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3739
methyl (POM) protection at N3 was introduced by
References and notes
formation of the anion with sodium hydride (1.2 equiv/
DMF/0 °C) and a subsequent quench with chloromethyl
pivalate (1.2 equiv/0 °C to rt/1 h) to give 9 in 63% yield.
Selective oxidation of the pyridine ring nitrogen with
m-CPBA (1.25 equiv/0 °C to rt/16 h) gave the N-oxide 10
in 50% yield. This reaction appeared to give cleanly a
single regioisomer, with no evidence of oxidation at N-1
of the pyrimidone ring. Despite this, we were unable to
improve the isolated yield beyond that reported here. As
anticipated, the crucial Meisenheimer N-oxide rear-
rangement was accomplished in a regioselective manner
with phosphorus oxychloride as solvent (100 °C/2 h) to
give 11, after work up with ice-cold saturated sodium
carbonate solution, in 66% yield. The structure of 11
was confirmed by NMR studies.15 Removal of the POM
protecting group proceeded uneventfully by treatment
with a solution of 7 N ammonia in methanol to give 4 in
94% yield. Finally, displacement of the chlorine was
accomplished by in situ generation of the alkoxide
nucleophile in 65% yield, in a manner analogous to that
used for synthesis of 1.1
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Introduction to Advanced Electronic Structure Theory;
MacMillan: New York, 1982.
In conclusion we have described the first synthesis of the
5-alkoxypyrido[4,3-d]pyrimidin-4(3H)-one ring system
in seven steps from the TFA salt of 4-aminonicotinic
acid in 9% overall yield. It is anticipated that a range of
alkoxides and other nucleophiles could be used to
introduce diversity at C-5 and that a subsequent chlo-
rination-displacement strategy at C-4 would introduce
further complexity to the molecule.
13. Koch, W.; Holthausen, M. C. A Chemist’s Guide to Density
Functional Theory, 2nd ed.; Wiley-VCH: Weinheim, 2001.
ꢀ
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G.; Wang, W.; Bedard, J.; May, S.; Yuen, L. J. Med.
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Chem. 1999, 42, 3023–3025.
15. NMR spectrum of compound 11 (DMSO-d6); 1.10 (s, 9H),
5.85 (s, 2H), 7.60 (d, 1H), 8.60 (d, 1H), 8.70 (s, 1H); MS:
MHþ 296.