Citric Acid → 1403960-81-5

HRID 1424748Notes

Reaction equation

HRID 1424748 reaction equation
[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]([OH:31])(=[O:30])[CH2:20][C:21]([CH2:26][C:27]([OH:29])=[O:28])([C:23]([OH:25])=[O:24])[OH:22]>C(OCC)(=O)C.CO>[C:19]([OH:31])(=[O:30])[CH2:20][C:21]([CH2:26][C:27]([OH:29])=[O:28])([C:23]([OH:25])=[O:24])[OH:22].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1

Participants

5

Reactant 2

HCID 311Citric AcidHCID 82148Agomelatine

Product 1

HCID 665744421403960-81-5

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

100 g N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide was slurried in 400 ml ethyl acetate at room temperature and heated to reflux to dissolve the entire solid. The solution was cooled to 60° C. and a solution of 78.9 g anhydrous citric acid dissolved in 300 ml methanol was added. The solution was concentrated by distillation to approximately half its volume then cooled to a temperature in the range 2-5° C. and 140 mg of seed crystals prepared by evaporation of a methanolic solution of agomelatine and citric acid were added. Precipitation was observed and a thick white slurry was formed during stirring for 1 hour. The white solid was isolated by filtration and washed with 100 ml ethyl acetate, the final yield of dry material was 97 g (54%) and the purity of agomelatin in the solid was 99.6% with no impurities above 0.4% by UPLC. The isolated solid gave the XRPD pattern shown in FIG. 1, the DSC thermograph shown in FIG. 2 with an onset of melting of approximately 123.5° C. and the Raman spectrum shown in FIG. 3.

Workup

  1. temperatureheated
  2. temperatureto reflux
  3. dissolutionto dissolve the entire solid
  4. additionwas added
  5. concentrationThe solution was concentrated by distillation to approximately half its volume
  6. temperaturethen cooled to a temperature in the range 2-5° C. and 140 mg of seed crystals
  7. customprepared by evaporation of a methanolic solution of agomelatine and citric acid
  8. additionwere added
  9. customPrecipitation
  10. customa thick white slurry was formed
  11. customThe white solid was isolated by filtration
  12. washwashed with 100 ml ethyl acetate
  13. customThe isolated solid gave the XRPD pattern
  14. customof melting of approximately 123.5° C.

Sources & evidence

ORD record
ord-afcc5a1ed5e34de38982c05ccfc0d44a
Source dataset
uspto-grants-2015_01
Patent number
US08927771B2

Reaction notes

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