Download PDF
Synthesis 2012(2): 207-214  
DOI: 10.1055/s-0031-1289654
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Practical Synthesis of Cefcapene Pivoxil

Jian-An Jianga, Jiao-Jiao Zhaia, Xin-Hong Yua, Xin Teng*b, Ya-Fei Ji*a
a School of Pharmacy, East China University of Science and Technology, Campus P.O. Box 363, 130 Meilong Road, Shanghai 200237, P. R. of China
Fax: +86(21)64253314; e-Mail: jyf@ecust.edu.cn;
b School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, P. R. of China
e-Mail: tengxin@ecust.edu.cn;
Further Information

Publication History

Received 12 October 2011
Publication Date:
22 December 2011 (online)

    Permissions and Reprints All articles of this category

Abstract

Cefcapene pivoxil monohydrochloride monohydrate, a broad spectrum third-generation cephalosporin for oral administration, was prepared by reacting three centers of 7β-amino-3-(hydroxymethyl)cephalosporinic acid (7-HACA), derived from 7β-aminocephalosporanic acid. The coupling of 7-HACA and (Z)-2-[2-(Boc-amino)thiazol-4-yl]pent-2-enoic acid, followed by carbamylation with chlorosulfonyl isocyanate, and precipitation with diisopropylamine gave the key intermediate, in which thiazole side chain and carbamoyl group had been introduced into the 7-amino and 3-hydroxymethyl groups of 7-HACA, respectively, in a continuous procedure. Afterwards, the intermediate was esterified with pivaloyloxymethyl iodide to complete the modification of the C4 carboxy group affording Boc-cefcapene pivoxil, from which the desired product was finally obtained by an economical Boc removal and successive formation of the hydrochloride in 36% overall yield on a decagram scale. This synthesis promises an easy entry to cefcapene pivoxil monohydrochloride monohydrate with convenient manipulation, simple isolation, and good yields; it is of potential value for production on an industrial scale.

Key words

antibiotics - cephalosporins - cefcapene pivoxil - 7-ACA - carbamylation - semisynthesis

