Phenol → 5-(1H-Pyrazol-1-yl)-2-(6-(pyrrolidin-3-yloxy)pyridazin-3-yl)phenol
Reaction equation
C1(O)C=CC=CC=1.C1(S)C=CC=CC=1.C[O:16][C:17]1[CH:22]=[C:21]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:18]=1[C:28]1[N:29]=[N:30][C:31]([O:34][CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[CH:32][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[N:23]1([C:21]2[CH:20]=[CH:19][C:18]([C:28]3[N:29]=[N:30][C:31]([O:34][CH:35]4[CH2:39][CH2:38][NH:37][CH2:36]4)=[CH:32][CH:33]=3)=[C:17]([OH:16])[CH:22]=2)[CH:27]=[CH:26][CH:25]=[N:24]1Participants
Reactant 4
Product 1
Reagents, catalysts & solvents 1
Procedure
Following GENERAL METHOD 3-1 for phenol deprotection using thiophenol, 3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(pyrrolidin-3-yloxy)pyridazine (91 mg, 0.24 mmol) was treated with thiophenol (30 mg, 0.27 mmol) and K2CO3 (30 mg, 0.22 mmol) in NMP (1.6 mL) for 15 min at 190° C. After HPLC purification (0.1% trifluoroacetic acid as modifier), the product-containing fractions were free based by catch and release using SiliaBond Propylsulfonic Acid® (2 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). Solvent was concentrated under reduced pressure and a pale brown solid (83 mg, 68%) was afforded. LCMS Rt=0.48 min (LCMS method Q); [M+H]: 324.1457; 1H NMR (400 MHz, CHLOROFORM-d) δ 13.62 (bs, 1H), 7.97 (d, J=2.5 Hz, 1H), 7.97 (d, J=9.5 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.39-7.43 (m, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.12 (d, J=9.5 Hz, 1H), 6.44-6.51 (m, 1H), 5.74 (ddt, J=7.0, 5.0, 2.5 Hz, 1H), 3.24-3.31 (m, 2H), 3.17-3.24 (m, 1H), 3.02 (ddd, J=11.0, 8.5, 5.5 Hz, 1H), 2.20-2.33 (m, 1H), 2.02-2.11 (m, 1H).
Workup
- customAfter HPLC purification (0.1% trifluoroacetic acid as modifier)
- concentrationSolvent was concentrated under reduced pressure
Sources & evidence
- ORD record
- ord-a9d40acafd46499aa2099f3ba2e8ebd2
- Source dataset
- uspto-grants-2014_05
- Patent number
- US08729263B2
Reaction notes
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