4,4-dimethyl-1,3-oxazolidin-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:; See reaction.notes.procedure_details.

Procedure: To a suspension of sodium hydride (0.24 g; 10.0 mmol) in tetrahydrofuran (100 ml) was added 4,4-dimethyloxazolidin-2-one (1.15 g; 10.0 mmol) at 0° C., and the resultant suspension was stirred at room temperature for 5 hours. To the gelatinous reaction mixture was added 2-bromopropionyl bromide (1.05 ml) at 0° C. After stirring for 1 hour, a saturated aqueous solution of potassium dihydrogen phosphate was added to quench the reaction. An aqueous layer was extracted with ethyl acetate. Combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a solid residue, which was purified by silica gel column chromatography (hexane:dichloromethane=1:1~0:1) to give 3-(2'-bromopropionyl)-4,4-dimethyloxazolidin-2-one (2.35 g, yield, 90%) as colorless crystals. to quench the reaction An aqueous layer was extracted with ethyl acetate Combined organic layers were dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure to give a solid residue, which was purified by silica gel column chromatography (hexane:dichloromethane=1:1~0:1)

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

Procedure: 12.3 g (0.11 mol) 4,4-dimethyl-2-oxazolidinone was dissolved in 180 ml of 1 M sodium hydroxide and the resulting solution was cooled to 0°. 19.2 g (0.012 mol) bromine was added dropwise with stirring over 0.25 hr and the reaction mixture was stirred at 0° for an additional 0.75 hr. The N-bromamine separated from the reaction mixture as an orange colored solid. The solid was isolated by filtration and thoroughly washed with cold water. Trituration of this material in petroleum ether (30°-60°) gave 16.2 g (0.084 mol), 76%, 3-bromo-4,4-dimethyl-2-oxazolidinone (NBDMO), mp 118°-120°; uv (H2O) λmax 274 nm, ε= 201 M-1 cm-1 ; ir (KBr): 2985, 1725, 1370, 1290, 1200, 1165, 1040 and 740 cm-1 ; pmr (CDCl3) δ 4.27 (s, 2H) and 1.33 (s, 6H) ppm. the resulting solution was cooled to 0° the reaction mixture was stirred at 0° for an additional 0.75 hr The N-bromamine separated from the reaction mixture as an orange colored solid The solid was isolated by filtration thoroughly washed with cold water

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

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

Procedure: By reaction and treatment in the same manner as in Example 1 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 118 and 4,4-dimethyloxazolidin-2-one (57.6 mg), the title compound (63.6 mg) was obtained. By reaction and treatment in the same manner as in Example 1

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

Procedure: By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (463 mg) described in Preparation Example 89 and 4,4-dimethyloxazolidin-2-one (106 mg), the title compound (85.6 mg) was obtained. By reaction and treatment in the same manner as in Example 111

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

Procedure: To a suspension of sodium hydride (0.24 g; 10.0 mmol) in tetrahydrofuran (100 ml) was added 4,4-dimethyloxazolidin-2-one (1.15 g; 10.0 mmol) at 0° C., and the resultant suspension was stirred at room temperature for 5 hours. To the gelatinous reaction mixture was added 2-bromopropionyl bromide (1.05 ml) at 0° C. After stirring for 1 hour, a saturated aqueous solution of potassium dihydrogen phosphate was added to quench the reaction. An aqueous layer was extracted with ethyl acetate. Combined organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a solid residue, which was purified by silica gel column chromatography (hexane:dichloromethane=1:1~0:1) to give 3-(2'-bromopropionyl)-4,4-dimethyloxazolidin-2-one (2.35 g, yield, 90%) as colorless crystals. to quench the reaction An aqueous layer was extracted with ethyl acetate Combined organic layers were dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure to give a solid residue, which was purified by silica gel column chromatography (hexane:dichloromethane=1:1~0:1)

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

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

Procedure: A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1 mmol), 4,4-dimethyl-oxazolidin-2-one (575 mg, 5 mmol), copper(I) iodide (115 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol), and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(4,4-dimethyl-2-oxo-oxazolidine-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (3 mg, 0.4%) as a light yellow oil: LC/MS m/e calcd for C23H26N2O4 (M+H)+: 395.47, observed: 395.1. Then the reaction mixture cooled to room temperature The reaction mixture was extracted with ethyl acetate (2×150 mL) washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL) dried over anhydrous sodium sulfate concentrated in vacuo Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water)

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

Procedure: A solution of 4,4-dimethyloxazolidin-2-one (0.103 g, 0.895 mmol) and 2,4,6-trichloropyrimidine (0.181 g, 0.984 mmol, 1.10 equiv) in DMF (3 mL) was treated with NaH (60%, 0.0429 g, 1.07 mmol, 1.2 equiv), then the resulting mixture (yellow) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided 3-(2,6-dichloropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one (0.146 g, white solid) in 62.3% yield. 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 4.16 (s, 2H), 1.74 (s, 9H); LCMS m/z 261.9 (M+H)+, Rt 0.91 min. washed with saturated aqueous NaCl (2×20 mL) dried over Na2SO4 filtered concentrated