Synthesis, stereochemistry and anti‐tetrabenazine activity of bicyclo analogues of 2‐phenylmorpholines

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Abstract
A series of bicyclo analogues of several 2‐phenylmorpholines were synthesized and tested for anti‐tetrabenazine activity in mice. Most of the target compounds were prepared by reaction of 2‐bromopropio‐phenone (22) with the appropriate amino alcohol to form 2‐phenylmorpholinols. Reduction of the 2‐phenyl‐morpholinols with sodium borohydride gave amino diols, which were cyclized to morpholines with acid. Alternatively, oxazines17and18were synthesized by alkylation of phenyl‐(2‐pyrrolo)carbinol(32a)and phenyl‐(2‐piperidyl)carbinol(32b)with 2‐bromoethanol, followed by cyclization of the resulting amino diols with acid. Only the spirocyclic compounds8and9had i.p. anti‐tetrabenazine activity comparable to the non‐cyclic compounds2a‐3b, but8and9were less active by the oral route of administration.