Methyl 4-fluoro-2-(trifluoroMethyl)benzoate

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

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4.48 g (22.5 mmol) 4-Fluoro-2-trifluoromethyl-benzoic acid methyl ester (Rarechem) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 13a was obtained in 72% yield (4.00 g, 16.2 mmol). was reduced with high vacuum rotation evaporator at 65° C The residue was diluted with dichloromethane washed twice with water The combined water phases were extracted with dichloromethane The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution dried with sodium sulphate concentrated The oily crude was purified by column chromatography

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4.48 g (22.5 mmol) 4-Fluoro-2-trifluoromethyl-benzoic acid methyl ester (Rarechem) and 60.0 ml dimethylsulfoxide were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 6 was obtained in 72% yield (4.00 g, 16.2 mmol). was reduced with high vacuum rotation evaporator at 65° C The residue was diluted with dichloromethane washed twice with water The combined water phases were extracted with dichloromethane The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution dried with sodium sulphate concentrated The oily crude was purified by column chromatography

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-fluoro-2-trifluoromethylbenzoate (4.95 g) in N,N-dimethylformamide was added 1,2,4-triazole (2.0 g) and potassium carbonate (4.0 g) at 20° C. and the mixture stirred for 4 hours at 60° C. The mixture was diluted (ether), washed (aqueous citric acid) and dried (magnesium sulfate). The residue was purified by chromatography to give methyl 4-(1,2,4-triazol-1-yl)-2-trifluoromethylbenzoate (5.07 g), NMR 3.98(s,3H),7.94-8.05(2H),8.15(2H),8.71(s,1H). washed (aqueous citric acid) dried (magnesium sulfate) The residue was purified by chromatography

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-fluoro-2-trifluoromethylbenzoate (4.95 g) in N,N-dimethylformamide was added 1,2,4-triazole (2.0 g) and potassium carbonate (4.0 g) at 20° C. and the mixture stirred for 4 hours at 60° C. The mixture was diluted (ether), washed (aqueous citric acid) and dried (magnesium sulfate). The residue was purified by chromatography to give methyl 4-(1,2,4-triazol-1-yl)-2-trifluoromethylbenzoate (5.07 g), NMR 3.98(s,3H),7.94-8.05(2H),8.15(2H),8.71(s,1H). washed (aqueous citric acid) dried (magnesium sulfate) The residue was purified by chromatography

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

Procedure: To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid in MeOH were added concentrated sulfuric acid at 0° C. The reaction mixture was heated and refluxed for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution, dried over MgSO4, and then concentrated under reduced pressure to obtain methyl 4-fluoro-2-(trifluoromethyl)benzoate as a colorless oily substance. The reaction mixture was heated refluxed for 2 days The reaction mixture was concentrated under reduced pressure the residue was diluted with EtOAc The organic layer was washed with a saturated aqueous NaHCO3 solution dried over MgSO4 concentrated under reduced pressure

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

Procedure: To a solution of methyl 4-fluoro-2-(trifluoromethyl)benzoate in DMF were added K2CO3 and piperidine, followed by stirring at 100° C. for 3 hours. The reaction mixture was cooled to 0° C., and water was added thereto, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 90:10) to obtain methyl 4-piperidin-1-yl-2-(trifluoromethyl)benzoate as a colorless oily substance. The reaction mixture was cooled to 0° C. followed by extraction with EtOAc The organic layer was washed with brine dried over MgSO4 concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 90:10)

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

Procedure: To a solution of 4-fluoro-2-(trifluoromethyl)benzoic acid in MeOH were added concentrated sulfuric acid at 0° C. The reaction mixture was heated and refluxed for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution, dried over MgSO4, and then concentrated under reduced pressure to obtain methyl 4-fluoro-2-(trifluoromethyl)benzoate as a colorless oily substance. The reaction mixture was heated refluxed for 2 days The reaction mixture was concentrated under reduced pressure the residue was diluted with EtOAc The organic layer was washed with a saturated aqueous NaHCO3 solution dried over MgSO4 concentrated under reduced pressure

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

Procedure: To a solution of methyl 4-fluoro-2-(trifluoromethyl)benzoate in DMF were added K2CO3 and piperidine, followed by stirring at 100° C. for 3 hours. The reaction mixture was cooled to 0° C., and water was added thereto, followed by extraction with EtOAc. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 90:10) to obtain methyl 4-piperidin-1-yl-2-(trifluoromethyl)benzoate as a colorless oily substance. The reaction mixture was cooled to 0° C. followed by extraction with EtOAc The organic layer was washed with brine dried over MgSO4 concentrated under reduced pressure The residue was purified by silica gel column chromatography (hexane:EtOAc=100:0 to 90:10)

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

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