Phosphorus oxychloride → Ethyl 4-chloro-6-methoxyquinoline-3-carboxylate

HRID 747486Notes

Reaction equation

HRID 747486 reaction equation
P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1>>[Cl:3][C:22]1[C:10]2[C:11](=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=2)[N:14]=[CH:15][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]

Participants

3

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 6189812-((4-Methoxy-phenylamino)-methylene)-malonic acid diethyl ester

Product 1

HCID 304558Ethyl 4-chloro-6-methoxyquinoline-3-carboxylateYield 61.2%

Conditions

Temperature
97.5 °C

Procedure

132 g of phosphoryl chloride are added, at 25° C., to 50 g of diethyl 2-[(4-methoxyphenylamino)methylene]malonate. The reaction medium is stirred for 15 minutes at this temperature, heated to 95-100° C. over 45 minutes, and then kept at this temperature for 4 hours. The excess phosphoryl chloride is then removed by heating at 125° C. for approximately 2 hours. The mixture is then cooled to 25° C. and 125 ml of dichloromethane are added. The medium is then stirred at 25° C. for 1 hour, and then run into 900 ml of water, over 30 minutes, while maintaining the temperature below 30° C. The pH is then adjusted to 7.5-8 by adding 172 g of a 47% sodium hydroxide solution, while maintaining the temperature at 20-25° C. The 2 phases are separated and the aqueous phase is extracted with dichloromethane. The organic phases are pooled and washed with water. The dichloromethane phase is half-concentrated and 190 ml of ethanol are added. The concentration is continued until the temperature of the reaction mass reaches 82° C. and the vapor temperature reaches 78° C. The reaction mass is cooled to 0-5° C. and then kept at this temperature for 2 hours. The precipitate is filtered off, washed with cold ethanol, and then dried at 50° C. under reduced pressure. 27.7 g (61%) of 4-chloro-3-ethoxycarbonyl-6-methoxyquinoline are obtained in the form of a yellow solid which melts at 93.7-95.7° C.

Workup

  1. waitkept at this temperature for 4 hours
  2. customThe excess phosphoryl chloride is then removed
  3. temperatureby heating at 125° C. for approximately 2 hours
  4. temperatureThe mixture is then cooled to 25° C.
  5. addition125 ml of dichloromethane are added
  6. stirringThe medium is then stirred at 25° C. for 1 hour
  7. waitrun into 900 ml of water, over 30 minutes
  8. temperaturewhile maintaining the temperature below 30° C
  9. additionby adding 172 g of a 47% sodium hydroxide solution
  10. temperaturewhile maintaining the temperature at 20-25° C
  11. customThe 2 phases are separated
  12. extractionthe aqueous phase is extracted with dichloromethane
  13. washwashed with water
  14. concentrationThe dichloromethane phase is half-concentrated
  15. addition190 ml of ethanol are added
  16. concentrationThe concentration
  17. customreaches 82° C.
  18. customreaches 78° C
  19. temperatureThe reaction mass is cooled to 0-5° C.
  20. waitkept at this temperature for 2 hours
  21. filtrationThe precipitate is filtered off
  22. washwashed with cold ethanol
  23. customdried at 50° C. under reduced pressure

Sources & evidence

ORD record
ord-6b10004b0c894d758ed8cb088cfaf2a8
Source dataset
uspto-grants-2008_07
Patent number
US07396934B2

Reaction notes

Loading…