Hydrochloric Acid → 2-Chloro-N-cyclopropyl-4-[3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)-prop-1-yn-1-yl]benzamide

HRID 339125

Reaction equation

HRID 339125 reaction equation
[Cl:1][C:2]1[CH:13]=[C:12](I)[CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5].[C:15]([OH:19])(=O)[C:16]#[CH:17].C(NC(C)C)(C)C.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[F:46][C:47]([F:61])([F:60])[CH:48]([C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=1)[NH2:49].Cl>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:13]=[C:12]([C:17]#[C:16][C:15](=[O:19])[NH:49][CH:48]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:57])([F:58])[F:59])[CH:51]=2)[C:47]([F:61])([F:60])[F:46])[CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH:7]1[CH2:9][CH2:8]1)=[O:5]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 7912DiisopropylamineHCID 10110Propiolic AcidHCID 231494114-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrateHCID 438251722,2,2-Trifluoro-1-(3-(trifluoromethyl)phenyl)ethanamineHCID 582479432-chloro-N-cyclopropyl-4-iodobenzamide

Product 1

HCID 582479322-Chloro-N-cyclopropyl-4-[3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)-prop-1-yn-1-yl]benzamide

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

2-Chloro-N-cyclopropyl-4-iodobenzamide (1.0 g, 3.11 mmol) and propiolic acid (222 mg, 3.11 mmol) were dissolved in N,N-dimethylformamide (1.2 ml) and cooled to 0° C. Then bis(triphenylphosphine)palladium(II) dichloride (43 mg, 0.06 mmol) and copper(I) iodide (23 mg, 0.12 mmol) were added and the mixture was cooled to −10° C. After addition of diisopropylamine (786 mg, 7.77 mmol), the mixture was warmed slowly to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed successively with hydrochloric acid (2 M) and saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 ml) and admixed with 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (973 mg, 3.52 mmol) and 2,2,2-trifluoro-1-[3-trifluoromethylphenyl]ethanamine (780 mg, 3.20 mmol) and stirred at room temperature overnight. The reaction solution was admixed with hydrochloric acid (1 M) and extracted with ethyl acetate. The organic phase was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure. The residue was purified by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% EA to 40% EA).

Workup

  1. temperaturethe mixture was cooled to −10° C
  2. temperaturethe mixture was warmed slowly to room temperature
  3. washwashed successively with hydrochloric acid (2 M) and saturated sodium chloride solution
  4. dry with materialdried over magnesium sulphate
  5. filtrationfiltered
  6. concentrationconcentrated to dryness under reduced pressure
  7. dissolutionThe residue was dissolved in N,N-dimethylformamide (1 ml)
  8. stirringstirred at room temperature overnight
  9. extractionextracted with ethyl acetate
  10. washThe organic phase was washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution
  11. dry with materialdried over sodium sulphate
  12. filtrationfiltered
  13. concentrationconcentrated to dryness under reduced pressure
  14. customThe residue was purified by means of silica gel chromatography with the eluent cyclohexane/ethyl acetate (EA) (0% EA to 40% EA)

Sources & evidence

ORD record
ord-0e70a4397434488785954eefe2989417
Source dataset
uspto-grants-2014_11
Patent number
US08889878B2

Linked notes

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