JP2000143605A - Production of cyanobenzoic acid chlorides - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject cyanobenzoyl chloride of high purity, particularly m- or p-isomer that are useful as a medicinal intermediate in high yield by allowing a cyanobenzoic acid to react with phosgene or its precursor. SOLUTION: A cyanobenzoic acid represented by formula I (-COOH is in the m- or p-position of the group -CN; X is chlorine, fluorine; n is 0-4) (preferably p- or m-cyanobenzoic acid) is allowed to react with a phosgene or a phosgene precursor to give the objective compound of formula II (-COCl is in the m- or p-position of the group -CN) (preferably p- or m-cyanobenzoyl chloride). In a preferred embodiment, this reaction is carried out in the presence of a tertiary amide, for example, a tertiary formamide or the like or a tertiary amine, for example, an aliphatic or aromatic tertiary or a nitrogen-containing heterocyclic compound at a molar ratio of 1.1-4 time molar amount of phosgene per one molar amount of the cyanobenzoic acid at 0-200 deg.C for 10 minutes to 10 hours.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a cyanobenzoic acid chloride compound represented by the general formula (2). Cyanobenzoic acid chloride compounds are important intermediates such as pharmaceuticals, pesticides, liquid crystals, and functional polymer monomers.

[0002]

2. Description of the Related Art Acid chlorination in the present invention is a reaction for converting a carboxyl group of a cyanobenzoic acid compound into a corresponding acid chloride group.

[0003] The acid chlorinating agent in the present invention is a general term for organic and inorganic reagents capable of converting a carboxyl group to a corresponding acid chloride group.

[0004] Several processes for producing cyanobenzoic acid chloride compounds are known. Here, p-
A method for producing cyanobenzoic acid chloride will be described. p-Cyanobenzoic acid chloride has been synthesized by the reaction of p-cyanobenzoic acid with an acid chlorinating agent. Examples of the acid cloning agent include thionyl chloride (Japanese Patent Publication No. 1-35011, Johan Kamphuis, et al.,
J. Chem. Soc. Perkin Trans, 2
(1987) 907), oxalyl chloride (Rob
ert J. et al. Weikert, et al. , J. et al. Me
d. Chem, 34 (1991) 1630), phosphorus pentachloride (Raffaello Fusco, et al.,
Ann. Chim (Rome), 42 (1952) 9
4) is used. As a method other than the acid chlorination of cyanobenzoic acid, a method of reacting 4-trichloromethylbenzamide in the presence of a ferric chloride catalyst (JP-A-63-313761), a method of reacting terephthalamate with phosphorus oxychloride (JP-A-52-39)
649).

[0005]

As a problem of the conventional acid chlorination of p-cyanobenzoic acid compounds, when thionyl chloride is used, sulfur dioxide is generated, and it is costly and economical to separate and detoxify sulfur dioxide. Is not a good way. When oxalyl chloride is used, oxalyl chloride produces highly toxic carbon monoxide, and it is not costly and economical to separate and remove carbon monoxide. When phosphorus pentachloride is used, a phosphorus compound is generated after the reaction, and the phosphorus compound causes eutrophication of lakes, rivers and the like. Therefore, there is a large environmental load in removing and discarding the phosphorus compound, which is not a practical method. In addition, a method using 4-trichloromethylbenzamide or terephthalamate as a raw material is not economically advantageous because it is difficult to obtain 4-trichloromethylbenzamide or terephthalamate as a raw material easily and inexpensively. .

[0006] As described above, p-cyanobenzoic acid chloride is dangerous or difficult to separate and remove by-products formed after the reaction by the conventionally known techniques, and there is a problem in obtaining raw materials. there were.

An object of the present invention is to produce a cyanobenzoic acid chloride compound of the general formula (2) in a high yield and a high purity by an industrially advantageous method. Another object is to produce a p-cyanobenzoic acid chloride compound with high purity and high yield.

[0008]

The present inventors have achieved the above object by using phosgene or a phosgene precursor from a cyanobenzoic acid compound represented by the general formula (1) as a starting material.

