JPH02115156A - Production of 2,3,5,6-tetrafluorobenzonitrile - Google Patents

Abstract

PURPOSE:To obtain the title compound useful as an intermediate for drugs in high yield and in high purity without requiring an expensive reaction tank by reacting pentafluorobenzonitrile with a solid metal, etc., in the presence of a water-soluble salt in an aqueous solvent at specific pH. CONSTITUTION:Pentafluorobenzonitrile is reacted with a solid metal (e.g., Zn, Sn or Fe) or a solid alloy (e.g., zinc amalgam or tin amalgam) in the presence of a water-soluble salt (e.g., ammonium sulfate, sodium sulfate, ammonium chloride or sodium nitrate) in an aqueous solvent (e.g., methyl alcohol, ethylene glycol, THF or acetone) at pH1-8, preferably 2-7 to give 2,3,5,6- tetrafluorobenzonitrile. In this method, relatively inexpensive stainless steel such as SUS304 can be used as a material for a reaction tank.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a method for producing 2.3.5.6-titrafluorobenzonitrile, which is extremely useful as an intermediate for pharmaceuticals, agricultural chemicals, industrial drugs, etc. Specifically, the production of 2,3.5.6-titrafluorobenzonitrile, which is characterized by reacting pentafluorobenzonitrile with a solid metal or solid alloy in an aqueous solvent at a specific pH in the presence of a water-soluble salt. It is about the method.

[Conventional technology]

A method for synthesizing 2,3.5.6-tetrafluorobenzonitrile is described in J, Org, Chem, '1
966-31 The above method first uses pentafluorobenzonitrile (hereinafter sometimes abbreviated as F, BN).
and hydrazine to form 4-cyano-2,3,5,6
-Titrafluorophenylhydrazine was synthesized, and then the 4-cyano-2,3,5,6-titrafluorophenylhydrazine was reacted with copper sulfate solution under heating.2,3
．． 5.6-titrafluorobenzonitrile (hereinafter referred to as F4
(sometimes abbreviated as BN).

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

The present inventors have conducted extensive research in order to solve the problems of the long process and insufficient reaction yield of the above-mentioned prior art, and previously published a paper titled "Pentafluoro benzonitrile.

2゜3.5.6 characterized in that it is reacted with a solid metal or solid alloy in an aqueous solvent, preferably in the presence of an acid.
-f) A method for producing lafluoropenzonitrile.''

However, when the above proposal is carried out industrially, if an acid is used to achieve high occlusion and to outperform the target compound, fluoride water volume may be generated as a by-product.

Therefore, a new intermittent injection has occurred in which a very expensive reaction tank must be used, such as a Teflon-lined tank that is acid-resistant and resistant to fluorohydrogen 1C.

[Solved by the invention 1-Beggi problem] The present inventors have solved one reaction by maintaining the pI of the aqueous medium in the range of 1 to 8 using an extremely expensive anti-salt in the reaction tank. Tank material: 5US304, SUS31
It will also be possible to use relatively inexpensive stainless steel such as No. 6.

In the proposal of the above-mentioned Japanese Patent Application No. 62-295964.

Completed the invention.

[Means for solving problems]

The present invention is characterized in that pentafluorobenzonitrile is reacted with a solid metal or solid alloy, preferably metallic zinc, in an aqueous solvent with a pH of 1 to 8 in the presence of a water-soluble salt.2.3. The object of the present invention is to provide a method for producing 5.6-titrafluorobenzonitrile.

Any one can be used as long as it dissolves in water by 0.612 or more per 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, and magnesium chloride.

Hydrochlorides such as barium chloride; for example, ammonium nitrate,
Nitrates such as sodium nitrate, potassium nitrate, calcium nitrate, magnesium nitrate: for example.

Ammonium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, etc. Phosphates: For example, borates such as sodium west borate: For example, citrates such as ammonium citrate, ammonium hydrogen citrate, sodium citrate, sodium hydrogen citrate, potassium citrate, potassium hydrogen citrate: For example, acetates such as ammonium acetate, sodium acetate, potassium acetate, calcium acetate; for example, sodium tartrate, sodium hydrogen tartrate; tartarates such as potassium tartrate, potassium hydrogen tartrate; oxalates such as potassium oxalate; : For example, lactate salts such as sodium lactate and calcium lactate; heptatarate salts such as ammonium phthalate, hydrated ammonium phthalate, sodium phthalate, sodium hydrogen phthalate, potassium phthalate, potassium hydrogen phthalate, etc. Strong acid weak base salts such as ammonium sulfate, ammonium chloride, ammonium nitrate; sodium hydrogen sulfate, potassium hydrogen sulfate,
Strong base hydrogen salts of inorganic acids such as sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, etc.: ammonium hydrogen citrate, sodium hydrogen citrate, potassium hydrogen citrate, hydrogen tartrate Strong base hydrogen salts of organic acids such as sodium, potassium hydrogen tartrate, sodium hydrogen phthalate, potassium hydrogen phthalate:
It is preferable to use . These salts can be used alone or in a mixture of two or more, and if necessary, e.g.

