Synthesis of Vildagliptin-β-O-Glucuronide

Yansong Jack Lu, Yugang Liu, Mahavir Prashad, Wen-Chung Shieh

Chemical and Analytical Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, USA.

DOI: 10.4236/aces.2012.23045                

Abstract

A linear 7-step synthesis of vildagliptin-β-O-glucuronide (2) starting from commercially available D-glucurono-6, 3-lactone (3) was herein achieved with 11.3% overall yield. Efficient preparation of compound 6 in pure α form was obtained, which was proved critical to achieve high anomeric selectivity in β-O-glycosylation later. The direct β-O-glycosylation of vildagliptin (1) containing both a tertiary alcohol and a secondary amine was studied and achieved in good yield. The deprotection step to afford product was delicately executed to avoid hydrolysis of nitrile group. The target compound 2 was obtained after purification by reversed-phase C18 chromatography.

Keywords

Vildagliptin; O-Glycosylation; DPP-4 Inhibitors; Type-2 Diabetes

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	E. B. Villhauer, J. A. Brinkman, G. B. Naderi, B. F. Burkey, B. E. Dunning, P. Kapa, B. L. Mangold, M. E. Russell and T. E. Hughes, “1-[[(3-Hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine: A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties,” Journal of Medicinal Chemistry, Vol. 46, No. 13, 2003, pp. 2774-2789.
[2]	U. Hassiepen and M. Kittelmann, “Adamantyl O-Glucuronide Derivatives as Inhibitors of Dipeptidyl Peptidase IV for the Treatment of Diabetes,” PCT International Application, WO 2009/068531.
[3]	R. Nakajima, M. Ono, S. Aiso and H. Akita, “Synthesis of Methyl 1-O-(4-Hydroxymethamphetaminyl)-α-D-Glucopyranouronate,” Chemical and Pharmaceutical Bulletin, Vol. 53, No. 6, 2005, pp. 684-687. doi:10.1248/cpb.53.684
[4]	K. Toshima and K. Tatsuta, “Recent Progress in O-Glycosylation Methods and Its pplication to Natural Products Synthesis,” Chemical Review, Vol. 93, No. 4, 1993, pp. 1503-1531.
[5]	H. Pellissier, “Use of O-Glycosylation in Total Synthesis,” Tetrahedron, Vol. 61, No. 12, 2005, pp. 2947-2993. doi:10.1016/j.tet.2005.01.070
[6]	Y. Okada, T. Mukae, K. Okajima, M. Taira, M. Fujita and H. Yamada, “Highly β-Selective O-Glucosidation Due to the Restricted Twist-Boat Conformation,” Organic Letters, Vol. 9, No. 8, 2007, pp. 1573-1576. doi:10.1021/ol070427b
[7]	K. S. Kim, J. H. Kim, Y. J. Lee, Y. J. Lee and J. Park, “2-(Hydroxycarbonyl)benzyl Glycosides: A Novel Type of Glycosyl Donors for Highly Efficient β-Mannopyranosylation and Oligosaccharide Synthesis by Latent-Active Glycosylation,” Journal of the American Chemical Society, Vol. 123, No. 35, 2001, pp. 8477-8481. doi:10.1021/ja015842s
[8]	C. Lacy and M. Sainsbury, “A Synthesis of Morphin-6-glucuronide,” Tetrahedron Letters, Vol. 36, No. 22, 1995, pp. 3949-3950. doi:10.1016/0040-4039(95)00649-W
[9]	S. Chittaboina, B. Hodges and Q. Wang, “A Facile Route for the Regioselective Deacetylation of Peracetylated Carbohydrates at Anomeric Position,” Letters in Organic Chemistry, Vol. 3, No. 1, 2006, pp. 35-38. doi:10.2174/157017806774964521