3,3,4,4,4-pentafluorobutan-2-ol

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

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

Procedure: Add (±)-3,3,4,4,4-pentafluoro-2-butanol (710 mg, 4.3 mmol) slowly to a slurry of sodium hydride (104 mg, 1.2 equiv, 60% mineral oil, washed with hexane) in hexamethylphosphoramide (2 mL) under nitrogen at 0° C. Allow the slurry to warm to ambient temperature and stir for 5 min. Add 5-chloro-pyridine-2-carbonitrile (300 mg, 2.2 mmol), then heat the mixture in a sealed flask at 130° C. for 4 h (monitor reaction by GC/MS). Cool the reaction to room temperature, adjust the mixture to pH 9 with saturated aqueous Na2CO3, then extract with diethyl ether (2×50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 7:3 gradient) to obtain the desired intermediate (380 mg, 66%). GC-MS m/z: 266 (M+). (monitor reaction by GC/MS) Cool the reaction to room temperature extract with diethyl ether (2×50 mL) Dry the combined organic extracts over Na2SO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 7:3 gradient)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add potassium carbonate (27.4 g, 198 mmol) to a mixture of 4-fluorobenzonitrile (8 g, 66 mmol) and (±)-3,3,4,4,4-pentafluoro-2-butanol (17.2 g, 105 mmol) in anhydrous DMF (60 mL). Heat the mixture in a sealed flask for 4 h at 130° C. Cool the reaction to ambient temperature, dilute with hexane/EtOAc (1:1, 350 mL) and wash with aqueous 5% sodium chloride (3×100 mL). Collect the organic layer, dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (17.1 g, 98%). GC-MS m/z: 432 (M+). Cool the reaction to ambient temperature wash with aqueous 5% sodium chloride (3×100 mL) Collect the organic layer dry over Na2SO4 filter concentrate in vacuo

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add potassium carbonate (27.4 g, 198 mmol) to a mixture of 4-fluorobenzonitrile (8 g, 66 mmol) and (±)-3,3,4,4,4-pentafluoro-2-butanol (17.2 g, 105 mmol) in anhydrous DMF (60 mL). Heat the mixture in a sealed flask for 4 h at 130° C. Cool the reaction to ambient temperature, dilute with hexane/EtOAc (1:1, 350 mL) and wash with aqueous 5% sodium chloride (3×100 mL). Collect the organic layer, dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (17.1 g, 98%). GC-MS m/z: 432 (M+). Cool the reaction to ambient temperature wash with aqueous 5% sodium chloride (3×100 mL) Collect the organic layer dry over Na2SO4 filter concentrate in vacuo

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

Procedure: A mixture of (S)-naproxen (9.23 g, 40.1 mmol), racemic 3,3,4,4,4-pentafluoro-2-butanol (6.58 g, 40.1 mmol), EDC (9.20 g, 48.0 mmol) and DMAP (4.89 g, 40.0 mmol) was dissolved in CH2Cl2 (40 mL) at room temperature. After stirring for 8 h at room temperature, the mixture was diluted with CH2Cl2, then washed successively with 1 N HCl, sat. NaHCO3, and brine. After drying over Na2SO4 and concentrating, a mixture of diastereomeric naproxen esters was obtained as a white solid. washed successively with 1 N HCl, sat. NaHCO3, and brine After drying over Na2SO4 concentrating a mixture of diastereomeric naproxen esters was obtained as a white solid

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

Procedure: A mixture of 4-carboxybenzaldehyde (21.9 g, 145.9 mmol), 3,3,4,4,4-pentafluoro-2-butanol (24.1 g, 146.9 mmol), EDC (33.5 g, 174.8 mmol) and DMAP (18.1 g, 148.1 mmol) was dissolved in DMF (60 ml) at rt. It was stirred for 36 h at rt. Hexane was added, it was washed with 1 N HCl, sat NaHCO3 and brine. The aqueous layers were extracted three times with hexane. It was dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel chromatography (ethyl acetate:hexane 1:10) to yield the desired aldehyde as a yellow oil (67%). it was washed with 1 N HCl The aqueous layers were extracted three times with hexane It was dried over Na2SO4 filtered concentrated the residue was purified by silica gel chromatography (ethyl acetate:hexane 1:10)

