Process for preparing pyridine-2,3-dicarboxylic acid compounds

A process for preparing pyridine-2,3-dicarboxylic acid compounds of the following formula: ##STR1## wherein R.sup.1 and R.sup.3 are, identical or different, each a hydrogen atom or a lower alkyl group, R.sup.2 is a hydrogen atom, a lower alkyl group, or a phenyl-(lower)alkyl group which may have halogen atom or lower alkyl group on its phenyl ring, and R.sup.4 and R.sup.5 are, identical or different, each a lower alkoxy group. The compounds are useful as an intermediate for preparing agricultural chemicals and pharmaceuticals.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a process for preparing pyridine-2,3-dicarboxylic 
acid compounds. More particularly, it relates to a process for preparing 
pyridine-2,3-dicarboxylic acid compounds which are useful as an 
intermediate for manufacturing agricultural chemicals and pharmaceuticals. 
2. Description of the Prior Art 
The pyridine-2,3-dicarboxylic acid compounds are useful intermediates for 
2-(2-imidazolin-2-yl)pyridine-3-carboxylic acid derivatives having weeding 
action as disclosed, for example, in European Patent Application 
Publication No.A-0041623. 
Heretofore, as the method of preparing pyridine-2,3-dicarboxylic acid 
compounds known are: 
(1) Oxidation with nitric acid of quinolines and quinolinols which are 
synthesized by Skraup reaction from aniline and glycerine with 
concentrated sulfuric acid and nitrobenzene. (J. Chem. Soc. page 4433, 
1956); 
(2) Reacting an .alpha., .beta.-unsaturated hydrazone compound and a maleic 
acid compound in an inert solvent to obtain 1-(substituted 
amino)-1,4-dihydropyridine-2,3-dicarboxylic acid derivative. Then, heating 
the resultant derivative to eliminate the substituted amino group in the 
1-position. (Japanese Patent Application Unexamined Publication 
No.246369/1985); 
(3) Treating a 1-(substituted 
amino)-1,2,3,4-tetrahydropyridine-2,3-dicarboxylic acid derivative with 
acid and/or by heat to convert into a 1,4-dihydropyridine-2,3-dicarboxylic 
acid derivative, and then oxidizing it. (Japanese Patent Application 
Unexamined Publication No.47482/1986); and 
(4) Oxidizing quinoline with excess hypochlorites in the presence of 
ruthenium oxide. (Japanese Patent Application Unexamined Publication 
No.212563/1986) 
As the method of synthesizing pyridinemonocarboxylic acid derivatives known 
is such a method as subjecting ethyl 2-methyl-1,4-dihydronicotinate which 
is produced by condensation and cyclization of .alpha., .beta.-unsaturated 
aldehydes such as acrolein and crotonaldehyde with ethyl 
.beta.-aminocrotonate to oxidation with nitric acid in a mixed acid. (J. 
Org. Chem. Soc. Vol. 21, page 800, 1956) 
However, the above method (1) not only has many reaction processes but also 
requires drastic oxidation with nitric acid, and involves possible 
hazards. Also, the pyridine-2,3-dicarboxylic acids, which are apt to cause 
decarboxylation, result in low yields by the oxidation with nitric acid, 
and, in addition, produce a large quantity of acidic waste liquid. Thus, 
the method (1) is not suited to the industrial manufacture of 
pyridine-2,3-dicarboxylic acids. 
The methods (2) and (3) mentioned above have many reaction processes 
leading to decreased total yields, and require the use of expensive 
starting materials. Particularly, they require elimination process of the 
substituted amino group in the intermediate. This decreases the yield and 
is a problem on resource saving. Therefore, it is difficult to manufacture 
pyridine-2,3-dicarboxylic acid derivatives industrially by the method (2) 
or (3). 
In the method (4), there are problems that a large excess of the oxidant 
must be used and that a large quantity of waste liquid is produced 
requiring expenses for its disposal. 
SUMMARY OF THE INVENTION 
Accordingly, it is an object of this invention to provide a process for 
preparing pyridine-2,3-dicarboxylic acid compounds in high yields by a 
reaction completing in one process from starting materials inexpensive and 
easily available. 
The foregoing object is accomplished by providing a process for preparing 
pyridine-2,3-dicarboxylic acid compounds shown by the formula (1): 
##STR2## 
wherein R.sup.1 and R.sup.3 are, identical or different, each a hydrogen 
atom or a lower alkyl group, R.sup.2 is a hydrogen atom, a lower alkyl 
group, or a phenyl-(lower)alkyl group which may have halogen atom or lower 
alkyl group on its phenyl ring, and R.sup.4 and R.sup.5 are, identical or 
different, each a lower alkoxy group, 
which comprises, 
(1) reacting a compound of the formula (2): 
##STR3## 
wherein R.sup.1, R.sup.2, and R.sup.3 are same as defined above, a 
compound of the formula (3): 
##STR4## 
wherein R.sup.4 and R.sup.5 are same as defined above, and X represents a 
halogen atom, 
and ammonia, or 
(2) reacting a compound of the formula (2): 
##STR5## 
wherein R.sup.1, R.sup.2, and R.sup.3 are same as defined above, and a 
compound of the formula (4): 
##STR6## 
wherein R.sup.4 and R.sup.5 are same as defined above, in the presence of 
an acid catalyst. 
It is well known by those skilled in the art that the compounds of the 
above formulae (3) and (4) can exhibit keto-enol or ketimine-enamine 
tautomerism as exemplified, for example, by the following formula: 
##STR7## 
In this specification, such tautomers are represented for convenience' sake 
by the above structural formulae (3) and (4).

DETAILED DESCRIPTION OF THE INVENTION 
Examples of the lower alkyl groups for R.sup.1, R.sup.2, and R.sup.3 in the 
above formulae include straight or branched alkyl groups having 1 to 8 
carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
tertiary-butyl, pentyl, hexyl, heptyl, octyl and the like. 
