JP2000128843A - Production of cyanobenzoic acid compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a cyanobenzoic acid compound useful as an intermediate for pharmaceuticals in high yield and purity on an industrial scale at a low cost by reacting a specific cyanobenzaldehyde compound with a hypohalous acid compound. SOLUTION: The objective compound of formula II is produced by reacting (A) a cyanobenzaldehyde compound of formula I (CHO and X are each a substituent on benzene ring; CHO is positioned at meta or para-position relative to CN; X is Cl or F; (n) is 0-4) (preferably m- or p-cyanobenzaldehyde) with (B) a hypohalous acid compound (e.g. sodium hypochlorite). The reaction is preferably carried out in an aqueous solvent in the presence of an apeoric polar solvent at a pH controlled to 5-10.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a cyanobenzoic acid compound represented by the general formula (2). The cyanobenzoic acid compound is an important intermediate such as a medicine, an agricultural chemical, a liquid crystal, and a functional polymer monomer.

[0002]

2. Description of the Related Art Several processes for producing cyanobenzoic acid compounds are known. Here, a method for producing p-cyanobenzoic acid will be described as a typical example. Classically, p-cyanobenzoic acid is synthesized by a Sandmeyer reaction in which p-aminobenzoic acid is diazotized and then reacted with copper cyanide (Lu).
cas et al. , J. et al. Am. Chem. Soc. ,
51 (1929) 2718). A method of oxidizing and synthesizing tolunitrile with a strong reagent oxidizing agent such as chromic acid or permanganic acid is also known (Levine et a).
l. , J. et al. Org. Chem. , 24 (1959) 11
5), (Kattwinkel et al., Che.
m. Ber. , 37 (1904) 3226).

Recently, it has been known that p-cyanobenzoic acid can be synthesized by carbonylating 4-chlorocyanobenzene using a palladium-phosphine catalyst in the presence of carbon monoxide (Japanese Patent Laid-Open No. 64-64). No. 47). As a prior art related to the present invention, p-tolunitrile is oxidized using a ruthenium compound as an oxidation catalyst, sodium hypochlorite as a reoxidizing agent, and a two-layer system of water and an organic solvent in the presence of a phase transfer catalyst. (Yel
et al. , J. et al. Org. Chem. , 51 (19
86) 2880). According to the report, p-cyanobenzoic acid is formed from tolunitrile via p-cyanobenzaldehyde. As a method for oxidizing p-cyanobenzaldehyde, a method using a cobalt catalyst in an oxygen atmosphere in the presence of acetic anhydride and n-butyraldehyde (Punnyamurthy et a).
l. , Tetrahedron Letters. , 3
5 (1994) 2959), a method using sodium perborate in an acetic acid solvent (Norich et al.,
Tetrahedron, 45 (1989) 3299)
It has been known.

However, there are some problems in these conventional methods for producing cyanobenzoic acid. That is, the Sandmeyer method requires dangerous copper cyanide, and it is difficult to isolate and purify p-cyanobenzoic acid under acidic conditions under which hydrogen cyanide is released. When a reagent oxidizing agent such as chromic acid or permanganic acid is used, a large amount of toxic heavy metal waste is generated in a stoichiometric amount or more, and a large amount of waste liquid containing toxic heavy metal causes many environmental problems. The carbonylation method is not economical because expensive palladium and phosphine are used. Further, in the method using a ruthenium compound, 1 mol of an expensive ruthenium compound is added to the raw material.
%, And 5 mol% of the phase transfer catalyst, which are not economical methods because they are essential components. Also p-
In the method based on the oxidation of cyanobenzaldehyde, both the oxygen oxidation method using a cobalt catalyst and the method using sodium perborate have low yields. As described above, p-cyanobenzoic acid has a problem that it is difficult to obtain a high-purity form by a conventionally known technique because it is complicated to synthesize and it is not easy to obtain a raw material.

[0005]

An object of the present invention is to produce a cyanobenzoic acid compound in a high yield and a high purity by an industrially advantageous method.
An object of the present invention is to develop a method for producing high-purity and high-yield m-cyanobenzoic acid.

