Synthesis 2009(9): 1428-1430  
DOI: 10.1055/s-0028-1088041
SHORTPAPER
© Georg Thieme Verlag Stuttgart ˙ New York

An Improved Synthesis of (4-{4-Hydroxy-3-isopropyl-5-[(4-nitrophenyl)ethynyl]benzyl}-3,5-dimethylphenoxy)acetic Acid (NH-3)

Madathil B. Gopinathan, Kenneth S. Rehder*
RTI International, Center for Organic and Medicinal Chemistry, Research Triangle Park, NC 27709-2194, USA
Fax: +1(919)5418868; e-Mail: [email protected];
Further Information

Publication History

Received 4 November 2008
Publication Date:
25 March 2009 (online)

Abstract

Sonogashira coupling of methyl {4-[3-iodo-5-isopropyl-4-(methoxymethoxy)benzyl]-3,5-dimethylphenoxy}acetate with (trimethylsilyl)acetylene afforded the corresponding (trimethylsilyl)ethynyl derivative in quantitative yield. Copper-free palladium-catalyzed coupling of this intermediate with 1-iodo-4-nitrobenzene afforded methyl (4-{3-isopropyl-4-(methoxymethoxy)-5-[(4-nitrophenyl)ethynyl]benzyl}-3,5-dimethylphenoxy)acetate in high yield. Saponification of the ester group, followed by the removal of the methoxymethyl group afforded (4-{4-hydroxy-3-isopropyl-5-[(4-nitrophenyl)ethynyl]benzyl}-3,5-dimethylphenoxy)acetic acid (NH-3).

    References

  • 1 Lazar MA. Endocr. Rev.  1993,  14:  184 
  • 2a Koehler K. Gordon S. Brandt P. Carlsson B. Backsbro-Saeidi A. Apelqvist T. Agback P. Grover GJ. Nelsson W. Grynfarb M. Farnegardh M. Rehnmark S. Malm J. J. Med. Chem.  2006,  49:  4635 
  • 2b Malm J. Gordon S. Brandt P. Carlsson B. Agback P. Saeidi AB. Sandberg J. Bioorg. Med. Chem. Lett.  2007,  17:  2018 
  • 3 Lim W. Nguyen NH. Yang HY. Scanlan TS. Furlow JD. J. Biol. Chem.  2002,  277:  35664 
  • 4 Grover GJ. Dunn C. Nguyen NH. Boulet J. Dong G. Domogauer J. Barbounis P. Scanlan TS. J. Pharmacol. Exp. Ther.  2007,  322:  385 
  • 5 Nguyen NH. Apriletti JW. Cunha Lima ST. Webb P. Baxter JD. Scanlan TS. J. Med. Chem.  2002,  45:  3310 
  • 6 Nguyen NH. Apriletti JW. Baxter JD. Scanlan TS. J. Am. Chem. Soc.  2005,  127:  4599 
  • 7 Takahashi S. Kuroyama Y. Sonogashira K. Hagihara N. Synthesis  1980,  627 
8

The spectral properties of the impurity were suggestive of a substituted benzofuran, but this was not verified.