2,6-Lutidine → HCID 67189923, compound

Participants

Reaction Conditions

Reaction Steps

In a flask (R)-3-cyclobutyl-2-(4-methanesulfonyl-3-methyl-phenyl)-propionic acid (88 mg, 0.30 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylformamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (2 mL) and added dropwise into a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 47 mg, 0.30 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (2 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with ethyl acetate (20 mL). This was then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and a saturated aqueous brine solution (10 mL). It was then dried over sodium sulfate, filtered and concentrated with silica gel (2 g) in vacuo and then purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 80% ethyl acetate) to afford (R)-3-cyclobutyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 72%) as a white foam: [α]2958932 −14.7° (c=0.19, methylene chloride); ES-HRMS m/e calcd for C22H31N3O4S (M+H)+ 434.2108, observed 434.2108; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.49-2.21 (m, 9 H, CH and 4×CH2), 2.62 (s, 3H, ArCH3), 3.17 (s, 3H, SO2CH3), 3.73 (m, 1H, ArCHCO), 3.86 (s, 2H, NCH2), 4.64 (s, 1H, OH), 6.44 (d, J=2.2 Hz, 1H, Ar), 7.42 (m, 2H, Ar), 7.50 (d, J=2.2 Hz, 1H, Ar), 7.84 (d, Jo=8.6 Hz, 1H, Ar), 10.70 (s, 1H, NH).

Provenance & Evidence