A Facile Synthesis of New 3-Substituted-2,3-dihydropyrido[3,2-d]pyrimidine-2,4-diones

Article abstract of DOI:10.1081/SCC-120026855

Pyrido[3,2-d]pyrimidine-2,4-diones derivatives have been synthesized in good yields by two efficient synthetic routes, the first one through an hetero-cyclization on the ureas derivatives 3a-e under alkaline conditions, the second one by condensation of the isocyanate 2 with various arylalkylamines in pyridine.

Full text of DOI:10.1081/SCC-120026855

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A Facile Synthesis of New 3-Substituted-2,3-
dihydropyrido[3,2-d]pyrimidine-2,4-diones
R. Mamouni a , M. Akssira a , M. Aadil a , A. Elhakmaoui a , J. Lasri b & E. Zaballos-Garcia b
a Laboratoire de Chimie Bioorganique et Analytique , Université Hassan II-Mohammedia ,
Mohammedia, Morocco
b Departamento de Química Orgánica , Facultad de Farmacia , Universidad de Valencia ,
Burjassot, Valencia, Spain
Published online: 21 Aug 2006.
To cite this article: R. Mamouni , M. Akssira , M. Aadil , A. Elhakmaoui , J. Lasri & E. Zaballos-Garcia (2003) A Facile Synthesis
of New 3-Substituted-2,3- dihydropyrido[3,2-d]pyrimidine-2,4-diones, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 33:24, 4259-4268, DOI: 10.1081/SCC-120026855
To link to this article: http://dx.doi.org/10.1081/SCC-120026855
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 24, pp. 4259–4268, 2003
A Facile Synthesis of New 3-Substituted-2,3-
dihydropyrido[3,2-d ]pyrimidine-2,4-diones
1
1
R. Mamouni,1 M. Akssira,1, M. Aadil, A. Elhakmaoui,
*
J. Lasri,2 and E. Zaballos-Garcia2
1Laboratoire de Chimie Bioorganique et Analytique,
Universite
Mohammedia, Morocco
2Departamento de Quı
mica Organica,
´
´
Hassan II-Mohammedia,
´
Facultad de Farmacia, Universidad de Valencia,
Burjassot, Valencia, Spain
ABSTRACT
Pyrido[3,2-d ]pyrimidine-2,4-diones derivatives have been synthesized
in good yields by two efficient synthetic routes, the first one through
an hetero-cyclization on the ureas derivatives 3a–e under alkaline
conditions, the second one by condensation of the isocyanate 2
with various arylalkylamines in pyridine.
*Correspondence: M. Akssira, Laboratoire de Chimie Bioorganique et
Analytique, Universite Hassan II-Mohammedia, BP 146, 20650 Mohammedia,
´
Morocco; E-mail: hakmaoui@uh2m.ac.ma.
4259
DOI: 10.1081/SCC-120026855
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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4260
Mamouni et al.
Compounds containing a fused pyrimidine ring have attracted
attention in the past few years owing to their wide range of biological
activity, particularly in cancer and virus research.[1] Among these
heterocycles, the pyridopyrimidine class is also of interest as inhibitor
of dihydrofolate reductase but also for its antibacterial,[2] antitumor,[3]
antiepileptic activity,[4] and recently as excellent phosphodiesterase 4
(PDE4) inhibitors.[5] Furthermore the pathologies associated with the
biological system of PDE4 represent some of the more currently
important therapeutic targets such as asthma,[6] type-II diabetes,[7] and
AIDS.[8] Moreover, it has been proved that some of the urea derivatives
established potent activity over a wide spectrum of tumor cell lines and
exhibited a good profile for preclinical antitumoral investigations.[9]
Therefore, the attention of the authors has been mainly devoted on
such compounds with structural and electronic profiles compatible with
proposed pharmacophore.
