ethyl N-ethylcarbamate

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

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (300 mg) is dissolved in tetrahydrofuran (3 ml) and thereto are added ethyl-carbamic ethyl ester (67 mg) and sodium hydride (60%) (23 mg) and the mixture is stirred at 120° C. under a condition of 192 W by a microwave instrument for 1 hour and thereto are added ethyl-carbamic ethyl ester (134 mg) and sodium hydride (60%) (46 mg) and the mixture is stirred at 120° C. under a condition of 192 W by a microwave instrument for an additional 1 hour. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-ethoxy-5-trifluoromethyl-benzyl)-amine (220 mg). MS (m/z): 602/604 [M+H]+ the mixture is stirred at 120° C. under a condition of 192 W by a microwave instrument for an additional 1 hour the mixture is separated the organic layer is washed with a saturated brine dried over magnesium sulfate concentrated under reduced pressure The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→9:1)

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

Procedure: Under general experimental conditions reported by Kelper, JOC, 52, 453-55 (1987), a slurry of Ba(OH)2 (46.0 mg, 266 μmol) in water (480 μL) was added to a mixture of N-ethylurethane (2.04 mL, 17.1 mmol) and a 37% aqueous solution of formalin (1.28 mL, 17.1 mmol) in one portion with stirring. The mixture became cool and gradually formed a cloudy solution. The mixture was stirred at room temperature and the disappearance of N-ethylurethane monitored by TLC analysis. After 2 h, the reaction was quenched by adding solid CO2, stirred for 30 minutes and filtered to remove the precipitated barium carbonate. The solvent was removed under vacuum to provide an oily residue. The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL) to provide 56 as a clear oil (2.50 g, quant.): 1H NMR (400 MHz, CDCl3) δ 4.88 (d, J=7.6 Hz, 1H), 4.79 (d, J=7.6 Hz, 2H), 4.18 (q, J=7.6 Hz, 2H), 3.40 (q, J=6.4 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H). The mixture became cool gradually formed a cloudy solution the reaction was quenched by adding solid CO2 stirred for 30 minutes filtered to remove the precipitated barium carbonate The solvent was removed under vacuum to provide an oily residue The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL)

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

Procedure: Under general experimental conditions reported by Kelper, JOC, 52, 453-55 (1987), a slurry of Ba(OH)2 (46.0 mg, 266 μmol) in water (480 μL) was added to a mixture of N-ethylurethane (2.04 mL, 17.1 mmol) and a 37% aqueous solution of formalin (1.28 mL, 17.1 mmol) in one portion with stirring. The mixture became cool and gradually formed a cloudy solution. The mixture was stirred at room temperature and the disappearance of N-ethylurethane monitored by TLC analysis. After 2 h, the reaction was quenched by adding solid CO2, stirred for 30 minutes and filtered to remove the precipitated barium carbonate. The solvent was removed under vacuum to provide an oily residue. The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL) to provide 56 as a clear oil (2.50 g, quant.): 1H NMR (400 MHz, CDCl3) δ 4.88 (d, J=7.6 Hz, 1H), 4.79 (d, J=7.6 Hz, 2H), 4.18 (q, J=7.6 Hz, 2H), 3.40 (q, J=6.4 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H). The mixture became cool gradually formed a cloudy solution the reaction was quenched by adding solid CO2 stirred for 30 minutes filtered to remove the precipitated barium carbonate The solvent was removed under vacuum to provide an oily residue The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL)

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

Procedure: Under general experimental conditions reported by Kelper, JOC, 52, 453-55 (1987), a slurry of Ba(OH)2 (46.0 mg, 266 μmol) in water (480 μL) was added to a mixture of N-ethylurethane (2.04 mL, 17.1 mmol) and a 37% aqueous solution of formalin (1.28 mL, 17.1 mmol) in one portion with stirring. The mixture became cool and gradually formed a cloudy solution. The mixture was stirred at room temperature and the disappearance of N-ethylurethane monitored by TLC analysis. After 2 h, the reaction was quenched by adding solid CO2, stirred for 30 minutes and filtered to remove the precipitated barium carbonate. The solvent was removed under vacuum to provide an oily residue. The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL) to provide 56 as a clear oil (2.50 g, quant.): 1H NMR (400 MHz, CDCl3) δ 4.88 (d, J=7.6 Hz, 1H), 4.79 (d, J=7.6 Hz, 2H), 4.18 (q, J=7.6 Hz, 2H), 3.40 (q, J=6.4 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H). The mixture became cool gradually formed a cloudy solution the reaction was quenched by adding solid CO2 stirred for 30 minutes filtered to remove the precipitated barium carbonate The solvent was removed under vacuum to provide an oily residue The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL)

