SYNTHESES OF PIPERIDINE AND PERHYDROAZEPINE DERIVATIVES, PRECURSORS OF 2 SELECTIVE ANTAGONISTS OF MUSCARINIC M(2) RECEPTORS - AF-DX-384 ANDITS PERHYDROAZEPINE ISOMER

Several routes to the synthesis of the polyamines 2a and 2b required f or the preparation of the muscarinic antagonists AF-DX 384 1a and its perhydroazepine isomer 1b respectively have been developed and compare d. Piperidine 2a has been obtained in 4 steps in 13-15% overall yield from 2-(chloromethyl)pyridine 3. The perhydroazepine 2b has been prepa red in 4 steps in 49% overall yield from 3-aminolactam 7. Transformati ons of piperidinemethanol 11 afford exclusively compound 2a (5 steps, 17-20% overall yield), via the N-tosylpiperidine 12, but lead to a 1:1 mixture of isomers 2a and 2b (4 steps, 15-20% overall yield for compo unds 2a and 2b) via the N-(cyanomethyl)piperidine 15. Limitations to t he ring enlargement of piperidine derivatives as a function of the het erocyclic nitrogen substituent are defined.