Transformations of diethyl 2-[(dimethylamino)methylene]-3-oxopentanedioate. A simple synthesis of substituted 2-amino-5-oxo-5,6-dihydropyrido[4,3-d] pyrimidine-8-carboxylates

Article abstract of DOI:10.3987/COM-08-S(F)90

Diethyl 2-[(dimethylamino)methylene]-3-oxopentanedioate (2), prepared from acetone- 1,3-dicarboxylates (1) and N,N-dimethylformamide dimethyl acetal (DMFDMA) was, without isolation, transformed by treatment with guanidine hydrochloride into ethyl 2-amino-

Full text of DOI:10.3987/COM-08-S(F)90

HETEROCYCLES, Vol. 77, No. 2, 2009
899
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 899 - 908. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd July, 2008, Accepted, 24th September, 2008, Published online, 25th September, 2008
DOI: 10.3987/COM-08-S(F)90
TRANSFORMATIONS OF DIETHYL 2-[(DIMETHYLAMINO)METHY-
LENE]-3-OXOPENTANEDIOATE.
A
SIMPLE
SYNTHESIS
OF
SUBSTITUTED 2-AMINO-5-OXO-5,6-DIHYDROPYRIDO[4,3-d]PYRI-
MIDINE-8-CARBOXYLATES
Silvo Zupančič, Jurij Svete, and Branko Stanovnik*
Faculty of Chemistry and Chemical Technology, University of Ljubljana,
Aškerčeva 5, P. O. Box 537, 1000 Ljubljana, Slovenia
E-mail: branko.stanovnik@fkkt.uni-lj.si
Dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his
75th birthday
Abstract – Diethyl 2-[(dimethylamino)methylene]-3-oxopentanedioate (2),
prepared from acetone-1,3-dicarboxylates (1) and N,N-dimethylformamide
dimethyl acetal (DMFDMA) was, without isolation, transformed by treatment
with guanidine hydrochloride into ethyl 2-amino-4-(2-ethoxycarbonylmethyl)-
pyrimidine-5-carboxylate (3). Compound 3 was transformed with DMFDMA first
into intermediate 4 and with an excess of DMFDMA into ethyl
4-[1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dimethylamino)methyle
neamino]pyrimidine-5-carboxylate (5). By treatment of compound 5 with
ammonia, primary amines, hydrazine or hydroxylamine intermediates 6a-j were
formed, which cyclized into 6-substituted 2-amino-5-oxo-5,6-dihydro-
pyrido[4,3-d]pyridine-8- carboxylates (7a-j).
INTRODUCTION
There are many methods described in the literature for the synthesis of pyridopyrimidines.1-3 Recently,
they have been prepared from 4-amino-6-chloro-5-phenyl-2-methylthiopyrimidine4 and from 4-amino-1-
benzyl-1,2,5,6-tetrahydropyridine-3-carboxylate.5 They are well-known pharmacophores,6,7 PDE-
inhibitors,8 inhibitors of tyrosine kinase activity in the epidermal growth factor receptor.9,10

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HETEROCYCLES, Vol. 77, No. 2, 2009
In connection with our interest in enaminones and related compounds, as building blocks for the
preparation of various heterocyclic systems,11 including also some natural products,12,13 dialkyl
acetone-1,3-dicarboxylates have been recently employed for the synthesis of heteroaryl substituted
pyrimidines,14 dialkyl 1-substituted 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates,15 pyrazolo[4,3-d]-
