JP2816855B2 - Process for producing pyridine-2,3-dicarboxylic acid derivative - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing a pyridine-2,3-dicarboxylic acid derivative, and more specifically, an intermediate useful for producing agricultural chemicals, medicaments and the like. The present invention relates to a method for producing a pyridine-2,3-dicarboxylic acid derivative.

<Problems to be Solved by the Prior Art and the Invention> Conventionally, as a method for producing pyridine-2,3-dicarboxylic acids, quinolines are obtained by a Skraup reaction in which aniline and glycerin are treated with concentrated sulfuric acid and nitrobenzene. Quinolinols and then nitric acid oxidation of quinolines and quinolinols (J. Chem. Soc. No. 4433).
P. 1956); reacting an α, β-unsaturated hydrazone compound with a maleic acid compound in an inert solvent to give 1-substituted amino-1,4
-Dihydropyridine-2,3-dicarboxylic acid derivative is obtained, and then the obtained derivative is heated to eliminate the substituted amino group at the 1-position (Japanese Patent Laid-Open No. 60-246369); A method in which a 1,2,3,4-tetrahydropyridine-2,3-dicarboxylic acid derivative is converted to a 1,4-dihydropyridine-2,3-dicarboxylic acid derivative by acid treatment and / or heat treatment, and then oxidized ( A method of oxidizing quinoline with an excess of hypochlorite in the presence of ruthenium oxide (JP-A-61-212563); A method is known in which an α, β-unsaturated aldehyde or ketone is condensed and cyclized in an organic solvent in the presence of at least 2 molar equivalents of an ammonium salt (JP-A-62-106081).

As a method for synthesizing a pyridine monocarboxylic acid derivative, 2-methyl-1,4- formed by condensation and cyclization of an α, β-unsaturated aldehyde such as acrolein or crotonaldehyde with ethyl β-aminocrotonate. Method of nitric acid oxidation of ethyl dihydronicotinate in a mixed acid (J.
Org. Chem. Soc. 21, p. 800, 1956).

However, according to one of the above methods,
Not only the number of reaction steps is large, but also nitric acid oxidation, which is an extreme reaction condition, is required, which is dangerous. Further, pyridine-2,3-dicarboxylic acids easily cause a decarboxylation reaction by heating under acidic conditions, so that the yield is low according to the nitric acid oxidation method, and a large amount of acidic waste liquid is generated. It is not suitable as an industrial production method for 1,3-dicarboxylic acids.

In the above production methods, not only the total yield is low due to the large number of reaction steps, but also expensive starting materials must be used. Further, since a step of removing the substituted amino group of the intermediate is required, the yield is reduced, and there is a problem in terms of resource saving. Therefore, in the above and the manufacturing method,
It is difficult to industrially produce pyridine-2,3-dicarboxylic acid derivatives.

In the above-mentioned production method, there is a problem in that it is necessary to use a large excess of the oxidizing agent, and a large amount of waste liquid is generated, so that waste liquid treatment is expensive.

In the above-mentioned production method, in the production of the α-halo-β-ketoester as a raw material, a conventionally known production method can obtain only a low yield, so that the raw material is expensive and the target product, pyridine-2,3-, is obtained. It is difficult to produce a dicarboxylic acid derivative industrially at low cost.

<Objective> The present invention has been made in view of the above-mentioned problems, and is a pyridine-2,3-dicarboxylic acid derivative which can obtain a target product in high yield by using an inexpensive and easily available starting material. It is to provide a manufacturing method of.

