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

HRID 450164

Reaction equation

HRID 450164 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]=[CH:36][C:31]=3[N:30]=[C:29]2[CH:37]([F:39])[F:38])[N:17]=1>C1COCC1.C(O)(=O)C.O>[F:39][CH:37]([F:38])[C:29]1[N:28]([C:18]2[N:19]=[C:20]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]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]=[CH:36][C:31]=2[N:30]=1

Participants

7

Reactant 3

HCID 52003433-Amino-4-methoxypyridineHCID 220368724-(4-chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholineHCID 178418339Butyllithium

Product 1

HCID 581027904-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amineYield 48%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 0.134 g (1.08 mmol) of 3-amino-4-methoxypyridine in THF (3 mL) was added 0.5 mL of butyllithium (2.5 M solution in hexanes), and the mixture was stirred for 15 min. A solution of 0.133 g (0.36 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-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 (1:1) and then with CH2Cl2/EtOAc (2:3) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.078 g (48% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(4-methoxy-3-pyridinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 161-163° C.; 1H NMR (DMSO-d6) δ9.43 (br s, 1H), 8.61-8.37 (m, 3H), 7.83-7.81 (m, 2H), 7.41 (br s, 2H), 7.20 (d, J=5.6 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 4H), 3.71 (s, 4H); Anal. Calcd. for C21H20F2N8O2: C, 55.5; H, 4.4; N, 24.7. Found: C, 55.5; H, 4.4; N, 24.5%.

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 (1:1)
  7. customwith CH2Cl2/EtOAc (2:3) gave a white powder
  8. customRecrystallization from ethanol/CH2Cl2

Sources & evidence

ORD record
ord-97e36050e0cb46439b2b7bb83d511e28
Source dataset
uspto-grants-2013_07
Patent number
US08486939B2

Linked notes

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