pyridine-7-carboxylates,16 pyrazolyl substituted pyridopyrimidines, pyranopyranediones, chromene-
diones,17 and pyrazolo[4,3-d][1,2]diazepines.18,19 We recently reported an efficient method for the
preparation and functionalisation of highly substituted 1-aminopyrroline, 1-aminopyrrole and
oxazoline-pyrroline fused systems from 1,2-diaza-1,3-butadienes and 3-dimethylaminopropenoates,20 and
the regio- and stereoselective one-pot synthesis of oxazoline-fused pyridazine via a “Michael
addition-pyridazine-cyclisation-oxazoline cyclisation” cascade reaction.21 Many fused pyrimidines are
formed by cyclisation of 3-heteroarylaminopropenoates, derived from 2-substituted 3-(dimethyl-
amino)propenoates and heterocylic α-amino compounds.11,22
RESULTS AND DISCUSSION
Diethyl acetone-1,3-dicarboxylate (1) gave with N,N-dimethylformamide dimethyl acetal (DMFDMA)
diethyl 2-[(2-dimethylamino)methylene]-3-oxopentanedioate (2), which was without isolation
transformed with guanidine hydrochloride into ethyl 2-amino-4-(2-ethoxycarbonylmethyl)pyrimidine-5-
carboxylate (3). When compound 3 was treated with one equivalent of DMFDMA in EtOH, amino group
at 2 position was transformed into dimethylaminomethylene amino group to form intermediate 4. By
further treatment with DMFDMA in n-propyl acetate as solvent under reflux also active methylene group
at 6-position was transformed into dimethylaminomethylene group to give ethyl 4-[1-(dimethyl-
amino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dimethylamino)methyleneamino]pyrimidine-5-carboxylate (5).
In the reaction of compound 5 with ammonia, primary amines, or hydrazine first the
dimethylaminomethylene group at 2-position was transformed into free amino group, followed by
substitution of the dimethylamino group on the side chain to give intermediates 6a-j, which were without
isolation cyclised into ethyl 6-substittued 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-
carboxylates (7a-i). Compound 5 was with hydroxylamine hydrochloride transformed into the
corresponding 6-hydroxy derivative (7j) (Scheme 1, Table 1).
STRUCTURE DETERMINATION
1
The structures of new compounds were determined by spectroscopic methods (IR, H and 13C NMR
spectroscopy, MS) and by elemental analyses for C, H, and N. 1H NMR spectrum of compound 3 exhibits

HETEROCYCLES, Vol. 77, No. 2, 2009
901
Me2N
EtO2C
CO2Et
i
ii
EtO2C
CO2Et
O
O
1
2
N
N
CHNMe2
N
NH2
N
EtO2C
EtO2C
iii
EtO2C
EtO2C
iv
N
4
3
CO2Et
CO2Et
RHN
R1
N
NH2
Me2N
N
N
CHNMe2
v
O
N
N
EtO2C
O
6a-i
5
vi
CO2Et
CO2Et
CO2Et
HOHN
N
N
CHNHOH
N
N
CHNHOH
N
NH2
N
N
O
N
N
N
HO
R
R
O
O
O
7j
7a-i
6j
Scheme 1. (i) DMFDMA, EtOH, rt, 45 min; (ii) guanidine hydrochloride, EtOH, reflux, 1h; (iii)
DMFDMA (1 equiv.), EtOH, reflux, 1h; (iv) DMFDMA (1.5 equiv.) EtOH, reflux, 6h; (v) RNH2 (3
equiv.), n-PrOAc, aq. HCl, (catalytic amount), reflux, 5h; (vi) NH2OH X HCl (3 equiv.), EtOH, reflux, 5h.
