JP2663125B2 - 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. More specifically, the present invention relates to a method for producing 2,3,5,6-tetrafluorobenzonitrile, wherein pentafluorobenzonitrile is reacted with a solid metal or a solid alloy at pH 3 or more and less than PH9 in an aqueous solvent. [Prior Art] A method for synthesizing 2,3,5,6-tetrafluorobenzonitrile is described in J. Org. Chem. In the above method, first, 4-cyano-2,3,5,6-tetrafluorophenylhydrazone is synthesized by reacting pentafluorobenzonitrile with hydrazone, and then the 4-cyano-2,3,5,6-tetrafluorophenylhydrazone is synthesized.
Cyano-2,3,5,6-tetrafluorophenylhydrazone is reacted with an aqueous solution of copper sulfate under heating to obtain 2,3,5,6-tetrafluorobenzonitrile. 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. [Problems to be Solved by the Invention] The inventors of the present invention have conducted intensive studies to solve the problems of the above-described prior art, in which the process length and the reaction yield are insufficient, and as a result, have found that pentafluoro By heating benzonitrile with PH3 or more and PH9 in an aqueous solvent together with a solid metal such as zinc metal, etc., fluorinated reduction can be performed very easily and in a short time, and high-purity 2,3,5,6-tetrafluoroethylene can be obtained. The present inventors have found that fluorobenzonitrile can be produced in high yield, and have completed the present invention. (Means for solving the problem) The present invention is to react pentafluorobenzonitrile with a solid metal or solid alloy, preferably zinc metal, in an aqueous solvent at PH3 or more and less than PH9, preferably in the presence of an acid. An object of the present invention is to provide a method for producing 2,3,5,6-tetrafluorobenzonitrile characterized by the following. Hereinafter, the present invention will be described in more detail. Although the reaction in the method of the present invention proceeds easily in an aqueous solvent, pentafluorobenzonitrile (hereinafter sometimes abbreviated as PFBN) as a starting material and 2,3,5,6 -Since tetrafluorobenzonitrile (hereinafter sometimes abbreviated as TFBN) is a hydrophobic oily substance, it has two liquid phases, an aqueous phase and an oil phase, and a solid phase [solid metal or solid alloy (hereinafter, solid metal). , Etc.)). Therefore, it is preferable to carry out this reaction by stirring while keeping the reaction system as uniform as possible. The aqueous solvent used in the present invention refers to water or a mixed solvent of water and an organic solvent soluble in water. By using such an organic solvent in combination, the solid phase and / or the oil phase is converted to an aqueous phase. In some cases, it can be dissolved in a single 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 Mono ethers of aliphatic monohydric alcohols having 1 to 3 carbon atoms; for example, tetrahydrofuran, dioxane (1,3, 1,4); and, for example, acetone, acetonitrile, lactonitrile, N, N
-Other water-soluble organic solvents such as 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. The present invention relates to a method for producing TFBN, which comprises reacting PFBN with a solid metal or a solid alloy in an aqueous solvent at PH3 or more and less than PH9. 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 the metal zinc used may theoretically be 1 mol per 1 mol of pentafluorobenzonitrile, but is usually 0.8 to 10 mol, preferably 1 to 5 mol. It is better to let. The reaction rate can be increased by setting the use amount to be equal to or more than the lower limit, and it is difficult to further increase the reaction rate even if the amount exceeds the upper limit.
