JP2691995B2 - Method for producing 2-fluoro-5-halogenoisophthalonitrile and 2-fluoro-5-halogenoisophthalic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention is a novel substance, 2-fluoro-5, which is useful as an intermediate raw material for medicines, agricultural chemicals, photosensitive materials, liquid crystal materials and the like.
-Halogenoisophthalonitrile and 2-fluoro-5-
The present invention relates to a method for producing halogenoisophthalic acid.

[Conventional technology and problems]

2-Fluoro-5 obtained by the production method of the present invention
-Halogenoisophthalonitrile and 2-fluoro-5-
For halogenoisophthalic acid, see Chemical Abstract
Etc., and as far as the present inventors know, there is no description in other documents, these substances are considered to be novel substances.

As a result of earnest studies to obtain the above-mentioned compounds that are extremely useful as intermediate raw materials for various substances as described above, the present inventors have found that 2,4,6-trifluoro-5-halogenoisophthalonitrile has a weak acidity. 2-Fluoro-5-halogenoisophthalonitrile is easily produced by defluorination reduction reaction simply by heating with metallic zinc in an aqueous solution, and then this 2-fluoro-5-halogenoisophthalonitrile is hydrolyzed in an acidic aqueous solution. 2-fluoro-5
-It was found that halogenoisophthalic acid can be obtained, and further research was conducted to complete the present invention.

[Means for solving the problem]

The present invention relates to a method for producing 2-fluoro-5-halogenoisophthalonitrile, which comprises reacting 2,4,6-trifluoro-5-halogenoisophthalonitrile with a solid metal in an aqueous solvent, Further, the present invention relates to a method for producing 2-fluoro-5-halogenoisophthalic acid, which comprises hydrolyzing the 2-fluoro-5-halogenoisophthalonitrile in an acidic aqueous solution.

 Hereinafter, the present invention will be described in detail.

The starting material of the present invention, 2,4,6-trifluoro-5-halogenoisophthalonitrile of the following general formula, is, for example, Journal of Industrial Chemistry, Vol. 73, No. 2, pp. 213-214 (1970).
It can be produced by a known method described in (Year).

(However, X represents a halogen group such as F, cl, Br, I.) Specific examples of such a compound include, for example, 2,4,5,
6-tetrafluoroisophthalonitrile, 2,4,6-trifluoro-5-chloroisophthalonitrile, 2,4,6-trifluoro-5-bromoisophthalonitrile and 2,4,6trifluoro-5- Examples thereof include iodoisophthalonitrile.

The method of the present invention is carried out using the above-mentioned starting materials by the following reaction steps.

(However, X represents a halogen group such as F, cl, Br, I.) Hereinafter, each step of the method of the present invention will be described in order.

Reduction Step (A) In the defluorination reduction step of the method of the present invention, the starting material 2,4,6-trifluoro-5-halogenoisophthalonitrile (sometimes abbreviated as F ₃ XIPN) is treated with, for example, an aqueous solution. Reacting with a solid metal in a solvent produces the desired product of this reduction step, 2-fluoro-5-halogenoisophthalonitrile (sometimes abbreviated as FXIPN).

F ₃ XI which can be used as a starting material for the process according to the invention
As PN, as described above, tetrafluoroisophthalonitrile, 2,4,6-trifluoro-5-chloroisophthalonitrile, 2,4,6-trifluoro-5-bromoisophthalonitrile and 2,4, 6-trifluoro-5-iodoisophthalonitrile and the like can be exemplified, and the above target product FX
IPN includes 2,5-difluoroisophthalonitrile, 2
Examples include -fluoro-5-chloroisophthalonitrile, 2-fluoro-5-bromoisophthalonitrile and 2-fluoro-5-iodoisophthalonitrile. Among these, in the method of the present invention, tetrafluoroisophthalonitrile and 2,4,6-trifluoro-5 were used as starting materials.
-Chloroisophthalonitrile can be particularly preferably used because of its availability and reactivity. Therefore,
Particularly preferred among the FXIPNs obtainable by the process of the present invention are 2,5-difluoroisophthalonitrile and 2-fluoro-5-chloroisophthalonitrile.