By using a base such as sodium hydroxide, potassium hydroxide, or ammonia in combination, the pH of the aqueous medium is 1 to 8 degrees, preferably 2 degrees.
It can also be adjusted and used so that it becomes -7.

Furthermore, 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. Such salts include sodium sulfate, potassium sulfate, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, barium chloride, sodium nitrate, potassium nitrate, and other neutral strong acids and strong bases; Strong base salts of inorganic acids whose bath liquid is alkaline, such as sodium phosphate, potassium phosphate, sodium tetraborate; sodium citrate, potassium citrate, sodium acetate, potassium acetate, calcium acetate, sodium tartrate, potassium tartrate, Examples include organic acid strong base normal salts whose aqueous solutions are alkaline, such as sodium lactate, calcium lactate, sodium heptalate, and potassium phthalate.

Acids suitable for combination with the above salts include:

Inorganic acids such as % hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid; eg citric acid, acetic acid, succinic acid.

Tartaric acid, oxalic acid, lactic acid, 7-talic acid, benzoic acid.

There is no particular restriction on the use of organic acids such as p-toluenesulfonic acid, as long as the pH when misunderstood in the confronting medium is in the range of 1 to 8. , generally in a total amount of 0.05 to 0.01 to 2 mol/1. The defluorination degree t6 of the method of the present invention, which is preferably 0.02 to 1 mol/l, is
As mentioned above, it is carried out in an aqueous medium.

The above aqueous solvent is water, or water and a water-soluble organic solvent.
By using such an organic solvent in combination, it may be possible to dissolve a solid phase and/or an oil phase into an aqueous phase to form a single liquid phase. When carrying out the reaction under reflux temperature conditions, it is also possible to adjust the reflux temperature.

Such organic solvents may be used without any particular restriction as long as they contain 50 parts by weight or more per 100 tff parts of water, such as methylalcohols; e.g. Other monohydric alcohols; for example, aliphatic polyhydric alcohols having 1 to 3 carbon atoms, such as evaporated ethylene glycol, propylene glycol r1.2-1.3-), and glycerin; for example, polyethylene that is liquid at room temperature Glycols; mono- or dietherified products of ethylene glycol and aliphatic alcohols having 1 to 4 carbon atoms, such as ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether; Mono- or dietherized products of diethylene glycol and aliphatic alcohols having 1 to 4 carbon atoms, such as diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether: for example, 1- Monoetherification of glycerin such as glycerin monomethyl ether with an aliphatic alcohol having 1 to 3 carbon atoms: Example; t, tetrahydrofuran,
Howling ethers such as dioxane (1,3-1,4-);
Other water-bathable organic solvents such as acetone, acetonitrile, lactonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and diethyl sulfoxide may also be mentioned.

These organic m-mediums can be used alone or in a mixture of 2 Pji or more. Among these organic solvents, aliphatic alcohols are particularly preferred from the viewpoint of availability and economy.

In the method of the present invention, the pH range of the aqueous solvent is 1 to
It should be 8, preferably 2 to 7.

If the pH of the solvent exceeds the upper limit, it is not preferable for F, BN, and the generated F4BN to be ortho and/or to the IJ group. On the other hand, in the strongly acidic region below the lower limit, for example, solid metals or solid alloys (
Hereinafter, it may be abbreviated as solid metal, etc.) as the most suitable metal zinc. ) may occur, wasting metallic zinc, and the by-product zinc fluoride may react with the acid to liberate corrosive hydrogen fluoride. In the present invention, if the pH of the aqueous solvent exceeds the lower limit, the material of the reaction tank must be acid-resistant and
There is a risk that an expensive material that can withstand arsenic will have to be used.

The present invention provides F, BN in the presence of a water bathing salt at a specific pH.
The present invention relates to a method for producing F and BN, which involves reacting with a solid metal or the like in an aqueous bath medium of a certain range.

Examples of the solid metal include zinc and tin.

