Enantioselective Synthesis of Ozanimod, the Active Pharmaceutical Ingredient of a New Drug for Multiple Sclerosis

We report here a short enantioselective synthesis of Ozanimod, a potent modulator of the enzyme Sphingosine-1-phosphate receptor (S1P(R)), recently approved by FDA and EMA for the treatment of relapsing-remitting multiple sclerosis. Amongst different synthetic approaches explored, we achieved the best result introducing the stereogenic centre in the last step through imine asymmetric transfer hydrogenation (ATH) using Wills' catalysts. Besides the reduced numbers of enantiomeric purity controls required, this process culminates in an exceptionally high enantioselective reductive amination obtained with commercially available tethered Ru catalysts. Starting from commercially available 4-cyano-indanone, enantiomerically pure Ozanimod was obtained in 5 steps in 62 % overall yield and 99 % ee.

Automated summary

A short enantioselective synthesis of Ozanimod was reported, with the stereogenic center introduced through imine asymmetric transfer hydrogenation, resulting in high enantioselectivity. Starting from commercially available 4-cyano-indanone, enantiomerically pure Ozanimod was obtained in only 5 steps with a high overall yield of 62% and 99% ee.