Examples of the solid metal include zinc, tin, iron, nickel, chromium, aluminum and copper. Among these, a fixed metal is preferably used, and zinc metal is particularly preferably used, from the viewpoints of easy availability and good reaction yield.

As the metal zinc, any commercially available metal zinc powder or the like can be used. The reaction formula when using metal zinc is as follows.

As shown in the above reaction formula, the amount of metallic zinc used may theoretically be 2 mol per 1 mol of F ₃ XIPN.
It is usually 2 to 10 mol, preferably 2.2 to 6 mol, and particularly preferably 2.5 to 6 mol. When metallic zinc is used in an amount larger than the lower limit of the above-mentioned range of use, the reaction rate is fast and the reaction yield is good, and on the other hand, even if it is used in excess of the upper limit, both the reaction rate and the reaction yield are difficult to improve. Therefore, it is preferable to use an amount within the above range of use.

The above reduction reaction easily proceeds in an aqueous solvent. However, since the starting material F ₃ XIPN and the target substance FXIPN in this reduction step are both water-insoluble substances,
Three phases of aqueous phase and two solid phases [solid consisting of starting material and target material and solid metal, etc.] or two liquid phases and solid phase (solid metal, etc.) of aqueous phase and oil phase depending on reaction temperature Since this is a three-phase heterogeneous reaction with, the reduction reaction is preferably carried out by stirring while keeping the reaction system as uniform as possible.

The aqueous solvent used in the reduction step refers to water or a mixed solvent of water and a water-soluble organic solvent. By using such an organic solvent in combination, the solid phase and / or the oil phase can be dissolved in the aqueous phase. In some cases, a single liquid phase can be formed, and when the reaction according to the present invention is performed under reflux temperature conditions as described below, the reflux temperature can be adjusted.

As such a water-soluble organic solvent, any solvent capable of dissolving 50 parts by weight or more with respect to 100 parts by weight of water can be used without particular limitation. Examples thereof include methyl alcohol, ethyl alcohol, n- or i-propyl alcohol. 1 to 3 aliphatic monohydric alcohols; for example, other monohydric alcohols such as allyl alcohol and furfuryl alcohol; for example, ethylene glycol, propylene glycol (1,2-, 1,3-), glycerin, etc. 1 carbon atom
~ 3 aliphatic polyhydric alcohols; for example, polyethylene glycol which is liquid at room temperature; ethylene glycol such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, ethylene glycol dimethyl ether, etc. and C1-4 carbon atoms A mono- or dietherified product with an aliphatic monohydric alcohol; for example, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, etc. and an aliphatic monohydric alcohol having 1 to 4 carbon atoms. A mono- or di-ether compound with; glycerin such as 1-glycerin monomethyl ether Of a monoether with an aliphatic monohydric alcohol having 1 to 3 carbon atoms; for example, cyclic ethers such as tetrahydrofuran and dioxane (1,3-, 1,4-); and, for example, acetone, acetonitrile, Other water-soluble organic solvents such as lactonitrile, N, N-dimethylformamide, dimethyl sulfoxide, diethyl sulfoxide and the like;

These organic solvents can be used alone or in combination of two or more. Among these organic solvents,
Aliphatic monohydric alcohols can be particularly preferably used from the viewpoint of availability and economics.

The reduction reaction can be generally performed at a temperature of 20 ° C. or higher, and is preferably performed at a temperature of 40 ° C. or higher from the viewpoint of the reaction rate.
This reduction reaction can be carried out at a high temperature and a high pressure in a closed pressure-resistant reaction vessel. However, it is preferable to carry out the reaction at 50 ° C. to a reflux temperature under the atmospheric pressure from the viewpoint of the cost of the reaction equipment. Further, from the viewpoint of reactivity, it is preferable to carry out the reaction in an aqueous solvent having a reflux temperature of 80 ° C. or higher at 80 ° C. to the reflux temperature, particularly at the reflux temperature.

