JP2649560B2 - Method for producing 3,4,6-trifluorophthalonitrile - Google Patents

Description

The present invention relates to a process for producing 3,4,6-trifluorophthalonitrile, which is extremely useful as an intermediate for pharmaceuticals, agricultural chemicals, industrial chemicals and the like. A process for producing 3,4,6-trifluorophthalonitrile, which comprises reacting tetrafluorophthalonitrile with a solid metal or a solid alloy in an aqueous solvent.

[Conventional technology]

As far as the present inventor knows, there is almost no literature on a method for industrially synthesizing 3,4,6-trifluorophthalonitrile. Only "J. Chem. Soc. Perkin II", Vol. 12, pp. 1288-1292 (1978 edition) states that "J. Org. Chem."
Volume 746 (1966 edition), 4-hydrazino-3,4,6-trifluorophthalonitrile was obtained from tetrafluorophthalonitrile, which was then reacted with cupric sulfate to give 3,4, The preparation of 6-trifluorophthalonitrile is described.

In the method described in "J. Org. Chem." Vol. 31, first, pentafluorobenzonitrile is reacted with hydrazine to synthesize 4-cyano-2,3,5,6-tetrafluorophenylhydrazine. -Cyano-2,3,5,6-tetrafluorophenylhydrazine is reacted with an aqueous solution of copper sulfate under heating to obtain 2,3,5,6-tetrafluorobenzonitrile.

Therefore, in J. Chem. Soc. Perkin II, Vol.
The method of synthesizing 6-trifluorophthalonitrile is considered to follow the following formula.

However, in this method, the steps are long and the yield is low as described in this document, so that it is difficult to say that this method is sufficient for industrial practice.

[Problems to be solved by the invention]

The present inventors have conducted intensive studies in order to solve the problems of the above-mentioned prior art processes having insufficient length and reaction yield. As a result, tetrafluorophthalonitrile (hereinafter referred to as F ₄ PN
Simply abbreviated as) in an aqueous solvent together with a solid metal such as zinc metal, it is extremely easy to win, is defluoridated and reduced in a short time, and has high purity 3,4,6-trifluorophthalonitrile. (Hereinafter sometimes abbreviated as F ₃ PN)
Was found to be able to be produced in high yield, and the present invention was completed.

[Means for solving the problem]

An object of the present invention is to provide a method for producing 3,4,6-trifluorophthalonitrile, which comprises reacting tetrafluorophthalonitrile with a solid metal or solid alloy in an aqueous solvent, preferably with zinc metal. It is assumed that.

 Hereinafter, the present invention will be described in detail.

The aqueous solvent used in the present invention refers to water or a mixed solvent of water and an organic solvent soluble in water, and the solid phase and / or the oil phase is converted into the aqueous phase by using such an organic solvent in combination. In some cases, it can be dissolved to form one liquid phase, and when the reaction according to the present invention is performed under reflux temperature conditions as described later, the reflux temperature can be adjusted.

As such an organic solvent, 5 parts per 100 parts by weight of water
As long as it dissolves in an amount of 0 parts by weight or more, it can be used without any particular limitation. For example, it has 1 to 3 carbon atoms such as methyl alcohol, ethyl alcohol propyl alcohol (n.-, i.-).
Aliphatic monohydric alcohols; for example, other monohydric alcohols such as allyl alcohol and furfuryl alcohol; and one carbon atom such as ethylene glycol, propylene glycol (1,2-, 1,3-) and glycerin Aliphatic polyhydric alcohols, such as polyethylene glycol which is liquid at room temperature; for example, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether;
Mono- or di-etherified products of ethylene glycol such as ethylene glycol monobutyl ether and ethylene glycol dimethyl ether and an aliphatic monohydric alcohol having 1 to 4 carbon atoms; for example, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether; Mono- or dietherified products of diethylene glycol such as diethylene glycol diethyl ether and an aliphatic monohydric alcohol having 1 to 4 carbon atoms; for example, glycerin such as 1-glycerin monomethyl ether and an aliphatic monohydric alcohol having 1 to 3 carbon atoms Monoetherified compounds; for example, cyclic ethers such as tetrahydrofuran and dioxane (1,3-, 1,4-); And other water-soluble organic solvents such as ton, acetonitrile, lactonitrile, N, N-dimethylformamide, dimethylsulfoxide and diethylsulfoxide.

