5-fluoro-2-(trifluoromethyl)benzonitrile

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ammonium hydroxide solution (50 mL) was added to a stirred solution of 5-fluoro-2-(trifluoromethyl)benzonitrile (commercially available, for example from Alfa Aesar, Ward Hill, Mass., USA, 2.0 g, 10.6 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was heated to 130° C. for 20 h under 200 psi pressure in a steel bomb. The reaction mixture was evaporated to dryness, and the residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% EtOAc/petroleum ether, to give the title compound (1.2 g). The reaction mixture was evaporated to dryness the residue was diluted with DCM washed with water The organic layer was dried over anhydrous Na2SO4 concentrated under reduced pressure to afford the crude product This was purified by column chromatography (100-200 mesh silica gel) eluting with 20%-40% EtOAc/petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ammonium hydroxide solution (50 mL) was added to a stirred solution of 5-fluoro-2-(trifluoromethyl)benzonitrile (commercially available, for example from Alfa Aesar, Ward Hill, Mass., USA, 2.0 g, 10.6 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was heated to 130° C. for 20 h under 200 psi pressure in a steel bomb. The reaction mixture was evaporated to dryness, and the residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% EtOAc/petroleum ether, to give the title compound (1.2 g). The reaction mixture was evaporated to dryness the residue was diluted with DCM washed with water The organic layer was dried over anhydrous Na2SO4 concentrated under reduced pressure to afford the crude product This was purified by column chromatography (100-200 mesh silica gel) eluting with 20%-40% EtOAc/petroleum ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5-FLUORO-2-(TRIFLUOROMETHYL)BENZONITRILE (compound 8h; Oakwood), K2CO3 (4 eq.) and DMF (5 mL) was shaken at 110° C. for 16 h. After cooling to room temperature, the mixture was diluted with water (20 mL), extracted with CHCl3 (3×20 mL), and concentrated. The residue was dissolved in THF/MeOH (10 mL/4 mL), and treated with HCl (1N, 3 mL) at room temperature for 12 h. The solvent was evaporated and the residue was diluted with CHCl3 (20 mL), neutralized with NH4OH (28% aqueous) and purified by column chromatography (CH3Cl/MeOH 10/1) to give: extracted with CHCl3 (3×20 mL) concentrated The residue was dissolved in THF/MeOH (10 mL/4 mL) treated with HCl (1N, 3 mL) at room temperature for 12 h The solvent was evaporated the residue was diluted with CHCl3 (20 mL) purified by column chromatography (CH3Cl/MeOH 10/1) to give

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-cyano-4-trifluoromethyl-1-fluorobenzene (70, g, 0.37, mol, Oakwood), 4-hydroxyphenylboronic acid (50, g, 0.36, mol, Boron Molecular), K2CO3, (70, g) and DMF/water (400, mL/40, mL) was heated to 100° C. for 3, h. After cooling to RT, the mixture was diluted with water (1, L) and extracted with EtOAc (1.5, L). The organic layer was washed with water (0.5, L) and brine, concentrated and purified by chromatographed over silica gel with 4% MeOH in chloroform to give (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid as pink solid (50, g, 45%). 1H NMR (400, MHz, CD3OD) 7.70-7.70, (3H, m), 7.35, (1H, d, J=2.4, Hz), 7.24, (1H, dd, J=2.2, & 8.8, Hz), 7.00, (2H, d, J=7.7, Hz). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17, mg, 0.022 mmol, Aldrich) was added to a mixture of 2-(6-bromopyridin-2-yl)-2-hydroxyacetamide (50, mg, 0.22, mmol), (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid (100, mg, 0.32, mmol) and cesium carbonate (140, mg, 0.43 mmol) in EtOH/DME/water (2, mL/2, mL/1, mL) at room temperature. The reaction mixture was flushed with argon, then, shaken at 90° C. for 3, h. After cooling to RT, the reaction was quenched with water (2, mL), and extracted with EtOAc (10 mL). The organic layer was separated, concentrated and purified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in water/0.1% TFA in ACN) to give 2-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2-hydroxyacetamide (Cpd. No. 6) as off-white solid (45, mg, 50%). LC/MS: m/z=414.1, [M+H]+, ; 1H NMR (400, MHz, DMSO-d6) 8.15, (2H, d, J=8.4, Hz), 7.93 (1H, d, J=9.2, Hz), 7.82-7.86, (3H, m), 7.37-7.45, (3H, m), 7.26, (2H, d, J=9.2, Hz), 4.95, (1H, s). After cooling to RT extracted with EtOAc (1.5, L) The organic layer was washed with water (0.5, L) and brine concentrated purified by chromatographed over silica gel with 4% MeOH in chloroform

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Ammonium hydroxide solution (50 mL) was added to a stirred solution of 5-fluoro-2-(trifluoromethyl)benzonitrile (commercially available, for example from Alfa Aesar, Ward Hill, Mass., USA, 2.0 g, 10.6 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was heated to 130° C. for 20 h under 200 psi pressure in a steel bomb. The reaction mixture was evaporated to dryness, and the residue was diluted with DCM and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% EtOAc/petroleum ether, to give the title compound (1.2 g). The reaction mixture was evaporated to dryness the residue was diluted with DCM washed with water The organic layer was dried over anhydrous Na2SO4 concentrated under reduced pressure to afford the crude product This was purified by column chromatography (100-200 mesh silica gel) eluting with 20%-40% EtOAc/petroleum ether