The reaction time is not particularly limited and is generally 15
It is good to carry out in the range of minutes to 10 hours, preferably 30 minutes to 6 hours.

The defluorination reduction reaction of the present invention proceeds when the reaction system is in any of neutral, acidic, and alkaline regions, but, for example, in an alkaline region of pH 9 or more,
2,6-Difluoro-5-halogeno-4-hydroxyisophthalonitrile in which 4-position fluorine is substituted with hydroxyl group, and 2,4,6-trifluoro-5-halogenoisophthalamide in which nitrile group is hydrolyzed For example, it is preferable to carry out the reaction in a reaction system having a pH of less than 9, and it is particularly preferable to carry out the reaction in a reaction system having a pH in the range of 2 to 7.

The above reduction reaction can be performed in the presence of an acid.
Acids that can be used in the present invention include, for example, sulfuric acid,
Inorganic acids such as hydrochloric acid and nitric acid; and any organic acids such as acetic acid, oxalic acid, benzoic acid, phthalic anhydride, p-toluenesulfonic acid, etc., which are acidic in an aqueous solution. Can be used. Of these acids, it is preferable to use inorganic acids such as sulfuric acid, hydrochloric acid, and nitric acid for reasons such as availability.

However, for example, when zinc, which is most suitable as a solid metal, is used, when the reaction system is in a strong acid region, a side reaction between the acid and metallic zinc (generates hydrogen to generate a zinc salt of the acid)
In some cases, zinc metal is wasted and water-insoluble zinc fluoride produced as a by-product reacts with an acid to release corrosive hydrogen fluoride. In addition, if the acid concentration is too high, the nitrile group undergoes hydrolysis to 2,4,
6-trifluoro-5-halogenoisophthalamide, 2,4
-Difluoro-5-halogenoisophthalamide, 2,4,6
-Trifluoro-5-halogenoisophthalic acid and 2,4
-Difluoro-5-halogenoisophthalic acid and the like and a mixture thereof may be by-produced. For this reason, it is preferable to use the acid in an amount of 0 to 5 equivalents, particularly 0.1 to 5 equivalents, relative to 1 mol of the raw material F ₃ XIPN, and the amount of the metallic zinc used (mole number). Is x and the amount of acid (equivalent number) is y, it is preferable to use it in an amount in the range satisfying the relational expression 1 ≦ 2x−y ≦ 3.

Furthermore, the acid concentration of the reaction was 1 per 1000 g of aqueous solvent.
It is preferably used in a range of 0 equivalent or less, more preferably in a range of 8 equivalent or less. As the method of adding the acid, a method such as sequential addition may be appropriately selected in addition to the method of adding the acid at the beginning of the reaction.

Furthermore, in the reaction according to the method of the present invention, a water-soluble salt is used instead of the acid, and the above-mentioned PH range, that is, PH
It can be carried out in a reaction system having a pH of less than 9, more preferably PH 2 to 7. According to this method, relatively inexpensive stainless steel such as SUS304 and SUS316 can be used in industrialization, and the target compound can be obtained with high purity and high yield as in the case of using acid. Exerts an excellent effect.

Such a water-soluble salt is not particularly limited, and any water-soluble salt can be used as long as it dissolves in 0.01 g or more, preferably 1 g or more in 100 g of water. Examples of such water-soluble salts include sulfates such as ammonium sulfate, sodium sulfate, sodium hydrogen sulfate, potassium sulfate, and potassium hydrogen sulfate; for example, ammonium chloride, sodium chloride, potassium chloride, calcium chloride,
Hydrochlorides such as magnesium chloride and barium chloride;
Nitrates such as ammonium nitrate, sodium nitrate, potassium nitrate, calcium nitrate, magnesium nitrate;
Ammonium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, sodium phosphate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, etc. Phosphates; for example, borate salts such as sodium tetraborate; for example, kunenoates such as ammonium citrate, ammonium hydrogen citrate, sodium citrate, sodium hydrogen citrate, potassium citrate, potassium hydrogen citrate; For example, acetate salts such as ammonium acetate, sodium acetate, potassium acetate, calcium acetate; for example, tartrate salts such as sodium tartrate, sodium hydrogen tartrate, potassium tartrate, potassium hydrogen tartrate;
Oxalates such as potassium oxalate; for example, lactates such as sodium lactate and calcium lactate; ammonium phthalate, ammonium hydrogen phthalate, sodium phthalate,
Examples thereof include phthalates such as sodium hydrogen phthalate, potassium phthalate, and potassium hydrogen phthalate;