That is, the present invention relates to the following inventions. (A) General formula (1)

Embedded image (Wherein -COOH and -X represent a substituent on a benzene ring, -COOH is an m-position or a p-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 cyanobenzoic acid compound of) is reacted with phosgene or a phosgene precursor.

Embedded image (Wherein -COCl and -X represent a substituent on a benzene ring, -COCl is an m-position or a p-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. )) A method for producing a cyanobenzoic acid chloride compound. (B) A process for producing a cyanobenzoic acid chloride compound of (a), wherein the reaction is carried out in the presence of a cyanobenzoic acid chloride compound of general formula (2) corresponding to the cyanobenzoic acid compound of general formula (1). (C) The method for producing a cyanobenzoic acid chloride compound according to (a) or (b), wherein the reaction is carried out in the presence of a tertiary amide compound or a tertiary amine compound. (D) The cyanobenzoic acid compound of the general formula (1) is m- or p-cyanobenzoic acid, and the cyanobenzoic acid compound of the general formula (2) is a corresponding m- or p-cyanobenzoic acid chloride ( The method for producing a cyanobenzoic acid compound according to any one of a) to (c).

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the reaction method of the present invention, when a cyanobenzoic acid compound is reacted with phosgene or a phosgene precursor to accelerate the reaction, a cyanobenzoic acid chloride compound corresponding to the cyanobenzoic acid compound,
This is performed by adding an additive such as a tertiary amide compound or a tertiary amine compound in the presence of an organic solvent and stirring the mixture at a predetermined temperature for a predetermined time. The charging and reaction of the reaction raw materials can be performed under atmospheric pressure, under pressure, or under reduced pressure. Glass and acid-resistant metal containers are suitable as reactors.

The cyanobenzoic acid compound used in the present reaction will be described. The unsubstituted cyanobenzoic acid compound is p
-Cyanobenzoic acid and m-cyanobenzoic acid, each of which undergoes a hydrolysis reaction of one side nitrile group of terephthalonitrile and isophthalonitrile (Berther et a).
l. Chem. Ber. , 92 (1959) 261
It can be easily synthesized in 6). Next, the cyanobenzoic acid compound substituted with halogen will be described. 4-cyano-
2,3,5,6-tetrachlorobenzoic acid, 3-cyano-
Chlorinated cyanobenzoic acid compounds such as 2,4,5,6-tetrachlorobenzoic acid are chlorinated terephthalonitrile compounds such as tetrachloroterephthalonitrile obtained by chlorination of terephthalonitrile and isophthalonitrile; It can be easily synthesized by a hydrolysis reaction of a nitrile group on one side of a chlorinated isophthalonitrile compound such as isophthalonitrile. 4-cyano-2,3,5,6-
Tetrafluorobenzoic acid, 3-cyano-2,4,5,6
A fluorinated cyanobenzoic acid compound such as tetrafluorobenzoic acid is obtained by a fluorination reaction of a chlorinated terephthalonitrile compound such as tetrachloroterephthalonitrile and a chlorinated isophthalonitrile compound such as tetrachloroisophthalonitrile; It can be easily synthesized by a hydrolysis reaction of one side nitrile group of a fluorinated terephthalonitrile compound such as terephthalonitrile and a fluorinated isophthalonitrile compound such as tetrafluoroisophthalonitrile.

The phosgene or phosgene precursor used in the present invention will be described. Phosgene is usually introduced into the reaction vessel as a gas, but may be liquefied and introduced under pressure or by cooling. The amount of phosgene used in the present invention must be at least equimolar with respect to the cyanobenzoic acid compound, and is preferably 1.1 or more with respect to the cyanobenzoic acid compound.
It is used in a molar amount of up to 4 times. Preferably, unreacted phosgene gas is recycled and reused, and is used in a molar amount of 1.1 to 1.5 times.

