PDF herunterladen
Synthesis 2009(20): 3391-3398  
DOI: 10.1055/s-0029-1216986
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

An Efficient Hemisynthesis of 20- and 21-[¹³C]-Labeled Cortexolone: A Model for the Study of Skin Sensitization to Corticosteroids

Emilie Claudel, Cécile Arbez-Gindre, Valérie Berl, Jean-Pierre Lepoittevin*
Institut de Chimie, Laboratoire de Dermatochimie, UMR 7177, CNRS et Université de Strasbourg, 4, rue Blaise Pascal, 67070 Strasbourg, France
Fax: +33(3)68851527; e-Mail: jplepoit@unistra.fr;
Weitere Informationen

Publikationsverlauf

Received 15 May 2009
Publikationsdatum:
03. September 2009 (online)

   Lizenzen und Reprints Alle Artikel dieser Rubrik
Preview

Abstract

A method is described for the synthesis of isotopomers of cortexolone from the commercially available andros-4-ene-3,17-dione. The strategy is based on the use of K¹³CN for labeling at position 20 and of ¹³CH3MgI, generated in situ, for labeling at position 21. Because of the early introduction of the [¹³C] labeling, our efforts aimed at reproducible experimental procedures giving high yields with respect to the isotope containing precursors. During the development of this hemisynthesis, we noted that judicious choice of protective groups was essential as this could lead not only to mixtures or unstable intermediates but also influence considerably the output of reactions.

Key words

steroids - medicinal chemistry - isotope labeled - allergen synthesis - protecting groups

