Ethyl Acetate → N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide

HRID 1049237Notes

Reaction equation

HRID 1049237 reaction equation
Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:20][CH2:21]OC(C)=O>CN(C=O)C.[Cu]I.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>[C:20]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1)#[CH:21]

Participants

6

Reactant 2

HCID 8857Ethyl AcetateHCID 90402585N-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide

Product 1

HCID 90403485N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamideYield 30%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
75 °C

Procedure

A solution of Example A5 (0.35 g, 1.260 mmol) in DMF (5 mL) was sparged with argon, treated with TEA (1 mL) trimethylsilylacetylene (0.531 mL, 3.78 mmol), copper(I) iodide (0.024 g, 0.126 mmol) and dichlorobis(triphenylphosphine)palladium(II) [Pd(PPh3)2Cl2](0.088 g, 0.126 mmol) and heated at 75° C. under argon for 16 h. The mixture was cooled to RT, treated with EtOAc, solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and H2O and the layers of the filtrate separated. The aqueous layer was extracted with EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The resulting material was dissolved in MeOH (20 mL), treated with K2CO3 (300 mg) and stirred at RT for 1 h. The mixture was concentrated to dryness, treated with EtOAc, sonicated, the solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (102 mg, 30%) as a light red solid. 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H); 8.40 (d, J=5.8 Hz, 1H); 8.01 (d, J=8.8 Hz, 1H); 7.60 (d, J=6.0 Hz, 1H); 7.04 (d, J=2.5 Hz, 1H); 6.89 (dd, J=5.8, 2.6 Hz, 1H); 4.34 (s, 1H); 2.22 (s, 3H); 2.07 (s, 3H); MS (ESI) m/z: 268.1 (M+H+).

Workup

  1. temperatureThe mixture was cooled to RT
  2. customremoved via filtration through diatomaceous earth
  3. washrinsed well with EtOAc and H2O
  4. customthe layers of the filtrate separated
  5. extractionThe aqueous layer was extracted with EtOAc (1×)
  6. washthe combined organics were washed with brine
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated to dryness
  9. dissolutionThe resulting material was dissolved in MeOH (20 mL)
  10. additiontreated with K2CO3 (300 mg)
  11. concentrationThe mixture was concentrated to dryness
  12. additiontreated with EtOAc
  13. customsonicated
  14. customthe solids removed via filtration through diatomaceous earth
  15. washrinsed well with EtOAc
  16. concentrationthe filtrate concentrated to dryness
  17. custompurified via silica gel chromatography (EtOAc/Hex)

Sources & evidence

ORD record
ord-13699938b4354adcb73a6794a447cf79
Source dataset
uspto-grants-2016_07
Patent number
US09382228B2

Reaction notes

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