EFFICIENT SYNTHESIS OF NYL-1,3,4,5-TETRAHYDROBENZ[B]AZEPIN-1-YL)ACETAMIDE AND RELATED CCKB ANTAGONISTS

An efficient synthesis of the CCKB antagonist nyl-1,3,4,5-tetrahydrobe nz[b]azepin-1-yl}acetamide [(R)-1a] in optically active form is presen ted, The synthesis of the core 3-amino-5-phenylbenzazepin-2-one moiety started with the coupling of 2-amino-4-methylbenzophenone (6a) and di ethyl 3-phosphono-2-(methoxyimino)propionic acid (8), The resulting am ide diethyl 2-(methoxyimino)propionamido]-4-methylbenzophenone (9a) un derwent intramolecular benzazepinone ring formation in tetrahydrofuran with 2 equiv of potassium tert-butoxide to provide 8-methyl-5-phenyl- 1H-benz-[b]azepine-2,3 dione 3-(O-methyloxine) (10a) in high yield, Hy drogenation over Raney nickel in methanol reduced bath the O-methyloxi me and the 4,5-double bond, giving tetrahydrobenz[b]azepin-2-one,3,4,5 -tetrahydrobenz (7a) with high selectivity, A classical resolution of amino lactam 7a and attachment of the N-1 and C-3 side chains-afforded the title compound, The sequence was repeated with other 2-aminopheny l ketones and was shown to work well for C-5 substituents such as meth yl and cyclohexyl or as part of a fluorenyl group, thus providing an e asy access to these molecules from readily available starting material s.