op7b00187_si_001.pdf (7.79 MB)
Developing an Asymmetric Transfer Hydrogenation Process for (S)‑5-Fluoro-3-methylisobenzofuran-1(3H)‑one, a Key Intermediate to Lorlatinib
journal contribution
posted on 2017-07-05, 00:00 authored by Shengquan Duan, Bryan Li, Robert W. Dugger, Brian Conway, Rajesh Kumar, Carlos Martinez, Teresa Makowski, Robert Pearson, Mark Olivier, Roberto Colon-CruzSynthesis
of (S)-5-fluoro-3-methylisobenzofuran-1(3H)-one (6), a key intermediate to lorlatinib,
is described. A few synthetic methodologies, that is, boron reduction,
enzymatic reduction, asymmetric hydrogenation, and asymmetric transfer
hydrogenation, were evaluated for the chiral reduction of the substituted
acetophenone intermediate (8). A manufacturing process,
on the basis of the asymmetric transfer hydrogenation, was developed.
This process was successfully scaled up to prepare 400 kg of 6.