Table 1. 6-Substituted 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylates (7a-j)
Yield (%) Mp (oC) solvent
Comp
R
7
a
b
c
H
96.5
93.1
39.5
289 – 291 (DMF)
298 – 300 (DMF)
240 – 245 (EtOH)
Me
CH2CH2OH

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HETEROCYCLES, Vol. 77, No. 2, 2009
iPr
83.6
74.7
87.9
67.7
170 –174 (EtOH)
d
e
f
cyclopropyl
benzyl
239 – 240 (DMF)
204 – 209 (DMF)
238 – 245 (EtOH)
240 – 246 (DMF)
278 – 290 (DMF)
245 – 250 (DMF)
4-methoxybenzyl
g
h
i
ethoxycarbonylmethyl 96.2
NH2
OH
93.9
92.6
j
two triplets at δ = 1.17 and 1.26 ppm and two quartets at δ = 4.07 and 4.20 ppm for two ester groups, a
singlet at δ = 3.91 ppm for CH2 group, a singlet at δ = 7.52 ppm for NH2 and a singlet at δ = 8.71 ppm for
H4. Compound 4 shows two triplets at δ = 1.25 and 1.38 ppm and two quartets at δ = 4.15 and 4.35 ppm
for two ester groups, a singlet at δ = 4.15 ppm for CH2 group and a singlet at δ = 8.81 ppm for H4 two
sinlets at δ = 3.22 and 3.25 ppm for NMe2 group and a singlet at δ = 9.01 ppm for the amidine proton.
Compound 5 shows again two triplets at δ = 1.13 and 1.32 ppm and two quartets at δ = 4.05 and 4.27 ppm
for two ester groups, a singlet at δ = 8.73 ppm for H4, a broad singlet at δ = 2.83 ppm for the NMe2 group
and a singlet at δ = 7.62 ppm of the dimethylaminomethylene group, two singlets at δ = 3.16 and 3.29
1
ppm for NMe2 and a singlet at δ = 8.87 ppm for the amidine part of the molecule. H NMR spectra of
compounds 7 exhibit two characteristic singlets for protons H4 and H7. While the signal for H4 appears for
all bicyclic compounds at δH4 = 9.00 ppm, the signal for the H7 appears in the range of δH7 = 8.00-8.50
ppm, dependent on the group R attached at 6-position, and the signals characteristic for R group.
EXPERIMENTAL
1
Melting points were determined on a Kofler micro hot stage. The H NMR spectra were obtained on a
Bruker Avance DPX 300 at 300 MHz for 1H and 75.5 MHz for 13C nucleus, using DMSO–d6 and CDCl3,
with TMS as the internal standard, as solvents (δ in ppm, J in Hz). All NMR experiments were carried out
at 302 K. Mass spectra were recorded on an AutoSpecQ spectrometer and Q-TOF Premier spectrometer,
IR spectra on a Perkin-Elmer Spectrum BX FTIR spectrophotometer (ν in cm-1). Microanalyses were
performed on a Perkin-Elmer Series II CHN Analyser 2400. Column chromatography (CC) was
performed on silica gel (Fluka, silica gel 60, 0.04–0.06 mm).
Ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)pyrimidine-5-carboxylate (3)
To a solution of diethyl 1,3-acetonedicarboxylate (0.95, 5 mmol), in EtOH (10 mL), DMFDMA (0.72 mL,
5 mmol) was added and the mixture was stirred at rt for 45 min. Guanidine hydrochloride (478 mg, 5

HETEROCYCLES, Vol. 77, No. 2, 2009
903
mmol) was then added and the mixture was stirred under reflux for 1 h. The volatile components were
evaporated and the crude product was recrystallized from EtOH to give 1. Yield 23% (290 mg), mp
125-127 oC. 1H NMR (DMSO-d6) : 1.17 (t, 3H: OCH2CH3, J = 7.2 Hz), 1.26 (t, 3H: OCH2CH3, J = 7.2
Hz), 3.91 (s, 2H: CH2COOEt), 4.07 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.20 (q, 2H: OCH2CH3, J = 7.2 Hz),
13
7.52 (s, 2H: NH2), 8.71 (s, 1H: H4); C NMR (DMSO-d6) : 14.00, 43.03, 60.18, 60.29, 111.61 (C5),
161.12, 163.89, 164.48, 165.61, 169.19; IR (KBr) ν (cm-1): 3327, 3157, 1732, 1715, 1667, 1266; MS
(M+) m/z: 253. Anal. Calcd for C9H11N3O4 (253.2): C 52.17, H 5.97, N 16.59. Found: C 51.95, H 6.24, N
16.37.
