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With 2-(Trimethylsilyl)ethanol; sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 20 h;
Preparation 53-Chloro-4-(trifluoromethyl)phenolTo a stirred sol ution of 2-chloro-4-fluorobenzotrifluoride (500 mg, 2.52 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 2-(trimethylsilyl)ethanol (0.40 mL, 2.77 mmol) and the reaction mixture was cooled to 0°C. Sodium hydride (302 mg, 60percent w/w dispersion in oil, 7.55 mmol) was then added portionwise. After 5 minutes a thick white suspension had formed . The reaction mixture was warmed to room temperature slowly and then stirred for a further 16 hours. The reaction mixture was then quenched with ice water (50 mL) and washed with diethyl ether (50 mL). The aqueous extracts were acidified with aqueous 2 M hydrogen chloride solution and extracted with diethyl ether (2 x 50 mL). The organic extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo for 16 hours to afford the title compound as a yellow oil (356 mg, 72percent).1H NMR (400 MHz, CDCI3): δ 6.75 (dd, 1 H), 6.95 (d, 1 H), 7.51 (d, 1 H).LCMS Rt = 1 .23 minutes MS m/z 195 [M-H]-
With tetrabutyl ammonium fluoride In tetrahydrofuran; 1,4-dioxane at 20℃; for 18 h; Inert atmosphere
To a solution of (2-(3-chloro-4-(trifluoromethyl)phenoxy)ethyl)trimethylsilane (Preparation 15, 3.1 g, 10 mmol) in 1,4-dioxane (5 mL) was added tetrabutylammonium fluoride (10 mL, 1M in THF) and the resulting mixture was stirred at room temperature for 18 hours under nitrogen. The mixture was poured onto water and neutralised with aq. ammonium chloride and extracted with ethyl acetate (3.x.30 mL). The organic layer was separated and washed with 1M sodium hydroxide (3.x.30 mL). The aqueous layers were separated, combined, acidified with aqueous 2M HCl and re-extracted with ethyl acetate (3.x.30 mL), dried (MgSO4), filtered and concentrated in vacuo to afford 2.46 g of a pale yellow oil. The crude oil was purified by silica gel column chromatography eluting with a gradient of 0-50percent ethyl acetate in heptane to afford 619 mg (31percent) of the title compound as a colourless oil.LCMS Rt=2.97 minutes MS m/z 195 [M-H]+1HNMR (400 MHz, CDCl3): δ 6.64 (br s, 1H), 6.76 (m, 1H), 6.96 (m, 1H), 7.50 (m, 1H),
To a sulfuric acid (14 ml) -H2O (14 ml) solution of 3-chloro-4-(trifluoromethyl)aniline (1.96 g, 10 mmol) was added a H2O (10 mL) solution of sodium nitrite (828 mg,12 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was poured into 10 M sulfuric acid (50 mL). The stirred mixture was refluxed at 110 ° C. for 2 hours. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate The organic layer was then washed with brine, dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a ethyl acetate/hexane= to furnish 945 mg (48percent yield) of the title compound as a brown oil. 1H NMR (CDCl3, 270 MHz) δ ppm 5.99 (1H, brs), 6.80 (1H, dd, J=2.6, 8.6 Hz), 7.00 (1H, d, J=2.6 Hz), 7.56 (1H, d, J=8.6 Hz). MS (ESI) m/z: 195[M-H-.
With potassium carbonate; for 14h;Heating / reflux;
<strong>[37900-81-5]3-chloro-4-(trifluoromethyl)phenol</strong> (940 mg, 4.8 mmol), potassium carbonate (2.0 g, 14.0 mmol) and tert-butyl bromoacetate (1.0 mL, 6.4 mmol) were stirred under reflux condition for 14 hours. The precipitate was filtered off and washed with acetone. The filtrate was concentrated under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (19/1 to 4/1) to furnish 1.2 g (80percent yield) of the title compound as a brown oil. 1H NMR (CDCl3, 300 MHz) delta ppm 1.50 (9H, s), 4.56 (2H, s), 6.84 (1H, dd, J=2.6, 8.6 Hz), 7.03 (1H, d, J =2.6 Hz), 7.61 (1H, d, J=8.6 Hz)
With sulfuric acid; water; sodium nitrite; at 0 - 110℃; for 3h;Heating / reflux;
To a sulfuric acid (14 ml) -H2O (14 ml) solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (1.96 g, 10 mmol) was added a H2O (10 mL) solution of sodium nitrite (828 mg,12 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was poured into 10 M sulfuric acid (50 mL). The stirred mixture was refluxed at 110 ° C. for 2 hours. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate The organic layer was then washed with brine, dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a ethyl acetate/hexane= to furnish 945 mg (48percent yield) of the title compound as a brown oil. 1H NMR (CDCl3, 270 MHz) delta ppm 5.99 (1H, brs), 6.80 (1H, dd, J=2.6, 8.6 Hz), 7.00 (1H, d, J=2.6 Hz), 7.56 (1H, d, J=8.6 Hz). MS (ESI) m/z: 195[M-H-.