Despite the extensive literature describing the synthesis of
pyrido[2,3-d ]pyrimidinediones, to the best of our knowledge, few general
process to obtain the pyrido[3,2-d ]pyrimidines have been reported.[10]
In our ongoing research program for new fused heterocyclic
systems,[11] we report here a new rapid and convenient preparation of
new isomeric pyrido[3,2-d ]pyrimidine-2,4-dione derivatives with the
nitrogen of the arylalkylamine component being incorporated in the
fused pyrimidine ring at position 3.
The first alternative synthesis that was designed used the quinolic
acid half-ester
1 as intermediary, obtained by methanolysis of
2,3-pyridine anhydride.[12] Activation of the half-ester 1 by ethyl
chloroformate in the presence of triethylamine and subsequent reaction
with sodium azide in the presence of small amount of water gives the
acyl azide, which was transformed, without purification, by the Curtius
rearrangement into isocyanate 2.
The isocyanate 2 reacted with various arylalkylamines in anhydrous
pyridine at reflux temperature affording directly the fused pyrido-
pyrimidine derivatives 4a–f. In the case of the 4-fluorobenzylamine the
reaction also took place at room temperature in DCM. The synthesis of
compounds 4a–e could be made in two steps by reaction of the amines
with isocyanate 2 at room temperature in DCM or THF and further
conversion of the intermediate derivatives 3a–e into the 3-substituted,-
2,3-dihydropyrido[3,2-d ]pyrimidine-2,4-diones 4a–e under alkaline
conditions. Spectroscopic analyses of 3a–e revealed that only traces of
compounds 4a–e were present in the crude mixtures (Sch. 1).
In conclusion, we have described two efficient and cheap routes for
the obtention of new class of pyrido[3,2-d ]pyrimidinedione derivatives

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3-Substituted-2,3-dihydropyrido[3,2-d ]pyrimidine-2,4-diones
4261
X
H
N
H
N
( )n
O
N
3a-e
CO2CH3
44-80%
(ii)
CO2H
NCO
(i)
(iv)
75-86%
CO2CH3
N
CO2CH3
N
(iii)
79-88%
H
N
1
2
X
O
N
( )n
N
O
4a-e
H
N
(ii)
O
F
NCO
+
65%
NH2-CH2
F
N
N
(iii)
N
CO2CH3
80%
O
4f
2
a)-EtN , ClCO Et
(i)
, -10˚C,Toluene, reflux.
b)-NaN3,H2O
, -10˚C
3
2
(ii)
Arylalkylamine, pyridine,reflux
Arylalkylamine, DCM or THF , r.t (iii)
(iv)
EtONa , EtOH, 80˚C
:
e : n=2, X=F.
d : n=2, X=OH;
c : n=2, X=H;
X
a : n=1, X=H;
b : n=1, X=Cl;
CH
(
)
NH
n
2
2
Arylalkylamine
Scheme 1.
in good yields, starting from the inexpensive 2,3-pyridinedicarboxylic
anhydride. The first method involved an hetero-cyclization via
the ureas derivatives, the second one used a rapid condensation of the
isocyanate 2 with different arylalkylamines in pyridine.
EXPERIMENTAL
Melting points were taken for samples in capillary tubes with
an electro thermal apparatus and are uncorrected. Flash column
chromatography was performed using silica gel (Merck 60, 70–230
mesh). The spectra IR were determined on a ATI Mattson Genesis
1
Series FTIR TMUNICAM instrument. H and 13C NMR spectra were

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4262
Mamouni et al.
recorded on a Bruker AC-300 instrument. Chemical shifts (ꢀ values) and
coupling constants (J values) given in ppm and Hz respectively. MS and
HRMS were obtained using a VG Autospec TRIO 1000 instrument. The
ionization mode used in mass spectra was electron impact (EI) or fast
atom bombardment (FAB). Elemental analyses were recorded by the
Servcio de Microanalisis of the University of Valencia (SCSIE).
Reagents and solvents were purified in the usual way.[13] All these reac-
tions were carried out under an argon atmosphere.