Ethyl 2-[(dimethylamino)methyleneamino]-4-(2-ethoxy-2-oxoethyl)pyrimidine-5-carboxylate (4)
2-Amino-5-ethoxycarbonyl-4-ethoxycarbonylmethylpirimidine (2; 253 mg, 1 mmol) was suspended in
EtOH (3 mL), DMFDMA (0.14 mL, 1 mmol) was added and the mixture was stirred under reflux for 1 h.
Then additional 0.07 mL DMFDMA (0.07 mL, 5 mmol) was added and the reaction mixture was heated
under reflux for 1 h. The mixture was cooled and concentrated under reduced pressure to give an oily
residue, to which Et2O (3 mL) was added and the precipitate was collected by filtration to give 4 Yield
83 % (255 mg), mp 99-101 oC (from t-BuOMe). 1H NMR (CDCl3) : 1.25 (t, 3H: OCH2CH3, J = 7.2 Hz),
1.38 (t, 3H: OCH2CH3, J = 7.2 Hz), 3.22 (s, 3H: N(CH3)2), 3.25 (s, 3H: N(CH3)2), 4.15 (s, 2H:
CH2COOEt), 4.15 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.35 (q, 2H: OCH2CH3, J = 7.2 Hz), 8.81 (s, 1H: H4),
9.01 (s, 1H: =CH); 13C NMR (CDCl3) : 14.11, 35.35, 41.36, 43.84, 60.85, 60.96, 116.84, 159.46, 161.07,
164.96, 165.85, 167.61, 169.66; IR (KBr) ν (cm-1): 2980, 1709, 1634, 1515; MS (M+) m/z: 308. Anal.
Calcd for C14H20N4O4 (308.3): C 54.54, H 6.54, N 18.17. Found: C 54.91, H 6.76, N 18.30.
Ethyl 4-[1-(dimethylamino)-3-ethoxy-3-oxoprop-1-en-2-yl]-2-[(dimethylamino)methyleneamino]py-
rimidine-5-carboxylate (5)
To a solution of compound 2 (3.10 g, 10 mmol) in n-propyl acetate (25 mL) DMFDMA (2.1 mL, 15
mmol) was added. The mixture was stirred under reflux for 6 hours. Then the mixture was cooled and
concentrated under reduced pressure to give an oily residue to which Et2O (5 mL) was added and the
o
precipitate was collected by filtration to give 5. Yield 55 % (1.78 g), mp 142-144 C (from tert-butyl
1
methyl ether). H NMR (CDCl3) : 1.13 (t, 3H: OCH2CH3, J = 7.2 Hz), 1.32 (t, 3H: OCH2CH3, J = 7.2
Hz), 2.83 (br s, 6H: C=CHN(CH3)2), 3.16 (s, 3H: N=CHN(CH3)2), 3.19 (s, 3H: N=CHN(CH3)2), 4.05 (q,
2H: OCH2CH3, J = 7.2 Hz), 4.27 (q, 2H: OCH2CH3, J = 7.2 Hz), 7.62 (s, 1H: C=CHN(CH3)2), 8.73 (s,
13
1H: H4), 8.87 (s, 1H: N=CHN(CH3)2); C NMR (CDCl3) : 14.17, 14.30, 35.22, 41.15, 43.93, 59.52,
60.63, 98.35, 119.35, 151.34, 158.77, 159.54, 165.76, 165.93, 166.63, 168.20; IR (KBr) ν (cm-1): 3420,
2984, 1690, 1600, 1563, 1426; MS (M+) m/z: 363. Anal. Calcd for C17H25N5O4 (363.4): C 56.19, H 6.93,

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HETEROCYCLES, Vol. 77, No. 2, 2009
N 19.27. Found: C 56.34, H 7.16, N 19.25.
6-Substituted ethyl 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7a-j).
General procedure.