The method of reacting phosgene with a cyanobenzoic acid compound will be described. When a phosgene monomer is used, the reaction between phosgene and a cyanobenzoic acid compound is performed discontinuously or continuously at normal pressure, reduced pressure or increased pressure. As the reaction proceeds, carbon dioxide and hydrochloric acid are produced with the production of the cyanobenzoic acid chloride compound. Phosgene is usually introduced into the reaction system until the evolution of carbon dioxide and hydrochloric acid has ceased and phosgene is no longer consumed. The phosgene precursor refers to a substance that can be easily converted back to phosgene by a treatment such as heating or a catalyst, and activated carbon or the like can be used as a catalyst. Examples include phosgene dimers and trimers.
The phosgene dimer may be charged directly into the reaction vessel, or phosgene gas may be generated in another reactor and introduced into the reactor. The phosgene trimer is a solid at room temperature and the required amount may be charged into a batch reactor, or the phosgene trimer may be dissolved in an inert solvent and introduced as a solution.

A method for isolating a cyanobenzoic acid chloride compound will be described. Excess phosgene and hydrochloric acid remaining in the reaction mixture are removed by distillation by heating or bubbling with an inert gas such as nitrogen, as necessary. When a solvent is used, the solvent is distilled off, and the resulting cyanobenzoic acid chloride compound can be isolated from the reaction mixture by a conventional method, for example, by distillation or crystallization.

Since the solubility of the cyanobenzoic acid compound in an organic solvent is generally low, the reaction can be carried out efficiently if the corresponding cyanobenzoic acid chloride compound is added during the reaction and used as a reaction solvent in some cases. At this time, the cyanobenzoic acid compound and the corresponding cyanobenzoic acid chloride compound alone may be mixed, or when stirring is difficult, the mixture may be diluted with an inert solvent and mixed.
The presence of the cyanobenzoic acid chloride compound during the reaction has the effect of accelerating the reaction.

The solvent used in this reaction is an aprotic organic solvent. Examples of the organic solvent that can be used include nitriles such as acetonitrile, tertiary formamides such as dimethylformamide and diethylformamide, sulfur-containing systems such as sulfolane, imidazolidones such as 1,3-dimethyl-2-imidazolidione,
Ethers such as dioxane, 1,2-dimethoxyethane, diglyme, dichloromethane, chloroform,
Halogen compounds such as 2-dichloroethane and aromatic hydrocarbon compounds such as benzene, toluene, and mixed xylene of m-, p- and o- are used. The organic solvents may be used alone or as a mixture.

The amount of the solvent in this reaction is preferably 5 to 100 times the weight of the cyanobenzoic acid compound. The reaction temperature is
Although it depends on reaction conditions, 0 ° C to 200 ° C is preferable. The reaction time of this reaction depends on the composition of the solvent, but is preferably 10 minutes to 10 hours.

In the present reaction, additives can be used to accelerate the reaction. Tertiary amide compounds can be used as additives for accelerating the reaction. Tertiary formamides such as dimethylformamide, diethylformamide, dimethylpropionamide and dibutylformamide can be used as additives. The amount of the tertiary amide compound is at least 0.01 molar equivalent relative to the carboxylic acid.

Tertiary amine compounds can be used as additives for accelerating the reaction. The tertiary amine compound serves as a catalyst for activating phosgene, or as a scavenger for hydrochloric acid generated by the acid chlorination reaction of cyanobenzoic acid,
It can be any of them. Examples of the tertiary amine compound include aliphatic tertiary amines such as trimethylamine, triethylamine and tribenzylamine, triphenylamine and aromatic tertiary amines such as tri-p-toluylamine;
Imidazole, pyridine, p-dimethylaminopyridine, N-methylmorpholine, quinoline, isoquinoline,
Nitrogen-containing heterocyclic compounds such as pyrimidine and piperazine are preferably used. When the tertiary amine compound is used as a catalyst for activating phosgene, it is used in an amount of at least 0.01 molar equivalent to the carboxylic acid. When used as a phosgene activation and hydrochloric acid scavenger, at least an equimolar amount of phosgene used in the reaction is required.

[0020]

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 analysis conditions of the gas chromatograph used in this example are as follows. Column DB1 (J & W) (30 m capillary column, inner diameter 0.32 mm) Carrier helium 3 cc / min Split ratio 40 Detector FID Analysis conditions Hold for 8 minutes) Detection 300 ℃

Example 1 16.6 g of p-cyanobenzoic acid chloride, 14.7 g of p-cyanobenzoic acid, 0.15 g of dimethylformamide
Were mixed, and 20 g of phosgene gas was blown in over 90 minutes while stirring vigorously at 120 ° C. 1 dry nitrogen gas
After introducing into the reaction mixture for a period of time, the mixture was distilled under reduced pressure to obtain 32.5 g of p-cyanobenzoic acid chloride (yield 98% based on p-cyanobenzoic acid) (bp. 110 ° C./2 mm).
Hg). P- obtained by gas chromatography analysis
The purity of cyanobenzoic acid chloride was 99% or more.

