JPH082879B2 - Process for producing 6-chloropyridine-2,3-dicarboxylic acid and heterocyclic dicarboxylic acid - Google Patents

Description

The present invention relates to a novel compound, 6-chloropyridine-2,
The present invention relates to a method for producing a nitrogen-containing heterocyclic dicarboxylic acid by oxidizing a 3-dicarboxylic acid and a nitrogen-containing heterocyclic aromatic compound.

2. Description of the Related Art Nitrogen-containing heterocyclic dicarboxylic acid is useful as a raw material for heat- and pressure-sensitive dyes, pharmaceuticals, agricultural chemicals and the like.

Conventionally, in order to produce a nitrogen-containing heterocyclic dicarboxylic acid, generally, a nitrogen-containing heterocyclic aromatic compound is oxidized with alkali permanganate under basic conditions to cleave the aromatic ring, or to generate a nitrogen-containing heterocyclic compound. When the heterocyclic compound has an alkyl group, it depends on a method of oxidizing the alkyl group.
However, when such an oxidation reaction with alkali permanganate is used, this oxidizing agent is required in an amount equivalent to that of the raw material oxide, and since alkali permanganate is relatively expensive, the production cost is high. I have no choice. Further, in the oxidation reaction, a large amount of manganese dioxide is produced as a by-product, which requires disposal treatment, which is disadvantageous as an industrial production method.

Further, JP-A-60-84270 and JP-A-61-212563.
The publication discloses a method for producing quinolinic acid by oxidizing quinoline with ruthenium tetraoxide in the presence of an aqueous hypochlorite solution and a base. However, the oxidation reaction of the quinoline derivative having a substituent or the quinoxaline derivative which may have a substituent used as a raw material in the present invention is not suggested by the production method described in the above publication. . When a heterocyclic compound having a substituent is oxidized, the oxidation of the substituent usually proceeds simultaneously with the cleavage of the benzene ring, and therefore, for example, in the oxidation reaction of 2-methylquinoline, pyridine-2,3,6 -The formation of tricarboxylic acids etc. is expected. Moreover, in the case of a quinoxaline derivative, the pyrazine ring is susceptible to oxidation and tends to be cleaved.

According to the present invention, the desired heterocyclic dicarboxylic acid can be unexpectedly produced in high yield.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention has been made in order to solve the above-mentioned problems in the conventional production of a nitrogen-containing heterocyclic dicarboxylic acid, wherein tetraoxidation is carried out in place of potassium permanganate as an oxidizing agent. An object of the present invention is to provide a method for industrially advantageously producing a nitrogen-containing heterocyclic dicarboxylic acid by using ruthenium.

Further, it is an object of the present invention to provide 6-chloropyridine-2,3-dicarboxylic acid, which is a novel nitrogen-containing heterocyclic dicarboxylic acid produced by such a method.

Means for Solving the Problems The method for producing a nitrogen-containing heterocyclic dicarboxylic acid according to the present invention has the general formula (In formula, X shows a carbon atom or a nitrogen atom, R shows a hydrogen atom, a C1-C4 alkyl group, or a halogen atom. However, when X is a carbon atom, R is not a hydrogen atom. Further, the benzene ring A may have a substituent which does not influence the reaction.) A heterocyclic compound represented by the following formula is oxidized with ruthenium tetroxide under basic conditions to give a compound of the general formula (In the formula, R and X are the same as the above.) The heterocyclic dicarboxylic acid represented by the formula is produced.

According to the method of the present invention, surprisingly, even when R in the heterocyclic compound represented by the general formula (I) is an alkyl group, the alkyl group is not substantially oxidized and only the benzene ring is It is preferentially oxidized to give the general formula (I
A nitrogen-containing heterocyclic dicarboxylic acid represented by I) can be obtained.

The raw material oxide used in the method of the present invention is represented by the above general formula (I), and R is a hydrogen atom or a carbon number of 1 to 4.
Is an alkyl group or a halogen atom. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group and a butyl group, and a methyl group is preferable. The halogen atom may be fluorine, chlorine, bromine or iodine, but chlorine is preferable. In the general formula (I), when X is a carbon atom, R is not a hydrogen atom. Further, the benzene ring A may have a substituent that does not influence the reaction, for example, a hydroxyl group.

