반응 #160913

반응 방정식

1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester

K3PO4

(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

→

title compound

6-((R)-3-Hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

용매

EtOAc

toluene

반응 조건

후처리

1. 1
   세척washed with water (2×1 L)
2. 2
   건조dried over Na2SO4
3. 3
   기타The solvent was evaporated off under reduced pressure
4. 4
   기타the crude residue was purified by flash chromatography (Silica gel, 2 kg, DCM/MeOH 95:5)
5. 5
   workup.DISSOLUTIONThe resulting material was dissolved in a mixture of MeOH (500 mL) and THF (800 mL)
6. 6
   여과The mixture was filtered
7. 7
   기타the solvent was evaporated off under reduced pressure
8. 8
   기타to give a residue which
9. 9
   기타was crystallized from MeOH

실험 절차

1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (59.9 g, 214.4 mmol), K3PO4 (105.7 g, 498.1 mmol) and Pd(PPh3)4 (9.6 g, 8.30 mmol) were added to a suspension of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 2.2, 74 g, 165.8 mmol) in toluene (740 mL) and stirred at 110° C. for 2.5 h under argon. The mixture was then diluted with EtOAc (2 L), washed with water (2×1 L) and dried over Na2SO4. The solvent was evaporated off under reduced pressure and the crude residue was purified by flash chromatography (Silica gel, 2 kg, DCM/MeOH 95:5). The resulting material was dissolved in a mixture of MeOH (500 mL) and THF (800 mL) and was treated with Si-Thiol (Biotage, 15 g, 19.5 mmol) at RT for 17 h. The mixture was filtered and the solvent was evaporated off under reduced pressure to give a residue which was crystallized from MeOH to give the title compound as a white crystalline solid. HPLC (Condition 5) tR=5.99 min, UPLC-MS (Condition 6) m/z=518.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.42 (br. s, 3H) 1.63-1.98 (m, 4H) 2.20-2.37 (m, 1H) 2.71-2.94 (m, 1H) 3.21 (d, J=6.65 Hz, 3H) 3.32-3.51 (m, 1H) 3.69-3.92 (m, 1H) 4.08-4.24 (m, 1H) 4.75-4.88 (m, 1H) 4.89-5.17 (m, 1H) 6.29-6.49 (m, 1H) 7.32 (d, J=8.99 Hz, 2H) 7.59 (s, 1H) 7.78-8.10 (m, 3H) 8.80 (t, J=2.54 Hz, 1H) 10.05-10.28 (m, 1H).

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