FR2728899A1 - A new process for the prepn. of fluoro-aniline(s) - Google Patents

Abstract

A new process for obtaining cpds. of general formula (I) comprises submitting a cpd. of formula (II) to catalytic hydrogenation in a liq. medium contg. a catalyst, under pressure of H2, to effect catalytic redn. and (if need be) a hydrogenolysis reaction. The cpd. (II) is added progressively to the medium in such a way that the content of (II) remains less than or equal to 1000 ppm (wt.), to selectively form cpd. (I). n = 1 to 5; Z = a radical stable in catalytic hydrogenation conditions; p = less than 5-n; X = a hydrogenolysable radical; q = 0 to (5-(n+p)).

Description

 The present invention relates to a process for the preparation of fluoroanilines, in particular difluoroanilines, from nitro fluorinated benzene compounds.

 Fluoroanilines are synthetic precursors which are of particular interest in the field of medicinal products and plant protection.

 However, their obtaining is not direct but results from multi-stage synthesis processes, which makes these products very expensive. In order to reduce the cost price of these compounds, it is advisable to use stages with the highest possible yield, in particular the last stage.

 The various synthesis methods proposed to reach fluoroanilines pass through nitro fluorinated compounds which are then reduced to amines. One particular access route consists in preparing a fluorinated and generally chlorinated nitrobenzene, then subjecting it to a hydrogenation operation in order to reduce the nitro function to the amine function while substituting any chlorine atoms with hydrogen atoms. .

 Thus, US Pat. No. 4,140,719 describes a synthesis of 2,4-difluoroaniline using the hydrogenation of Schlom 2,4-difluoro nitrobenzene with a yield of 84%.

 Likewise, US Pat. No. 5,294,742 describes the hydrogenation of 2,6-dichloro 3,5-difluoro nitrobenzene to give 3,5-difluoroaniline with a yield of 88.9%.

 Such yields are acceptable in the laboratory but imply a certain shortfall, which should be avoided with a view to industrial application.

 In addition, it should be noted that these yields are accompanied by quantitative conversion rates, the rest of the starting material being transformed into compounds of azo or azoxy type, but also, as the present inventors have discovered, into polyanilines by polycondensation, these by-products being known to be highly toxic. Their presence, even in trace amounts after purification is therefore a major drawback with a view to the use of fluoroanilines in the synthesis of drugs or products in contact with the environment (especially in products for agriculture).

 Thus, the object of the present invention is to provide a process for the preparation of fluoroanilines, in particular difluoroanilines, from nitrated fluorinated benzene compounds with an almost quantitative yield, without significant formation of toxic by-products.

 To this end, the invention relates to a process for the preparation of a compound containing an aniline substituted by one or more halogen atoms, at least one of which is a fluorine atom, in particular a fluoroaniline, comprising a step in which a compound containing a nitrobenzene substituted by one or more halogen atoms, at least one of which is a fluorine atom, in particular a chlorofluoro nitrobenzene, is subjected to catalytic hydrogenation so as to reduce the nitro group to amino group in substituting hydrogen atoms for halogen atoms other than fluorine atoms, step in which said nitrated benzene compound is introduced progressively into an enclosure under hydrogen pressure containing a hydrogenation catalyst in a liquid medium of so that the content of nitro-functional compound in the hydrogenation medium remains less than or equal to 1000 ppm (by mass).

 Preferably, the nitro fluorinated benzene compound carries at least one chlorine substituent.

 This process applies in particular to the preparation of fluoroanilines by catalytic hydrogenation of chloro fluoro nitrobenzenes, very particularly to the preparation of difluoroaniline by catalytic hydrogenation of chloro dfluoro nitrobenzene, dichloro difluoro nitrobenzene or trichioro difluoro nitrobenzene. The process of the invention then achieves the reduction of the nitro group and the substitution of the chlorine atom (s) by one or more hydrogen atoms.

 It is very particularly advantageous for preparing 2,4difluoroaniline from 3chloro 2,4-difluoronitrobenzene or chloro 2,4ifluoronitrobenzene, or 3,5-difluoroaniline from 2,4dichloro 3,5-difluoronitrobenzene , 6dichloro 3,5-difluoronitrobenzene or 2,4,6-trichloro 3,5-difluoronitrobenzene.