It is preferable to use an amount within the range of use. The reaction 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. . However, from the viewpoint of reaction equipment costs,
The reaction is preferably carried out at atmospheric pressure in the range of 50 ° C to reflux temperature. Further, from the viewpoint of reactivity, the reflux temperature, especially 10
It is particularly preferable to carry out the reaction at a reflux temperature of 0 ° C. or higher. 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 of the present invention proceeds when the reaction system is in any of neutral, acidic and alkaline regions,
In the alkaline region, 2,3,5,6-tetrafluoro-4-hydroxybenzonitrile in which para-fluorine is substituted with a hydroxyl group, pentafluorobenzamide in which a nitrile group is hydrolyzed, 2,3,5, Since 6-tetrafluorobenzamide, pentafluorobenzoic acid, 2,3,5,6-tetrafluorobenzoic acid and salts of these benzoic acids may be by-produced, for example, the reaction is carried out in a reaction system having a pH of less than 9. The reaction is preferably carried out in a reaction system having a pH of from 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 acids such as sulfuric acid, hydrochloric acid, and nitric acid; and aqueous solutions such as organic acids such as acetic acid, oxalic acid, benzoic acid, phthalic anhydride, and p-toluenesulfonic acid. Any substance can be used as long as it shows acidity. Further, zinc hydroxide by-produced in the reaction of the present invention is poor in water solubility,
The activity of the metal zinc is reduced by depositing and adhering to the surface of the metal zinc, etc., which may hinder the smoothness of the reaction or may hinder the post-treatment of the reaction solution, in which case, for example,
By using acids such as sulfuric acid, hydrochloric acid, nitric acid and acetic acid,
Such trouble occurrence can be suppressed. 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-product water-insoluble zinc fluoride and the acid react with each other to release corrosive hydrogen fluoride. In addition, if the acid concentration is too high, the nitrile group undergoes hydrolysis to give pentafluorobenzamide, 2,3,5,6-tetrafluorobenzamide, pentafluorobenzoic acid and 2,3,5,6-tetrafluorobenzamide. Benzoic acid and the like may be by-produced. For these reasons, the amount of the acid used is preferably 0 to 5 gram equivalents, particularly preferably 0.2 to 5 gram equivalents, per mol of the raw material PFBN, and the used amount (molar number) of the metal zinc.
Is x, and the amount of acid (gram equivalent number) is y, 2x−y ≧ 1
It is preferable to use an amount in a range satisfying the relational expression. Furthermore, the acid concentration in the reaction is preferably used in a range of 10 gram equivalent or less, more preferably in a range of 5 gram equivalent or less based on 1000 g of the aqueous solvent. 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. After completion of the reaction, the solid matter is separated by means of steam distillation or excess, and then the organic layer is extracted with an extraction solvent, for example, ether, chloroform or the like, and then the solvent is distilled off to remove 2,3,
5,6-tetrafluorobenzonitrile can be obtained. Further, if necessary, the obtained product can be further purified by means such as distillation. EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples. Example 1 4.8 g (25 mmol) PFBN zinc powder in a 50 ml flask 2.
6 g (40 mmol, 1.6 mol per 1 mol of PFBN), 26 g of water
, And reacted under heating at reflux temperature (about 100 ° C.) for 6 hours with stirring. During the reaction, the stirring was stopped every hour to separate the two layers, and the oil layer was separated with a micropipette to about 0.02-
0.05 ml was collected, diluted appropriately with ether, and analyzed by internal standard method using gas chromatography.
A TFBN yield check was performed. After the reaction was allowed to cool, the mixture was allowed to cool, and then separated to separate a solid.The solid was washed with ether, and a mixture of the obtained liquid and an ether wash was extracted with ether, and the ether layer was washed with magnesium sulfate. Dried. The ether layer was analyzed by gas chromatography using an internal standard method. As a result, the target substance, TFBN, was obtained in a yield of 100 mol% based on the charged PFBN. Examples 2 and 3 In Example 1, instead of 2.6 g of zinc powder (1.6 mol / mol of PFBN), 2.0 g (1.2 mol / mol of PFBN) or 4.9 g (3 mol) of zinc powder was used.
(Mol / PFBN 1 mol) The experiment was carried out in the same manner as in Example 1 except that mol was used. In Example 3, in the third hour of the reaction,
Since the TFBN yield was about 100 mol%, the subsequent reaction was terminated. The reaction conditions and the reaction results are shown in Table 1. Example 4 An experiment was performed in the same manner as in Example 1 except that 26 g of a 50% by weight aqueous ethanol solution was used instead of 26 g of water as the aqueous solvent. The reaction conditions and the reaction results are shown in Table 1. Example 5 4.8 g (25 mmol) of PFBN, zinc powder in a 50 ml flask
4.9 g (75 mmol, 3 mol per 1 mol of PFBN), water 13
g, 97% by weight sulfuric acid 3.0 g (59 mg equivalent, PFBN1
The solution was charged with 2.4 g equivalents per mole and 4.6 g equivalents per 1000 g of water, and heated under reflux for 15 hours under stirring (about 110 g).
