attenni, B.; Avolio, S.; Malancona, S.; Harper, S.; Altamura, S.; Koch, U.; Narjes, F. ARKIVOC 2006, vii) 479
18. Koch, U.; Attenni, B.; Malancona, S.; Colarusso, S.; Conte, I.; Di Filippo, M.; Harper, S.; Pacini, B.; Giomini, C.; Thomas, S.; Incitti, I.; Tomei, L.; De Francesco, R.; Altamura, S.; Matassa, V. G.; Narjes, F. J. Med. Chem. 2006, 49, 1693
19. Ferrara, M.; Crescenzi, B.; Donghi, M.; Muraglia, E.; Nizi, E.; Pesci, S.; Summa, V.; Gardelli, C. Tetrahedron Lett. 2007, 48, 8379
20. Zhong, Y.-L.; Pipik, B.; Lee, J.; Kohmura, Y.; Okada, S.; Igawa, K.; Kadowaki, C.; Takezawa, A.; Kato, S.; Conlon, D.; Zhou, H.; King, A. O.; Reamer, R. A.; Gauthier, D. R., Jr.; Askin, D. Org. Process Res. Dev. 2008, 12, 1245-1252
21. Naidu, B. N. Synlett. 2008, 547-550
22. Pacini, B.; Avolio, S.; Ercolani, C.; Koch, U.; Migliaccio, G.; Narjes, F.; Pacini, L.; Tomei, L.; Harper, S. Bioorg. Med. Chem. Lett. 2009, 19, 6245-6249
23. For solvent screening on the reaction, please see: reference 7e.
24. For details of the thermal rearrangement mechanism of 6, please see
25. Pye, P. J.; Zhong, Y.-L.; Jones, G. O.; Reamer, R. A.; Houk, K. N.; Askin, D. Angew. Chem., Int. Ed. 2008, 47, 4134
26. Treatment of 6 with sodium methoxide afforded a Z / E mixture of methyl [3-(2-{[(benzyloxy)carbonyl]amino}propan-2-yl)-5-oxo-4,5-dihydro-6 H -1,2,4-oxadiazin-6-ylidene]ethanoate, which could not be converted to hydroxypyrimidinone 7 in the typical thermal rearrangement conditions and decomposed at higher temperature.
27. In one instance the thermal isomerization in the presence of DABCO resulted in an uncontrolled exotherm causing product decomposition and low yield.
28. About 5% of the imidazole was generated from the reaction.
29. Ogilvie, W.; Rank, W. Can. J. Chem. 1987, 65, 166
30. PMI = product mass intensity [total raw material input (kg)/quantity of bulk API (kg)]. Augé, J. Green Chem. 2008, 10, 225
31. Malik, S.; Nadir, U. K.; Pandey, P. S. Synth. Commun. 2008, 38, 3074
32. The scope, generality, and mechanism of the O -Me to N -Me rearrangement is under investigation and will be reported separately in due course.
33. Humphrey, G. R.; Miller, R. A.; Maligres, P. E.; Weissman, S. Process for preparing N -substituted hydroxypyrimidinone carboxamides. PCT Int. Appl. WO/2009/088729, 2009.
34. Des-F 34 results in formation of des-F 1, an impurity not rejected by crystallization.
35. Taillades, J.; Commeyras, A. Tetrahedron 1974, 30, 3407-3414
36. Rousset, A.; Lasperas, M.; Taillades, J.; Commeyras, A. Tetrahedron 1980, 36, 2649-2661
37. Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525-2527
38. Crescenzi, B.; Gardelli, C.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Petrocchi, A.; Poma, M.; Rowley, M.; Scarpelli, R.; Summa, V. Preparation of N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase. PCT Int. Appl. WO/2003/035077, 2003.