N-Ethylaniline → Laquinimod

HRID 1470324Notes

Reaction equation

HRID 1470324 reaction equation
[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.[CH2:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:19].ClP(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:19][CH2:18][N:20]([C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:12])[C:11]=2[C:2]=1[OH:1])=[O:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1

Participants

5

Reactant 3

HCID 7670N-EthylanilineHCID 260420Triphenylphosphine dichlorideHCID 547202275-Chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

Product 1

HCID 54677946LaquinimodYield 71.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
27.5 °C

Procedure

1,2-Dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (2 gm) and N-ethyl aniline (1 gm) were taken in toluene (50 ml) and stirred for 30 minutes at 25-30° C. under nitrogen atmosphere. The resulting mass was followed by the addition of dichlorotriphenyl phosphorane (10.5 gm) at 25-30° C., followed by heating to reflux (110-115° C.) and then maintained for 3 hours at reflux. Toluene was distilled out from the reaction mass under vacuum at below 60° C. The resulting residue was dissolved in ethyl acetate (100 ml) at 25-30° C. followed by the addition of water (100 ml) at 25-30° C. and then pH of the resulting mass was adjusted to 10-12 with 10% sodium hydroxide solution at 25-30° C. The resulting mass was stirred for 30 minutes at 20-25° C. followed by separation of the layers. The resulting aqueous layer was cooled to 15-20° C. and pH was adjusted to 2 by using concentrated hydrochloric acid. The resulting mass was stirred for 30 minutes at 15-20° C. The separated solid was filtered, washed with water and then dried to yield 2 gm of laquinimod (HPLC purity: 98.4%).

Workup

  1. temperatureby heating
  2. temperatureto reflux (110-115° C.)
  3. temperaturemaintained for 3 hours
  4. temperatureat reflux
  5. distillationToluene was distilled out from the reaction mass under vacuum at below 60° C
  6. dissolutionThe resulting residue was dissolved in ethyl acetate (100 ml) at 25-30° C.
  7. additionfollowed by the addition of water (100 ml) at 25-30° C.
  8. customwas adjusted to 10-12 with 10% sodium hydroxide solution at 25-30° C
  9. stirringThe resulting mass was stirred for 30 minutes at 20-25° C.
  10. customfollowed by separation of the layers
  11. temperatureThe resulting aqueous layer was cooled to 15-20° C.
  12. stirringThe resulting mass was stirred for 30 minutes at 15-20° C
  13. filtrationThe separated solid was filtered
  14. washwashed with water
  15. customdried

Sources & evidence

ORD record
ord-2a83de80a734470889082629df47421b
Source dataset
uspto-grants-2015_04
Patent number
US09006443B2

Reaction notes

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