Efficient Synthesis of 8-Oxa-3-aza-bicyclo[3.2.1]octane Hydrochloride†

A four-step process to generate 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride starting with 5-hydroxymethyl-2-furfuraldehyde is described. Raney nickel-mediated reduction of 5-hydroxymethyl-2-furfuraldehyde afforded 2,5-bis(hydroxymethyl)tetrahydrofuran with a predominantly cis configuration. Conversion of the diol to a ditosylate, followed by cyclization with benzylamine generated the 8-oxa-3-aza-bicyclo[3.2.1]octane core. The title compound was prepared via hydrogenolysis of the N-benzyl group with Pearlman’s catalyst and isolated as the hydrochloride salt from a mixture of 2-propanol and heptane. The overall yield for the process was 43−64%. An impurity generated during scale up highlighted the need for a strict in-process specification for acetonitrile content prior to performing the final hydrogenolysis. Ethanol conditioning of all processing equipment that had acetonitrile contact prior to the introduction of the substrate stock solution is highly recommended.