With 2-(Trimethylsilyl)ethanol; sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 20h;
Preparation 53-Chloro-4-(trifluoromethyl)phenolTo a stirred sol ution of 2-chloro-4-fluorobenzotrifluoride (500 mg, 2.52 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added 2-(trimethylsilyl)ethanol (0.40 mL, 2.77 mmol) and the reaction mixture was cooled to 0°C. Sodium hydride (302 mg, 60percent w/w dispersion in oil, 7.55 mmol) was then added portionwise. After 5 minutes a thick white suspension had formed . The reaction mixture was warmed to room temperature slowly and then stirred for a further 16 hours. The reaction mixture was then quenched with ice water (50 mL) and washed with diethyl ether (50 mL). The aqueous extracts were acidified with aqueous 2 M hydrogen chloride solution and extracted with diethyl ether (2 x 50 mL). The organic extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo for 16 hours to afford the title compound as a yellow oil (356 mg, 72percent).1H NMR (400 MHz, CDCI3): delta 6.75 (dd, 1 H), 6.95 (d, 1 H), 7.51 (d, 1 H).LCMS Rt = 1 .23 minutes MS m/z 195 [M-H]-
With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 18h;Inert atmosphere;
To <strong>[37900-81-5]3-chloro-4-(trifluoromethyl)phenol</strong> (Preparation 16, 110 mg, 0.56 mmol) and 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (Preparation 13, 150 mg, 0.56 mmol) dissolved in dimethylsulfoxide (5 ml) was added potassium carbonate (232 mg, 1.68 mmol) and the mixture stirred at 90° C. for 18 hours under nitrogen. The mixture was poured onto ammonium chloride (aq) and extracted with ethyl acetate (3.x.20 mL), washed with water (3.x.20 mL) and dried (MgSO4). Purification of the crude product by silica gel column chromatography using 80percent Ethyl acetate in heptane furnished the title compound as white solid (12.2 mg, 4.9percent).LCMS Rt=2.87 minutes MS m/z 446 [MH]+1HNMR (400 MHz, CDCl3): delta 3.30 (s, 3H), 6.58 (m, 1H), 6.79 (m, 1H), 6.95 (m, 1H), 7.58 (m, 1H), 7.93 (m, 1H).
With tetrabutyl ammonium fluoride; In tetrahydrofuran; 1,4-dioxane; at 20℃; for 18h;Inert atmosphere;
To a solution of (2-(3-chloro-4-(trifluoromethyl)phenoxy)ethyl)trimethylsilane (Preparation 15, 3.1 g, 10 mmol) in 1,4-dioxane (5 mL) was added tetrabutylammonium fluoride (10 mL, 1M in THF) and the resulting mixture was stirred at room temperature for 18 hours under nitrogen. The mixture was poured onto water and neutralised with aq. ammonium chloride and extracted with ethyl acetate (3.x.30 mL). The organic layer was separated and washed with 1M sodium hydroxide (3.x.30 mL). The aqueous layers were separated, combined, acidified with aqueous 2M HCl and re-extracted with ethyl acetate (3.x.30 mL), dried (MgSO4), filtered and concentrated in vacuo to afford 2.46 g of a pale yellow oil. The crude oil was purified by silica gel column chromatography eluting with a gradient of 0-50percent ethyl acetate in heptane to afford 619 mg (31percent) of the title compound as a colourless oil.LCMS Rt=2.97 minutes MS m/z 195 [M-H]+1HNMR (400 MHz, CDCl3): delta 6.64 (br s, 1H), 6.76 (m, 1H), 6.96 (m, 1H), 7.50 (m, 1H),
Example 2 [illustrates Method D14-[3-Chloro-4-(trifluoromethyl)phenoxy1methyl)-2,5-difluoro-N- (methylsulfonyl)benzamideA solution of <strong>[37900-81-5]3-chloro-4-(trifluoromethyl)phenol</strong> (Preparation 5, 50 mg, 0.26 mmol), 4- (bromomethyl)-2,5-difluoro-N-(methylsulfonyl)benzamide (Preparation 4, 84 mg , 0.26 mmol) and potassium carbonate (71 mg, 0.51 mmol) in dimethyl sulfoxide (5 ml_) was stirred at room temperature for 16 hours. A 2M aqueous solution of hydrogen chloride was added to the reaction mixture. The resulting precipitate was filtered, washed with diethyl ether (5 ml_) and dried. The material was purified by reverse phase column chromatography (12 g C-18 biotage cartridge; eluents: MeCN + 0.1 percent formic acid, and H2O + 0.1 percent formic acid; Gradient: 30percent MeCN, followed by gradient to 100percent MeCN, 100percent MeCN. Fractions containing product were combined and concentrated in vacuo to afford the title compound as a colourless solid (65 mg, 56percent).1H NMR (400 MHz, d6-DMSO): delta 3.30 (s, 3H), 5.35 (s, 2H), 7.20 (m, 1 H), 7.48 (m, 1 H), 7.60 (m, 2H), 7.80 (m, 1 H).LCMS Rt = 4.03 minutes MS m/z 442, 444 [M-H]-