Examples of the phenyl-(lower)alkyl group for R.sup.2 which may have 
halogen atom or lower alkyl group on its phenyl ring include phenyl-alkyl 
groups having a straight or branched C.sub.1-6 alkyl group in the alkyl 
moiety, and which may have a substituent of halogen atom or straight or 
branched alkyl group having 1 to 6 carbon atoms on the phenyl ring 
thereof, for example, benzyl, 2-phenylethyl, 1-phenylethyl, 
3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 
2-methyl-3-phenylpropyl, 4-chlorobenzyl, 3-fluorobenzyl, 2-bromobenzyl, 
4-iodobenzyl, 2,4-dichlorobenzyl, 2-(2-fluorophenyl)ethyl, 
1-(3-bromophenyl)ethyl, 3-(4-chlorophenyl)propyl, 4-(2-chlorophenyl)butyl, 
5-(4-chlorophenyl)pentyl, 6-(4-bromophenyl)hexyl, 4-methylbenzyl, 
3-methylbenzyl, 4-ethylbenzyl, 4-isopropyl-benzyl, 4-hexylbenzyl, 
2-(4-methylphenyl)ethyl, 2-(4propylphenyl)ethyl, 3-(4-methylphenyl)propyl, 
3-(3-ethylphenyl)propyl, 4-(4-methylphenyl)butyl, 4-(4-butylphenyl) butyl, 
5-(2-methylphenyl)pentyl, 6-(4-hexylphenyl)hexyl and the like. 
Examples of the lower alkoxy groups for R.sup.4 and R.sup.5 include 
straight or branched alkoxy groups having 1 to 6 carbon atoms such as 
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary-butoxy, 
pentyloxy, hexyloxy and the like. 
The halogen atom X may be chlorine atom and bromine atom. 
Examples of the compound of the formula (2) include, for example, acrolein, 
crotonaldehyde, 2-pentenal, 4-methyl-2-pentenal, 2-hexenal, 
5-methyl-2-hexenal, 2-heptenal, 2-octenal, 2-nonenal, 2-decenal, 
2-undecenal, 2-methyl-2-propenal, 2-ethyl-2-propenal, 2-propyl-2-propenal, 
2-isopropyl-2-propenal, 2-butyl-2-propenal, 2-pentyl-2-propenal, 
2-hexyl-2-propenal, 2-heptyl-2-propenal, 2-octyl-2-propenal, 
2-benzyl-2-propenal, 2-.beta.-phenethyl-2-propenal, 
2-(3-phenylpropyl)-2-propenal, 2-(4-chlorobenzyl)-2propenal, 
2-(4-bromobenzyl)-2-propenal, 2-(4-methylbenzyl)-2-propenal, 
2-(3-methylbenzyl)-2-propenal, 2-(4-ethylbenzyl)-2-propenal, 
2-(4-isopropylbenzyl)-2-propenal, 2-methyl-2-butenal, 2-ethyl-2-butenal, 
2-benzyl-2-butenal, 2-methyl-2-pentenal, 2-ethyl-2-pentenal, 
2-methyl-2-hexenal, 2-ethyl-2-hexenal, 2-methyl-2-heptenal, 
2-ethyl-2-heptenal, 2-methyl-2-octenal, 2-ethyl-2-octenal, 
2-methyl-2-nonenal, 2-ethyl-2-nonenal, 2-methyl-2-decenal, 
2-ethyl-2-decenal, 2-methyl-2-undecenal, 2-ethyl-2-undecenal, 
2-hexyl-2-undecenal, 3-buten-2-one, 3-benzyl-3-buten-2-one, 
3-(4-chlorobenzyl)-3-buten-2-one, 3-(4-methylbenzyl)-3-buten-2-one, 
1-penten-3-one, 3-penten-2-one, 4-hexen-3-one, 3-hepten-2-one, 
4-hepten-3-one, 2-hepten-4-one, 3-methyl-3-buten-2-one, 
3-ethyl-3-buten-2-one, 2-methyl-1-penten-3-one, 2-ethyl-1-penten-3-one, 
4-ethyl-4-hexen-3-one and the like. 
Examples of the compound of the formula (3) include, for example, dimethyl 
.alpha.-chlorooxalacetate, diethyl .alpha.-chlorooxalacetate, dipropyl 
.alpha.-chlorooxalacetate, diisopropyl .alpha.-chlorooxalacetate, dibutyl 
.alpha.-chlorooxalacetate, dipentyl .alpha.-chlorooxalacetate, dihexyl 
.alpha.-chlorooxalacetate, methylethyl .alpha.-chlorooxalacetate, dimethyl 
.alpha.-bromooxalacetate, diethyl .alpha.bromooxalacetate, dipropyl 
.alpha.-bromooxalacetate, diisopropyl .alpha.-bromooxalacetate, dibutyl 
.alpha.-bromooxalacetate, dipentyl .alpha.-bromooxalacetate, dihexyl 
.alpha.-bromooxalacetate and the like. 
Examples of the compound of the formula (4) include, for example, methyl 
.beta.-amino-.beta.-methoxycarbonylacrylate, ethyl 
.beta.-amino-.beta.-ethoxycarbonylacrylate, propyl 
.beta.-amino-.beta.-propoxycarbonylacrylate, isopropyl 
.beta.-amino-.beta.-isopropoxycarbonylacrylate, butyl 
.beta.-amino-.beta.-butoxycarbonylacrylate, isobutyl 
.beta.-amino-.beta.-isobutoxycarbonylacrylate, pentyl 
.beta.-amino-.beta.-pentyloxycarbonylacrylate, hexyl 
.beta.-amino-.beta.hexyloxycarbonylacrylate, ethyl 
.beta.-amino-.beta.-methoxycarbonylacrylate, methyl 
.beta.-amino-.beta.-ethoxycarbonylacrylate and the like. 
The process according to the invention can be represented by the following 
reaction schemes: 
Reaction Scheme 1 
##STR8## 
Reaction Scheme 2 
##STR9## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and X are same 
defined before. 