Examples of solid alloys include metal amalgams such as zinc amalgam, tin amalgam, and aluminum amalgam; examples include brass, bronze, aluminum-nickel alloy, and aluminum-nickel alloy. Other metal alloys such as lead alloys: etc. Among these, it is preferable to use solid metals from the viewpoint of easy availability and good reaction yield, and it is particularly preferable to use metallic zinc.

As the above-mentioned metal zinc, any commercially available metal zinc powder or the like can be used. As shown in the reaction formula below, metal zinc should be used in an amount of 1 mole per mole of F and BN, but it is usually present in an amount of 8 to 10 moles, preferably 1 to 5 moles. Good. By using metallic zinc above the lower limit of the usage range,
It is preferable to use a value within the range, since the reaction rate can be increased and the reaction rate will not deteriorate any further even if the amount exceeds the upper limit.

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

The reaction I6 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 reaction rate. However, from the viewpoint of the cost of reaction equipment, etc., it is possible to do so under atmospheric pressure.

It is preferable to carry out the reaction in a temperature range of 50°C to reflux temperature. In addition, from the viewpoint of reactivity, the reflux temperature, especially the reflux temperature of 1
In a reaction system at a temperature of 00°C or higher, it is more preferable to carry out the reaction at a temperature of %80°C to reflux temperature.

The reaction time is not particularly limited, but is usually 30
The reaction in the method of the present invention proceeds easily in an aqueous bath medium.
Since 4BN is a hydrophobic oily substance, it is a heterophasic reaction that involves two liquid phases, an aqueous phase and an oil phase, and a solid phase (solid metal, etc.). Therefore, this reaction is done by stirring to make the warped system as uniform as possible. It is best to do this while maintaining

After the completion of the reaction, solid matter is separated by steam distillation, filtration, etc., the organic layer is extracted using an extraction medium such as ether, chloroform, etc., and Mu is distilled off to obtain F4B.
You can get N. Father, if it is the essence of the soul, it is possible to further refine the superior product by means such as distillation.

〔Example〕

The present invention will be described below with reference to examples. - Describe the layers in detail.

Example 1 Cooling was carried out in a 300-flask equipped with a flow tube and thermometer.
RBN 39 y (purity 99w 1f%% 0.20 mol), powdered zinc 15f (M degree 96w 1f%, 0.22 mol)
and 1,252 ml of water, and while stirring, add 2.82 ml of potassium dihydrogen phosphate (purity 983 ft1%) as a water-soluble salt.
, 0.02 mol) and reacted at 100°C for 2 hours. In addition, the pH of the aqueous medium immediately before the reaction and after the completion of the reaction is as follows:
They were 4.5.6.5, respectively.

After 15 minutes of incubation, cool and add 160 g of ethyl ether.
.

After addition, filtration is performed to separate the solid matter, this solid matter is washed with ethyl ether, the resulting mixed solution of the p liquid and the ether washing solution is separated to isolate the ether layer, and this ether layer is It was analyzed by the internal m$ method using liquid chromatography (hereinafter sometimes abbreviated as LC).

The reaction conditions and analysis results are shown in Table fA1.

Examples 2 to 6 Reactions and analyzes were carried out in the same manner as in Example 1 except that the type of water-soluble salt and the sound used were changed. The reaction conditions and analysis results are shown in Table 1.

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, and the ether layer obtained by separating the mixture from the furnace liquid and ether washing liquid was added with magnesium sulfate. and dried. Next, magnesium sulfate was poured into the mixture, and the ether was distilled off. After distilling off the ether, the residue from the pot is distilled under reduced pressure to achieve a purity of 100 tc! J) Tetrafluorobenzonitrile 29.8? (Yield 85 mol%) was obtained.

○ Mass spectrum EI M/Z= 175 CM') Infrared absorption spectrum 2325crn (C=N) 3060on (C-tI)'I-1l-
1-N solvent: CDC4, internal standard substance: TMS) δ
=7.41 pprn (LH, t-t, J=9.5
l-1z, 7.3Hz)”F-NMR (solvent: C
DCj, , Internal standard substance: (CF, C00I-1)
δ = −59,1 pPm (2F, d-d-d, J
-6,911z, 6.9 l-1z10, 1 Hz) -56,4ppm (2F, d-dd, J=6.9H
z, 6.9l-1z10, IHz)

Claims (1)

[Claims] (1) The production of 2,3,5,6-tetrafluorobenzonitrile, which is characterized by reacting pentafluorobenzonitrile with a solid metal or solid alloy in an aqueous solvent of pH 1 to 8 in the presence of a water-soluble salt. Production method.