1-Methylimidazole → 4-(3-chloro-4-fluoro-phenyl)-2-(1-methyl-1H-imidazol-2-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine

HRID 230962Notes

Reaction equation

HRID 230962 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)[N:3]=1.[CH3:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:18][CH2:17]3)[N:3]=[C:2]([C:34]3[N:33]([CH3:32])[CH:37]=[CH:36][N:35]=3)[N:7]=2)[CH:13]=[CH:12][C:11]=1[F:14]

Participants

7

Reactant 3

HCID 13901-MethylimidazoleHCID 11776TriphenylphosphineHCID 577614902-Chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-pyrimidine

Product 1

HCID 577614534-(3-chloro-4-fluoro-phenyl)-2-(1-methyl-1H-imidazol-2-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

To a mixture of 2-chloro-4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine (200 mg, 0.43 mmol), 1-methyl-1H-imidazole (42 mg, 0.51 mmol), CuI (161 mg, 0.86 mmol), MgO (21 mg, 051 mmol), and PPh3 (22 mg, 0.086 mmol) in dioxane add Pd(OAc)2 (5 mg, mg, 0.021 mmol). Purge the reaction mixture for 10 minutes with dry N2. Heat the mixture at 150° C. for 24 hours, cool to room temperature, and partition between water and EtOAc. Dry the solution (Na2SO4), concentrate under reduced pressure. Purify the residue by flash column chromatography eluting with DCM:MeOH:NH4OH (95:5:1) to afford 4-(3-chloro-4-fluoro-phenyl)-2-(1-methyl-1H-imidazol-2-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine. 1H NMR (2HCl salt, 300 MHz, DMSO-d6): δ3.35 (m, 4H); 4.01 (m, 4H); 4.31 (s, 3H, NCH3); 7.23 (m, 1H, Ar—H); 7.63 (m, 2H); 7.89 (s, 1H); 7.97 (s, 1H); 8.11 (m, 1H); 8.43 (m, 1H); 8.54 (m, 1H); 8.66 (m, 1H).

Workup

  1. customPurge the reaction mixture for 10 minutes with dry N2
  2. temperaturecool to room temperature
  3. custompartition between water and EtOAc
  4. dry with materialDry the solution (Na2SO4)
  5. concentrationconcentrate under reduced pressure
  6. customPurify the residue by flash column chromatography
  7. washeluting with DCM:MeOH:NH4OH (95:5:1)

Sources & evidence

ORD record
ord-6738c364f6e0497f88e50e8d98a33f5c
Source dataset
uspto-grants-2009_07
Patent number
US07566712B2

Reaction notes

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