3-Isocyanatepyridine-2-carboxylate (2). To a solution of half-ester 1
(1.0 g, 5.52 mmol) in dry tetrahydrofuran (15 mL) cooled at ꢀ10ꢁC
was added drop-wise triethylamine (1.52 mL, 11.04 mmol) then ethyl
chloroformate (0.79 mL, 8.28 mmol). The mixture was stirred for
30 min at ꢀ10ꢁC. Analysis by TLC showed complete conversion to a
very nonpolar product. A solution of sodium azide (0.61 g, 9.38 mmol)
in water (4 mL) was then added drop wise continued stirring for 1 h at
ꢀ10ꢁC. The resulting mixture was filtered, evaporated, and the aqueous
phase was extracted with ethyl acetate (3 ꢂ 15 mL). The combined
organic layer were washed with brine, dried over magnesium sulfate,
filtered, and concentrated in vacuo. The acyl azide was slowly brought
to reflux in toluene for 2 h to give, after evaporation of the organic layer
in vacuo, the clean isocyanate 2 (0.86 g, 87%). IR (KBr): ꢁ 2260
(N¼C¼O), 1720 (C¼O). 1H NMR (DMSO-d6): ꢀ 4.01 (s, 3H, CH3),
7.50 (dd, 1H, J ¼ 4.6, 8.5 Hz, H5), 8.18 (dd, 1H, J ¼ 1.7, 4.6 Hz, H4),
8.8 (dd, 1H, J ¼ 1.7, 8.5 Hz, H6).
General Procedure for the Preparation of the
Ureido Derivatives 3a–e
To a solution of 3-isocyanatepyridine-2-carboxylate 2 (0.80 g,
4.5 mmol) in dry dichloromethane (7 mL), arylalkylamine (4.5 mmol)
was added, stirred at room temperature for 2–3 h. After evaporation of
the solvent at reduced pressure, the residue was purified using column
chromatography (silica gel, ethyl acetate/hexane: 7/3) to give the urea
derivatives in good to moderate yields 3a–e.
Methyl 3-[3-benzylureido]-2-pyridinecarboxylate (3a). This compound
was obtained as a white solid 80% yield. M.p.: 201–202ꢁC (from petroleum
ether). IR (KBr): ꢁ 3425 (NH), 1730 (C¼O), 1718 (C¼O), 1679 (C¼N).
1H NMR (CDCl3): ꢀ 3.81 (s, 3H, CH3), 4.16 (d, 2H, J ¼ 5.86 Hz, CH2),
6.2 (br s, 1H, NHCH2), 7.1–7.5 (m, 6H, 5Harom þ H5), 8.2 (dd, 1H,
J ¼ 1.2, 4.4 Hz, H4), 8.92 (dd, 1H, J ¼ 1.2, 8.5 Hz, H6), 10.21 (s, 1H,
NH-Py). 13C NMR (CDCl3): ꢀ 44.64 (CH2), 53.13 (CH3), 127.78 (CH),

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3-Substituted-2,3-dihydropyrido[3,2-d ]pyrimidine-2,4-diones
4263
127.85 (2CH), 128.34 (2CH), 128.88 (CH), 129.15 (CH), 138.53 (C),
139.24 (C), 141.06 (C), 142.25 (CH), 154.53 (CO), 167.10 (CO). MS:
m/z 286 [M þ 1].
Anal. calcd. for C15H15N3O3: C, 63.16; H, 5.26; N, 14.74. Found:
C, 63.24; H, 5.23; N, 14.84.
