Reaction Steps
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (168 mg, 0.51 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylfomamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 291 μL, 0.58 mmol) which produced gas evolution and it was then stirred at 0° C. for 15 minutes and 30 min at 25° C. After this time, the reaction was concentrated in vacuo to ⅓ of the original volume. In a separate flask a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 86 mg, 0.56 mmol), 2,6-lutidine (84 μL, 0.76 mmol) and methylene chloride (10 mL) was cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 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 was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×20 mL) and the aqueous layers were than extracted with methylene chloride (2×10 mL). The combined organic layers were then washed with a 1 N aqueous hydrochloric acid solution (1×20 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 70% ethyl acetate/hexanes to 90% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-furan-2(R)-yl)-propionamide (155 mg, 65%) as a mixture of roughly 1:1 mixture of diastereomers as a white foam: ES-HRMS m/e calcd for C21H28N3O5SCl (M+H)+ 470.1511, observed 470.1504; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02, 1.03 (2×s, 6H, 2×CH3), 1.37-1.52 (m, 1H, CH of CH2), 1.64-1.99 (m, 4H, 4×CH of CH2), 2.08-2.40 (m, 1H, CH of CH2), 3.34, 3.35 (2×s, 3H, SO2CH3), 3.43-3.77 (m, 3H, OCH2 and OCH), 3.86 (brs, 2H, NCH2), 3.97-4.12 (m, 1H, ArCH), 4.62, 4.63 (2×s, 1H, OH), 6.43 (m, 1H, Ar), 7.49 (m, 1H, Ar), 7.59 (2×dd, Jo=8.2 Hz, Jm=1.7 Hz, 1H, Ar), 7.69 (2×d, Jm=1.7 Hz, 1H, Ar), 7.99 (2×d, Jo=8.2 Hz, 1H, Ar), 10.75, 10.81 (2×s, 1 H, NH).
