5-Amino-2-fluoropyridine → 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(6-fluoro-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine

HRID 450167Notes

Reaction equation

HRID 450167 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Li])CCC.Cl[C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:18]=[C:17]([N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:30]=3[N:29]=[C:28]2[CH:38]([F:40])[F:39])[N:16]=1>C1COCC1.C(O)(=O)C.O>[F:40][CH:38]([F:39])[C:28]1[N:27]([C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([NH:1][C:2]3[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=3)[N:16]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:30]=2[N:29]=1

Participants

7

Reactant 3

HCID 8194405-Amino-2-fluoropyridineHCID 534881021-[4-Chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazoleHCID 178418339Butyllithium

Product 1

HCID 581028064-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(6-fluoro-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amineYield 40.2%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To 0.240 g (2.14 mmol) of 5-amino-2-fluoropyridine in THF (5 mL) was added 0.94 mL of n-butyllithium (2.5 M solution in hexanes), and the mixture was stirred for 10 min. A solution of 0.283 g (0.71 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 alumina eluting first with hexanes/EtOAc (1:1) and then CH2Cl2/EtOAc (1:3) gave a brown powder. Recrystallization from ethanol/CH2Cl2 gave 0.135 g (40% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(6-fluoro-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 261-263° C.; 1H NMR (CDCl3) δ8.44 (br s, 1H), 8.03-8.01 (m, 1H), 7.90 (br s, 1H), 7.61-7.31 (m, 2H), 7.07 (br s, 1H), 6.99 (dd, J=8.3, 3.4 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.93-3.88 (m, 4H), 3.80 (s, 4H); Anal. Calcd. for C21H19F3N8O2: C, 53.4; H, 4.05; N, 23.7. Found: C, 53.5; H, 4.0; N, 23.8%.

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. customCH2Cl2/EtOAc (1:3) gave a brown powder
  7. customRecrystallization from ethanol/CH2Cl2

Sources & evidence

ORD record
ord-9e9c939dd26549e08ea057fc2a8daac7
Source dataset
uspto-grants-2013_07
Patent number
US08486939B2

Reaction notes

Loading…