Synthesis of diethyl 5-Ethyl-2,3-Pyridinedicarboxylate

Article abstract of DOI:10.14233/ajchem.2014.16235

Diethyl 5-ethyl-2,3-pyridinedicarboxylate was synthesized using ammonium acetate as the nitrogen source. The optimum process conditions were obtained by exploring the reaction mechanism and researching the effects of reactant ratio, reaction temperature and solvent amount on the yield from all sides. Diethyl 5-ethyl-2,3-pyridinedicarboxylate yield was 98 % analysis by HPLC and the overall yield 96.8 % calculated by 2-chloro-3-oxo-succinic acid diethyl ester. The optimum process has the advantages of available initial material, simple waste-water treatment and environmental friendliness which are more applicable for industrial production.

Full text of DOI:10.14233/ajchem.2014.16235

Asian Journal of Chemistry; Vol. 26, No. 3 (2014), 918-920
http://dx.doi.org/10.14233/ajchem.2014.16235
Synthesis of Diethyl 5-Ethyl-2,3-Pyridinedicarboxylate
*
CHUNSHENG CHENG , XIAOHUA MA and ZHENYUN WEI
Technical Development Department, Shenyang Sciencreat Chemicals Co., LTD. Shenyang, Liaoning, P.R. China
*Corresponding author: Fax: +86 24 25336106; Tel: +86 24 25336109; E-mail: chengchunsheng@sinochem.com; tomorrow88166@163.com
Received: 24 August 2013;
Accepted: 2 December 2013;
Published online: 30 January 2014;
AJC-14668
Diethyl 5-ethyl-2,3-pyridinedicarboxylate was synthesized using ammonium acetate as the nitrogen source. The optimum process conditions
were obtained by exploring the reaction mechanism and researching the effects of reactant ratio, reaction temperature and solvent amount
on the yield from all sides. Diethyl 5-ethyl-2,3-pyridinedicarboxylate yield was 98 % analysis by HPLC and the overall yield 96.8 %
calculated by 2-chloro-3-oxo-succinic acid diethyl ester. The optimum process has the advantages of available initial material, simple
waste-water treatment and environmental friendliness which are more applicable for industrial production.
Keywords: Diethyl 5-ethyl-2,3-pyridinedicarboxylate, Ammonium acetate, Synthetic methods, Reaction mechanisms, Solvent effects.
which will causes secondary pollution. Finally, ammonium
sulfamate is not suitable for the large-scale production because
of its high cost.
INTRODUCTION
Diethyl 5-ethyl-2,3-pyridinedicarboxylate is an important
organic intermediate and used in the field of dye, medicine
and pesticide widely. Meanwhile, it also shows some biological
activity. With the application of the efficient imidazolinone
herbicides1-9 which developed by American Cyanamid Com-
pany in the 1980's, the market demand risen dramatically10.
However, because of the backward domestic technology and
equipment conditions, current process for diethyl 5-ethyl-2,3-
pyridinedicarboxylate comes with many disadvantages, such
as high cost, low yield, serious pollution, etc., which signifi-
cantly decrease the economic and social benefits. Therefore,
a new efficient method for the preparation of diethyl 5-ethyl-
O
O
Cl
O
NaOEt
O
Cl
O
+
O
O
O
O
O
O
O
H
Cl
O
COOEt
COOEt
O
O
NH4SO3NH2
O
O
N
Scheme-I
EXPERIMENTAL
All solvents and reagents were obtained from commercial
2,3-pyridinedicarboxylate is desired11-15
.
The general process of diethyl 5-ethyl-2,3-pyridine-
dicarboxylate is shown in Scheme-I. It takes diethyl oxalate and
ethyl chloroacetate as raw materials, sodium ethoxide as catalyst
to synthesize 2-chloro-3-oxo-succinic acid diethyl ester (M1)
via Claisen condensation. Then in the presence of ammonium
sulfamate, diethyl 5-ethyl-2,3-pyridinedicarboxylate is obtained
by cyclizing M1 and 2-ethyl acrolein. However, there are a lot
of problems about this process. Firstly, the current molar ratio
of M1 and ammonium sulfamate is 1: 2.2. But the theoretical
ratio is only 1:1, the excess nitrogen atom in the reaction flows
into the waste water, which increases the difficulty of waste-
water treatment. Secondly, the general method to deal with
waste-water is evaporating concentration and burning organic
substance in the waste water. Besides, burning the organic
substances containing S atoms may give off sulfur dioxide
sources and used without further purification. 1H NMR spectra
was recorded in CDCl3 solution on a Mercury 300 MHz spec-
trometer.
Typical experimental procedure for the synthesis of
2-chloro-3-oxo-succinic acid diethyl ester (M1): According
to the reference16,17, a four-necked flask equipped with a mecha-
nical stirrer and a thermometer was charged with sodium
ethoxide (11.7 g, 0.170 mol) and toluene (65.0 mL). The mixture
was stirred at room temperature for 45 min. Then diethyl
oxalate (17.7 g, 0.121 mol) was added in 1 h at 25-40 °C.
After another 0.5 h, the mixture was cooled to 25 °C and ethyl
chloroacetate (12.4 g, 0.101 mol) was added in 2 h. Keeping
the temperature at 32-35 °C for 3 h, ice-water (20 mL) and
hydrochloric acid (30 %, 22.1 g, 0.181 mol) were added. The

