2-(2,2,2-trifluoroethoxy)ethanol

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: 2-(2,2,2-trifluoroethoxy)ethanol (intermediate BR) (12.7 g) was dissolved in anhydrous pyridine, then TsCl (1.3 eq) was added, and the mixture was stirred at room temperature for 16 h, after which TLC showed the reaction was complete. Then the mixture was poured into water, extracted with EA, washed with water and brine, and dried with anhydrous Na2SO4. The solvent was removed and the residue purified by column chromatography to obtain intermediate BS (0.3 g). extracted with EA washed with water and brine dried with anhydrous Na2SO4 The solvent was removed the residue purified by column chromatography to obtain intermediate BS (0.3 g)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,2,2-trifluoroethanol (15 g), 1,3-dioxolan-2-one (19.8 g) and Et3N (15 g) were mixed together, and then the mixture was heated to 100° C. and stirred for 24 h. Then the reaction mixture was distilled to obtain intermediate BR (12.7 g). Then the reaction mixture was distilled to obtain intermediate BR (12.7 g)

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

Procedure: Prepare by the method of Preparation 9 using 2-hydroxyethyl 2,2,2-trifluorethyl ether and 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (2.0 g, 6.1 mmol) to give 1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine.

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

Procedure: 2-(2,2,2-Trifluoroethoxy)ethanol (0.462 g, 3.21 mmol) was dissolved in THF (5 mL) and cooled to 0 C. Potassium tert-butoxide (0.360 g, 3.21 mmol) was added, the mixture was stirred for 5 min and methyl 6-chloronicotinate (0.500 g, 2.91 mmol) was added. The mixture was warmed to room temperature and stirred for 3 h. Brine (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a yellow oil, which was purified by FCC to afford the title compound as a colourless oil (0.453 g, 56%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.73 (1H, d), 8.10 (1H, dd), 6.74 (1H, d), 4.50 (2H, t), 3.93 (2H, t), 3.87 (2H, q) and 3.84 (3H, s). cooled to 0 C stirred for 3 h the mixture was extracted with EtOAc (3×20 mL) The combined organic layers were dried over sodium sulfate concentrated to yield a yellow oil, which was purified by FCC

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

Procedure: Combine 2-hydroxyethyl 2,2,2-trifluorethyl ether (0.5 mmol) and N,N-diisopropylethylamine (1 mmol) in dichloromethane (20 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.6 mmol). After 2 hours, extract with 1 M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give the title compound. Cool in a ice-bath Add dropwise extract with 1 M hydrochloric acid solution and 5% sodium bicarbonate solution Dry the organic layer over MgSO4 filter concentrate in vacuo

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

Procedure: Combine 2-tetrahydropyran-2-yloxyethyl 2,2,2-trifluorethyl ether (2 mmol) and magnesium bromide (6 mmol) in diethyl ether (10 mL). After 24 hours, extract with water and then brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give 2-hydroxyethyl 2,2,2-trifluorethyl ether. extract with water Dry the organic layer over Na2SO4 filter concentrate in vacuo

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

Procedure: The title compound was synthesized as described for Intermediate example I-92 in 71% yield starting from ethyl 6-chloronicotinate and 2-(2,2,2-trifluoroethoxy)ethanol. The reaction between sodium hydride and 2-(2,2,2-trifluoroethoxy)ethanol was performed at 0° C. for 3 min, then ambient temperature for 15 min and then cooled to 0° C. before ethyl 6-s chloronicotinate was added; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (d, 1 H), 8.15 (dd, 1 H), 6.93 (d, 1 H), 4.42-4.52 (m, 2 H), 4.14 (q, 2 H), 3.92-3.97 (m, 2 H); MS (APPI/APCI) m/z 266[M+H+]. ambient temperature for 15 min was added

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

Procedure: 2-(2,2,2-Trifluoroethoxy)ethanol (0.57 mL, 3.60 mmol) was dissolved in THF (5 mL), NaH (146 mg, 60% dispersion in mineral oil, 3.60 mmol) was added and the reaction mixture was stirred for 10 min. 4-Nitrophenyl chloroformate (726 mg, 3.60 mmol) was added and the reaction mixture was stirred for 16 h. Intermediate 1 (297 mg, 1.80 mmol) was dissolved in THF (5 mL) and added to the reaction mixture which was stirred at room temperature. Three additional such portions of NaH, 2-(2,2,2-trifluoroethoxy)ethanol and 4-nitrophenyl chloroformate in THF were added after 8, 24 and 32 h, respectively. After 104 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (6 mL) and stirred for 1.5 h. The solvents were removed in vacuo and the residue is dissolved in EtOAc (100 mL). The organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water to give 2-(2,2,2-trifluoroethoxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (3 mg, 0.5%) as a pale yellow gum. the reaction mixture was stirred for 16 h added to the reaction mixture which was stirred at room temperature After 104 h the reaction mixture was quenched with water (10 mL) the solvents were removed in vacuo The residue was dissolved in MeOH (10 mL) 1 M aq NaOH solution (6 mL) and stirred for 1.5 h The solvents were removed in vacuo the residue is dissolved in EtOAc (100 mL) The organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL) dried (MgSO4) the solvents were removed in vacuo The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water

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

Procedure: 2-(2,2,2-Trifluoroethoxy)ethanol (0.57 mL, 3.60 mmol) was dissolved in THF (5 mL), NaH (146 mg, 60% dispersion in mineral oil, 3.60 mmol) was added and the reaction mixture was stirred for 10 min. 4-Nitrophenyl chloroformate (726 mg, 3.60 mmol) was added and the reaction mixture was stirred for 16 h. Intermediate 1 (297 mg, 1.80 mmol) was dissolved in THF (5 mL) and added to the reaction mixture which was stirred at room temperature. Three additional such portions of NaH, 2-(2,2,2-trifluoroethoxy)ethanol and 4-nitrophenyl chloroformate in THF were added after 8, 24 and 32 h, respectively. After 104 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (6 mL) and stirred for 1.5 h. The solvents were removed in vacuo and the residue is dissolved in EtOAc (100 mL). The organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water to give 2-(2,2,2-trifluoroethoxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (3 mg, 0.5%) as a pale yellow gum. the reaction mixture was stirred for 16 h added to the reaction mixture which was stirred at room temperature After 104 h the reaction mixture was quenched with water (10 mL) the solvents were removed in vacuo The residue was dissolved in MeOH (10 mL) 1 M aq NaOH solution (6 mL) and stirred for 1.5 h The solvents were removed in vacuo the residue is dissolved in EtOAc (100 mL) The organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL) dried (MgSO4) the solvents were removed in vacuo The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water