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 elegance.

The present invention relates to a method for producing F ₃ PN, comprising reacting F ₄ PN with a solid metal or a solid alloy (hereinafter, sometimes abbreviated as a solid metal or the like) in an aqueous solvent.

Examples of the solid metal include zinc, tin, iron, nickel, chromium, aluminum, and copper. Examples of the solid alloy include metal amalgams such as zinc amalgam, tin amalgam, and aluminum amalgam; For example, other metal alloys such as brass, bronze, aluminum / nickel alloy, aluminum / lead alloy; and the like can be mentioned. Among these, it is preferable to use a solid metal from the viewpoints of easy availability and good reaction yield, and it is particularly preferable to use metal zinc.

As the metal zinc, any commercially available metal zinc powder or the like can be used. As shown in the following reaction formula, the amount of the metal zinc used may theoretically be 1 mol per 1 mol of F ₄ PN, but usually 0.8 to 10 mol, preferably 0.9 to 5 mol, and particularly preferably Preferably, 1 to 2 moles are present. By using metal zinc at or above the lower limit of the above usage range, the reaction rate can be increased, and by using the metal at or below the upper limit, it is produced.
Since the generation of by-product 3,6-difluorophthalonitrile (hereinafter sometimes abbreviated as F ₂ PN) by the further defluorination reduction reaction of F ₃ PN can be suppressed to an extremely small amount, the amount within the above-mentioned use range can be suppressed. It is better to use

The reaction formula when zinc is used as the solid metal is considered as follows.

The above-mentioned reaction according to the present invention proceeds when the aqueous solvent in the reaction form is in any of neutral, acidic and alkaline regions.For example, in an alkaline region of pH 9 or more, the 5-position fluorine has a hydroxyl group. 3,4,6-trifluoro-5-hydroxyphthalonitrile or a phthalocyanine-based compound obtained by an addition reaction between nitrile groups, tetrafluorophthalamide in which the nitrile group is hydrolyzed, etc. For example, it is preferable to carry out the reaction in an aqueous solvent having a pH of less than 9, more preferably pH 2 to 7, particularly pH 3 to 6.

The reaction in the method of the present invention can be carried out in the presence of an acid. Examples of the acid that can be used in the present invention include inorganic compounds such as sulfuric acid, hydrochloric acid, and nitric acid; and aqueous solutions such as organic acids such as acetic acid, acid, benzoic acid, phthalic anhydride, and p-toluenesulfonic acid. Any one can be used as long as it shows acidity. Of these acids,
It is preferable to use inorganic acids such as sulfuric acid, hydrochloric acid, and nitric acid for reasons such as easy 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 the by-produced hardly water-soluble zinc fluoride reacts with an acid to release corrosive hydrogen fluoride. Further, if the concentration of the acid is excessive, the nitrile group undergoes hydrolysis to cause tetrafluorophthalimide, 3,4,6-trifluorophthalimide, tetrafluorophthalic acid and 3,4,6-trifluorophthalic acid, and the like. These mixtures may be by-produced. For this reason, the amount of acid used depends on the raw material F ₄ PN1
It is preferably used in an amount of 0 to 5 equivalents, particularly 0.1 to 5 equivalents, based on the mole. Further, when the amount of the metal zinc used (the number of moles) is x and the amount of the acid (the number of equivalents) is y, 1 ≦ 2x−y ≦
It is preferable to use an amount in a range satisfying the relational expression (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 using an acid, and the above-mentioned pH range, that is, pH
The reaction can be carried out in a reaction system having a pH of less than 9, more preferably in the range of pH 2 to 7. According to this method, relatively inexpensive stainless steel such as SUS304 and SUS316 can be used during industrialization, and the target compound can be obtained with the same high purity and high yield as in the case of using an acid. It has an excellent effect of being able to do it.

