반응 #162787

반응 방정식

DIAD

Intermediate 22d

1-[5-tert-Butyl-2-(3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

4-hydroxy-1-piperidine-ethanol

Ph3P

→

title compound

1-(5-tert-Butyl-2-{3-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea Formate Salt

용매

THF

반응 조건

후처리

1. 1
   기타then partitioned between EtOAc and water
2. 2
   추출The aqueous layer was extracted with EtOAc (3×)
3. 3
   세척The combined organic layers were washed with brine
4. 4
   건조dried (MgSO4)
5. 5
   여과filtered
6. 6
   기타evaporated in vacuo
7. 7
   기타The residue was purified by FCC
8. 8
   기타Further purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H)

실험 절차

DIAD (51.0 μL, 0.260 mmol) was added to a solution of Intermediate 22d (75.0 mg, 0.13 mmol), 4-hydroxy-1-piperidine-ethanol (28.0 mg, 0.19 mmol), and Ph3P (68.0 mg, 0.26 mmol) in THF (1.5 mL) at 0° C. The reaction was stirred at RT over the weekend then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM. Further purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (57 mg, 62%). LCMS (Method 5): Rt 3.32 min, m/z 707.4 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.31 (9H, s), 1.42 (3H, d, J 6.8), 1.45 (3H, d, J 6.8), 1.62-1.72 (2H, m), 1.86-2.04 (4H, m), 2.04-2.14 (1H, m), 2.21-2.30 (1H, m), 2.69-2.79 (2H, m), 3.11-3.19 (4H, m), 3.51 (1H, sept, J 6.9), 3.70-3.78 (1H, m), 4.26 (2H, t, J 5.3), 4.89 (1H, dd, J 8.9, 5.8), 5.45 (1H, t, J 4.1), 6.33 (1H, s), 7.05 (1H, ddd, J 8.4, 2.7, 0.8), 7.09-7.13 (2H, m), 7.19-7.25 (3H, m), 7.26-7.33 (2H, m), 7.42 (1H, t, J 8.1), 7.61 (1H, dd, J 9.7, 0.6), 8.01 (1H, d, J 1.7), 8.42 (1H, br s).

출처