An efficient process for the manufacture of carmegliptin

Organic Process Research and Development

Volumn 15, Issue 3, 2011, Pages 503-514

  Abrecht, Stefan ^a,b   Adam, Jean Michel ^a,b   Bromberger, Ulrike ^a,c   Diodone, Ralph ^a,c   Fettes, Alec ^a,b   Fischer, Rolf ^a,c   Goeckel, Volker ^a,c   Hildbrand, Stefan ^a,c   Moine, Gérard ^a,b   Weber, Martin ^a,c  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

^b Pharma Research and Early Development Process Research and Synthesis   (Switzerland)

^c Pharma Technical Development Actives   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

AMINE DEPROTECTION; CRYSTALLIZATION-INDUCED DYNAMIC RESOLUTIONS; DIASTEREOSELECTIVE; EFFICIENT PROCESS; ENAMINES; FUNCTIONALIZED; HOFMANN REARRANGEMENT; LARGE-SCALE PRODUCTION; STEREOGENIC CENTERS;

AMIDES; MANUFACTURE; ORGANIC COMPOUNDS;

CYCLIZATION;

EID: 79957446940     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op2000207     Document Type: Article

References (60)

1. http://www.cdc.gov/chronicdisease/resources/publications/AAG/ddt.htm.
2. http://www.diabetesatlas.org/content/diabetes-and-impaired-glucose- tolerance.
3. Gupta, R.; Walunj, S. S.; Tokala, R. K.; Parsa, K. V. L.; Singh, S. K.; Pal, M. Current Drug Targets 2009, 10, 71
4. Böhringer, M.; Fischer, H.; Hennig, M.; Hunziker, D.; Huwyler, J.; Kuhn, B.; Löffler, B. M.; Lübbers, T.; Mattei, P.; Narquizian, R.; Sebokova, E.; Sprecher, U.; Wessel, H. P. Bioorg. Med. Chem. Lett. 2010, 20, 1106
5. Mattei, P.; Böhringer, M.; Di Giorgio, P.; Fischer, H.; Hennig, M.; Huwyler, J.; Kocer, B.; Kuhn, B.; Löffler, B. M.; MacDonald, A.; Narquizian, R.; Rauber, E.; Sebokova, E.; Sprecher, U. Bioorg. Med. Chem. Lett. 2010, 20, 1109
6. Böhringer, M.; Kuhn, B.; Lübbers, T.; Mattei, P.; Narquizian, R.; Wessel, H. P. (F. Hoffmann-La Roche AG). U.S. Pat. Appl. 2004/0259902, 2004.
7. For an overview on DPP-IV inhibitor syntheses, see: Mulakayala, N.; Reddy, C. H. U.; Iqbal, J.; Pal, M. Tetrahedron 2010, 66, 4919
8. 3 is J = 11.5 Hz, which is typical for a diaxial orientation of these protons.
9. Brossi, A.; Lindlar, H.; Walter, M.; Schnider, O. Helv. Chim. Acta 1958, 41, 119
10. Abrecht, S.; Adam, J.-M.; Fettes, A.; Hildbrand, S. (F. Hoffmann-La Roche AG). PCT Int. Appl. WO/2008/031749 A1, 2008.
11. Bromberger, U.; Diodone, R.; Hildbrand, S.; Meier, R. (F. Hoffmann-La Roche AG). PCT Int. Appl. WO/2009/027276 A1, 2009.
12. Details on the synthesis of the requisite (S)-fluoromethyl lactone 31 are described elsewhere: Adam, J.-M.; Foricher, J.; Hanlon, S.; Lohri, B.; Moine, G.; Schmid, R.; Stahr, H.; Weber, M.; Wirz, B.; Zutter, U. Org. Process Res. Dev. 2011, 15, DOI: 10.1021/op200019k.
13. Xu, L. W.; Li, J.-W.; Xia, C.-G.; Hu, X.-X. Synlett 2003, 2425
14. Chapman, J. H.; Holton, P. G.; Ritchie, A. C.; Walker, T.; Webb, G. B.; Whiting, K. D. E. J. Chem. Soc. 1962, 2471
15. Schneider, W.; Kämmerer, E.; Schilken, K. Pharmazie 1966, 26
16. Walker, T.; England, W.; Frederick, K.; Rhondda, M.; Wales, G.; Ritchie, A. C. U.S. Patent 3,105,835, 1963.
17. Decomposition was observed at room temperature as also previously observed in the literature; see reference 9.
18. 6. For keto-enol form analytical data see also: Kiang, A. K.; Tan, S. F.; Wong, W. S. J. Chem. Soc (C) 1971, 2721
19. For earlier preparations see: Findlay, S. P. J. Org. Chem. 1957, 22, 1385-1394
20. Ray, J. A.; Harris, T. M. Tetrahedron Lett. 1982, 23, 1971
21. Kozikowski, A. P.; Schmiesing, R. Tetrahedron Lett. 1978, 19, 4241
22. Ruminski, P. G.; Dhingra, O. P. U.S. Patent 4,747,871.
23. Sharma, V. K.; Shahriari-Zavareth, H.; Garratt, P. J.; Sondheimer, F. J. Org. Chem. 1983, 48, 2379
24. Meltzer, P. C.; Wang, B.; Chen, Z.; Blundell, P.; Jayaraman, M.; Gonzales, M. D.; George, C.; Madras, B. K. J. Med. Chem. 2001, 44, 2619 and references cited therein.
25. Precharging of the diacid in acetic acid led to clump formation.
26. For reviews on crystallization-induced dynamic transformations, see: Brands, K. M. J.; Davies, A. J. Chem. Rev. 2006, 106, 2711
27. Kolarovic, A.; Berkes, D. A.; Baran, P.; Povazanec, F. Tetrahedron Lett. 2005, 46, 975
28. Berkes, D.; Jakubec, P.; Winklerova, D.; Povazanec, F.; Daich, A. Org. Biomol. Chem. 2007, 5, 121
29. Openshaw, H. T.; Whittaker, N. J. Chem. Soc. 1963, 1461
30. Clark, R. D.; Kern, J. R.; Kurz, L. J.; Nelson, J. T. Heterocycles 1990, 31, 353
31. Dibenzoyltartaric acid was preferred over dibenzoyltartaric acid monodimethylamide for cost reasons.
32. Temperatures higher than 60 °C for extended periods of time led to decomposition of the resolving agent.
