Syntheses of piperidine and perhydroazepine derivatives, precursors of two selective antagonists of muscarinic M2 receptors: AF-DX 384 and its perhydroazepine isomer
Abstract
Several routes to the synthesis of the polyamines 2a and 2b required for the preparation of the muscarinic antagonists AF-DX 384 1a and its perhydroazepine isomer 1b respectively have been developed and compared. Piperidine 2a has been obtained in 4 steps in 13–15% overall yield from 2-(chloromethyl)-pyridine 3. The perhydroazepine 2b has been prepared in 4 steps in 49% overall yield from 3-aminolactam 7. Transformations of piperidinemethanol 11 afford exclusively compound 2a (5 steps, 17–20% overall yield)via the N-tosylpiperidine 12, ut lead o a 1:1 mixture of isomers 2a and 2b (4 steps, 15–20% overall yield for compounds 2a and 2b)via the N-(cyanomethyl)piperidine 15. Limitations to the ring enlargement of piperidine derivatives as a function of the heterocyclic nitrogen substituent are defined.