[0006]

The inventor of the present invention uses a cyanobenzaldehyde compound of the general formula (1) as a starting material to convert an aldehyde group (-CHO) into a carboxyl group without damaging the cyano group on the benzene ring. Thereby, the above object was achieved. That is, the present invention relates to the following inventions. [1] General formula (1)

Embedded image (Wherein -CHO and -X represent a substituent on a benzene ring, -CHO is a meta or para position of -CN,
X represents a chlorine atom or a fluorine atom, and n represents an integer of 0 to 4. However, when n is 2 or more, X may be the same or different. Wherein the cyanobenzaldehyde compound represented by the formula) is reacted with a hypohalous acid compound.

Embedded image (Wherein -COOH and -X represent a substituent on a benzene ring, -COOH is a meta or para position of -CN, X represents a chlorine atom or a fluorine atom, and n is an integer of 0 to 4. Where n is 2 or more, X
May be the same or different. A method for producing a cyanobenzoic acid compound represented by

[2] The reaction between a cyanobenzaldehyde compound and a hypohalous acid compound is carried out in an aqueous solvent,
The method for producing a cyanobenzoic acid compound according to the above [1], which is performed in the presence of an aprotic polar solvent,
[3] The method for producing a cyanobenzoic acid compound according to the above [1] or [2], wherein the reaction of the cyanobenzaldehyde compound with the hypohalous acid compound is performed in an aqueous solvent at a pH of 5 to 10, 4] General formula (1)
The above object is attained by developing the method for producing a cyanobenzoic acid compound according to any one of the above [1] to [3], wherein the cyanobenzaldehyde compound represented by the formula is m- or p-cyanobenzaldehyde. Achieved.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The process for producing a cyanobenzoic acid compound according to the present invention comprises the steps of: charging a cyanobenzaldehyde compound and a hypohalous acid compound together with water or water and an aprotic polar solvent as a solvent in a reaction vessel; The reaction is performed at a predetermined temperature for a predetermined time. The raw materials can be charged and the reaction can be performed under normal pressure or under pressure. Preferably, it is performed under normal pressure. As the reactor, glass, an acid-resistant metal container, or the like is used.

The cyanobenzaldehyde compound used in the present reaction will be described. The unsubstituted cyanobenzaldehyde compound is m-cyanobenzaldehyde or p-
M-cyanobenzaldehyde, which is obtained by a reduction reaction of one nitrile group of isophthalonitrile and terephthalonitrile, respectively (JP-A-49-85041).
It can be synthesized easily and in large quantities by an oxidative deamination reaction such as a Sommelet reaction of cyanobenzylamine or p-cyanobenzylamine.

Next, the halogenated cyanobenzaldehyde compound substituted with halogen will be described. 3-cyano-2,4,5,6-tetrachlorobenzaldehyde,
Chlorinated cyanobenzaldehyde compounds such as 4-cyano-2,3,5,6-tetrachlorobenzaldehyde are
Chlorinating isophthalonitrile or terephthalonitrile, and then reducing one nitrile group of the tetrachloroisophthalonitrile or tetrachloroterephthalonitrile to obtain 3-cyano-2,4,4 obtained by the reduction reaction;
It can be synthesized easily and in large quantities by subjecting 5,6-tetrachlorobenzylamine or 4-cyano-2,3,5,6-tetrachlorobenzylamine to an oxidative deamination reaction.

[0011] The fluorinated cyanobenzaldehyde compound may be a fluorine-containing compound such as tetrafluoroisophthalonitrile or tetrafluoroterephthalonitrile obtained by a fluorination reaction of a chlorinated phthalonitrile compound such as tetrachloroisophthalonitrile or tetrachloroterephthalonitrile. 3-cyano-2,4,5,6-tetrafluorobenzylamine or 4-cyano-2,3,5,6- obtained by a reduction reaction of one of the nitrile groups of the phthalonitrile compound It can be synthesized easily and in large quantities by oxidative deamination of cyanofluorobenzylamine compounds such as tetrafluorobenzylamine.

