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

HRID 450157

Reaction equation

HRID 450157 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1

Participants

7

Reactant 3

HCID 344373Pyrimidin-5-amineHCID 2724254Sodium bis(trimethylsilyl)amideHCID 220368724-(4-chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine

Product 1

HCID 498693544-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(5-pyrimidinyl)-1,3,5-triazin-2-amineYield 47%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 0.186 g (1.96 mmol) of 5-aminopyrimidine in THF (4 mL) at 0° C. was added 1.1 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 15 min. A solution of 0.238 g (0.65 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (5 mL) was added and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting first with CH2Cl2/EtOAc (1:9) and then with CH2Cl2/EtOAc (1:3) to CH2Cl2/EtOAc (7:3) gave an off-white powder. Recrystallization from ethanol gave 0.123 g (47% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(5-pyrimidinyl)-1,3,5-triazin-2-amine: mp 290-292° C.; 1H NMR (CDCl3) δ9.07 (s, 2H), 9.02 (s, 1H), 8.37 (d, J=7.2 Hz, 1H), 7.89 (dd, J=7.7, 1.5 Hz, 1H), 7.57 (t, J=53.7 Hz, 1H), 7.47-7.40 (m, 2H), 7.11 (s, 1H), 3.95-3.92 (m, 4H), 3.83 (br s, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.1; N, 29.6. Found: C, 53.4; H, 4.2; N, 29.4%.

Workup

  1. stirringthe resulting mixture was stirred for 1 hr at RT
  2. extractionextracted with EtOAc
  3. washThe organic layer was washed sequentially with water and aq. NH3
  4. customdried
  5. concentrationconcentrated
  6. washChromatography on alumina, eluting first with CH2Cl2/EtOAc (1:9)
  7. customwith CH2Cl2/EtOAc (1:3) to CH2Cl2/EtOAc (7:3) gave an off-white powder
  8. customRecrystallization from ethanol

Sources & evidence

ORD record
ord-fc675a5eeff2466db00fa2e042b59a98
Source dataset
uspto-grants-2013_07
Patent number
US08486939B2

Linked notes

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