반응 #612899

반응 방정식

6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

3-methylpyrrolidin-3-ol hydrochloride

DIPEA

HCl

NaHCO3

→

title product

N-(4-(Chlorodifluoromethoxy)phenyl)-6-(3-hydroxy-3-methylpyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide

용매

iPrOH

MeOH

반응 조건

후처리

1. 1
   기타was subjected to MW irradiation at 140° C. for 1.5 h
2. 2
   추출extracted with EtOAc
3. 3
   세척the combined extracts were washed with water and brine
4. 4
   건조dried over Na2SO4
5. 5
   기타the solvent was evaporated off under reduced pressure
6. 6
   기타to give the crude product which
7. 7
   기타was crystallized from toluene/EtOAc

실험 절차

A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2, 500 mg, 1.035 mmol), 3-methylpyrrolidin-3-ol hydrochloride (244 mg, 1.77 mmol), DIPEA (0.723 mL, 4.14 mmol) and iPrOH (1.4 mL) in a MW vial was subjected to MW irradiation at 140° C. for 1.5 h. The cooled mixture was treated with aqueous HCl (37%) and MeOH (2 mL) and stirred for 1 h. The mixture was basified with sat. aq. NaHCO3, extracted with EtOAc and the combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was crystallized from toluene/EtOAc to afford the title product as a white solid. UPLC-MS (Condition 3) tR=0.95 min, m/z=464.1 [M+H]+, m/z=508.1 [M+formic acid-H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 3H) 1.60-1.85 (m, 2H) 2.93-3.12 (m, 2H) 3.25-3.31 (m, 1H) 3.42-3.54 (m, 1H) 4.61-4.76 (m, 1H) 6.31-6.42 (m, 1H) 7.33 (d, J=8.80 Hz, 2H) 7.51-7.84 (m, 1H) 7.87 (d, J=9.05 Hz, 2H) 8.03 (d, J=2.32 Hz, 1H) 8.73 (m, J=2.32 Hz, 1H) 10.19 (s, 1H) 12.86-13.15 (m, 1H).

출처