Acetamide → 2-Amino-6-chloronicotinic acid

HRID 1171193Notes

Reaction equation

HRID 1171193 reaction equation
Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([NH2:15])(=O)C.C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC.Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cu]Cl.C(OCC)(=O)C.O.C1(C)C(C)=CC=CC=1>[NH2:15][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]

Participants

11

Reactant 6

HCID 178AcetamideHCID 311Citric AcidHCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 112414Ethanamine, 2-(2-methoxyethoxy)-N,N-bis[2-(2-methoxyethoxy)ethyl]-HCID 8540472,6-Dichloronicotinic acid

Product 1

HCID 122639922-Amino-6-chloronicotinic acidYield 4.5%

Reagents, catalysts & solvents 4

HCID 62652Cuprous chlorideCatalyst2×HCID 962WaterSolventHCID 7237O-XyleneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
145 °C

Procedure

To a mixture of 2,6-dichloronicotinic acid (40 g (purity: 90%), 0.19 mol), acetoamide (80 g, 1.4 mol), potassium carbonate (78 g, 0.56 mol), copper (I) chloride (0.93 g, 9.4 mmol) and xylene (80 mL) was added tris(2-(2-methoxyethoxy)ethyl)amine (3.0 mL, 9.4 mmol), which was stirred overnight at 145° C. After allowing to cool on standing, to the reaction mixture was added copper (I) chloride (0.46 g, 4.6 mmol), followed by stirring overnight at 145° C. After cooling the reaction mixture to 105° C., water (100 mL) was added followed by stirring for 1 hour at the same temperature and allowing to cool to room temperature on standing. After neutralizing the reaction mixture with 5 N hydrochloric acid (150 mL) and aqueous citric acid, ethyl acetate was added. This mixture was filtered through Celite. After separating the organic phase and washing with sat. NaCl, the solvent was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from an ethyl acetate-hexane system to obtain the title compound (1.4 g, 8.3 mmol, 4.5%) as white crystals.

Workup

  1. temperatureto cool
  2. stirringby stirring overnight at 145° C
  3. temperatureAfter cooling the reaction mixture to 105° C.
  4. stirringby stirring for 1 hour at the same temperature
  5. temperatureto cool to room temperature
  6. additionwas added
  7. filtrationThis mixture was filtered through Celite
  8. customAfter separating the organic phase
  9. washwashing with sat. NaCl
  10. concentrationthe solvent was concentrated under a reduced pressure
  11. customThe residue was purified by silica gel column chromatography (ethyl acetate)
  12. customrecrystallized from an ethyl acetate-hexane system

Sources & evidence

ORD record
ord-70a9ff027a3b4184b0879952e39950d0
Source dataset
uspto-grants-2010_11
Patent number
US07829585B2

Reaction notes

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