In the above reaction scheme 1, the reaction of the compound of the formula 
(2), that of the formula (3), and ammonia is carried out without solvent 
or in an organic solvent. Any organic solvent, regardless of polarity or 
protonic property, can be used in the reaction unless it affects the 
reaction. Such organic solvent may be alcohols such as methanol, ethanol, 
isopropanol, and butanol; halogenated hydrocarbons such as chloroform, 
1,2-dichloroethane, and carbon tetrachloride; aromatic hydrocarbons such 
as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, and 
nitrobenzene; ethers such as dimethyl ether, diethyl ether, dibutyl ether, 
tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol 
diethyl ether, diethylene glycol dimethyl ether and dibenzyl ether; esters 
such as methyl acetate and ethyl acetate; aprotic polar solvents, for 
example, sulfoxides such as dimethy sulfoxide, carboamides such as 
N,N-dimethylformamide, sulfones such as dimethyl sulfone and sulfolane, 
and hexamethyl phosphoric triamide, and the like. These organic solvents 
can be used signly or in a mixture of two or more types. Among these 
organic solvents, preferable are aprotic organic solvents. 
The reaction can be carried out without solvent. The non-solvent method can 
reduce the cost because of no expences for solvent and solvent recovery 
and purification. 
The reaction temperature of the reaction between the compound of the 
formula (2), the compound of the formula (3), and ammonia is not limited, 
but preferably it is in the range of 20.degree. to 200.degree. C., 
particularly, in the range of 35.degree. to 130.degree. C. For 
advantageous progress of the reaction, the reaction is preferably carried 
out under an ammonia gas pressure of 0 to 3 kg/cm.sup.2, more preferably 
0.3 to 2.5 kg/cm.sup.2. The reaction is completed in 30 minutes to 24 
hours, generally in 1 to 10 hours. The proportion of the compound of the 
formula (2) to the compound of the formula (3) is not limited, and can be 
varied widely. For example, the compound of the formula (2) and the 
compound of the formula (3) are present in a molar ratio of 0.8:1 to 
1.5:1, preferably 1:1 to 1.5:1. Ammonia is usually used in an excess 
amount to the compounds of the formulae (2) and (3). 
To increase the yield of the compound of the formula (1), desired compound 
in the above reaction, the reaction is carried out in the presence of a 
secondary or tertiary amine such as dimethylamine, trimethylamine, 
diethylamine, triethylamine, pyridine, 4-(N,N-dimethylamino)pyridine, 
morpholine, N-methylmorpholine, 1,5-diazabicyclo-[4.3.0]nonene-5(DBN), 
1,4-diazabicyclo[5.4.0]undecene-7(DBU), 
1,8-diazabicyclo[2.2.2]octane(DABCO) and the like. 
To effectively produce the desired compound, the above reaction is carried 
out preferably in the presence of an ammonium salt such as ammonium 
carbonate, ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium 
phosphate, ammonium acetate and the like. 
The secondary and tertiary amines and ammonium salt can be used in adequate 
quantities, but are used preferably in 0.05 to 1.0 mol per mol of the 
compound of the formula (3). 
In a preferred embodiment of the reaction scheme 1, the compound of the 
formula (2) and the compound of the formula (3) are reacted under an 
ammonia gas pressure of 0.3 to 2.5 kg/cm.sup.2, without solvent or in an 
aprotic organic solvent, at temperatures of 70.degree. to 130.degree. C. 
More preferably, the secondary or tertiary amine and/or the ammonium salt 
are added to the reaction system in addition. 
In the above reaction scheme 2, the compound of the formula (2) and the 
compound of the formula (4) are reacted in the presence of an acid 
catalyst without solvent or in an organic solvent. 
The acid catalyst used in this reaction may be, for example, inorganic 
acids such as sulfuric acid, hydrochloric acid, phosphoric acid, 
hydrobromic acid, and sulfamic acid; organic acids including aliphatic 
carboxylic acids such as formic acid, acetic acid, propionic acid, oxalic 
acid, maleic acid, and maleic anhydride, aromatic carboxylic acids such as 
benzoic acid, sulfonic acids such as benzenesulfonic acid, 
p-toluenesulfonic acid, and methanesulfonic acid; and acid salts of di- or 
trialkylamine such as dimethylamine hydrochloride, diethylamine 
hydrochloride, dimethylamine sulfate, dimethylamine methanesulfonate, 
trimethylamine hydrochloride, triethylamine hydrochloride, triethylamine 
benzenesulfonate, morpholine hydrochloride, piperidine hydrochloride, and 
the like. 
The suitable amount of the acid catalyst to be used is 0.02 mol or more per 
mol of the compound of the formula (4), and when the acid catalyst is a 
liquid such as formic acid, acetic acid or propionic acid, it is used 
preferably combined as a solvent. 
Any organic solvent can be used in the reaction regardless of the polarity 
and protonic property, unless it affects the reaction. Such organic 
solvent is the same as mentioned in the reaction scheme 1. 
The reaction temperature of the reaction between the compound of formula 
(2) and the compound of the formula (4) is not particularly limited, but 
preferably it is in the range of 20.degree. to 200.degree. C., more 
preferably in the range of 35.degree. to 150.degree. C. The reaction is 
completed in 1 to 24 hours, generally in 2 to 10 hours. The reaction is 
preferably carried out under mild oxidation condition such as bubbling air 
through the reaction mixture, and the like. 
The compounds of the formula (2) and formula (4) can be used in an adequate 
molar ratio, but preferably the compound of the formula (2) and the 
compound of the formula (4) are present in a molar ratio of 0.8:1 to 
2.0:1, preferably 1:1 to 1.5:1. 
The compounds of the formulae (2), (3) and (4) are known or can be 
synthesized by known methods. For example, the compound of the formula (3) 
can be prepared by the method described in J. of American Chemical 
Society, 72, 5221, (1950), and the comound of the formula (4) can be 
prepared by the method described in Chem. Ber, 98 (9), 2920-5 (1965). 
