MXPA99011898A - Method for production of 2,4,5-trifluorobenzonitrile - Google Patents

Abstract

The invention relates to a method for the production of 2,4,5-trifluorobenzonitrile of formula (I), comprising the following steps:A) reacting 2,4,5-trifluoroaniline of formula (II) with a nitrosation agent in the presence of a diluent, and B) reacting the product of step A) with an alkaline metal cyanide in the presence of a transition metal compound, an acid scavenger and a diluent.

Description

PROCEDURE FOR THE OBTAINING OF 2,, 5-TRIFLUOR-BENZONITRILO Field of the Invention The invention relates to a process for the preparation of 2,4,5-trifluorobenzonitrile, which finds application as a starting product for active products in the field of medicine and agriculture.

Description of the Prior Art It is known that 2, 4, 5-trifluoro-benzonitrile is obtained if l-bromo-2,4,5-trifluoro-benzene is heated with cuprous cyanide (I) and N-methyl-pyrrolidone in a reaction vessel closed for several hours at temperatures between 170 ° C and 190 ° C (see EP-A-191 185). According to this synthesis method, however, a strongly impurified product is obtained which can only be isolated with sufficient purity after column chromatography. According to another method, something modified can be transformed l-bromo-2,4,4,5-trifluorobenzene with cuprous cyanide (I) also using N, N, -dimethyl-formamide as solvent and prolonged heating at reflux, in 2, 4,5-trifluorobenzonitrile (see J. Med. Chem. 31 (1988), 983-991). However, the isolation of pure 2, 4, 5-trifluoro-benzonitrile has not been described in this publication.

REF. : 32278 The reaction of 2-dichloro-5-fluoro-benzonitrile with potassium fluoride is also known, if appropriate in the presence of reaction aids, such as for example cesium fluoride and octadecyltrimethylammonium chloride, in the presence of diluents, such as for example dimethyl sulfoxide, tetramethylene sulfone (sulfolane) and toluene, at temperatures above 105 ° C (see EP-A-431 373, EP-A-433 124, EP-A-497 239, EP -A-635 486). In this case, however, most of the times 2, 4, 5-trifluoro-benzonitrile is obtained together with other products only with small or moderate yields. Only when large amounts of phase transfer catalysts, especially tetraalkylphosphonium halides, are used would 2,4,5-trifluorobenzonitrile be obtained in high yields (see EP-A-557 949). It is further known that 2, 4, 5-trifluoro-benzonitrile can be obtained in admixture with other fluorination products also by reaction of 2,4-difluoro-benzonitrile with elemental fluorine at low temperatures (see EP-A-566 268). . It has also been described the synthesis of some trihalobenzonitriles, but not that of 2,4,5-trifluorobenzonitrile, from corresponding trihalogenanilines through the diazonium salts and their reaction with metal cyanides (in relation to these processes from Sandmeyer "see GB-A-951 770, Coll. Czech, Chem. Com. 42 (1977), 2001-2017). However, neither the quality and the yields of the products obtained in this way are satisfactory.

Detailed description of the invention. The object of the present invention is to provide a process with which 2,4,5-trifluorobenzonitrile can be obtained in high purity and in high yields from 2,4,5-trifluoroaniline. The task is solved by means of a process for the preparation of 2, 4, 5-trifluoro-benzonitrile of the formula (I) wherein 2, 4, 5-trifluoro-aniline of the formula (II) is reacted (n: in a first step A) with a nitrosating agent in the presence of a diluent and in which, in a second step B), the reaction product obtained in step A) is reacted with an alkali metal cyanide in the presence of a transition metal compound, an acid acceptor and a diluent. Surprisingly, 2, 4, 5-trifluorobenzonitrile can be obtained according to the process of the invention in high yield and high purity. The reaction temperatures can vary within wide limits in carrying out the process according to the invention. In general, the first stage is carried out at temperatures between -20 ° C and + 30 ° C, preferably between -10 ° C and + 20 ° C, in the second stage in general at temperatures between -10 ° C and + 40 ° C, preferably between -10 ° C and + 40 ° C, preferably between 0 ° C and +30 ° C. The two steps of the process according to the invention are carried out, in general, under normal pressure. However, it is also possible to carry out the process according to the invention at higher pressure or under reduced pressure, in general between 0.1 bar and 10 bar. The starting material 2, 4, 5-trifluoroaniline is known and can be prepared easily (see GB-A-11 31 501, EP-A-415 585). The first step of the process according to the invention is carried out using a nitrosating agent. In this case, suitable nitrosating agents, customary for obtaining diazonium salts, are suitable. As an example, mention may be made in this case of alkali metal nitrites, such as, for example, sodium and potassium nitrite (in the presence of an acid, such as, for example, sulfuric acid, methanesulfonic acid, formic acid or acetic acid), nitrites of alkyl, such as, for example, methyl, ethyl, n-, or i-propyl nitrite, of n-, i-, s- or t-butyl, of n-, i-, s- or t-pentyl, in addition also nitrosilsulfuric acid. The nitrosylsulfuric acid will be particularly preferred as the nitrosating agent in carrying out the first step of the process according to the invention. The second stage of the process according to the invention is carried out using an alkali metal cyanide. Like sodium cyanide or potassium cyanide. In addition, a transition metal compound is used, preferably a copper compound, such as, for example, copper cyanide or copper sulfate. Surprisingly, the transition metal compound can be used in a much smaller amount than the stoichiometric amount, ie in catalytic amounts. The second step of the process according to the invention is further carried out in the presence of an acid acceptor.

