methyl 2-bromo-2-methylbutanoate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A slurry of 60% sodium hydride suspension in mineral oil (0.80 g, 20.4 mmol) in tetrahydrofuran (28 mL) is cooled at 0° C. under a nitrogen atmosphere. A solution of substantially optically pure (S)-4-(2,2-difluoro-vinyl)-pyrrolidin-2-one (IIIb) (2 g, 13.6 mmol) in tetrahydrofuran (8 mL) is added over a 30 minutes period. The reaction mixture is stirred 10 minutes at 0° C. then a solution of 2-bromo-butyric acid methyl ester (V) (3.20 g, 17.6 mmol) in tetrahydrofuran (2 mL) is added over a 15 minutes period. The reaction mixture is stirred at 0° C. for 4.5 h then the reaction mixture is allowed to warm to room temperature and diluted with water (15 mL). Tetrahydrofuran is removed by evaporation and the residue is extracted with isopropyl acetate (2×10 mL). The combined organic layers are dried over anhydrous magnesium sulfate and evaporated to afford 3 g (12.1 mmol, 89%) of compound (VIb), as a mixture respectively of epimer (VIba) and epimer (VIbb). The reaction mixture is stirred at 0° C. for 4.5 h to warm to room temperature Tetrahydrofuran is removed by evaporation the residue is extracted with isopropyl acetate (2×10 mL) The combined organic layers are dried over anhydrous magnesium sulfate evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A slurry of 60% sodium hydride suspension in mineral oil (0.94 g, 23.4 mmol) in tetrahydrofuran (30 mL) is cooled at 0° C. under a nitrogen atmosphere. A solution of substantially optically pure (R)-4-propyl-pyrrolidin-2-one (IIIa) (2 g, 15.7 mmol) in tetrahydrofuran (2 mL) is added over a 15 minutes period. The reaction mixture is stirred 10 min at 0° C. then a solution of methyl-2-bromo-butyric acid methyl ester (V) (3.69 g, 20.4 mmol) in tetrahydrofuran (2 mL) was added over a 20 minutes period. The reaction mixture is stirred at 0° C. until maximum conversion of starting material and the reaction mixture is then allowed to warm to room temperature and diluted with water (20 mL). Tetrahydrofuran is removed by evaporation and the residue is extracted with isopropyl acetate (20 ml+10 mL). The combined organic layers are dried on anhydrous magnesium sulfate and evaporated to afford 3 g (13.2 mmol, 86%) of a mixture of epimers of compound (VIa), as a mixture respectively of epimer (VIaa) and epimer (VIab). The reaction mixture is stirred at 0° C. until maximum conversion of starting material to warm to room temperature Tetrahydrofuran is removed by evaporation the residue is extracted with isopropyl acetate (20 ml+10 mL) The combined organic layers are dried on anhydrous magnesium sulfate evaporated