1,1,2,2-tetrafluoro-1-iodoethane

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-5-fluorophenol (104 mmol crude), prepared as described in Step 1, Procedure 7, and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was cooled to rt, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina The filtrate was concentrated under reduced pressure to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification. LCMS: RT=1.91 min, [M+H] No Ionizable peak (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.76 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, Purity 100%); NMR: 400 MHz 1H(CDCl3) ppm 7.19 (m, 2 H), 6.92 (d, J=8.35 Hz, 1 H), 5.88 (tt; J=52.95 Hz and J=2.64 Hz, 1 H). The reaction mixture was sealed in a thick walled glass pressure round bottom flask The reaction mixture was cooled to rt extracted with ether (3×200 mL) The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL) The combined organic layers were dried over Na2SO4 filtered concentrated under reduced pressure to yield a residue filtered through a plug of activated basic alumina The filtrate was concentrated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-5-fluorophenol (104 mmol crude), prepared as described in Step 1, Procedure 7, and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was cooled to rt, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina The filtrate was concentrated under reduced pressure to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification. LCMS: RT=1.91 min, [M+H] No Ionizable peak (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.76 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, Purity 100%); NMR: 400 MHz 1H(CDCl3) ppm 7.19 (m, 2 H), 6.92 (d, J=8.35 Hz, 1 H), 5.88 (tt; J=52.95 Hz and J=2.64 Hz, 1 H). The reaction mixture was sealed in a thick walled glass pressure round bottom flask The reaction mixture was cooled to rt extracted with ether (3×200 mL) The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL) The combined organic layers were dried over Na2SO4 filtered concentrated under reduced pressure to yield a residue filtered through a plug of activated basic alumina The filtrate was concentrated under reduced pressure

Conditions: temp:122.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Iodo-3-pentafluoroethyl-1H-pyrazole (6.24 g), copper powder (3.81 g), Iodo-1,1,2,2-tetrafluoroethane (9.12 g) and DMF (30 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 120-125° C. After cooling to room temperature, the insoluble material was filtered off through Celite and washed with diethyl ether. The filtrate was diluted with water and extracted with diethyl ether. The organic phase was washed with water and dried over sodium sulfate, and concentrated under the reduced pressure. The crude product was distilled under reduced pressure to obtain 3-pentafluoroethyl-4-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole (0.60 g), bp. 125-135° C./20 mbar. heated After cooling to room temperature the insoluble material was filtered off through Celite washed with diethyl ether The filtrate was diluted with water extracted with diethyl ether The organic phase was washed with water dried over sodium sulfate concentrated under the reduced pressure The crude product was distilled under reduced pressure

