1-fluoro-2-(trifluoromethyl)benzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1.78 g (14 mmol) of 3-quinuclidinol in 20 ml of dry N,N-dimethylformamide (DMF) was added dropwise under nitrogen to a suspension of 0.6 g (15 mmol) of sodium hydride in 20 ml of dry DMF. The mixture was stirred for 15 min at 70° C., and a solution of 3.8 ml (30 mmol) of 2-fluoro-(trifluoromethyl)benzene in 8 ml of dry DMF was added dropwise. The mixture was stirred for another 1.5 h, after which the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with brine. The ethyl acetate layer was separated, dried over magnesium sulfate and evaporated to dryness. The crude compound was purified by column chromatography on silica using methanol-dichloromethane (2:8) as eluent to give 3.0 g (59% yield) of 3-[2-(trifluoromethyl)phenoxy]-1-azabicyclo[2.2.2 ]octane, which was converted into the oxalate salt by treatment with oxalic acid and recrystallization from methanol. m.p. 174° C. The mixture was stirred for another 1.5 h after which the solvent was evaporated The residue was dissolved in ethyl acetate washed with brine The ethyl acetate layer was separated dried over magnesium sulfate evaporated to dryness The crude compound was purified by column chromatography on silica

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1.78 g (14 mmol) of 3-quinuclidinol in 20 ml of dry N,N-dimethylformamide (DMF) was added dropwise under nitrogen to a suspension of 0.6 g (15 mmol) of sodium hydride in 20 ml of dry DMF. The mixture was stirred for 15 min at 70° C., and a solution of 3.8 ml (30 mmol) of 2-fluoro-(trifluoromethyl)benzene in 8 ml of dry DMF was added dropwise. The mixture was stirred for another 1.5 h, after which the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with brine. The ethyl acetate layer was separated, dried over magnesium sulfate and evaporated to dryness. The crude compound was purified by column chromatography on silica using methanol-dichloromethane (2:8) as eluent to give 3.0 g (59% yield) of 3-[2-(trifluoromethyl)phenoxy]-1-azabicyclo[2.2.2 ]octane, which was converted into the oxalate salt by treatment with oxalic acid and recrystallization from methanol. m.p. 174° C. The mixture was stirred for another 1.5 h after which the solvent was evaporated The residue was dissolved in ethyl acetate washed with brine The ethyl acetate layer was separated dried over magnesium sulfate evaporated to dryness The crude compound was purified by column chromatography on silica

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

実験手順: To a stirred suspension of 1.0 g of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After stirring for one hr at ambient temperature, 3.75 ml of 2-fluorobenzotrifluoride was added. The reaction mixture was heated to 90° C. and stirred for 17 hrs. The mixture was then poured into water, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was purified using flash chromatography (silica gel, diethylamine-ethyl acetate, 1:9). The appropriate fractions were evaporated. The residue was recrystallized once from hexane, then combined with a previously prepared sample (1.1 g), and recrystallized from hexane to yield 2.17 g of (24%) of product, mp 110°-111° C. was added The reaction mixture was heated to 90° C. stirred for 17 hrs extracted with ether dried over anhydrous magnesium sulfate concentrated The residue was purified The appropriate fractions were evaporated The residue was recrystallized once from hexane recrystallized from hexane

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

実験手順: To a stirred suspension of 1.0 g of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After stirring for one hr at ambient temperature, 3.75 ml of 2-fluorobenzotrifluoride was added. The reaction mixture was heated to 90° C. and stirred for 17 hrs. The mixture was then poured into water, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was purified using flash chromatography (silica gel, diethylamine-ethyl acetate, 1:9). The appropriate fractions were evaporated. The residue was recrystallized once from hexane, then combined with a previously prepared sample (1.1 g), and recrystallized from hexane to yield 2.17 g of (24%) of product, mp 110°-111° C. was added The reaction mixture was heated to 90° C. stirred for 17 hrs extracted with ether dried over anhydrous magnesium sulfate concentrated The residue was purified The appropriate fractions were evaporated The residue was recrystallized once from hexane recrystallized from hexane

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

実験手順: Prepared using a procedure adapted from Miyazawa et al. (Miyazawa, E.; et al. Org. Prep. Proced. Int. 1997, 29, 594-600) tBuOK (0.78 g, 6.7 mmol) was added to a stirring solution of ethyl-N-hydroxyacetimidate (1.00 g, 6.06 mmol) in anhydrous DMF (6 mL) at 0° C. under an Ar atmosphere. After tBuOK addition was completed the reaction was stirred at room temperature. After 30 min 2-fluorobenzotrifluoride (1.29 mL, 6.06 mmol) was added and the reaction was heated at 80° C. for 2 h. Upon cooling the reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (2×50 mL), dried with MgSO4, and concentrated to afford a dark oil. Flash chromatographic purification over silica (10% EtOAc in hexanes) afforded 15 as a clear liquid (1.33 g, 89%). 1H-NMR (500 MHz, CDCl3) δ 1.36 (t, J=7.1 Hz, 3H), 2.15 (s, 3H), 4.20 (q, J=7.1 Hz, 2H), 6.99 (apparent t, J=7.5 Hz, 1H), 7.47 (apparent dt, J=7.9 Hz, 1H), 7.52-7.57 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 14.3, 14.5, 63.2, 114.2, 116.2 (q, JC-F=31 Hz), 120.3, 123.7 (q, JC-F=272 Hz), 126.4 (q, JC-F=4.8 Hz), 133.2, 157.2 (q, JC-F=1.9 Hz), 167.1; LC-MS 248 m/z[MH]+, C11H13F3NO2 requires 248. Prepared the reaction was heated at 80° C. for 2 h Upon cooling the reaction mixture extracted with EtOAc (3×40 mL) The combined organic layers were washed with brine (2×50 mL) dried with MgSO4 concentrated to afford a dark oil Flash chromatographic purification over silica (10% EtOAc in hexanes)

