1,1'-Carbonyldiimidazole → 2-N-Methyl-2-N-phenyl-6-(5-{6-[2-(2,2,2-trifluoroethoxy)ethoxy]pyridin-3-yl}-1,2,4-oxadiazol-3-yl)-1,3,5-triazine-2,4-diamine

HRID 341447Notes

Reaction equation

HRID 341447 reaction equation
[F:1][C:2]([F:18])([F:17])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[N:37]=[C:36]([N:38]([CH3:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:35]=[C:34]([C:46](=[NH:49])[NH:47]O)[N:33]=1.NC1N=C(N(C)C2C=CC=C(C)C=2)N=C(C(NO)=N)N=1>N1C=CC=CC=1>[CH3:45][N:38]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:36]1[N:37]=[C:32]([NH2:31])[N:33]=[C:34]([C:46]2[N:47]=[C:14]([C:11]3[CH:12]=[N:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:1])([F:18])[F:17])=[CH:9][CH:10]=3)[O:16][N:49]=2)[N:35]=1

Participants

6

Reactant 4

HCID 682631,1'-CarbonyldiimidazoleHCID 593549156-(2-(2,2,2-Trifluoroethoxy)ethoxy)nicotinic acid2×HCID 1784255374-amino-N-hydroxy-6-(methyl-3-methylphenyl-amino)-[1,3,5]triazine-2-carboxamidineHCID 1784821214-Amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-triazine-2-carboximidamide

Product 1

HCID 668030182-N-Methyl-2-N-phenyl-6-(5-{6-[2-(2,2,2-trifluoroethoxy)ethoxy]pyridin-3-yl}-1,2,4-oxadiazol-3-yl)-1,3,5-triazine-2,4-diamineYield 61%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

6-[2-(2,2,2-Trifluoroethoxy)ethoxy]pyridine-3-carboxylic acid (Intermediate 242, 0.133 g, 0.50 mmol) and 1,1′-carbonyldiimidazole (0.081 g, 0.50 mmol) were combined in pyridine (3 mL) and stirred at room temperature for 3 h. 4-Amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1, 0.100 g, 0.39 mmol) was added and the mixture stirred at room temperature for 4 h before being heated to 80 C for 16 h. Pyridine was removed under vacuum and the residue was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was dried over sodium sulfate and concentrated to yield an orange solid. This was purified by FCC, using a gradient of 30-70% EtOAc in heptane to afford the title compound as a white solid (0.116 g, 61%). Method A HPLC-MS: MH+ requires m/z=489 Found: m/z=489, Rt=4.58 min (100%). 1H NMR (500 MHZ, CDCl3) δ ppm 9.06 (1H, s), 8.41 (1H, d), 7.47 (2H, m), 7.34 (3H, m), 6.96 (1H, d), 5.34 (2H, br s), 4.64 (2H, t), 4.04 (2H, t), 3.97 (2H, q) and 3.65 (3H, s).

Workup

  1. additionwas added
  2. stirringthe mixture stirred at room temperature for 4 h
  3. temperaturebefore being heated to 80 C for 16 h
  4. customPyridine was removed under vacuum
  5. customthe residue was partitioned between EtOAc (20 mL) and water (20 mL)
  6. dry with materialThe organic layer was dried over sodium sulfate
  7. concentrationconcentrated
  8. customto yield an orange solid
  9. customThis was purified by FCC

Sources & evidence

ORD record
ord-2ec8d2ac0cde4061bcdb62e4032f69a2
Source dataset
uspto-grants-2014_11
Patent number
US08895733B2

Reaction notes

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