2-Bromo-5-methylpyridine → 5-methyl-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine

HRID 473642Notes

Reaction equation

HRID 473642 reaction equation
[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([NH:18][C:17]2[CH:16]=[CH:15][C:14]([O:13][C:8]3[C:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:20][CH:19]=2)=[N:23][CH:24]=1

Participants

5

Reactant 3

HCID 5642162-Bromo-5-methylpyridineHCID 23676156Sodium t-butoxideHCID 593271274-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline

Product 1

HCID 593741535-methyl-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine

Reagents, catalysts & solvents 1

HCID 25112666BrettPhos PalladacycleCatalyst

Conditions

Temperature
90 °C

Procedure

A glass microwave reaction vessel was charged with 4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline (0.167 g, 0.619 mmol), 2-bromo-5-methylpyridine (0.0888 g, 0.516 mmol), BrettPHOS precatalyst (8.26 mg, 10.32 μmol), and sodium tert-butoxide (0.124 g, 1.291 mmol). The flask was placed under vacuum then flushed with argon. Dioxane (1.7 mL) was added and the reaction was heated to 90° C. to stir overnight. After cooling to room temperature, the reaction mixture was concentrated and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide 5-methyl-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 362.1 (M+1). IC50 (uM) 0.002387.

Workup

  1. customA glass microwave reaction vessel
  2. customthen flushed with argon
  3. additionDioxane (1.7 mL) was added
  4. temperatureAfter cooling to room temperature
  5. concentrationthe reaction mixture was concentrated
  6. customchromatographed through a Biotage pre-packed silica gel column (40S)
  7. washeluting with a gradient of 10% to 100% EtOAc in hexane

Sources & evidence

ORD record
ord-f9f3bc2a2e6f4bf5a2202024b9c40f3e
Source dataset
uspto-grants-2014_01
Patent number
US08637500B2

Reaction notes

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