Potassium Carbonate → tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-(1-methyl-1H-pyrazol-3-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate

HRID 450201

Reaction equation

HRID 450201 reaction equation
Cl[C:2]1[N: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]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:33]([F:35])[F:34])[N:3]=1.[CH3:36][N:37]1[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:35][CH:33]([F:34])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:39]3[CH:40]=[CH:41][N:37]([CH3:36])[N:38]=3)[N: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]=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 112635011-Methyl-1H-pyrazole-4-boronic acidHCID 86645852HCID 86645852, compound

Product 1

HCID 66870620tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-(1-methyl-1H-pyrazol-3-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamateYield 69%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
20 °C

Procedure

A mixture of tert-butyl 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (Example 64) (313 mg, 0.61 mmol), 1-methyl-1H-pyrazol-4-ylboronic acid (155 mg, 1.22 mmol), and aq. 2 M K2CO3 (4.1 mL) in 1,4-dioxane (20 mL) was degassed with N2 for 30 min and then Pd(dppf)Cl2 (30 mg) was added, and the mixture was degassed for a further 10 min. The reaction mixture was heated under reflux for 1 hr, cooled to 20° C., diluted with water, and extracted with CH2Cl2 (20 mL×3). The combined CH2Cl2 extracts were dried (Na2SO4) and the solvents were removed to gave a crude product which was purified by chromatography on silica, eluting with CH2Cl2/EtOAc (4:1) to give tert-butyl 2-(difluoromethyl)-4-methoxy-1-[4-(1-methyl-1H-pyrazol-3-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazol-6-ylcarbamate (233 mg, 69% yield): mp (CH2Cl2/hexanes) 224-227° C.; 1H NMR (DMSO-d6) δ 9.60 (s, 1H), 8.75 (s, 1H), 8.64 (s, 1H), 8.28 (m, 1H), 7.82 (t, JHF=53.1 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 3.99-3.96 (m, 4H), 3.96 (s, 3H), 3.92 (s, 3H), 3.76 (m, 4H), 1.53 (s, 9H); Anal. Calcd. for C25H29F2N9O4.0.25H2O: C, 53.4; H, 5.3; N, 22.4. Found: C, 53.3; H, 5.3; N, 22.3%.

Workup

  1. customwas degassed with N2 for 30 min
  2. additionPd(dppf)Cl2 (30 mg) was added
  3. customthe mixture was degassed for a further 10 min
  4. temperatureThe reaction mixture was heated
  5. temperatureunder reflux for 1 hr
  6. additiondiluted with water
  7. extractionextracted with CH2Cl2 (20 mL×3)
  8. dry with materialThe combined CH2Cl2 extracts were dried (Na2SO4)
  9. customthe solvents were removed
  10. customto gave a crude product which
  11. customwas purified by chromatography on silica
  12. washeluting with CH2Cl2/EtOAc (4:1)

Sources & evidence

ORD record
ord-cdb3d449673b44448951d39ee27c8457
Source dataset
uspto-grants-2013_07
Patent number
US08486939B2

Linked notes

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