2-(trifluoromethoxy)phenol

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

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

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

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

Procedure: 2-trifluoromethoxyphenol (10.00 g) was dissolved in chloroform (30 mL), and triethylamine (6.11 mL) and acetic anhydride (6.37 mL) was added to the solution, and then the mixture was stirred at room temperature for 2 hours. To the reaction solution, 10% potassium carbonate was added, and then the mixture was extracted with chloroform. The organic layer was washed with an aqueous 5% citric acid solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (11.39 g) as a colorless oily substance. the mixture was extracted with chloroform The organic layer was washed with an aqueous 5% citric acid solution and saturated brine dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure

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

Procedure: 2-trifluoromethoxyphenol (10.00 g) was dissolved in N,N-dimethylformamide (50 mL), and potassium carbonate (15.52 g) and chloromethyl methyl ether (4.70 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and then the mixture was extracted with n-hexane. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (12.21 g) as a colorless oily substance. the mixture was extracted with n-hexane The organic layer was washed with saturated brine dried over anhydrous sodium sulfate The solvent was distilled off under reduced pressure

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

Procedure: 2-(Trifluoromethoxy)phenol (6.0 g, 32.7 mmol) was dissolved in methylene chloride and triethylamine (9.1 mL, 65.4 mmol). The mixture was cooled to 0° C. and methyl chloroformate (2.8 mL, 36.0 mmol) was added dropwise. The mixture was stirred for 2 h at room temperature then quenched with saturated NH4Cl. The reaction was diluted with water and the aqueous layer extracted with dichloromethane (2×30 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to provide methyl 2-(trifluoromethoxy)phenyl carbonate (7.1 g, 92% yield). 1H NMR (400.0 MHz, DMSO-d6) δ7.36-7.26 (m, 4H), 3.93 (s, 31-1). then quenched with saturated NH4Cl The reaction was diluted with water the aqueous layer extracted with dichloromethane (2×30 mL) The combined extracts were washed with water (100 mL) and brine (100 mL) dried over MgSO4 filtered concentrated in vacuo

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

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

Procedure: 1.55 mL (30.3 mmol) bromine in 50 mL DCM is added dropwise to a solution of 5.0 g (28.1 mmol) 2-trifluoromethoxy-phenol in 70 mL DCM at −78° C. The reaction solution is heated to RT and stirred for a further 48 h. Then 70 mL Na2SO3 solution are added and the mixture is stirred until the orange colour has disappeared. The solution is diluted with DCM, the organic phase is washed with NaCl solution, dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: PE to PE:EtOAc 4:1). the mixture is stirred until the orange colour the organic phase is washed with NaCl solution dried over MgSO4 The purification

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

Procedure: 1.55 mL (30.3 mmol) bromine in 50 mL DCM is added dropwise to a solution of 5.0 g (28.1 mmol) 2-trifluoromethoxy-phenol in 70 mL DCM at −78° C. The reaction solution is heated to RT and stirred for a further 48 h. Then 70 mL Na2SO3 solution are added and the mixture is stirred until the orange colour has disappeared. The solution is diluted with DCM, the organic phase is washed with NaCl solution, dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (gradient: PE to PE:EtOAc 4:1). the mixture is stirred until the orange colour the organic phase is washed with NaCl solution dried over MgSO4 The purification

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

Procedure: 1-ethoxycarbonyl-4-mesyloxypiperidine (13.6 g), trifluoromethoxyphenol (4.0 g), tetrabutylammonium chloride (1.2 g) and potassium carbonate (7.72 g) were suspended in water (20 mL) and the suspension was refluxed for 3 hours. The reaction solution was cooled to room temperature, and then the reaction product was extracted with toluene (24 mL). The extract was washed with water (20 mL×2), and then the solvent was concentrated under reduced pressure to obtain a target compound as a light yellow oily substance. The yield amount was 12.03 g (%). The obtained target compound was used, for the subsequent reaction without being purified. the suspension was refluxed for 3 hours the reaction product was extracted with toluene (24 mL) The extract was washed with water (20 mL×2) the solvent was concentrated under reduced pressure to obtain a target compound as a light yellow oily substance The obtained target compound was used, for the subsequent reaction without being purified

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-trifluoromethoxyphenol (25 μL, 0.187 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-trifluoromethoxy-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (30 mg, 74%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.94 (d, J=8.4 Hz, 2H), 7.54-7.63 (m, 3H), 7.26-7.41 (m, 3H), 6.97-7.07 (m, 1H), 5.29 (s, 2H). evaporated to dryness The residue was purified by chromatography (66-75% EtOAc/hexanes)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-trifluoromethoxyphenol (25 μL, 0.187 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-trifluoromethoxy-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (30 mg, 74%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.94 (d, J=8.4 Hz, 2H), 7.54-7.63 (m, 3H), 7.26-7.41 (m, 3H), 6.97-7.07 (m, 1H), 5.29 (s, 2H). evaporated to dryness The residue was purified by chromatography (66-75% EtOAc/hexanes)