In the compound of the formula (1), carboxylic acid compounds of the 
formula (1), wherein R.sup.4 and/or R.sup.5 represent a hydroxy group, can 
be obtained by subjecting ester compounds of the formula (1), wherein 
R.sup.4 and/or R.sup.5 represent an alkoxy group, to hydrolysis. This 
hydrolysis can be carried out by a conventional method using, for example, 
an alkali metal hydroxide such as sodium hydroxide and potassium 
hydroxide. Since the carboxylic acid is readily soluble in water leading 
to complex separation and purification of the product, the reaction is 
preferably carried out in a mixed solvent of water and water-insoluble 
organic solvent such as benzene, toluene, xylene, chlorobenzene etc. in 
the presence of the basic compound mentioned above, and then the 
carboxylic acid salt, produced by the hydrolysis, in the water layer is 
precipitated with a mineral acid such as hydrochloric acid, sulfuric acid, 
nitric acid, phosphoric acid, etc. This hydrolysis reaction is carried out 
at room temperature to 150.degree. C., preferably at 40.degree. to 
100.degree. C. and completed generally in 1 to 24 hours. 
The pyridine-2,3-dicarboxylic acid compound obtained by the process 
according to the invention is useful as an intermediate for preparing 
various compounds such as agricultural chemicals and pharmaceuticals. For 
example, it is a useful intermediate for 
2-(2-imidazolin-2-yl)pyridine-3-carboxylic acid derivatives known as a 
herbicide as disclosed in European Patent Application Publication 
No.A-0041623. 
The process for preparing pyridine-2,3-dicarboxylic acid compounds 
according to the invention completes the reaction in one step without 
passing through any intermediate and gives the desired compound in a high 
yield. It permits the use of inexpensive and readily available starting 
materials, and the reaction proceeds safely under mild conditions. In 
addition, the disposal of waste liquid is easy. Thus, the process of the 
invention can be applied to the industrial scale manufacture of 
pyridine-2,3-dicarboxylic acid compounds. 
EXAMPLES 
Hereinafter, this invention will be described in greater detail with 
reference to Reference Example and Examples, but it should be understood 
that the invention is not limited to these examples. 
REFERENCE EXAMPLE 1 
To a mixture of triethylamine hydrochloride 27.5 g (0.20 mol) and 37% 
formalin 16.3 g (0.201 mol) was added dropwise 
.beta.-phenylpropionaldehyde 25 g (0.183 mol) at 20.degree. to 35.degree. 
C. and the mixture was reacted at 110.degree. to 115.degree. C. for 4 
hours. After the completion of the reaction, the reaction mixture was 
cooled to 20.degree. C. and extracted with 100 ml of diethyl ether. The 
extract was dried over anhydrous sodium sulfate, the solvent was distilled 
off, and the residue was distilled to give 2-benzyl-2-propenal (bp.sub.10 
: 99.degree. to 101.degree. C.) in a yield of 71%. 
IR (Neat): 3050 to 2800, 1680 cm.sup.-1 
NMR (CDCl.sub.3) ppm: 3.60 (2 H,s), 6.1 (2 H,d), 7.2 (5 H,m) 
EXAMPLE 1 
In a 1000 ml four neck distillation flask with a reflux condenser were 
placed chlorobenzene 350 ml and 2-ethyl-2-propenal 21.0 g (0.25 mol) and 
heated on an oil bath. When the inside temperature was raised to 
88.degree. C., a mixture of diethyl .alpha.-chlorooxalacetate 44.5 g (0.20 
mol) and chlorobenzene 250 ml was added dropwise thereto at 88.degree. to 
94.degree. C. for 40 minutes, while the reaction system was being bubbled 
with dry ammonia gas. After the dropping was completed, the temperature 
was raised to 115.degree. C. and ammonia gas was bubbled therein further 
for 4 hours. The reaction mixture was cooled down to room temperature, 
insoluble matters were filtered off and the filtrate was concentrated. The 
residue was distilled to give 5-ethyl-2,3-diethoxycarbonylpyridine 
(bp.sub.2 : 151.degree. to 152.degree. C.) in a yield of 76.5%. 
The above reaction was carried out by use of various solvents. The types of 
solvent and reaction conditions used, and the yield of the desired 
compound determined by gas chromatography are shown in Table 1. 
TABLE 1 
______________________________________ 
Reaction 
temperature Reaction time 
Solvent (.degree.C.) (hr) Yield (%) 
______________________________________ 
Amyl 110 4 40 
alcohol 
Benzene 76 5 26.1 
Toluene 105 4 60.5 
______________________________________ 
The 5-ethyl-2,3-diethoxycarbonylpyridine obtained above was hydrolyzed by 
the method shown below to give 5-ethylpyridine-2,3-dicarboxylic acid. 
Toluene 50 ml, 5-ethyl-2,3-diethoxycarbonylpyridine 10.3 g (0.041 mol), and 
water 29 ml were mixed in a 200 ml four neck distillation flask with a 
reflux condenser, and 48% aqueous sodium hydroxide solution 21.9 g was 
added thereto under vigorous stirring in nitrogen atmosphere and refluxed 
for 3.5 hours. The reaction mixture was allowed to cool to room 
temperature and stand still to separate into water layer and toluene 
layer. The water layer was acidified at 45.degree. to 55.degree. C. with 
28.3 g of 50% sulfuric acid, and slowly cooled to 20.degree. C. The 
resultant white crystals were filtered and washed with 10 ml of cold 
water. Dried under reduced pressure at 50.degree. to 60.degree. C., 5.9 g 
of 5-ethylpyridine-2,3-dicarboxylic acid was obtained. The melting point 
of the obtained crystals was 154.degree. to 156.degree. C. (decomposed). 
The 5-ethylpyridine-2,3-dicarboxylic acid obtained was recrystallized from 
a mixed solvent of acetone and n-hexane and gave a melting point of 
156.5.degree. C. to 157.5.degree. C. (decomposed). 
EXAMPLE 2 
Toluene 120 ml was mixed with diethyl .alpha.-chlorooxalacetate 9.4 g 
(0.042 mol) and 2-ethyl-2-propenal 4.2 g (0.05 mol) in a glass autoclave. 
with an ammonia pressure held to 0.5 kg/cm.sup.2, the temperature in the 
autoclave was raised from 20.degree. C. to 100.degree. C. over a period of 
about 30 minutes. After further reacting at 100.degree. C. for 4 hours, 
the contents of the autoclave were allowed to cool to room temperature, 
and insoluble matters were filtered off. The production of 
5-ethyl-2,3-diethoxycarbonylpyridine in a yield of 66.6% was observed by 
the analysis of the filtrate using gas chromatography. 
