反应详情

温度

12.5 °C

Sodium borohydride (2.0 eq, 0.212 wt) was suspended in dry THF (10 vol) with stirring at 10-15° C. under nitrogen. Glacial acetic acid (2.0 eq, 0.321 vol) was then added dropwise over at least 15 mins at 10-25° C. at such a rate as to control effervescence (small exotherm, evolves hydrogen). Once the addition was complete, the resultant suspension was stirred for at least 15 mins under a flow of nitrogen until all visible effervescence has ceased. 5-bromo-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-7-carboxamide hydrochloride (which may be prepared, for example, by following the method outlined for Intermediate 8) (1 wt) was then added as a solid. The resultant suspension was then stirred at 20-25° C. under nitrogen for 3.5-4.5 hrs with HPLC monitoring. The batch was then cooled to 0-4° C. Hydrochloric acid (36% w/v, 0.90 vol) was then added in a dropwise manner over at least 30 mins maintaining the internal temperature at 0-4° C. throughout (exothermic, evolves hydrogen). The resultant slurry was stirred at 0-4° C. for 2 hrs, warmed to 20-25° C. and stirred for a further 2 hrs before recooling to 0-4° C. Water (8 vol) was then added slowly over at least 15 mins maintaining the internal temperature at 0-10° C. throughout (exothermic, evolves hydrogen). The resultant acidic solution was then stirred for at least 1 hr. A solution of aqueous sodium hydroxide (40% w/v, ca 2.5 vols) was added in a dropwise manner to neutralize to pH>12, maintaining the temperature at 0-15° C. throughout1. The resultant biphase was settled and separated. The aqueous was back-extracted with ethyl acetate (4 vols) and then discarded. The combined organics are washed with saturated brine (2×2 vols) before being concentrated in vacuo to ca 4 vols2. Ethyl acetate (8 vols) was added, and the batch was reconcentrated in vacuo to ca 4 vols. The resultant slurry was cooled to 0-5° C. and stirred for at least 30 mins. Solids are then collected by vacuum filtration and washed with ethyl acetate (2×1 vol). Dried in vacuo at 40-45° C. to constant weight.

1. additionOnce the addition
2. additionwas then added as a solid
3. temperatureThe batch was then cooled to 0-4° C
4. stirringThe resultant slurry was stirred at 0-4° C. for 2 hrs
5. temperaturewarmed to 20-25° C.
6. stirringstirred for a further 2 hrs
7. custombefore recooling to 0-4° C
8. stirringThe resultant acidic solution was then stirred for at least 1 hr
9. temperaturemaintaining the temperature at 0-15° C. throughout1
10. customseparated
11. extractionThe aqueous was back-extracted with ethyl acetate (4 vols)
12. washThe combined organics are washed with saturated brine (2×2 vols)
13. concentrationbefore being concentrated in vacuo to ca 4 vols2
14. additionEthyl acetate (8 vols) was added
15. temperatureThe resultant slurry was cooled to 0-5° C.
16. stirringstirred for at least 30 mins
17. filtrationSolids are then collected by vacuum filtration
18. washwashed with ethyl acetate (2×1 vol)
19. customDried in vacuo at 40-45° C. to constant weight