Reaction Steps
2(R)-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (75 mg, 0.23 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 120 μL, 0.24 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was concentrated in vacuo and the residue was then taken up in methylene chloride (2 mL). This solution was then added dropwise to a flask containing a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 36 mg, 0.23 mmol), 2,6-lutidine (54 μL, 0.46 mmol), and methylene chloride (2 mL) which was cooled to 0° C. The reaction was allowed to warm to 25° C. and stirred for a period of 2 h. After this time, the reaction quenched with a small amount of methanol and then concentrated in vacuo. It was then dissolved in ethyl acetate (25 mL) and washed with a 1N hydrochloric acid solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was then dried over sodium sulfate and concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 10% methanol/ethyl acetate) to afford N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionamide (70 mg, 66%) as a white foam: [α]30589=−6.9° (c=0.16, methanol); ES-HRMS m/e calcd for C23H33N3O5S (M+H)+ 464.2214, observed 464.2208; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03, 1.04 (2×s, 6 H, 2×CH3), 1.07-1.43 (m, 3H, 3×CH of 2×CH2), 1.49-1.70 (m, 3H, 3×CH of 2×CH2), 1.98-2.12 (m, 1H, CH), 2.62 (s, 3H, ArCH3), 3.14-3.25 (m, 2H, OCH2), 3.17 (s, 3H, SO2CH3), 3.73-3.83 (m, 2H, OCH2), 3.84 (s, 2H, NCH2), 3.90-3.99 (m, 1H, ArCH), 4.64 (s, 1H, OH), 6.43 (d, J=2.3 Hz, 1H, Ar), 7.41-7.46 (m, 2H, Ar), 7.48 (d, J=2.3 Hz, 1H, Ar),), 7.83 (d, J=8.5 Hz, 1H, Ar), 10.72 (s, 1H, NH)
