2-(2-bromophenyl)-2-methylpropanenitrile

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

Procedure: A mixture of 2-(2-bromophenyl)-2-methylpropanenitrile A33 (0.377 g, 1.68 mmol), NaOH (0.135 g, 3.37 mmol) and t-BuOH (4 mL) was stirred in a sealed vessel at 100° C. for 40 hours. The reaction mixture was cooled, diluted with DCM and filtered through Celite. The filtrate solvent was removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A34 as a colourless oil (0.192 g, 48%). LCMS-D: rt 3.06 min; m/z 242/244 [M+H]+. The reaction mixture was cooled filtered through Celite The filtrate solvent was removed in vacuo the residue was purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)

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

Procedure: The derivative 2-(2'-bromophenyl)-2-methylpropionitrile from Example 1/A (2.24 g; 10 mmole) was dissolved in THF (25 ml) in an inert atmosphere. A solution of borane BH3 in THF (1 M; 25 ml; 25 mmole) was slowly added to the reaction medium. The new solution obtained was refluxed for 3 h. After cooling to room temperature, an aqueous solution of trifluoroacetic acid (50 ml; 1/1) was added dropwise to the reaction mixture. The mixture was refluxed for 1 h, then the solvents were evaporated off under reduced pressure. The residue was taken up in 60 ml of hydrochloric acid HCl (10%) and washed with 3×100 ml of ethyl acetate. The aqueous phase was alkalinised (12<pH<14) then extracted with 3×50 ml of dichloromethane. The organic phases were combined, washed with 2×100 ml of a saturated NaCl solution, dried over MgSO4 then filtered. The solvent was evaporated off under reduced pressure. The desired compound was obtained as a yellowish oil. The new solution obtained was refluxed for 3 h The mixture was refluxed for 1 h the solvents were evaporated off under reduced pressure washed with 3×100 ml of ethyl acetate then extracted with 3×50 ml of dichloromethane washed with 2×100 ml of a saturated NaCl solution dried over MgSO4 then filtered The solvent was evaporated off under reduced pressure

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

Procedure: The derivative 2-(2'-bromophenyl)-2-methylpropionitrile from Example 1/A (2.24 g; 10 mmole) was dissolved in THF (25 ml) in an inert atmosphere. A solution of borane BH3 in THF (1 M; 25 ml; 25 mmole) was slowly added to the reaction medium. The new solution obtained was refluxed for 3 h. After cooling to room temperature, an aqueous solution of trifluoroacetic acid (50 ml; 1/1) was added dropwise to the reaction mixture. The mixture was refluxed for 1 h, then the solvents were evaporated off under reduced pressure. The residue was taken up in 60 ml of hydrochloric acid HCl (10%) and washed with 3×100 ml of ethyl acetate. The aqueous phase was alkalinised (12<pH<14) then extracted with 3×50 ml of dichloromethane. The organic phases were combined, washed with 2×100 ml of a saturated NaCl solution, dried over MgSO4 then filtered. The solvent was evaporated off under reduced pressure. The desired compound was obtained as a yellowish oil. The new solution obtained was refluxed for 3 h The mixture was refluxed for 1 h the solvents were evaporated off under reduced pressure washed with 3×100 ml of ethyl acetate then extracted with 3×50 ml of dichloromethane washed with 2×100 ml of a saturated NaCl solution dried over MgSO4 then filtered The solvent was evaporated off under reduced pressure

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

Procedure: The derivative 2-(2'-bromophenyl)-2-methylpropionitrile from Example 1/A (2.24 g; 10 mmole) was dissolved in THF (25 ml) in an inert atmosphere. A solution of borane BH3 in THF (1 M; 25 ml; 25 mmole) was slowly added to the reaction medium. The new solution obtained was refluxed for 3 h. After cooling to room temperature, an aqueous solution of trifluoroacetic acid (50 ml; 1/1) was added dropwise to the reaction mixture. The mixture was refluxed for 1 h, then the solvents were evaporated off under reduced pressure. The residue was taken up in 60 ml of hydrochloric acid HCl (10%) and washed with 3×100 ml of ethyl acetate. The aqueous phase was alkalinised (12<pH<14) then extracted with 3×50 ml of dichloromethane. The organic phases were combined, washed with 2×100 ml of a saturated NaCl solution, dried over MgSO4 then filtered. The solvent was evaporated off under reduced pressure. The desired compound was obtained as a yellowish oil. The new solution obtained was refluxed for 3 h The mixture was refluxed for 1 h the solvents were evaporated off under reduced pressure washed with 3×100 ml of ethyl acetate then extracted with 3×50 ml of dichloromethane washed with 2×100 ml of a saturated NaCl solution dried over MgSO4 then filtered The solvent was evaporated off under reduced pressure

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

Procedure: A mixture of 2-(2-bromophenyl)-2-methylpropanenitrile A33 (0.377 g, 1.68 mmol), NaOH (0.135 g, 3.37 mmol) and t-BuOH (4 mL) was stirred in a sealed vessel at 100° C. for 40 hours. The reaction mixture was cooled, diluted with DCM and filtered through Celite. The filtrate solvent was removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A34 as a colourless oil (0.192 g, 48%). LCMS-D: rt 3.06 min; m/z 242/244 [M+H]+. The reaction mixture was cooled filtered through Celite The filtrate solvent was removed in vacuo the residue was purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)