<Means for Solving the Problems> A method for producing a pyridine-2,3-dicarboxylic acid derivative of the present invention, which has been made to solve the above-mentioned problems, comprises a pyridine-2,3 represented by the following general formula (1). In a method for producing a 3-dicarboxylic acid derivative, (Wherein, R ¹ and R ² are the same or different and represent a lower alkyl group, and R ³ represents a hydrogen atom or a lower alkyl group) A compound represented by the following general formula (2): (Wherein, R ¹ and R ² are the same as above, and M represents an alkali metal) By reacting with an acid and a halogenating agent, the following general formula (3)
To obtain a compound represented by (Wherein, R ¹ and R ² are the same as above, and X represents a halogen atom) Then, a compound represented by the above general formula (3) and a compound represented by the following general formula (4) (Wherein R ³ is the same as described above), and a compound represented by the following general formula (5): (Wherein, R ² is the same as described above). A compound represented by the following general formula (6): (Wherein R ¹ and X are the same as described above) By reacting in an aprotic solvent in the presence of an alkali metal or basic alkali metal salt, a compound represented by the following general formula (7) is obtained, (Wherein R ¹ , R ² , X and M are the same as above) Then, the compound represented by the above general formula (7) is treated with an acid to obtain a compound represented by the following general formula (3) , (Wherein R ¹ , R ² and X are the same as described above) Further, a compound represented by the above general formula (3) and a compound represented by the following general formula (4) (Wherein R ³ is the same as above) and ammonia.

In each of the above formulas, lower alkyl groups for R ¹ , R ² and R ³ include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, 2-octyl Examples thereof include a linear or branched alkyl group having 1 to 8 carbon atoms such as an ethylhexyl group.

Examples of the alkali metal of M include sodium and potassium.

Examples of the halogen atom for X include a fluorine atom, a chlorine atom, and a bromine atom.

Specific examples of the compound represented by the general formula (2) include, for example, dimethyl sodium oxalate acetate, diethyl sodium oxalate acetate, sodium methylethyl oxalate acetate, dimethyl potassium oxalate acetate, diethyl potassium oxalate oxalate, Examples thereof include di-tert-butyl oxalacetate, di-tert-butyl oxalate acetate, sodium dipropyl oxalate, and potassium dipropyl oxalate.

Specific examples of the compound represented by the general formula (3) include, for example, α-dimethyl chlorooxalate, diethyl α-chlorooxalate, methyl ethyl α-chlorooxalate, dimethyl α-bromooxalate, diethyl α-bromooxalate, α-diethyl Di-tert-butyl chlorooxalacetate, dipropyl α-chlorooxalacetate, dipropyl α-fluorooxalacetate and the like.

Specific examples of the compound represented by the general formula (4) include, for example, acrolein, 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 and the like can be exemplified.

Specific examples of the compound represented by the general formula (5) include, for example, dimethyl oxalate, diethyl oxalate, dipropyl oxalate, diisopropyl oxalate, dibutyl oxalate, ditertiary butyl oxalate, dipentyl oxalate, Examples include dihexyl oxalate, diheptyl oxalate, and dioctyl oxalate.

Specific examples of the compound represented by the general formula (6) include, for example, methyl chloroacetate, methyl bromoacetate, methyl fluoroacetate, ethyl chloroacetate, ethyl bromoacetate, ethyl fluoroacetate, propyl chloroacetate, isopropyl chloroacetate, Propyl bromoacetate, butyl chloroacetate,
Examples thereof include isobutyl chloroacetate, tertiary butyl chloroacetate, butyl bromoacetate, hexyl chloroacetate, hexyl bromoacetate, and octyl chloroacetate.

Specific examples of the compound represented by the general formula (7) include, for example, α-chlorooxalacetic acid dimethyl sodium salt,
α-chlorooxalacetic acid diethyl sodium salt, α-chlorooxalacetic acid methylethyl sodium salt, α-bromooxalacetic acid dimethylpotassium salt, α-bromooxalacetic acid diethylpotassium salt, α-chlorooxalacetic acid ditertiary butyl sodium salt, α-chlorooxalacetic acid diacid Examples thereof include tert-butyl potassium salt, α-chlorooxalacetic acid dipropyl sodium salt, α-fluorooxalacetic acid dipropyl potassium salt and the like.

The production method of the present invention can be represented by the following reaction schemes-1 and 2.

(In the above formula, R ¹ , R ² , R ³ , X and M are the same as described above.) In the above reaction process, the production method represented by the reaction process formula-1 is a compound represented by the general formula (2) And a step of reacting the compound with an acid and a halogenating agent to obtain a compound represented by the general formula (3) (first step);
And a step of reacting the compound represented by the general formula (4) with ammonia to obtain a compound represented by the general formula (1) (second step).

In the reaction of the first step, examples of the acid used here include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid; lower alkanoic acids such as formic acid, oxalic acid, acetic acid, and propionic acid; methanesulfonic acid; Examples thereof include organic acids such as sulfonic acids such as ethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. Examples of the halogenating agent include sulfuryl chloride, bromine, chlorine and the like.

