Download PDF
Synthesis 2003(11): 1739-1743
DOI: 10.1055/s-2003-40891
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Solid-Phase Synthesis of Pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones

Nadège Graveleau, Thierry Masquelin*
Combinatorial & Parallel Chemistry, Basilea Pharmaceutica Ltd, Grenzacherstrasse 487, 4002 Basel, Switzerland
Fax: thierry.masquelin@basileapharma.com;
Further Information

Publication History

Received 7 April 2003
Publication Date:
25 July 2003 (online)

    Permissions and Reprints All articles of this category

Abstract

We report a novel, and versatile solid-phase synthesis of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones starting from the polymer-bound pyrimidine 3. The key step is based on the reaction of the support-bound pyrimidine 3 with isocyanates 4, involving formation of a carbamate intermediate, followed by a base-catalysed intramolecular ring closure, to give polymer-bound 3-monosubstituted 1H-pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones 5. At this stage, subsequent treatment with alkyl halides 6 lead to 1,3-disubstituted 2H-pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione intermediates 7, which after oxidation and cleavage with various amines 8 gave 1,3-disubstituted 7-amino-2H-pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones 9 in moderate yields and high purity.

Key words

solid-phase - pyrimidine - base-catalysed ring clo­sure - intramolecular cyclisation - pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-diones

    References

  • 1 Gallop MA. Barrett RW. Dower WJ. Fodor SPA. Gordon EM. J. Med. Chem.  1994,  37:  1233 
    CrossrefPubMedGoogle Scholar
  • 2 Gordon EM. Barrett RW. Dower WJ. Fodor SPA. Gallop MA. J. Med. Chem.  1994,  37:  1386 
    Google Scholar
  • 3 Ellman JA. Chemtracts: Org. Chem.  1995,  8:  1 
    Google Scholar
  • 4 Pirrung MC. Chemtracts: Org. Chem.  1995,  8:  5 
    Google Scholar
  • 5 Hermkens PHH. Ottenheijm HCJ. Rees D. Tetrahedron  1996,  52:  4527 
    CrossrefGoogle Scholar
  • 6 Hermkens PHH. Ottenheijm HCJ. Rees D. Tetrahedron  1997,  53:  5643 
    CrossrefGoogle Scholar
  • 7 Obrecht D. Villalgordo JM. Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries   Vol. 17:  Elsevier; Oxford: 1998. 
    Google Scholar
  • 8 Roth HJ. Pharmaceutical Chemistry. Drug Synthesis   Vol. 1:  Wiley; : 1988. 
    Google Scholar
  • 9a Roth HJ. Troschuetz R. Arch. Pharm. (Weinheim, Ger.)  1978,  318:  542 
    Google Scholar
  • 9b Roth HJ. Troschuetz R. Arch. Pharm. (Weinheim, Ger.)  1978,  318:  406 
    Google Scholar
  • 10 Press JB, and Russel RK. inventors; US  Patent.  , 1989; Chem. Abstr. 1989, 111, 174121
  • 11 Lowe JA. Archer RL. Chapin DS. Chen JB. Helweg D. Johnson JL. Koe BK. Lebel LA. Moore PF. Nielsen NA. J. Med. Chem.  1991,  34:  624 
    CrossrefGoogle Scholar
  • 12 Smith AL. Thomson CG. Leeson PD. Bioorg. Med. Chem. Lett.  1996,  6:  1483 
    CrossrefGoogle Scholar
  • 13 Mignani S. Damour D. Doble A. Labaudiniere R. Malleron JL. Piot O. Gueremy C. Bioorg. Med. Chem. Lett.  1993,  3:  1913 
    Google Scholar
  • 14 Montginoul C. Pastor G. Vigne C. Giral L. Ann. Pharm. Fr.  1989,  46:  223 ; Chem. Abstr. 1989, 110, 165551
    Google Scholar
  • 15 Shimazaki N, Yamazaki H, and Yatabe T. inventors; Eur. Patent Appl. EP  481342.  ; Chem. Abstr. 1989, 117, 131217
  • 16 Hirota K. Kitade Y. Sajiki M. Maki Y. Synthesis  1984,  589 
    Article in Thieme ConnectGoogle Scholar
  • 17 Hirota K. Kitade Y. Sajiki H. Maki Y. J. Chem. Soc., Perkin Trans 1  1990,  123 
    CrossrefGoogle Scholar
  • 18 Gulevskaya AV. Pozharsky AF. Shorshnev SV. Zheltushkina EA. Khim. Geterotsikl. Soedin.  1994,  1249 ; Chem. Abstr. 1995, 122, 239631
    Google Scholar
  • 19 Srivastava SW. Haq W. Chauhan PMS. Bioorg. Med. Chem. Lett.  1999,  9:  965 
    Google Scholar
  • 20 Strekowski D. Harden RA. Watson RA. Synthesis  1988,  70 
    Article in Thieme ConnectGoogle Scholar
  • 21 Shishoo CJ. Jain KS. J. Heterocycl. Chem.  1992,  29:  883 
    CrossrefGoogle Scholar
  • 22 Gayo LM. Suto MJ. Tetrahedron Lett.  1997,  38:  211 
    CrossrefGoogle Scholar
  • 23 Chucholowski A. Masquelin T. Obrecht D. Stadlwieser J. Villalgordo JM. Chimia  1996,  50:  525 
    Google Scholar
  • 24 Masquelin T. Sprenger D. Baer R. Gerber F. Mercadal Y. Helv. Chim. Acta  1998,  81:  646 
    Google Scholar
  • 25 Obrecht D. Abrecht C. Grieder F. Villalgordo J.-M. Helv. Chim. Acta  1997,  80:  65 
    CrossrefGoogle Scholar
  • 26 Griffiths P. Chemical Analysis   Vol. 43:  Wiley; New York: 1974. 
    Google Scholar
  • 27 Xin Z. Pei Z. von Geldem T. Jirousek M. Tetrahedron Lett.  2000,  41:  1147 
    CrossrefGoogle Scholar
  • 28 Davis FA. Stringer OD. J. Org. Chem.  1982,  47:  1774 
    CrossrefGoogle Scholar
  • 29 Masquelin T. Meunier N. Gerber F. Rosse G. Heterocycles  1998,  48:  2489 
    Google Scholar
  • 30 Masquelin T. Obrecht D. Tetrahedron  2001,  57:  153 
    CrossrefGoogle Scholar
  • 31 Masquelin T. Delgado Y. Baumle V. Tetrahedron Lett.  1998,  39:  5725 
    Google Scholar
  • 32 Masquelin T. Baer R. J. Comb. Chem.  2001,  3:  16 
    CrossrefGoogle Scholar