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Synthesis 2007(14): 2121-2124  
DOI: 10.1055/s-2007-983754
PAPER
© Georg Thieme Verlag Stuttgart · New York

An Efficient Synthesis of Nilotinib (AMN107)

Wei-Sheng Huang*, William C. Shakespeare
ARIAD Pharmaceuticals, 26 Landsdowne Street, Cambridge, MA 02139, USA
Fax: +1(617)4948144; e-Mail: wei-sheng.huang@ariad.com;
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Publikationsverlauf

Received 18 January 2007
Publikationsdatum:
03. Juli 2007 (online)

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Abstract

A concise synthesis of AMN107, a compound currently undergoing several phase II/III clinical trials for chronic myelogenous leukemia is described. The new procedure reduces the number of synthetic steps from eight to four, with an overall yield of 65%.

Key words

AMN107 - Abl kinase inhibitor - Cu-catalyzed N-arylation - Pd-catalyzed N-arylation - atom economy

    References

  • 1 Capdeville R. Buchdunger E. Zimmermann J. Matter A. Nat. Rev. Drug Discovery  2002,  1:  493 
    CrossrefSuche in Google Scholar
  • 2a Weisberg E. Manley PW. Breitenstein W. Brueggen J. Cowan-Jacob SW. Ray A. Huntly B. Fabbro D. Fendrich G. Hall-Meyers E. Kung AL. Mestan J. Daley GQ. Callahan L. Catley L. Cavazza C. Mohammed A. Neuberg D. Wright RD. Gilliland DG. Griffin JD. Cancer Cell  2005,  7:  129 
    CrossrefSuche in Google Scholar
  • 2b O’Hare T. Walters DK. Deininger MWN. Druker BJ. Cancer Cell  2005,  7:  117 
    CrossrefSuche in Google Scholar
  • 2c Doggrell SA. Exp. Opin. Invest. Drugs  2005,  14:  1063 
    CrossrefSuche in Google Scholar
  • 2d Manley PW. Cowan-Jacob SW. Mestan J. Biochim. Biophy. Acta, Proteins and Proteomics  2005,  3:  1754 
    CrossrefSuche in Google Scholar
  • 2e Walz C. Sattler M. Crit. Rev. Oncol. Hematol.  2006,  57:  145 
    CrossrefSuche in Google Scholar
  • 2f O’Hare T. Corbin AS. Druker BJ. Curr. Opin. Genet. Dev.  2006,  16:  92 
    CrossrefSuche in Google Scholar
  • 2g Kantarjian H. Giles F. Wunderle L. Bhalla K. O’Brien S. Wassmann B. Tanaka C. Manley P. Rae P. Mietlowski W. Bochinski K. Hochhaus A. Griffin JD. Hoelzer D. Albitar M. Dugan M. Cortes J. Alland L. Ottmann OG. N. Engl. J. Med.  2006,  354:  2542 
    CrossrefSuche in Google Scholar
  • 2h Prenen H. Guetens G. De Boeck G. Debiec-Rychter M. Manley P. Schoeffski P. Van Oosterom AT. De Bruijn E. Pharmacology  2006,  77:  11 
    CrossrefSuche in Google Scholar
  • 3a Azam M. Nardi V. Shakespeare WC. Metcalf CA. Bohacek RS. Wang Y. Sundaramoorthi R. Sliz P. Veach DR. Bornmann WG. Clarkson B. Dalgarno DC. Sawyer TK. Daley GQ. Proc. Natl. Acad. Sci. U.S.A.  2006,  103:  9244 
    CrossrefSuche in Google Scholar
  • 3b Dalgarno D. Stehle T. Narula S. Schelling P. van Schravendijk MR. Adams S. Andrade L. Keats J. Ram M. Jin L. Grossman T. MacNeil I. Metcalf C. Shakespeare W. Wang Y. Keenan T. Sundaramoorthi R. Bohacek R. Weigele M. Sawyer T. Chem. Biol. Drug Design  2006,  67:  46 
    CrossrefSuche in Google Scholar
  • 3c Brunton VG. Avizienyte E. Fincham VJ. Serrels B. Metcalf CA. Sawyer TK. Frame MC. Cancer Res.  2005,  65:  1335 
    CrossrefSuche in Google Scholar
  • 3d O’Hare T. Walters DK. Stoffregen EP. Sherbenou DW. Heinrich MC. Deininger MWN. Druker BJ. Clin. Cancer Res.  2005,  11:  6987 
    CrossrefSuche in Google Scholar