363 mg (1 mmol) of compound 3 was dissolved in 5 mL of EtOH and 3 mmol of the corresponding amine
and one drop of concentrated HCl was added. The mixture was stirred under reflux for 5 h. Then the
mixture was cooled on the ice bad and the product was filtered. The crude product was recrystallised from
corresponding solvent.
Ethyl 2-amino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7a)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5 mL), and 25 % NH4OH (0.20 mL, 3
o
1
mmol). Yield 97 % (225 mg), mp 289-291 C (from DMF). H NMR (DMSO-d6) : 1.30 (t, 3H:
OCH2CH3, J = 6.9 Hz), 4.22 (q, 2H: OCH2CH3, J = 6.9 Hz), 7.44(br s, 2H: NH2), 8.01 (s, 1H: H7), 8.97 (s,
13
1H: H4), 11.69 (br s, 1H: NH); C NMR (DMSO-d6) : 14.17, 60.08, 106.83, 109.59, 143.17, 158.67,
160.33, 161.22, 163.22, 164.19; IR (KBr) ν (cm-1): 3429, 3140, 1717, 1674, 1614, 1443; MS (M+) m/z:
234. Anal. Calcd. for C10H10N4O3 (234.2): C 51.28, H 4.30, N 23.92. Found: C 51.42, H 4.02, N 23.60;
HRMS: Calcd. for C10H10N4O3: 234,075290, found: 234,076020.
.
Ethyl 2-amino-6-methyl-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7b)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and methylamine (aqueous sol.
1
11.8 M, 0.25 mL, 3 mmol) Yield 93 % (230 mg), mp 298-300 oC (from DMF). H NMR (DMSO-d6) :
1.31 (t, 3H: OCH2CH3, J = 7.2 Hz), 3.48 (s, 3H: CH3), 4.24 (q, 2H: OCH2CH3, J = 7.2 Hz), 7.43 (br.s,
13
2H: NH2), 8.40 (br s, 1H: H7), 9.00 (s, 1H: H4); C NMR (DMSO-d6) : 14.22, 36.17, 60.15, 106.71,
108.96, 147.41, 157.82, 160.55, 160.84, 163.23, 163.99; IR (KBr) ν (cm-1): 3375, 3184, 1729, 1641,
1574; MS (M+) m/z: 248. Anal. Calcd for C11H12N4O3 (248.2): C 53.22, H 4.87, N 22.57. Found: C 53.17,
H 4.92, N 22.63.
Ethyl 2-amino-6-(2-hydroxyethyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7c)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and ethanolamine (0.18 mL, 3
o
1
mmol). Yield 40 % (112 mg), mp 240-245 C (from EtOH). H NMR (DMSO-d6): 1.31 (t, 3H:
OCH2CH3, J = 6.9 Hz), 3.65 (m, 2H: NCH2), 4.01 (m, 2H: CH2OH), 4.25 (q, 2H: OCH2CH3, J = 6.9 Hz)
4.93 (t, 1H: CH2OH, J = 5.7 Hz), 7.44 (br s, 2H: NH2), 8.30 (s, 1H: H7), 9.01 (s, 1H: H4); 13C NMR
(DMSO-d6): 14.24, 50.96, 58.56, 60.16, 106.27, 109.07, 147.72, 157.87, 160.52, 160.66, 163.35,
164.03; IR (KBr) ν (cm-1): 3385, 3177, 1716, 1680, 1650, 1611, 1468; MS (M+) m/z: 278. Anal. Calcd

HETEROCYCLES, Vol. 77, No. 2, 2009
905
for C12H14N4O4 (278.3): C 51.80, H 5.07, N 20.13. Found: C 52.09, H 5.33, N 20.07.