Suitable acid acceptors are, in general, the bases or customary inorganic or organic acid acceptors. Preference is given to acetates, amides, carbonates, bicarbonates, hydrides, hydroxides or alkanolates of alkali metals or alkaline earth metals, such as, for example, sodium, potassium or calcium acetate, lithium amide, sodium or potassium amide. of calcium, sodium, potassium or calcium carbonate, sodium, potassium or calcium bicarbonate, lithium, sodium, potassium or calcium hydride, lithium, sodium, potassium or calcium hydroxide, ethanolate , ethanolate, n- or i-propanolate, n-, i-, s- or sodium or potassium t-butanolate; also basic organic nitrogenous compounds such as, for example, trimethylamine, triethylamine, tripropylamine, tributylamine, ethyldiisopropylamine, N, N, -dimethylcyclohexylamine, dicyclohexylamine, ethy-dicyclohexylamine, N, N-dimethyl-aniline, N, N-dimethyl-benzylamine, pyridine. , 2-methyl, 3-methyl, 4-methyl-, 2,4-dimethyl-, 2,6-dimethyl-, 3,4-dimethyl- and 3,5-dimethyl-pyridine, 5-ethyl-2-methyl -? iridine, 4-dimethylamino-pyridine, N-methyl-piperidine, 1,4-diazobicyclo- [2, 2, 2] -octane (DABCO), 1,5-diazabicyclo [4, 3, 0] -non- 5-ene (DBN), or 1,8-diazabicyclo [5, 4-, 0] -undec-7-ene (DBU). Preference is given to using carbonates or bicarbonates of alkali metals or alkaline earth metals, such as, for example, sodium or potassium (b) carbonate. The process according to the invention is carried out in the presence of a diluent. Suitable diluents for carrying out the process according to the invention are, in particular, inert organic solvents. These include, in particular, aliphatic, alicyclic or aromatic halogenated hydrocarbons, such as, for example, benzine, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl or dietiéther; ketones, such as acetone, butanone, or methyl isobutyl ketone; carboxylic acids, such as for example formic acid, acetic acid or propionic acid; nitriles, such as for example acetonitrile, propionitrile or butyronitrile; amides, such as for example N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-formanilide, N-methyl-pyrrolidone or hexamethylphosphorotriamide; esters such as methyl acetate or ethyl acetate, sulfoxides, such as dimethyl sulfoxide, alcohols, such as methanol, ethanol, n- or i-propanol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, their mixtures with water or pure water.

Particular preference will be given to carboxylic acids as diluents when carrying out the first step of the process according to the invention. In the embodiment of the second stage of the process according to the invention, water will preferably be used as the solvent. For carrying out the first stage of the process according to the invention, they are used per 1 mole of 2, 4, 5-trifluoro-aniline of the formula (II), in general between 0. 9 and 1. "2 moles, preferably between 1.0 and 1.1 moles of a nitrosating agent In a preferred embodiment of the first step of the process according to the invention, the 2,4,5-trifluoroaniline of the formula (II) in a suitable diluent and the nitrosating agent is dosed slowly with stirring.The reaction mixture is continued stirring until the reaction has been practically concluded according to the first step .For carrying out the second step of the process according to invention are employed per 1 mole of the 2,4,4-trifluor aniline used in the first step, of the formula (II), in general, between 1 and 10 moles, preferably between 2 and 8 moles of a metal cyanide alkali and generally between 0.01 and 0.5 moles, preferably between 0.05 and 0.2 moles of a transition metal compound.

