Reaction Steps
A solution of 3-cyclopentyl-2-(1,1-dioxo-benzo[b]thiophen-5-yl)-propionic acid (36 mg, 0.12 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 67 μL, 0.14 mmol) which produced gas evolution and it was stirred at 0° C. for 10 min and it was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to ˜1.5 mL. In a separate flask, a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 20 mg, 0.13 mmol), 2,6-lutidine (20 μL, 0.18 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (1 mL), dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and transferred to a separatory funnel where it was extracted with methylene chloride (3×10 mL). The organic layers were then washed with a 1 N aqueous hydrochloric acid solution (20 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(1,1-dioxo-benzo[b]thiophen-5-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (23 mg, 43%) as an off-white foam (as a racemic mixture): ES-HRMS m/e calcd for C23H29N3O4S (M+H)+ 444.1952, observed 444.1949; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 3 H, CH3), 1.05 (s, 3H, CH3), 1.11 (m, 2H, CH2), 1.37-1.78 (m, 8H, 4×CH2), 2.06 m, 1 H, CH), 3.87 (s, 2H, NCH2), 3.93 (t, J=7.5 Hz, 1H, ArCHCO), 4.64 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.35 (d, J=6.9 Hz, 1H, Ar), 7.51 (d, J=2.1 Hz, 1H, Ar), 7.58 (dd, Jo=7.8 Hz, Jm=1.3 Hz, 1H, Ar), 7.61 (d, Jm=1.3 Hz, 1H, Ar), 7.67 (d, J=6.9 Hz, 1H, Ar), 7.79 (d, Jo=7.8 Hz, 1H, Ar), 10.78 (s, 1H, NH).
