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

Published on 2018-02-09T23:13:53Z (GMT) by
Synthesis of (<i>S</i>)-5-fluoro-3-methylisobenzofuran-1­(3<i>H</i>)-one (<b>6</b>), 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 (<b>8</b>). A manufacturing process, on the basis of the asymmetric transfer hydrogenation, was developed. This process was successfully scaled up to prepare 400 kg of <b>6</b>.

Cite this collection

Duan, Shengquan; Li, Bryan; Dugger, Robert W.; Conway, Brian; Kumar, Rajesh; Martinez, Carlos; Makowski, Teresa; Pearson, Robert; Olivier, Mark; Colon-Cruz, Roberto (2018): Developing an Asymmetric Transfer Hydrogenation Process

for (S)‑5-Fluoro-3-methylisobenzofuran-1(3H)‑one, a Key Intermediate to Lorlatinib. ACS Publications.