Reaction Steps
2-(3-Bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (95 mg, 0.17 mmol, Example 69), potassium (4-(tert-butyldimethylsilyloxy)but-1-ynyl)trifluoroborate (75 mg, 0.26 mmol, ASDI, Newark, Del.), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (14 mg, 0.02 mmol, Strem Chemical Inc, Newburyport, Mass.), and cesium carbonate (182 mg, 0.56 mmol) were combined in toluene (1.5 mL) and water (0.2 mL). The reaction mixture was purged with nitrogen gas for several minutes and then stirred and heated in an Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 135° C. for 30 min. The reaction mixture was filtered through a pad of Celite® (diatomaceous earth) eluting with CH2Cl2 and the filtrate was concentrated in vacuo. The residue was suspended in 1N HCl (5 mL) and stirred at room temperature for 30 min. The mixture was partitioned between CH2Cl2 (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The layers were separated, the organic material was dried (Na2SO4), filtered, and concentrated. This crude material was subjected to reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (150×30 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (30% to 100% over 10 min) to provide 4-(2-(4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-3-butyn-1-ol (22 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.11 (dd, J=1.27, 4.99 Hz, 1H), 7.71 (dd, J=1.37, 3.72 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J=8.61 Hz, 1H), 7.35 (dd, J=3.81, 4.99 Hz, 1H), 7.08 (d, J=8.80 Hz, 1H), 4.88 (t, J=5.38 Hz, 1H), 3.50-3.59 (m, 2H), 3.27-3.32 (m, 4H), 3.08-3.15 (m, 4H) 2.56 (t, J=6.70 Hz, 2H); m/z (ESI, +ve ion) 543.1 (M+H)+. GK-GKRP IC50 (Binding)=0.656 μM. GK-GKRP EC50 (LC MS/MS-2)=0.895 μM.
