Synthesis 2012; 44(20): 3152-3157
DOI: 10.1055/s-0032-1316756
practical synthetic procedures
© Georg Thieme Verlag Stuttgart · New York

Efficient Synthesis of 4-Amino-2-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-5-ones: Practical Access to a Novel Chemotype in the Development of DGAT-1 Inhibitors

Kevin B. Bahnck*
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Andrei Shavnya
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Yong Tao*
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Susan C. Lilley
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Melissa P. Andrews
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Gary E. Aspnes
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
David J. Bernhardson
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
David R. Bill
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Mark W. Bundesmann
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Robert L. Dow
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
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Kapil Karki
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Tung Le
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Qifang Li
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
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Michael J. Munchhof
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
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Asaad Nematalla
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
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Mohammed Nihlawi
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Leena Patel
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
,
Christian Perreault
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
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Michael Waldo
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA, Fax: +1(860)6860605   eMail: kevin.b.bahnck@pfizer.com   eMail: yong.tao@pfizer.com
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Publikationsverlauf

Received: 03. März 2012

Accepted after revision: 26. April 2012

Publikationsdatum:
03. Juli 2012 (online)


Abstract

A practical access to an unprecedented, fused bicyclic 4-amino-2-alkoxy-7,8-dihydropyrido[4,3-d]pyrimidin-5-one scaffold is developed. The synthesis of the potent inhibitor, 2-{4-[4-amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]phenyl}-2-methylpropanamide is detailed, with particular emphasis placed on synthetic efficiency and scalability. With the isolation of solid intermediates, the routes described offer clear elements of practicality and facilitate production of the target compound on large scale (>10 g) without chromatography.

 
  • References

    • 1a Birch AM, Buckett LK, Turnbull AV. Curr. Opin. Drug Discovery Dev. 2010; 13: 489
    • 1b Zammit VA, Buckett LK, Turnbull AV, Wure H. Pharmacol. Ther. 2008; 118: 295
    • 2a Dow RL, Li J.-C, Pence MP, Gibbs ME, LaPerle JL, Litchfield J, Piotrowski DW, Munchhof MJ, Manion TB, Zavadoski WJ, Walker GS, McPherson RK, Tapley S, Sugarman E, Guzman-Perez A, DaSilva-Jardine P. ACS Med. Chem. Lett. 2011; 2: 407 ; and references cited therein
    • 2b Dow RL, Munchhof MJ. US Patent 0197590, 2010
    • 2c Aspnes GE, Dow RL, Munchhof MJ. US Patent 0197591, 2010
  • 3 To the best of our knowledge, this aminoalkoxypyrimido pyridone scaffold was unprecedented in the chemical literature, prior to the disclosure of such structures in our recent patents. For a related system accessed through N-aryl imines, see: Wada A, Hirai S, Hanaoka M. Chem. Pharm. Bull. 1991; 39: 1189
    • 4a Surry DS, Buchwald SL. Angew. Chem. Int. Ed. 2008; 47: 6338
    • 4b Huang X, Anderson KW, Zim D, Jiang L, Klapars A, Buchwald SL. J. Am. Chem. Soc. 2003; 125: 6653
  • 5 X-Phos was chosen as the ligand in this catalyst system based on its commercial availability and low cost, relative to BrettPhos, which specializes in the mono N-arylation of primary amines, see: Fors BP, Watson DA, Biscoe MR, Buchwald SL. J. Am. Chem. Soc. 2008; 130: 13552

    • For similar Dieckmann-type condensations en route to five-membered rings, see:
    • 6a Yendapally R, Hurdle JG, Carson EI, Lee RB, Lee RE. J. Med. Chem. 2008; 51: 1487
    • 6b Kulkarni BA, Ganesan A. Angew. Chem. Int. Ed. 1997; 36: 2454
  • 7 Several organic and inorganic bases also effected this cyclization, however, the use of DBU consistently resulted in the cleanest and most efficient reactions
  • 8 Farr RN, Alabaster RJ, Chung JY. L, Craig R, Edwards JS, Gibson AW, Ho G.-J, Humphrey GR, Johnson SA, Grabowski EJ. J. Tetrahedron: Asymmetry 2003; 14: 3503
  • 9 This aza-Michael addition proceeded under acidic or basic conditions, both of which afforded aniline 8 with similar conversion profiles
  • 10 The use of trimethylsilyldiazomethane proved useful in the mild O-methylation of substrates containing acid-sensitive functionalities incompatible with the oxalyl chloride protocol. Surprisingly, vinylogous carbamates such as 12 were inert to standard O-alkylation conditions (base and methyl iodide or dimethyl sulfate), presumably due to the weak nucleophilicity of the corresponding anions. Attempts to drive Fischer-type esterifications to completion with chemoselectivity and mild conditions were not successful

    • Based on modifications of procedures reported for de novo syntheses of aminopyrimidines, see:
    • 11a Schmidt H.-W, Koitz G, Junek H. J. Heterocycl. Chem. 1987; 24: 1305
    • 11b Perez MA, Soto JL, Guzman F, Alcala H. J. Chem. Soc., Perkin Trans. 1 1985; 87
  • 12 To date, efforts to eliminate completely the formation of amine 20 have not been realized
  • 13 For analogue production, the addition of O-alkylisoureas to vinylogous carbamates such as 17 (step f) offered a convenient point of divergence in the rapid exploration of structure–activity relationships around the methoxy substituent of the pyrimidine