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Advances in Heterocylic Chemestry. Vol 10 - Boulton A.J.

Boulton A.J. Advances in Heterocylic Chemestry. Vol 10 - Academic Press, 1969. - 347 p.
Download (direct link): advensisheroklinik1969.pdf
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4-Amino-6-ethoxycarbonylpyrimidine68 and the 2-methyl derivative09 have been shown to undergo reaction with a-methylene
Ph
h2n.
\o
I

111
CH
1 H. Bredereck, F. Effenberger, E. Henseleit, and E. H. Schweizer, Chem. Ber. 96, 1868(1963).
1 A. DornowandE. Hinz, Chem. Ber. 91, 1834 (1958).
esters,68'69 ketones,68 and nitriles68 to yield 5-hydroxypyrido[2,3-rf]-pyrimidines variously substituted at the 6- and 7-positions. 4-Amino-5-ethoxycarbonylpyrimidine and ethyl propionate, for example, yield 5-hydroxy-6-methylpyrido[2,3-dJpyrimidin-7(8Z/)-one (83) when heated together with metallic sodium.
Ethyl acetate, however, yielded the diamide (84) under similar conditions, and the pyrido[2,3-d]pyrimidine (85) was obtained only when sodium ethoxide was used as the catalyst.68
A further convenient synthesis is that developed by Taylor and Garcia70 who showed that pyrido[2,3-d]pyrimidmcs (86 and 87) were obtained by the action of malononitrile on 5-acetyl-4-aminopyrimidin-6(l//)-one or 4-amino-5-benzoyl-l-methylpyrimidin-6(li7)-one.
Phenylacetonitrile, ethyl cyanoacetate, and cyanoacetamide failed to yield pyrido[2,3-d]pyrimidines.70
c. Route (in) Syntheses. In contrast to the previous syntheses which have been described, pyrido[2,3-d]pyrimidines prepared by this route
70 E. C. Taylor and E. E. Garcia, J. Org. Chem. 29, 2116 (1964).
H
Me
COOEt
CH;
OH
(83)
H
CH3
COOEt
EtOOC
h2n ~
H (84)
EtONa
H
OH
(85)
^CN CH2
CN MeCO
Jl NH
h2nv
NC'
NH
Me (86)
^cx h2n.
ch2 +
CN PhCO
h2n
NC
^N4
Me
Ph (87)
are not completely afomatic compounds, or tautomers of aromatic compounds, and are obtained by cyclization of an aliphatic propionyl derivative.
Alkylation of diethyl acetamidomalonate with the bromomethyl-pyrimidine (88) yielded 6-aeetamido-6-ethoxy carbonyl-5,6-dihy dro-2-methylthiopyi'ido[2,3-rf]pyrimidin-7(8//)-one (90), via the cyclization of the intermediate ester (89).71
SMe
BrCH2
(88)
Similar ready cyclizations of propionyl derivatives are exemplified by the cyclization of the ester (91) to yield the pyrido[2,3-d]pyrimidine
71 B. Blank and W. T. Caldwell, 7. Org. Chem. 24, 1137 (1959).
(92) when treated with ammonia.72-72 This pyrido[2,3-d]pyrimidine
(92) was also obtained by the action of nitrous acid on the hydrazide
(93).
ci^/N4 .Me COOMe {I J
I
CH2-------CH2 ^^
(91)
COOMe
I
CH2------CH2
H2N^/N Me
CONHNHa CH2----CH2
H2N\ /N. ^.Me
T HNOa
A^n
(93)
CON3
CH2
H2N.
-CH.
The propionitrile (94) also yielded a pyrido[2,3-ri]pyrimidinc (96) when treated with ammonia or methylamine, the intermediate amidine (95) undergoing hydrolysis during the reaction.73 Animation was shown to be the rate-determining stage.
cyNvNH!

(94)
CN
I
CH2CH2
CN
NH2
CH2CH2
h2n.
^NH2 N
(96)
72 J. Biggs and P. Sykes, J. Chem. Soc. p. 1849(1959).
72a L. Suranyi and L. Schuler, German Patent No. 1,100,030 (1961); Chem. Abstr. 57, 2231 (1962).
73 B. R. Baker and P. I. Almaula, J. Heterocyclic Ghem. 1, 263 (1964).
Other 4-aminopyrimidyl-5-propionitriles, obtained by cyanoethyl-ation of the required pyrimidine, have also been converted into pyrido [2,3-d]pyrimidines.7 4
B. PYHIDO[3,2-rf]PYEIMIDINES
1. FromPyridines
The syntheses of pyrido[3,2-d]pyrimidines from pyridines utilize a
2,3-disubstituted pyridine and insert the C-2 and N-3 atoms, either previously linked (route i) or in separate stages (route ii).
rr
N N
a. Route (i) Syntheses. As in the case of the pyri do [ 2,3-rf ]py ri m i di nes, the first reported pyrido[3,2-d]pyrimidines were prepared by an extension of the von Niementowski quinazolone synthesis. Thus, the fusion of 3-aminopicolinic acid with formamide yielded pyrido[3,2-rf]-pyrimidin-4(3#)-one (97)76,76 and similar treatment of 3-amino-
|ӹ HCONHi.
^N^COOH

(97)
N^NHs ^\/NHCXNH2
'%T'/4Y'NH 'cooh

(99) (100)
V. Papesch, U.S. Patent No. 3,235,554 and No. 3,235,555 (1966); Chem. Abstr. 64, 14198(1966).
75 . C. Price and D. Y. Curtin, J. Am. Chem. Soc. 68, 914 (1946).
76 A. Albert and A. Hampton, J. Chem. Soc. p. 505 (1954).
picolinic acid10'77 or 3-amino-6-methylpicolinic acid78 with urea gave pyrido[3,2-d]pyrimidine-2,4(li?,3il7)-diones (98, R = H and R = Me).
The 6-methyl derivative (98, R = Me) was an important intermediate in the synthesis of analogs (e.g., 183) of folic acid.79,80 Korte81 has shown that 2-aminopyrido[3,2-rf]pyrimidin-4(3//)-one (99)isformed by fusion of guanidine carbonate with 3-aminopicolinic acid and that treatment of the same acid with ammonium thiocyanate or potassium cyanate yields the thioureido and ureido derivatives (100, X = S and X = 0). In contrast to the pyrido[2,3-cf]pyrirnidine system both of these compounds could be cyclized by heat and the latter (100, X = 0) is a likely intermediate in the synthesis of the dione (98) by the fusion with urea.
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