Ethyl Acetate → HCID 67188846, compound

Participants

Reaction Conditions

Reaction Steps

In a two-necked round bottom flask under argon was placed dry tetrahydrofuran (20 mL) and 1,1,1,3,3,3-hexamethyldisilazane (1.42 mL, 6.72 mmol). This solution was then cooled to −78° C. and treated dropwise with a solution of n-butyl lithium (2.5 M solution in hexanes, 2.60 mL, 6.42 mmol). It was then stirred at −78° C. for 15 min. To this was then slowly added a solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-acetamide (prepared as in PCT WO 2004/052869 A1, Example 1, 1.06 g, 2.92 mmol) in dry tetrahydrofuran (20 mL). The solution was then warmed to 0° C. and stirred for 1 h. After this time the yellow solution was then cooled back to −78° C. and treated dropwise with a solution of bromomethyl-cyclobutane (610 mg, 4.09 mmol) in 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.80 mL, 6.42 mmol). The reaction was then warmed and stirred at 0° C. for 16 h. The reaction was then diluted with ethyl acetate (120 mL) and transferred to a separatory funnel and washed with a saturated aqueous ammonium chloride solution (40 mL) and then a saturated aqueous brine solution (40 mL). The organic layers were combined and then dried over sodium sulfate and concentrated in vacuo with silica gel (4 g) and purified on Biotage Flash chromatography system (40M column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) to afford (R)-2-(3-chloro-4-methylsulfanyl-phenyl)-3-cyclobutyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (361 mg, 29%).

Provenance & Evidence