DEUTERIUM LABELING OF THE ANTIDEPRESSANT DRUG DOXEPIN FOR DISPOSITION STUDIES IN HUMAN-SUBJECTS

Two methods have been developed for the introduction of deuterium into the doxepin molecule. The key intermediate (6,11‐dihydro‐1,2,3,4‐2H4‐dibenz[b,e]oxepin‐11‐one, 5) was prepared by condensation of ethyl 2‐bromomethylbenzoate with [2H6]‐phenol, saponification of the resulting ester, and dehydration with trifluoroacetic anhydride. Using this key intermediate, E‐(1,2,3,4)‐2H4‐doxepin was prepared for administration to human subjects. (1,2,3,4)‐2H4‐N‐desmethyldoxepin, (1,2,3,4,1′,2′,2′)‐2H7‐doxepin, (1,2,3,4)‐2H4‐(N2H3)2‐doxepin (2H10‐doxepin) and (1,2,3,4,1′,2′,2′)‐2H7‐N‐desmethyldoxepin were also prepared for use as internal standards in GC/MS assays. The deuterated compounds contained less than 0.5% protium impurity. Copyright © 1990 John Wiley & Sons, Ltd.