This reaction is carried out by reacting a compound represented by the general formula (2) with a halogenating agent in the presence of an acid;
The compound represented by is treated with an acid and then reacted with a halogenating agent.

The reaction is preferably carried out in an organic solvent.As the organic solvent, any solvent can be used as long as it does not affect the reaction, but aromatic hydrocarbons such as toluene and benzene, chloroform, 1 , 2-dichloroethane,
Aprotic solvents such as halogenated hydrocarbons such as carbon tetrachloride are preferred.

The reaction temperature of the reaction between the compound represented by the general formula (2) or the acid-treated compound represented by the general formula (2) and the halogenating agent is not particularly limited, but is usually 0 to 100 ° C., preferably Performed at 0-50 ° C. The reaction time is 30 minutes to 10
The operation is completed in a time, usually, about 1 to 5 hours.

The ratio of the compound represented by the general formula (2) and the halogenating agent can be used in an appropriate molar ratio.
A halogenating agent is added to the compound represented by the general formula (2).
It is preferable to use about 0.6 to 1.5 moles, preferably about 1 to 1.3 moles. The acid is used in an amount at least equimolar to the compound represented by the general formula (2), preferably a slight excess.

The combination of the above-mentioned acid, organic solvent and halogenating agent is optional, but as the acid, alkanoic acids, especially formic acid,
Most preferred is a combination of halogenated hydrocarbons, especially chloroform, as the organic solvent and sulfuryl chloride as the halogenating agent.

The compound represented by the general formula (3) thus obtained is
It is used for the reaction of the second step without isolation or after isolation and purification by means such as distillation and column chromatography.

The reaction in the second step is represented by the general formula (1) by reacting the compound represented by the general formula (3) obtained above with the compound represented by the general formula (4) and ammonia. This is a reaction for obtaining a compound.

This reaction is carried out without a solvent or in an organic solvent.As the organic solvent, any solvent that does not affect the reaction can be used irrespective of polar, non-polar solvent, protic, or aprotic solvent. Alcohols such as methanol, ethanol, isopropanol and butanol; halogenated hydrocarbons such as chloroform, 1,2-dichloroethane and carbon tetrachloride; aromatics such as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene and nitrobenzene. Hydrocarbons; ethers such as diethyl ether, diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, dibenzyl ether; methyl acetate, ethyl Esters such as Seteto; sulfoxides such as dimethyl sulfoxide, N, N-carbamide compounds such as dimethylformamide, dimethyl sulfone, sulfones such as sulfolane, aprotic polar solvents such as hexamethylphosphoric acid triamide can be exemplified. The above organic solvents may be used as a mixture of two or more kinds. Among the above organic solvents, aprotic organic solvents are preferred.

The reaction temperature of this reaction is not particularly limited, and it can be carried out at various temperatures, for example, it is preferably carried out in a temperature range of 10 to 200 ° C, particularly preferably in a temperature range of 35 to 130 ° C. The reaction is preferably carried out under pressure, and particularly preferably under the pressure of ammonia of 0.3 to 2.5 kg / cm ² . The reaction time is completed in 30 minutes to 24 hours, usually about 1 to 10 hours.

The compound represented by the general formula (3) and the compound represented by the general formula (4) can be used in an appropriate molar ratio. For example, the compound represented by the general formula (3) On the other hand, it is preferable to use the compound represented by the general formula (4) in a molar amount of 0.8 to 1.5 times, particularly 1.0 to 1.2 times. Ammonia is usually used in excess with respect to the compounds represented by the general formulas (3) and (4).

In addition, the above reaction is preferably performed in the presence of an ammonium salt, for example, ammonium carbonate, ammonium chloride, ammonium sulfate, ammonium nitrate, ammonium phosphate, ammonium acetate, etc., in order to efficiently produce the target compound.

The above ammonium salt can be used in an appropriate amount, but it is used in an amount of 0.05 to 1. based on the compound represented by formula (4).
It is preferable to use a 0-fold molar amount.

