Fatty acid amide hydrolase inhibitors. 2. Novel synthesis of sterically hindered azabenzhydryl ethers and an improved synthesis of VER-156084

Tetrahedron Letters

Volumn 51, Issue 39, 2010, Pages 5191-5194

  Roughley, Stephen D ^a   Hart, Terance ^a,b  

^a Vernalis PLC   (United Kingdom)

^b Geistlich Pharma AG   (Switzerland)

Author keywords

Azabenzhydryl ether; Azetidine ether; Etherification; Fatty acid amide hydrolase (FAAH) inhibitor; Green chemistry; Hindered ether

Indexed keywords

ALCOHOL DERIVATIVE; ETHER DERIVATIVE; FATTY ACID AMIDASE INHIBITOR; UNCLASSIFIED DRUG; VER 156084;

ARTICLE; DRUG SYNTHESIS; ETHERIFICATION;

EID: 77956225478     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2010.07.136     Document Type: Article

References (18)

1. T. Hart, A.T. Macias, K. Benwell, T. Brooks, J. D'Alessandro, P. Dokurno, G. Francis, B. Gibbons, T. Haymes, G. Kennett, S. Lightowler, H. Mansell, N. Matassova, A. Misra, A. Padfield, R. Parsons, R. Pratt, A. Robertson, S. Walls, M. Wong, and S. Roughley Bioorg. Med. Chem. Lett. 19 2009 4241
2. Davidson, J. E. P.; Bentley, J. M.; Dawson, C. E.; Harrison, K.; Mansell, H. L.; Pither, A. L.; Pratt, R. M.; Roffey, J. R. A.; Ruston, V. J.; WO2004/096794, 2004; Chem. Abstr. 2004, 141, 410806.
3. R.H. Rynbrandt, B.D. Tiffany, D.P. Balgoyen, E.E. Nishizawa, and A.R. Mendoza J. Med. Chem. 22 1979 525
4. A.D. Dunn, and R. Norrie Z. Chem. 30 1990 245
5. All reagents were purchased from the Sigma-Aldrich Chemical Company except for (R)- and (S)-1-Boc-3-hydroxymethylpiperidine (CNH Technologies Inc., Woburn, MA), 3-hydroxyazetidine hydrochloride (Atlantic SciTech Group Inc., Linden, NJ) and 1-benzhydrylazetidin-3-ol (Fluorochem Ltd, Old Glossop, Derbyshire, UK). All commercial reagents were used as supplied without further purification.
6. P. Belmont, J.-C. Andrez, and C.S.M. Allan Tetrahedron Lett. 45 2004 2783
7. B. Bhat, and A.P. Bhaduri Synthesis 1984 673
8. See: e.g. T.W. Greene, and P.G.M. Wuts Protective Groups in Organic Synthesis 3rd ed. 1999 Wiley-Interscience New York
9. For a direct etherification, see: e.g. G. De Martino, G. La Regina, A. Di Pasquali, R. Ragno, A. Bergamini, C. Ciaprini, A. Sinistro, G. Maga, E. Crespan, M. Artico, and R. Silvestri J. Med. Chem. 48 2005 4378
10. Many alternative examples are prepared by indirect substrate-specific methods, see: e.g. Boyd, M.; Gagnon, M.; Lau, C.; Mellon, C.; Scheigetz, J. WO2004/022526, 2003; Chem. Abstr. 2003, 140, 270877.
11. M.-Q. Zhang, Y. Wada, F. Sato, and H. Timmerman J. Med. Chem. 38 1995 2472
12. K. Omura, and D. Swern Tetrahedron 34 1978 1651
13. S.L. Huang, K. Omura, and D. Swern Synthesis 1978 297
14. A.J. Mancuso, S.-L. Huang, and D. Swern J. Org. Chem. 43 1978 2480
15. G.V.M. Sharma, T.R. Prasad, and A.K. Mahalingam Tetrahedron Lett. 42 2001 759
16. 2
17. 2O: 427.1344.
18. In order to investigate further the difference in reactivity of the N-benzhydryl azetidin-3-ol and unprotected 3-hydroxyazetidine, we attempted the reaction of 4 with 3-hydroxyazetidine hydrochloride under our original Dean-Stark conditions, but no product formation was observed.