1273664-66-6Relevant articles and documents
Chemoenzymatic Synthesis of a Chiral Ozanimod Key Intermediate Starting from Naphthalene as Cheap Petrochemical Feedstock
Uthoff, Florian,L?we, Jana,Harms, Christina,Donsbach, Kai,Gr?ger, Harald
, p. 4856 - 4866 (2019)
Ozanimod represents a recently developed, promising active pharmaceutical ingredient (API) molecule in combating multiple sclerosis. Addressing the goal of a scalable, economically attractive, and technically feasible process for the manufacture of this drug, a novel alternative synthetic approach toward (S)-4-cyano-1-aminoindane as a chiral key intermediate for ozanimod has been developed. The total synthesis of this intermediate is based on the utilization of naphthalene as a readily accessible, economically attractive, and thus favorable petrochemical starting material. At first, naphthalene is transformed into 4-carboxy-indanone within a four-step process by means of an initial Birch reduction, followed by an isomerization of the C=C double bond, oxidative C=C cleavage, and intramolecular Friedel-Crafts acylation. The transformation of the 4-carboxy-indanone into (S)-4-cyano-1-aminoindane then represents the key step for introducing the chirality and the desired absolute S configuration. When evaluating complementary biocatalytic approaches based on the use of a lipase and transaminase, respectively, the combination of a chemical reductive amination of the 4-carboxyindanone followed by a subsequent lipase-catalyzed resolution turned out to be the most efficient route, leading to the desired key intermediate (S)-4-cyano-1-aminoindane in satisfactory yield and with excellent enantiomeric excess of 99%.