The production method represented by the reaction step formula-2 is a method for preparing a compound represented by the general formula (5) and a compound represented by the general formula (6) in an aprotic solvent in an alkali metal or a basic alkali metal. Reacting in the presence of a salt to obtain a compound represented by the general formula (7) (first step); treating the resulting compound represented by the general formula (7) with an acid to obtain a compound represented by the general formula (3) )), And then reacting the obtained compound represented by the general formula (3) with the compound represented by the general formula (4) and ammonia. A step (third step) of obtaining a compound represented by the formula (1).

The reaction of the first step is carried out by reacting a compound represented by the general formula (5) with a compound represented by the general formula (6) in an aprotic solvent in the presence of an alkali metal or a basic alkali metal salt. In the reaction for condensing the aprotic solvent used herein, for example, dimethyl ether, diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, ether such as dibenzyl ether And aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, and nitrobenzene.

Examples of the alkali metal used include sodium and potassium. Examples of the basic alkali metal salt include alkali metal alcoholates such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide, and methyllithium. And alkyl alkali or aryl alkali such as ethyl lithium, propyl lithium, n-butyl lithium, tertiary butyl lithium and phenyl lithium, and alkali metal hydrides such as sodium hydride and potassium hydride.

This reaction is usually carried out at room temperature to heating (about 60 ° C.), and the reaction time is about 10 hours to 3 days, usually 24 to
It ends in about 48 hours.

The compound represented by the general formula (5) and the compound represented by the general formula (6) can be used in an appropriate molar ratio, but usually the compound represented by the general formula (5) is used. On the other hand, the compound represented by the general formula (6) is preferably used in a molar amount of 0.8 to 2 times, preferably 1 to 1.5 times. The amount of the alkali metal or basic alkali metal salt used is at least equimolar to the compound represented by the general formula (5), preferably slightly excessive.

The compound represented by the general formula (7) thus obtained is
It is used for the reaction of the second step without isolation, or after isolation and purification by means such as washing and recrystallization.

The reaction of the second step is a reaction of treating the compound represented by the general formula (7) obtained above with an acid to obtain a compound represented by the general formula (3), and is used in this reaction. As the acid, any of an inorganic acid and an organic acid can be used, and the acids exemplified in the first step of the reaction process formula-1 can be used.

The above-mentioned acid treatment is usually carried out in the presence of a water-insoluble solvent (eg, diethyl ether, dibutyl ether, benzene, toluene, xylene, chlorobenzene, etc.) and water in excess of the compound represented by the general formula (7). The reaction is carried out by allowing an acid to act to separate the water-insoluble solvent phase.

The compound represented by the general formula (3) thus obtained is
It is used for the reaction of the third step without isolation or after isolation and purification by means such as distillation and column chromatography.

The reaction of the third step is represented by the general formula (1) by reacting the compound represented by the general formula (3) obtained above with the compound represented by the general formula (4) and ammonia. This is a reaction for obtaining a compound.

This reaction is the same as the second step in the reaction scheme 1, and the reaction conditions (eg, solvent, reaction temperature, reaction time, molar ratio of compound used, etc.) are the same as those in the reaction step.

The corresponding pyridine-2,3-dicarboxylic acid can be obtained by hydrolyzing the ester compound represented by the general formula (1) obtained by the method of the present invention by a known method. The hydrolysis reaction is performed in water or an aqueous solvent, for example, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium carbonate, alkali metal carbonates such as potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like. The reaction can be carried out by a conventional method using a basic compound such as an alkali metal hydrogencarbonate, but an alkali metal hydroxide is preferable for performing the reaction completely. The hydrolysis reaction is performed at room temperature to 150 ° C, preferably 40 to 100 ° C.
And usually ends in about 1 to 24 hours.

The dicarboxylic acid salt produced by the above hydrolysis reaction is subjected to acid precipitation with a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid at a temperature of 20 to 60 ° C. to obtain a desired carboxylic acid. .

In the reaction formulas -1 and 2, the compounds represented by the general formulas (2), (5) and (6), which are starting materials, are known compounds. As a method for producing the compound represented by the general formula (3), for example, J. Amer., Chem., So
c., Vol. 72, 5221, (1950), the method described in the literature, that is, in the compound represented by the general formula (2), R ² is an ethyl group And the method of reacting a compound in which M is sodium with sulfuryl chloride or bromine in chloroform has a low yield of about 31%, which is not suitable for industrial production of the compound represented by the general formula (3). In contrast to the above method, in the method of the present invention, the compound represented by the general formula (3) is obtained in high yield by reacting the compound represented by the general formula (2) with an acid and a halogenating agent. As a result, the yield of the compound represented by the general formula (1) can be increased.

