methyl 2-bromobutanoate

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:0.00; pressure:0.00; stir:

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

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

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 2 l three necked flask fitted with reflux condenser, magnetic stirrer and dropping funnel under inert atmosphere, 54.4 g (278 mmoles, 1 eq) of 4-(3-chlorophenyl)-2-pyrrolidinone 379 are dissolved in 1.4 l acetonitrile. 64 ml (100.7 g, 556 mmoles, 2 eq) of methyl 2-bromobutanoate are added and the temperature raised to 50° C. 22.24 g (556 mmoles, 2 eq) of sodium hydride are added by portions, the temperature raising to 65° C. The mixture is stirred one more hour at 50° C. The mixture is concentrated to dryness, the residue suspended in ethyl acetate, washed with water, the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness. The residue is purified by PrepLC (1 kg SiO2, pet. ether/EtOAc, 70:30) to give 56.7 g of pure 380, 69%. 1H NMR (250 MHz, (CD3)2SO): 0.80-1.00 (m, 3H), 1.60-1.90 (2H, m), 2.35-2.55 (m, 1H: partially overlapped with solvent), 2.60-2.90 (m, 1H: partially overlapped with solvent), 3.70 (s, 3H), 3.50-3.80 (m, 3H), 4.50 (m, 1H), 7.20-7.50 (m, 4H). with reflux condenser, magnetic stirrer the temperature raising to 65° C The mixture is concentrated to dryness washed with water The combined organic phases are dried over magnesium sulfate filtered concentrated to dryness The residue is purified by PrepLC (1 kg SiO2, pet. ether/EtOAc, 70:30) to give 56.7 g of pure 380, 69%

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

Procedure: To a 50° C. solution of 33.8 g (60% in mineral oil, 845 mmol) of sodium hydride in 2-methyltetrahydrofuran (550 mL) was added a solution of 240 g (750 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in 2-methyltetrahydrofuran (550 mL) over a period of 45 min. After an additional 1.25 h at 50° C., 105 mL (912 mmol) of methyl 2-bromobutyrate was added over a 20 min period. The resulting slurry was stirred at 50° C. for 3.5 h, and then was cooled to room temperature and quenched with saturated aq. NH4Cl solution. Water was added to dissolve the precipitate and the resulting mixture was extracted with ethyl acetate (4×). The combined organic layers were washed with sat. aq. NaCl solution (1×), dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap™ column (Biotage, LLC, Charlotte, N.C.), 0 to 35% EtOAc/DCM, gradient elution) provided the title compound as a white oily solid. was cooled to room temperature quenched with saturated aq. NH4Cl solution Water was added to dissolve the precipitate the resulting mixture was extracted with ethyl acetate (4×) The combined organic layers were washed with sat. aq. NaCl solution (1×) dried over Na2SO4 filtered the filtrate was concentrated Purification of the residue by chromatography on silica gel (Biotage® Snap™ column (Biotage, LLC, Charlotte, N.C.), 0 to 35% EtOAc/DCM, gradient elution)