3-(Trifluoromethyl)benzoic acid → HCID 58349020, compound

HRID 2190513Notes

Reaction equation

HRID 2190513 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:11]([CH3:20])[C:10]=2[CH:21]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].Cl.C(N=C=NCCCN(C)C)C.[OH-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CO>[CH:17]1([C:15]([NH:14][C:12]2[N:11]([CH3:20])[C:10]3[CH:21]=[C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:24]=[CH:23][CH:22]=4)[CH:7]=[CH:8][C:9]=3[N:13]=2)=[O:16])[CH2:19][CH2:18]1

Participants

8

Reactant 4

HCID 99633-(Trifluoromethyl)benzoic acidHCID 14798Sodium HydroxideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 57388052HCID 57388052, compound

Product 1

HCID 58349020HCID 58349020, compoundYield 45.3%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 1049PyridineSolvent

Procedure

To a solution of N-[6-(3-aminophenoxy)-1-methyl-1H-benzimidazol-2-yl]cyclopropanecarboxamide (200 mg, 620 μmol) in pyridine (5 mL) were added 3-(trifluoromethyl)benzoic acid (241 mg, 1.27 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (479 mg, 2.50 mmol) and N,N-dimethylpyridine-4-amine (28.3 mg, 232 μmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added methanol (2 mL) and 8N aqueous sodium hydroxide solution (2 mL), and the mixture was further stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL) and methanol (1 mL). This solution was washed with water (50 ml), 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane=2/98→80/20), and further purified by reversed phase silica gel column chromatography (containing 0.1% trifluoroacetic acid, water/acetonitrile=95/5→0/100). The fraction containing the object product was concentrated, and the residue was dissolved in ethyl acetate (50 mL) and methanol (10 mL). The mixture was washed with saturated aqueous sodium hydrogencarbonate solution (50 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was recrystallized from acetone and diisopropyl ether to give the title compound (139 mg, 45%) as colorless crystals.

Workup

  1. stirringthe mixture was further stirred at room temperature for 30 min
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. dissolutionthe residue was dissolved in ethyl acetate (50 mL)
  4. washThis solution was washed with water (50 ml), 0.1N hydrochloric acid (50 mL) and saturated aqueous sodium hydrogencarbonate solution (50 mL)
  5. dry with materialsuccessively, and dried over anhydrous magnesium sulfate
  6. filtrationthe insoluble material was filtered off
  7. concentrationThe filtrate was concentrated under reduced pressure
  8. customfurther purified by reversed phase silica gel column chromatography (containing 0.1% trifluoroacetic acid, water/acetonitrile=95/5→0/100)
  9. additionThe fraction containing the object product
  10. concentrationwas concentrated
  11. dissolutionthe residue was dissolved in ethyl acetate (50 mL)
  12. washThe mixture was washed with saturated aqueous sodium hydrogencarbonate solution (50 mL)
  13. dry with materialdried over anhydrous magnesium sulfate
  14. filtrationThe insoluble material was filtered off
  15. concentrationthe filtrate was concentrated
  16. customThe obtained residue was recrystallized from acetone and diisopropyl ether

Sources & evidence

ORD record
ord-77529afe668049b7b87e7c6b709a97cb
Source dataset
uspto-grants-2012_12
Patent number
US08324395B2

Reaction notes

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