Practical synthesis of chiral 2-morpholine: (4-Benzylmorpholin-2-(s)-yl)- (tetrahydropyran-4-yl) Methanone mesylate, a useful pharmaceutical intermediate

Organic Process Research and Development

Volumn 13, Issue 2, 2009, Pages 209-224

  Kopach, Michael E ^a,b   Singh, Utpal K ^a   Kobierski, Michael E ^a   Trankle, William G ^a   Murray, Michael M ^a   Pietz, Mark A ^a   Forst, Mindy B ^a   Stephenson, Gregory A ^a   Mancuso, Vincent ^a   Giard, Thierry ^c   Vanmarsenille, Michel ^a   De France, Thierry ^a  

^a ELI LILLY AND COMPANY   (United States)

^b GSK   (Belgium)

^c UCB Pharma SA Belgium ^*

Author keywords

[No Author keywords available]

Indexed keywords

EID: 65949108365     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op800247w     Document Type: Article

References (59)

1. (a) Berzewski, H.; Van Moffaert, M.; Gagiano, C. A. Eur. Neurov-sychopharmacoL 1997, 7, S37.
2. (b) Hajos, M.; Fleishaker, J. C.; Filipak-Resiner, J. K.; Brown, M. T.; Wong, E. H. F. CMS Drus Rev. 2004, 10, 23.
3. (c) Greenwood, D. T.; Mallion, K. B.; Todd, A. H.; Turner, W. J. Med. Chem. 1975, 18, 573.
4. (a) Greenwood, D. T.; Mallion, K. B.; Todd, A. H.; Turner, W. J. Med. Chem. 1975, 18, 573.
5. (b) Mallion, K. B.; Todd, A. H.; Turner, R. W.; Bainbridge, J. T.; Greenwood, D. T.; Madinaveitia, J.; Somerville, A. R.; Whittle, B. A. Nature (London). 1972, 238, 157.
6. Wong, E. H. F.; Ahmed, S.; Marshall, R. C.; McArthur, R.; Taylor, D. P.; Birgerson, L.; Cetera, P. WO 2001001973, 2001.
7. Zhao, M. M.; McNamara, J. M.; Ho, G.; Emerson, J. M.; Song, Z. J.; Tschaen, D. M.; Brands, K. M. J.; Dolling, U.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 2002, 67, 6743.
8. Tatsumi, Y.; Yokoo, M.; Senda, H.; Kakehi, K. Antimicrob. Aeents Chemother. 2002, 46, 3797.
9. Blythin, D. J.; Kuo, S.; Shue, Ft.; McPhail, A. T.; Chapman, R. W.; Kreutner, W.; Rizzo, C.; She, H.; West, R. Biors. Med. Chem. Lett. 1996, 6, 1529.
10. (a) Henegar, K. E.; Ball, C. T.; Horvath, C. M.; Maisto, K. D.; Mancini, S. E. Org. Process Res. Dev. 2007, 11, 346.
11. (b) Henegar, K. E.; Cebula, M. Org. Process Res. Dev. 2007, 11, 354.
12. (c) Cossy, J.; Pardo, D. G.; Metro, X. J. Org. Chem. 2008, 73, 707.
13. (d) Melloni, P.; Delia Torre, A.; Lazzari, E.; Mazzini, G.; Meroni, M. Tetrahedron 1985, 41, 1393.
14. Campbell, G. I.; Cases-Thomas, M. J.; Man, T.; Masters, J. J.; Eugenie Rudyk, H. C.; Walter, M. W. U.S. Patent Appl. 2007/0083046 Al, 2007.
15. (a) King, F. D.; Martin, R. T. Tetrahedron Lett. 1991, 32, 2281.
16. (b) Cases-Thomas, M. J.; Masters, J. J.; Walter, M. W.; Campbell, G.; Haughton, L.; Gallagher, P. T.; Dobson, D. R.; Mancuso, V.; Bonnier, B.; Giard, T.; Defrance, T.; Vanmarsenille, M.; Ledgard, A.; White, C.; Ouwerkerk-Mahadevan, S.; Brunelle, F. J.; Dezutter, N. A.; Herbots, C. A.; Lienard, J. Y.; Findlay, J.; Hayhurst, L.; Boot, J.; Thompson, L. K.; Hemrick-Luecke, S. Bioorg. Med. Chem. Lett. 2006, 16, 2022.
17. (c) Clark, B. P.; Gallagher, P. T.; Haughton, H. C. WO2004018440 Al, 2004.
18. (a) 4-Chlorotetrahydropyran is available in small quantities from Aldrich (CAS no. 1768-64-5) at 96.60/5 g. Larger quantities can be readily prepared via the following methods: Nikolic, N. A.; Gonda, E.; Longford, C. P.; Lane, N. T.; Thompson, D. W. J. Org. Chem. 1989, 54, 2748.
19. (b) Bunnelle, W. H.; Seamon, D. W.; Mohler, D. L.; Ball, T. F.; Thompson, D. W. Tetrahedron Lett. 1984, 25, 2653.
20. (a) Bachman, W. E., Ill; Hetzner, H. P. Organic Syntheses; John Wiley & Sons: New York, 1955; Collect. Vol. Ill, p 839.
21. (b) Colonge, J.; Marey, R. Organic Syntheses; John Wiley & Sons: New York, 1963; Collect. Vol. IV, p 601.
22. (a) Knochel, P.; Krasovsky, A. Angew. Chem., Int. Ed. 2004, 43, 3333.
23. (b) Murso, A.; Lang, S.; Hawk, D. Org. Process Res. Dev. 2006, 10, 733.
24. The mesylate salt la is defined as a regulatory starting material. For 2-substituted morpholine systems, mesylate salts are common and generally deliver excellent impurity control. See ref 7a and Berg, S.; Larsson, L.-G.; Renyi, L.; Ross, S. B.; Thorbery, S.-O.; Thorell-Swantessen, G. J. Med. Chem. 1998, 41, 1934.