The pyridine-2,3-dicarboxylic acid derivative obtained by the method of the present invention is useful as an intermediate when synthesizing various compounds such as agricultural chemicals and pharmaceuticals.

<Effect of the Invention> According to the method for producing a pyridine-2,3-dicarboxylic acid derivative of the present invention, the number of steps is small, and the desired product can be obtained in high yield. Particularly, the reaction can be carried out without isolating an intermediate. Can be performed. In addition, it is possible to use inexpensive and easily available starting materials, and it is safe because the reaction proceeds under mild conditions, and it is also easy to treat waste liquid, etc., so that the pyridine-2,3-dicarboxylic acid derivative can be used. Can be produced on an industrial scale.

<Examples> Hereinafter, the present invention will be described in more detail based on Production Examples and Examples, but the present invention is not limited to these Examples.

Production Example 1 41 g of dimethylamine hydrochloride was placed in a 300 ml four-necked flask.
(0.502 mol) and 42.7 g (0.527 mol) of 37% formalin were added, and 84 g (0.527 mol) of n-decylaldehyde was added to 20-30.
The mixture was added dropwise at about 1 hour over about 1 hour. After reacting at 70-75 ° C for 6 hours, it was further heated at 110 ° C for 30 minutes. The mixture was cooled to room temperature and separated into an oil layer and an aqueous layer. The oil layer (88 g) was distilled under reduced pressure to give 2- (n-octyl) -2-.
60 g of propenal (bp ₁₅ : 108.5 to 110 ° C.) was obtained.

IR (liquid film): 2930, 2850, 1700 cm ^-1 Example 1 To a 500 ml four-necked flask equipped with a reflux condenser were added 221 ml of chloroform and 13.1 g (0.26 mol) of 90% formic acid, and sodium oxalate acetate diethyl ester. 44.2g (0.21
Mol) was added at room temperature. After stirring at 20 to 25 ° C for 2 hours, sulfuryl chloride 41.1 was added at 20 to 30 ° C for about 2 hours.
g (0.30 mol) was added dropwise and reacted at 40 ° C. for 5 hours. After cooling the content to room temperature, degassing was performed under reduced pressure, and the generated inorganic salt was separated by filtration. The filtrate was analyzed by gas chromatography to obtain α-chlorooxalacetic acid diethyl ester in a yield of 78%.

Next, the above filtrate and 2-ethyl-2-propenal 1
7.7 g (0.21 mol) was mixed in a 100 ml glass autoclave and sealed, then the internal temperature was raised to 110 ° C., and ammonia gas was introduced so that the partial pressure of ammonia became 0.5 to 2.5 kg / cm ^2, and 5 hours Reacted. The contents were cooled to room temperature, and insolubles were removed by filtration. The filtrate was concentrated, and the residue was distilled to give 5-ethyl-2,3-diethoxycarbonylpyridine (bp ₂ : 151 to 152 ° C.) in a yield of 62.4% based on the charged oxalacetate diethyl ester sodium salt. Obtained.

The above reaction was carried out using various solvents, acids and halogenating agents. Table 1 shows the types of the solvent, the acid, the halogenating agent, and the yield of the target product (by gas chromatography analysis).

Example 2 In a 200 glass-lined kettle equipped with a reflux condenser, 104 kg of chloroform, 4.7 kg (89.9 mol) of 88% formic acid and 1.4 kg of ethanol were mixed at room temperature, and 14.1 kg (67.1 mol) of sodium oxalacetate diethyl ester was mixed. ) 20-25
After stirring at 10 to 25 ° C for 2 hours, 11.4 kg (84.5 mol) of sulfuryl chloride was added dropwise at 10 to 25 ° C over about 2 hours. After stirring at 40 ° C. for 3 hours, the mixture was refluxed at 60 ° C. for 2 hours to expel gas generated by the reaction. After the content was cooled to room temperature, 30 water was injected to dissolve the inorganic salt generated by the reaction, and separated into a chloroform layer and an aqueous layer.
When 120.6 kg of the separated chloroform solution was analyzed by gas chromatography, 12.3 kg (55.2 mol) of α-chlorooxalacetic acid diethyl ester was obtained. This gives a yield of 82.3%, based on the charged sodium salt of oxalic acetic acid diethyl ester.

