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Developing an Asymmetric Transfer Hydrogenation Process for (S)‑5-Fluoro-3-methylisobenzofuran-1(3H)‑one, a Key Intermediate to Lorlatinib

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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-Cruz
Synthesis 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.

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