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 </A>
Ishikura K.
Kubota T.
Minami K.
Hamashima Y.
Nakashimizu H.
Motokawa K.
Kimura Y.
Miwa H.
Yoshida T.
J. Antibiot.
1994,
47:
466
1b </A>
Hwu JR.
Tsay SC.
Hakimelahi S.
J.
Med. Chem.
1998,
41:
4681
1c </A>
Cazzola M.
Expert
Opin. Invest. Drugs
2000,
9:
237
2a </A>
Kim OK.
Hudyma TW.
Mtiskella JD.
Ueda Y.
Bronson JJ.
Mansuri MM.
Bioorg. Med. Chem. Lett.
1997,
7:
2753
2b </A>
Haddad J.
Vakulenko S.
Mobashery S.
J.
Am. Chem. Soc.
1999,
121:
11922
2c </A>
Lee W.
Li Z.-H.
Vakulenko S.
J.
Med. Chem.
2000,
43:
128
2d </A>
Williams DH.
Bardsley B.
Angew.
Chem. Int. Ed.
1999,
38:
1172
2e </A>
Pechere JC.
J. Antimicrob. Chemother.
1999,
44
(suppl. 1):
11
3 </A>
The Japanese Pharmacopoeia Fifteenth
Edition at http://www.drugfuture.com/Pharmacopoeia/JP15/ JP15e.html.
4a </A>
Sakata H.
J. Infect. Chemother.
2008,
14:
208
4b </A>
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
4c </A>
Fujimoto M.
Int.
J. Antimicrob. Agent.
2001,
18:
489
4d </A>
Lee JE.
Han DH.
Won TB.
Rhee CS.
Clin. Exp. Otorhinolar.
2011,
4:
83
4e </A>
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
5a </A>
Durckheimer W.
Blumbach J.
Lattrell R.
Scheunemann KH.
Angew.
Chem., Int. Ed. Engl.
1985,
24:
180
5b </A>
Ishikura K.
Kubota T.
Minami K.
Hamashima Y.
Nakashimizu H.
Motokawa K.
Kimura Y.
Miwa H.
Yoshida T.
J.
Antibiot.
1994,
47:
453
6a </A>
Mizojiri K.
Futaguchi S.
Norikura R.
Katsuyama Y.
Nagasaki T.
Yoshimori T.
Nakanishi M.
Antimicrob. Agents Chemother.
1995,
7:
1445
6b </A>
He X.
Sugawara M.
Takekuma Y.
Miyazaki K.
Antimicrob. Agents Chemother.
2004,
48:
2604
7a </A>
Hamashima Y,
Ishikura K,
Minami K,
Kubota T, and
Yoshida T. inventors; US 4731361.
7b </A>
Hamashima Y,
Tsuji T,
Okada T,
Minami K,
Ishitobi H, and
Ishikura K. inventors; US 4731362.
7c </A>
Gedi S,
Ramakrishna K, and
Udayam-palayam PS. inventors; WO 2008155615.
8a </A>
Takaya T.
Takasugi H.
Murakawa T.
Nakano H.
J.
Antibiot.
1981,
34:
1300
8b </A>
Gonzalez R.
Rodriguez Z.
Tolon B.
Rodriguez JC.
Velez H.
Valdes B.
Lopez MA.
Fini A.
Farmaco
2003,
58:
409
8c </A>
Zhao G.
Miller MJ.
Franzblau S.
Wan B.
Mollmann U.
Bioorg.
Med. Chem. Lett.
2006,
16:
5534 ;
see supplementary data
8d </A>
Kumar Singh S.
Tiwari RP.
Jain P.
Synth. Commun.
2003,
33:
2475
<A NAME="RH97111SS-9">9 </A>
Sammes PG.
Chem.
Rev.
1976,
76:
113
10a </A>
Murphy CF.
Koehler RE.
J. Org. Chem.
1970,
35:
2429
10b </A>
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
10c </A>
Woodward RB.
Heusler K.
Gosteli J.
Naegeli P.
Oppolzer W.
Ramage R.
Ranganathan S.
Vorbruggen H.
J. Am.
Chem. Soc.
1966,
88:
852
10d </A>
Morin RB.
Jackson BG.
Mueller RA.
Lavagnino ER.
Scanlon WB.
Andrews SL.
J. Am. Chem. Soc.
1969,
91:
1401
10e </A>
Bentley PH.
Brooks G.
Zomaya I.
Tetrahedron Lett.
1976,
17:
3739
10f </A>
Wang Y.
Lambert P.
Zhao L.
Wang DN.
Eur. J. Med. Chem.
2002,
37:
323
11a </A>
Chauvette RR.
Pennington PA.
J. Org. Chem.
1973,
38:
2994
11b </A>
Cocker JD.
Eardley S.
Gregory GI.
Hall ME.
Long AG.
J. Chem. Soc.
1966,
1142
11c </A>
Mobashery S.
Johnston M.
J. Biol. Chem.
1986,
17:
7879
11d </A>
Yu K.
Sun N.
Fang S.
Mo W.
Hu B.
Shen Z.
Hu X.
Org. Process Res. Dev.
2009,
13:
815
12a </A>
Christensen BG,
Cama LD, and
Kern JA. inventors; DE 2264651.
; Chem. Abstr . 1974 , 81 , 120653j
12b </A>
Tanino H.
Nakata T.
Kaneko T.
Kishi Y.
J. Am. Chem. Soc.
1977,
99:
2818
13a </A>
Kraus A.
Ghorai P.
Birnkammer T.
Schnell D.
Elz S.
Seifert R.
Dove S.
Bernhardt G.
Buschauer A.
ChemMedChem
2009,
4:
232
13b </A>
Zepik HH.
Benner SA.
J.
Org. Chem.
1999,
64:
8080
<A NAME="RH97111SS-14">14 </A>
Cabi W.
Ghetti P.
Pozzi G.
Alpegiani M.
Org. Process Res. Dev.
2007,
11:
64
