A new efficient route to Tolterodine

Tolterodine, an important urological drug, can be conveniently prepared
starting from 1-((2-hydroxy-5-methyl)phenyl)-1-phenylethylene, accessible
in high yield by alumina-promoted ortho alkenylation of p-cresol with
phenylacetylene. The hydroformylation of this olefin, catalyzed by
rhodium complexes both in homogeneous or in aqueous biphasic system,
affords the desired linear aldehyde in about 80-90% yield. The reductive
amination of this aldehyde, in the presence of HN(i-Pr)2 and Pd/C (5%) as
the catalytic precursor at 4 atm H2 and 48°C, produces directly
tolterodine in more than 90% yield. Some experiments of enantioselective
hydroformylation of 1-(2-hydroxy-5-methylphenyl)-1-phenylethylene
catalyzed by Rh(CO)2acac/(S,R)-Binaphos and other enantiopure
ferrocenyldiphosphines afforded only low yields of the expected chiral
aldehyde; unfortunately, the achieved ee did not exceed 8%.