Potassium Carbonate → 2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4,5'-bipyrimidine

HRID 450189Notes

Reaction equation

HRID 450189 reaction equation
Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:30]3[CH:31]=[N:26][CH:27]=[N:28][CH:29]=3)[CH:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 2795193(Pyrimidin-5-yl)boronic acid2×HCID 442492591-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-1H-benzimidazole

Product 1

HCID 498692142-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4,5'-bipyrimidineYield 79%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst2×HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 1-[4-chloro-6-(4-morpholinyl)-2-pyrimidinyl]-2-(difluoromethyl)-1H-benzimidazole (200 mg, 0.547 mmol), pyrimidine-5-boronic acid (203 mg, 1.64 mmol), PdCl2(dppf) (45 mg, 0.0551 mmol), and aq. K2CO3 (2M, 4 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 2.5 hrs. Additional pyrimidine-5-boronic acid (203 mg, 1.64 mmol) and PdCl2(dppf) (23 mg, 0.0282 mmol) were added, and the mixture was refluxed for additional 16.5 hrs under nitrogen. The mixture was cooled to room temperature, diluted with H2O, extracted with CH2Cl2 (4×), and the combined organic extracts were dried (Na2SO4), and the solvents were removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 97:3), followed by recrystallization from CH2Cl2/MeOH/i-Pr2O gave 2-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4,5′-bipyrimidine (177 mg, 79%): mp 209-211° C.; 1H NMR (CDCl3) δ9.37 (s, 2H), 9.37 (s, 1H), 8.37 (m, 1H), 7.93 (m, 1H), 7.59 (t, JHF=53.7 Hz, 1H), 7.49-7.41 (m, 2H), 6.86 (s, 1H), 3.91 (m, 4H), 3.85 (m, 4H); Anal. Calcd. for C20H17F2N7O: C, 58.7; H, 4.2; N, 23.95. Found: C, 58.4; H, 3.9; N, 23.9%.

Workup

  1. temperaturewas refluxed under nitrogen for 2.5 hrs
  2. temperaturethe mixture was refluxed for additional 16.5 hrs under nitrogen
  3. extractionextracted with CH2Cl2 (4×)
  4. dry with materialthe combined organic extracts were dried (Na2SO4)
  5. customthe solvents were removed under vacuum
  6. washChromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 97:3)
  7. customfollowed by recrystallization from CH2Cl2/MeOH/i-Pr2O

Sources & evidence

ORD record
ord-a4cab8581ae9443983c684b26b29ba40
Source dataset
uspto-grants-2013_07
Patent number
US08486939B2

Reaction notes

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