Synthesis 2011(1): 79-82  
DOI: 10.1055/s-0030-1258968
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Novel Synthesis of the Antidepressant Agomelatine

Christian Markla, Darius P. Zlotos*b
a Institute of Pharmacy and Food Chemistry, Pharmaceutical Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
b The German University in Cairo, Department of Pharmaceutical Chemistry, New Cairo City, Al-Tagamoa Al Khames, 11835 Cairo, Egypt
Fax: +20(2)27581041; e-Mail: darius.zlotos@guc.edu.eg ;
Further Information

Publication History

Received 31 August 2010
Publication Date:
09 November 2010 (eFirst)

Abstract

Agomelatine was synthesized from (2-methoxynaphthalene-8-yl)oxoacetic acid in a four-step approach involving borane reduction, semipinacol rearrangement of the resulting diol, ald­oxime formation, and Ra-Ni hydrogenation/acetylation in 51% overall yield. The reaction sequence includes a novel one-pot conversion of an aldoxime into an N-acetylamine. The synthetic route could be useful as a new approach towards N-acetylarylethyl­amines.

    References

  • 1 De Bodinat C. Guardiola-Lemaitre B. Mocaer E. Renard P. Munoz C. Millan MJ. Nat. Rev. Drug Discovery  2010,  9:  628 
  • 2a Tang J.-D. Cen J.-D. Org. Prep. Proced. Int.  2009,  41:  164 
  • 2b Silverman IR. Daub GH. VanderJagt DL. J. Org. Chem.  1985,  50:  5550 
  • 3 Yous S. Andrieux J. Howell HE. Morgan PJ. Renard P. Pfeiffer B. Lesieur D. Guardiola-Lemaitre B. J. Med. Chem.  1992,  35:  1484 
  • 4a Zhou S, and Jian F. inventors; Faming Zhuanli Shenqing CN  101759591.  2010; Chem. Abstr. 2010, 153, 174638
  • 4b Hu W, Xu Q, and Yang L. inventors; Faming Zhuanli Shenqing CN  101792400.  2010; Chem. Abstr. 2010, 153, 310977
  • 4c Zhang Z, Li P, Xu J, Chen L, and Lu W. inventors; Faming Zhuanli Shenqing Gongkai Shuomingshu CN  101735091.  2010; Chem. Abstr. 2010, 153, 87525
  • 4d Hardouin C, Lecouve J.-P, and Bragnier N. inventors; PCT Int. Appl. WO  2010015745.  2010; Chem. Abstr, 2010, 152, 238612
  • 4e Bontempelli P, Jalenques X, Starck J.-B, and Sery J.-P. inventors; PCT Int. Appl. WO  2010015744.  2010; Chem. Abstr, 2010, 152, 238611
  • 4f Dubuffet T, Lecouve J.-P, and Hermet J.-P. inventors; PCT Int. Appl. WO  2009053545.  2009; Chem. Abstr. 2009, 150, 447581
  • 4g Dubuffet T, Lecouve J.-P, and Hermet J.-P. inventors; Fr. Demande FR  2919606.  2009; Chem. Abstr. 2009, 150, 191168
  • 4h Souvie J.-C, Blanco IG, Thominot G, Chapuis G, Horvath St, and Damien G. inventors; Patent US  2008004352.  2008; Chem. Abstr. 2008, 148, 100395
  • 4i Souvie J.-C, Blanco IG, Thominot G, Chapuis G, Horvath St, and Damien G. inventors; Eur. Pat. Appl. EP  1564202.  2008; Chem. Abstr. 2008, 143, 193816
  • 4j Poissonnier-Durieux S. Ettaoussi M. Peres B. Boutin J.-A. Audinot V. Bennejean C. Delagrange P. Caignard D.-H. Renard P. Berthelot P. Lesieur D. Yous S. Bioorg. Med. Chem.  1998,  16:  8339 
  • 5 Hardouin C, and Lecouve J.-P. inventors; PCT Int. Appl. WO  2010015746.  2010; Chem. Abstr. 2010, 152, 238613
  • 6 Buehrdel G. Beckert R. Petrlikova E. Herzigova P. Klimesova V. Fleischhauer J. Goerls H. Synthesis  2010,  3071 
  • 7 Staudinger H. Goldstein H. Schlenker E. Helv. Chim. Acta  1921,  6:  342 
  • 8 Gottlieb L. Kellner D. Loewenthal HJE. Synth. Commun.  1989,  19:  2987 
  • 9 Naves YR. Helv. Chim. Acta  1967,  50:  319 
  • 10 Gottlieb L. Hassner A. Gottlieb HE. Synth. Commun.  2000,  14:  2445 
  • 11 Spadoni G. Bedini A. Guidi T. Tarzia G. Lucini V. Pannacci M. Fraschini F. ChemMedChem  2006,  1:  1099