In the method for producing a cyanobenzoic acid compound of the present invention, a hypohalous acid compound is used in the oxidation of the aldehyde group. In the reaction, hypohalous acid or a compound thereof has a relatively wide pH range of acidic, neutral and basic.
However, if the pH of the reaction solution is too low, decomposition not involving the reaction of the hypohalous acid compound becomes remarkable, the basic unit of the hypohalous acid compound until the reaction is completed becomes worse, and the pH becomes lower. If the pH is too high, a side reaction in which the nitrile group of the cyanobenzaldehyde compound or the cyanobenzoic acid compound formed by the reaction is likely to be decomposed easily, and the purity of the cyanobenzoic acid compound becomes low. Therefore, the pH is preferably 5 to 10. In the reaction, the hypohalous acid compound may be added all at once at the start of the reaction. However, it is usually preferable to add the hypohalous acid compound over 5 minutes to 10 hours because the reaction may occur rapidly and a side reaction may occur.

Examples of the hypohalous acid compound which can be used in the production of the cyanobenzoic acid compound of the present invention include hypohalous acid such as hypochlorous acid, hypobromous acid and hypoiodic acid, and hypochlorous acid. Hypohalous acid such as sodium, potassium hypochlorite, calcium hypochlorite, barium hypochlorite, sodium hypobromite, potassium hypobromite, sodium hypoiodite, potassium hypoiodite, etc. And salt. The amount of the hypohalous compound used in the reaction of the present invention is preferably 1 to 5 in a molar ratio to the cyanobenzaldehyde compound.

In the production method of the present invention, as the cyanobenzaldehyde compound is oxidized, the cyanobenzoic acid compound is generated and starts to precipitate. In general, when the pH of the reaction solution is 4 or less, a large amount of cyanobenzoic acid compound rapidly precipitates, making stirring difficult, and unreacted cyanobenzaldehyde compound is incorporated into the precipitated cyanobenzoic acid compound to complete the reaction. There are problems such as difficulty. In such a case, a base can be added to the reaction system, and the cyanobenzoic acid compound can be dissolved as a salt in the reaction solution to make the reaction system a homogeneous solution and the reaction can proceed efficiently. The base may be initially added in a necessary amount all at once, or may be added continuously as the reaction proceeds so that the cyanobenzoic acid compound is not precipitated.

The base which can be used in the production of the cyanobenzoic acid compound of the present invention includes alkali metals and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide and calcium hydroxide. Hydroxides, sodium bicarbonate, alkali metal bicarbonates such as potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and other alkali metal and alkaline earth metal carbonates, magnesium oxide; Metal oxides such as calcium oxide and alkaline earth metals can be used. The amount of the base used in the above depends on the type and amount of the coexisting hypochlorous acid compound, but the total amount of the base contained in the hypochlorous acid compound and the base to be added to the reaction is at least equimolar to the cyanobenzaldehyde compound. The amount is such that the pH of the reaction system can be maintained at 5 to 10 during the reaction.

The method of the present invention can carry out the reaction in an aqueous solution. When the solubility of the cyanobenzaldehyde compound is low when water is used as the solvent, the reaction can be performed efficiently by coexisting an aprotic polar solvent. Examples of aprotic polar solvents that can be used in this reaction include ethers such as dioxane and diglyme, amides such as dimethylformamide, sulfur-containing systems such as dimethylsulfoxide and sulfolane, and nitriles such as acetonitrile. The amount of the aprotic polar solvent used in this reaction is at least 0.1 (part by weight) with respect to 1 (part by weight) of the cyanobenzaldehyde compound, and may be used in a range that can be mixed with water. it can. Preferably, one of the cyanobenzaldehyde compounds
(Parts by weight) to 0.3 to 3 (parts by weight).

If the reaction temperature is too low, the reaction rate is low, and if it is too high, the nitrile group is decomposed. Therefore, the reaction temperature is preferably 10 to 80 ° C, more preferably 30 to 50 ° C. The reaction time of this reaction depends on the pH, the composition of the solvent and the like, but is preferably 10 minutes to 12 hours.

