Convenient synthesis of 3-(1-carboxyalkyl)pyrido-[2,3-d]pyrimidine-2,4-diones

Article abstract of DOI:10.1023/A:1015635303954

A cheap and safe synthetic route to obtain 3-(1-carboxyalkyl)pyrido[2,3-d]pyrimidinediones (carboxyalkyl = -CHRCO₂H; R = H; CH₂; CH₂Ph: Ph; CH₂ (C₃H₃N₂); (CH₂)₂CO₂H; CH₂CO₂H) starting from 2,3-pyridinedicarboxylic acid is described. A process scheme consistent with empirical observations is proposed.

Full text of DOI:10.1023/A:1015635303954

Chemistry of Heterocyclic Compounds, Vol. 38, No. 3, 2002
CONVENIENT SYNTHESIS OF
3-(1-CARBOXYALKYL)PYRIDO-
[
2,3-d]PYRIMIDINE-2,4-DIONES
1
1
1
2
M. Saoud , F. B. Benabdelouahab , F. El Guemmout , and A. Romerosa
A cheap and safe synthetic route to obtain 3-(1-carboxyalkyl)pyrido[2,3-d]pyrimidinediones
(
carboxyalkyl = –CHRCO
2
H; R = H; CH
2
; CH
2
Ph; Ph; CH
2
(C
3
H
3
N
2
); (CH
2
)
2
CO
2
H; CH
2
CO H)
2
starting from 2,3-pyridinedicarboxylic acid is described. A process scheme consistent with empirical
observations is proposed.
Keywords: amino acids, pyrido[2,3-d]pyrimidine, pyridinecarboxylic acids.
Pyrimidine derivatives are common sources for new potential therapeutic agents. In particular,
pyrido[2,3-d]pyrimidines have been found to have important biological properties such as antibacterial or
antitumor activities [1-5]. Despite this fact and the ubiquitous character of that kind of compounds, few general
processes to obtain 3-(1-carboxyalkyl)pyrido[2,3-d]pyrimidine-2,4-diones have been reported, which is quite
surprising considering the intense research activity centered on such compounds [6, 7]. On the other hand, the
utility of compounds with notable biological properties could be limited by its synthetic cost. This premise
demands an accurate selection of reagents, solvents, and procedures. We now wish to report a general method,
cheap and safe, for the successful synthesis of 3-(1-carboxyalkyl)pyrido[2,3-d]pyrimidine-2,4-dione derivatives.
A convenient starting compound to obtain the desired pyridopyrimidinediones was found to be the
2
,3-pyridinedicarboxylic acid (1), which is a cheap, stable, and nontoxic compound.
This reagent was easily dehydrated in refluxed acetic anhydride to give anhydride 2. Previous report [8]
showed that 2 reacts with refluxed methanol to afford two isomeric methyl carboxypyridinecarboxylates 3a and
3
b (Scheme 1), 3a increasing as the heating is prolonged.
Scheme 1
O
CO H
2
Ac O
MeOH/∆
2
O
∆
N
CO H
N
2
O
1
2
CO Me
CO H
2
2
Heating
prolonged
N
CO H
N
CO Me
2
2
3
a
3b
_
_________________________________________________________________________________________
1
2
Univ. Abdelmalek Essaadi, Fac. of Sciences-Tetouan, B. P. 2121, Tetouan, Morroco. Area de Quimica
Inorganica, Facultad de Ciencias, Universidad de Almeria, 04071, Almeria, Spain; e-mail: romerosa@ual.es.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 342-345, March, 2002. Original article
submitted December 14, 2000.
3
06
0009-3122/02/3803-0306$27.00©2002 Plenum Publishing Corporation

Reaction of monoester 3a with ClCO
unstable anhydride 4. This compound is moisture sensitive, decomposing on air within 1 h. If dried solvent and
atmosphere was used, the compound remained stable for a time longer than 1 day. It was determined by
using thin layer chromatography standard methods that a fresh solution of 4 had to be used in 30 min.
Compound 4 prepared in such a manner reacted with an aqueous solution of NaN to afford the acyl azide 5
2
Et in dry basic media (NEt
3
/KOH) led to the formation of the
N
2
3
-1
with the CON
3
group in position 2, which was characterized by the ν(N ) IR absorption (2160 cm ). Refluxing
3
azide 5 in toluene gaves rise to isocyanate 6 by the Curtius rearrangement [9, 10], which was supported by IR
and elemental analysis.
Scheme 2
CO Me
CO Me
CO Me
2
2
2
NaN /H O
ClCO Et/NEt , 0 °C
3
2
2
3
N
CO H
N
CO COEt
N
CON3
2
2
3
a
4
5
Toluene/∆
O
N
R
O
CO Me
2
CO H
2
N
N
H
α−amino acids:
N
NCO
glycine (7); L-alanine (8); L-phenylalanine (9);
L-phenylglycine (10); L-histidine (11);
L-glutamic acid (12); L-aspartic acid (13)
6
1
4–20
R = H (14); Me (15); CH Ph (16); Ph (17); CH (C H N ) (18); (CH ) CO H (19); CH CO H (20)
2
2
3
3
2
2 2
2
2
2
Finally, reaction of α-amino acids 7-13 with isocyanate 6 in an alkaline (NaOH, pH 8-9) refluxed
dioxane/water mixture gave the desired 3-sub-stituted pyrido[2,3-d]pyrimidine-2,4-diones 14-20 in good yield
(
Scheme 3).
A pathway for this step likely includes (Scheme 3) attack of the α-amino acid nitrogen atom on the
isocyanate group carbon, which leads to the formation of the ortho-carbomethoxyureide intermediate 21.
Subsequent ring closure with elimination of methanol gives rise to compounds 14-20.
Scheme 3
MeO
CO Me
O
2
NH CH(R)CO H
2
2
H
N
–
N
NCO
N
NH CO H
– MeOH
2
O
R
6
2
1
O
R
N
CO H
2
N
N
H
O
1
4–20
3
07

