反应详情

温度

0 °C

To a three-necked SOL flask equipped with a mechanic stirrer, a nitrogen inlet, cooling bath and a thermometer was added (S)-3-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (2.5 kg, 8.93 mol) and dichloromethane (20 L) and this mixture was stirred until the solid dissolved. The reaction mixture was then cooled to 0° C. and 7,7-dimethoxy-heptanal (1.71 kg, 9.82 mol) was added slowly while maintaining the reaction temperature below 5° C. This reaction mixture was stirred at 0 to 5° C. for 1 hr and then sodium triacetoxyborohydride (2.27 kg, 10.72 mol) was added in small portions over 30 minutes while maintaining the reaction temperature below 5° C. The reaction mixture was then stirred at room temperature for 6 hrs. An aqueous 5% potassium carbonate solution (20 L) was then added while maintaining the reaction temperature below 20° C. and the reaction mixture was then stirred for 1 hr at room temperature. The layers were then separated and the organic layer was washed with brine (10 L) and then dried over sodium sulfate (2 kg) for about 3 hrs. After separating the organic layer from the sodium sulfate, the organic layer was concentrated to about 10 L under reduced pressure. This mixture was then purified by silica gel chromatography (40 kg) using the following sequence of eluents: dichloromethane (100 L); 3% MeOH, 97% DCM, as needed; 5% MeOH, 95% DCM, as needed; and 10% MeOH, 90% DCM, as needed. The fractions containing the desired intermediate were then combined (Rf 0.3; 10% MeOH/90% DCM) and concentrated at a temperature less than 30° C. to afford 3.3 kg of the title intermediate.

1. customTo a three-necked SOL flask equipped with a mechanic stirrer, a nitrogen inlet
2. temperaturecooling bath
3. dissolutiondissolved
4. temperaturewhile maintaining the reaction temperature below 5° C
5. stirringThis reaction mixture was stirred at 0 to 5° C. for 1 hr
6. temperaturewhile maintaining the reaction temperature below 5° C
7. stirringThe reaction mixture was then stirred at room temperature for 6 hrs
8. temperaturewhile maintaining the reaction temperature below 20° C.
9. stirringthe reaction mixture was then stirred for 1 hr at room temperature
10. customThe layers were then separated
11. washthe organic layer was washed with brine (10 L)
12. dry with materialdried over sodium sulfate (2 kg) for about 3 hrs
13. customAfter separating the organic layer from the sodium sulfate
14. concentrationthe organic layer was concentrated to about 10 L under reduced pressure
15. customThis mixture was then purified by silica gel chromatography (40 kg)
16. additionThe fractions containing the desired intermediate
17. concentrationconcentrated at a temperature less than 30° C.