Subsequently, the above chloroform solution, 2-ethyl-2-propenal 5.6 kg (66.6 mol) and ammonium acetate 1.0 kg
(13.0 mol) was mixed and sealed in a glass autoclave of 100, the internal temperature was raised to 60 ° C, and after the air in the gas phase was discharged, the temperature was raised to 105 ° C and it took 8 hours.
The reaction was performed by introducing ammonia gas so that the internal pressure became 3.5 to 6.0 kg / cm ² . After cooling the contents to room temperature,
Water 16 was injected to dissolve the inorganic salt generated by the reaction, and separated into a chloroform layer and an aqueous layer. The separated chloroform layer was concentrated to obtain 17.4 kg of a brown oily substance. The concentrate is distilled to give 5-ethyl-2,3-diethoxycarbonylpyridine 1
2.0 kg (47.8 mol) were obtained. This gives a yield of 71.2% for the charged sodium salt of oxalacetic acid diethyl ester and a yield of 86.6% for the chlorinated product.

Example 3 130 ml of toluene and 35% hydrochloric acid were placed in a 300 ml four-necked flask.
Add 21g and 40g of water, and under vigorous stirring under nitrogen atmosphere
At 20 to 25 ° C, 40 g (0.19 mol) of sodium oxalate acetate was added. After stirring for 2 hours, the mixture was allowed to stand, and separated into a toluene layer and an aqueous layer. 100m water in toluene layer
and washed with anhydrous sodium sulfate overnight and filtered. While maintaining the filtrate at 10 to 20 ° C., 17 g of sulfuryl chloride
(0.126 mol) was added dropwise over 1 hour and reacted at 40 ° C. for 5 hours. The contents were cooled to room temperature and degassed under reduced pressure. When the obtained solution was analyzed by gas chromatography, α-chlorooxalacetic acid diethyl ester was obtained in a yield of 64% based on the charged oxalic acid diethyl ester sodium salt.

Then, in a 300 ml glass autoclave, the solution obtained above, 2-methyl-2-propenal 8.2 g
(0.117 mol) and 1.8 g of ammonium acetate (0.023 mol)
Was mixed and sealed, the internal temperature was raised to 110 ° C., then ammonia gas was introduced so that the internal pressure became 1.5 kg / cm ² or less, and the mixture was reacted at 105 to 110 ° C. for 7 hours. The contents were cooled to room temperature, and insolubles were removed by filtration. The obtained filtrate was analyzed by gas chromatography.
5-methyl-2,3-diethoxycarbonylpyridine was obtained in a yield of 42.6%.

To the solution obtained above, 50 g of water and 61.6 g of a 48% aqueous sodium hydroxide solution were added, and at 85 to 88 ° C. under a nitrogen atmosphere.
Stir for 8.5 hours. After the completion of the reaction, the reaction solution was separated into a toluene layer and an aqueous layer, the aqueous layer was decolorized with activated carbon, and then acid-deposited with 50% sulfuric acid to give white crystals of 5-methylpyridine-2,3-dicarboxylic acid (mp : 184 to 186 ° C). The melting point of what was recrystallized from a methanol-acetone mixed solvent was 187-188.5 ° C.
(Decomposition).

Elemental analysis: As C ₈ H ₇ NO ₄ , calculated for CH N 53.06 3.90 7.73 found 52.63 3.95 7.68 NMR (CDCl ₃ ) ppm: 2.45 (3H, s), 8.15 (1H, s), 8.57 (1H, s) Example 4 450 ml of toluene and 35% hydrochloric acid
5 ml and 150 ml of water were added, and under a nitrogen atmosphere, 143 g of oxalacetate diethyl ester sodium salt with vigorous stirring
(0.68 mol) was added at room temperature. After stirring at 20 to 25 ° C for 2 hours, the mixture was separated into a toluene layer and an aqueous layer. The toluene layer was washed successively with a dilute aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate overnight, and filtered. Filtrate 10 ~ 20 ℃
87.2 g (0.65 mol) of sulfuryl chloride
It was added dropwise over 2.5 hours. Thereafter, the internal temperature was raised to 45 ° C., and the reaction was performed for 3 hours. Cool the contents to room temperature,
Degassing was performed under reduced pressure. When the obtained solution was analyzed by gas chromatography, α-chlorooxalacetic acid diethyl ester was obtained at a yield of 65% based on the charged oxalic acid diethyl ester sodium salt.

