4-methylpentanoyl chloride

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:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-4-Benzyl-2-oxazolidinone (15.1 g, 85.0 mmol) was dissolved in THF (200 mL, 2.5 mol), cooled at −78° C. under nitrogen, and stirred for 10 minutes. 1.6 M of n-butyllithium in hexane (53.1 mL) was added dropwise and stirred for 15 minutes. 4-Methylpentanoyl chloride (12.6 g, 93.5 mmol) was added dropwise, stirred for 30 minutes at −78° C., then warmed to 0° C. for 2 hours. 150 mL of saturated NaHCO3 was added and the mixture was warmed to room temperature for 30 minutes. The mixture was extracted with DCM, washed with Na2CO3 (5%) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Excess oxazolidinone was removed using hexanes to provide intermediate (2a) (14.5 g). stirred for 15 minutes stirred for 30 minutes at −78° C. warmed to 0° C. for 2 hours the mixture was warmed to room temperature for 30 minutes The mixture was extracted with DCM washed with Na2CO3 (5%) and saturated aqueous NaCl dried over MgSO4 filtered concentrated Excess oxazolidinone was removed

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: 4-Methylpentanoyl chloride (3.0 g, 22.3 mmol) was added dropwise to phenol (2.1 g, 22.3 mmol). After 3 hours, H2O was added and the reaction mixture was extracted with Et2O. The organic phase was washed with NaHCO3, then brine to neutrality, then dried (Na2SO4), concentrated and bulb-to-bulb distilled to afford the title compound in 88% yield. the reaction mixture was extracted with Et2O The organic phase was washed with NaHCO3 brine to neutrality, then dried (Na2SO4) concentrated bulb-to-bulb distilled

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-4-Benzyl-2-oxazolidinone (15.1 g, 85.0 mmol) was dissolved in THF (200 mL, 2.5 mol), cooled at −78° C. under nitrogen, and stirred for 10 minutes. 1.6 M of n-butyllithium in hexane (53.1 mL) was added dropwise and stirred for 15 minutes. 4-Methylpentanoyl chloride (12.6 g, 93.5 mmol) was added dropwise, stirred for 30 minutes at −78° C., then warmed to 0° C. for 2 hours. 150 mL of saturated NaHCO3 was added and the mixture was warmed to room temperature for 30 minutes. The mixture was extracted with DCM, washed with Na2 CO3 (5%) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Excess oxazolidinone was removed using hexanes to provide intermediate (2a) (14.5 g). stirred for 15 minutes stirred for 30 minutes at −78° C. warmed to 0° C. for 2 hours the mixture was warmed to room temperature for 30 minutes The mixture was extracted with DCM washed with Na2 CO3 (5%) and saturated aqueous NaCl dried over MgSO4 filtered concentrated Excess oxazolidinone was removed

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-4-Benzyl-2-oxazolidinone (15.1 g, 85.0 mmol) was dissolved in THF (200 mL, 2.5 mol), cooled at −78° C. under nitrogen, and stirred for 10 minutes. 1.6 M of n-butyllithium in hexane (53.1 mL) was added dropwise and stirred for 15 minutes. 4-Methylpentanoyl chloride (12.6 g, 93.5 mmol) was added dropwise, stirred for 30 minutes at −78° C., then warmed to 0° C. for 2 hours. 150 mL of saturated NaHCO3 was added and the mixture was warmed to room temperature for 30 minutes. The mixture was extracted with DCM, washed with Na2 CO3 (5%) and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Excess oxazolidinone was removed using hexanes to provide intermediate (2a) (14.5 g). stirred for 15 minutes stirred for 30 minutes at −78° C. warmed to 0° C. for 2 hours the mixture was warmed to room temperature for 30 minutes The mixture was extracted with DCM washed with Na2 CO3 (5%) and saturated aqueous NaCl dried over MgSO4 filtered concentrated Excess oxazolidinone was removed

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

Procedure: The procedure is as in Example 7, but starting with 2-(7-fluoro-1,8-naphthyridin-2yl)-3-hydroxy-1-isoindolinone (5 g) in methylene chloride (60 cc), triethylamine (6.5 g), 4-methylpentanoyl chloride (3.66 g) and 4-dimethylaminopyridine (10 mg). After recrystallization in ethanol, 2-(7-fluoro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-methylpentanoate (1.2 g), m.p. 154° C., is obtained. After recrystallization in ethanol

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

Procedure: Triethylamine (27 cc) is added to a solution, maintained at a temperature in the region of 20° C., of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinone (12.3 g) in methylene chloride (200 cc). 4-Methylpentanoyl chloride (10.8 g) and 4-dimethylaminopyridine (50 mg) are then introduced dropwise in the course of 20 minutes, and the reaction mixture is then heated for 19 hours under reflux. The suspension obtained in poured into water (800 cc) and the solid obtained is separated by filtration and removed. The organic phase is separated after settling has occurred, washed with water, dried and concentrated to dryness under reduced pressure (2.7 kPa). The oily residue obtained is purified by chromatography on silica gel (0.063-0.2 mm; 150 g) contained in a column 2.7 cm in diameter (eluant: methylene chloride), eluting 50-cc fractions. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After the solid obtained has been recrystallized in acetonitrile, 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-methylpentanoate (4.9 g), m.p. 133° C., is obtained. the reaction mixture is then heated for 19 hours under reflux The suspension obtained the solid obtained is separated by filtration removed The organic phase is separated after settling washed with water dried concentrated to dryness under reduced pressure (2.7 kPa) The oily residue obtained is purified by chromatography on silica gel (0.063-0.2 mm; 150 g) eluting 50-cc fractions concentrated to dryness under reduced pressure (2.7 kPa) at 40° C After the solid obtained has been recrystallized in acetonitrile