The above reaction was carried out by use of various solvents. The types of 
solvent, reaction conditions, and the yield of the desired compound are 
shown in Table 2. 
TABLE 2 
______________________________________ 
Ammonia Reaction 
pressure temperature 
Reaction 
Yield 
Solvents (kg/cm.sup.2) 
(.degree.C.) 
time (hr) 
(%) 
______________________________________ 
Chloroform 2.5 100 13 64.0 
Benzene 0.5 80 8 69.5 
o-Dichlorobenzene 
0.5 110 4 66.4 
Dibenzyl ether 
0.5 110 4 78.3 
Diethylene glycol 
0.5 110 4 78.8 
dimethyl ether 
______________________________________ 
EXAMPLE 3 
Toluene 120 ml was mixed with diethyl .alpha.-chlorooxalacetate 9.4 g 
(0.042 mol), 2-ethyl-2-propenal 4.2 g (0.05 mol), and triethylamine 0.9 g 
(0.009 mol) in a glass autoclave. With an ammonia pressure held to 0.5 
kg/cm.sup.2, the temperature in the autoclave was raised from 20.degree. 
C. to 100.degree. C. over a period of about 30 minutes. After further 
reaction at 100.degree. C. for 4 hours, the contents of the autoclave were 
allowed to cool to room temperature, and insoluble matters were filtered 
off. The production of 5-ethyl-2,3-diethoxycarbonylpyridine in a yield of 
71% was observed by the analysis of the filtrate using gas chromatography. 
Similar reaction to the above by use of dimethylamine, diphenylamine, 
ammonium acetate, and ammonium carbonate respectively, instead of the 
triethylamine, gave the desired compound in good yield like the above as 
shown in Table 3. 
TABLE 3 
__________________________________________________________________________ 
Amine Ammonium salt 
Quantity Quantity 
used (mol used (mol 
Solvent 
Type ratio) 
Type ratio) 
Yield (%) 
__________________________________________________________________________ 
Toluene 
Triethylamine 
0.20 -- -- 71.0 
Toluene 
-- -- Ammonium 
0.20 71.6 
acetate 
Toluene 
-- -- Ammonium 
0.20 75.5 
carbo- 
nate 
Toluene 
Diphenylamine 
0.20 -- -- 70.0 
Toluene 
Dimethylamine 
0.20 -- -- 70.3 
__________________________________________________________________________ 
in the table, the (mol ratio) of the "quantity used" for amine and ammonium 
salt means the molar ratio to 2-ethyl-2-propenal. 
EXAMPLE 4 
Toluene 360 ml, diethyl .alpha.-chlorooxalacetate 78.2 g (0.351 mol), and 
2-methyl-2-propenal 24.6 g (0.351 mol) were mixed in a glass autoclave. 
After closing, the temperature in the autoclave was raised to 90.degree. 
C. Then, with an ammonia pressure held to 1.5 kg/cm.sup.2 in the 
autoclave, the inside temperature was raised to 110.degree. C. and the 
reaction was conducted for 4.5 hours. The contents of the autoclave were 
cooled to room temperature, and insoluble matters were filtered off. The 
filtrate was concentrated, and the residue was distilled through Widmer 
spiral to give 48 g (yield 57.6%) of 5-methyl-2,3-diethoxycarbonylpyridine 
(bp.sub.3.5 : 160.degree. to 161.degree. C.). 
By use of diethyl .alpha.-bromooxalacetate instead of diethyl 
.alpha.-chlorooxalacetate, the reaction was carried out in the same manner 
and gave the desired compound in good yield like the above. 
EXAMPLE 5 
Diethyl .alpha.-chlorooxalacetate 69 g (0.31 mol), 2-ethyl-2-propenal 33 g 
(0.39 mol), and ammonium acetate 4.8 g (0.06 mol) were mixed in a glass 
autoclave. After the inside temperature was raised to 110.degree. C., the 
contents of the autoclave were reacted for 1.5 hours under an ammonia 
pressure of 0.5 kg/cm.sup.2, for 1.5 hours under 1.5 kg/cm.sup.2, AND for 
2 hours under 2.5 kg/cm.sup.2. After completing of the reaction, the 
reaction mixture was cooled to room temperature. Insoluble matters were 
filtered off and the filtrate was distilled to give 
5-ethyl-2,3-diethoxycarbonylpyridine in a yield of 67%. 
EXAMPLE 6 
A mixture of diethyl .alpha.-chlorooxalacetate 37.6 g (0.168 mol), 
2-ethyl-2-butenal 19.6 g (0.20 mol), and chlorobenzene 480 ml were placed 
in a glass autoclave, and the inside temperature of the autoclave was 
raised from 35.degree. C. to 105.degree. C. over a period of about 1 hour, 
while the ammonia pressure being kept to 0.5 kg/cm.sup.2. After being 
reacted further 3.5 hours at 105.degree. C., the contents of the autoclave 
were cooled to room temperature, and insoluble matters were filtered off. 
The filtrate was concentrated, and the residue was distilled through 
Widmer spiral to give 6.6 g of 
5-ethyl-4-methyl-2,3-diethoxycarbonylpyridine (bp.sub.2 : 158.degree. to 
161.degree. C.). 
EXAMPLE 7 
In a glass autoclave, diethyl o-bromooxalacetate 25 g (0.094 mol), 
2-benzyl-2-propenal 16.4 g (0.112 mol), ammonium acetate 1.5 g, and 
toluene 200 ml were mixed, and after the inside temperature was raised to 
110.degree. C., the mixture was reacted under an ammonia pressure of 0.5 
kg/cm.sup.2 for 12.5 hours. After being cooled to room temperature, the 
reaction mixture was, with an addition of 40 g of anhydrous sodium 
sulfate, stirred for one night and solid matters were separated out. The 
filtrate was concentrated and the residue was distilled to give 8 g of 
5-benzyl-2,3-diethoxycarbonylpyridine (bp.sub.3 : 191.degree. to 
194.degree. C.). 
