3-(2-Nitrophenoxy)benzonitrile → 3-(2-Aminophenoxy)benzonitrile

HRID 2362799Notes

Reaction equation

HRID 2362799 reaction equation
[N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])([O-])=O>CCO>[NH2:1][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]

Participants

3

Reactant 1

HCID 91948883-(2-Nitrophenoxy)benzonitrile

Product 1

HCID 225963353-(2-Aminophenoxy)benzonitrileYield 99%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of 2-fluoro nitrobenzene (1.41 g, 10 mmol, 1.0 equiv) and 3-hydroxybenzonitrile (1.19 g, 1.0 equiv) in 10 mL of DMF was added K2CO3 (2.76 g, 2 equiv). After stiffing at 60° C. for 3 h, the mixture was diluted with EtOAc and washed with H2O. The organic layer was dried over MgSO4, filtered and evaporated to give 3-(2-nitrophenoxy)benzonitrile (2.38 g, 99%). MS found for C13H9N2O3 (M+H)+: 241. Step 2: A solution of 3-(2-nitrophenoxy)benzonitrile (1.21 g, 5 mmol, 1.0 equiv) in 30 mL of EtOH was treated with SnCl22H2O (3.38 g, 3 equiv) at reflux for 4 h. The volatile was evaporated and the residue was redissolved in EtOAc, washed with saturated aqueous NaHCO3 and 1N NaOH. The organic layer was dried over MgSO4, filtered and evaporated to give 3-(2-aminophenoxy)benzonitrile (1.04 g, 99%). MS found for C13H11N2O (M+H)+: 211. Step 3: A mixture of 3-(2-aminophenoxy)benzonitrile (210 mg, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1 equiv), Bop reagent (880 mg, 2 equiv) and TEA (1.39 mL, 10 equiv) in 3 mL of DMF was stirred at rt overnight. The mixture was diluted with EtOAc, washed with H2O. The organic layer was dried over MgSO4, filtered and evaporated. Flash chromatography on silica gel gave 3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)phenoxy)benzonitrile (300 mg, 57%). MS found for C30H28N3O4S (M+H)+: 526. Step 4: A stream of HCl(g) was bubbled through a 0° C. solution of 3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)phenoxy)benzonitrile (53 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture was stirred at rt overnight and evaporated. The resulting residue was treated with ammonium acetate (39 mg, 5 equiv) in 10 ml methanol at reflux temperature for 2 h. The solvent was removed at reduced pressure and the crude benzamidine was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H2O/CH3CN to give 3-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino) phenoxy)benzamidine (40 mg, 83%). MS found for C26H23N4O4S (M+H)+: 487.

Workup

  1. temperatureat reflux for 4 h
  2. customThe volatile was evaporated
  3. dissolutionthe residue was redissolved in EtOAc
  4. washwashed with saturated aqueous NaHCO3 and 1N NaOH
  5. dry with materialThe organic layer was dried over MgSO4
  6. filtrationfiltered
  7. customevaporated

Sources & evidence

ORD record
ord-d8f61e1b2a9d45a7b987ac3bb44c306a
Source dataset
uspto-grants-2014_04
Patent number
US08691847B2

Reaction notes

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