Diisopropylethylamine → 4-(((1R,3S)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile

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Reaction Conditions

Reaction Steps

A mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (3.71 g, 20 mmol)), 3-amino-1-methylcyclohexanol (3.0 g, crude), DIEA (3.23 g, 25 mmol) in isopropanol (30 mL) was heated at 100° C. for 3 h. The organic solvents were removed under reduced pressure. The residue was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum) to afford the cis-isomer (0.90 g, 3.24 mmol, 17% yield over 3 steps) and trans-isomer (1.80 g, 6.47 mmol, 34% yield over 3 steps). The cis-isomer (0.90 g, 3.24 mmol) was separated by chiral SFC (Column IF; method: 70-30-CO2-MeOH; CO2 Flow Rate: 2.1; Col. Temp.=40° C.) to give 4-(((1S,3R)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (peak 1: 300 mg, 1.08 mmol, 33% yield, 100% e.e.) and 4-(((1R,3S)-3-hydroxy-3-methylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (peak 2: 310 mg, 1.12 mmol, 34% yield, 100% e.e.), MS (ESI) m/z 279.1 [M+H]+.

Provenance & Evidence