Ethyl 2-amino-6-isopropyl-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7d)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5 mL), and isopropylamine (0.26 mL, 3
o
1
mmol). Yield 84 % (232 mg), mp 170-174 C (from EtOH). H NMR (DMSO-d6) : 1.34 (m, 9H:
OCH2CH3, CH(CH3)2), 4.26 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.01 (m, 1H: CH, J = 6.6 Hz), 7.44 (br s, 2H:
NH2), 8.25 (s, 1H: H7), 9.02 (s, 1H: H4); 13C NMR (DMSO-d6): 14.19, 21.03, 46.83, 60.36, 107.90,
109.05, 141.86, 157.15, 160.14, 160.88, 163.60, 164.07; IR (KBr) ν (cm-1): 3430, 3175, 1735, 1630, 1574,
1188. Anal. Calcd for C13H16N4O3 (276.3): C 56.51, H 5.84, N 20.28. Found: C 56.60, H 5.94, N 20.06.
Ethyl 2-amino-6-cyclopropyl-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7e)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and cyclopropylamine (0.21 mL, 3
o
1
mmol). Yield 75 % (206 mg), mp 239-240 C (from DMF). H NMR (DMSO-d6) : 0.85-0.92 (m, 2H:
CH2 (cyclopropyl)), 0.96 - 1.06 (m, 2H: CH2 (cyclopropyl)), 1.31 (t, 3H: OCH2CH3, J = 7.2 Hz),
3.22.-.3.31 (m, 1H: CH (cyclopropyl)), 4.24 (q, 2H: OCH2CH3, J = 7.2 Hz), 7.44 (br s, 2H: NH2), 8.11 (s,
13
1H: H7), 8.99 (s, 1H: H4); C NMR (DMSO-d6): 6.35, 14.21, 31.86, 60.29, 106.96, 109.08, 145.90,
157.51, 160.60, 161.51, 163.27, 164.09; IR (KBr) ν (cm-1): 3414, 3163, 1723, 1670, 1634, 1574. Anal.
Calcd for C13H14N4O3 (274.3): C 56.93, H 5.14, N 20.43. Found: C 57.01, H 5.25, N 20.34.
Ethyl 2-amino-6-benzyl-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7f)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5 mL), and benzylamine (0.33 mL, 3
o
1
mmol). Yield 88 % (285 mg), mp 204-209 C (from DMF). H NMR (DMSO-d6): 1.30 (t, 3H:
OCH2CH3, J = 7.2 Hz), 4.24 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.19 (s, 2H: CH2Ph), 7.26 - 7.40 (m, 5H: Ph),
13
7.50 (br s, 2H: NH2), 8.50 (s, 1H: H7), 9.02 (s, 1H: H4); C NMR (DMSO-d6): 14.19, 50.81, 60.34,
107.75, 109.13, 127.55, 127.63, 128.66, 136.90, 146.30, 157.80, 160.44, 160.82, 163.28, 164.11; IR
(KBr) ν (cm-1): 3475, 3175, 1640, 1579, 1456. Anal. Calcd for C17H16N4O3 (324.3): C 62.95, H 4.97, N
17.27. Found: C 63.23, H 4.87, N 17.28.
Ethyl 2-amino-6-(4-methoxybenzyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7g)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5 mL), and 4-methoxybenzylamine (0.39
o
1
mL, 3 mmol). Yield 68 % (240 mg), mp 238-245 C (from EtOH). H NMR (DMSO-d6) : 1.30 (t, 3H:
OCH2CH3 , J = 7.2 Hz), 3.73 (s, 3H: OCH3), 4.24 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.10 (s, 2H: CH2Ph),
6.91 (d, 2H: Ar, J = 9.0 Hz), 7.30 (d, 2H: Ar, J = 9.0 Hz), 7.48 (br s, 2H: NH2), 8.47 (s, 1H: H7), 9.01 (s,
1H: H4); 13C NMR (DMSO-d6) : 14.18, 50.19, 55.09, 60.31, 107.65, 109.12, 144.05, 128.81, 129.34,

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HETEROCYCLES, Vol. 77, No. 2, 2009
146.06, 157.71, 158.84, 160.41, 160.78, 163.32, 164.07; IR (KBr) ν (cm-1): 3398, 3190, 1727, 1677, 1632,
