N-Ethylaniline → Laquinimod

HRID 1039623Notes

Reaction equation

HRID 1039623 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.C(N(C(C)C)CC)(C)C.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28].S(Cl)(Cl)=O>C(Cl)Cl>[CH3:28][CH2:27][N:29]([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:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1

Participants

6

Reactant 4

HCID 7670N-EthylanilineHCID 24386Thionyl ChlorideHCID 81531DiisopropylethylamineHCID 547202275-Chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid

Product 1

HCID 54677946LaquinimodYield 91.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
7.5 °C

Procedure

The mixture of 1,2-dihydro-4-hydroxy-5-chloro- 1 -methyl-2-oxo-quinoline-3-carboxylic acid (15 gm) and methylene chloride (105 ml) was cooled to 5-10° C. under nitrogen atmosphere. Diisopropylethyl amine (26.7 gm) was added to the resulting mass for 5 minutes at 5-10° C. to form a clear solution. The solution was followed by the addition of N-ethyl aniline (7.8 gm) in one portion at 5-10° C. and then thionyl chloride (9.1 gm) was added at 5-10° C. The resulting mixture was stirred for 7 hours followed by evaporation of methylene chloride under vacuum. The resulting residue was dissolved in ethyl acetate (200 ml) followed by washings with 5% sodium hydroxide solution (65 ml) at 25-30° C. The resulting aqueous layer was cooled to 10-15° C. followed by adjusting pH of the mass to 1 by using 18% aqueous hydrochloric acid solution (25 ml). The resulting mass was stirred for 1 hour at 10-15° C. The separated white colored solid was filtered and dried at 55-60° C. to yield 19.3 gm of laquinimod (HPLC Purity: 98.41%).

Workup

  1. customto form a clear solution
  2. customfollowed by evaporation of methylene chloride under vacuum
  3. dissolutionThe resulting residue was dissolved in ethyl acetate (200 ml)
  4. washfollowed by washings with 5% sodium hydroxide solution (65 ml) at 25-30° C
  5. temperatureThe resulting aqueous layer was cooled to 10-15° C.
  6. stirringThe resulting mass was stirred for 1 hour at 10-15° C
  7. filtrationThe separated white colored solid was filtered
  8. customdried at 55-60° C.

Sources & evidence

ORD record
ord-6d451926ee7647ca99168653fefbc5ae
Source dataset
uspto-grants-2013_10
Patent number
US08552194B2

Reaction notes

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