IR (Neat): 3000 to 2800, 1700 cm.sup.-1. 
EXAMPLE 8 TO 22 
In a similar manner to Example 6, pyridine-2,3-dicarboxylic acid compounds 
represented by the following formula: 
##STR10## 
where obtained from adequate starting materials, being hydrolized, as 
required, in the same manner as shown in Example 1. 
TABLE 4 
__________________________________________________________________________ 
Example 
R.sup.1 
R.sup.2 
R.sup.3 
R.sup.4 and R.sup.5 
Physical properties 
__________________________________________________________________________ 
8 H H H OC.sub.2 H.sub.5 
bp.sub.3 : 138.5 to 140.degree. C. 
9 H CH.sub.3 
H OC.sub.2 H.sub.5 
bp.sub.3.5 : 160 to 161.degree. C. 
10 H C.sub.2 H.sub.5 
H OC.sub.2 H.sub.5 
bp.sub.2 : 151 to 152.degree. C. 
11 H i-C.sub.3 H.sub.7 
H OC.sub.2 H.sub.5 
Oily material 
12 H n-C.sub.8 H.sub.17 
H OC.sub.2 H.sub.5 
Oily material 
13 H H CH.sub.3 
OC.sub.2 H.sub.5 
14 CH.sub.3 
H H OCH.sub.3 
15 n-C.sub.3 H.sub.7 
C.sub.2 H.sub.5 
H OC.sub.2 H.sub.5 
Oily material 
16 H H H OH Colorless to light 
yellow needles 
17 H CH.sub.3 
H OH mp: 184 to 186.degree. C. 
(dec.) 
18 H C.sub.2 H.sub.5 
H OH mp: 156.5 to 157.5.degree. C. 
19 H i-C.sub.3 H.sub.7 
H OH 
20 H H CH.sub.3 
OH mp: 164 to 166.degree. C. 
21 CH.sub.3 
H H OH mp: 190 to 191.degree. C. 
22 H C.sub.2 H.sub.5 
CH.sub.3 
OH 
__________________________________________________________________________ 
EXAMPLE 23 
Glacial acetic acid 100 g and 2-ethyl-2-propenal 30 g (0.357 mol) were 
placed in a 200 ml four neck distillation flask: with a reflux condenser 
and heated on an oil bath. When the inside temperature reached 90.degree. 
C., ethyl .beta.-amino-.beta.-ethoxycarbonylacrylate 60 g (0.321 mol) was 
added dropwise thereto at 90.degree. to 95.degree. C. over a period of 4 
hours. After completion of the dropping, the mixture was reacted at 
90.degree. to 95.degree. C. for 3 hours. After completion of the reaction, 
the reaction mixture was distilled to give 36.2 g of 
5-ethyl-2,3-diethoxycarbonylpyridine (bp.sub.2 : 151.degree. to 
152.degree. C.). 
EXAMPLE 24 
In a similar manner to Example 23 by use of propionic acid instead of 
glacial acetic acid in Example 23, 35.8 g of 
5-ethyl-2,3-diethoxycarbonylpyridine was obtained. 
EXAMPLE 25 
In a similar manner to Example 23 by use of a mixed solvent of glacial 
acetic acid 30 g and toluene 70 ml instead of glacial acetic acid 100 g in 
Example 23, 34.8 g of 5-ethyl-2,3-diethoxycarbonylpyridine was obtained. 
EXAMPLE 26 
In a 500 ml four neck distillation flask with a reflux condenser were 
placed 2-ethyl-2-propenal 100 g (1.19 mol) and dimethylamine hydrochloride 
2.0 g, and heated on an oil bath. When the inside temperature reached 
90.degree. C., ethyl .beta.-amino-.beta.-ethoxycarbonylacrylate 200 g 
(1.07 mol) was added dropwise thereto at 90.degree. to 95.degree. C. over 
a period of 4 hours. After completion of the dropping, the mixture was 
heated at 90.degree. to 95.degree. C. for 10 hours. Then, the reaction 
mixture was cooled to 50.degree. C., and 30 ml of water was added thereto. 
The mixture was then allowed to stand still to separate into a water layer 
and an oil layer. The oil layer was distilled to give 123.0 g of 
5-ethyl-2,3-diethoxycarbonylpyridine. 
EXAMPLE 27 
In a similar manner to Example 26 by use of diethylamine hydrochloride 
instead of dimethylamine hydrochloride in Example 26, 125.0 g of 
5-ethyl-2,3-diethoxycarbonylpyridine was obtained. 
EXAMPLE 28 
Ethyl .beta.-amino-.beta.-ethoxycarbonylacrylate 18.7 g (0.1 mol), 
2-methyl-2-propenal 7.5 g (0.107 mol), and glacial acetic acid 50 g were 
placed in a 100 ml four neck distillation flask with a reflux condenser 
and the temperature of the mixture was raised to 80.degree. C. on an oil 
bath over a period of 1 hour. Then, the mixture was reacted at 80.degree. 
to 85.degree. C. for 5 hours. After completion of the reaction, the 
reaction mixture was distilled to give 6.8 g of 
5-methyl-2,3-diethoxycarbonylpyridine (bp.sub.3.5 : 160.degree. to 
161.degree. C.). 
EXAMPLE 29 TO 43 
By a similar process to Example 28, pyridine-2,3-dicarboxylic acid 
compounds represented by the following formula: 
##STR11## 
were obtained from adequate starting materials, being hydrolyzed, as 
required, in the same manner as shown in Example 1. 
TABLE 5 
__________________________________________________________________________ 
Example 
R.sup.1 
R.sup.2 
R.sup.3 
R.sup.4 and R.sup.5 
Physical properties 
__________________________________________________________________________ 
29 H H H OC.sub.2 H.sub.5 
bp.sub.3 : 138.5 to 140.degree. C. 
30 CH.sub.3 
C.sub.2 H.sub.5 
H OC.sub.2 H.sub.5 
bp.sub.2 : 158 to 161.degree. C. 
31 H C.sub.2 H.sub.5 
H OC.sub.2 H.sub.5 
bp.sub.2 : 151 to 152.degree. C. 
