Highly efficient acidic etherification using a trichloroacetimidate for the preparation of (4-chlorophenyl)(2-pyridyl)methyl-4-piperidyl ether, a key intermediate of bepotastine

Bepotastinebesilate(TAU-284,(+)-(S)-4-{4-[(4-chlorophenyl) (2-pyridyl)methoxy]piperidino}butyric acid monobenzenesulfonate) is a nonsedative antiallergic drug with antihistamine activity that is used in the treatment of allergic rhinitis or allergic skin diseases. The bepotastine base, 1, is composed of two major parts: a 2-(4-chlorobenzyl)pyridyl moiety and an N-alky-lated-piperidyl moiety. The trichloroacetimidate method has been adopted for the synthesis of the key ether intermediate 3 of bepotastine, an antiallergic drug. Reaction of the trichloroace-timidate intermediate 4b with N -Boc-4-hydroxypiperidine and 1 equiv of Cu(OTf )₂ gave the ether 3 in 91% yield. Various alcohols were also reacted with trichloroacetimidate intermediate 4b in presence of Lewis acids to yield the corresponding ether products 7 in modest to high yields. A highly efficient and mild synthesis of racemic bepotastine free base has been developed using the trichloacetimidate etherification method under acidic conditions