4,4,5,5,5-Pentafluoropentan-1-ol

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:

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

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

Procedure: 10 g of 4,4,5,5,5-pentafluoro-2-penten-1-ol (obtained according to J. Am. Chem. Soc., 107, (1985), 5186-5191: T. Kitazume and N. Ishikawa) is dissolved in 100 cm3 of methanol, and hydrogenation is carried out in the presence of 0.5 g of Raney nickel. The catalyst is filtered, followed by washing with ethanol and after distillation at ordinary pressure, the expected alcohol is collected B.p.: 133° C. nD23: 1.3305 The catalyst is filtered by washing with ethanol after distillation at ordinary pressure the expected alcohol is collected B.p.: 133° C.

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

Procedure: 10 g of 4,4,5,5,5-pentafluoro-2-penten-1-ol (obtained according to J. Am. Chem. Soc., 107, (1985), 5186-5191: T. Kitazume and N. Ishikawa) is dissolved in 100 cm3 of methanol, and hydrogenation is carried out in the presence of 0.5 g of Raney nickel. The catalyst is filtered, followed by washing with ethanol and after distillation at ordinary pressure, the expected alcohol is collected B.p.: 133° C. nD23: 1.3305 The catalyst is filtered by washing with ethanol after distillation at ordinary pressure the expected alcohol is collected B.p.: 133° C.

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

Procedure: To a solution of 100 μl (0.416 mmol) of 4,4,5,5,5-pentafluoropentan-1-ol in 2 mL of dichloromethane were added 69 μl (1.2 eq) of triethylamine and 36 μl (1.1 eq) of methanesulfonyl chloride in the order, followed by stirring at room temperature for 30 min. The solution was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate, filtrated and concentrated to produce a colorless oil. 60 μl of the oil, 30 mg of (R)-tert-butyl (2-(3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-5-(piperazin-1-yl)-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.049 mmol), and 21 mg (0.149 mmol) of potassium carbonate were dissolved at 80° C. for 7 hrs in 2 mL of acetonitrile, with stirring. The solution was concentrated, diluted with dichloromethane, and washed with an aqueous saturated sodium bicarbonate solution. After concentration of the organic layer thus formed, the residue was purified by prep-TLC (eluent: hexane/ethyl acetate, 1/1) and dried in a vacuum to afford 8 mg of the compound as a colorless oil (yield 21%). 1H NMR (300 MHz, CDCl3) δ 1.36 (9H, s), 1.77 (2H, m), 2.14 (4H, m), 2.36 (3H, s), 2.42 (2H, m), 2.53 (2H, m), 2.75 (2H, m), 3.61 (2H, m), 4.05 (1H, m), 4.28 (1H, m), 5.01 (1H, m), 5.33 (1H, m), 5.51 (1H, m), 5.82 (1H, d), 7.19-7.44 (7H, m), 7.55 (1H, m) The solution was washed with an aqueous saturated sodium bicarbonate solution dried over sodium sulfate filtrated concentrated to produce a colorless oil with stirring The solution was concentrated diluted with dichloromethane washed with an aqueous saturated sodium bicarbonate solution After concentration of the organic layer thus formed the residue was purified by prep-TLC (eluent: hexane/ethyl acetate, 1/1) dried in a vacuum

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

Procedure: A mixture of 4,4,5,5,5-pentafluoropentan-1-ol (1 g, 5.6 mmol), p-toluenesulfonylchloride (1.3 g, 6.8 mmol), and triethylamine (1.2 mL, 8.4 mmol) in DCM (20 mL) was stirred at room temperature for 18 h. Water was added to the reaction mixture, the two layers were separated, and the aqueous layer was extracted with DCM (2×). The organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to afford 1.7 g of 4,4,5,5,5-pentafluoropentyl 4-methylbenzenesulfonate as a colorless oil. the two layers were separated the aqueous layer was extracted with DCM (2×) dried over sodium sulfate evaporated to dryness The residue was purified by column chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes

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

Procedure: A mixture of 4,4,5,5,5-pentafluoropentan-1-ol (1 g, 5.6 mmol), p-toluenesulfonylchloride (1.3 g, 6.8 mmol), and triethylamine (1.2 mL, 8.4 mmol) in DCM (20 mL) was stirred at room temperature for 18 h. Water was added to the reaction mixture, the two layers were separated, and the aqueous layer was extracted with DCM (2×). The organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to afford 1.7 g of 4,4,5,5,5-pentafluoropentyl 4-methylbenzenesulfonate as a colorless oil. the two layers were separated the aqueous layer was extracted with DCM (2×) dried over sodium sulfate evaporated to dryness The residue was purified by column chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of the product of step (a) (500 mg) and 4,4,5,5,5-pentafluoropentan-1-ol (284 mg) in tetrahydrofuran (10 ml) was added potassium tert-butoxide (1M in tetrahydrofuran; 1.6 ml) and the reaction was stirred at 200° C. for 2 hours. An additional charge of potassium tert-butoxide (1M in tetrahydrofuran; 1.6 ml) was added and the reaction was stirred for a further 18 hours. Ethanol (5 ml) was added and the reaction was stirred for 30 mlnutes. The reaction mixture was partitioned between dichloromethane (300 ml) and water (300 ml). The organic layer was dried over magnesium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel (5 g Bond Elut cartridge) eluting with 20% ethyl acetate in cyclohexane gave the title compound as a clear oil (100 mg). was added the reaction was stirred for a further 18 hours the reaction was stirred for 30 mlnutes The reaction mixture was partitioned between dichloromethane (300 ml) and water (300 ml) The organic layer was dried over magnesium sulphate the solvent was removed in vacuo Purification by column chromatography on silica gel (5 g Bond Elut cartridge) eluting with 20% ethyl acetate in cyclohexane

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