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Synthesis 2013; 45(11): 1534-1540
DOI: 10.1055/s-0033-1338467
paper
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (2-{4-[4-Fluoro-3-(trifluoromethyl)phenyl]-2-piperidin-4-yl-1H-imidazol-1-yl}ethyl)dimethylamine

Radhe K. Vaid*
a   Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA   Fax: +1(317)2764507   Email: vaid_radhe_k@lilly.com
,
Sathish Boini
a   Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA   Fax: +1(317)2764507   Email: vaid_radhe_k@lilly.com
,
Jeremy T. Spitler
a   Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA   Fax: +1(317)2764507   Email: vaid_radhe_k@lilly.com
,
Yangwei John Pu
a   Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA   Fax: +1(317)2764507   Email: vaid_radhe_k@lilly.com
,
Scott A. May
a   Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA   Fax: +1(317)2764507   Email: vaid_radhe_k@lilly.com
,
Hannah Yu
a   Chemical Product Research and Development, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA   Fax: +1(317)2764507   Email: vaid_radhe_k@lilly.com
,
Wu Sizhong
b   Shanghai PharmExplorer, Shanghai, 20120, P. R. of China
,
Jie Fu
b   Shanghai PharmExplorer, Shanghai, 20120, P. R. of China
,
Guoliang Zhang
b   Shanghai PharmExplorer, Shanghai, 20120, P. R. of China
› Author Affiliations
Further Information

Publication History

Received: 01 February 2013

Accepted after revision: 25 March 2013

Publication Date:
16 April 2013 (online)

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Abstract

An efficient eight-step synthesis of the title compound, starting from oxoacetic acid monohydrate, was developed. Condensation of oxoacetic acid monohydrate with N,N-dimethylethanamine followed by reductive amination and protection gave N-(tert-butoxycarbonyl)-N-[2-(dimethylamino)ethyl]glycine. Activation of this intermediate with 1,1′-carbonylbis-1H-imidazole followed by treatment with (methoxyamino)methane gave tert-butyl [2-(dimethylamino)ethyl]{2-[methoxy(methyl)amino]-2-oxoethyl}carba­mate, which upon reaction with [4-fluoro-3-(trifluoromethyl)phenyl]magnesium bromide, generated in situ, and subsequent deprotection gave 2-{[2-(dimethylamino)ethyl]amino}-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone dihydrochloride. Coupling of this diamine with an activated carboxylic acid gave tert-butyl 4-{1-[2-(dimethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-imidazol-2-yl}piperidine-1-carboxylate, which on treatment with sodium acetate in ethanol followed by deprotection in situ and neutralization gave the title compound in good yield.

Key words

alkylation - heterocycles - imidazoles

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    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synthesis.
  • Supporting Information
 

  • 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 O, Karaburun NG, Işikdağ 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, Shah B, Whilton D, Morgan l, Patel T, Chung R, Desmond D, Staddon JM, Sato N, Inoue A. Bioorg. Med. Chem. Lett. 2005; 15: 4666
    Crossref
  • 5 Laufer SA, Zimmermann W, Ruff KJ. J. Med. Chem. 2004; 47: 6311
    Crossref
  • 6 Black JW, Durant GI, Emmett JC, Ganellin CR. Nature (London) 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, De Lombaert 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 Dally RD, Joseph S, Shepherd TA. US 2010120801, 2010
  • 12 Vaid RK, Spitler J, Boini S, Henry K, Jiansheng X, Gao B, Lu X. Synthesis 2012; 44: 2231
    Article in Thieme Connect
  • 13 Blackaby WP, Goodacre SC, Hallett DJ, Jennings A, Lewis RT, Street LJ, Wilson K. US 2004192692, 2004
  • 14 Gajda T, Zwierzak A. Synthesis 1981; 1005
    Article in Thieme Connect
  • 15 Brehme R. Synthesis 1976; 1005
  • 16 Koziara A, Zawadzki S, Zwierzak A. Synthesis 1979; 527
    Article in Thieme Connect
  • 17 Emmons GT, Kongsamut S, Karson CN, Legoff CM. US 2008138413, 2008
  • 18 Guillemont JE. G, Motte MM. S, Andries KJ. L, Koul A. WO 200868269, 2008
  • 19 May SA, Johnson MD, Braden TM, Calvin JR, Haeberle BD, Jines AR, Miller RD, Plocharczyk E, Rener GA, Richey RN, Schmid CR, Vaid RK, Yu H. Org. Process Res. Dev. 2012; 16: 982
    Crossref