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 sulfate, sodium nitrate, potassium nitrate, calcium nitrate, magnesium nitrate;
Phosphorus such as ammonium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, sodium phosphate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate Acid salts; borates such as, for example, sodium tetraborate;
For example, ammonium citrate, ammonium hydrogen citrate, sodium citrate, sodium hydrogen citrate,
Citrates such as potassium citrate and potassium hydrogen citrate, for example, acetates such as ammonium acetate, sodium acetate, potassium acetate and calcium acetate; for example, sodium tartrate, sodium hydrogen tartrate, potassium tartrate;
Tartrate such as potassium hydrogen tartrate; oxalate such as potassium oxalate; lactate such as sodium lactate, calcium lactate; ammonium phthalate, ammonium hydrogen phthalate, sodium phthalate, sodium hydrogen phthalate, phthalate And phthalic acid salts such as potassium hydrogen phthalate; and the like.

Among these water-soluble salts, strong acid weak base salts such as ammonium sulfate, ammonium hydrochloride, and ammonium nitrate whose aqueous solutions show 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 can be used alone or in combination of two or more.If necessary, for example, sodium hydroxide, potassium hydroxide, and a base such as ammonia are used in combination to form an aqueous solvent.
The pH can also be adjusted to be in the preferred pH range.

Further, by using the above salts in combination with an appropriate acid, the pH of the aqueous solvent of the reaction system can be adjusted to the above-mentioned preferable 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,
When the aqueous solution of 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,
The aqueous solution of calcium lactate, sodium phthalate, potassium phthalate and the like can be exemplified by alkaline organic acid strong base normal salt 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 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.For the total amount of the starting material F ₄ PN1 mol, for example, , 0.01 to 1.0 mol, particularly preferably 0.03 to 0.5 mol. Further, the aqueous solvent of the reaction system of the water-soluble salt 10
The concentration in 00 g is, for example, 0.01 to 2.0 mol in total amount,
In particular, it is preferably from 0.02 to 1.0 mol.

The reaction in the method of the present invention can generally be carried out at a temperature of 20 ° C. or higher, and is preferably carried out at a temperature of 50 ° C. or higher from the viewpoint of the reaction rate. is there. However, it is preferable to carry out the reaction at 50 ° C. to reflux temperature under atmospheric pressure from the viewpoint of reaction equipment cost and the like. Further, from the viewpoint of reactivity, the reflux temperature,
80 ° C especially in a reaction system with a reflux temperature of 100 ° C or higher.
It is more preferable to carry out the reaction within the range of -reflux temperature.

The reaction time is not particularly limited, but if the time is too long, the side reaction of F ₂ PN generation may proceed, so that the reaction time is generally in a range of about 15 minutes to 10 hours, preferably about 30 minutes to 6 hours. It is good to do in.

The reaction in the method of the present invention proceeds easily in an aqueous solvent, but the starting material F ₄ PN has a melting point of 86 to
F ₃ which is a water-insoluble solid at 87 ° C and the target substance
Since PN is a hydrophobic solid having a melting point of 36.5 to 37.5 ° C., an aqueous phase and two solid phases (a solid composed of a starting material and a target substance and a solid metal such as metallic zinc, etc.) depending on the reaction temperature, or , An aqueous phase and an oil phase, and a three-phase hetero-phase reaction between a liquid phase and a solid phase (such as a solid metal). Therefore, this reaction is preferably carried out while keeping the reaction system as homogeneous as possible by stirring.

After completion of the reaction, the solid is separated by steam distillation, filtration or the like, and then the organic layer is extracted with an extraction solvent, for example, ether or chloroform.
6-trifluorophthalonitrile can be obtained.
If necessary, the obtained product can be further purified by means such as distillation.

〔Example〕

 Hereinafter, the present invention will be described in more detail with reference to examples.

