Cesium carbonate → N-(2-chloro-5-pyrimidinyl)-4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine

HRID 450181Notes

Reaction equation

HRID 450181 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]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][C:29]1[CH:30]=[N:31][C:32]([Cl:35])=[N:33][CH:34]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:35][C:32]1[N:33]=[CH:34][C:29]([NH:28][C:2]2[N:3]=[C:4]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=4[N:16]=[C:15]3[CH:25]([F:26])[F:27])[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:30][N:31]=1

Participants

8

Reactant 5

HCID 10796Cesium carbonateHCID 516892Sodium BicarbonateHCID 634876Binap, (A+-)-HCID 122159932-Chloropyrimidin-5-amineHCID 534881021-[4-Chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole

Product 1

HCID 49869077N-(2-chloro-5-pyrimidinyl)-4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-amineYield 36.5%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 0.28 g (0.71 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole, 0.076 g (0.56 mmol) of the above amine, 0.026 g (0.04 mmol) of BINAP, 0.01 g (0.04 mmol) of Pd(OAc)2, and 0.266 g (0.82 mmol) of Cs2CO3 in 1,4-dioxane (4 mL) was heated at 100° C. for 3 hrs under nitrogen. The mixture was cooled to room temperature, sat. NaHCO3 solution was added, and the resulting mixture was extracted with EtOAc (×4). The organic layer was washed with brine, dried (Na2SO4), and concentrated. Chromatography on silica, eluting with CH2Cl2/EtOAc (6:1), gave 0.10 g (36% yield) of N-(2-chloro-5-pyrimidinyl)-4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-amine, as a white powder: mp 295° C. (decomp.); 1H NMR (DMSO-d6) δ 10.43 (s, 1H), 9.08 (s, 2H), 8.09-7.69 (m, 2H), 7.42 (t, J=8.0 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H), 3.98 (s, 3H), 3.83 (s, 4H), 3.75-3.73 (m, 4H); Anal. Calcd. for C20H18ClF2N9O2: C, 49.0; H, 3.7; N, 25.7. Found: C, 49.2; H, 3.9; N, 25.45%.

Workup

  1. temperatureThe mixture was cooled to room temperature
  2. extractionthe resulting mixture was extracted with EtOAc (×4)
  3. washThe organic layer was washed with brine
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated
  6. washChromatography on silica, eluting with CH2Cl2/EtOAc (6:1)

Sources & evidence

ORD record
ord-92b713aea0d04c58be04a3fb3d076f62
Source dataset
uspto-grants-2013_07
Patent number
US08486939B2

Reaction notes

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