Lithium Carbonate → 2-Chloro-4-[[(1S,2R)-2-hydroxy-2-methyl-cyclopentyl]amino]-3-methyl-benzonitrile

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In a sealed pressure vessel, a mixture of 2-chloro-4-fluoro-3-methyl-benzonitrile (1.2 g, 7.08 mmol), (1R,2S)-2-amino-1-methyl-cyclopentanol (1.63 g, 14.2 mmol) and lithium carbonate (1.10 g, 14.9 mmol) in DMSO (14.4 mL) and water (1.4 mL) is heated at 130° C. overnight. After allowing the reaction to cool to room temperature, the mixture is diluted with EtOAc and washed twice with 1 N hydrochloric acid. The organic phase is concentrated under reduced pressure and purified using radial chromatography eluting with EtOAc/hexanes (20 to 50% EtOAc/hexanes gradient). The resulting residue is repurified using radial chromatography with 1% methanol/dichloromethane. The isolated product is recrystallized with ether/hexanes, collected by filtration, and dried under reduced pressure to yield the title compound as a white solid (450 mg, 24%). A second crop (84 mg) is also isolated. LC-ES/MS m/z (35Cl/37Cl) 265/267 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 1.16 (s, 3H), 1.71-1.73 (m, 5H), 2.12-2.13 (m, 1H), 2.14 (s, 3H), 3.46-3.50 (m, 1H), 4.93 (s, 1H), 5.26-5.30 (m, 1H), 6.63 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H). Chiral HPLC showed the material had an enantiomeric excess of 67%. The enantiomeric excess is determined by SFC on a CHIRALPAK® AS-H (4.6×150 mm, 5 μm) column using 20% ethanol/carbon dioxide. Flow rate: 5 mL/min. Detection: 225 nm. Isomer 1 (title compound): TR=1.39 min; Isomer 2: TR=1.99 min. The absolute stereochemistry of Isomer 1 (1S,2R) is known by correlation of retentions times with Isomer 1 and Isomer 2 as described in Example 3.

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