Bicarbonate Ion → 2-(Chloromethyl)-1-propyl-1H-benzimidazole-5-carbonitrile

HRID 895513

Reaction equation

HRID 895513 reaction equation
C(=O)(O)[O-].[NH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[NH:14][CH2:15][CH2:16][CH3:17])[C:9]#[N:10].C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=O>C(OCC)(=O)C.O.C(O)(=O)C>[CH2:15]([N:14]1[C:13]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=2[N:5]=[C:27]1[CH2:26][Cl:25])[CH2:16][CH3:17]

Participants

8

Reactant 4

HCID 769Bicarbonate IonHCID 6577Chloroacetyl chlorideHCID 8471TriethylamineHCID 223802993-Amino-4-(propylamino)benzonitrile

Product 1

HCID 223800642-(Chloromethyl)-1-propyl-1H-benzimidazole-5-carbonitrile

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 3-amino-4-n-propylaminobenzonitrile (7.38 g, 42.1 mmol) and ethyl chloroacetimidate hydrochloride (9.92 g, 63.2 mmol) in ethanol (100 mL) is heated at reflux for 17 h, then cooled and concentrated to give 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole hydrochloride. Prior to use in the next step, this material is converted to free base by adding aqueous bicarbonate and extracting with dichloromethane, drying (Na2SO4), and concentrating. ii) Alternatively, chloroacetylchloride rather than ethyl chloroacetimidate can by used: To a solution of 3-amino-4-n-propylaminobenzonitrile (5.15 g, 29.4 mmol) and triethylamine (4.51 mL) in ethyl acetate (52 mL) at room temperature, chloroacetyl chloride (2.57 mL) is added slowly. After stirring the reaction mixture for 30 minutes at room temperature, acetic acid (5 mL) is added and the reaction mixture heated to reflux. After heating for 20 h, the reaction mixture is cooled to room temperature and diluted with water (50 mL). The organic solution is washed twice with 1.0 M sodium hydroxide (2×50 mL), then washed with an aqueous solution of 0.25 M KH2PO4 (50 mL), followed by brine (50 mL). The organic layer is dried (sodium sulfate), concentrated in vacuo, and the solid recrystallized by heating in ethyl acetate (20 mL), adding hexane (40 mL) and cooling to room temperature with stirring to afford 1-n-Propyl-2-chloromethyl-5-cyanobenzimidazole as brown crystals. 1H NMR (CDCl3): δ 8.08 (d, J=0.8 Hz, 1H), 7.57 (dd, J=1.65, 8.52 Hz, 1H), 7.45 (d, J=8.24 Hz, 1H), 7.26 (s, 1H), 4.84 (s, 2H), 4.24 (t, J=7.6 Hz, 2H), 1.94 (pentet, J=7.4. 7.6 Hz, 2H), 1.03 (t, J=7.4 Hz, 3H). (B) Preparation of 1-Propyl-2-{([2-(2-fluoropyrid-6-yl)-1H-imidazol-1-yl]methyl}-5-cyano-1H-benzimidazole

Workup

  1. extractionextracting with dichloromethane
  2. dry with materialdrying (Na2SO4)
  3. concentrationconcentrating
  4. temperaturethe reaction mixture heated to reflux
  5. temperatureAfter heating for 20 h
  6. temperaturethe reaction mixture is cooled to room temperature
  7. washThe organic solution is washed twice with 1.0 M sodium hydroxide (2×50 mL)
  8. washwashed with an aqueous solution of 0.25 M KH2PO4 (50 mL)
  9. dry with materialThe organic layer is dried (sodium sulfate)
  10. concentrationconcentrated in vacuo
  11. customthe solid recrystallized
  12. temperatureby heating in ethyl acetate (20 mL)
  13. additionadding hexane (40 mL)
  14. temperaturecooling to room temperature
  15. stirringwith stirring

Sources & evidence

ORD record
ord-3e3d52ae967f465a89eb981a650f9540
Source dataset
uspto-grants-2005_07
Patent number
US06916819B2

Linked notes

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