Among these water-soluble salts, strong acid weak base salts such as ammonium sulfate, ammonium chloride, and ammonium nitrate whose aqueous solution shows weak acidity; sodium hydrogen sulfate, potassium hydrogen sulfate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid Strong base hydrogen salts of inorganic acids such as potassium monohydrogen and potassium dihydrogen phosphate; ammonium hydrogen citrate;
It is preferable to use a strong base hydrogen salt of an organic acid such as sodium hydrogen citrate, potassium hydrogen citrate, sodium hydrogen tartrate, potassium hydrogen tartrate, sodium hydrogen phthalate and potassium hydrogen phthalate. These salts may be used alone or in a mixture of two or more, and if necessary, for example, a base such as sodium hydroxide, potassium hydroxide or ammonia may be used to form an aqueous solvent.
The pH can also be adjusted to be in the preferred pH range.

Furthermore, by using the above salts in combination with an appropriate acid, the pH of the aqueous solvent in the reaction system can be adjusted to the above suitable pH range. Examples of such salts include sodium sulfate, potassium sulfate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, barium chloride, sodium nitrate, potassium nitrate, and the like, which are almost neutral in the form of a strong acid strong base strong salt; sodium phosphate , Potassium phosphate,
An aqueous solution of an alkaline acid such as sodium tetraborate or the like is an alkaline inorganic acid strong base normal salt; sodium citrate, potassium citrate, sodium acetate, potassium acetate, calcium acetate,
Sodium tartrate, potassium tartrate, sodium lactate,
Examples of the aqueous solution of calcium lactate, sodium phthalate, potassium phthalate, etc. are alkaline organic acid strong base normal salts and the like.

Acids suitable for combination with the salts as described above include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid;
For example, organic acids such as citric acid, acetic acid, succinic acid, tartaric acid, oxalic acid, lactic acid, phthalic acid, benzoic acid and p-toluenesulfonic acid can be mentioned.

The amount of the above water-soluble salt is not particularly limited, but it is preferable to use an amount such that the pH of the reaction system falls within the above range, and the total amount is, for example, 1 mol of the starting material F ₃ XIPN. , 0.01 to 1.0 mol, particularly 0.03 to 0.5 mol is preferably used. The concentration of the water-soluble salt in the aqueous solvent of the reaction system is, for example, 0.01 to 2.0 mol / total amount.
In particular, it is preferably 0.02 to 1.0 mol /.

After the reaction in the reduction step (A) is completed, the solid matter is separated by means such as steam distillation and filtration, and the organic layer is extracted with an extraction solvent such as ether and chloroform, and then the solvent is distilled off to give 2-fluoro- 5-halogenoisophthalonitrile (FXIPN) can be obtained. If necessary, the obtained product can be further purified by means such as distillation.

In case of continuously producing FXIPN, reduction process (A)
After completion of the above, the solid content is filtered by hot filtration, or the reaction system is cooled and a non-water-soluble extraction solvent that dissolves the intermediate product FXIPN is added and mixed, and then the solid content is filtered off. Then, the aqueous layer is removed from the filtrate by liquid separation to obtain an extraction mixture containing the product FXIPN, and then an inorganic acid aqueous solution is added to this extraction mixture, followed by heating to carry out the hydrolysis step (B). To do.

Hydrolysis Step (B) The hydrolysis reaction in the method of the present invention proceeds easily in an aqueous solution of an inorganic acid (for example, sulfuric acid, hydrochloric acid or hydrobromic acid, preferably sulfuric acid). For example, 2-fluoro-5-halogenoisophthalonitrile (FXIP obtained by reduction reaction
N) in 50-90% by weight sulfuric acid aqueous solution, for example 100-180
A method of obtaining 2-fluoro-5-halogenoisophthalic acid (hereinafter sometimes abbreviated as FXIPA) by heating at a temperature of ° C can be preferably adopted.