Therefore, in the present invention, examples of the compound used as the raw material oxide are 2-methylquinoline, 3-methylquinoline, 4-methylquinoline and 2-methyl-8-
Hydroxyquinoline, 3-methyl-8-hydroxyquinoline, 4-methyl-8-hydroxyquinoline, 2-methyl-5-hydroxyquinoline, 3-methyl-5-hydroxyquinoline, 4-methyl-5-hydroxyquinoline,
2-ethylquinoline, 3-ethylquinoline, 4-ethylquinoline, 2-ethyl-5-hydroxyquinoline, 3-
Ethyl-8-hydroxyquinoline, 2-n-propylquinoline, 3-n-propylquinoline, 4-n-propylquinoline, 2-n-butylquinoline, 2-chloroquinoline, 3-chloroquinoline, 4-chloroquinoline, 2-chloro-5-hydroxyquinoline, 3-chloro-8-hydroxyquinoline, 2-bromoquinoline, 3-iodoquinoline, quinoxaline, 2-methylquinoxaline, 3-methylquinoxaline, 2-methyl-5-hydroxyquinoxaline, 3-methyl-5-hydroxyquinoxaline, 2
-Methyl-8-hydroxyquinoxaline, 3-methyl-
8-hydroxyquinoxaline, 2-ethylquinoxaline, 3-ethylquinoxaline, 2-ethyl-5-hydroxyquinoxaline, 3-ethyl-8-hydroxyquinoxaline, 2-n-propylquinoxaline, 3-n-propylquinoxaline, 2-bromo Examples thereof include quinoxaline, 2-chloroquinoxaline, 3-chloroquinoxaline, 2-chloro-5-hydroxyquinoxaline and 3-chloro-8-hydroxyquinoxaline.

In the method of the present invention, ruthenium tetroxide is used as the oxidizing agent. However, a catalytic amount may be present in the reaction system by using the co-oxidant together. That is, ruthenium tetroxide is itself reduced to ruthenium dioxide by an oxidation reaction, and this ruthenium dioxide is oxidized by a co-oxidant to generate ruthenium tetroxide again. Therefore, in the present invention, a ruthenium compound which gives ruthenium tetroxide by a co-oxidant,
For example, ruthenium dioxide, ruthenium trichloride, etc. can also be used.

In the present invention, the amount of ruthenium compound used in the reaction is in the range of 10 ⁻⁵ to 10 ⁻² mol with ^respect to 1 mol of the raw material. It is advantageous to use the ruthenium compound in an amount of 10 ^-2 mol or more from the viewpoint of shortening the reaction time, but it reduces the economic efficiency of the reaction process, and therefore, as an industrial production method,
It is a disadvantage. On the other hand, use of 10 ^-5 mol or less is not preferable because the reaction time becomes extremely long.

In the present invention, the co-oxidant is not particularly limited as long as it can oxidize a ruthenium compound to ruthenium tetraoxide, and usually periodate or hypochlorite is used. The co-oxidant is preferably used in the range of 1 to 2 times the theoretical amount. This is because even if it is used twice or more, for example, a large amount of tricarboxylic acid or the like is not produced as a by-product, but it is economically disadvantageous.

In the method of the present invention, when the raw material oxide is a solid at the reaction temperature, the reaction rate is remarkably slow, so the reaction is preferably carried out in an organic solvent. In such cases,
The organic solvent is not particularly limited as long as it is inert to the reaction, but normally, an aliphatic halogenated hydrocarbon such as carbon tetrachloride or chloroform is preferably used. The amount of the organic solvent used is sufficient as long as it can dissolve the raw material oxide.

In the present invention, the reaction is carried out under basic conditions. Under neutral and acidic conditions, the nitrogen-containing ring of the raw material oxide is also oxidized, and the yield is reduced. As the basic compound, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are preferably used. The amount used is usually at least 5 times the molar amount of the raw material oxide, and it is preferable to maintain the reaction system at a high alkalinity of pH 11 or higher throughout the reaction.

The reaction temperature mainly affects the reaction rate. Therefore,
In the present invention, the reaction temperature is usually in the range of 10 to 70 ° C, preferably 20 to 60 ° C. The reaction temperature is
If the temperature is lower than 10 ° C, the reaction rate is too slow, while if the temperature is higher than 70 ° C, the self-decomposition of the co-oxidant is promoted. The reaction time is usually 5 to 50 hours, though it depends on the reaction temperature.