    References

  • 1 Schimmer BP. Parker KL. In Goodman & Gilman’s : The Pharmacological Basis of Therapeutics, 11th ed.   Brunton LL. Lazo JS. Parker KL. McGraw Hill; New York: 2006.  p.1587-1612  
  • 2a Wilkinson SM. Cartwright PH. English JSC. Lancet  1991,  337:  761 
    Suche in Google Scholar
  • 2b Lauerma AI. Contact Dermatitis  1991,  24:  123 
    Suche in Google Scholar
  • 2c Dooms-Goossens A. Morren M. Contact Dermatitis  1992,  26:  182 
    Suche in Google Scholar
  • 2d Matura M. Goossens A. Allergy  2000,  55:  698 
    Suche in Google Scholar
  • 2e Hennge UR. Ruzicka T. Schwartz RA. Cork MJ. J. Am. Acad. Dermatol.  2006,  54:  1 
    Suche in Google Scholar
  • 3a Lepoittevin J.-P. Drieghes J. Goossens A. Arch Dermatol.  1995,  131:  31 
    Suche in Google Scholar
  • 3b Bircher AJ. Thürlimann W. Hunziker Th. Pasche-Koo F. Hunziker N. Perrenoud D. Elsner P. Schultheiss R. Dermatology  1995,  191:  109 ; the author list also includes members of the Swiss contact dermatitis research group
    Suche in Google Scholar
  • 3c Isaksson M. Andersen KE. Brandão FM. Bruynzeel DP. Bruze M. Camarasa JG. Diepgen T. Ducombs G. Frosch PJ. Goossens A. Lahti A. Menné T. Rycroft RJG. Seidenari S. Shaw S. Tosti A. Wahlberg JE. White IR. Wilkinson JD. Contact Dermatitis  2000,  42:  27 
    Suche in Google Scholar
  • 4 Rustemeyer T. van Hoogstraten IMW. von Blomberg BME. Scheper RJ. In Textbook of Contact Dermatitis   Rycroft RJG. Menné T. Frosch PJ. Lepoittevin J.-P. Springer-Verlag; Berlin: 2001.  p.13-58  
  • 5 Lepoittevin J.-P. In Textbook of Contact Dermatitis   Rycroft RJG. Menné T. Frosch PJ. Lepoittevin J.-P. Springer-Verlag; Berlin: 2001.  p.59-89  
  • 6a Bundgaard H. Arch. Pharm. Chem., Sci. Ed.  1980,  8:  83 
    Suche in Google Scholar
  • 6b Matura M. Lepoittevin J.-P. Arbez-Gindre C. Goossens A. Contact Dermatitis  1998,  38:  106 
    Suche in Google Scholar
  • 7a Demoulin JD. Armbruster A.-M. Pullman B. J. Quantum Chem.  1979,  16:  631 
    Suche in Google Scholar
  • 7b Lo TWC. Westwood ME. McLellan AC. Selwood T. Thornalley PJ. J. Biol. Chem.  1994,  269:  32299 
    Suche in Google Scholar
  • 7c Wilkinson SM. Jones MF. Br. J. Dermatol.  1996,  165:  225 
    Suche in Google Scholar
  • 8a Franot C. Benezra C. Lepoittevin J.-P. Bioorg. Med. Chem.  1993,  1:  389 
    Suche in Google Scholar
  • 8b Goetz G. Meschkat E. Lepoittevin J.-P. Bioorg. Med. Chem. Lett.  1999,  9:  1141 
    Suche in Google Scholar
  • 9 Patchett AA. In Biographical Memoirs, National Academy of Sciences   Vol. 81:  The National Academy Press; Washington: 2002.  p.278-293  
    Suche in Google Scholar
  • 10a Andrews DR. Giusto RA. Sudhakar AR. Tetrahedron Lett.  1996,  37:  3417 
    Suche in Google Scholar
  • 10b Batist JNM, Marx AF, van Zoest WJ, and Kapur JC. inventors; European Patent, EP  0263569.  ; Chem. Abstr. 1988, 109, 129460
  • 10c Barton DHR. Motherwell WB. Zard SZ. J. Chem. Soc., Chem. Commun.  1981,  774 
  • 10d Daniewski AR. Wojciechowska W. Synthesis  1984,  132 
  • 10e Murahashi S.-I. Saito TS. Hanaoka H. Murakami Y. Naota T. Kumobayashi H. Akutagawa S. J. Org. Chem.  1993,  58:  2929 
    Suche in Google Scholar
  • 10f Lett R, and Melnyk O. inventors; US Patent, US  5723638.  ; Chem. Abstr. 1996, 124, 176619
  • 11a Horiguchi Y. Nakamura E. Kuwajima I. Org. Synth.  1995,  73:  123 
    Suche in Google Scholar
  • 11b Batist JNM. Barendse NCME. Marx AF. Steroids  1990,  55:  109 
    Suche in Google Scholar
  • 11c VanRheenen VH. inventors; US Patent, US  4500461.  ; Chem. Abstr. 1985, 103, 22844
  • 11d Livingston DA. Petre JE. Bergh CL. J. Am. Chem. Soc.  1990,  112:  6449 
    Suche in Google Scholar
  • 11e Reid JG. Debiak-Krook T. Tetrahedron Lett.  1990,  31:  3669 
    Suche in Google Scholar
  • 11f VanRheenen VH. inventors; European Patent, EP  0153001.  ; Chem. Abstr. 1986, 105, 60816
  • 11g Carruthers NI. Andrews DR. Garshasb S. Giusto RA. J. Chem. Soc., Perkin Trans. 1  1992,  1195 
  • 11h Nitta I. Fujimori S. Ueno H. Bull. Chem. Soc. Jpn.  1985,  58:  978 
    Suche in Google Scholar
  • 11i Carruthers NI. Garshasb S. J. Org. Chem.  1992,  57:  961 
    Suche in Google Scholar
  • 12a Dauben HJ. Löken B. Ringold HJ. J. Am. Chem. Soc.  1954,  76:  1359 
    Suche in Google Scholar
  • 12b Nitz TJ. Paquette LA. Tetrahedron Lett.  1984,  25:  3047 
    Suche in Google Scholar
  • 13a Jackson WR. Jacobs HA. Jayatilake GS. Matthews BR. Watson KG. Aust. J. Chem.  1990,  43:  2045 
    Suche in Google Scholar
  • 13b Luly JR. Hsiao CN. BaMaung N. Plattner JJ. J. Org. Chem.  1988,  53:  6109 
    Suche in Google Scholar
  • 14 Arbez-Gindre C. Berl V. Lepoittevin J.-P. Chem. Commun.  1999,  431 
    Crossref
  • 15 Moriarty RM. John LS. Du PC. J. Chem. Soc., Chem. Commun.  1981,  641 
    Crossref
  • 16 Moriarty RM. J. Org. Chem.  2005,  70:  2893 
    CrossrefPubMedSuche in Google Scholar
  • 17a Ringold HJ. Stork G. J. Am. Chem. Soc.  1958,  80:  250 
    Suche in Google Scholar
  • 17b Ringold HJ. Perez Ruelas J. Batres E. Djerassi C. J. Am. Chem. Soc.  1959,  81:  3712 
    Suche in Google Scholar
  • 17c Rothman ES. Perlstein T. Wall ME. J. Org. Chem.  1960,  25:  1966 
    Suche in Google Scholar
  • 17d Nitta I. Fujimori S. Ueno H. Bull. Chem. Soc. Jpn.  1985,  58:  978 
    Suche in Google Scholar
  • 18 Moreland WT. J. Org. Chem.  1956,  21:  820 
    CrossrefSuche in Google Scholar
  • 20 Bodor N. Fey L. Kircz M. Hodosan F. Rev. Roum. Chim.  1964,  9:  147 ; Chem. Abstr. 1964, 61, 61819
    Suche in Google Scholar
  • 21a Gadsby B, and Leeming MRG. inventors; US Patent, US  3646012.  ; Chem. Abstr. 1969, 71, 81648
  • 21b Bradford HW. inventors; US Patent, US  3444160.  ; Chem. Abstr. 1969, 71, 61687
  • 22 Numazawa M. Nagaoka M. J. Org. Chem.  1985,  50:  81 
    CrossrefSuche in Google Scholar
  • 23 Julian PL. Meyer EW. Ryden I. J. Am. Chem. Soc.  1950,  72:  367 
    CrossrefSuche in Google Scholar
  • 24 Ringold HJ. Rosenkranz G. Sondheimer F. J. Am. Chem. Soc.  1956,  78:  820 
    CrossrefSuche in Google Scholar
19

THF containing a certain amount of peroxide (titration with KI and thiosulfate) was prepared as follows: In a typical procedure, THF was exposed to sunlight in an open bottle until the peroxide content reached the expected value. Alternatively, THF could be first distilled from CaO before exposure to sunlight. Fresh and aged THF may be combined to give the proper peroxide content.