4-Cyanobenzoic acid → 4-{5-[2-(2,6-Dichloro-phenyl)-3H-benzoimidazol-5-yl]-[1,3,4]oxadiazol-2-yl}-benzonitrile

HRID 1513220Notes

Reaction equation

HRID 1513220 reaction equation
[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]1[NH:21][C:22]2[CH:28]=[C:27]([C:29]([NH:31][NH2:32])=O)[CH:26]=[CH:25][C:23]=2[N:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOP(O)N(C(C)C)C(C)C.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>O.CCOC(C)=O.CN(C=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[C:20]1[NH:21][C:22]2[CH:28]=[C:27]([C:29]3[O:9][C:7]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)=[N:32][N:31]=3)[CH:26]=[CH:25][C:23]=2[N:24]=1

Participants

9

Reactant 5

HCID 120874-Cyanobenzoic acidHCID 1954513'-O-ethyl-N,N-diisopropylphosphoramiditeHCID 2724994Methyl N-(triethylammoniosulfonyl)carbamateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 577865852-(2,6-Dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide

Product 1

HCID 252358554-{5-[2-(2,6-Dichloro-phenyl)-3H-benzoimidazol-5-yl]-[1,3,4]oxadiazol-2-yl}-benzonitrileYield 41%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

Combine 4-cyano-benzoic acid (120 mg, 0.817 mmol), 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (250 mg, 0.778 mmol), HATU (445 mg, 1.17 mmol), EDIPA (204 uL, 1.17 mmol), and DMF (5 mL) and stir for 25 hr. Dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Take the concentrate up in DMF (3 mL) and add Burgess reagent (555 mg, 2.33 mmol). Heat the reaction to 150° C. for 20 min by microwave irradiation. Dilute the reaction with EtOAc (75 mL) and extract with water (20 mL). Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the concentrate by silica gel chromatography (10-40% ACN/DCM) to afford a white solid. Suspend the solid in water and stir for 6 hr. Collect the solid by filtration and wash with Et2O. Dry the solid under vacuum at 40° C. for 2 days to afford the title compound (138 mg) as a white solid: 1H NMR (400 MHz, DMSO-d6) ppm 7.63-7.68 (m, 1 H) 7.70-7.74 (m, 2 H) 7.79-7.85 (tautomer, m, 1 H) 7.96 (tautomer, d, J=8.59 Hz, 1 H) 8.06-8.15 (m, 3 H) 8.35-8.40 (m+tautomer, 2 H) 8.52-8.60 (m, 1 H) 13.39 (d, J=12.76 Hz, 1H); LCMS tR=1.35 min, MS (m/z) 432.0.

Workup

  1. additionDilute
  2. extractionextract with water (15 mL)
  3. dry with materialDry the organic phase over Na2SO4
  4. concentrationconcentrate under reduced pressure
  5. concentrationconcentrate up in DMF (3 mL)
  6. temperatureHeat
  7. customthe reaction to 150° C. for 20 min
  8. customby microwave irradiation
  9. additionDilute
  10. extractionextract with water (20 mL)
  11. dry with materialDry the organic phase over Na2SO4
  12. concentrationconcentrate under reduced pressure
  13. customPurify the
  14. concentrationconcentrate by silica gel chromatography (10-40% ACN/DCM)
  15. customto afford a white solid
  16. customCollect the solid
  17. filtrationby filtration
  18. washwash with Et2O
  19. customDry the solid under vacuum at 40° C. for 2 days

Sources & evidence

ORD record
ord-7bbd2cd3a15d4235a4b4996eb7e2b3c9
Source dataset
uspto-grants-2012_07
Patent number
US08217065B2

Reaction notes

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