Phosphorus oxychloride → 4-Chloro-6,7-dimethoxyquinoline

HRID 2201892Notes

Reaction equation

HRID 2201892 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2O.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychloride2×HCID 178486804HCID 178486804, compound

Product 1

HCID 4596104-Chloro-6,7-dimethoxyquinolineYield 69.5%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
60 °C

Procedure

A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60° C. and phosphorus oxychloride (POCl3, 130.6 kg) was added. After the addition of POCl3, the temperature of the reaction mixture was raised to approximately 77° C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7° C. and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26% NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25° C., and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to −20 to −25° C. and held for 2.5 hours resulting in solid precipitate, which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25° C. under nitrogen to afford the title compound (35.6 kg).

Workup

  1. temperaturethe temperature of the reaction mixture was raised to approximately 77° C
  2. temperatureThe reaction mixture was cooled to approximately 2 to 7° C.
  3. customquenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26% NH4OH (251.3 kg), and water (900 L)
  4. temperatureThe resulting mixture was warmed to approximately 20 to 25° C.
  5. customphases were separated
  6. filtrationThe organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg)
  7. washthe filter bed was washed with DCM (118.9 kg)
  8. washThe combined organic phase was washed with brine (282.9 kg)
  9. additionmixed with water (120 L)
  10. customThe phases were separated
  11. concentrationthe organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume)
  12. additionDCM (686.5 kg) was charged to the reactor
  13. additioncontaining organic phase
  14. concentrationconcentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume)
  15. additionMethyl t-butyl ether (MTBE, 226.0 kg) was then charged
  16. customwas adjusted to −20 to −25° C.
  17. customresulting in solid precipitate, which
  18. filtrationwas then filtered
  19. washwashed with n-heptane (92.0 kg)
  20. customdried on
  21. filtrationa filter at approximately 25° C. under nitrogen

Sources & evidence

ORD record
ord-f1c0c7a73c234f6ca2e2a9a5266fddb6
Source dataset
uspto-grants-2016_06
Patent number
US09365516B2

Reaction notes

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