Hydrochloric Acid → 2-chloro-5,6-difluoro-1H-benzimidazole

HRID 9581

Reaction equation

HRID 9581 reaction equation
N(OC(C)(C)C)=O.[F:8][C:9]1[C:18]([F:19])=[CH:17][C:12]2[NH:13][C:14](N)=[N:15][C:11]=2[CH:10]=1.[ClH:20]>CC(C)=O.[Cu](Cl)Cl>[Cl:20][C:14]1[NH:13][C:12]2[CH:17]=[C:18]([F:19])[C:9]([F:8])=[CH:10][C:11]=2[N:15]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 10906Tert-Butyl nitrite2×HCID 106787085,6-difluoro-1H-1,3-benzodiazol-2-amine

Product 1

HCID 4694162-chloro-5,6-difluoro-1H-benzimidazoleYield 73%

Reagents, catalysts & solvents 2

HCID 24014Cupric ChlorideCatalystHCID 180AcetoneSolvent

Procedure

The procedure used was similar to that reported in J. Med. Chem. 40:811–818, 1997. To a mixture of copper(II) chloride (795 mg, 5.91 mmol) in acetone (20 mL) was added tert-butyl nitrite (0.53 mL, 4.43 mmol). The reaction mixture was stirred at rt for 20 minutes, 5,6-difluoro-1H-benzimidazol-2-amine (500 mg, 2.96 mmol) was then added, and the mixture was heated at reflux for 2 h (with additional portions of tert-butyl nitrite added every 0.5 h). The reaction mixture was then cooled to rt, treated with 2 N HCl, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford 2-chloro-5,6-difluoro-1H-benzimidazole (580 mg, 73%), which was used without further purification in the next step. LC-MS m/z 189.2 (MH+), ret. time 1.96 min; 1H NMR (300 MHz, DMSO-d6) δ 7.62 (t, 2H), 13.5 (br s, 1H).

Workup

  1. temperaturethe mixture was heated
  2. additionadded every 0.5 h)
  3. temperatureThe reaction mixture was then cooled to rt
  4. extractionextracted with ethyl acetate
  5. dry with materialThe organic phase was dried over sodium sulfate
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0467d96bb5b948119f036634bf79f67c
Source dataset
uspto-grants-2006_08
Patent number
US07091228B2

Linked notes

Loading…