2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4′-Bromo-2,2,2-trifluoracetophenone (1.80 mL, 11.9 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to 0° C., and methylmagnesium bromide (19.8 mL, 59.3 mmol) was added. The reaction mixture was maintained at 0° C. for 1 hour and then allowed to warm to ambient temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, concentrated in vacuo and the crude residue was purified directly by MPLC on silica gel (using a gradient elution of 0-25% ethyl acetate in hexanes to afford a racemic mixture of the title compound. The mixture was resolved to the constituent enantiomers by Chiral SFC purification (Chiral Technology AZ-H 2.1×25 cm, 5 uM column; mobile phase: 5% methanol/CO2) to afford the title compounds as single enantiomers. Intermediate #11-1: First enantiomer to elute; (S or R)-2-(4-Bromophenyl)-1,1,1-trifluoropropan-2-ol; 1H NMR (500 MHz, CDCl3) δ 7.53-7.52 (d, 2H), 7.46-7.45 (d, 2H), 2.64 (bs, 1H), 1.76 (s, 3H). Intermediate #11-2: Second enantiomer to elute; (S or R)-2-(4-Bromophenyl)-1,1,1-trifluoropropan-2-ol; 1H NMR (500 MHz, CDCl3) δ 7.53-7.52 (d, 2H), 7.46-7.45 (d, 2H), 2.64 (bs, 1H), 1.76 (s, 3H). The reaction mixture was maintained at 0° C. for 1 hour to warm to ambient temperature overnight The reaction was quenched with saturated aqueous ammonium chloride extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous MgSO4 filtered concentrated in vacuo the crude residue was purified directly by MPLC on silica gel ( a gradient elution of 0-25% ethyl acetate in hexanes to afford

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Commercial 1-(4-bromophenyl)-2,2,2-trifluoroethanone (1 g, 4 mmoles) in diethyl ether (8 mL) was cooled to −78° C. for the addition of commercial methylmagnesium bromide (2.65 mL, 7.9 mmoles, 3 M in diethyl ether). The cloudy reaction media was allowed to reach room temperature and stirred overnight. The reaction mixture was transferred to a separatory funnel containing 1.2 M hydrochloric acid (20 mL). This aqueous layer was extracted 3 times with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The clear oil was pure enough to be used without further purification. The cloudy reaction media to reach room temperature The reaction mixture was transferred to a separatory funnel This aqueous layer was extracted 3 times with ethyl acetate (30 mL) The combined organic layers were washed with brine dried over magnesium sulphate concentrated under reduced pressure to be used without further purification

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Commercial 1-(4-bromophenyl)-2,2,2-trifluoroethanone (1 g, 4 mmoles) in diethyl ether (8 mL) was cooled to −78° C. for the addition of commercial methylmagnesium bromide (2.65 mL, 7.9 mmoles, 3 M in diethyl ether). The cloudy reaction media was allowed to reach room temperature and stirred overnight. The reaction mixture was transferred to a separatory funnel containing 1.2 M hydrochloric acid (20 mL). This aqueous layer was extracted 3 times with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The clear oil was pure enough to be used without further purification. The cloudy reaction media to reach room temperature The reaction mixture was transferred to a separatory funnel This aqueous layer was extracted 3 times with ethyl acetate (30 mL) The combined organic layers were washed with brine dried over magnesium sulphate concentrated under reduced pressure to be used without further purification

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Commercial 1-(4-bromophenyl)-2,2,2-trifluoroethanone (1 g, 4 mmoles) in diethyl ether (8 mL) was cooled to −78° C. for the addition of commercial methylmagnesium bromide (2.65 mL, 7.9 mmoles, 3 M in diethyl ether). The cloudy reaction media was allowed to reach room temperature and stirred overnight. The reaction mixture was transferred to a separatory funnel containing 1.2 M hydrochloric acid (20 mL). This aqueous layer was extracted 3 times with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The clear oil was pure enough to be used without further purification. The cloudy reaction media to reach room temperature The reaction mixture was transferred to a separatory funnel This aqueous layer was extracted 3 times with ethyl acetate (30 mL) The combined organic layers were washed with brine dried over magnesium sulphate concentrated under reduced pressure to be used without further purification