25. The Weinreb amide 7, described in reference 8, was chemically unresolvable, and the high cost of N, O-dimethylhydroxyamine hy-drochloride would be untenable.
26. Aldrich [79-37-8]; up to 1.0% phosgene content is listed for reagent grade material.
27. (a) Prashad, M.; Har, D.; Ho, B.; Kim, H.; Girgis, M. J.; Chaudhary, A.; Repic, O.; Blacklock, T. J. Org. Process Res. Dev. 2004, 8, 330.
28. (b) Prashad, M.; Prashad, K.; Repic, O.; Blacklock, T. J. Org. Process Res. Dev. 1999, 3, 409.
29. (c) Shie, H. W.; Carlson, J. A.; Shore, M. G. Tetrahedron Lett. 1999, 40, 7167.
30. (a) Boggs, S. D.; Cobb, J. D.; Gudmundsson, K. S.; Jones, L. A.; Matsuoka, R. T.; Millar, A.; Patterson, D. E.; Samano, V.; Trone, M. D.; Xie, S.; Zhou, X.-m. Org. Process Res. Dev. 2007, 11, 539.
31. (b) Rzepecki, P.; Geib, N.; Cernovska, K.; Konig, B.; Schrader, J. J. Org. Chem. 2004, 69, 5169.
32. (c) Liu, J. O.; Su, Z.; Dai, X. Tetrahedron Lett. 2000, 44.
33. (d) Wissman, H.; Hoescht, A. G. Phosphorous Sulfur 1987, 30, 643.
34. (e) Wissman, H.; Kleiner, H. J.; Hoescht, A. G. Angew. Chem. 1980, 92, 129.
35. T3P is purchased as a 50 wt % solution in ethyl acetate. While the cost is significantly higher than IBCF (200/kg vs 20/kg), the 5% yield improvement would more than offset the extra reagent cost
36. Extraction of the aqueous layer reduced this amount to 0.27%.
37. In the aqueous process streams ~2-3% product was lost.
38. (a) E-factor = total kg of all materials/per kg of active pharmaceutical ingredient (API). See: Sheldon, R. D. Chem. Ind. (London). 1992, 93.
39. (b) Sheldon, R. D. CHEMTECH. 1994, 24, 38.
40. (a) Dale, D. J. Org. Process Res. Dev. 2002, 6, 933.
41. (b) Delhaye, L.; Stevens, C.; Merschaert, A.; Delbeke, P.; Brione, W.; Tilstam, U.; Borghese, A.; Geldoff, G.; Diker, K.; Dubois, A.; Barberis, M.; Casarubios, L. Org. Process Res. Dev. 2007, 11, 1104.
42. (c) Stefanick, S.; Grim, J.; Liu, F.; Sorgi, K. L.; Maryanoff, C. A. Org. Process Res. Dev. 2003, 7, 1067.
43. (d) Cajaiba da Silva, J. F.; Machado e Silva, C. F. P. Org. Process Res. Dev. 2002, 6, 829.
44. Measurement of the instantaneous heat flow is a direct measurement of reaction rate which in turn allows calculation of conversion and reaction rate constants. Effective use requires correlation of the observed heat effect with other analytical techniques such as NMR or LC to ensure that other thermal events, i.e., side reactions, mixing, and crystallization are not confounding the results.
45. Reactions near reflux were faster, but the kinetics were not feed-limited.
46. Typical heat capacity value of 2 J/g/°C was used for calculation of the adiabatic heat rise.
47. Tilstam, U.; Weinman, H. Org Process Res. Dev. 2002, 6, 905.
48. Based on vapor pressure of THF at 80 °C since the reaction temperature in the pilot plant was 60 °C.
49. Since 8a is added neat, a much higher water toleration is allowed for this substrate (1500 ppm).
50. (a) Wiss, J.; Lanzlinger, M.; Wermuth, M. Org. Process Res. Dev. 2005, 9, 365.
51. (b) Wiss, J.; Ermini, G. Org. Process Res. Dev. 2006, 10, 1282.
52. (c) am Ende, D. J.; Clifford, P. J.; Deantonis, D. M.; Santamaria, C.; Brenek, S. J. Org. Process Res. Dev. 1999, 3, 319.
53. Residual toluene <1% was readily achieved via solvent exchange due to the favorable azeotrope with 2-propanol/toluene.
54. Specification of residual 14 contained in la isolated solid for production lots was established at 0.50%. If necessary, recrystallization with 2-propanol reduces the level by ~50%.
55. (a) Van Alsten, J. G.; Reeder, L. M.; Stanchina, C. L.; Knoechel, D. J. Org. Process Res. Dev. 2008, 12, 989.
56. (b) Smith, A. A. Org. Process Res. Dev. 1997, 1, 165.
57. (c) Harrington, P. J.; Lodewijk, E. Org. Process Res. Dev. 1997, 1, 75.
58. Klokov, B. A. Org. Process Res. Dev. 2001, 5, 234.
59. The results underscore the necessity to avoid moisture. This is less of a concern on a pilot plant or commercial scale where process streams can easily be fully inerted and dried.