A convenient synthesis of 1-benzhydryl-N-arylsulfonyl-3-oxo-1,2-diazetidine-2-carboxamides.

In a search for novel compounds possessing potent antibiotic activity, a synthetic program was initiated aimed at the preparation of 1,2diazetidin-3-ones (monocyclic aza-p-lactams). The pioneering work of TAYLOR and coworkers1,2) provided a paradigm for this study as well as facile entry into this fascinating class of compounds. One aspect of the present study focused on the incorporation of an arylsulfonamidocarbonyl unit at N-2 in the diazetidinone nucleus which might increase the lability of the N-2, C-3 bond. Activation of the amide bond in classical (3-lactam derivatives is critical for good antibacterial action. In addition, the arylsulfonamidocarbonyl moiety should be sufficiently acidic to provide a properly positioned anionic charge which is also consonant with good activity.3) Herein is described a convenient one step procedure for the preparation of the most accessible members of this series. The synthesis of the starting 1-benzhydryl-1,2diazetidin-3-ones (1a c) was readily accomplished in three steps by the literature procedure.') Treatment of la with p-toluenesulfonylisocyanate or p-chlorophenylsulfonylisocyanate in CHZC12 at ambient temperature afforded acylated diazetidinone derivatives 2a (90%) and 3a (73%), respectively.' Analogously, compounds 2b,c and 3b,c were prepared utilizing diazetidinones 1b,c and the appropriate arylsulfonylisocyanate. When evaluated in vitro against representative strains of Gram-positive and Gram-negative bacteria, the title compounds of this limited study were ineffective at the concentrations tested (MIC> 128 ug/ml). Unexpectedly, these acylated diazetidinone derivatives displayed slight activity against a variety of pathogenic fungi, including: Cryptococcus neoformans (ATCC 14115), Trichophyton mentagrophytes (ATCC 9533), Histoplasma capsulatum (ATCC 11407), Blastomyces dermatitidis (ATCC 28839). General Procedure for the Synthesis of 1Benzhydryl-N-arylsulfonyl-3-oxo-1,2-diazetidine2-carboxamides To a solution of 4 mmol of the requisite 1benzhydryl1,2-diazetidin-3-one (1)1) and 20 ml of CH2Cl2 at ambient temperature under a nitrogen atmosphere was added in one portion a solution of 4 mmol of the appropriate arylsulfonylisocyanate and 5 ml of CH2C12. The reaction mixture was stirred at ambient temperature for 24~72 hours. Removal of the solvent under reduced pressure followed by trituration with Et2O furnished the title compounds.