Arformoterol tartrate

Synthesis

There are several reports on the synthesis of arformoterol. A large-scale synthesis of enantio/diastereomerically pure (R,R)-formoterol is cited here. Bromoalcohol 22 was synthesized in 84% yield with 94% e.e. through the catalytic enantioselective reduction of bromo ketone 21. The nitro functional group in 22 was reduced in quantitative yield by hydrogena-tion in the presence of Adams catalyst and the resulting aniline was isolated by filtration of the catalyst and removal of the solvent. In order to avoid auto-oxidation, the aniline was treated with a mixture of formic acid and acetic anhydride immediately after the removal of the platinum catalyst. Upon concentrating the reaction mixture, bromohydrin 23 crystallized and could be isolated in 75% yield with 98.6% e.e. It was further enriched to >99.5% e.e. by a single re-crystallization from ethylacetate. Next, a mixture of bromohydrin 23 and amine salt (R)-26-(S)-mandelic acid was treated with K2CO3 resulting in generation of the corresponding epoxide of 23 and liberation of the free base of (R)-26. After an aqueous work up to remove salts and mandelic acid, the reaction mixture was heated to 120°C to affect epoxide opening with the amine of 26. Removal of the benzyl protecting groups of the resulting crude product via catalytic hydrogenation followed by salt formation with tartaric acid afforded arformoterol tartrate (III) in 70% yield upon crystallization.