반응 #160929

반응 방정식

EDCI.HCl

4-(chlorodifluoromethoxy)aniline

NMM

hydroxybenzotriazole hydrate

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid

→

title compound

(R)—N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide

용매

water

THF

반응 조건

후처리

1. 1
   기타Alternatively, Stage 9.1 was prepared
2. 2
   workup.WAITat 65° C. for 16 h
3. 3
   온도After cooling the RM to 35° C.
4. 4
   workup.STIRRINGthe RM was stirred for 1.5 h at 35° C.
5. 5
   workup.WAITagain at 65° C. for 16 h
6. 6
   온도After cooling the RM to 35° C.
7. 7
   기타the THF was removed under reduced pressure, EtOAc (180 mL)
8. 8
   workup.ADDITIONwas added
9. 9
   workup.STIRRINGthe mixture was stirred for at 35° C. for 1 h
10. 10
    기타The two layers were separated
11. 11
    추출the aq. phase was then extracted with EtOAc (60 mL)
12. 12
    세척The combined organic layers were washed with water (90 mL), brine (90 mL)
13. 13
    기타The solvent was evaporated off under reduced pressure
14. 14
    기타to give a brown solid which
15. 15
    기타was purified by column chromatography (Silica gel, DCM/MeOH 40:1 to 20:1)

실험 절차

Alternatively, Stage 9.1 was prepared by adding 4-(chlorodifluoromethoxy)aniline (16.6 g, 84.9 mmol), NMM (21.7 g, 212.1 mmol), hydroxybenzotriazole hydrate (HOBt.H2O, 11.9 g, 77.77 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 20.9 g, 109.0 mmol) to a solution of 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid (Stage 9.4, 29.83 g, 70.7 mmol) in THF (271 mL). The mixture was stirred for 1.5 h at 25° C. and then at 65° C. for 16 h. After cooling the RM to 35° C., further EDCI.HCl (13.3 g, 69.4 mmol) was added and the RM was stirred for 1.5 h at 35° C. then again at 65° C. for 16 h. After cooling the RM to 35° C., water (150 mL) was added, the THF was removed under reduced pressure, EtOAc (180 mL) was added and the mixture was stirred for at 35° C. for 1 h. The two layers were separated and the aq. phase was then extracted with EtOAc (60 mL). The combined organic layers were washed with water (90 mL), brine (90 mL). The solvent was evaporated off under reduced pressure to give a brown solid which was purified by column chromatography (Silica gel, DCM/MeOH 40:1 to 20:1) to afford the title compound as a yellow solid.

출처