To a solution of <strong>[37900-81-5]3-chloro-4-(trifluoromethyl)phenol</strong> (1 10 mg, 0.56 mmol) in DMSO (5.0 ml_) was added potassium carbonate (155 mg, 1 .1 mmol). The reaction mixture was stirred at room temperature for 10 minutes, before addition of ethyl 4-(bromomethyl)benzoate (136 mg, 0.56 mmol). The resulting mixture was heated to 70 °C with stirring for 3 hours before cooling back to room temperature. Water (50 ml_) and EtOAc (50 ml_) were added and the layers partitioned. The aqueous layers were washed with EtOAc (2 x 50 ml_) and the combined organic layers dried over magnesium sulfate, filtered and concentrated in vacuo to yield a white solid as the title compound (198 mg, 99percent). 1 H NMR (400 MHz, CDCI3): delta 1 .40 (t, 3H), 4.39 (q, 2H), 5.16 (s, 2H), 6.90 (dd, 1 H), 7.10 (d, 1 H), 7.48 (d, 2H), 7.59 (d, 1 H), 8.08 (d, 2H). LCMS Rt = 1 .65 minutes no mass ion observed
4-[3-chloro-4-(trifluoromethyl)phenoxy]methyl}-N-[(dimethylamino)sulfonyl]difluorobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
10%
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 18h;
To a solution of 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1 , 167 mg, 0.47 mmol) in dimethylsulfoxide (2 mL) was added 2-chloro-4- hydroxybenzotrifluoride (92 mg, 0.47 mmol) followed by addition of potassium carbonate (129 mg, 0.94 mmol). The reaction was left to stir at room temperature for 18 hours. The reaction was diluted with dichloromethane (20 mL) and washed with aqueous potassium hydrogen sulfate (5 mL). The organic phase was separated and the aqueous phase extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine (30 mL) and filtered through a phase separation cartridge. The solvent was removed under reduced pressure and the crude product purified by reverse phase preparative HPLC. The correct fractions were combined and reduced to dryness to afford the title compound as white solid (23 mg, 10percent). 1 H NMR (400 MHz, CDCI3): delta 3.05 (s, 6H), 5.20 (s, 2H), 6.92 (m, 1 H), 7.12 (d, 1 H), 7.39 (m, 1 H), 7.64 (d, 1 H), 7.82 (dd, 1 H), 8.75 (br s, 1 H). LCMS Rt = 4.02 minutes MS m/z 471 [M35CI-H]-
With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 48h;
To a solution of <strong>[37900-81-5]3-chloro-4-(trifluoromethyl)phenol</strong> (200 mg, 1 .02 mmol) in dimethylsulfoxide (7 mL) was added potassium carbonate (281 mg, 2.04 mmol) followed by 4-fluorobenzonitrile (123 mg, 1 .02 mmol). The reaction mixture was stirred at 1 10 °C for 48 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (25 ml_) and water (25 ml_). The organic phase was separated and washed with water (2 x 15 ml_), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to obtain the title compound as a colourless gum (335 mg) which was used in the next step without further purification. 1H NMR (400 MHz, CDCI3): delta ppm 7.01 -7.07 (m, 2H), 7.15-7.19 (m, 1 H), 7.39 (d, 1 H), 7.53 (d, 1 H), 7.64-7.69 (m, 2H). LCMS Rt = 1 .80 minutes MS m/z mass ion not observed
5-chloro-2-iodo-4-(trifluoromethyl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; acetic acid; at 20℃; for 48h;
A mixture of <strong>[37900-81-5]3-chloro-4-(trifluoromethyl)phenol</strong> (3.00 g, 15.3 mmol) and N-iodosuccinimide (95percent, 3.61 g, 15.2 mmol) in acetic acid (10 mL) was stirred for 5 minutes, whereupon sulfuric acid (18 M, 0.25 mL, 4.5 mmol) was added. After the reaction mixture had been stirred at room temperature for 2 days, it was partitioned between diethyl ether and water. The organic layer was washed with water and with 2 M aqueous sodium thiosulfate solution, then treated with activated carbon and dried over magnesium sulfate. The mixture was filtered through a pad of diatomaceous earth and silica gel, and the filtrate was concentrated in vacuo to afford an oil (4.9 g) containing product, acetic acid, and solvent. This material was taken into the following step without additional purification. GCMS m/z 322.0 [M+]. 1H NMR (400 MHz, CDCl3), product peaks only: delta 7.95 (s, 1H), 7.12 (s, 1H).