Reaction Steps
A 20 mL vial was charged with toluene (1.2 mL), sodium tert-butoxide (69.2 mg, 720 μmol) were added to (R)-2-cyclopropyl-piperazine (59.7 mg, 300 μmol, Anichem, North Brunswick, N.J.), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (97 mg, 300 μmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos), (21.0 mg, 45.0 μmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (13.7 mg, 15.00 μmol, Strem Chemical Inc, Newburyport, Mass.). The reaction was heated to 90° C. for 40 h, then cooled to 23° C., and diluted with water (15 mL) and extracted with CH2Cl2 (15 mL). The organic layer was loaded onto an AccuBOND II SCX cartridge (Krackeler Scientific, Inc., Albany, N.Y.) (6 g), washed with MeOH (5 mL) and eluted with 2N NH3 in MeOH (10 mL) to give (R)-2-(4-(3-cyclopropylpiperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol. To this was added a solution of 2-thiophenesulfonyl chloride (54.8 mg, 300 μmol, Sigma-Aldrich, St. Louis, Mo.) and Hünig's base (57.5 μL, 330 μmol) in CH2Cl2 (0.6 mL). The reaction was stirred at 23° C. for 18 h and then concentrated to dryness. The crude material was purified by reverse-phase preparative HPLC using a Gemini C18 100 A column (150×30 mm), eluting with 0.1% TFA in CH3CN/H2O (10% to 90% over 12 min) to give 2-(4-((3R)-3-cyclopropyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.93 (dd, J=5.3 1.3 Hz, 1H), 7.71 (dd, J=3.7, 1.1 Hz, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.18 (dd, J=4.8, 4.0 Hz, 1H), 6.95 (d, J=9.7 Hz, 2H), 2.67 (dd, J=12.5, 3.7 Hz, 1H), 2.52-2.60 (m, 4H), 1.30-1.42 (m, 1H), 0.35-0.56 (m, 6H). m/z (ESI, +ve ion) 515.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=5.0 μM.
