반응 #586065

반응 방정식

3-(dimethylamino)propyl-N′-ethylcarbodimide hydrochloride

methanesulfonic acid

1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid potassium salt hydrate

1-hydroxybenzotriazole hydrate

(S)-N-benzyl-N-methyl-2-phenylglycinamide hydrochloride hydrate

→

(S)-N-{2-[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxamide

용매

dichloromethane

dichloromethane

dichloromethane

dichloromethane

dichloromethane

Triethylamine

반응 조건

후처리

1. 1
   기타Alternatively and preferably, the title compound is prepared
2. 2
   workup.STIRRINGthe resulting mixture stirred at 0° C. for 30 minutes
3. 3
   온도to warm to 20° C. for 16 hours
4. 4
   세척The mixture was twice washed with saturated aqueous sodium hydrogen carbonate (2×2040 mL)
5. 5
   세척once washed with 0.25M aqueous hydrochloric acid solution (2040 mL)
6. 6
   세척once washed with demineralized water (2040 mL)
7. 7
   농축The resulting product solution was concentrated to 595 mL under reduced pressure
8. 8
   workup.STIRRINGThe mixture was stirred for 2 hours
9. 9
   여과before filtering
10. 10
    세척washing the solids
11. 11
    workup.ADDITIONwith a 50/50 mixture of propan-2-ol and dichloromethane (170 mL)
12. 12
    농축concentrating to a volume of 595 mL
13. 13
    workup.ADDITIONThe solution was diluted with propan-2-ol (510 mL)
14. 14
    농축re-concentrated to a volume of 595 mL
15. 15
    workup.ADDITIONbefore diluting with tert-butyl methyl ether (1700 mL)
16. 16
    온도The resulting solution was cooled to 20° C.
17. 17
    workup.STIRRINGthe mixture stirred for 18 hours
18. 18
    농축before concentrating to a volume of 920 mL under reduced pressure
19. 19
    여과After further granulation at 20° C. for an additional 48 hours the slurry was filtered
20. 20
    세척washed with cold propan-2-ol (340 mL)
21. 21
    기타The product solids were dried

실험 절차

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).

출처