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

✍ Scribed by Chandra Prakash; Samir Saleh; Douglass F. Taber; Grant R. Wilkinson; Ian A. Blair

• Publisher: John Wiley and Sons
• Year: 1990
• Tongue: French
• Weight: 528 KB
• Volume: 28
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.2580280908

✦ Synopsis

Abstract

Two methods have been developed for the introduction of deuterium into the doxepin molecule. The key intermediate (6,11‐dihydro‐1,2,3,4‐^2^H~4~‐dibenz[b,e]oxepin‐11‐one, 5) was prepared by condensation of ethyl 2‐bromomethylbenzoate with [^2^H~6~]‐phenol, saponification of the resulting ester, and dehydration with trifluoroacetic anhydride. Using this key intermediate, E‐(1,2,3,4)‐^2^H~4~‐doxepin was prepared for administration to human subjects. (1,2,3,4)‐^2^H~4~‐N‐desmethyldoxepin, (1,2,3,4,1′,2′,2′)‐^2^H~7~‐doxepin, (1,2,3,4)‐^2^H~4~‐(N^2^H~3~)~2~‐doxepin (^2^H~10~‐doxepin) and (1,2,3,4,1′,2′,2′)‐^2^H~7~‐N‐desmethyldoxepin were also prepared for use as internal standards in GC/MS assays. The deuterated compounds contained less than 0.5% protium impurity.