 The hydrogenation according to the present invention of a nitrated, chlorinated and fluorinated benzene compound in fact performs two reactions, which can be concomitant or preferably successive, namely the reduction of the nitro group to the amino group, which leads transiently or effective to the corresponding chlorinated and fluorinated amino benzene compound, and the substitution of the chlorine atom (s) by hydrogen atoms (hydrogenodechlorination). This substitution may take place on the amino compound as an intermediate or intermediate transition compound, or else concomitantly with the reduction of the nitro compound. Advantageously, the reaction conditions according to the present invention make it possible to first obtain the benzene compound chlorinated and fluorinated amine, in particular thanks to a relatively low temperature, in particular below 70 ° C., the chlorine substituents of this chlorinated and fluorinated amino benzene compound being substituted by hydrogen in a second step, in particular under temperature conditions relatively high, in particular at a temperature above 80 C, preferably above 100 - 120 ° C.

 According to the present invention, the progressive introduction of the benzene compound into the hydrogenation medium makes it possible to remarkably avoid the formation of undesirable by-products.

 Preferably, the nitrated benzene compound is introduced continuously into the hydrogenation enclosure under hydrogen pressure.

 This introduction must be carried out so that the content of nitrated benzene compound in the hydrogenation medium remains less than 1000 ppm.

 Preferably, this content is kept below 500 ppm, in particular in the range from 200 to 500 ppm. It is possible to choose to maintain this content at a very low value, in particular much less than 200 ppm, the only drawback which results therefrom is that the time necessary for the completion of the reaction will be inversely lengthened. In a particular embodiment, the hydrogenation reaction can advantageously be carried out in an enclosure provided with means for measuring the content of nitro benzene compound in the reaction medium, to which the means for introducing the nitro benzene compound are optionally controlled. .

 Advantageously, the nitrated benzene compound is gradually introduced into a liquid hydrogenation medium with stirring, so as to uniformly distribute the small amount of nitrated compound in the volume of liquid.

 Preferably, the liquid medium in which the hydrogenation of the nitro benzene compound is carried out is a liquid solvent for both the nitro benzene compound and the various products of the reaction.

 In fact, the process according to the invention is particularly effective when the reaction takes place in solution in a homogeneous liquid medium, that is to say in the presence of a single liquid phase.

 This homogeneous or monophasic liquid medium may however comprise solid particles in suspension, namely catalyst particles.

 This catalyst can be chosen from all known hydrogenation catalysts, in particular metals such as nickel, palladium or metals of platinum mine, optionally on an inorganic or organic support such as carbon black.

 The hydrogenation catalyst can be chosen to selectively obtain the amino, chlorinated and fluorinated benzene compound. In this regard, nickel is preferred, in particular Raney nickel, or a metal catalyst slightly poisoned in a manner known in the hydrogenation technique. The reaction is then preferably carried out at a temperature below 70 ° C.

 Dechlorination can also be avoided by operating with a catalyst of the palladium-on-charcoal type but at a relatively low temperature, in particular less than 70 ° C., in particular less than or equal to 60 ° C.

 The solvent is preferably a polar solvent, which can be protic or aprotic. Methanol or ethyl acetate can in particular be used. Advantageously, the solvent can be chosen from solvents miscible with water.

 Solvents containing sulfur capable of being reduced under the conditions of hydrogenation, for example DMSO, are to be avoided because they lead to unwanted by-products which can in particular make the catalyst inactive. A sulfur solvent such as sulfolane is however acceptable because it is very difficult to reduce.

 Generally, it may be advantageous to work in a relatively high boiling solvent to isolate the reaction product by distillation. This is particularly advantageous in the case where it is desired to separate the chlorinated and fluorinated amino benzene compound, that is to say simply reduced, so as to carefully separate this intermediate product by distillation, possibly as it is synthesized.

 Preferably, the gradual introduction of the nitrated benzene compound into the enclosure under hydrogen pressure is carried out at a temperature of 0 to 100 "C., in particular from 50 to 80" C.

 An inert gas, in particular nitrogen, can be used in admixture with hydrogen.

 The hydrogen pressure, possibly partial pressure in the case where a mixing gas is used, in the hydrogenation chamber during the progressive introduction of the nitrated benzene compound is preferably from 105 to 2.105 Pa.

 Under these temperature and pressure conditions, the reaction for reducing the nitro group to amino is carried out mainly.

