Deuterium labelling of the antidepressant drug doxepin for disposition studies in human subjects

Abstract

SUMMARYTwo methods have been developed for the introduction of deuterium into the doxepin molecule. The key intermediate (6,1l-dihydr0-1,2,3,4-~H,-dibenz b,e]oxepin-11-one, 5 ) was prepared by condensation of ethyl 2-bromomethylbenzoate with ['&&J-phenol, saponification of the resulting ester, and dehydration with trifluoroacetic anhydride. Using this key intermediate, E-( 1,2,3,4)-2H,-doxepin was repared for administration to human subjects.(1,2,3,4)-2H4-N-desrnethyldoxe in, (1,2,!,4,1',2',2')-21-17-doxepin, (1,2,3,4)-2H,-(N2H -doxepin (2H,o-doxepin) and (1,%3,4, 1',2',2')-2H,-N-desmethyldoxepin were also prepared q2 or use as internal standards in GC/MS assays. The deuterated compounds contained less than 0.5 % protiurn impurity.