Conditions: temp:122.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Iodo-3-pentafluoroethyl-1H-pyrazole (6.24 g), copper powder (3.81 g), Iodo-1,1,2,2-tetrafluoroethane (9.12 g) and DMF (30 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 120-125° C. After cooling to room temperature, the insoluble material was filtered off through Celite and washed with diethyl ether. The filtrate was diluted with water and extracted with diethyl ether. The organic phase was washed with water and dried over sodium sulfate, and concentrated under the reduced pressure. The crude product was distilled under reduced pressure to obtain 3-pentafluoroethyl-4-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole (0.60 g), bp. 125-135° C./20 mbar. heated After cooling to room temperature the insoluble material was filtered off through Celite washed with diethyl ether The filtrate was diluted with water extracted with diethyl ether The organic phase was washed with water dried over sodium sulfate concentrated under the reduced pressure The crude product was distilled under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-5-fluorophenol (104 mmol crude) and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and saturated NaCl (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification LCMS: RT=1.91 min, [M+H] No Ionizable peak (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.19 ppm, 2H, m; 6.92 ppm, 1H, d, J=8.35 Hz; 5.88 ppm, 1H, tt; J=52.95 Hz and 2.64 Hz. The reaction mixture was sealed in a thick walled glass pressure round bottom flask to cool to room temperature extracted with ether (3×200 mL) The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and saturated NaCl (200 mL) The organic layer was dried over sodium sulfate filtered concentrated The residue was dissolved in ether (150 mL) filtered through a plug of activated basic alumina The filtrate was concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-5-fluorophenol (104 mmol crude) and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification LCMS: 1.91 min, [M+1] No Ionizable peak (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.76 min (4 min gradient, MeOH/H2O 0.2% PPA) Purity 100%; NMR: 400 MHz 1H (CDCl3) 7.19 ppm, 2H, m; 6.92 ppm, 1H, d, J=8.35 Hz; 5.88 ppm, 1H, tt; J=52.95 Hz and J=2.64 Hz. The reaction mixture was sealed in a thick walled glass pressure round bottom flask to cool to room temperature extracted with ether (3×200 mL) The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and brine (200 mL) The organic layer was dried over sodium sulfate filtered concentrated The residue was dissolved in ether (150 mL) filtered through a plug of activated basic alumina The filtrate was concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-5-fluorophenol (104 mmol crude), prepared as described in Step 1, Procedure 7, and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was cooled to rt, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated under reduced pressure to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification. LCMS: RT=1.91 min, [M+H] No Ionizable peak (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.76 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, Purity 100%); NMR: 400 MHz 1H (CDCl3) ppm 7.19 (m, 2 H), 6.92 (d, J=8.35Hz, 1 H), 5.88 (tt; J=52.95 Hz and J=2.64 Hz, 1 H). The reaction mixture was sealed in a thick walled glass pressure round bottom flask The reaction mixture was cooled to rt extracted with ether (3×200 mL) The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL) The combined organic layers were dried over Na2SO4 filtered concentrated under reduced pressure to yield a residue filtered through a plug of activated basic alumina The filtrate was concentrated under reduced pressure

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-5-fluorophenol (104 mmol crude) and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina. The filtrate was concentrated to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification LCMS: 1.91 min, [M+1] No Ionizable peak (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.76 min (4 min gradient, MeOH/H2O 0.2% PPA) Purity 100%; NMR: 400 MHz 1H (CDCl3) 7.19 ppm, 2H, m; 6.92 ppm, 1H, d, J=8.35 Hz; 5.88 ppm, 1H, tt; J=52.95 Hz and J=2.64 Hz. The reaction mixture was sealed in a thick walled glass pressure round bottom flask to cool to room temperature extracted with ether (3×200 mL) The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and brine (200 mL) The organic layer was dried over sodium sulfate filtered concentrated The residue was dissolved in ether (150 mL) filtered through a plug of activated basic alumina The filtrate was concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-bromo-5-fluorophenol (104 mmol crude), prepared as described in Step 1, Procedure 7, and iodo-1,1,2,2,-tetrafluoroethane (28.4 g, 125 mmol) in DMSO (80 mL) was added K2CO3 (57.0 g, 420 mmol). The reaction mixture was sealed in a thick walled glass pressure round bottom flask and heated at 70° C. for 18 h. The reaction mixture was cooled to rt, diluted with water (500 mL) and extracted with ether (3×200 mL). The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was dissolved in ether (150 mL) and filtered through a plug of activated basic alumina The filtrate was concentrated under reduced pressure to give 1-bromo-3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)benzene as a pale yellow oil (27.2 g, 88% for two steps) which was used without further purification. LCMS: RT=1.91 min, [M+H] No Ionizable peak (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.76 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, Purity 100%); NMR: 400 MHz 1H(CDCl3) ppm 7.19 (m, 2 H), 6.92 (d, J=8.35 Hz, 1 H), 5.88 (tt; J=52.95 Hz and J=2.64 Hz, 1 H). The reaction mixture was sealed in a thick walled glass pressure round bottom flask The reaction mixture was cooled to rt extracted with ether (3×200 mL) The combined ether layers were washed with 1N NaOH (2×200 mL), water (2×200 mL) and sat. NaCl (200 mL) The combined organic layers were dried over Na2SO4 filtered concentrated under reduced pressure to yield a residue filtered through a plug of activated basic alumina The filtrate was concentrated under reduced pressure