JP2649563B2 - Method for producing 2,3,5,6-tetrafluorobenzonitrile - Google Patents

Description

The present invention relates to a method for producing 2,3,5,6-tetrafluorobenzonitrile, which is extremely useful as an intermediate for pharmaceuticals, agricultural chemicals, industrial chemicals and the like. Specifically, pentafluorobenzonitrile is reacted with a solid metal or solid alloy in an aqueous solvent having a specific pH in the presence of a water-soluble salt.
The present invention relates to a method for producing 2,3,5,6-tetrafluorobenzonitrile.

[Conventional technology]

A method for synthesizing 2,3,5,6-tetrafluorobenzonitrile is described in "J. Org. Chem." 1966, Vol. 31, pp. 746-749.

In the above method, first, 4-cyano-2,3,5,6-tetrafluorophenylhydrazine is synthesized by reacting pentafluorobenzonitrile (hereinafter, may be abbreviated as F ₅ BN) with hydrazine, Then the 4-cyano-2,3,5,
6-Tetrafluorophenylhydrazine is reacted with an aqueous solution of copper sulfate under heating to obtain 2,3,5,6-tetrafluorobenzonitrile (hereinafter sometimes abbreviated as F ₄ BN).

However, in this method, the steps are long and the total yield is as low as 49.8%, so that it is difficult to say that this method is sufficient for industrial implementation.

The present inventors have conducted intensive studies to solve the above-mentioned problems of the length of the process of the prior art and the insufficient reaction yield. First, in Japanese Patent Application No. 62-295964, "pentafluoro Reacting benzonitrile with a solid metal or solid alloy in an aqueous solvent, preferably in the presence of an acid, to produce 2,3,5,6-tetrafluorobenzonitrile. " Natsuta

However, when the above-mentioned proposal is carried out industrially, if an acid is used to obtain the target compound in a high yield, hydrogen fluoride may be generated as a by-product. A new problem has arisen in that extremely expensive materials, such as a Teflon lining tank, which can withstand hydrogen fluoride, must be used.

[Problems to be solved by the invention]

The present inventors have further studied to solve the new problem that an extremely expensive reaction tank is required for the above-mentioned reaction tank, and as a result, instead of using an acid, a water-soluble salt was used instead of using an acid. By maintaining the pH in the range of 1 to 8, relatively inexpensive stainless steel such as SUS304 and SUS316 can be used as the material of the reaction tank, and the proposal of Japanese Patent Application No. 62-295964 is proposed. High purity,
The present inventors have found that the excellent effect that the target compound can be obtained in a high yield can be maintained, and completed the present invention.

[Means for solving the problem]

The present invention is characterized in that pentafluorobenzonitrile is reacted with a solid metal or a solid alloy, preferably zinc metal, in an aqueous solvent having a pH of 1 to 8 in the presence of a water-soluble salt 2,3,5, An object of the present invention is to provide a method for producing 6-tetrafluorobenzonitrile.

 Hereinafter, the present invention will be described in more detail.

The water-soluble salt used in the method of the present invention is not particularly limited, and any water-soluble salt can be used as long as it dissolves in an amount of 0.1 g or more per 100 g of water. As such water-soluble salts, for example, 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, magnesium chloride, barium chloride Hydrochloride such as ammonium nitrate, sodium nitrate, potassium nitrate, calcium nitrate, etc.
Nitrates such as magnesium nitrate; for example, ammonium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, sodium phosphate, sodium hydrogen phosphate;
Phosphates such as sodium dihydrogen phosphate, potassium phosphate, potassium-hydrogen phosphate, potassium dihydrogen phosphate; borates such as sodium tetraborate; for example, ammonium citrate, ammonium hydrogen citrate Citrates, such as sodium citrate, sodium hydrogen citrate, potassium citrate, potassium hydrogen citrate;
Acetates such as ammonium acetate, sodium acetate, potassium acetate, calcium acetate; for example, sodium tartrate;
Tartrate salts such as sodium hydrogen tartrate, potassium tartrate and potassium bitartrate; oxalate salts such as potassium oxalate; lactates such as sodium lactate and calcium lactate; ammonium phthalate, ammonium hydrogen phthalate and sodium phthalate And phthalic acid salts 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. Each of these salts may be used alone or in combination of two or more.If necessary, for example, sodium hydroxide, potassium hydroxide, a base such as ammonia may be used in combination to form an aqueous solvent.
The pH can be adjusted to 1 to 8, preferably 2 to 7, and used.

Further, by using the above salts in combination with an appropriate acid, the pH of the aqueous solvent can be adjusted to the above range as described above. 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. The aqueous solution of sodium, potassium phosphate, 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 exemplified.

The amount of the water-soluble salts include, but are not particularly limited as long as the range of 1 to 8 pH when dissolved in an aqueous solvent in the present invention, the starting material F ₅ BN1 mol, Generally, the total amount is 0.05 to 1 mol, preferably 0.03 to 0.
The total concentration of the water-soluble salt in the aqueous solvent is generally from 0.01 to 2 mol /, preferably from 0.02 to 1 mol /.

The defluoridation reaction of the method of the present invention is performed in an aqueous solvent as described above.