Example 2 16.6 g of p-cyanobenzoic acid chloride, 14.7 g of p-cyanobenzoic acid, 0.2 g of imidazole and 150 ml of xylene were mixed at 140 ° C. and stirred vigorously, and 20 g of phosgene gas was added for 2 hours. I blew it. 20 g of phosgene gas was blown in over 90 minutes. After introducing dry nitrogen gas into the reaction mixture for 1 hour, the reaction mixture was distilled under reduced pressure to obtain 31.8 g of p-cyanobenzoic acid chloride (96% based on p-cyanobenzoic acid). Purity was over 99%.

Example 3 14.7 g of p-cyanobenzoic acid, 300 acetonitrile
of phosgene gas.
0 g was blown in over 4 hours. After introducing dry nitrogen gas into the reaction mixture for 1 hour, acetonitrile was distilled off at normal pressure, and further distilled under reduced pressure to obtain 16.2 g of p-cyanobenzoic acid chloride (98% yield based on p-cyanobenzoic acid). Obtained. Purity was 99%.

Example 4 16.6 g of m-cyanobenzoic acid chloride and 14.7 g of m-cyanobenzoic acid were mixed, and 20 g of phosgene gas was blown in at 130 ° C. for 2 hours while stirring vigorously. After introducing dry nitrogen gas into the reaction mixture for one hour, the reaction mixture was distilled under reduced pressure and 31.8 g of m-cyanobenzoic acid chloride was obtained.
(96% yield based on m-cyanobenzoic acid) was obtained (bp. 127 ° C / 11 mmHg). Purity was over 99%.

Example 5 8.7 g of pyridine and 150 ml of dichloromethane were mixed and stirred at room temperature, and 10.4 g of phosgene was added to dichloromethane 1
A solution dissolved in 50 ml was added and stirred. 14.7 g of p-cyanobenzoic acid was added and stirred vigorously at room temperature for 1 hour. Gas chromatography analysis showed that the yield of p-cyanobenzoic acid chloride was 98%. Purity was over 99%.

Example 6 14.7 g of m-cyanobenzoic acid, phosgene trimer
8 g, pyridine 11.9 g, 1,2-dichloroethane 3
And mixed vigorously at 90 ° C. for 4 hours. After cooling, the yield of m-cyanobenzoic acid chloride was determined by gas chromatography analysis to be (9 based on m-cyanobenzoic acid).
9%). Purity was over 99%.

[0028]

According to the present invention, a cyanobenzoic acid chloride compound can be easily produced with a high yield from a cyanobenzoic acid compound easily obtained from a phthalonitrile compound and phosgene or a phosgene precursor.

Claims (4)

[Claims] 1. A compound of the general formula (1) (Wherein -COOH and -X represent a substituent on a benzene ring, -COOH is an m-position or a p-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 cyanobenzoic acid compound of) is reacted with phosgene or a phosgene precursor. (Wherein -COCl and -X represent a substituent on a benzene ring, -COCl is an m-position or a p-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. )) A method for producing a cyanobenzoic acid chloride compound. 2. The production of a cyanobenzoic acid chloride compound according to claim 1, wherein the reaction is carried out in the presence of a cyanobenzoic acid chloride compound of the general formula (2) corresponding to the cyanobenzoic acid compound of the general formula (1). Method. 3. The process for producing a cyanobenzoic acid chloride compound according to claim 1, wherein the reaction is carried out in the presence of a tertiary amide compound or a tertiary amine compound. 4. The cyanobenzoic acid compound of the general formula (1) is m- or p-cyanobenzoic acid, and the cyanobenzoic acid chloride compound of the general formula (2) corresponds to the m- or p-cyanobenzoic acid chloride. The method for producing a cyanobenzoic acid compound according to any one of claims 1 to 3, wherein