Next, in a glass autoclave, the solution obtained above and 78.9 g (0.47 mol) of 2- (n-octyl) -2-propenal were mixed, and the mixture was sealed.
The temperature was raised to 10 ° C., ammonia gas was introduced so that the internal pressure became 0.8 to 2.0 kg / cm ^2, and the reaction was performed at 110 to 115 ° C. for 10 hours. Cool the contents to room temperature, filter out insolubles,
The filtrate was sequentially washed with 70 ml of a 0.3N aqueous hydrochloric acid solution and 50 ml of water.
107 g of a 48% aqueous sodium hydroxide solution and water were added to this toluene solution.
168 ml was added, and the mixture was refluxed under a nitrogen atmosphere at 85 to 87 ° C. for 2 hours. After the completion of the reaction, the mixture was diluted with 300 ml of hot water, and separated into an aqueous layer and a toluene layer. The aqueous layer was subjected to acid precipitation with a 12% aqueous hydrochloric acid solution at 70 to 80 ° C. to obtain 26 g of a white plate crystal of 5- (n-octyl) pyridine-2,3-dicarboxylic acid (mp: 156 to 158 ° C.). . This was recrystallized with an ethanol-water mixed solvent, and the melting point was 16
0.5-162 ° C.

IR (KBr): 3040,2900,2835,1700~1600,1560cm ^-1 Elemental Analysis: as _{C 15 H 21 NO 4, C} H N Calculated 64.51 7.58 5.01 Found _{64.63 7.52 5.32 NMR (CDCl 3)} ppm: 0.95 (3H, t), 1.26-3.0 (14H, m), 9.15 (1H, s), 9.
20 (1H, s) Example 5 In a 500 ml four-necked flask, 210 ml of chloroform and 90 ml
% Formic acid 14.0 g (0.274 mol) was added, and oxaxalacetic acid diethyl ester sodium salt 44.2 g (0.21 mol) was added at room temperature. After stirring at 20 to 25 ° C for 2 hours, 40 g (0.25 mol) of bromine is added dropwise at 10 to 15 ° C over 30 minutes, and 30 to 40 ° C
For 3 hours and at 60 ° C. for 1 hour. The content was cooled to room temperature, and the generated inorganic salt was separated by filtration.

Then, in a 100 ml glass autoclave, 15 g of the filtrate obtained above and 2-ethyl-2-propenal were obtained.
(0.178 mol) and 3.2 g of ammonium acetate were mixed and sealed, then the internal temperature was raised to 110 ° C., and the internal pressure was increased to 2.5 to
Ammonia gas was introduced at 3.0 kg / cm ² and reacted for 9.5 hours. After the content was cooled to room temperature, insolubles were removed by filtration, and the filtrate was analyzed by gas chromatography. As a result, 5-ethyl-2,3 -Diethoxycarbonylpyridine was obtained.

Example 6 5.8 g (0.252) of metallic sodium was added to 100 ml of diethyl ether.
Mol) and 29.5 g (0.250 mol) of dimethyl oxalate,
At room temperature, 40 g (0.369 mol) of ethyl chloroacetate was added dropwise over 2 hours. After reacting for 48 hours at 25-30 ° C, 35%
The mixture was diluted with 95 g of an aqueous acetic acid solution, and separated into an ether layer and an aqueous layer. The aqueous layer was further extracted with 100 ml of diethyl ether, mixed with the previous ether layer, and dried over anhydrous sodium sulfate.
After distilling off diethyl ether, the residue was distilled under reduced pressure to obtain 22 g of dimethyl α-chlorooxalacetate (bp ₈ : 122 ° C.) (yield: 45.2).
%)Obtained.