The above-mentioned aqueous solvent 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 particular limitation. For example, aliphatic monohydric alcohols having 1 to 3 carbon atoms such as methyl alcohol, ethyl alcohol, and propyl alcohol (n.-, i.-) And other monohydric alcohols such as allyl alcohol and furfuryl alcohol; for example, having 1 to 1 carbon atoms such as ethylene glycol, propylene glycol (1,2-, 1,3-) and glycerin.
3 aliphatic polyhydric alcohols; for example, polyethylene glycol liquid at room temperature; for example, ethylene glycol such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, and ethylene glycol dimethyl ether; Mono- or di-etherified product with an aliphatic monohydric alcohol; for example, diethylene glycol such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and an aliphatic monohydric alcohol having 1 to 4 carbon atoms; Mono- or di-etherified compounds; for example, glycerol such as 1-glycerin monomethyl ether With monohydric aliphatic monohydric alcohols having 1 to 3 carbon atoms; for example, cyclic ethers such as tetrahydrofuran and dioxane (1,3-, 1,4-); and, for example, acetone, acetonitrile, lactone Other water-soluble organic solvents such as nitrile, N, N-dimethylformamide, dimethylsulfoxide and diethylsulfoxide; 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.

In the method of the present invention, the pH range of the aqueous solvent is 1 to
8 and preferably 2-7. If the pH of the solvent exceeds the upper limit, a side reaction such that ortho- and / or para-fluorine to the nitrile group of F ₅ BN and the generated F ₄ BN may be substituted with a hydroxyl group is not preferred. . On the other hand, in the strongly acidic region less than the lower limit, as described later, for example, when metal zinc, which is most suitable as a solid metal or a solid alloy (hereinafter, sometimes abbreviated as a solid metal or the like), is used, acid and metal Metallic zinc may be wasted by the side reaction with zinc (generating hydrogen to form the zinc salt of acid), and the by-product zinc fluoride reacts with the acid to cause corrosion. Hydrogen fluoride may be liberated, and further, a side reaction such as hydrolysis of the nitrile group of the starting material and the target product may occur, which is not preferable.

Furthermore, when the pH of the aqueous solvent in the present invention deviates from the above lower limit, there is a possibility that an expensive acid-resistant material that can withstand hydrogen fluoride must be used as the material of the reaction tank.

The present invention is characterized in that F ₅ BN is reacted with a solid metal or the like in an aqueous solvent having a specific pH range in the presence of a water-soluble salt.
The present invention relates to a method for producing F ₄ BN.

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, and aluminum / lead alloy; 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 metal zinc used may theoretically be 1 mol per 1 mol of F ₅ BN, but is usually 0.8 to 10 mol, preferably 1 to 5 mol. Good. The use of metallic zinc at or above the lower limit of the use range can increase the reaction rate, and the use of metal zinc beyond the upper limit makes it difficult to further increase the reaction rate. It is preferred to use an amount of

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

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.
More preferably, the reaction is carried out at a reflux temperature.

The reaction time is not particularly limited, but is usually 30
It is best to do this within a range of minutes to 48 hours.

The reaction in the method of the present invention proceeds easily in an aqueous solvent.However, since F ₅ BN as a starting material and F ₄ BN as a target substance are hydrophobic oily substances, an aqueous phase and an oily phase are used. This is a heterogeneous reaction involving three phases, two liquid phases and a solid phase (solid metal or the like). Therefore, this reaction is preferably carried out while stirring to keep the reaction system as uniform as possible.

After completion of the reaction steam distillation, after separation of the solids by means of over-like, the organic layer extracted solvent, such as ether, F ₄ BN by distilling off the solvent was extracted with chloroform
Can be obtained. Further, 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 A 300 ml flask equipped with a cooling reflux tube and a thermometer was charged with F ₅ BN3
9 g (purity 99% by weight, 0.20 mol), powdered zinc 15 g (purity 96
Wt., 0.22 mol) and 125 g of water were added, and while stirring, 2.8 g of potassium dihydrogen phosphate (98 wt.%, 0.02 mol) as a water-soluble salt was added and reacted at 100 ° C. for 2 hours.
The pH of the aqueous medium immediately before and after the reaction was 4.5 and 6.5, respectively. After completion of the reaction, the reaction mixture was cooled, 60 g of ethyl ether was added thereto, and the solid was separated by filtration.The solid was washed with ethyl ether, and the mixture of the obtained liquid and the ether washing liquid was separated to give ether. Isolate the layers,
This ether layer is subjected to liquid chromatography (hereinafter, LC
), And analyzed by an internal standard method.

 Table 1 shows the reaction conditions and analysis results.

Examples 2 to 6 The reaction and analysis were carried out in the same manner as in Example 1 except that the kind and amount of the water-soluble salt were changed. Table 1 shows the reaction conditions and analysis results.

Example 7 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 added with magnesium sulfate. Dried. Then, magnesium sulfate was separated, and ether was distilled off. The bottoms after ether distillation were distilled under reduced pressure to obtain 29.8 g (yield 85 mol%) of tetrafluorobenzonitrile having a purity of 100% by weight.

Mass spectrum EI M / Z = 175 (M ⁺ ) Infrared absorption spectrum 2325 cm ⁻¹ (C≡N) 3060 cm ⁻¹ (CH) ¹ H-NMR (solvent: CDCl ₃ , internal standard: TMS) δ = 7.41 ppm (1H, tt, J = 9.5 Hz, 7.3 Hz) ¹⁹ F-NMR (solvent: CDCl ₃ , internal standard: (CF ₃ COO
H) δ = -59.1 ppm (2F, d-dd, J = 6.9 Hz, 6.9 Hz 1
0.1Hz) -56.4ppm (2F, dd-d, J = 6.9Hz, 6.9Hz 10.1H
z)

Claims (1)

(57) [Claims] 1. A method of reacting pentafluorobenzonitrile with a solid metal or solid alloy in an aqueous solvent having a pH of 1 to 8 in the presence of a water-soluble salt. Nitrile production method.