Synthesis of a 6-aryloxymethyl-5-hydroxy-2,3,4,5-tetrahydro-[1H]-2-benzazepin-4-one: a muscarinic (M3) antagonist

Abstract

A synthesis of the racemic 6-aryloxymethyl-5-hydroxy-2,3,4,5-[1H]-2-tetrahydrobenzazepin-4-one 2, for evaluation as a muscarinic (M₃) antagonist, is described. 2-[2-tert-Butyldimethylsilyloxymethyl-6-(2,6-dimethoxyphenoxymethyl)phenyl]propan-2-ol 10 was prepared from 2,6-dimethyl-1-bromobenzene 5 and taken through to N-[3-(2,6-dimethoxyphenoxymethyl)-2-(propen-2-yl)phenyl]methyl-N-prop-2-enyl 2-nitrobenzene sulfonamide 4. However, attempts to cyclise this diene by alkene metathesis were unsuccessful, the open-chain alkene 15 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 24 was converted into (Z)-3-[2-hydroxymethyl-6-(2,6-dimethoxyphenoxymethyl)phenyl]but-2-enyl 2-nitrobenzene sulfonamide 17 which was cyclised under Mitsunobu conditions to the corresponding 2,3-dihydro-[1H]-2-benzazepine 3. The structure of this was confirmed by an X-ray crystal structure of its 2-(4-bromophenylsulfonyl) analogue 28, and functional group modification including hydroxylation, attachment of the requisite side-chain at C(2) and further oxidation gave the target compound 2 which was assayed for muscarinic (M₃) activity.