Synthesis 2007(19): 3051-3055  
DOI: 10.1055/s-2007-990774
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 1-Oxo-1-(3-pyridazinyl) Derivatives - Potent Inhibitors of Fatty Acid Amide Hydrolase (FAAH): An Improved and Optimized Procedure

Goffredo Rosini*a, Daniele G. Andreottib, Primiano D’Ambrosioa, Emanuela Marottaa, Alessandro Tinarellia, Paolo Righia
a Dipartimento di Chimica Organica ‘A. Mangini’ - Alma Mater Studiorum, Università di Bologna, Viale del Risorgimento 4, 40136 Bologna, Italy
Fax: +39(051)2093654; e-Mail: [email protected];
b GlaxoSmithKline, Medicine Research Centre, Via A. Fleming 4, 37135 Verona, Italy
Further Information

Publication History

Received 18 May 2007
Publication Date:
11 September 2007 (online)


A greatly improved procedure for the preparation of long-chain α-ketopyridazines, a class of potent inhibitors of fatty acid amide hydrolase (FAAH), is described. This optimization study shows a great dependence of the yields of desired products on the pyrididazinyl lithium/Weinreb amide ratio and offers a general approach to this kind of compound.


  • 1a Cravatt BF. Giang DK. Mayfield SP. Boger DL. Lerner RA. Gilula NB. Nature (London)  1996,  384:  83 
  • 1b McKinney MK. Cravatt BF. Ann. Rev. Biochem.  2005,  74:  411 
  • 2a Boger DL. Sato H. Lerner AE. Hedrick MP. Fecik RA. Miyauchi H. Wilkie GD. Austin BJ. Patricelli MP. Cravatt BF. Proc. Natl. Acad. Sci. U.S.A.  2000,  97:  5044 
  • 2b Boger DL. inventors; (The Scripps Research Institute)  US Patent 6462054 B1.  2002; Chem. Abstr. 2002, 137, 279215
  • 3 The use of α-keto heterocycles as inhibitors was first disclosed by Edwards et al. in 1992: Edwards PD. Meyer EF. Vijayalakshimi J. Tuthill PA. Andisik DA. Gomes B. Strimpler A. J. Am. Chem. Soc.  1992,  114:  1854 
  • 4 Plé N. Turck A. Couture K. Quéguiner G. J. Org. Chem.  1995,  60:  3781 
  • 5a More recently, a new strategy for deprotonative func­-tionalization of aromatics with excellent chemoselectivity and unique regioselectivity using t-Bu-P4 base in the presence of ZnI2 has appeared in the literature: Imahori T. Kondo Y. J. Am. Chem. Soc.  2003,  125:  8082 
  • 5b

    Using this approach, pyridazine was treated with diphenyl ketone and gave a 4-substituted 1,2-adduct in 91% yield.

  • 6a Nahm S. Weinreb SM. Tetrahedron Lett.  1981,  22:  3815 
  • 6b Ballini R. Marcantoni E. Torreggiani E. J. Nat. Prod.  1997,  60:  505 
  • 7 Kofron WG. Baclawski LM. J. Org. Chem.  1976,  41:  1879