1-phenylimidazolidin-2-one

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:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-phenylimidazolidin-2-one (211) (100 mg, 0.62 mmol) [P. Mayer, P. Brunel, C. Chaplain, C. Piedecoq, F. Calmel, P. Schambel, P. Chopin, T. Wurch, P. J. Pauwels, M. Marien, J.-L. Vidaluc, T. Imbert J. Med. Chem. 2000, 43, 3653-3664; W. Su, Y. Zhang J. Chem. Res. Synop. 2000, 9, 440-441] in THF (6 mL) was added triphosgene (189 mg, 0.62 mmol) and the solution was stirred for 3 hrs at 60° C. The reaction mixture was cooled to RT before the addition of aniline 15 (229 mg, 0.65 mmol) and DIPEA (648 μL, 3.72 mmol) and stirring was continued for an hour. The reaction mixture was concentrated and partitioned between EtOAc and water. A precipitate was formed which was collected by filtration. The organic layer was separated, dried and concentrated. The residue was combined with the collected precipitate, dry loaded to a column and eluted with EtOAc/MeOH (9:1), to produce title compound 210 (150 mg, 43% yield) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 10.57 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 7.95 (d, J=1.1 Hz, 1H), 7.83 (dd, J=2.5 and 13.3 Hz, 2H), 7.77 (d, J=1.2 Hz, 1H), 7.66 (s, 1H), 7.61 (dd, J=1.0 and 8.8 Hz, 1H), 7.49-7.41 (m, 4H), 7.16 (t, J=7.2 Hz, 1H), 6.57 (d, J=5.5 Hz, 1H), 4.03 (q, 2H), 4.04-3.92 (m, 4H), 1.38 (t, 3H). MS (m/z): 543.0 (M+H). stirring was continued for an hour The reaction mixture was concentrated partitioned between EtOAc and water A precipitate was formed which was collected by filtration The organic layer was separated dried concentrated dry loaded to a column eluted with EtOAc/MeOH (9:1)

Conditions: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of phenyl isocyanate (50 mmoles), 2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a yield of 48 percent of the desired product, m.p. 157° C.-159° C. the resulting solution is washed with water twice The dichloromethane solution is dried evaporated the residue distilled at reduced pressure The distillate is recrystallized from hot hexane

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

Procedure: The title compound, light yellow solid, MS: m/e=354.3 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 1-phenyl-imidazolidin-2-one.

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

Procedure: The title compound, light yellow solid, MS: m/e=354.3 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 1-phenyl-imidazolidin-2-one.