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

実験手順: Prepared using a procedure adapted from Miyazawa et al. (Miyazawa, E.; et al. Org. Prep. Proced. Int. 1997, 29, 594-600) tBuOK (0.78 g, 6.7 mmol) was added to a stirring solution of ethyl-N-hydroxyacetimidate (1.00 g, 6.06 mmol) in anhydrous DMF (6 mL) at 0° C. under an Ar atmosphere. After tBuOK addition was completed the reaction was stirred at room temperature. After 30 min 2-fluorobenzotrifluoride (1.29 mL, 6.06 mmol) was added and the reaction was heated at 80° C. for 2 h. Upon cooling the reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (2×50 mL), dried with MgSO4, and concentrated to afford a dark oil. Flash chromatographic purification over silica (10% EtOAc in hexanes) afforded 15 as a clear liquid (1.33 g, 89%). 1H-NMR (500 MHz, CDCl3) δ 1.36 (t, J=7.1 Hz, 3H), 2.15 (s, 3H), 4.20 (q, J=7.1 Hz, 2H), 6.99 (apparent t, J=7.5 Hz, 1H), 7.47 (apparent dt, J=7.9 Hz, 1H), 7.52-7.57 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 14.3, 14.5, 63.2, 114.2, 116.2 (q, JC-F=31 Hz), 120.3, 123.7 (q, JC-F=272 Hz), 126.4 (q, JC-F=4.8 Hz), 133.2, 157.2 (q, JC-F=1.9 Hz), 167.1; LC-MS 248 m/z[MH]+, C11H13F3NO2 requires 248. Prepared the reaction was heated at 80° C. for 2 h Upon cooling the reaction mixture extracted with EtOAc (3×40 mL) The combined organic layers were washed with brine (2×50 mL) dried with MgSO4 concentrated to afford a dark oil Flash chromatographic purification over silica (10% EtOAc in hexanes)

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

実験手順: To a stirred suspension 1.0 g of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After stirring for one hr at ambient temperature, 3.75 ml of 2-fluorobenzotrifluoride was added. The reaction mixture was heated to 90° C. and stirred for 17 hrs. The mixture was then poured into water, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was purified using flash chromatography (silica gel, diethylamine-ethyl acetate, 1:9). The appropriate fractions were evaporated. The residue was recrystallized once from hexane, then combined with a previously prepared sample (1.1 g), and recrystallized from hexane to yield 2.17 g (24%) of product, mp 110°-111° C. The reaction mixture was heated to 90° C. stirred for 17 hrs extracted with ether dried over anhydrous magnesium sulfate concentrated The residue was purified The appropriate fractions were evaporated The residue was recrystallized once from hexane recrystallized from hexane

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

実験手順: To a stirred suspension 1.0 g of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After stirring for one hr at ambient temperature, 3.75 ml of 2-fluorobenzotrifluoride was added. The reaction mixture was heated to 90° C. and stirred for 17 hrs. The mixture was then poured into water, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was purified using flash chromatography (silica gel, diethylamine-ethyl acetate, 1:9). The appropriate fractions were evaporated. The residue was recrystallized once from hexane, then combined with a previously prepared sample (1.1 g), and recrystallized from hexane to yield 2.17 g (24%) of product, mp 110°-111° C. The reaction mixture was heated to 90° C. stirred for 17 hrs extracted with ether dried over anhydrous magnesium sulfate concentrated The residue was purified The appropriate fractions were evaporated The residue was recrystallized once from hexane recrystallized from hexane

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

実験手順: To a stirred suspension of 1.0 g of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After stirring for one hr at ambient temperature, 3.75 ml of 2-fluorobenzotrifluoride was added. The reaction mixture was heated to 90° C. and stirred for 17 hrs. The mixture was then poured into water, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was purified using flash chromatography (silica gel, diethylamine-ethyl acetate, 1:9). The appropriate fractions were evaporated. The residue was recrystallized once from hexane, then combined with a previously prepared sample (1.1 g), and recrystallized from hexane to yield 2.17 g (24%) of product, mp 110°-111° C. was added The reaction mixture was heated to 90° C. stirred for 17 hrs extracted with ether dried over anhydrous magnesium sulfate concentrated The residue was purified The appropriate fractions were evaporated The residue was recrystallized once from hexane recrystallized from hexane

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

実験手順: The general procedure was followed using 11.0 g of 1-vinyl-2-trifluoromethyl-2,3,3-trifluorocyclobutane dissolved in 11.15 g of benzene as the liquid feed at a flow rate of 1 ml/hr. Nitrogen was used as the inert carrier. The reactor was charged with 2.0 g of activated carbon. At 400° C. 41% of o-trifluoromethylfluorobenzene was produced. The reactor was charged with 2.0 g of activated carbon At 400° C

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

実験手順: The general procedure was followed using 11.0 g of 1-vinyl-2-trifluoromethyl-2,3,3-trifluorocyclobutane dissolved in 11.15 g of benzene as the liquid feed at a flow rate of 1 ml/hr. Nitrogen was used as the inert carrier. The reactor was charged with 2.0 g of activated carbon. At 400° C. 41% of o-trifluoromethylfluorobenzene was produced. The reactor was charged with 2.0 g of activated carbon At 400° C