Triethylamine → 4-[2-(5,6-difluoro-1H-benzoimidazol-2-yl)-benzyloxy]-3-fluoro-benzonitrile

HRID 1875770Notes

Reaction equation

HRID 1875770 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[C:18]([C:20]1[CH:36]=[CH:35][C:23]([O:24][CH2:25][C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28](Cl)=O)=[C:22]([F:37])[CH:21]=1)#[N:19].C([O-])(=O)C.[Na+]>ClCCl.C(O)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:28]([C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[CH2:25][O:24][C:23]3[CH:35]=[CH:36][C:20]([C:18]#[N:19])=[CH:21][C:22]=3[F:37])=[N:10][C:4]=2[CH:3]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 517045Sodium AcetateHCID 27367551,2-Diamino-4,5-difluorobenzeneHCID 866522892-(4-Cyano-2-fluoro-phenoxymethyl)-benzoyl chloride

Product 1

HCID 670499324-[2-(5,6-difluoro-1H-benzoimidazol-2-yl)-benzyloxy]-3-fluoro-benzonitrileYield 16%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a mixture of 4,5-difluoro-benzene-1,2-diamine (501 mg, 3.47 mmol; CAS Reg. No. 76179-40-3) and triethylamine (0.64 ml, 4.74 mmol) in dichloromethane (10 ml) at 0° C. was added a solution of 2-(4-cyano-2-fluoro-phenoxymethyl)-benzoyl chloride (1.06 g, 3.65 mmol) in dichloromethane (15 ml) drop wise over 10 minutes. After stirring for 3 h at 0° C. the volatiles were removed in vacuo to give a yellow solid. The solid was dissolved in glacial acetic acid (15 ml), and sodium acetate was added to the solution, and the mixture was refluxed for 13 h. The reaction mixture was cooled to 25° C., evaporated in vacuo, and partitioned between dichloromethane and water. The biphasic mixture was cooled in an ice bath, and neutralized with solid potassium carbonate while maintaining vigorous stirring. The phases were separated, and the extraction was completed with additional portions of dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography over silica gel (15% ethyl acetate/n-hexane) to yield the desired compound as a brown solid (16%). MS (Turbo Spray): m/z=380.4 (M+H).

Workup

  1. customwere removed in vacuo
  2. customto give a yellow solid
  3. temperaturethe mixture was refluxed for 13 h
  4. temperatureThe reaction mixture was cooled to 25° C.
  5. customevaporated in vacuo
  6. custompartitioned between dichloromethane and water
  7. temperatureThe biphasic mixture was cooled in an ice bath
  8. temperaturewhile maintaining vigorous stirring
  9. customThe phases were separated
  10. extractionthe extraction
  11. dry with materialThe combined organic extracts were dried over sodium sulfate
  12. filtrationfiltered
  13. customevaporated under reduced pressure
  14. customThe crude product was purified by flash chromatography over silica gel (15% ethyl acetate/n-hexane)

Sources & evidence

ORD record
ord-481ee1462df34ea09887ff4fe9516124
Source dataset
uspto-grants-2012_11
Patent number
US08309581B2

Reaction notes

Loading…