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

HRID 450169
Notes
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Reaction equation

HRID 450169 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C([Li])CCC.Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:17]=[C:16]([N:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:29]=3[N:28]=[C:27]2[CH:37]([F:39])[F:38])[N:15]=1>C1COCC1.C(O)(=O)C.O>[F:39][CH:37]([F:38])[C:27]1[N:26]([C:16]2[N:17]=[C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:19]=[C:14]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[N:15]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:29]=2[N:28]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 344373Pyrimidin-5-amineHCID 534881021-[4-Chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazoleHCID 178418339Butyllithium

Product 1

HCID 498699184-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(5-pyrimidinyl)-1,3,5-triazin-2-amineYield 22.6%

Reagents, catalysts & solvents 3

HCID 176
Acetic Acid
Solvent
HCID 962WaterSolvent
HCID 8028TetrahydrofuranSolvent2×

Procedure

To 0.207 g (2.18 mmol) of 5-aminopyrimidine in THF (4 mL) was added 0.96 mL of n-butyllithium (2.5 M solution in hexanes) and the mixture stirred for 10 min. A solution of 0.260 g (0.66 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 hexanes/EtOAc (1:1) gave a yellow powder. Recrystallization from ethanol/CH2Cl2 gave 0.068 g (20% yield) of 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(5-pyrimidinyl)-1,3,5-triazin-2-amine: mp 293-295° C.; 1H NMR (CDCl3) δ 9.07 (s, 2H), 9.01 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.48 (t, JHF=53.2 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 7.14 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 4.05 (s, 3H), 3.95-3.90 (m, 4H), 3.82-3.81 (m, 4H); Anal. Calcd. for C20H19F2N9O2: C, 52.75; H, 4.2; N, 27.7. Found: C, 52.9; H, 4.2; N, 27.7%.

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 yellow powder
  7. customRecrystallization from ethanol/CH2Cl2

Sources & evidence

ORD record
ord-ef3c1590b1ad4e2386b3211d43f5bde9
Source dataset
uspto-grants-2013_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08486939B2

Reaction notes

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