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealable vial (S)-1,3-dibenzylpiperazine (0.617 g, 2.316 mmol, Alfa Aeser, Ward Hill, Mass.), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (0.623 g, 2.316 mmol, Example 27, Step 1), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.071 g, 0.058 mmol, Strem Chemicals, Newburyport, Mass.), Pd2(dba)3 (0.067 g, 0.116 mmol, Strem Chemicals, Newburyport, Mass.), and sodium tert-butoxide (0.556 g, 5.79 mmol) were combined and suspended in toluene (5 mL). The vial was purged with N2 for 5 min and was then heated at 100° C. for 15 h. The mixture was diluted with EtOAc (20 mL), the layers were separated and the organics were washed with water (10 mL) and brine (10 mL). The organic extracts were dried over MgSO4, filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes) to give 2-(4-((2S)-2,4-dibenzyl-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.355 g). The vial was purged with N2 for 5 min The mixture was diluted with EtOAc (20 mL) the layers were separated the organics were washed with water (10 mL) and brine (10 mL) The organic extracts were dried over MgSO4 filtered concentrated The crude material was absorbed onto silica gel purified via column chromatography (40 g silica gel, 0 to 100% EtOAc in hexanes)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 20-mL vial was charged with (3S)-3-methyl-4-(((2S)-4-(1,3-thiazol-2-ylsulfonyl)-2-piperazinyl)methyl)morpholine (210 mg, 0.61 mmol), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (326 mg, 1.21 mmol, Example 27, Step 1), sodium tert-butoxide (175 mg, 1.82 mmol), Pd2(dba)3 (55.5 mg, 0.061 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (42.4 mg, 0.091 mmol, Strem Chemicals, Newburyport, Mass.) and toluene (5 mL). the vial was sealed and heated to 100° C. for 3 h. The reaction was filtered, concentrated and purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min) to give 1,1,1-trifluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (20 mg) that was a mixture of two isomers. the vial was sealed The reaction was filtered concentrated purified via reverse-phase preparative HPLC eluting with 0.1% TFA in CH3CN/H2O (5% to 100% over 15 min)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 350 mL pressure tube was charged with 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (7.22 g, 26.8 mmol, Example 27, step 1), N-Boc-piperazine (5.00 g, 26.8 mmol), sodium tert-butoxide (3.87 g, 40.3 mmol), 50 mL of toluene, dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.253 g, 2.68 mmol, Strem Chemical Inc, Newburyport, Mass.) and tris(dibenzylideneacetone)dipalladium (0) (1.229 g, 1.342 mmol, Strem Chemical Inc, Newburyport, Mass.). The tube was sealed and heated at 100° C. for 2 h. After that time, the mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL) to give a dark oil. Purification via column chromatography (120 g of silica gel, 0 to 40% EtOAc in hexanes) gave tert-butyl 4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (8.61 g) as an off-white brittle foam. The tube was sealed extracted with EtOAc (2×100 mL) to give a dark oil Purification via column chromatography (120 g of silica gel, 0 to 40% EtOAc in hexanes)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-(benzyloxymethyl)-1-(thiophen-2-ylsulfonyl)piperazine (2.95 g, 8.37 mmol), 2-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (2.70 g, 10.04 mmol, Example 27, step 1), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (0.156 g, 0.335 mmol, Strem Chemicals, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (0.153 g, 0.167 mmol, Strem Chemicals, Newburyport, Mass.), sodium tert-butoxide (2.011 g, 20.92 mmol) and toluene (50 mL) was added to a high-pressure reaction vessel. The vessel was sealed and heated at 100° C. for 16 h. The solution was then diluted with EtOAc (200 mL). The organic solution was washed with water (100 mL) and brine (100 mL) then dried (MgSO4), filtered and concentrated. The crude material was subjected to flash chromatography on silica gel (120 g, 5-80% (10% MeOH-EtOAc) in hexanes) to give 2-(4-(2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (3.95 g) as a mixture of four isomers. was added to a high-pressure reaction vessel The vessel was sealed The organic solution was washed with water (100 mL) and brine (100 mL) then dried (MgSO4) filtered concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Bromophenyl)-1,1,1-trifluoro-2-propanol (330 mg, 1.226 mmol, Example 27, step 1), benzyl 1-piperazinecarboxylate (270 mg, 1.226 mmol, Sigma-Aldrich, St. Louis, Mo.), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (86 mg, 0.184 mmol, Strem Chemical Inc, Newburyport, Mass.), sodium tert-butoxide (283 mg, 2.94 mmol), and tris(dibenzylideneacetone)dipalladium (0) (56.2 mg, 0.061 mmol, Strem Chemical Inc, Newburyport, Mass.) were combined in toluene (5 mL) and stirred in a sealed tube overnight at 100° C. The reaction was poured into saturated aqueous sodium bicarbonate (100 mL) and EtOAc (100 mL). The organic extracts were separated washed with brine (25 mL), dried (Na2SO4), filtered and concentrated. The residue was dissolved in methanol (10 mL). Under nitrogen, 10% Pd/C (100 mg) was added and the resulting black suspension was placed under a hydrogen atmosphere (1 atm) for 1 h. After that time, the mixture was filtered through a 0.45 micron filter and concentrated. This crude material, 2-thiazolesulfonyl chloride (225 mg, 1.225 mmol, Bioorg. Med. Chem., 2006, 14, 6628), and Hünig's base (214 μL, 1.225 mmol) were combined in CH2Cl2 (10 mL). This was allowed to stir for at room temperature 3 h. After that time, the reaction was concentrated then dissolved in methanol (3 mL) and filtered through a 0.45 micron filter. The crude material was purified by reverse-phase preparative HPLC using a Phenomenex Gemini (C18 column (150×30 mm, 10 μm) eluting with a 0.1% TFA in CH3CN/H2O, gradient (10% to 90% over 30 min)) to afford 1,1,1-trifluoro-2-(4-(4-(1,3-thiazol-2-ylsulfonyl)-1-piperazinyl)phenyl)-2-propanol trifluoroacetate (120 mg) as a mixture of two enantiomers. The organic extracts were separated washed with brine (25 mL) dried (Na2SO4) filtered concentrated The residue was dissolved in methanol (10 mL) Under nitrogen, 10% Pd/C (100 mg) was added for 1 h After that time, the mixture was filtered through a 0.45 micron filter concentrated to stir for at room temperature 3 h After that time, the reaction was concentrated then dissolved in methanol (3 mL) filtered through a 0.45 micron filter The crude material was purified by reverse-phase preparative HPLC eluting with a 0.1% TFA in CH3CN/H2O, gradient (10% to 90% over 30 min))