Synthesis of a 6-aryloxymethyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one: a muscarinic (M3) antagonist.
A synthesis of the racemic 6-aryloxymethyl-5-hydroxy-2,3,4,5-[1H]-2-tetrahydrobenzazepin-4-one , for evaluation as a muscarinic (M(3)) antagonist, is described. 2-[2-tert-Butyldimethylsilyloxymethyl-6-(2,6-dimethoxyphenoxymethyl)phenyl]propan-2-ol was prepared from 2,6-dimethyl-1-bromobenzene and taken through to N-[3-(2,6-dimethoxyphenoxymethyl)-2-(propen-2-yl)phenyl]methyl-N-prop-2-enyl 2-nitrobenzene sulfonamide . However, attempts to cyclise this diene by alkene metathesis were unsuccessful, the open-chain alkene being the only product isolated in yields of up to 70%. In a second approach to the 6-aryloxymethyl-5-hydroxytetrahydrobenzazepin-4-one, methyl (Z)-3-[2-(1-tert-butyldimethylsilyloxymethyl)-6-(1,6-dimethoxyphenoxymethyl)phenyl]but-2-enoate was converted into (Z)-3-[2-hydroxymethyl-6-(2,6-dimethoxyphenoxymethyl)phenyl]but-2-enyl 2-nitrobenzene sulfonamide which was cyclised under Mitsunobu conditions to the corresponding 2,3-dihydro-[1H]-2-benzazepine . The structure of this was confirmed by an X-ray crystal structure of its 2-(4-bromophenylsulfonyl) analogue , and functional group modification including hydroxylation, attachment of the requisite side-chain at C(2) and further oxidation gave the target compound which was assayed for muscarinic (M(3)) activity.
Evans
Paul
P
The School of Chemistry, The University of Manchester, Manchester, UK.
Lee
Alan T L
AT
Thomas
Eric J
EJ
D001552:Benzazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*
D001552:Benzazepines; D043587:Receptor, Muscarinic M3