反应详情

温度

-70 °C

(5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 15a) (78.34 g, 201.7 mmol) was added to a 5 L three necked round bottomed flask containing an overhead stirrer, 500 ml pressure-equalising dropping funnel with a nitrogen inlet and thermometer. To this was added DCM (1000 mL) and the stirred mixture cooled to approx. −70° C. The dropping funnel was charged with a pre-sonicated solution of borane tert-butylamine (19.3 g, 221.87 mmol) in DCM (200 mL). The borane complex was added slowly maintaining the temperature below −70° C. over approx. 30 minutes. After addition the reaction was stirred at below −70° C. for 90 minutes. The dropping funnel was charged with 6M HCl (400 ml) and this was added dropwise over approx. 15 minutes. The reaction temperature warmed to −50° C. during the addition. After addition was complete the acetone/dry-ice bath was removed and the reaction mixture warmed to room temperature then stirred for a further 30 minutes. In a separate 10 L flask was added sodium carbonate (200 g) and water (1 L). To this flask was added an overhead stirrer. The reaction mixture was carefully added (note: gas evolution) to the sodium carbonate solution and stirring was maintained until gas evolution ceased. The mixture was transferred to a 6 L separating funnel and the phases were separated. The aqueous layer was washed with DCM (2×200 ml) and the combined organics were dried (MgSO4). The solvent was evaporated to afford 7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one as an amber oil (77.8 g), a 96:4 ratio of (2R,5S) and (2S,5S) isomers.

1. additioncontaining an overhead stirrer
2. additionThe borane complex was added slowly
3. temperaturemaintaining the temperature below −70° C. over approx. 30 minutes
4. additionAfter addition the reaction
5. additionthis was added dropwise over approx. 15 minutes
6. temperatureThe reaction temperature warmed to −50° C. during the addition
7. additionAfter addition
8. customwas removed
9. temperaturethe reaction mixture warmed to room temperature
10. stirringthen stirred for a further 30 minutes
11. additionIn a separate 10 L flask was added sodium carbonate (200 g) and water (1 L)
12. additionTo this flask was added an overhead stirrer
13. additionThe reaction mixture was carefully added (note: gas evolution) to the sodium carbonate solution
14. stirringstirring
15. temperaturewas maintained until gas evolution
16. customseparating funnel
17. customthe phases were separated
18. washThe aqueous layer was washed with DCM (2×200 ml)
19. dry with materialthe combined organics were dried (MgSO4)
20. customThe solvent was evaporated