Streamlining Vorinostat Synthesis: A Chemoenzymatic Continuous Flow Approach

Abstract

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.