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Synthesis 2012; 44(14): 2231-2236
DOI: 10.1055/s-0031-1290371
paper
© Georg Thieme Verlag Stuttgart · New York

A Practical Synthesis of 2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-(piperidin-4-yl)-1H-imidazol-1-yl}-N,N-dimethylethanamine

Radhe K. Vaid*
a   Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
,
Jeremy Spitler
a   Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
,
Sathish Boini
a   Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
,
Kenneth Henry
b   Discovery Chemistry Research and Technologies, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
,
Xu Jiansheng
c   Shanghai PharmaExplorer, Shanghai 20120, P. R. of China, Fax: +1(317)2764507   Email: vaid_radhe_k@lilly.com
,
Baitao Gao
c   Shanghai PharmaExplorer, Shanghai 20120, P. R. of China, Fax: +1(317)2764507   Email: vaid_radhe_k@lilly.com
,
Xiaoquan Lu
c   Shanghai PharmaExplorer, Shanghai 20120, P. R. of China, Fax: +1(317)2764507   Email: vaid_radhe_k@lilly.com
› Author Affiliations
Further Information

Publication History

Received: 16 March 2012

Accepted after revision: 26 April 2012

Publication Date:
13 June 2012 (online)

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Abstract

A practical synthesis of the title compound was accomplished by hydrogenation of 2-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-(pyridin-4-yl)-1H-imidazol-1-yl}-N,N-dimethylethanamine. The latter was obtained by N-alkylation of 4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}pyridine. Treatment of N-{2-[4-fluoro-3-(trifluoromethyl)phenyl]-2-oxoethyl}isonicotinamide hydrochloride with ammonium acetate in acetic acid provided 4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}pyridine. Coupling of 2-amino-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone 4-methylbenzene sulfonate with pyridine 4-carboxylic acid using either T3P or EDCI-HOBt provided N-{2-[4-fluoro-3-(trifluo­romethyl)phenyl]-2-oxoethyl}isonicotinamide hydrochloride.

Key words

imidazole - EDCI - T3P - ammonium acetate - hydrogenation
 

  • References

  • 1 Fromtling RA. Clin. Microbiol. Rev. 1988; 1: 187
  • 2 Sharpe TR, Cherfolsky SC, Hewes WE, Smith DH, Gregory WA, Haber SB, Leadbetter MR, Whitney JG. J. Med. Chem. 1985; 28: 1188
    Crossref
  • 3 Uçucu Ü, Gündoğdu N, Işikadağ I. Farmaco 2001; 56: 285
    Crossref
  • 4 Graczyk PP, Khan A, Bhatia GS, Palmer V, Medland D, Numata H, Oinuma H, Catchick J, Dunne A, Ellis M, Smales C, Whitfield J, Neame SJ, Sha B, Whilton D, Morgan L, Patel T, Chung R, Desmond D, Staddon JM, Sato N, Inoue A. Bioorg. Med. Chem. Lett. 2005; 15: 4664
  • 5 Laufer SA, Zimmermann W, Ruff J. J. Med. Chem. 2004; 47: 6311
    Crossref
  • 6 Black JW, Durant GI, Emmett JC, Ganellin CR. Nature 1974; 248: 65
    Crossref
  • 7 Srinivas N, Palne S, Nishi Gupta S, Bhandari K. Bioorg. Med. Chem. Lett. 2009; 19: 324
    Crossref
  • 8 Kiselyov AS, Semenova M, Semenov VV. Bioorg. Med. Chem. Lett. 2006; 16: 1440
    Crossref
  • 9 Blum CA, Zheng X, DeLombaert S. J. Med. Chem. 2004; 47: 2318
    Crossref

      • For leading references, see:
    • 10a Jin Z. Nat. Prod. Rep. 2009; 26: 382
      Crossref
    • 10b Jin Z. Nat. Prod. Rep. 2006; 23: 464
      CrossrefPubMed
    • 10c Jin Z. Nat. Prod. Rep. 2005; 22: 196
      Crossref
    • 10d Cui B, Zheng BL, He K, Zheng QY. J. Nat. Prod. 2003; 66: 1101
      CrossrefPubMed
  • 11 Shepherd TA, Dally RD, Joseph S. US Patent 120801 A1, 2010
    • 12a Bellina F, Rossi R. Adv. Synth. Catal. 2010; 352: 1 ; and references cited therein
      Crossref
    • 12b Zuliana V, Cocconcelli G, Fantini M, Ghiron C, Rivara M. J. Org. Chem. 2007; 72: 4551
      Crossref
  • 13 Jennings LD, Foreman KW, Rush TS, Tsao DH. H, Mosyak L, Kincaid SL, Sukhdeo MN, Sutherland AG, Ding W, Kenny CH, Sabus CL, Liu H, Dushhin EG, Moghazeh SL, Labthavikul P, Peterse PJ, Tuckman M, Ruzin AV. Bioorg. Med. Chem. 2004; 12: 5115
    Crossref
  • 14 Phillips JG, Jaworska M, Lew W. Synthesis 2010; 71