32 H i-C.sub.3 H.sub.7 
H OC.sub.2 H.sub.5 
Oily material 
33 H n-C.sub.8 H.sub.17 
H OC.sub.2 H.sub.5 
Oily material 
34 H H CH.sub.3 
OC.sub.2 H.sub.5 
35 CH.sub.3 
H H OCH.sub.3 
36 n-C.sub.3 H.sub.7 
C.sub.2 H.sub.5 
H OC.sub.2 H.sub.5 
Oily material 
37 H H H OH Colorless to light 
yellow needles 
38 H CH.sub.3 
H OH mp: 184 to 186.degree. C. 
(dec.) 
39 H C.sub.2 H.sub.5 
H OH mp: 156.5 to 157.5.degree. C. 
40 H i-C.sub.3 H.sub.7 
H OH 
41 H H CH.sub.3 
OH mp: 164 to 166.degree. C. 
42 CH.sub.3 
H H OH mp: 190 to 191.degree. C. 
43 H C.sub.2 H.sub.5 
CH.sub.3 
OH 
__________________________________________________________________________ 
EXAMPLE 44 
Benzene 225 ml, 90% formic acid 20.5 g (0.401 mol), and ethyl 
.beta.-amino-.beta.-ethoxycarbonylacrylate 50.0 g (0.267 mol) were placed 
in a 300 ml four-neck flask equipped with a reflux condenser. After 
heating the content to 75.degree. C., 2-ethyl-2-propenal 33.7 g (0.401 
mol) was added dropwise thereto with air-bubbling and the mixture was 
reacted at 78.degree.-82.degree. C. for 13 hours. After the reaction, 100 
ml of water was added to the mixture and benzene layer was separated from 
water layer. The benzene layer contained 27.9 g of 
5-ethyl-2,3-diethoxycarbonylpyridine (by gas-chromatography). 
The above described reaction was carried out using various solvents and 
acid-catalysts. Table 6 shows solvents, acid-catalysts, reaction 
conditions and yields of the desired compound. 
TABLE 6 
______________________________________ 
Reaction Reaction 
temperature 
time Yield 
Solvent Acid catalyst 
(.degree.C.) 
(hr) (%) 
______________________________________ 
Ethylene glycol 
Formic acid 
80 7 44.1 
Sulfolane Formic acid 
80 14 45.1 
Toluene Sulfuric acid 
110 20 38.6 
Chlorobenzene 
Nitric acid 
90 20 20.4 
Isopropyl Formic acid 
80 10 55.0 
alcohol 
______________________________________ 
EXAMPLE 45 
Isopropyl alcohol 225 ml and ethyl 
.beta.-amino-.beta.-ethoxycarbonylacrylate 50.0 g (0.267 mol) were placed 
in 300 ml four-neck flask equipped with a reflux condenser. After heating 
the content to 65.degree. C., 33.7 g (0.401 mol) of 2-ethyl-2-propenal and 
20.5 (0.401 mol) of 90% formic acid were added dropwise thereto 
simultaneously with air-bubbling and the mixture was refluxed for 10 
hours. After the reaction, isopropyl alcohol was removed from the mixture 
and the mixture was neutralized with sodium bicarbonate aqueous solution. 
Oil layer was separated and concentrated under reduced pressure to obtain 
71.6 g of oily substance, which was analyzed by gas-chromatography. It was 
found that the oily substance contained 36.9 g of 
5-ethyl-2,3-diethoxycarbonylpyridine. 
EXAMPLE 46 
Isopropyl alcohol 225 ml, 90% formic acid 20.5 g (0.401 mol) and ethyl 
.beta.-amino-.beta.-ethoxycarbonylacrylate 50.0 g (0.267 mol) in order 
were placed in 300 ml four-neck flask equipped with a reflux condenser. 
After heating the content to 65.degree. C., 2-ethyl-2-propenal 33.7 g 
(0.401 mol) was added dropwise thereto with air-bubbling and the mixture 
was refluxed for 10 hours. 
After the reaction, isopropyl alcohol was removed from the mixture and the 
mixture was neutralized with sodium bicarbonate aqueous solution. Oil 
layer was separated and concentrated under reduced pressure to obtain 71.0 
g of oily substance, which was analyzed by gas-chromatography. It was 
found that the oily substance contained 36.6 g of 
5-ethyl-2,3-diethoxycarbonylpyridine. 
EXAMPLE 47 
Isopropyl alcohol 225 ml and ethyl 
.beta.-amino-.beta.-ethoxycarbonylacrylate 50.0 g (0.267 mol) were placed 
in 300 ml four-neck flask equipped with a reflux condenser. After heating 
the content to 65.degree. C., a mixture of 33.7 g (0.401 mol) of 
2-ethyl-2-propenal and 20.5 g (0.401 mol) of 90% formic acid was added 
dropwise thereto with air-bubbling and the mixture refluxed for 10 hours. 
The reaction mixture was neutralized with sodium bicarbonate aqueous 
solution, and separated oil layer was concentrated under reduced pressure 
to obtain 74.5 g of oily substance, which was analyzed by 
gaschromatography. It was found that the oily substance contained 36.6 g 
of 5-ethyl-2,3-diethoxycarbonylpyridine. 
EXAMPLE 48 
Isopropyl alcohol 225 ml, 90% formic acid 20.5 g (0.401 mol) and ethyl 
.beta.-amino-.beta.-ethoxycarbonylacrylate 50.0 g (0.267 mol) were placed 
in 300 ml four-neck flask equipped with a reflux condenser. After heating 
the content to 65.degree. C., 2-ethyl-2-propenal 33.7 g (0.401 mol) was 
added dropwise thereto and the mixture was refluxed for 10 hours. 
After the reaction, isopropyl alcohol was removed from the mixture and the 
mixture was neutralized with sodium bicarbonate aqueous solution. Oil 
layer was separated and concentrated under reduced pressure to obtain 75.5 
g of oily substance, which was analyzed by gas-chromatography. It was 
found that the oily substance contained 33.6 g of 
5-ethyl-2,3-diethoxycarbonylpyridine. 
