反应详情

温度

0 °C

Alternatively and preferably, the title compound is prepared as follows: A solution of methanesulfonic acid (34.0 g) in dichloromethane (85 mL) was added to a mixture of 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid potassium salt hydrate (170 g), from step (d) alternative C, and 1-hydroxybenzotriazole hydrate (54.6 g) in dichloromethane (3400 mL) at 0° C. N-[3-(dimethylamino)propyl-N′-ethylcarbodimide hydrochloride (88.4 g) in dichloromethane (680 mL) was then added over 30 minutes and the resulting mixture stirred at 0° C. for 1 hour. Triethylamine (53.9 g) in dichloromethane (170 mL) was then added over 10 minutes followed by a solution of (S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride hydrate (120.6 g), from step (e), in dichloromethane (680 mL) and the resulting mixture stirred at 0° C. for 30 minutes before allowing to warm to 20° C. for 16 hours. The mixture was twice washed with saturated aqueous sodium hydrogen carbonate (2×2040 mL), once washed with 0.25M aqueous hydrochloric acid solution (2040 mL) and once washed with demineralized water (2040 mL). The resulting product solution was concentrated to 595 mL under reduced pressure and the concentrate combined with an acidic ion-exchange resin (240 g) in propan-2-ol (595 mL). The mixture was stirred for 2 hours before filtering, washing the solids with a 50/50 mixture of propan-2-ol and dichloromethane (170 mL) and concentrating to a volume of 595 mL. The solution was diluted with propan-2-ol (510 mL) and then re-concentrated to a volume of 595 mL before diluting with tert-butyl methyl ether (1700 mL). The resulting solution was cooled to 20° C. and seeded and the mixture stirred for 18 hours before concentrating to a volume of 920 mL under reduced pressure. After further granulation at 20° C. for an additional 48 hours the slurry was filtered and washed with cold propan-2-ol (340 mL). The product solids were dried, yielding the product (S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide in Form A (192 g, 80%). HPLC retention time 11.50 minutes using the conditions specific to this example (noted above).

1. stirringthe resulting mixture stirred at 0° C. for 30 minutes
2. temperatureto warm to 20° C. for 16 hours
3. washThe mixture was twice washed with saturated aqueous sodium hydrogen carbonate (2×2040 mL)
4. washonce washed with 0.25M aqueous hydrochloric acid solution (2040 mL)
5. washonce washed with demineralized water (2040 mL)
6. concentrationThe resulting product solution was concentrated to 595 mL under reduced pressure
7. stirringThe mixture was stirred for 2 hours
8. filtrationbefore filtering
9. washwashing the solids
10. additionwith a 50/50 mixture of propan-2-ol and dichloromethane (170 mL)
11. concentrationconcentrating to a volume of 595 mL
12. additionThe solution was diluted with propan-2-ol (510 mL)
13. concentrationre-concentrated to a volume of 595 mL
14. additionbefore diluting with tert-butyl methyl ether (1700 mL)
15. temperatureThe resulting solution was cooled to 20° C.
16. stirringthe mixture stirred for 18 hours
17. concentrationbefore concentrating to a volume of 920 mL under reduced pressure
18. filtrationAfter further granulation at 20° C. for an additional 48 hours the slurry was filtered
19. washwashed with cold propan-2-ol (340 mL)
20. customThe product solids were dried