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• 作者：Frank J. Urban ; Ralph Breitenbach ; Dianne Gonyaw ; and Bernard S. Moore
• 刊名：Organic Process Research & Development
• 出版年：1997
• 出版时间：March 1997
• 年：1997
• 卷：1
• 期：2
• 页码：131 - 136
• 全文大小：192K
• 年卷期：v.1,no.2(March 1997)
• ISSN：1520-586X

文摘

An efficient synthesis of the CCK_B antagonistN-tert-butyl-2-{3(R)-[3-(3-chlorophenyl)ureido]-8-methyl-2-oxo-5(R)-phenyl-1,3,4,5-tetrahydrobenz[b]azepin-1-yl}acetamide[(R)-1a] in optically active form is presented. The synthesis of thecore3-amino-5-phenylbenzazepin-2-one moiety started with thecoupling of 2-amino-4-methylbenzophenone (6a) anddiethyl3-phosphono-2-(methoxyimino)propionic acid (8).The resultingamide diethyl2-[3-phosphono-2-(methoxyimino)propionamido]-4-methylbenzophenone (9a) underwent intramolecularbenzazepinone ring formation in tetrahydrofuran with 2 equiv ofpotassium tert-butoxide to provide8-methyl-5-phenyl-1H-benz[b]azepine-2,3-dione 3-(O-methyloxime)(10a) in high yield.Hydrogenation over Raney nickel in methanol reducedboththe O-methyloxime and the 4,5-double bond, givingcis-3-amino-8-methyl-5-phenyl-1,3,4,5-tetrahydrobenz[b]azepin-2-one(7a)with high selectivity. A classical resolution of aminolactam7a and attachment of the N-1 and C-3 side chains affordedthetitle compound. The sequence was repeated with other2-aminophenyl ketones and was shown to work well for C-5substituents such as methyl and cyclohexyl or as part of afluorenyl group, thus providing an easy access to thesemolecules from readily available starting materials.