Methyl 3-[3-(4-chlorobenzyl)ureido]-2-pyridinecarboxylate (3b). This
compound was obtained as a white solid 65% yield. M.p.: 196–197ꢁC
(from diethylether/petroleum ether). IR (KBr): ꢁ 3429 (NH), 1731
(C¼O), 1715 (C¼O), 1678, 1603 (C¼N), 1715 (C¼O). 1H NMR
(DMSO-d6): ꢀ 3.87 (s, 3H, CH3), 4.28 (d, 2H, J ¼ 5.8 Hz, CH2),
7.27–7.57 (m, 4H, 4Harom), 8.15 (dd, 1H, J ¼ 4.5, 8.5 Hz, H5), 8.23 (dd,
1H, J ¼ 1.7, 4.5 Hz, H4), 8.71 (dd, 1H, J ¼ 1.7, 8.5 Hz, H6), 9.69 (s, 1H,
NH-Py). 13C NMR (DMSO-d6): ꢀ 42.19 (CH2), 52.33 (CH3), 127.62
(CH), 127.66 (CH), 128.23 (CH), 128.97 (CH), 129.09 (CH), 129.49
(CH), 131.32 (C), 131.68 (C), 138.90 (C), 139.39 (C), 141.60 (CH),
154.62 (CO), 167.16 (CO). MS: m/z 319.5 [M þ 1]. Anal. calcd.
for C15H14ClN3O3: C, 56.34; H, 4.38; N, 13.14. Found: C, 56.40; H,
4.36; N, 13.37.
Methyl 3-[3-ethylphenylureido]-2-pyridinecarboxylate (3c). This
compound was obtained as a white solid 45% yield. M.p.: 188ꢁC (from
petroleum ether). IR (KBr): ꢁ 3460 (NH), 1734 (C¼O), 1718 (C¼O), 1676
1
(C¼N). H NMR (DMSO-d6): ꢀ 3.85 (s, 3H, CH3), 2.98–3.01 (m, 2H,
CH2Ar), 3.42–3.50 (m, 2H, NHCH2), 7.1–7.22 (m, 5H, Harom), 7.79 (dd,
1H, J ¼ 4.5, 8.5 Hz, H5), 8.35 (dd, 1H, J ¼ 1.2, 4.5 Hz, H4), 8.98 (dd, 1H,
J ¼ 1.2, 8.5 Hz, H6), 10.36 (s, 1H, NH-Py). 13C NMR (DMSO-d6): ꢀ 35.60
(CH2), 42.74 (CH2), 53.89 (CH3), 115.12 (2CH), 128.45 (2CH), 128.60
(CH), 129.54 (CH), 129.70 (CH), 138.71 (C), 139.46 (C), 141.50 (C),
142.62 (CH), 154.65 (CO), 166.88 (CO). MS: m/z 300 [M þ 1].
Anal. calcd. for C16H17N3O3: C, 64.21; H, 5.68; N, 14.05. Found:
C, 64.14; H, 5.82; N, 14.01.
Methyl 3-[3-(4-hydroxyethylphenyl)ureido]-2-pyridinecarboxylate (3d).
This compound was obtained as a white solid 48% yield. M.p.:
190–192ꢁC (from diethylether/petroleum ether). IR (KBr): ꢁ 3479
1
(NH), 1720 (C¼O), 1699 (C¼O), 1679 (C¼N). H NMR (DMSO-d6): ꢀ
2.63 (t, 2H, J ¼ 7.53 Hz, CH2Ar), 3.24 (m, 2H, NHCH2), 3.88 (s, 3H,
CH3), 6.67 (d, 2H, J ¼ 8.5 Hz, Harom), 7.01 (d, 2H, J ¼ 8.5 Hz, Harom),
7.52 (dd, 1H, J ¼ 4.5, 8.5 Hz, H5), 7.64 (s, 1H, OH), 8.21 (dd, 1H, J ¼ 1.5,
4.5 Hz, H4), 8.7 (dd, 1H, J ¼ 1.5, 8.5 Hz, H6), 9.54 (s, 1H, NH-Py).
13C NMR (DMSO-d6): ꢀ 34.71 (CH2), 41.27 (CH2), 52.35 (CH3), 115.11
(2CH), 127.62 (CH), 127.74 (CH), 129.45 (CH), 129.52 (CH), 131.71 (C),
139.56 (C), 141.39 (CH), 154.50 (CO), 155.64 (C), 167.13 (CO). MS: m/z
316 [M þ 1].

