Hydrochloric Acid → 4-{[(5-Cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid

HRID 2091157Notes

Reaction equation

HRID 2091157 reaction equation
Cl[CH:2]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Li+]>C(O)C.O.O1CCCC1.CN(C)C=O>[C:13]([C:10]1[CH:11]=[CH:12][C:5]2[O:4][C:3]([CH:2]([NH:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:7]([CH3:8])[C:6]=2[CH:9]=1)#[N:14]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 5238Sodium IodideHCID 10340Sodium CarbonateHCID 12082Methyl 4-aminobenzoateHCID 667789602-[Chloro(cyclohexyl)methyl]-3-methyl-1-benzofuran-5-carbonitrile

Product 1

HCID 667776914-{[(5-Cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acidYield 53%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

To a mixture of 2-[chloro(cyclohexyl)methyl]-3-methyl-1-benzofuran-5-carbonitrile (868 mg) synthesized above, methyl 4-aminobenzoate (546 mg), sodium iodide (902 mg) and N,N-dimethylformamide (10 mL) was added sodium carbonate (638 mg), and the mixture was stirred at 80° C. overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give a pale-brown solid. To a mixture of the obtained solid, tetrahydrofuran (20 mL), water (8 mL) and ethanol (10 mL) was added 1N lithium hydroxide aqueous solution (3.38 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1N hydrochloric acid (3.50 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (621 mg, 53%) as a white solid.

Workup

  1. customto quench
  2. customthe reaction
  3. extractionthe mixture was extracted with ethyl acetate
  4. washThe extract was washed with saturated brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel column chromatography (30% ethyl acetate/hexane)
  8. customto give a pale-brown solid
  9. stirringthe mixture was stirred overnight
  10. temperaturewith heating
  11. temperatureunder reflux
  12. concentrationconcentrated under reduced pressure
  13. dissolutionThe residue was dissolved in water (40 mL)
  14. addition1N hydrochloric acid (3.50 mL) was added at 0° C
  15. filtrationThe resulting precipitate was collected by filtration

Sources & evidence

ORD record
ord-edd6b325f8564c0496c6d68fcf694a92
Source dataset
uspto-grants-2013_05
Patent number
US08436043B2

Reaction notes

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