EXPERIMENTAL
All reagents were of analytical grade and were used without further purification. All reactions were
monitored by thin layer chromatography (TLC) performed on glass-backed silica gel 60 F254, 0.2 mm plates
MERCK), and compounds were visualized under UV light (254 nm). Deuterated solvents for NMR
(
1
13
1
measurements were dried over molecular sieves (0.4 nm). H, C NMR { H} spectra were recorded on Bruker
AVANCE DRX 300 relative to tetramethylsilane. IR spectra were recorded (for KBr discs) on an IR-ATI
Mattson Infinity Series instrument. Mass spectra were obtained using JEOL JMS DX 100 and DX 300
spectrometers. Elemental analysis (C, H, N, S) was performed on an EAGER 200 elemental analyser.
3
-Methyl-2-carboxypyridine-3-carboxylate (3a). A suspension of 2,3-pyridinedicarboxylic acid (1)
1.50 g, 8.98 mmol) in acetic anhydride (15 ml) was refluxed for 4 h under dry air and the resulting solution was
(
kept at 8°C for 12 h. The white precipitate was dissolved in MeOH (20 ml) and stirred at 45°C for 24 h. The
solvent was removed and the solid washed with hexane and recrystallized from hot toluene. Yield 76%;
-1
1
mp 111-113°C. IR spectrum (KBr), ν, cm : 1730 (C=O), 1680 (C=O). H NMR spectrum (CDCl ), δ, ppm: 3.99
3
(
3H, s, OCH
-Carbomethoxy-2-pyridylisocyanate (6). Into an efficiently stirred solution of 3a (1 g, 5.25 mmol) in
THF (15 ml) at 0°C, were slowly added NEt /KOH (1.54 ml, 11.05 mmol) and ClCO Et (0.80 ml, 8.28 mmol).
After 30 min a solution of NaN (0.90 g, 13.74 mmol) in H O (5.40 ml) was slowly added and the mixture
stirred for 1 h at room temperature. The THF was eliminated by reduced pressure and the resulting mixture
3
); 7.40-7.80 (3H, m, Py).
3
3
2
3
2
extracted with AcOEt (3 × 10 ml). The different fractions were collected, dried with Na
2
SO , the solvent
4
removed by reduced pressure, and the resulting yellow solid refluxed in toluene for 2 h. The organic phase was
decanted, concentrated to half volume, and kept at room temperature overnight. The compound precipitated as a
white powder was filtered off, washed with Et O (3 × 5 ml), and air dried. 0.90 g (Yield 91%). IR spectrum
2
-1
(
1
KBr), ν, cm : 2253 (N=C=O), 1725 (C=O). Mass spectrum, found, m/z: 178 [M]. C
8
H
6
N
2
O
3
. Calculated, m/z:
1
78.147. H NMR (CDCl
3
), δ, ppm: 3.90 (3H, s, OCH ); 7.30-7.70 (3H, m, Py).
3
3
-(1-Carboxyalkyl)pyrido[2,3-d]pyrimidine-2,4-diones (14-20). Into H
2
O (10 ml) was introduced the
respective α-amino acids 7-13 (11 mmol) and 1 N NaOH (10 ml or 20 ml if 12 or 13 is used). The mixture was
stirred for 10 min at room temperature and a solution of the isocyanate 6 (10 mmol) in dioxane (10 ml) added.
The resulting yellow solution was kept at 60°C for 4.5 h and the solvent removed. The resulting molasses
obtained was dissolved in water (5 ml) and the solution was acidified to pH 2 by adding 2 N HCl. The
precipitate was filtered off, washed with H
obtained by recrystallization from hot MeOH.
-Carboxymethylpyrido[2,3-d]pyrimidine-2,4-(1H,3H)-dione (14). Yield 85%; mp 328-330°C.
2
O (2 × 2 ml), and air dried. Analytically pure compounds were
3
-
1
1
IR spectrum (KBr), ν, cm : 3125 (NH), 1662 (C=O), 1725 (C=O). H NMR spectrum (DMSO-d ), δ, ppm: 4.56
6
(
2H, s, CH
2
); 7.60-7.80 (m, 3, Py); 11.79 (s, 1, NH). Mass spectrum, found, m/z: 222 [M+1]. C
H
9 7
N
3
4
O .
Calculated, m/z: 221.1720. Found, %: C 48.90; H 3.29; N 18.86. C
9
H
7
N
3
4
O . Calculated, %: C 48.87; H 3.19;
N 19.00.
3
-(1-Carboxyethyl)pyrido[2,3-d]pyrimidine-2,4-(1H,3H)-dione (15). Yield 80%; mp 228-230°C.
-1 1
IR spectrum (KBr), ν, cm : 3120 (NH), 1682 (C=O), 1720 (C=O). H NMR spectrum (methanol-d
4
), δ, ppm:
); 5.88 (1H, q, CH); 8.00-8.60 (3H, m, Py); 8.65 (1H, s, NH). Mass spectrum, found, m/z:
. Calculated, m/z: 235.2067. Found, %: C 51.11; H 3.90; N 17.70. C10 O .
1
2
.63 (3H, d, CH
36 [M+1]. C10
3
H
9
N
3
O
4
H
9
N
3
4
Calculated, %: C 51.06; H 3.85; N 17.86.
3
-(1-Carboxyphenyl)pyrido[2,3-d]pyrimidine-2,4-(1H,3H)-dione (16). Yield 90%; mp 203-205°C.
-
1
1
IR spectrum (KBr), ν, cm : 3120 (NH), 1662(C=O), 1725 (C=O). H NMR spectrum (DMSO-d ), δ, ppm: 6.49
6
(
1H, s, CHPh); 7.60-8.50 (3H, m, Py); 10.29 (1H, s, NH). Mass spectrum, found, m/z: 298 [M+1]. C15
H
11
N
3
O .
4
Calculated, m/z: 297.2775. Found, %: C 60.78; H 3.85; N 13.98. C15
H
11
N
3
O . Calculated, %: C 60.60; H 3.73;
4
N 14.13.
3
08