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4264
Mamouni et al.
Anal. calcd. for C16H17N3O4: C, 60.90; H, 5.40; N, 13.33. Found:
C, 60.81; H, 5.81; N, 13.37.
Methyl 3-[3-(4-Fluoroethylphenyl)ureido]-2-pyridinecarboxylate (3e).
This compound was obtained as a white solid 44% yield. M.p.:
178–180ꢁC (from petroleum ether). IR (KBr): ꢁ 3453 (NH), 1732
1
(C¼O), 1719 (C¼O), 1678 (C¼N). H NMR (DMSO-d6): ꢀ 2.74 (t, 2H,
J ¼ 7.60 Hz, CH2Ar), 3.50–3.60 (m, 2H, NHCH2), 3.9 (s, 3H, CH3), 6.8–7
(m, 2H, Harom), 7.05–7.2 (m, 2H, Harom), 7.58 (dd, 1H, J ¼ 4.5, 8.5 Hz,
H5), 8.28 (dd, 1H, J ¼ 1.2, 4.5 Hz, H4), 8.7 (dd, 1H, J ¼ 1.2, 8.5 Hz, H6),
11.23 (s, 1H, NH-Py). 13C NMR (DMSO-d6): ꢀ 34.50 (CH2), 42.35 (CH2),
52.88 (CH3), 115.15 (2CH), 127.78 (CH), 128.20 (CH), 129.54 (CH),
129.60 (CH), 134.92 (C), 138.75 (C), 139.60 (C), 141.45 (CH), 154.70
(CO), 161.58 (CF), 167.20 (CO). MS: m/z 318 [M þ 1].
Anal. calcd. for C16H16N3O3F: C, 60.57; H, 5.05; N, 13.25. Found:
C, 60.61; H, 5.05; N, 13.48.
General Procedure for the Preparation of
Pyridopyrimidine Derivatives 4a–f
Method A
The appropriate urea derivatives 3a–e in ethanol (10 mL) were added
to a solution of sodium (1.1 equiv.) in ethanol (10 mL). The mixture was
stirred at 80ꢁC for 8 h. After cooling to room temperature, the solvent
was removed under reduced pressure. The residue was dissolved in water
and acidified with acetic acid (10%) to pH ¼ 2. The precipitate was col-
lected by filtration and washed with diethyl-ether to give the correspond-
ing pyridopyrimidine 4a–e.
Method B
Arylalkylamine (4.5 mmol) was dissolved in 10 mL of pyridine.
Isocyanate 2 (0.80 g, 4.5 mmol) dissolved in minimum of toluene
was added, and the mixture was refluxed for 6 h. The dark red solution
was evaporated to dryness. The residue was refluxed with 15 mL of
ethanol; the precipitate was filtered out and washed with ethanol to led
pyridopyrimidine derivatives 4a–e. In the case of the 4-fluorobenzylamine
the reaction in DCM at room temperature afforded directly compound 4f.

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3-Substituted-2,3-dihydropyrido[3,2-d ]pyrimidine-2,4-diones
4265
3-(Benzyl)-1,2-dihydropyrido[3,2-d ]pyrimidine-2,4-dione (4a). This
compound was obtained as a white solid from ethyl acetate, with
method A (80% yield), with method B (82% yield). M.p.: 346ꢁC. IR
1
(KBr): ꢁ 3419 (NH), 1735 (C¼O), 1702 (C¼O), 1680 (C¼N). H NMR
(DMSO-d6): ꢀ 5.1 (s, 2H, CH2), 7.2–7.4 (m, 5H, Harom), 7.61 (dd, 1H,
J ¼ 1.5, 8.0 Hz, H8), 7.67 (dd, 1H, J ¼ 4.0, 8.0 Hz, H7), 8.5 (dd, 1H,
J ¼ 1.5, 4.0 Hz, H6). 13C NMR (DMSO-d6): ꢀ 43.57 (CH2), 123.79
(CH), 127.48 (CH), 128.23 (2CH), 128.32 (2CH), 128.97 (CH), 130.75
(C), 136.94 (C), 137.17 (C), 145.08 (CH), 149.76 (CO), 160.65
(CO).
