Green Synthesis of Repotrectinib: Impact of Aqueous Micellar Media on Chemoenzymatic Transformations

Abstract

A greener, milder, and scalable route for the synthesis of the anticancer drug repotrectinib has been developed. The effect of aqueous micellar media on the synthesis of the key chiral amine intermediate followed by repotrectinib has been studied. The synthesis of 2-[(1R)-1-aminoethyl]-4-fluorophenol ((R)-1) from a commercially available ketone was carried out using the enzyme ATA-025 in the surfactant TPGS-750-M, resulting in an 82% yield and an enantiomeric excess (ee) > 99%. This method avoids the use of expensive chiral auxiliaries and hazardous reagents. Furthermore, the chiral amine ((R)-1) was used in the synthesis of repotrectinib in an aqueous medium, resulting in a high yield and an ee > 99%.