Chemoenzymatic Synthesis of a Chiral Ozanimod Key Intermediate Starting from Naphthalene as Cheap Petrochemical Feedstock

Abstract

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%.

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

“…H NMR (400 MHz, CDCl 3 ,): δ 8.28 (s, 1H), 8.22 (d, J = 8.0, 1H), 7.96 (d, J = 8.0, 1H), 7.41 (d, J = 7.6, 1H), 7.28 (t, J = 7.6, 1H), 7.03 (d, J = 9.2, 1H), 5.16 (d, J = 7.2, 1H), 4.85 (t, J = 6.4, 1H), 4.75-4.69 (m, 1H), 3.38-3.32 (m, 1H), 3.10-3.01 (m, 1H), 2.58-2.56 (m, 1H), 1.82-1.73 (m, 1H), 1.43-1.39 (m, 15H) ppm. 13 C NMR (400 MHz, CDCl 3 ): δ 172.9, 168. 8 To a solution of ketone 3 (30 g, 0.19 mol) in toluene (200 mL), neopentyl glycol (19.6 g, 0.19 mol) and PTSA (0.72 g, 0.0038 mol) were added under stirring at 25°C.…”

“…Recently, Gröger and co-workers described an alternative route to amine (S)-2 based on enzymatic catalysis. [13] Transaminase derived from Vibrio fluvialis (VF-TA) worked on carboxymethyl indanone (7), in the presence of L-Ala as amine donor, to give the corresponding amino indanone carboxylate (8) in good conversion and ee. Alternatively, acylation of the racemic amine rac- (2) with lipase B from Candida antarctica (CALÀ B) and isopropyl methoxy acetate as the acyl donor, gave amine (S)-2 with modest overall yield 19 %) although with excellent ee (99 %).…”

“…[10] The process relies on the use of low temperature requiring cryogenic liquids, use of dangerous solvents and extensive application of protective groups. Recently, Gröger and co‐workers described an alternative route to amine ( S )‐ 2 based on enzymatic catalysis [13] . Transaminase derived from Vibrio fluvialis (VF‐TA) worked on carboxymethyl indanone ( 7 ), in the presence of L‐Ala as amine donor, to give the corresponding amino indanone carboxylate ( 8 ) in good conversion and ee.…”

“….85 (t, J = 6.4, 1H), 4.75-4.69 (m, 1H), 3.38-3.32 (m, 1H), 3.10-3.01 (m, 1H), 2.58-2.56 (m, 1H), 1.82-1.73 (m, 1H), 1.43-1.39 (m, 15H) ppm. 13 To a solution of ketone 3 (30 g, 0.19 mol) in toluene (200 mL), neopentyl glycol (19.6 g, 0.19 mol) and PTSA (0.72 g, 0.0038 mol) were added under stirring at 25°C. Trimethyl orthoformate (26.4 g, 0.24 mol) was added and the mixture was maintained under stirring at 20-25°C until complete conversion (about 12 hours).…”

“…H NMR (400 MHz, CDCl 3 ): δ 7.89 (bm, 1H), 7.46 (m, 2H), 7.29 (t, J = 7.2, 1H), 5.92 (bs, 1H), 4.85 (bs, 3H), 3.27 (m, 1H), 3.08 (m, 1H), 2.46 (m, 1H), 2.12 (m, 1H) ppm 13. C NMR (101 MHz, CDCl 3 ) δ 147.0, 141.9, 131.4, 128.6, 127.2, 116.6, 108.8, 65.1, 31.4, 29.8 ppm.…”