In a preferred embodiment of the second stage of the process according to the invention, the reaction mixture, obtained according to the first stage, is added, under stirring, to an aqueous solution of alkali metal cyanide and transition metal compound, maintaining the pH value approximately in the neutral range, by simultaneous addition of an acid acceptor. The reaction mixture is continued stirring until the reaction is practically complete. Preferably, the product of the reaction, obtained in the first stage, is not isolated before the reaction in the second stage. The working up and the isolation of the reaction product of the formula (I) can be carried out in the usual manner. For example, it is shaken with an organic solvent, practically immiscible with water, such as for example ethyl acetate, and then the solvent is carefully removed by distillation under reduced pressure of the organic extraction solution, leaving as residue the product of the formula (I). The 2, 4, 5-trifluoro-benzonitrile compound of the formula (I), to be obtained according to the process of the invention, can be used as an intermediate product for the production of active products in the field of medicine and agriculture ( see EP-A-191 185, EP-A-597 360, EP-A-617 026, EP-A-654 468) Preparation examples: Example 1. 4.4 g (30 mol) of 2,4,5-trifluoroaniline are dissolved in 25 ml of acetic acid ("glacial acetic acid") and cooled with an ice bath. Subsequently, 4.5 g (31.5 mol) of nitrosylsulfuric acid are added under stirring and the reaction mixture is stirred for an additional 1 hour, after removal of the ice bath (first stage). The diazonium salt obtained in this way is then added, under stirring, to a solution, cooled at 5 ° C, of 7.8 g (160 mmol) of sodium cyanide and 0.3 g (3 mmol) of cuprous cyanide ( I) in 40 ml of water. By the simultaneous addition of approximately 80 ml of a 25% aqueous solution of sodium carbonate, the pH value is maintained approximately in the neutrality range. The reaction mixture is then stirred for about 15 more minutes and then extracted twice with 110 ml each time of ethyl acetate. The solvent is carefully removed by vacuum distillation of the water tube from the combined organic extraction solutions. 4.1 g (92% product according to the analysis by gas chromatography, ie 80% of theory) of 2,4,4-trifluorobenzonitrile are obtained in the form of an oily residue.

It is noted that in relation to this date, in a better method known to the applicant, to carry out the aforementioned invention, is that which is clear from the manufacture of the objects to which it refers. Having described the invention as above, the content of the following is claimed as property.

Claims (7)

1. Process for the preparation of 2, 4, 5-trifluoro-benzonitrile, characterized by the following steps: A) reaction of 2,4,5-trifluoro-aniline with a nitrosating agent in the presence of a diluent; B) reaction of the product of the reaction, obtained in the stage

A), with an alkali metal cyanide in the presence of a .. composed of transition metal, an acid acceptor and a diluent. Method according to claim 1, characterized in that the reaction of step A) is carried out at a temperature comprised between -20 ° C and + 30 ° C, preferably between -10 ° C and + 20 ° C, and the reaction in step B) is carried out at a temperature comprised between -10 ° C and + 40 ° C, preferably between 0 ° C and + 30 ° C.

3. Process according to one of claims 1 or 2, characterized in that alkali metal nitrites, alkyl nitrites and / or nitrosylsulfuric acid are used as the nitrosating agent.

4. Process according to claim 3, characterized in that nitrosylsulfuric acid is used as the nitrosating agent. Process according to one of Claims 1 to 4, characterized in that, as alkali metal cyanide, -CSV employs sodium cyanide and / or potassium cyanide. Method according to one of claims 1 to 5, characterized in that a copper compound, preferably copper cyanide and / or copper sulphate, is used as the transition metal compound. Process according to one of claims 1 to 6, characterized in that carbonates and / or bicarbonates of alkali metals and / or alkaline earth metals, preferably (bi) carbonate of sodium and / or potassium are used as the acid acceptor. Process according to one of Claims 1 to 7, characterized in that one or more inert organic solvents are used as diluent. The process according to claim 8, characterized in that carboxylic acids are used as diluent in step A) and water is additionally used in step B). Process according to one of Claims 1 to 9, characterized in that the reaction product obtained, in stage A), is not isolated as a previous step for the reaction in step B).