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

Procedure: Under general experimental conditions reported by Kelper, JOC, 52, 453-55 (1987), a slurry of Ba(OH)2 (46.0 mg, 266 μmol) in water (480 μL) was added to a mixture of N-ethylurethane (2.04 mL, 17.1 mmol) and a 37% aqueous solution of formalin (1.28 mL, 17.1 mmol) in one portion with stirring. The mixture became cool and gradually formed a cloudy solution. The mixture was stirred at room temperature and the disappearance of N-ethylurethane monitored by TLC analysis. After 2 h, the reaction was quenched by adding solid CO2, stirred for 30 minutes and filtered to remove the precipitated barium carbonate. The solvent was removed under vacuum to provide an oily residue. The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL) to provide 56 as a clear oil (2.50 g, quant.): 1H NMR (400 MHz, CDCl3) δ 4.88 (d, J=7.6 Hz, 1H), 4.79 (d, J=7.6 Hz, 2H), 4.18 (q, J=7.6 Hz, 2H), 3.40 (q, J=6.4 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H). The mixture became cool gradually formed a cloudy solution the reaction was quenched by adding solid CO2 stirred for 30 minutes filtered to remove the precipitated barium carbonate The solvent was removed under vacuum to provide an oily residue The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL)

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

Procedure: Under general experimental conditions reported by Kelper, JOC, 52, 453-55 (1987), a slurry of Ba(OH)2 (46.0 mg, 266 μmol) in water (480 μL) was added to a mixture of N-ethylurethane (2.04 mL, 17.1 mmol) and a 37% aqueous solution of formalin (1.28 mL, 17.1 mmol) in one portion with stirring. The mixture became cool and gradually formed a cloudy solution. The mixture was stirred at room temperature and the disappearance of N-ethylurethane monitored by TLC analysis. After 2 h, the reaction was quenched by adding solid CO2, stirred for 30 minutes and filtered to remove the precipitated barium carbonate. The solvent was removed under vacuum to provide an oily residue. The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL) to provide 56 as a clear oil (2.50 g, quant.): 1H NMR (400 MHz, CDCl3) δ 4.88 (d, J=7.6 Hz, 1H), 4.79 (d, J=7.6 Hz, 2H), 4.18 (q, J=7.6 Hz, 2H), 3.40 (q, J=6.4 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H). The mixture became cool gradually formed a cloudy solution the reaction was quenched by adding solid CO2 stirred for 30 minutes filtered to remove the precipitated barium carbonate The solvent was removed under vacuum to provide an oily residue The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL)

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

Procedure: Under general experimental conditions reported by Kelper, JOC, 52, 453-55 (1987), a slurry of Ba(OH)2 (46.0 mg, 266 μmol) in water (480 μL) was added to a mixture of N-ethylurethane (2.04 mL, 17.1 mmol) and a 37% aqueous solution of formalin (1.28 mL, 17.1 mmol) in one portion with stirring. The mixture became cool and gradually formed a cloudy solution. The mixture was stirred at room temperature and the disappearance of N-ethylurethane monitored by TLC analysis. After 2 h, the reaction was quenched by adding solid CO2, stirred for 30 minutes and filtered to remove the precipitated barium carbonate. The solvent was removed under vacuum to provide an oily residue. The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL) to provide 56 as a clear oil (2.50 g, quant.): 1H NMR (400 MHz, CDCl3) δ 4.88 (d, J=7.6 Hz, 1H), 4.79 (d, J=7.6 Hz, 2H), 4.18 (q, J=7.6 Hz, 2H), 3.40 (q, J=6.4 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H). The mixture became cool gradually formed a cloudy solution the reaction was quenched by adding solid CO2 stirred for 30 minutes filtered to remove the precipitated barium carbonate The solvent was removed under vacuum to provide an oily residue The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL)