Usually, after the completion of the reaction, the desired nitrogen-containing heterocyclic dicarboxylic acid can be isolated by acidifying the obtained reaction mixture. Further, when the desired nitrogen-containing heterocyclic dicarboxylic acid is readily soluble in water, after acidifying the obtained reaction mixture, copper sulfate, copper chloride, copper compounds such as copper oxide may be added thereto. The desired nitrogen-containing heterocyclic dicarboxylic acid can be isolated as a copper salt.

In the above copper salt formation reaction, when the reaction temperature is too high, for example, under reflux conditions, there is a risk of causing the separation of the desired nitrogen-containing heterocyclic dicarboxylic acid, on the other hand, when it is too low, the copper salt is formed. hard. Therefore, the copper compound may be added in an amount of approximately equivalent to the raw material oxide in the range of 10 to 98 ° C, preferably 60 to 80 ° C. The objective dicarboxylic acid can be obtained by decomposing the thus obtained copper dicarboxylic acid salt with hydrogen sulfide, sodium hydroxide or the like.

EFFECTS OF THE INVENTION As described above, according to the method of the present invention, a substituted or unsubstituted heterocyclic dicarboxylic acid can be obtained from a substituted quinoline, a quinoxaline and a substituted quinoxaline by oxidative cleavage of an aromatic ring. . The 6-chloropyridine-2,3-dicarboxylic acid obtained by the method of the present invention is a novel compound.

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples. still,
In the following,% means% by weight.

Example 1 16.4 g of 2-chloroquinoline, ruthenium trichloride (RuCl ₃
・ 3H ₂ O) 1% aqueous solution 5.2 ml, 50% sodium hydroxide aqueous solution 52 g, and 12% sodium hypochlorite aqueous solution 650 g 3
The mixture was stirred at a temperature of 8 to 42 ° C for 48 hours. Then, the remaining available chlorine was decomposed with a small amount of isopropanol, and sodium chloride was filtered off. 50 ml of carbon tetrachloride was added to the filtrate, and after stirring, the aqueous layer was separated.

Next, 135 g of 17.5% hydrochloric acid was added to the above aqueous layer to adjust to pH 2, 125 g of a 20% copper sulfate aqueous solution was added thereto, and the temperature was adjusted to 70 to 75 ° C.
The mixture was stirred for 30 minutes. After cooling, the precipitate was collected by filtration, washed with water and dried. The obtained copper salt was suspended in 300 ml of water at 60 to 65 ° C., and hydrogen sulfide gas was bubbled at 100 ml / min for 20 minutes,
Filtered. The obtained filter paper was concentrated to dryness under reduced pressure. After adding 5 ml of water thereto, it was filtered, washed with water and dried to obtain 8.71 g of 6-chloropyridine-2,3-dicarboxylic acid monohydrate (yield
39.7%) was obtained as a pale yellowish white powder. Melting point is 134-137 ℃
It was (decomposition).

Elemental analysis (C ₇ H ₆ NO ₅ Cl) CHN Experimental value 38.38 2.73 6.32 Calculated value 38.28 2.76 6.38 Infrared absorption spectrum (cm ^-1 ) 1725 (νC = O) Mass spectrum m / e 183 (M ⁺ -HOH) Further, the above 6-chloropyridine-2,3-dicarboxylic acid was converted to dimethyl ester by a conventional method.

Elemental analysis (C ₉ H ₈ NO ₄ Cl) C H N Experimental value 47.21 3.56 6.15 Calculated value 47.06 3.52 6.10 Mass spectrum m / e 229 (M ⁺ ) Proton nuclear magnetic resonance spectrum (δ (CDCl ₃ ) ) 3.92 (s, 3H), 3.98 (s, 3H), 7.50 (d, 1H, J = 8Hz), 8.
17 (d, 1H, 8Hz). Example 2 65 g quinoxaline, ruthenium trichloride (RuCl ₃ .3H ₂ O)
1% aqueous solution 1.3 ml, 50% sodium hydroxide aqueous solution 260
g, and 3250 g of 12% sodium hypochlorite aqueous solution 35 to 37
Stirred at a temperature of ° C for 24 hours. Then, the remaining available chlorine was decomposed with a small amount of isopropanol, and sodium chloride was filtered off. The filtrate was adjusted to pH 1 with 50% sulfuric acid and crystallized copper sulfate 1
After adding 25 g, the mixture was stirred at 70 to 75 ° C for 30 minutes. After cooling, the precipitate was collected by filtration, washed with water and dried, and pyrazine-2,3-
115 g (yield 92.9%) of dicarboxylic acid copper salt (1: 1 copper salt) was obtained as a dark green powder.

