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

HRID 2367601Notes

Reaction equation

HRID 2367601 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]([NH2:17])[N:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29])#[N:19].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>[NH2:17][C:4]1[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[C:21]([F:29])[CH:22]=2)[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]=1

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2783130(4-Cyano-3-fluorophenyl)boronic acidHCID 585047754-Chloro-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine

Product 1

HCID 585046534-{2-Amino-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrileYield 77.3%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

4-Chloro-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-2-pyrimidinamine (350 mg, 1.36 mmol), (4-cyano-3-fluorophenyl)boronic acid (337 mg, 2.05 mmol, 1.5 equiv), tricyclohexylphosphine (57.3 mg, 0.20 mmol, 0.15 equiv), Pd2(dba)3 (94 mg, 0.10 mmol, 0.075 equiv) and K3PO4 (492 mg, 2.32 mmol, 1.7 equiv) were charged into a 30 mL microwave vial, followed by addition of 5 mL of 1,4-dioxane and 1.6 mL of water. The mixture was bubbled with argon for 10 minutes, followed by capping and heating in a oil bath at 100° C. for 20 hours. LCMS showed conversion complete. The mixture was filtered through celite and rinsed with EtOAc (40 mL). The filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine (10 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 80% EtOAc in CHCl3 to afford the title compound (359 mg) as an off-white foam with a light yellow tint. LC-MS (ES) m/z=342 [M+H]+.

Workup

  1. customThe mixture was bubbled with argon for 10 minutes
  2. filtrationThe mixture was filtered through celite
  3. washrinsed with EtOAc (40 mL)
  4. concentrationThe filtrate was concentrated in vacuo
  5. customThe residue was partitioned between EtOAc (50 mL) and brine (10 mL)
  6. dry with materialThe organic was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by silica gel column chromatography
  10. washelution of 1% EtOAc in CHCl3 to 80% EtOAc in CHCl3

Sources & evidence

ORD record
ord-f04df9f7c08c42b4a4a0a012e46a52da
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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