C). During the reaction, the yield of TFBN was checked in the same manner as in Example 1 every three hours. After the reaction,
When post-treatment and quantification were performed in the same manner as in Example 1, the target product, TF, was obtained.
BN was obtained in a yield of 99.3 mol%, and the starting material PF
0.7 mol% of BN remained. Examples 6 to 13 Example 5 except that the amount of zinc powder, the type and amount of aqueous solvent, the type and amount of acid and its concentration, and the reaction temperature were changed.
An experiment was performed as in. In addition, about reaction time, 15
Even before the time elapses, the yield at the time of the PFBN yield check is almost
When the reaction reached 100 mol%, the reaction was terminated. The reaction conditions and the reaction results are shown in Table 1. Example 14 48 g (250 mmol) of PFBN zinc powder 4 in a 500 ml flask
9 g (750 mmol, 3 mol per 1 mol of PFBN), 250 g of water
And heated at reflux temperature (about 100 ° C.) for 10 hours with stirring. During the reaction, every 2 hours, as in Example 1.
A TFBN yield check was performed. The reaction conditions and the reaction results are shown in Table 1. Example 15 In a 500 ml flask, 48 g (250 mmol) of PFBN, 49 g (750 mmol, 3 mol per mol of PFBN) of zinc powder, and water 2
50 g, 6.3 g of 97% by weight sulfuric acid (125 mg equivalent, PF
0.5 gram equivalent to 1 mol of BN, 0.5 gram equivalent to 1000 g of water) and heat to reflux temperature under stirring (about 100 ° C)
Was reacted. During the reaction, the yield of TFBN was checked every two hours in the same manner as in Example 1, and the reaction was stopped when the yield became approximately 100 mol%. The reaction time was 4 hours. The reaction conditions and the reaction results are shown in Table 1. Examples 16 and 17 The experiment was performed in the same manner as in Example 15, except that the amount of sulfuric acid used and the concentration of sulfuric acid were changed. The reaction conditions and the reaction results are shown in Table 1. Example 18 An experiment was performed in the same manner as in Example 15 except that the amounts of zinc powder and sulfuric acid used were changed. The reaction conditions and the reaction results are shown in Table 1. Example 19 In a 34-neck flask, 290 g (1.5 mol) of PFBN, zinc powder 2
94 g (4.5 mol, 3 mol per mol of PFBN), 1.5 kg of water and 182 g of sulfuric acid having a concentration of 97% by weight (1.8 mol, 2.4 g equivalent to 1 mol of PFBN, 2.4 g equivalent to 1000 g of water) Under stirring, heat to reflux temperature for 9 hours (reaction temperature about 110
C). Next, let it cool down and separate solids.
The liquid is extracted with ether. The ether layer was dried over magnesium sulfate, the ether was distilled off under reduced pressure, and the residue was distilled under reduced pressure. The target product, TFBN, was 218 g (melting point: 3
0.5-31.5 ° C., boiling point: 75 ° C./14 mmHg) The yield was 83 mol%. This fraction was analyzed by gas chromatography to find TF
Peaks of components other than BN were not observed. Various analytical values of the obtained target compound are as follows, and it is clear that this substance is 2,3,5,6-tetrafluorobenzonitrile. 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 = -59.4ppm (2F, dd, J = 14.6Hz, 7.3Hz) -56.4ppm (2F, dd, J = 14.6Hz, 7.3Hz)

Claims (1)

(57) [Claims] Pentafluorobenzonitrile, PH3 in aqueous solvent
A method for producing 2,3,5,6-tetrafluorobenzonitrile, characterized by reacting with a solid metal or a solid alloy at a pH of less than 9 or more. 2. 2. The method according to claim 1, wherein said reaction is carried out at substantially atmospheric pressure in a temperature range from 50 DEG C. to the reflux temperature of the aqueous solvent. 3. The method according to claim (1) or (2), wherein the reaction is performed in the presence of an acid. 4. The method according to any one of claims (1) to (3), wherein the solid metal is metallic zinc. 5. The method according to claim 4, wherein the amount of said metallic zinc is 0.9 to 5 mol per 1 mol of pentafluorobenzonitrile.