Methanol → HCID 178493783, compound

HRID 2200774Notes

Reaction equation

HRID 2200774 reaction equation
Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([O:15][C:16]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:23]=[C:22]4[C:17]=3[N:18]=[CH:19][CH:20]=[N:21]4)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[C:32](=O)([O-])[O-:33].[Cs+].[Cs+].CO>C1(C)C=CC=CC=1.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].CC1C=CC(OC)=C(P(C(C)(C)C)C(C)(C)C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C>[CH3:32][O:33][C:2]1[CH:3]=[N:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@@H:12]([O:15][C:16]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:23]=[C:22]4[C:17]=3[N:18]=[CH:19][CH:20]=[N:21]4)[CH2:11][CH2:10]2)=[N:6][CH:7]=1

Participants

7

Reactant 3

HCID 887MethanolHCID 10796Cesium carbonateHCID 178419459HCID 178419459, compound

Product 1

HCID 178493783HCID 178493783, compoundYield 63.6%

Reagents, catalysts & solvents 3

HCID 61538Palladium, di-mu-chlorobis(eta3-2-propenyl)di-CatalystHCID 56641709(2',4'-Diisopropyl-3-methoxy-6-methyl-6'-propyl-2-biphenylyl)[bis(2-methyl-2-propanyl)]phosphineCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

As shown in step 6-ix of Scheme 6, to a mixture 5-bromo-N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (75 mg, 0.155 mmol), cesium carbonate (101 mg, 0.309 mmol), allylpalladium(II) chloride dimer (0.28 mg, 0.0015 mmol), RockPhos (2.17 mg, 0.0046 mmol) and MeOH (9.9 mg, 12.5 μL, 0.31 mmol) in toluene (2 mL) was flushed with nitrogen gas and heated to 100° C. for 18 hours. The reaction mixture was diluted with EtOAc, filtered though a layer of diatomaceous earth, and concentrated under reduced pressure. Purification by medium pressure silica gel chromatography (0-8% MeOH/DCM gradient) yielded 5-methoxy-N-((cis)-4-((7-morpholinoquinoxalin-5-yl)oxy)cyclohexyl)pyrimidin-2-amine (compound 134, 43 mg): 1H-NMR (300 MHz, CDCl3) δ 8.70 (d, J=1.9 Hz, 1H), 8.63 (d, J=1.9 Hz, 1H), 8.07 (s, 2H), 6.96 (d, J=2.5 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 5.01 (d, J=8.1 Hz, 1H), 4.80 (q, J=5.6, 4.2 Hz, 1H), 4.03-3.87 (m, 5H), 3.80 (s, 3H), 3.42-3.27 (m, 4H), 2.29-2.10 (m, 2H), 1.99-1.82 (m, 6H).

Workup

  1. customwas flushed with nitrogen gas
  2. additionThe reaction mixture was diluted with EtOAc
  3. filtrationfiltered though a layer of diatomaceous earth
  4. concentrationconcentrated under reduced pressure
  5. customPurification by medium pressure silica gel chromatography (0-8% MeOH/DCM gradient)

Sources & evidence

ORD record
ord-0bd770be36f945c5b9fa6c3fd29608b8
Source dataset
uspto-grants-2016_06
Patent number
US09359380B2

Reaction notes

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