EXAMPLE 49 
Isopropyl alcohol 150 ml and maleic acid 30.7 g (0 264 mol) were placed in 
200 ml four-neck flask equipped with a reflux condenser. After heating the 
content to 70.degree. C., a mixture of 22.2 g (0.264 mol) of 
2-ethyl-2-propenal and 32.9 g (0.176 mol) of ethyl 
.beta.-amino-.beta.-ethoxycarbonylacrylate were added dropwise thereto 
with air-bubbling and refluxed for 10 hours. After removal of isopropyl 
alcohol, 100 ml of water was added thereto and the reaction mixture was 
neutralized with sodium carbonate. Oil layer was separated and 
concentrated under reduced pressure to obtain 16.5 g of 
5-ethyl-2,3-diethoxycarbonylpyridine. 
EXAMPLE 50 
In Example 49, maleic acid was replaced by maleic anhydride 12.9 g (0.131 
mol) and 22.0 g of 5-ethyl-2,3-diethoxycarbonylpyridine was obtained. 
EXAMPLE 51 
Isopropyl alcohol 150 ml and sulfamic acid 20.5 (0.211 mol) were placed in 
200 ml four-neck flask equipped with a reflux condenser. After heating the 
content to 70.degree. C., a mixture of 2-ethyl-2-propenal 22.2 g (0.264 
mol) and ethyl .beta.-amino-.beta.-ethoxycarbonylacrylate 32.9 g (0.176 
mol) was added dropwise thereto with air-bubbling and refluxed for 10 
hours. After removing isopropyl alcohol, 130 ml of water was added thereto 
and the resulting oil layer (57.6 g) was analyzed by gas-chromatography. 
The oil layer contained 25.0 g of 5-ethyl-2,3-diethoxycarbonylpyridine. 
Then, the oil layer was added dropwise to 81 g of 20% sodium hydroxide 
aqueous solution at 85.degree.-90.degree. C. over a period of 30 minutes 
and the mixture was refluxed for 30 minutes to hydrolyze. Ethanol thus 
produced was removed in vacuo. Water 45 g was added thereto, and pH was 
adjusted to 4 with 63% sulfuric acid at 50.degree.-60.degree. C. and 
treated with active carbon, which was separated by filtration and the 
filtrate was treated with 63% sulfuric acid. n-Buthanol 120 ml was added 
to the mixture and stirred. Butanol layer was separated and concentrated. 
Crystals thus precipitated were filtered, washed with small amount of 
ethanol and dried in vacuo to obtain 15 g of 
5-ethylpyridine-2,3-dicarboxylic acid. 
The above described reaction was repeated varying amount of sulfamic acid 
used. As is shown in Table 7, 5-ethyl-2,3-diethoxycarbonylpyridine was 
obtained in good yield. 
TABLE 7 
______________________________________ 
Amount of Reaction Reaction 
sulfamic temperature time Yield 
acid used* 
(.degree.C.) (hr) (%) 
______________________________________ 
0.8 80 10 57.3 
0.5 80 10 57.9 
0.1 80 10 56.1 
0.05 80 10 53.1 
______________________________________ 
*molar ratio of sulfamic acid to ethyl amino-ethoxycarbonylacrylate 
EXAMPLE 52 
Isopropyl alcohol 675 ml and 90% formic acid 61.5 g (1.20 mol) were placed 
in 1 liter four-neck flask equipped with a reflux condenser. After heating 
the content to 70.degree. C., 2-methyl-2-propenal 84.3 g (1.20 mol) and 
ethyl .beta.-amino-.beta.-ethoxycarbonylacrylate 150 g (0.801 mol) were 
simultaneously added dropwise thereto over a period of 1 hour with 
air-bubbling and refluxed for 10 hours. After removing isopropyl alcohol, 
400 ml of water was added thereto and neutralized with sodium bicarbonate. 
After standing at 65.degree.-67.degree. C., separated oil layer was 
concentrated under reduced pressure to obtain 200 g of oily substance, 
which was distilled under reduced pressure to give 95 g of 
5-methyl-2,3-diethoxycarbonylpyridine. 
Then, the above described ester 95 g was added dropwise to 330 g of 20% 
sodium hydroxide aqueous solution at 80.degree.-90.degree. C. over a 
period of 30 minutes and the mixture was refluxed for 30 minutes to 
hydrolyze. Ethanol thus produced was removed in vacuo. Water 177 ml was 
added thereto, and pH was adjusted to 4 with 63% sulfuric acid at 
40.degree.-45.degree. C. and treated with active carbon, which was 
separated by filteration and the filtrate was treated with 63% sulfuric 
acid. Crystals thus precipitated were filtered, washed with 50 ml of water 
and dried in vacuo to obtain 62 g of 5-methylpyridine-2,3-dicarboxylic 
acid. 
EXAMPLE 53 
Isopropyl alcohol 300 ml and 90% formic acid 12.8 g (0.250 mol) were placed 
in 500 ml four-neck flask equipped with a reflux condenser. After heating 
the content to 70.degree. C., a mixture of 2-ethyl-2-butenal 21.6 g (0.22 
mol) and ethyl .beta.-amino-.beta.-ethoxycarbonylacrylate 31.1 g (0.166 
mol) was added dropwise thereto with air-bubbling and refluxed for 48 
hours. To this reaction mixture, conc. hydrochloric acid 10 ml was added 
dropwise thereto to precipitate remaining ethyl 
.beta.-amino-.beta.-ethoxy-carbonylacrylate as its hydrochloride form and 
filtered off at 20.degree. C. Concentration of the filtrate gave 52.2 g of 
oily substance, which was subjected to silica gel column-chromatography 
(eluent; ethyl acetate: benzene=1:3) and 10.7 g of 
5-ethyl-4-methyl-2,3-diethoxycarbonylpyridine was obtained. 
MMR (CDCl.sub.3): 1.25 ppm (3H,t), 1.41 ppm (6 H,tx2), 2.35 ppm (3 H,s), 
2.74 ppm (2 H,q), 4.45 ppm (4 H,qx2), 8.50 ppm (1 H,s).