HRMS Calcd. for C14H11N3O2 253.0851. Found: 253.0852.
3-(4-Chlorobenzyl)-1,2-dihydropyrido[3,2-d ]pyrimidine-2,4-dione (4b).
This compound was obtained as a white solid from ethyl acetate, with
method A (75% yield), with method B (88% yield). M.p.: 362ꢁC. IR
1
(KBr): ꢁ 3443 (NH), 1734 (C¼O), 1720 (C¼O), 1678 (C¼N). H NMR
(DMSO-d6): ꢀ 5.08 (s, 2H, CH2), 7.26–7.46 (m, 4H, Harom), 7.57 (dd, 1H,
J ¼ 1.5, 8.0 Hz, H8), 7.70 (dd, 1H, J ¼ 4.0, 8.0 Hz, H7), 8.5 (dd, 1H,
J ¼ 1.5, 4.0 Hz, H6), 11.63 (s, 1H, NH). 13C NMR (DMSO-d6): ꢀ 42.99
(CH2), 123.75 (CH), 128.25 (2CH), 128.97 (C), 129.48 (2CH), 130.76
(CH), 131.68 (C), 136.17 (C), 136.90 (C), 145.08 (CH), 149.67 (CO),
160.61 (CO).
HRMS Calcd. for C14H10ClN3O2 287.0461. Found: 287.0458.
3-(Ethylphenyl)-1,2-dihydropyrido[3,2-d ]pyrimidine-2,4-dione
(4c).
This compound was obtained as a white solid from ethyl acetate,
with method A (70% yield), with method B (79% yield). M.p.: 329ꢁC.
IR (KBr): ꢁ 3456 (NH), 1731 (C¼O), 1717 (C¼O), 1680 (C¼N).
1H NMR (CDCl3 þ TFA): ꢀ 2.86–2.97 (m, 2H, CH2Ar), 4.17–4.28 (m,
2H, CH2N), 7.00–7.26 (m, 5H, Harom), 7.78 (dd, 1H, J ¼ 1.5, 8.0 Hz,
H8), 7.92 (dd, 1H, J ¼ 4.0, 8.0 Hz, H7), 8.76 (dd, 1H, J ¼ 1.5, 4.0 Hz,
H6), 10.93 (s, 1H, NH). 13C NMR (CDCl3 þ TFA): ꢀ 33.47 (CH2),
43.45 (CH2), 126.93 (CH), 127.68 (C), 128.53 (2CH), 128.69 (2CH),
128.88 (CH), 130.61 (CH), 136.59 (C), 137.31 (C), 144.06 (CH), 151.43
(CO), 158.52 (CO).
HRMS Calcd. for C15H13N3O2: 267.1008. Found: 267.1014.
3-(4-Hydroxyethylphenyl)-1,2-dihydropyrido[3,2-d ]pyrimidine-2,4-dione
(4d). This compound was obtained as a white solid from ethyl acetate,
with method A (86% yield), with method B (82% yield). M.p.: 320ꢁC. IR
1
(KBr): ꢁ 3373 (NH), 1719 (C¼O), 1702 (C¼O), 1675 (C¼N). H NMR
(DMSO-d6): ꢀ 2.7–2.8 (m, 2H, CH2Ar), 3.98–4.10 (m, 2H, CH2N), 6.68
(d, 2H, J ¼ 8.5 Hz, Harom), 7.01 (d, 2H, J ¼ 8.5 Hz, Harom), 7.58 (dd, 1H,
J ¼ 1.5, 8.0 Hz, H8), 7.64 (dd, 1H, J ¼ 4.0, 8.0 Hz, H7), 8.48 (dd, 1H,
J ¼ 1.5, 4.0 Hz, H6). 13C NMR (DMSO-d6): ꢀ 32.36 (CH2), 42.00 (CH2),

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4266
Mamouni et al.