[0018]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. The purity of the obtained cyanobenzoic acid compound was measured by high performance liquid chromatography. [High-performance liquid chromatograph analysis conditions] Column Shodex DE-513L (Shodex is a registered trademark of Showa Denko KK) + Precolumn eluent water / acetonitrile / acetic acid = 2250/750/15 (ml) sodium 1-octanesulfonate 6.45g Condition Flow rate 1ml / min UV 254nm Column oven 40 ℃

Example 1 13.1 g of p-cyanobenzaldehyde and 50 g of water were mixed and stirred, and 13% by weight was obtained.
A 150 g aqueous sodium hypochlorite solution having a concentration of sodium hydroxide was added dropwise at room temperature over 2 hours, and the mixture was further stirred for 1 hour. Then, 3 g of urea was added and the mixture was stirred for 20 minutes.
g and 150 g of water. The precipitated crystals were collected by filtration, washed with water and dried to obtain 12.1 g of p-cyanobenzoic acid (yield: 82
%). The purity of p-cyanobenzoic acid obtained by high-performance liquid chromatography analysis was 95% or more.

Example 2 26.2 g of p-cyanobenzaldehyde, 26 g of acetonitrile, sodium carbonate 1
While mixing and stirring 0.5 g and 100 g of water, 210 g of a 13.5% by weight aqueous solution of sodium hypochlorite was added dropwise over 1 hour while maintaining the internal temperature of the reaction system at 50 ° C. or lower, and further stirred for 1 hour. . Next, 3.6 g of urea was added and the mixture was stirred for 20 minutes, and 12 g of 98% by weight sulfuric acid and 300 g of water were further added. The precipitated crystals were collected by filtration, washed with water and dried to obtain 27.6 g (yield 94%) of p-cyanobenzoic acid. Purity 9
8% or more.

Example 3 26.2 g of p-cyanobenzaldehyde, 26 g of acetonitrile, 17.6 g of sodium hydrogen carbonate and 100 g of water were mixed and stirred. 210 g of a 13.5% by weight aqueous sodium hypochlorite solution adjusted to pH = 9 was added dropwise over 1 hour while maintaining the reaction system internal temperature at 40 ° C., and the mixture was further stirred for 1 hour. Then 3.6 g of urea
Stir for 20 minutes, and further add 12 g of 98% by weight sulfuric acid.
300 g of water were added. The precipitated crystals were collected by filtration, washed with water and dried to obtain 28.8 g (yield 98%) of p-cyanobenzoic acid. Purity was over 99%.

Example 4 26.2 g of m-cyanobenzaldehyde, 40 g of dioxane, sodium hydrogen carbonate 1
7.6 g and 100 g of water were mixed and stirred. A 13.5% by weight aqueous sodium hypochlorite solution 210 adjusted to pH = 9
g was added dropwise over 1 hour while maintaining the internal temperature of the reaction system at 50 ° C. or lower, and the mixture was further stirred for 1 hour. Next, 3.6 g of urea was added and the mixture was stirred for 20 minutes, and 12 g of 98% by weight sulfuric acid and 300 g of water were further added. The precipitated crystals were collected by filtration, washed with water and dried to obtain 27 g of p-cyanobenzoic acid (yield 92%).
Purity was over 98%.

Example 5 26.2 g of m-cyanobenzaldehyde, 18 g of dimethylformamide and 70 g of water were mixed and stirred. 220 g of a 13% by weight aqueous sodium hypochlorite solution was added dropwise over 2 hours while maintaining the internal temperature of the reaction system at 35 to 45 ° C., and at the same time, a dropping funnel with a pH controller was used so that the pH of the reaction solution became 7 to 8. The sodium hydroxide solution was added dropwise. Then 3.6 g of urea
Stir for 20 minutes, and further add 12 g of 98% by weight sulfuric acid.
300 g of water were added. The precipitated crystals were collected by filtration, washed with water and dried to obtain 26.5 g (yield 90%) of p-cyanobenzoic acid. Purity was over 98%.