Then, toluene 1 was placed in a 500 ml glass autoclave.
20 ml, 6.5 g (0.077 mol) of 2-ethyl-2-propenal and the dimethyl α-chlorooxalacetate obtained above
After charging 10 g (0.051 mol) and raising the internal temperature to 90 ° C., blowing of ammonia gas was started at an ammonia pressure of 0.5 kg / cm ² , and the reaction was carried out at 105 ° C. for 9 hours. The contents were cooled to room temperature, and insolubles were removed by filtration. After the filtrate was dried over anhydrous sodium sulfate, toluene was distilled off, and the residue was left to leave 5-ethyl-2,3-dimethoxycarbonylpyridine (b
p _4: 158.5-161 ℃) to give 6.6 g (58.0% yield).

IR (liquid film): 2950, 2850, 1740, 1720 cm ^-1 Mass spectrometry: M ⁺ = 223 Example 7 To 250 ml of toluene was added 5.8 g (0.252 mol) of sodium metal and 29.5 g (0.250 mol) of dimethyl oxalate, and the mixture was stirred at room temperature. , 40 g (0.369 mol) of methyl chloroacetate was added dropwise over 1 hour. The reaction was performed at 45 to 55 ° C for 48 hours. Then water 60
ml and 35 g of 35% hydrochloric acid were added, and the mixture was separated into a toluene layer and an aqueous layer. After the toluene layer was dried over anhydrous sodium sulfate, sodium sulfate was separated by filtration. This filtrate and 13.2 g (0.157 mol) of 2-ethyl-2-propenal were charged into a 500 ml glass autoclave, the internal temperature was raised to 90 ° C., and then blowing of ammonia gas was started at an ammonia pressure of 0.5 kg / cm ^2. At 105 ° C. for 4 hours. The contents were cooled to room temperature, and insolubles were removed by filtration. When the filtrate was analyzed by gas chromatography, the dimethyl oxalate was charged.
5-Ethyl-2,3-dimethoxycarbonylpyridine was obtained with a yield of 30.6%.

Example 8 To 250 ml of dibutyl ether was added 5.8 g (0.2%) of metallic sodium.
52 mol) and 11.6 g (0.252 mol) of absolute ethanol
After stirring for 3 hours, 36.8 g (0.252 mol) of diethyl oxalate and 33.0 g (0.269 mol) of ethyl chloroacetate were added at 30 to 35 ° C. for 1 hour.
It was dropped over time. After reacting for 38 hours at room temperature, water 80
ml and 35 g of 35% hydrochloric acid were added, and the mixture was separated into an ether layer and an aqueous layer. After the ether layer was dried over anhydrous sodium sulfate, sodium sulfate was separated by filtration. This filtrate and 21.2 g (0.252 mol) of 2-ethyl-2-propenal were charged into a 500 ml glass autoclave, the internal temperature was raised to 90 ° C., and then the blowing of ammonia gas was started at an ammonia pressure of 0.5 kg / cm ^2. At 105 ° C. for 4 hours. The contents were cooled to room temperature, and insolubles were removed by filtration. The filtrate was analyzed by gas chromatography.
5-Ethyl-2,3-diethoxycarbonylpyridine was obtained with a yield of 46.6%.

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁶ , DB name) C07D 213/79-213/803 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] (1) General formula (Wherein, R ¹ and R ² are the same or different and each represents a lower alkyl group, and M represents an alkali metal).
General formula (Wherein, R ¹ and R ² are the same as above, and X represents a halogen atom). Wherein R ³ represents a hydrogen atom or a lower alkyl group, and ammonia. (Wherein, R ¹ , R ² and R ³ are the same as described above). 2. The general formula (Wherein R ² represents a lower alkyl group) and a compound represented by the general formula: (Wherein, R ¹ represents a lower alkyl group and X represents a halogen atom), in an aprotic solvent in the presence of an alkali metal or a basic alkali metal salt, formula (Wherein R ¹ , R ² and X are the same as above and M represents an alkali metal), and then treated with an acid to obtain a compound represented by the general formula (Wherein R ¹ , R ² and X are the same as described above). Wherein R ³ represents a hydrogen atom or a lower alkyl group, and a compound represented by the general formula: (Wherein, R ¹ , R ² and R ³ are the same as described above).