3
-(1-Carboxybenzyl)pyrido[2,3-d]pyrimidine-2,4-(1H,3H)-dione (17). Yield 88%; mp 269-271°C.
-1 1
IR spectrum (KBr), ν, cm : 3125 (NH), 1665 (C=O), 1725 (C=O). H NMR spectrum (methanol-d
.86 (1H, m, CH); 3.54 (2H, m, CH ); 8.30-9.00 (3H, m, Py); 7.20-7.60 (5H, m, Ph); 8.50 (1H, s, NH).
Found, %: C 61.80; H 4.36; N 13.49. C16 . Calculated, %: C 61.73; H 4.21; N 13.50.
-(1-(5-Methylimidazolyl)pyrido[2,3-d]pyrimidine-2,4-(1H,3H)-dione (18). Yield 78%; mp 212-214°C.
4
), δ, ppm:
5
2
H
13
N
3
O
4
3
-
1
1
IR spectrum (KBr), ν, cm : 3000 (NH), 1670 (C=O), 1720 (C=O). H NMR spectrum (methanol-d
4
), δ, ppm:
5
.83 (1H, m, CH); 3.65 (2H, m, CH
2
); 7.38 (2H, m, imidazol); 8.50 (1H, br. s, NH imidazol); 7.70-7.60 (3H, m,
Py); 8.81 (1H, s, NH). Found, %: C 51.88; H 3.80; N 23.20. C13
N 23.24.
H
11
N
5
4
O . Calculated, %: C 51.83; H 3.68;
3
-(1,3-Dicarboxypropyl)pyrido[2,3-d]pyrimidine-2,4-(1H,3H)-dione (19). Yield 79%; mp 251-253°C.
-
1
1
IR spectrum (KBr), ν, cm : 3375 (NH), 1650 (C=O), 1725 (C=O). H NMR spectrum (D
2
O), δ, ppm, J (Hz):
2
.99 (2H, dd, J = 6.38, (CH
2
)CH
2
CO
2
H)); 3.31 (2H, dt, J = 7.67, CH
2
(CH
2
)CO
2
H); 5.82 (1H, dd, J = 6.96,
N–CH); 8.53 (1H, s, NH); 7.70-7.94 (3H, m, Py). Found, %: C 49.16; H 3.88; N 14.29. C12
Calculated, %: C 49.15; H 3.78; N 14.33.
H
11
N
3
6
O .
3
-(1,2-Dicarboxyethyl)pyrido[2,3-d]pyrimidine-2,4-(1H,3H)-dione (20). Yield 81%; mp 240-241°C.
-
1
1
IR spectrum (KBr), ν, cm : 3330 (NH), 1660 (C=O), 1725 (C=O). H NMR spectrum (D
2
O), δ, ppm, J (Hz):
CO H); 8.55 (1H, s,
. Calculated, %: C 47.32; H 3.25;
3
.17 (2H, dd, J = 6.28, CH(CH
2
)CO
2
H); 5.95 (1H, t, J = 6.77, NCH); 7.80 (1H, s, CH
2
CH
2
2
NH); 7.60-7.85 (3H, m, Py). Found, %: C 47.34; H 3.32; N 14.97. C11
H N O
9 3 6
N 15.05.
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09