    References

  • 1a Ishikura K. Kubota T. Minami K. Hamashima Y. Nakashimizu H. Motokawa K. Kimura Y. Miwa H. Yoshida T. J. Antibiot.  1994,  47:  466 
    Search in Google Scholar
  • 1b Hwu JR. Tsay SC. Hakimelahi S. J. Med. Chem.  1998,  41:  4681 
    Search in Google Scholar
  • 1c Cazzola M. Expert Opin. Invest. Drugs  2000,  9:  237 
    Search in Google Scholar
  • 2a Kim OK. Hudyma TW. Mtiskella JD. Ueda Y. Bronson JJ. Mansuri MM. Bioorg. Med. Chem. Lett.  1997,  7:  2753 
    Search in Google Scholar
  • 2b Haddad J. Vakulenko S. Mobashery S. J. Am. Chem. Soc.  1999,  121:  11922 
    Search in Google Scholar
  • 2c Lee W. Li Z.-H. Vakulenko S. J. Med. Chem.  2000,  43:  128 
    Search in Google Scholar
  • 2d Williams DH. Bardsley B. Angew. Chem. Int. Ed.  1999,  38:  1172 
    Search in Google Scholar
  • 2e Pechere JC. J. Antimicrob. Chemother.  1999,  44 (suppl. 1):  11 
    Search in Google Scholar
  • 4a Sakata H. J. Infect. Chemother.  2008,  14:  208 
    Search in Google Scholar
  • 4b Takahashi S. Kurimura Y. Takeyama K. Hashimoto K. Miyamoto S. Ichihara K. Igarashi M. Hashimoto J. Furuya R. Hotta H. Uchida K. Miyao N. Yanase M. Takagi Y. Tachiki H. Taguchi K. Tsukamoto T. J. Infect. Chemother.  2009,  15:  390 
    Search in Google Scholar
  • 4c Fujimoto M. Int. J. Antimicrob. Agent.  2001,  18:  489 
    Search in Google Scholar
  • 4d Lee JE. Han DH. Won TB. Rhee CS. Clin. Exp. Otorhinolar.  2011,  4:  83 
    Search in Google Scholar
  • 4e Saito A. Hiraga Y. Watanabe A. Saito A. Shimada K. Kobayashi H. Odagiri S. Miki F. Soejima R. Oizumi K. Hara K. Nakashima M. J. Int. Med. Res.  2004,  32:  590 
    Search in Google Scholar
  • 5a Durckheimer W. Blumbach J. Lattrell R. Scheunemann KH. Angew. Chem., Int. Ed. Engl.  1985,  24:  180 
    Search in Google Scholar
  • 5b Ishikura K. Kubota T. Minami K. Hamashima Y. Nakashimizu H. Motokawa K. Kimura Y. Miwa H. Yoshida T. J. Antibiot.  1994,  47:  453 
    Search in Google Scholar
  • 6a Mizojiri K. Futaguchi S. Norikura R. Katsuyama Y. Nagasaki T. Yoshimori T. Nakanishi M. Antimicrob. Agents Chemother.  1995,  7:  1445 
    Search in Google Scholar
  • 6b He X. Sugawara M. Takekuma Y. Miyazaki K. Antimicrob. Agents Chemother.  2004,  48:  2604 
    Search in Google Scholar
  • 7a Hamashima Y, Ishikura K, Minami K, Kubota T, and Yoshida T. inventors; US  4731361. 
  • 7b Hamashima Y, Tsuji T, Okada T, Minami K, Ishitobi H, and Ishikura K. inventors; US  4731362. 
  • 7c Gedi S, Ramakrishna K, and Udayam-palayam PS. inventors; WO  2008155615. 
  • 8a Takaya T. Takasugi H. Murakawa T. Nakano H. J. Antibiot.  1981,  34:  1300 
    Search in Google Scholar
  • 8b Gonzalez R. Rodriguez Z. Tolon B. Rodriguez JC. Velez H. Valdes B. Lopez MA. Fini A. Farmaco  2003,  58:  409 
    Search in Google Scholar
  • 8c Zhao G. Miller MJ. Franzblau S. Wan B. Mollmann U. Bioorg. Med. Chem. Lett.  2006,  16:  5534 ; see supplementary data
    Search in Google Scholar
  • 8d Kumar Singh S. Tiwari RP. Jain P. Synth. Commun.  2003,  33:  2475 
    Search in Google Scholar
  • 9 Sammes PG. Chem. Rev.  1976,  76:  113 
    Search in Google Scholar
  • 10a Murphy CF. Koehler RE. J. Org. Chem.  1970,  35:  2429 
    Search in Google Scholar
  • 10b Singh J. Kim OK. Kissick TP. Natalie KJ. Zhang B. Crispino GA. Springer DM. Wichtowski JA. Zhang Y. Goodrich J. Ueda Y. Luh BY. Burke BD. Brown M. Dutka AP. Zheng B. Hsieh DM. Humora MJ. North JT. Pullockaran AJ. Livshits J. Swaminathan S. Gao Z. Schierling P. Ermann P. Perrone RK. Lai MC. Gougoutas JZ. DiMarco JD. Bronson JJ. Heikes JE. Grosso JA. Kronenthal DR. Denzel TW. Mueller RH. Org. Process Res. Dev.  2000,  4:  488 
    Search in Google Scholar
  • 10c Woodward RB. Heusler K. Gosteli J. Naegeli P. Oppolzer W. Ramage R. Ranganathan S. Vorbruggen H. J. Am. Chem. Soc.  1966,  88:  852 
    Search in Google Scholar
  • 10d Morin RB. Jackson BG. Mueller RA. Lavagnino ER. Scanlon WB. Andrews SL. J. Am. Chem. Soc.  1969,  91:  1401 
    Search in Google Scholar
  • 10e Bentley PH. Brooks G. Zomaya I. Tetrahedron Lett.  1976,  17:  3739 
    Search in Google Scholar
  • 10f Wang Y. Lambert P. Zhao L. Wang DN. Eur. J. Med. Chem.  2002,  37:  323 
    Search in Google Scholar
  • 11a Chauvette RR. Pennington PA. J. Org. Chem.  1973,  38:  2994 
    Search in Google Scholar
  • 11b Cocker JD. Eardley S. Gregory GI. Hall ME. Long AG. J. Chem. Soc.  1966,  1142 
  • 11c Mobashery S. Johnston M. J. Biol. Chem.  1986,  17:  7879 
    Search in Google Scholar
  • 11d Yu K. Sun N. Fang S. Mo W. Hu B. Shen Z. Hu X. Org. Process Res. Dev.  2009,  13:  815 
    Search in Google Scholar
  • 12a Christensen BG, Cama LD, and Kern JA. inventors; DE  2264651.  ; Chem. Abstr. 1974, 81, 120653j
  • 12b Tanino H. Nakata T. Kaneko T. Kishi Y. J. Am. Chem. Soc.  1977,  99:  2818 
    Search in Google Scholar
  • 13a Kraus A. Ghorai P. Birnkammer T. Schnell D. Elz S. Seifert R. Dove S. Bernhardt G. Buschauer A. ChemMedChem  2009,  4:  232 
    Search in Google Scholar
  • 13b Zepik HH. Benner SA. J. Org. Chem.  1999,  64:  8080 
    Search in Google Scholar
  • 14 Cabi W. Ghetti P. Pozzi G. Alpegiani M. Org. Process Res. Dev.  2007,  11:  64 
    Search in Google Scholar
3

The Japanese Pharmacopoeia Fifteenth Edition at http://www.drugfuture.com/Pharmacopoeia/JP15/ JP15e.html.