反应详情

温度

72 °C

5-bromo-1H-indole-7-carboxamide (which may be prepared according to Intermediate 7, WO2005067923) (1 wt), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (1.20 wt, 1.5 eq) and sulfamic acid (0.5 eq, 0.2031 wt) were all charged sequentially to an empty reactor. Acetic acid (5 vols) was added and the mixture was heated to 70-74° C. Held thus with stirring under nitrogen for 15-25 hrs until the level of 5-bromo-1H-indole-7-carboxamide by HPLC is <5% a/a uncorrected. A mixture of hydrochloric acid (36%, 0.52 vol, 1.5 eq) and acetic acid (0.5 vol) was prepared. This mixture was then added drop-wise to the batch over ca 30 mins, maintaining an internal temp of 65-74° C. The batch was stirred for a further 30 mins at 65-74° C. before warming to 93-97° C. Stirred within this temp range under nitrogen for 15-25 hrs, until the 2:1 dimer impurity (rrt 1.15 on 8 min reverse phase LC method) is <10% a/a uncorrected. Batch then cooled back to 15-25° C. and aged within this temp range for at least 60 mins. Product then collected by vacuum filtration and washed with IMS (2×2 vol). Dried to constant weight at 40° C. in vacuo.

1. additionall charged sequentially to an empty reactor
2. customwas prepared
3. additionThis mixture was then added drop-wise to the batch over ca 30 mins
4. temperaturemaintaining an internal temp of 65-74° C
5. temperaturebefore warming to 93-97° C
6. stirringStirred within this temp range under nitrogen for 15-25 hrs, until the 2:1 dimer impurity (rrt 1.15 on 8 min reverse phase LC method)
7. temperatureBatch then cooled back to 15-25° C.
8. waitaged within this temp range for at least 60 mins
9. filtrationProduct then collected by vacuum filtration
10. washwashed with IMS (2×2 vol)
11. customDried to constant weight at 40° C. in vacuo