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

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

Procedure: A mixture of (S)-naproxen (9.23 g, 40.1 mmol), racemic 3,3,4,4,4-pentafluoro-2-butanol (6.58 g, 40.1 mmol), EDC (9.20 g, 48.0 mmol) and DMAP (4.89 g, 40.0 mmol) was dissolved in CH2Cl2 (40 mL) at room temperature. After stirring for 8 h at room temperature, the mixture was diluted with CH2Cl2, then washed successively with 1 N HCl, sat. NaHCO3, and brine. After drying over Na2SO4 and concentrating, a mixture of diastereomeric naproxen esters was obtained as a white solid. washed successively with 1 N HCl, sat. NaHCO3, and brine After drying over Na2SO4 concentrating a mixture of diastereomeric naproxen esters was obtained as a white solid

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

Procedure: A mixture of 4-carboxybenzaldehyde (21.9 g, 145.9 mmol), 3,3,4,4,4-pentafluoro-2-butanol (24.1 g, 146.9 mmol), EDC (33.5 g, 174.8 mmol) and DMAP (18.1 g, 148.1 mmol) was dissolved in DMF (60 ml) at rt. It was stirred for 36 h at rt. Hexane was added, it was washed with 1 N HCl, sat NaHCO3 and brine. The aqueous layers were extracted three times with hexane. It was dried over Na2SO4, filtered, concentrated, and the residue was purified by silica gel chromatography (ethyl acetate:hexane 1:10) to yield the desired aldehyde as a yellow oil (67%). it was washed with 1 N HCl The aqueous layers were extracted three times with hexane It was dried over Na2SO4 filtered concentrated the residue was purified by silica gel chromatography (ethyl acetate:hexane 1:10)

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

Procedure: Add (±)-3,3,4,4,4-pentafluoro-2-butanol (710 mg, 4.3 mmol) slowly to a slurry of sodium hydride (104 mg, 1.2 equiv, 60% mineral oil, washed with hexane) in hexamethylphosphoramide (2 mL) under nitrogen at 0° C. Allow the slurry to warm to ambient temperature and stir for 5 min. Add 5-chloro-pyridine-2-carbonitrile (300 mg, 2.2 mmol), then heat the mixture in a sealed flask at 130° C. for 4 h (monitor reaction by GC/MS). Cool the reaction to room temperature, adjust the mixture to pH 9 with saturated aqueous Na2CO3, then extract with diethyl ether (2×50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 7:3 gradient) to obtain the desired intermediate (380 mg, 66%). GC-MS m/z: 266 (M+). (monitor reaction by GC/MS) Cool the reaction to room temperature extract with diethyl ether (2×50 mL) Dry the combined organic extracts over Na2SO4 filter concentrate in vacuo Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 7:3 gradient)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add potassium carbonate (27.4 g, 198 mmol) to a mixture of 4-fluorobenzonitrile (8 g, 66 mmol) and (±)-3,3,4,4,4-pentafluoro-2-butanol (17.2 g, 105 mmol) in anhydrous DMF (60 mL). Heat the mixture in a sealed flask for 4 h at 130° C. Cool the reaction to ambient temperature, dilute with hexane/EtOAc (1:1, 350 mL) and wash with aqueous 5% sodium chloride (3×100 mL). Collect the organic layer, dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (17.1 g, 98%). GC-MS m/z: 432 (M+). Cool the reaction to ambient temperature wash with aqueous 5% sodium chloride (3×100 mL) Collect the organic layer dry over Na2SO4 filter concentrate in vacuo

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

Procedure: A mixture of (S)-naproxen (9.23 g, 40.1 mmol), racemic 3,3,4,4,4-pentafluoro-2-butanol (6.58 g, 40.1 mmol), EDC (9 20 g, 48.0 mmol) and DMAP (4.89 g, 40.0 mmol) was dissolved in CH2Cl2 (40 mL) at room temperature. After stirring for 8 h at room temperature, the mixture was diluted with CH2Cl2, then washed successively with 1 N HCl, sat. NaHCO3, and brine. After drying over Na2SO4 and concentrating, a mixture of diastereomeric naproxen esters was obtained as a white solid. washed successively with 1 N HCl, sat. NaHCO3, and brine After drying over Na2SO4 concentrating a mixture of diastereomeric naproxen esters was obtained as a white solid