Synthesis of N-Alkyl-1,2,4-oxadiazinones as Angiotensin-II (AT1) Receptor Antagonists

Abstract

a& 4-Alkyl-1,2,4-oxadiazinones were prepared by regiospecific alkylation of the corresponding 4H-oxadiazinones, which were synthesized by a trimethylaluminum mediated cyclization reaction.Alkylation was regiospecific and generally facile; in one example, however, an unusual fragmentation reaction occurred.A homochiral oxadiazineone was also prepared and alkylated under the described conditions.4-Biphenylmethyl-1,2,4-oxadi-adnones were potent angiotensin-I1 receptor antagonists.In the course of our research into preparation of novel angiotensin-I1 receptor antagonists, we sougbt to identify bioisosteric heterocycles to replace the imidazole ring in prototype antagonists such as Exp-7711,l DoP-753,' and SKF 108,566.2Alky-(4E)-1,2,4-oxadiazin-5-ones, exemplified by 1, appeared to be attractive targets and have not been previously reported in the literature.An obvious synthetic approach to such targets would be N-alkylation of the parent heterocycles.The literature states, however, that the 1,2,4-oxadiazinone ring "appears to have acidic properties but is resistant to alkylation or acylation"? and even if alkylation were to be achieved questions of regiochemistry would remain to be addressed.We have overcome these difficulties and now report an improved synthesis of 4H-1,2,4-oxadiazinones and their regiospecific 4-alkylation, resulting in a series of novel and potent angiotensin-I1 receptor antagonists.In addition, we report synthesis of a homochiral 1,2,4-oxadiazinone.Oxadiazinones have been prepared by reaction of amidoximes with a-halo acid chlorides4 or a-halo esters.5In our hands, reaction of amidoxime (2)7with a-bromoesters (3) led smoothly to the Q-alkyl ester intermediates (4),