Streamlining Vorinostat Synthesis: A Chemoenzymatic Continuous Flow Approach

Anticancer agent vorinostat is one of the only three commercialized histone deacetylase inhibitors approved by the Food and Drug Administration for the treatment of cutaneous T‐cell lymphoma. Several synthetic pathways and only one biocatalytic approach have been designed over the years. However, no chemoenzymatic approaches have been described to date. Herein, the first two‐step protocol for the obtainment of vorinostat is presented, which combines the chemical acylation of aniline followed by the lipase‐catalyzed (immobilized lipase B from Candida antarctica ) condensation and the final hydrolysis with an acidic resin. Initially, batch studies allow to obtain vorinostat in high yield (70%) in 16 h using eco‐friendly t ‐amyl alcohol as the reaction medium. Subsequently, the protocol is transferred to a continuous flow reactor, which reduces the overall time to 4 h while keeping the same final yield. Furthermore, the developed procedure minimizes solvent waste and enhances system automation, paving the way for a feasible application to further hydroxamic acid moieties of pharmaceutical interest.