5-(chloromethyl)-5-methyl-1,3-oxazolidin-2-one

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

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture was sodium hydride (401 mg, 60% dispersion) in 50 ml of dimethylformamide was added 5-(chloromethyl)-5-methyl-1,3-oxazolidin-2-one (1.00 g, INTERMEDIATE 16) followed by 4-methoxybenzylchloride (1.05 g). The mixture was stirred at 90° C. for 4 h. Excess sodium hydride was quenched by addition of 3 ml of methanol. The sample was then transferred to a Biotage 65i column and purified via column chromatography on a Biotage Horizon eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 50% ethyl acetate in hexanes (over 6 column volumes), and held at 50% ethyl acetate (2 column volumes) to provide the title compound (1.41 g, 78%). Mass spectrum (ESI) 271.9 (M+2). Excess sodium hydride was quenched by addition of 3 ml of methanol purified via column chromatography on a Biotage Horizon eluting with 0% ethyl acetate in hexanes (1 column volume)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-(chloromethyl)-5-methyl-1,3-oxazolidin-2-one (1.50 g, INTERMEDIATE 16), 2-bromo-5-chloropyridine (1.92 g), cesium carbonate (4.89 g), bispalladium tribenzylideneacetone (1.37 g) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.30 g) in 25 ml of dioxane was stirred at 85° C. for 12 h. The sample was then cooled to room temperature, and filtered through a plug of silica gel (15×15 ml) of silica gel eluting with ethyl acetate. The eluent then was concentrated in vacuo and purified via column chromatography on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 60% ethyl acetate in hexanes (over 10 column volumes), and held at 60% ethyl acetate for 4 column volumes to provide the title compound (1.01 g, 39%). Mass spectrum (ESI) 262.9 (M+2).). 1H NMR (500 MHz, CDCl3): δ 8.27 (d, J=2.5 Hz, 1), 8.21 (d, J=8.9 Hz, 1H), 7.68 (dd, J=8.9, 2.5 Hz, 1H), 4.31 (d, J=10.8 Hz, 1H), 3.95 (d, J=10.7 Hz, 1H), 3.73 (d, J=11.7 Hz, 1H), 3.63 (d, J=11.7 Hz, 1H), 1.66 (s, 3H). The sample was then cooled to room temperature filtered through a plug of silica gel (15×15 ml) of silica gel eluting with ethyl acetate The eluent then was concentrated in vacuo purified via column chromatography on a Biotage Horizon 65i column eluting with 0% ethyl acetate in hexanes (1 column volume)

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

Procedure: Potassium cyanate (7.61 g) was dissolved in 350 ml of water, and 2-(chloromethyl)-2-methyloxirane was slowly added (5.00 g). The solution was stirred overnight (15 h) at reflux. The reaction mixture was then extracted while still moderately warm with ethyl acetate (5×200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide the title compound an off-white solid (3.32 g, 47%). Mass spectrum (ESI) 150.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 5.23 (bs, 1H), 3.70 (d, J=8.7 Hz, 1H), 3.68 (d, J=11.0 Hz, 1H), 3.56 (d, J=11.2 Hz, 1H), 3.34 (d, J=8.9 Hz, 1H), 1.59 (s, 3H). at reflux The reaction mixture was then extracted while still moderately warm with ethyl acetate (5×200 ml) The combined organic layers were dried over sodium sulfate concentrated in vacuo