反应详情

温度

-70 °C

To a solution of 2-methyl-2-(1-pyrrolidinyl)propanenitrile D4 (10.7 g; 77.54 mmol) in THF (400 ml) at −70° C. under argon was added over 10 minutes a solution of phenyllithium in dibutylether (86.3 ml of a 1.8M solution; 155 mmol). The reaction mixture was stirred at −70° C. for 2 hours then allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled in ice as saturated aqueous sodium hydrogen carbonate (400 ml) was added. After stirring for a further 30 minutes the layers were separated, and the aqueous layer extracted with ether (200 ml). Combined organics were dried (MgSO4) and evaporated. The residual amber oil was dissolved in methanol (400 ml), cooled in ice and sodium borohydride (5.2 g; 137 mmol) added in four portions over 5 minutes. The reaction mixture was stirred with ice cooling for 30 minutes, the ice removed and stirred at room temperature for 1.5 hours. The mixture was cooled in ice as water (50 ml) was added prior to concentration in vacuo to approx 70 ml. The mixture was partitioned between 2N HCl (100 ml) and ethyl acetate (400 ml) and the organics extracted with 2N HCl (2×100 ml). Combined acidic aqueous layers were washed with ethyl acetate (200 ml), basified with 50% NaOH and extracted with DCM (3×150 ml). Combined DCM organic extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a colourless solid (15 g: 88%) 1H NMR (CDCl3), δ: 0.75 (3H, s), 0.99 (3H, s), 1.70-1.76 (4H, m), 1.80 (2H, bs), 2.65-2.70 (4H, m), 4.08 (1H, s), 7.20-7.42 (5H, m).

1. temperatureto warm to room temperature
2. stirringstirred overnight
3. additionwas added
4. stirringAfter stirring for a further 30 minutes the layers
5. customwere separated
6. extractionthe aqueous layer extracted with ether (200 ml)
7. dry with materialCombined organics were dried (MgSO4)
8. customevaporated
9. dissolutionThe residual amber oil was dissolved in methanol (400 ml)
10. temperaturecooled in ice
11. stirringThe reaction mixture was stirred with ice cooling for 30 minutes
12. customthe ice removed
13. stirringstirred at room temperature for 1.5 hours
14. temperatureThe mixture was cooled in ice as water (50 ml)
15. additionwas added
16. concentrationto concentration in vacuo to approx 70 ml
17. customThe mixture was partitioned between 2N HCl (100 ml) and ethyl acetate (400 ml)
18. extractionthe organics extracted with 2N HCl (2×100 ml)
19. washCombined acidic aqueous layers were washed with ethyl acetate (200 ml)
20. extractionextracted with DCM (3×150 ml)
21. dry with materialCombined DCM organic extracts were dried (Na2SO4)
22. customevaporated in vacuo