33. The kinetic studies were performed on a Multimax ART workstation (Mettler-Toledo) equipped with a 16 × 5 mL reactor block. Dosing of the solvents as well as sampling (quench and dilution) was fully automated. HPLC analyses were performed off-line (the quench and dilution protocol provided stable samples).
34. Negative values of the enantiomeric excess indicate that crystallization of the (R)-enamine (-)-DBTA salt has started, in which case the (R)-enantiomer becomes predominant, and analytical sampling becomes difficult because of the heterogeneous reaction mixture.
35. Dichloromethane is the only solvent which can be used to extract the relatively polar unprotected ester.
36. Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 102, 6203
37. Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151
38. Liang, H. Synlett 2008, 2554
39. Hofmann rearrangements can also be problematic upon scale-up because the reactions tend to be exothermic.
40. Allred, E. L.; Hurwitz, M. D. J. Org. Chem. 1965, 30, 2376
41. Approximately 2% of the methyl ester (which is formed immediately when sodium methoxide is added to the reaction mixture) usually remained after the reaction.
42. Hofmann, A. W. v. Chem. Ber. 1881, 14, 2725
43. Wallis, E. S.; Lane, J. F. Org. React. 1949, 3, 267
44. Zhang, L. H.; Kauffman, G. S.; Pesti, J. A.; Yin, J. G. J. Org. Chem. 1997, 62, 6918
45. Radhakrishna, A. S.; Parham, M. E.; Riggs, R. M.; Loudon, G. M. J. Org. Chem. 1979, 44, 1746
46. Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.; Blodgett, J. K.; Boutin, R. H. J. Org. Chem. 1984, 49, 4272
47. This byproduct is presumably formed by intramolecular trapping of the intermediate isocyanate, followed by intermolecular addition to a second isocyanate.
48. During this distillation 29 is quantitatively hydrolyzed to yield 30.
49. The urea byproduct 30 is carried through to the final step where it is deprotected. It could not be depleted by crystallization in any step and hence must be limited to max. 0.25% in isolated amine 10.
50. -31 was typically produced with 99.0-99.5% ee. See reference 8 for details.
51. Openshaw, H. C.; Whittaker, N. J. Chem. Soc. C 1969, 89
52. The cyclization was also performed under Mitsunobu conditions using diethyl azodicarboxylate (DEAD), di- tert -butyl azodicarboxylate (DTAD) or diisopropyl azodicarboxylate (DIAD) in combination with triphenylphosphine or tributylphosphine. However, the crude yield usually was below 70%, the separation from the phosphine oxides was difficult, and the cost of the reagents was an issue. This variant was therefore abandoned in favor of above cheap and effective mesylation-cyclization method. For related cyclizations under Mitsunobu conditions, see: Bell, I. M.; Beshore, D. C.; Gallicchio, S. N.; Williams, T. M. Tetrahedron Lett. 2000, 41, 1141
53. During workup, silicon-containing byproducts (e.g., hexamethyldisiloxane or trimethylsilanol) are formed, which are present in all organic and aqueous waste streams and which cause plugging of the pipes upon incineration if no appropriate incineration facilities are in place.
54. Lithium tert -butoxide is commercially available as a 20% (w/w) solution in THF from e.g. Chemetall.
55. If hydroxybutyramide 32 is heated over the weekend in toluene (10 mL/g hydroxybutyramide) at 105 °C in the presence of 2-hydroxypyridine, 20% by area (HPLC) of amine 10 are formed, showing that it is indeed a reversible reaction.
56. This catalyst was found to be considerably more active than 2-hydroxypyridine.
57. The reaction was originally conducted at higher concentration (10 L/kg amine) and in a full batch mode. However, under such conditions, the product crashed out already during the heating period, leading to an extremely thick suspension and crust formation on the reactor walls. Also, a constant reaction temperature of 85 °C was probed, leading to an overall considerably lower and incomplete conversion.
58. The deprotection of 13 with HCl in acetone revealed only traces of the nongenotoxic aldol condensation products mesityloxide and isomesityloxide. For discussion, see: Coffey, D. S.; Hawk, M. K. N.; Pedersen, S. W.; Ghera, S. J.; Marler, P. G.; Dodson, P. N.; Lytle, M. L. Org. Process Res. Dev. 2004, 8, 945
59. Although all distillates are recyclable, recycling of the solvent was not taken into account.
60. Typically, yields of 80% were obtained instead of the 85% in the experiment described herein. This high yield is due to holdup from the previous batches.