The obtained copper salt was suspended in water 2 at 60 to 65 ° C., hydrogen sulfide gas was bubbled at 200 ml / min for 1 hour, and then filtered. The filtrate was concentrated to dryness under reduced pressure. After adding 20 ml of water, filtering, washing with water and drying, 74 g of pyrazine-2,3-dicarboxylic acid
(Yield 88.1%) was obtained as a white powder. Melting point is 179-180
℃ (decomposition).

Example 3 14.3 g of quinaldine (2-methylquinoline), 5.2 ml of 1% aqueous solution of ruthenium trichloride (RuCl ₃ .3H ₂ O), 52 g of 50% aqueous sodium hydroxide solution, and 650 g of 12% aqueous sodium hypochlorite solution. The mixture was stirred at a temperature of 30 to 35 ° C for 24 hours. Then, the same treatment as in Example 1 is performed to obtain 6-methylpyridine-
6.08 g (yield 33.6%) of 2,3-dicarboxylic acid was obtained as a white powder. The melting point was 161-162 ° C (decomposition).

Example 4 14.3 g of 3-methylquinoline, ruthenium trichloride (RuCl ₃
・ 3H ₂ O) 1% aqueous solution 5.2 ml, 50% sodium hydroxide aqueous solution 52 g, and 12% sodium hypochlorite aqueous solution 650 g 3
The mixture was stirred at a temperature of 0 to 35 ° C for 15 hours. Then, the same treatment as in Example 1 was carried out to obtain 6.56 g (yield 36.2%) of 5-methylpyridine-2,3-dicarboxylic acid as a white powder. The melting point was 180-181 ° C (decomposition).

Example 5 Lepidine (4-methylquinoline) 14.3 g, ruthenium trichloride (RuCl ₃ .3H ₂ O) 1% aqueous solution 5.2 ml, 50% sodium hydroxide aqueous solution 650 g were stirred at a temperature of 30 to 35 ° C. for 24 hours. . Then, the same treatment as in Example 1 was performed to obtain 7.24 g (yield 40.4%) of 4-methylpyridine-2,3-dicarboxylic acid as a white powder. The melting point was 183-184 ° C (decomposition).

Example 6 2-Methylquinoxaline 14.4 g, ruthenium trichloride (R
uCl ₃ 3H ₂ O) 1% aqueous solution 5.2 ml, 50% sodium hydroxide aqueous solution 52 g, and 12% sodium hypochlorite aqueous solution 650
g was stirred at a temperature of 30-35 ° C for 24 hours. Then, the remaining available chlorine was decomposed with a small amount of isopropanol, and sodium chloride was filtered off. 50 ml of carbon tetrachloride was added to the filtrate, and after stirring, the aqueous layer was separated.

To this, 110 g of 17.5% hydrochloric acid was added to adjust the pH to 3, 70 g of a 30% copper (II) chloride aqueous solution was added, and the mixture was stirred at 70 to 75 ° C for 30 minutes. After cooling, the precipitate was collected by filtration, washed with water and dried. The obtained copper salt was suspended in 300 ml of water at 60 to 65 ° C., and hydrogen sulfide gas was passed at 100 ml / min for 20 minutes, followed by filtration. The filtrate was concentrated to dryness under reduced pressure. After adding 5 ml of water, filtration,
After washing with water and drying, 4.45 g (yield 24.5%) of 4-methylpyrazine-2,3-dicarboxylic acid was obtained as a white powder. The melting point was 182-183 ° C (decomposition).

Claims (2)

[Claims] 1. A 6-chloropyridine-2,3-dicarboxylic acid. 2. General formula (In formula, X shows a carbon atom or a nitrogen atom, R shows a hydrogen atom, a C1-C4 alkyl group, or a halogen atom. However, when X is a carbon atom, R is not a hydrogen atom. The benzene ring A may have a substituent which does not influence the reaction.) A general formula characterized by oxidizing a heterocyclic compound represented by the formula (4) with ruthenium tetroxide under basic conditions. (In the formula, R and X have the same meanings as described above.) A method for producing a heterocyclic dicarboxylic acid represented by: