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

HRID 450165

Reaction equation

HRID 450165 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([Li])CCC.Cl[C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:19]=[C:18]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:31]=3[N:30]=[C:29]2[CH:39]([F:41])[F:40])[N:17]=1>C1COCC1.C(O)(=O)C.O>[F:41][CH:39]([F:40])[C:29]1[N:28]([C:18]2[N:19]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:21]=[C:16]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][C:7]=3[O:8][CH3:9])[N:17]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:31]=2[N:30]=1

Participants

7

Reactant 3

HCID 52003433-Amino-4-methoxypyridineHCID 534881021-[4-Chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazoleHCID 178418339Butyllithium

Product 1

HCID 581027814-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amineYield 42%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 0.121 g (0.98 mmol) of 3-amino-4-methoxypyridine in THF (3 mL) was added 0.44 mL of butyllithium (2.5 M solution in hexanes), and the mixture stirred for 15 min. A solution of 0.128 g (0.32 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr. 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 hexanes/EtOAc (8:2) and then with CH2Cl2/EtOAc (2:1) to CH2Cl2/EtOAc (1:1) gave a yellow powder. Recrystallization from ethanol/CH2Cl2 gave 0.065 g (42% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 239-241° C.; 1H NMR (CDCl3) δ9.43 (br s, 1H), 8.31 (d, J=5.6 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.54 (t, JHF=53.4 Hz, 1H), 7.39-7.35 (m, 2H), 6.89 (d, J=5.6 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H), 3.94 (s, 4H), 3.82-3.80 (m, 4H); Anal. Calcd. for C22H22F2N8O3: C, 54.5; H, 4.6; N, 23.1. Found: C, 54.4; H, 4.5; N, 22.9%.

Workup

  1. stirringthe resulting mixture was stirred for 1 hr
  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 hexanes/EtOAc (8:2)
  7. customwith CH2Cl2/EtOAc (2:1) to CH2Cl2/EtOAc (1:1) gave a yellow powder
  8. customRecrystallization from ethanol/CH2Cl2

Sources & evidence

ORD record
ord-11fed200964843e1ba2ac602ceedd10f
Source dataset
uspto-grants-2013_07
Patent number
US08486939B2

Linked notes

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