Example 1 F ₄ PN4 was placed in a 300 ml flask equipped with a cooling reflux tube and a thermometer.
2 g (purity 96 wt%, 0.20 mol), powdered zinc 15 g (purity 96
% By weight, 0.22 mol) and 125 g of water, and with stirring, 6.2 g of sulfuric acid (purity: 98% by weight, 0.062 gram equivalent) was added.
The reaction was performed at 00 ° C. for 2 hours. At the beginning and end of the reaction
The pH was 0.6, 4.1 respectively. After completion of the reaction, the reaction mixture was cooled and added with 60 g of ethyl ether, followed by separation of a solid substance.The solid substance was washed with ethyl ether, and a liquid mixture of the obtained liquid and an ether washing liquid was separated to form an ether layer. Was isolated, and the ether layer was analyzed by an internal standard method using liquid chromatography.

 Table 1 shows the reaction conditions and analysis results.

Examples 2 to 5 The reaction and analysis were performed in the same manner as in Example 1 except that the amount of sulfuric acid used was changed and the sulfuric acid concentration was changed. Table 1 shows the reaction conditions and analysis results.

Example 6 A reaction and analysis were carried out in the same manner as in Example 1 except that the amounts of water and sulfuric acid were changed. Table 1 shows the reaction conditions and analysis results.

Example 7 A reaction and analysis were performed in the same manner as in Example 1 except that the reaction temperature and the reaction time were changed. Table 1 shows the reaction conditions and analysis results.

Examples 8 to 10 The reaction and analysis were performed in the same manner as in Example 1 except that the amounts of zinc and sulfuric acid were changed and the sulfuric acid concentration was changed. Table 1 shows the reaction conditions and analysis results.

Examples 11 and 12 The reaction and analysis were carried out in the same manner as in Example 1 except that hydrochloric acid and acetic acid were used instead of sulfuric acid. Table 1 shows the reaction conditions and analysis results.

Example 13 A reaction and analysis were carried out in the same manner as in Example 1 except that a 50% by weight aqueous ethanol solution was used instead of water. Table 1 shows the reaction conditions and analysis results.

Example 14 In Example 1, instead of using 6.2 g of sulfuric acid, 2.8 g of potassium dihydrogen phosphate was used as a water-soluble salt (purity: 98% by weight, 0.1%).
The reaction and analysis were carried out in the same manner except that the reaction time was 2 hours. Table 2 shows the reaction conditions and analysis results.

Examples 15 to 19 In Example 14, the reaction was carried out in the same manner as in Example 14, except that the type and amount of the water-soluble salt were changed and the reaction temperature was set to 95 ° C. Was performed. Table 2 shows the reaction conditions and analysis results.

Example 20 A reaction was carried out in the same manner as in Example 1, the reaction product was treated in the same manner as in Example 1, and the ether layer obtained by separating a liquid mixture of a liquid and an ether washing solution was dried over magnesium sulfate. did. After drying, pass magnesium sulfate,
The ether was distilled off. The kettle residue after ether distillation was distilled under reduced pressure to obtain 32.7 g (yield: 88.0% mol%) of trifluorophthalonitrile having a purity of 98.0% by weight.

In addition, the analysis value of the obtained trifluorophthalonitrile was as follows.

Mass spectrum EI M / e = 182 (M +) · Infrared spectrum ^{2250cm -1 (C≡N) 3090cm -1 (} C-H) · 19 F-NMR ( solvent; CDCl _3, internal standard; CF ₃ COOH): ¹
H-decoupling δ = -26.0ppm (1F, dd, J = 9.2Hz, 13.4Hz) -41.3ppm (1F, dd, J = 9.2Hz 20.8Hz) -53.2ppm (1F, dd , J = 13.4Hz 20.8Hz

Claims (1)

(57) [Claims] 1. A method for producing 3,4,6-trifluorophthalonitrile, comprising reacting tetrafluorophthalonitrile with a solid metal or a solid alloy in an aqueous solvent.