2,5-Dichlorophenol → 2-Chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinic acid ethyl ester

HRID 1025901Notes

Reaction equation

HRID 1025901 reaction equation
[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:14])[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.[Cu]I.[Cu].C(OCC)(=O)C>[CH2:11]([O:10][C:8](=[O:9])[C:7]1[C:6]([O:23][C:17]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[Cl:15])=[CH:5][C:4]([CH3:14])=[N:3][C:2]=1[Cl:1])[CH3:12]

Participants

9

Reactant 4

HCID 662,5-DichlorophenolHCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 604813Ethyl 2,4-dichloro-6-methylnicotinate

Product 1

HCID 866869362-Chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinic acid ethyl esterYield 18%

Reagents, catalysts & solvents 4

HCID 23978CopperCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 500 mg (2.136 mmol) ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (commercially available, CAS RN 86129-63-7) in 7.5 mL dry N,N-dimethylformamide was added 366 mg (2.243 mmol) 2,5-dichlorophenol and 590 mg (4.272 mmol) potassium carbonate and 41 mg (0.214 mmol) copper(I)iodide and 41 mg (0.641 mmol) copper nanopowder (avg. particle size 100 nm). The reaction mixture was stirred at 120° C. for 18 hours and then poured on 30 ml, 1N aqueous hydrochloric acid and 30 mL ethyl acetate. The layers were separated and the aqueous layer was extracted a second time with 30 mL ethyl acetate. The combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (50:50 to 100:0) to afford 35 mg (18%) of the title compound as a light yellow oil. MS (ESI): 359.995 [M+H]+.

Workup

  1. customThe layers were separated
  2. extractionthe aqueous layer was extracted a second time with 30 mL ethyl acetate
  3. washThe combined organic layers were washed with 30 mL brine
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe residue was purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (50:50 to 100:0)

Sources & evidence

ORD record
ord-28857069a12544428f20ae35754d344f
Source dataset
uspto-grants-2014_05
Patent number
US08729091B2

Reaction notes

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