According to the method for producing a cyanobenzoic acid compound of the present invention, first, a starting material cyanobenzaldehyde compound can be easily obtained in large quantities and at low cost. In addition, the reaction conditions are simple, and it is not necessary to use dangerous compounds such as hydrogen cyanide in the reaction.
There is no need for expensive catalysts without catalysts, and the effluent of the reaction is safe and clean, and there are no by-products such as heavy metal-containing substances that pollute the environment. Furthermore, the obtained cyanobenzoic acid compound is characterized by the fact that it has high purity and the product can be obtained in high yield, and it is easy to increase the production unit and is a very excellent method for producing a cyanobenzoic acid compound.

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[Procedure amendment]

[Submission date] October 19, 1998 (1998.10.
19)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claim 1

[Correction method] Change

[Correction contents]

Embedded image (Wherein -CHO and -X represent a substituent on a benzene ring, -CHO is a meta or para position of -CN,
X represents a chlorine atom or a fluorine atom, and n represents an integer of 0 to 4. However, when n is 2 or more, X may be the same or different. Wherein the cyanobenzaldehyde compound represented by the formula) is reacted with a hypohalous acid compound.

Embedded image (Wherein -COOH and -X represent a substituent on a benzene ring, -COOH is a meta or para position of -CN, X represents a chlorine atom or a fluorine atom, and n is an integer of 0 to 4. Where n is 2 or more, X
May be the same or different. A method for producing a cyanobenzoic acid compound represented by the formula:

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0006

[Correction method] Change

[Correction contents]

[0006]

The inventor of the present invention uses a cyanobenzaldehyde compound of the general formula (1) as a starting material to convert an aldehyde group (-CHO) into a carboxyl group without damaging the cyano group on the benzene ring. Thereby, the above object was achieved. That is, the present invention relates to the following inventions. [1] General formula (1)

Embedded image (Wherein -CHO and -X represent a substituent on a benzene ring, -CHO is a meta or para position of -CN,
X represents a chlorine atom or a fluorine atom, and n represents an integer of 0 to 4. However, when n is 2 or more, X may be the same or different. Wherein the cyanobenzaldehyde compound represented by the formula) is reacted with a hypohalous acid compound.

Embedded image (Wherein -COOH and -X represent a substituent on a benzene ring, -COOH is a meta or para position of -CN, X represents a chlorine atom or a fluorine atom, and n is an integer of 0 to 4. Where n is 2 or more, X
May be the same or different. A method for producing a cyanobenzoic acid compound represented by

Claims (4)

[Claims] 1. A compound of the general formula (1) (Wherein -CHO and -X represent a substituent on a benzene ring, -CHO is a meta or para position of -CN,
X represents a chlorine atom or a fluorine atom, and n represents an integer of 0 to 4. However, when n is 2 or more, X may be the same or different. Wherein the cyanobenzaldehyde compound represented by the formula) is reacted with a hypohalous acid compound. (Wherein -COOH and -X represent a substituent on a benzene ring, -COOH is a meta or para position of -CN, X represents a chlorine atom or a fluorine atom, and n is an integer of 0 to 4. Where n is 2 or more, X
May be the same or different. A method for producing a cyanobenzoic acid compound represented by the formula: 2. The method for producing a cyanobenzoic acid compound according to claim 1, wherein the reaction between the cyanobenzaldehyde compound and the hypohalous acid compound is carried out in an aqueous solvent in the presence of an aprotic polar solvent. 3. The reaction of a cyanobenzaldehyde compound and a hypohalous acid compound in an aqueous solvent at a pH of 5
The method for producing a cyanobenzoic acid compound according to claim 1 or 2, wherein the method is carried out in the range of 1 to 10. 4. The method for producing a cyanobenzoic acid compound according to claim 1, wherein the cyanobenzaldehyde compound represented by the general formula (1) is m- or p-cyanobenzaldehyde.