Formaldehyde → 5-(5-methyl-1-((2-(4-methylpiperazin-1-yl)pyridin-4-yl) methyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole

HRID 1475188Notes

Reaction equation

HRID 1475188 reaction equation
F[C:2](F)(F)C([O-])=O.[CH3:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][NH2+:24][CH2:23][CH2:22]3)[CH:16]=2)[N:12]=[C:11]([C:27]2[O:31][N:30]=[C:29]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=3)[N:28]=2)[N:10]=1.C=O.[BH3-]C#N.[Na+]>CCO>[CH3:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH3:2])[CH2:23][CH2:22]3)[CH:16]=2)[N:12]=[C:11]([C:27]2[O:31][N:30]=[C:29]([C:32]3[CH:33]=[CH:34][C:35]([O:38][C:39]([F:42])([F:40])[F:41])=[CH:36][CH:37]=3)[N:28]=2)[N:10]=1

Participants

5

Reactant 3

HCID 712Formaldehyde2×HCID 5003444Sodium cyanoborohydrideHCID 867118804-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazin-1-ium 2,2,2-trifluoroacetate

Product 1

HCID 732117755-(5-methyl-1-((2-(4-methylpiperazin-1-yl)pyridin-4-yl) methyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazoleYield 45%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

The mixture of 4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)pyridin-2-yl)piperazin-1-ium trifluoroacetate (100 mg, 0.2 mmol), formaldehyde (0.5 mL, 6.0 mmol, 38% in H2O) and paraformaldehyde (100 mg, 3.3 mmol) in EtOH (1 mL) was stirred at RT, then treated with NaBH3CN (63 mg, 1.0 mmol) in one portion. The mixture was stirred at RT for 3 h, and then concentrated under reduced pressure to give the crude product, which was purified by pre-HPLC (Mobile phase: A=10 mM NH4HCO3/H2O, B=MeCN; Gradient: B=60%-95% in 18 min; Column: XBridge C18, 5 um, 30 mm×150 mm) to afford 5-(5-methyl-1-((2-(4-methylpiperazin-1-yl)pyridin-4-yl) methyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (45 mg, 45%). MS (ES+) C23H23F3N8O2 requires: 500. found: 501 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 8.22 (d, J=8.3 Hz, 2H), 8.08 (d, J=5.3 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 6.77 (s, 1H), 6.42 (d, J=5.3 Hz, 1H), 5.50 (s, 2H), 3.50-3.48 (m, 4H), 2.58 (s, 3H), 2.41-2.32 (m, 4H), 2.20 (s, 3H).

Workup

  1. stirringThe mixture was stirred at RT for 3 h
  2. concentrationconcentrated under reduced pressure
  3. customto give the crude product, which
  4. customwas purified by pre-HPLC (Mobile phase

Sources & evidence

ORD record
ord-f39751ccb2bd4ad0848715d52da57f95
Source dataset
uspto-grants-2015_04
Patent number
US09018380B2

Reaction notes

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