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

Procedure: To a solution of cis 4-(4-bromo-2-fluorobenzyl)-2,6-dimethylmorpholine (0.76 g, 2.5 mmol) in 1,4-dioxane (7.5 mL) under nitrogen was added ethyl urethane (1.2 mL, 10.0 mmol) followed by portionwise addition of sodium hydride (60% dispersion in mineral oil, 0.40 g, 10.0 mmol). The reaction mixture was heated at 100° C. for 24 h then partitioned between DCM and water and the phases were separated. The aqueous phase was further extracted with DCM and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in pentane) to afford the title compound (0.114 g, 14%). 1H NMR (CD3OD and CDCl3, 300 MHz): 7.22 (d, J=8.0 Hz, 1H), 7.05 (dd, J=8.1, 1.9 Hz, 1 H), 6.97 (d, J=1.9 Hz, 1H), 4.01 (q, J=7.0 Hz, 2H), 3.75-3.62 (m, 2H), 3.47 (s, 2 H), 2.75-2.66 (m, 2H), 1.86-1.76 (m, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.14 (d, J=6.3 Hz, 6H). LCMS (Method G): RT=3.24 min, M+H+=328. then partitioned between DCM and water the phases were separated The aqueous phase was further extracted with DCM the combined organic layers were dried over sodium sulfate filtered evaporated The residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in pentane)

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (306 mg, 60%, 7.6 mmol) was added in portions to a solution of 1-(4-bromo-2-fluorobenzyl)-piperidine (520 mg, 1.9 mmol) and ethyl urethane (0.91 mL, 7.6 mmol) in dioxane (10 mL) under an atmosphere of nitrogen. The reaction mixture was then sonicated for 30 minutes until gas evolution ceased then heated at 140° C. overnight in a sealed tube. The reaction mixture was diluted with water and extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a colourless oil that was then purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (416 mg, 74%). 1H NMR (CDCl3, 400 MHz): 7.23 (d, J=8.1 Hz, 1H), 7.03 (dd, J=8.1, 1.9 Hz, 1H), 6.95 (d, J=1.9 Hz, 1H), 3.99 (q, J=7.0 Hz, 2H), 3.47 (s, 2H), 2.46-2.35 (m, 4H), 1.61-1.53 (m, 4H), 1.45-1.36 (m, 5H). The reaction mixture was then sonicated for 30 minutes until gas evolution extracted with DCM (3×30 mL) The combined organic layer was dried over anhydrous sodium sulfate filtered evaporated in vacuo to afford a colourless oil that was then purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM)

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

Procedure: To a solution of cis 4-(4-bromo-2-fluorobenzyl)-2,6-dimethylmorpholine (0.76 g, 2.5 mmol) in 1,4-dioxane (7.5 mL) under nitrogen was added ethyl urethane (1.2 mL, 10.0 mmol) followed by portionwise addition of sodium hydride (60% dispersion in mineral oil, 0.40 g, 10.0 mmol). The reaction mixture was heated at 100° C. for 24 h then partitioned between DCM and water and the phases were separated. The aqueous phase was further extracted with DCM and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in pentane) to afford the title compound (0.114 g, 14%). 1H NMR (CD3OD and CDCl3, 300 MHz): 7.22 (d, J=8.0 Hz, 1H), 7.05 (dd, J=8.1, 1.9 Hz, 1H), 6.97 (d, J=1.9 Hz, 1H), 4.01 (q, J=7.0 Hz, 2H), 3.75-3.62 (m, 2H), 3.47 (s, 2H), 2.75-2.66 (m, 2H), 1.86-1.76 (m, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.14 (d, J=6.3 Hz, 6H). LCMS (Method G): RT=3.24 min, M+H÷=328. then partitioned between DCM and water the phases were separated The aqueous phase was further extracted with DCM the combined organic layers were dried over sodium sulfate filtered evaporated The residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in pentane)