Potassium Phosphate, Tribasic → 2,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile

HRID 2367507Notes

Reaction equation

HRID 2367507 reaction equation
Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@H:9]2[CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=1.[C:19]([C:21]1[C:26]([F:27])=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:31])#[N:20].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[F:27][C:26]1[CH:25]=[C:24]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@H:9]3[CH:14]([CH3:16])[CH3:15])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=2)[CH:23]=[C:22]([F:31])[C:21]=1[C:19]#[N:20]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 55252910(4-Cyano-3,5-difluorophenyl)boronic acidHCID 585044624-Chloro-N-methyl-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine

Product 1

HCID 585046702,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrileYield 69.9%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

4-Chloro-N-methyl-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine (1.70 g, 6.28 mmol), (4-cyano-3,5-difluorophenyl)boronic acid (1.72 g, 9.42 mmol, 1.5 equiv), tricyclohexylphosphine (0.264 g, 0.94 mmol, 0.15 equiv), Pd2(dba)3 (0.431 g, 0.47 mmol, 0.075 equiv), and K3PO4 (2.27 g, 10.67 mmol, 1.7 equiv) were charged into a 250 mL RB flask, followed by addition of 1,4-dioxane (30 mL) and water (10 mL). The mixture was degassed and back flushed with argon (5×). The mixture was heated in an oil bath at 100° C. for 20 hours. LCMS showed complete conversion. The mixture was filtered through celite and rinsed with EtOAc (150 mL). The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (150 mL) and brine (40 mL). The organic was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc, to afford the title compound (1.64 g) as a yellow foam. LC-MS (ES) m/z=374 [M+H]+.

Workup

  1. customThe mixture was degassed
  2. customback flushed with argon (5×)
  3. filtrationThe mixture was filtered through celite
  4. washrinsed with EtOAc (150 mL)
  5. concentrationThe filtrate was concentrated in vacuo
  6. customThe residue was partitioned between EtOAc (150 mL) and brine (40 mL)
  7. dry with materialThe organic was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by silica gel column chromatography
  11. washelution of 1% EtOAc in CHCl3 to 100% EtOAc

Sources & evidence

ORD record
ord-98881d701efc428aa69ae0d9ead8ef32
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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