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

Procedure: To a 0° C. suspension of 5.00 g (30.8 mmol) 1-phenylimidazolidin-2-one in 50 mL of dimethylformamide was added 1.48 g (37.0 mmol, 1.2 equiv) of sodium hydride (60% oil dispersion). After 45 minutes, 6.7 mL (8.88 g, 37.0 mmol, 1.2 equiv) of octyl iodide was added. The mixture was allowed to stir overnight with gradual warming to room temperature. TLC analysis indicated the presence of starting material. An additional 830 mg portion of sodium hydride was added. After 5 hours, TLC analysis again indicated the presence of starting material, so 0.5 g more sodium hydride and 6 mL of octyl iodide were added. After 2 hours, the reaction was complete as judged by TLC analysis. The mixture was concentrated in vacuo, and partitioned between 200 mL of ethyl acetate and 50 mL of water. The organic phase was washed sequentially with three 50-mL portions of water and one portion of brine, dried over magnesium sulfate, and concentrated in vacuo. Purification by flash chromatography (silica gel, 10-25% ethyl acetate/hexane) provided 3.97 g (47%) of 3-octyl-1-phenylimidazolidin-2-one. A 3.93 g portion of this material was added over 45 min to 6 mL of chlorosulfonic acid in a salt/ice bath. Stirring was continued at -5° C. until gas evolution ceased (~3 hours). The reaction mixture was poured into 50 mL of ice and extracted with 3 150-mL portions of ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (25% ethyl acetate/hexane) provided 2.49 g of the title compound: 1H NMR (500 MHz, CDCl3) δ7.94 (d, 2H), 7.76 (d, 2H), 3.87 (dd, 2H), 3.55 (dd, 2H), 3.31 (t, 2H), 1.56 (m, 2H), 1.36-1.21 (m, 10H), 0.85 (m, 3H). After 5 hours were added After 2 hours The mixture was concentrated in vacuo partitioned between 200 mL of ethyl acetate and 50 mL of water The organic phase was washed sequentially with three 50-mL portions of water and one portion of brine dried over magnesium sulfate concentrated in vacuo Purification by flash chromatography (silica gel, 10-25% ethyl acetate/hexane)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-phenylimidazolidin-2-one (211) (100 mg, 0.62 mmol) [P. Mayer, P. Brunel, C. Chaplain, C. Piedecoq, F. Calmel, P. Schambel, P. Chopin, T. Wurch, P. J. Pauwels, M. Marien, J.-L. Vidaluc, T. Imbert J. Med. Chem. 2000, 43, 3653-3664; W. Su, Y. Zhang J. Chem. Res. Synop. 2000, 9, 440-441] in THF (6 mL) was added triphosgene (189 mg, 0.62 mmol) and the solution was stirred for 3 hrs at 60° C. The reaction mixture was cooled to RT before the addition of aniline 15 (229 mg, 0.65 mmol) and DIPEA (648 μL, 3.72 mmol) and stirring was continued for an hour. The reaction mixture was concentrated and partitioned between EtOAc and water. A precipitate was formed which was collected by filtration. The organic layer was separated, dried and concentrated. The residue was combined with the collected precipitate, dry loaded to a column and eluted with EtOAc/MeOH (9:1), to produce title compound 210 (150 mg, 43% yield) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 10.57 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 7.95 (d, J=1.1 Hz, 1H), 7.83 (dd, J=2.5 and 13.3 Hz, 2H), 7.77 (d, J=1.2 Hz, 1H), 7.66 (s, 1H), 7.61 (dd, J=1.0 and 8.8 Hz, 1H), 7.49-7.41 (m, 4H), 7.16 (t, J=7.2 Hz, 1H), 6.57 (d, J=5.5 Hz, 1H), 4.03 (q, 2H), 4.04-3.92 (m, 4H), 1.38 (t, 3H). MS (m/z): 543.0 (M+H). stirring was continued for an hour The reaction mixture was concentrated partitioned between EtOAc and water A precipitate was formed which was collected by filtration The organic layer was separated dried concentrated dry loaded to a column eluted with EtOAc/MeOH (9:1)

Conditions: temp:195.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of phenyl isocyanate (50 mmoles), 2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a yield of 48 percent of the desired product, m.p. 157° C.-159° C. the resulting solution is washed with water twice The dichloromethane solution is dried evaporated the residue distilled at reduced pressure The distillate is recrystallized from hot hexane

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

Procedure: To a solution of 1-phenyl-2-imidazolidinone (0.10 g, 0.62 mmol) dissolved in 10 mL dimethylformamide cooled in an ice bath was added NaH (60% dispersion in mineral oil, 27.0 mg, 0.68 mmol). The mixture was stirred at room temperature for 30 minutes; then cooled in ice bath. 1-Bromo-4-[(5-bromopentyl)oxy] benzene (0.20 g, 0.62 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvents were pumped off. Saturated aqueous NH4Cl and dichloromethane (15 mL) were added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 9) as a yellow solid (0.19 g, 77%). cooled in an ice bath then cooled in ice bath the mixture was stirred at room temperature for additional 4 hours The reaction was quenched with MeOH Saturated aqueous NH4Cl and dichloromethane (15 mL) were added to the residue The dichloromethane layer was separated dried over MgSO4 filtered evaporated purified by column chromatography (ethyl acetate:MeOH=10:1)