  • 3e Corbin AS. Demehri S. Griswold IJ. Wang Y. Metcalf CA. Sundaramoorthi R. Shakespeare WC. Snodgrass J. Wardwell S. Dalgarno D. Iuliucci J. Sawyer TK. Heinrich MC. Druker BJ. Deininger MWN. Blood  2005,  106:  227 
    CrossrefSuche in Google Scholar
  • 3f O’Hare T. Pollock R. Stoffregen EP. Keats JA. Abdullah OM. Moseson EM. Rivera VM. Tang H. Metcalf CA. Bohacek RS. Wang Y. Sundaramoorthi R. Shakespeare WC. Dalgarno D. Clackson T. Sawyer TK. Deininger MW. Druker BJ. Blood  2004,  104:  2532 
    CrossrefSuche in Google Scholar
  • 4 Breitenstein W, Furet P, Jacob S, and Manley PW. inventors; WO  2004005281.  ; Chem. Abstr. 2004, 140, 77161
  • 5a Altman RA. Buchwald SL. Org. Lett.  2006,  8:  2779 
    CrossrefSuche in Google Scholar
  • 5b Antilla JC. Baskin JM. Barder TE. Buchwald SL. J. Org. Chem.  2004,  69:  5578 
    CrossrefSuche in Google Scholar
  • 5c Zhang H. Cai Q. Ma D. J. Org. Chem.  2005,  70:  5164 
    CrossrefSuche in Google Scholar
  • 5d Cristau H.-J. Cellier PP. Spindler J.-F. Taillefer M. Chem. Eur. J.  2004,  10:  5607 
    CrossrefSuche in Google Scholar
  • 5e Kiyomori A. Marcoux J.-F. Buchwald SL. Tetrahedron Lett.  1999,  40:  2657 
    CrossrefSuche in Google Scholar
  • 6a Muci AR. Buchwald SL. Top. Curr. Chem.  2002,  219:  131 
    Suche in Google Scholar
  • 6b Hartwig JF. Handbook of Organopalladium Chemistry for Organic Synthesis   Vol. 1:  Wiley; Hoboken: 2002.  p.1051-1096  
    Suche in Google Scholar
  • 7a Zhou JC, Confalone PN, Li H.-Y, Oh LM, Rossano LT, Clark CG, and Teleha CA. inventors; WO  200208199.  ; Chem. Abstr. 2002, 136, 134674
    CrossrefPubMed
  • 7b Liu L. Frohn M. Xi N. Dominguez C. Hungate R. Reider P. J. Org. Chem.  2005,  70:  10135 
    CrossrefPubMedSuche in Google Scholar
  • 8 Mathews HR. Rapoport H. J. Am. Chem. Soc.  1973,  95:  2297 
    CrossrefSuche in Google Scholar
  • 9 Bennett GB. Mason RB. Alden LJ. Roach JB. J. Med. Chem.  1978,  21:  623 
    CrossrefSuche in Google Scholar
  • 10 Loiseleur O, Kaufmann D, Abel S, Buerger HM, Meisenbach M, Schmitz B, and Sedelmeier G. inventors; WO  2003066613. A cross-coupling of amine 5 and aryl bromide under similar conditions was known for the preparation of Gleevec: ; Chem. Abstr. 2003, 139, 180080
  • 11 Ali MH. Buchwald SL. J. Org. Chem.  2001,  66:  2560 
    CrossrefSuche in Google Scholar
  • 12 Trost BM. Science  1991,  254:  1471 
    Suche in Google Scholar
  • After this manuscript was submitted for review, we became aware that Novartis published a patent on the synthesis of AMN107 based on the amide bond formation from 1 and 3. Several synthetic approaches to 3 were also reported, which included a Cu-catalyzed coupling of 3-bromo-(5-trifluoro­-methyl)aniline and 4-methylimidazole by using cyclo-hexanediamine as the ligand:
  • 13a Abel S, Acemoglu M, Erb B, Krell C, Sclafani J, Meisenbach M, Prashad M, Shieh W.-C, and Xue S. inventors; WO 2006135640  .  , ; Chem. Abstr. 2007, 146, 81866
  • 13b Mckenna J, and Shieh W.-C. inventors; WO 2006135641  .  , ; Chem. Abstr. 2007, 146, 81883
  • In addition, after the revised manuscript was submitted, the authors became aware of two recent patents which involve Cu-catalyzed coupling of 3-bromo-(5-trifluoromethyl)-aniline and 4-methylimidazole:
  • 13c Kim D.-Y, Cho D.-J, Lee G.-Y, Kim H.-Y, Woo S.-H, Kim Y.-S, Lee S.-A, and Han B.-C. inventors; WO 2007018325  .  , ; Chem. Abstr. 2007, 146, 251858
  • 13d Mauger C, Mignani G, and Jacqot R. inventors; FR 2889524  .  , ; Chem. Abstr. 2007, 146, 229345