4-Amino-6-methoxypyrimidine → 4-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-N-(6-methoxypyrimidin-4-yl)-6-morpholino-1,3,5-triazin-2-amine

HRID 450170Notes

Reaction equation

HRID 450170 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:21]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:24]=[C:23]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=3[N:35]=[C:34]2[CH:44]([F:46])[F:45])[N:22]=1>C1COCC1.C(O)(=O)C.O>[F:46][CH:44]([F:45])[C:34]1[N:33]([C:23]2[N:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:26]=[C:21]([NH:1][C:2]3[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=3)[N:22]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:36]=2[N:35]=1

Participants

7

Reactant 3

HCID 7357314-Amino-6-methoxypyrimidineHCID 2724254Sodium bis(trimethylsilyl)amideHCID 534881021-[4-Chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole

Product 1

HCID 581028034-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-N-(6-methoxypyrimidin-4-yl)-6-morpholino-1,3,5-triazin-2-amineYield 30%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To 0.282 g (2.25 mmol) of 4-amino-6-methoxypyrimidine in THF (4 mL) was added 1.30 mL of NaHMDS (2 M solution in THF) and the mixture was stirred for 10 min. A solution of 0.297 g (0.75 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) in THF (5 mL) was added. The resulting mixture was stirred at room temperature for 1 hr. After neutralization with acetic acid, the mixture was diluted with water, and extracted with EtOAc. The organic layer was washed successively with water and aqueous NH3, and dried. Removal of the solvent, followed by chromatography on silica eluting with CH2Cl2/EtOAc (1:1) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.103 g (30% yield) of 4-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-N-(6-methoxypyrimidin-4-yl)-6-morpholino-1,3,5-triazin-2-amine: mp 256-259° C.; 1H NMR (CDCl3) δ8.52 (s, 1H), 7.96-7.94 (m, 2H), 7.59 (s, 1H), 7.49 (t, JHF=53.5 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 4.06 (s, 3H), 4.00 (s, 3H), 3.99-3.96 (m, 4H), 3.84 (s, 4H); HRMS (FAB MH+) Calcd for C21H22F2N9O3: m/z 486.1808. Found: m/z 486.1808.

Workup

  1. stirringThe resulting mixture was stirred at room temperature for 1 hr
  2. extractionextracted with EtOAc
  3. washThe organic layer was washed successively with water and aqueous NH3
  4. customdried
  5. customRemoval of the solvent
  6. customgave a white powder
  7. customRecrystallization from ethanol/CH2Cl2

Sources & evidence

ORD record
ord-4313d3285a854d3d968bf4bb2ccc6a02
Source dataset
uspto-grants-2013_07
Patent number
US08486939B2

Reaction notes

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