Nitrogen → HCID 59536627, compound

Temperature

0 °C

Charge a 1 L, 3-neck round bottom flask equipped with a magnetic stirrer, thermal couple, addition funnel and N2 inlet with crude (R)-1-benzyl-3-((S)-1-hydroxy-3-methylbutyl)pyrrolidin-2-one (38.26 mmoles, assumed) and toluene (100 mL). Cool the slightly heterogeneous stirring solution to 0° C. (salt/ice bath) and add a solution of Vitride™ (Rohm & Haas) (65 wt % in toluene, 24 mL, 86.085 mmoles) and toluene (70 mL) drop wise while maintaining a temperature at or below 5° C. Rinse the addition funnel with toluene (10-20 mL). Stir at room temperature overnight (˜16 hr). Cool the reaction mixture to 0° C. (salt/ice bath) and quenched with saturated Rochell's salt solution (200 mL) followed by MTBE (200 mL). Allow the mixture to warm to room temperature with stirring and then stir at this temperature for 1 hour. Separate the organic and aqueous layers and wash the organic layer with H2O (2×200 mL), then brine (200 mL), and then dry over Na2SO4. Filter and concentrate to give the desired intermediate as a brown oil (9.61 g, 38.85 mmoles, >100% yield). 1H NMR (300 MHz, CDCl3) δ 7.36-7.18 (m, 5H), 3.82-3.72 (m, 1H), 3.58 (dd, 2H, 7.61, 20.51 Hz), 2.87 (td, 1H, J=4.10, 8.79 Hz), 2.79-2.70 (m, 1H), 2.48-2.38 (m, 1H), 2.26-2.04 (m, 2H), 1.98-1.64 (m, 3H), 1.46-1.32 (m, 1H), 1.14-0.98 (m, 1H), 0.92 (d, 3H, J=1.18 Hz), 0.89 (d, 3H, J=1.76 Hz). LC/MS=248.1 (M+1).

1. additionCharge a 1 L, 3-neck round bottom flask
2. customequipped with a magnetic stirrer
3. temperaturewhile maintaining a temperature at or below 5° C
4. washRinse the addition funnel with toluene (10-20 mL)
5. temperatureCool the reaction mixture to 0° C. (salt/ice bath)
6. customquenched with saturated Rochell's salt solution (200 mL)
7. temperatureAllow the mixture to warm to room temperature
8. stirringwith stirring
9. stirringstir at this temperature for 1 hour
10. customSeparate the organic and aqueous layers
11. washwash the organic layer with H2O (2×200 mL)
12. dry with materialbrine (200 mL), and then dry over Na2SO4
13. filtrationFilter
14. concentrationconcentrate

ORD record

ord-d9e0156f5ec54e1b965030770d4bd5ac

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08173821B2