1568. Anal. Calcd for C18H18N4O4 (354.4): C 61.01, H 5.12, N 15.81. Found: C 60.69, H 5.21, N 15.82.
Ethyl 2-amino-6-(2-ethoxycarbonylmethyl)-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxy-
late (7h)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and glycine ethyl ester
o
1
hydrochloride (419 mg, 3 mmol). Yield 96 % (307 mg), mp 240-246 C (from DMF). H NMR
(DMSO-d6): 1.22 (t, 3H: CH2COOCH2CH3, J = 7.2 Hz), 1.31 (t, 3H: OCH2CH3, J = 7.2 Hz), 4.16 (q,
2H: CH2COOCH2CH3, J = 7.2 Hz), 4.23 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.79 (s, 2H: CH2COOCH2CH3),
13
7.55 (br s, 2H: NH2), 8.45 (s, 1H: H7), 8.99 (s, 1H: H4); C NMR (DMSO-d6): 14.02, 14.21, 49.51,
60.33, 61.22, 107.46, 108.69, 146.96, 158.08, 160.33, 160.67, 163.13, 164.20, 168.03; IR (KBr) ν (cm-1):
3501, 3170, 1750, 1687, 1663, 1631, 1576. Anal. Calcd for C14H16N4O5 (320.3): C 52.50, H 5.03, N
17.49. Found: C 52.78, H 5.08, N 17.29.
Ethyl 2,6-diamino-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-carboxylate (7i)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and hydrazine (0.094 mL, 3 mmol)
o
1
Yield 94 % (234 mg), mp 278-290 C (from DMF). H NMR (DMSO-d6): 1.30 (t, 3H: OCH2CH3, J =
7.2 Hz), 4.23 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.99 (s, 2H: NNH2), 7.46 (rs, 2H: NH2), 8.31 (s, 1H: H7),
13
9.04 (s, 1H: H4); C NMR (DMSO-d6): 14.17, 60.18, 105.48, 108.69, 146.48, 157.17, 159.93, 160.58,
162.72, 163.93; IR (KBr) ν (cm-1): 3373, 3178, 1728, 1650, 1619, 1573, 1205; MS (M+) m/z: 249. Anal.
Calcd for C10H11N5O3 (249.2): C 48.19, H 4.45, N 28.10. Found: C 47.96, H 4.72, N 28.05.
Ethyl 6-hydroxy-2-[(hydroxyamino)methyleneamino]-5-oxo-5,6-dihydropyrido[4,3-d]pyrimidine-8-
carboxylate (7j)
This compound was prepared from 3 (363 mg, 1 mmol), EtOH (5mL), and hydroxylamine (50 % aqueous
sol. 0.20 mL, 3 mmol). Yield 93 % (272 mg), mp 245-250 oC (from DMF). 1H NMR (DMSO-d6) : 11.33
(t, 3H: OCH2CH3, J = 7.2 Hz), 4.29 (q, 2H: OCH2CH3, J = 7.2 Hz), 7.94 (d, 1H: NHCH=NOH, J = 9.6
Hz), 8.63 (s, 1H: H7), 9.26 (s, 1H: H4), 9.69 (br d, 1H: NHCH=NOH), 10.61 (br s, 2H: OH,
NHCH=NOH); IR (KBr) ν (cm-1): 3342, 1725, 1677, 1588, 1541; MS (M+) m/z: 293. Anal. Calcd for
C11H11N5O5 (293.3): C 45,06, H 3,78, N 23,88. Found: C 44,88, H 4,01, N 23,62.
ACKNOWLEDGEMENTS
The financial support from the Slovenian Research Agency, Slovenia through grants P0-0502-0103,

HETEROCYCLES, Vol. 77, No. 2, 2009
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P1-0179, and J1-6689-0103-04 is gratefully acknowledged. Financial support by the pharmaceutical
companies LEK-SANDOZ, Ljubljana, and KRKA, Novo mesto, is fully appreciated.
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