ChemInform Abstract: One‐Pot, Regiospecific Assembly of (E)‐Benzamidines from δ‐ and γ‐Amino Acids via an Intramolecular Aminoquinazolinone Rearrangement.

Abstract

The utility of the effective method is demonstrated by its incorporation in the synthesis of various novel benzamidine structures of pharmaceutical interest.

Development of (E)-2-((1,4-Dimethylpiperazin-2-ylidene)amino)-5-nitro-N-phenylbenzamide, ML336: Novel 2-Amidinophenylbenzamides as Potent Inhibitors of Venezuelan Equine Encephalitis Virus

“…Examination of reactions employing a two-carbon-tethered, acyclic diamine revealed the formation of a rearranged (E)-amidine 45 that was structurally confirmed by 1 H and 13 C NMR, NOESY, and 2D NMR spectroscopy (Scheme 2). 35 The reaction was initially carried out with mono-BOC protected diamines, thus providing a snapshot of the reaction pathway leading to the amidine product by proceeding through intermediate 44; however, a onepot conversion was achieved with symmetrically substituted diamines to afford 45 in a reasonable 69% yield. Amidines were the only isolated products from the reaction, and the exclusive isolation of the (E)-configured double bond amidine was presumed to result from electronic and steric contributions in the transition state.…”

“…To our knowledge, this rearrangement has not been previously reported, and as such, a more comprehensive examination of the scope of this transformation is underway and will be disclosed in due course. 35 2-Amidinephenylbenzamide SAR. The conversion of quinazolinone intermediate 43 to amidine 45 represented a fortuitous scaffold modification, resulting in a nearly a 7-fold improvement in antiviral potency over the best quinazolinebased analogs while preserving the viral titer reduction capability and noncytotoxic attributes (45, Table 4).…”