Dichloromethane → 2-Fluoro-6-hydroxy-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile

HRID 2367543Notes

Reaction equation

HRID 2367543 reaction equation
Br[C:2]1[CH:9]=[C:8]([OH:10])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.C([O-])(=O)C.[K+].C(Cl)Cl.Cl[C:21]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[CH3:33])[N:24]=[C:23]([NH:34][CH3:35])[N:22]=1.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[F:11][C:4]1[CH:3]=[C:2]([C:21]2[CH:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][C@H:28]3[CH3:33])[N:24]=[C:23]([NH:34][CH3:35])[N:22]=2)[CH:9]=[C:8]([OH:10])[C:5]=1[C:6]#[N:7]

Participants

9

Reactant 5

HCID 6344Dichloromethane2×HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 585046304-Bromo-2-fluoro-6-hydroxybenzonitrileHCID 585047304-Chloro-N-methyl-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine

Product 1

HCID 585048172-Fluoro-6-hydroxy-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrileYield 93.7%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
100 °C

Procedure

To a 20-mL screw-cap vial was added 4-bromo-2-fluoro-6-hydroxybenzonitrile (500 mg, 2.315 mmol), bis-pinacolato diboron (705 mg, 2.78 mmol), potassium acetate (568 mg, 5.79 mmol), PdCl2(dppf).CH2Cl2 adduct (95 mg, 0.116 mmol), and 1,4-dioxane (8 mL). The vial was capped and stirred for 4 h at 100° C. on a stirrer hot-plate. The reaction mixture was allowed to cool, then was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was added to a 20 mL microwave vial and 4-chloro-N-methyl-6-[(3R)-3-methyl-4-morpholinyl]-2-pyrimidinamine (0.279 g, 1.15 mmol), PdCl2(dppf).CH2Cl2 adduct (0.047 g, 0.058 mmol), K2CO3 (2 M, 1.725 mL, 3.45 mmol), and 1,4-dioxane (6 mL) were added. The resulting mixture was heated at 140° C. for 10 minutes in a microwave reactor. The organic layer was separated and the aqueous was diluted with water (10 mL), neutralized with 0.1 N HCl (pH paper), then extracted with EtOAc (3×50 mL). The organics were combined, and then dried over Na2SO4. The dried solution was concentrated, then purified by flash chromatography 0-10% CH3OH in CH2Cl2 (24 g column, dry-loaded) to afford the title compound (0.37 g) as a brown solid. LC-MS (ES) m/z=344 [M+H]+.

Workup

  1. customTo a 20-mL screw-cap vial
  2. customThe vial was capped
  3. temperatureto cool
  4. washwashed with water (20 mL)
  5. dry with materialThe organic layer was dried over Na2SO4
  6. concentrationconcentrated
  7. additionThe residue was added to a 20 mL microwave vial
  8. temperatureThe resulting mixture was heated at 140° C. for 10 minutes in a microwave reactor
  9. customThe organic layer was separated
  10. additionthe aqueous was diluted with water (10 mL)
  11. extractionextracted with EtOAc (3×50 mL)
  12. dry with materialdried over Na2SO4
  13. concentrationThe dried solution was concentrated
  14. custompurified by flash chromatography 0-10% CH3OH in CH2Cl2 (24 g column, dry-loaded)

Sources & evidence

ORD record
ord-f7c8f0566dc941d5b494455d1cf3cff2
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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