Reaction Steps
2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (117 mg, 0.21 mmol, Example 69), propargyl alcohol (25 μL, 0.42 mmol, Sigma-Aldrich, St. Louis, Mo.), diethylamine (44 μL, 0.42 mmol, Sigma-Aldrich, St. Louis, Mo.), bis(triphenylphosphine) palladium(II) dichloride (15 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), triphenylphosphine (11 mg, 0.04 mmol, Sigma-Aldrich, St. Louis, Mo.), and copper iodide (4 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.) were combined in DMF (1 mL). The reaction mixture was purged with nitrogen for several minutes, and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 30 min. The reaction was diluted with CH2Cl2 (10 mL) and water (10 mL). The organic extracts were separated, washed with water (10 mL), dried (Na2SO4), filtered, and concentrated. Purification via column chromatography (12 g silica gel, 0 to 1% MeOH in CH2Cl2) afforded 3-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-2-propyn-1-ol (49 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.09 (br s, 1H), 7.45-7.75 (m, 3H), 7.33 (br s, 1H), 7.09 (d, J=7.63 Hz, 1H), 5.29 (br s, 1H), 4.27 (br s, 2H), 3.24-3.36 (m, 4H), 3.07-3.17 (m, 4H); m/z (ESI, +ve ion) 529.1 (M+H)+. GK-GKRP IC50 (Binding)=0.712 μM. GK-GKRP EC50 (LC MS/MS-2)=0.557 μM.