Examples of the FXIPN include 2,5-difluoroisophthalonitrile, 2-fluoro-5-chloroisophthalonitrile, 2-fluoro-5-bromoisophthalonitrile and 2-fluoro-5-iodoisophthalonitrile. The FXIPA is, for example, 2,5
Mention may be made of difluoroisophthalic acid, 2-fluoro-5-chloroisophthalic acid, 2-fluoro-5-bromoisophthalic acid and 2-fluoro-5-iodoisophthalic acid.

After completion of the reaction, the target product is extracted with an extraction solvent such as ether, and then the extraction solvent is distilled off, or
2-Fluoro-5-halogenoisophthalic acid can be obtained by obtaining an aqueous solution of the desired product by steam distillation, distilling off water and drying.

〔Example〕

Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

Example 1 In a 100 ml flask equipped with a cooling reflux tube and a thermometer, tetrafluoroisophthalonitrile (F ₄ IPN) 20 g (10 mmol), powdered zinc 4.1 g (purity 96 wt%, about 60 mmol) water.
Charge 20 g and stir 1.8 g of glacial acetic acid (30 meq)
Was added. The contents were reacted under heating under reflux (about 100 ° C.) for 1.5 hours. During this period, the pH of the reaction system was 2, 1 at the start of the reaction and 2, 2 after the reaction was completed. After the reaction was completed, the reaction solution was analyzed by gas chromatography (hereinafter sometimes abbreviated as GC), and it was found that 2,5-difluoroisophthalonitrile (F ₂ IPN) was produced in a yield of 100%. Was confirmed. The reaction solution was cooled and 50 ml of ethyl ether was added, followed by filtration to separate a solid matter. The solid matter was washed with ethyl ether, and the mixture of the obtained filtrate and the ether washing solution was separated to form an ether layer. Was isolated and the ether layer was dried over magnesium sulfate. After drying, magnesium sulfate was filtered and ether was distilled off to remove F ₂ IPN of about 1.6.
g (purity 97% by weight, yield 95%) was obtained.

The physical properties of the obtained F ₂ IPN were as follows.

Melting point: 84 to 86 ° C. Mass spectrum (EI): m / e = 164 (M ⁺ ) ¹⁹ F-NMR: (acetone-d ⁶ : internal standard substance CF ₃ COOH) ¹ H-
Decoupling δ = −33.1 (1F, d, J = 15.6Hz) −38.2 (1F, d, J = 15.6Hz) ¹⁹ NMR: (acetone −d ⁶ : internal standard CF ₃ COOH) δ = −33.1 (1F , d−t, J = 15.6Hz, 4.9Hz) −38.2 (1F, d−t, J = 15.6Hz, 7.6Hz) ¹ H-NMR: (acetone −d ⁶ : internal standard substance TMS) δ = 8.17 ( 2H, d-d, J = 4.9 Hz, 7.3 Hz) Example 2 The reaction was carried out in substantially the same manner as in Example 1 except that the amount of zinc powder used was 2.0 g (about 29 mmol). The reaction conditions and the yield of P ₂ IPN are shown in Table 1.

Examples 3 and 4 The reaction was carried out in the same manner as in Example 1 except that sulfuric acid or hydrochloric acid was used instead of glacial acetic acid. The reaction conditions and the yield of F ₂ IPN are shown in Table 1.

Example 5 A reaction was carried out in the same manner as in Example 1 except that 0.44 g of potassium dihydrogen phosphate (purity: 98% by weight, 3.2 mmol) was used as a water-soluble salt instead of using 1.8 g of glacial acetic acid. The reaction conditions and the yield of F ₂ IPN are shown in Table 1.

Examples 6 to 10 The reaction was performed in the same manner as in Example 5, except that the kind and the amount of the water-soluble salt used were changed. Reaction conditions and
The yield of F ₂ IPN is shown in Table 1.