115.23 (2CH), 123.66 (CH), 128.62 (CH), 128.81 (CH), 129.51 (CH),
130.79 (C), 136.82 (C), 136.84 (C), 144.92 (CH), 149.55 (CO), 155.80
(C), 160.42 (CO).
HRMS Calcd. for 283.0956. Found: 283.0945.
3-(4-Fluoroethylphenyl)-1,2-dihydropyrido[3,2-d ]pyrimidine-2,4-dione
(4e). This compound was obtained as a white solid from ethyl acetate,
with method A (82% yield), with method B (84% yield). M.p.: 332ꢁC. IR
1
(KBr): ꢁ 3460 (NH), 1735 (C¼O), 1718 (C¼O), 1676 (C¼N). H NMR
(DMSO-d6): ꢀ 2.87 (t, 2H, J ¼ 7.53 Hz, CH2Ar), 4.09 (t, 2H, J ¼ 7.53 Hz,
CH2N), 7.11–7.33 (m, 4H, Harom), 7.53–7.70 (m, 2H, H7 and H8), 8.50
(dd, 1H, J ¼ 1.5, 4.0 Hz, H6), 11.51 (s, 1H, NH). 13C NMR (DMSO-d6): ꢀ
32.34 (CH2), 41.68 (CH2), 115.02 (CH), 115.30 (CH), 123.64 (CH), 128.87
(CH), 130.44 (CH), 130.54 (CH), 130.76 (C), 134.78 (C), 136.74 (C),
144.99 (CH), 149.51 (CO), 160.43 (CO), 161.43 (CF).
HRMS Calcd. for C15H12FN3O2: 285.0914. Found: 285.0911.
3-(4-Fluorobenzyl)-1,2-dihydropyrido[3,2-d ]pyrimidine-2,4-dione (4f ).
To a solution of 3-isocanatopyridine-2-carboxylate 2 (0.80 g, 4.5 mmol)
in dry dichloromethane (7 mL), 4-fluorobenzylamine (4.5 mmol) was
added, stirred at room temperature for 3 h. The precipitate was collected
by filtration and washed with diethyl-ether to give the corresponding
pyridopyrimidine 4f (65% yield). M.p.: 396ꢁC (from ethanol). IR
1
(KBr): ꢁ 3435 (NH), 1734 (C¼O), 1717 (C¼O), 1679 (C¼N). H NMR
(CDCl3 þ TFA): ꢀ 5.24 (s, 2H, CH2), 6.98–7.1 (m, 2H, Harom,), 7.4–7.5
(m, 2H, Harom), 8.23 (dd, 1H, J ¼ 1.5, 8.0 Hz, H8), 8.35 (dd, 1H, J ¼ 4.0,
8.0 Hz, H7), 8.93 (dd, 1H, J ¼ 1.5, 4.0 Hz, H6). 13C NMR (DMSO-d6): ꢀ
45.24 (CH2), 115.69 (CH), 115.98 (CH), 120.06 (C), 129.69 (C), 129.73
(C), 131.44 (CH), 131.56 (CH), 131.94 (CH), 133.37 (CH), 137.72 (C),
141.06 (CH), 151.11 (CO), 155.51 (CF), 156.21 (CO).
HRMS Calcd. for C14H10FN3O2: 271.0756. Found: 271.0757.
This compound was obtained by method B with the same character-
istics described above in 80% yield.
ACKNOWLEDGMENTS
The authors would like to acknowledge the financial support
provided by the ministry ESRSFC of the Moroccan Government
(PROTARS P2T2/07) and Mr. J. Sepulveda-Arques from Universidad
de Valencia, Spain (Departamento de Quimica Organica, Facultad de
Farmacia, for Spectral Data.

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Received in the UK July 24, 2003