合成路线1

oxidation of 8-acetyl-6-benzyloxy-1,4-benzoxazin-3-one (I) with Seo2 in refluxing dioxane/water yields the arylglyoxal hydrate (II) (1), which is subjected to reductive amination with 2-(4-methoxyphenyl)-1,1-dimethylethylamine (III) using either LiBH4 in THF or naBH4 in EtoH to give benzyl-protected racemic olodaterol (IV). Debenzylation of intermediate (IV) using H2So4 in the presence of t-Buono in MeoH or by catalytic hydrogenolysis over Pd/C in MeoH affords racemic olodaterol (V) , which is finally resolved by means of chiral HPLC and the (R)-enantiomer (VI) treated with hydrochloric acid in i-ProH .
In an alternative procedure, a-halogenation of ketone (I) with benzyltrimethylammonium chloroiodate (BTMA-ICl) or dichloroiodate (BTMA-ICl2) in DCE/AcoH/H2o , or with tetrabutylammonium tribromide (TBATB) in dioxane , yields the respective 8-(halo acetyl)-1,4-benzoxazin-3-ones (VIIa) and (VIIb) . Enantio selective transfer hydrogenation of the chloroacetophenone derivative (VIIa) with HCooH and Et3n in the presence of RhCl[(S,S)-TsDPEn(p-cymene)] or RuCl[(S,S)-TsDPEn(p-cymene)] in DMF , or chiral reduction of bromoacetophenone derivative (VIIb) with (–)-DIPCl in THF , provides the corresponding (R)-halohydrins (VIIIa) or (VIIIb) . Cyclization of these halohydrins by means of naoH in DMF results in the chiral epoxide (IX) , which then couples with 2-(4-methoxyphenyl)-1,1-dimethylethylamine (III) in refluxing i-ProH or dioxane to produce the benzyl-protected (R)-olodaterol (X) . Finally, compound (X) is debenzylated by means of H2 over Pd/C in MeoH to afford olodaterol (VI) , and then treated with HCl in i-ProH .