Example 11 Using the same apparatus as in Example 1, 2,4,6 was used as a starting material.
-Trifluoro-5-chloroisophthalonitrile (F ₃ Cl
IPN) 5.4 g (about 25 mmol), powdered zinc 5.1 g (about 75 mmol), glacial acetic acid 1.8 g (about 30 milliequivalent) and water 25 g were used in the same manner as in Example 1 for reaction and GC analysis. The same procedure as in Example 1 was carried out to give 2-fluoro-
4.5 g of 5-chloroisophthalonitrile (FClIPN) (purity 99
Wt%, yield 99%). The physical properties of the obtained FCLPN were as follows.

Melting point: 130 to 132 ° C. Mass spectrum (EI): m / e = 182 (M + 2), 180 (M ⁺ ), 145 ¹⁹ F-NMR: (acetone-d ⁶ : internal standard substance CF ₃ COOH) ¹ H-
Decoupling δ = −29.6 (1F, S) ¹⁹ F-NMR: (acetone-d ⁶ : internal standard CF ₃ COOH) δ = −29.6 (1F, t, J = 5.4 Hz) ¹ H-NMR: (acetone -d ^6: internal standard TMS) δ = 8.36 (2H, d, in f = 5.4 Hz) examples 12 and 13 example 11, substantially the same reaction except using sulfuric acid or hydrochloric acid, instead of using glacial acetic acid I did. The reaction conditions and the yield of FCLPN are shown in Table 1.

Examples 14 and 15 The reaction was carried out in the same manner as in Example 11 except that 0.44 g of potassium dihydrogen phosphate or 0.41 g of potassium hydrogen phthalate was used as a water-soluble salt instead of using 1.8 g of glacial acetic acid. The reaction conditions and the yield of FCLPN are shown in Table 1.

Example 16 Using the same apparatus as in Example 1, the F ₂ obtained in Example 1 was used.
IPN 1.3g (about 8 mmol) and 70% by weight sulfuric acid 20g at 150 ℃
Heat and stir for 3 hours. After cooling, the mixture was extracted with ether, the ether layer was dried over calcium chloride, and the solvent was evaporated under reduced pressure to give 2.5-difluoroisophthalic acid (F ₂ IPA) 1.1 g.
(Purity 98% by weight, yield 67%) was obtained.

The physical properties of the obtained F ₂ IPA are as follows.

Melting point: 211-213 ° C ¹⁹ F-NMR: (acetone-d ₆ : internal standard substance CF ₃ COOH) ¹ H-
Decoupling δ = -37.4 (1F, d, J = 19.5Hz) -42.0 (1F, d, J = 19.5Hz) ¹⁹ F-NMR: (acetone -d ⁶ : internal standard CF ₃ COOH) δ = -37.4 (1F, d-t, J = 19.5Hz, 4.9Hz) -42.0 (1F, d-t, J = 19.5Hz, 7.6Hz) in example 17 example 16, instead of F ₂ IPN1.3g FClIPN0. 4 g
2-fluoro-5-chloroisophthalic acid (FClIPA) 0.4 g (purity 98
Wt%, yield 81%).

 The physical properties of the obtained FClIPA are as follows.

Melting point: 122 to 123 ° C. ¹⁹ F-NMR: (acetone-d ⁶ : internal standard substance CF ₃ COOH) ¹ H-
Decoupling δ = −34.2 (1F, S)

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Claims (2)

(57) [Claims] 1. A method for producing 2-fluoro-5-halogenoisophthalonitrile, which comprises reacting 2,4,6-trifluoro-5-halogenoisophthalonitrile with metallic zinc in an aqueous solvent. 2. A reaction of 2,4,6-trifluoro-5-halogenoisophthalonitrile with metallic zinc in an aqueous solvent to give 2-fluoro-5-halogenoisophthalonitrile,
Then, the 2-fluoro-5-halogenoisophthalonitrile is hydrolyzed in an acidic aqueous solution.
Method for producing fluoro-5-halogenoisophthalic acid.