Vol. 26, No. 3 (2014)
Synthesis of Diethyl 5-Ethyl-2,3-Pyridinedicarboxylate 919
organic phase was dried, filtered and concentrated to a red
liquid (15.7 g) which was the compound M1.
at least. Besides, the solubility of nitrogen source in ethanol
and the cost of nitrogen source were also taken into account.
Based on above principles, we have tried following nitrogen
sources: ammonium acetate, ammonia chloride21, ammonium
sulfate and ammonia and ammonium acetate were chosen as
the most suitable nitrogen source22. Based on the process infor-
mation retrieval, this is the first time to use ammonium acetate
as nitrogen source for the synthesis of diethyl 5-ethyl-2,3-
pyridinedicarboxylate.
Typical experimental procedure for the synthesis of
diethyl 5-ethyl-2,3-pyridinedicarboxylate: A four-necked
flask equipped with a mechanical stirrer and a thermometer
was charged with ammonium acetate18,19 (19.3 g, 0.248 mol)
and absolute ethanol (70 mL) and heated to 80 °C. Then a
mixture of M1 (26.9 g, 0.099 mol) and 2-ethyl acrolein (10.1
g, 0.119 mol) was added. After 5 h, the solvent was removed
under reduce pressure and the residue solved in toluene (60
mL) was washed to be neutral with water (10 mL × 2). The
organic phase was dried, filtered and concentrated into a dark
brown liquid (26.4 g) which was the target product diethyl
Effects of molar ratios of raw materials on the yield:
The effects of molar ratios of M1, 2-ethyl acrolein and ammo-
nium acetate were studied in this part. The results are shown
in Table-1.
1
5-ethyl-2,3-pyridinedicarboxylate with the yield 96.5 %. H
It can be inferred from Table-1, keeping the reaction at
80 °C for 5 h, the molar ratios of the raw materials have
pronounced effect on the yield. When the amount of 2-ethyl
acrolein was constant, the yield increased due to the amount
of ammonium acetate (Entries 1-3). But when the molar ratio
of M1 and ammonium acetate exceeded 2.5 equivalents, the
yield decreased slightly (Entries 3-5). Therefore, it is reason-
able that the molar ratio of M1 and ammonium acetate was 1:
2.5. Furthermore, fixing the molar ratio of M1 and ammonium
acetate, the effect of different amount of 2-ethyl acrolein was
investigated (entries 6-9). It shows that the yield was higher
when the molar ratio of M1, 2-ethyl acrolein and ammonium
acetate was 1:1.2:2.5. Finally, the optimized molar ratio of
M1, 2-ethyl acrolein and ammonium acetate was 1:1.2:2.5.
NMR (CDCl3, 300 MHz) δ:1.30 (t, J = 7.5 Hz, 3H), 1.36-1.44
(m, 6H), 2.76 (q, J = 7.5 Hz, 2H), 4.33-4.52 (m, 4H), 7.96 (s,
1H), 8.60 (s, 1H).
RESULTS AND DISCUSSION
In order to explore a route with high yield and environ-
mental friendliness, we first discussed the mechanism20 of the
reaction. We inferred that the mechanism belonged to
Knoevenagel-Fries modification based on reaction substrates
and reaction conditions.
As shown in Scheme-II, the nitrogen source not only
offers N atom to participate the reaction, but also absorbs
hydrochloric acid. Thus, 1 mol reagent consumes 2 mol N atoms
Cl
O
Cl
O
O
Cl
O
O
O
O
O
O
H2N
OH2
OH
O
O
H3N
O
OH
NH3
NH2
O
NH
O
O
O
-H2O
O
O
O
Cl
O
Cl
O
Cl
Cl
O
Cl
O
O
O
O
O
O
O
O
NH2
O
NH2
O
NH
O
O
H
OH
H
O
NH4Cl
NH3
O
Cl
O
O
Cl
O
O
O
-H2O
-HCl
O
O
O
NH
O
N
N
O
Scheme-II

920 Cheng et al.
Asian J. Chem.
98
96
94
92
90
88
86
84
82
80
78
76
TABLE-1
EFFECTS OF MOLAR RATIOS OF RAW MATERIALS ON
THE YIELD AMOUNT OF ETHANOL (550 g/mol) AT 80 °C
Entry
Molar ratioa
1:1.2:2.0
1:1.2:2.2
1:1.2:2.5
1:1.2:3.0
1:1.2:3.2
1:1.05:2.5
1:1.1:2.5
1:1.4:2.5
1:1.5:2.5
Yield (%)
75.0
1
2
3
4
5
6
7
8
9
85.5
96.5
93.3
92.1
78.8
85.9
90.3
89.9
a Molar ratio of M1, 2-ethyl acrolein and ammonium acetate
Effects of different temperatures on the yield: Making
the molar ratio of M1:2-ethyl acrolein: ammonium acetate at
1:1.2:2.5. We required to emphasize the reaction temperature
is different. The results are shown in Fig. 1.
400
450
500
550
600
650
700
Amount of ethanol (g/mol)
Fig. 2. Effects of different solvent amount on the yield
acrolein. In addition, we have taken ammonium acetate for
the first time as the source of nitrogen to synthesize diethyl
5-ethyl-2,3-pyridinedicarboxylate. The optimum process is
obtained: ethanol as the solvent, M1:2-ethyl acrolein: ammonium
acetate = 1:1.2:2.5 (molar ratio), keeping reaction temperature
at 80 °C for 5 h. Under this condition, the yield can reach 96.8 %.
Besides the new process can decrease the salinity of the waste-
water and reduce the pressure to environment, which is expected
to apply to the large-scale industrial production.
100
90
80
70
60
50
40
30
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80
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Conclusion
In conclusion, we have successfully developed an easy,
efficient and versatile method for the synthesis of diethyl 5-
ethyl-2,3-pyridinedicarboxylate starting from M1 and 2-ethyl
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