The substitution reaction of chlorine atoms with hydrogen atoms can take place under such conditions, but in an incomplete manner.

 Recall that the use of a selective catalyst makes it possible to avoid the elimination of chlorine, in particular under the conditions of temperature and'or pressure stated above.

 To carry out dechlorination, the temperature of the reaction mixture is advantageously greater than approximately 100 ° C., in particular greater than or equal to 120 ° C.

 The reaction of substitution of chlorine atoms by hydrogen atoms releases chlorine in the form of hydrochloric acid.

 It is advantageous to operate in the presence of a base to neutralize the acid released during the hydrogenation reaction.

 This base is preferably an alkaline base, in particular sodium hydroxide, which can be introduced into the medium in the form of an aqueous solution.

 It is also possible to use alkaline earth oxides, such as in particular MgO and CaO. These compounds are however hardly soluble in water, or at least have very slow dissolution kinetics, so that their use risks introducing too many solids into the hydrogenation medium and thus not making it possible to reach results as good as those obtained in homogeneous solution (apart from the solid catalyst).

 Alternatively, a basic ion exchange resin may also be used as the acid absorbing agent.

 In the case where a basic aqueous solution is used, it is preferable to choose, to constitute the hydrogenation medium, a solvent miscible with water so that the hydrogenation takes place in a homogeneous solution.

 During the reaction, it is preferable that the quantity of reagents present is such that the concentration of the products (such as the nitrogenous base, or its hydrochloric salt, or the salts resulting from the reaction of the hydrochloric acid released with the base introduced) remains below the solubility limit of each of these products in the reaction medium. Preferably, the precipitation of solids in the reaction medium is avoided by keeping the concentrations of the species in solution at less than 90%, more particularly less than 80%, of their solubility limit.

 In this respect, the modification of pH implied by the basic input in the reaction medium can be advantageously used to modify said limits of solubility and continue to operate in homogeneous solution.

 Preferably, the concentration of said base present in the reaction medium for this purpose is less than or equal to 1 mol / l, in particular less than or equal to 0.5 mol / l.

 The base can be introduced into the reaction medium at the start of the hydrogenation reaction. It can also be introduced as the hydrochloric acid is released during the reaction.

 As a variant, it is possible to operate in the presence of base only from the end of the gradual introduction of nitrated benzene compound, possibly raising the temperature of the reaction medium. In this case, the base can also be introduced as the hydrochloric acid is released.

 When a selective catalyst is used in order not to carry out the hydrodechlorination reaction, it is preferable not to operate in the presence of a base to limit the risks of side reactions.

 After the gradual introduction of the nitrated benzene compound, the latter is completely in reduced form as an amine and optionally still carries all or part of the chlorine atoms on the benzene ring.

 If the reaction mixture contains fluorinated and chlorinated amino benzene compound (aniline), the hydrogenation operations can be continued to reach the non-chlorinated product with a quantitative yield.

 At this stage, the catalytic hydrogenation can be continued directly on the reaction mixture. If we have operated up to now with a selective catalyst which does not allow the substitution of chlorine atoms by hydrogen, it is advisable to introduce another active catalyst this time for dechlorination in the hydrogenation enclosure. .

 Alternatively, the reaction product can also be separated from the hydrogenation, in the form of isolated chlorinated and non-chlorinated products, or in the form of a mixture of said products.

 The chlorinated fluorinated aniline can then be subjected, alone or as a mixture with the non-chlorinated fluorinated aniline, to a new catalytic hydrogenation operation in a hydrogenation chamber containing a liquid solvent medium for the fluorinated anilines in the presence of a hydrogenation catalyst and a base. The reaction medium may be identical to or different from the reaction medium of the first hydrogenation, preferably respecting the advantageous variants set out above (in particular by choosing a polar solvent, advantageously miscible with water, etc.).

 In particular, the hydrogenation catalyst must be chosen different from the previous one in the case where a selective catalyst was used which does not allow dechlorination of the nitro or amino benzene compound.

 Preferably, the hydrogenation is carried out in a single medium by linking the reduction and hydrodechlorination reactions to obtain, in fine, the fluorinated but non-chlorinated amino benzene compound. The operation is preferably carried out in the presence of palladium-on-carbon, as a catalyst. The catalyst can advantageously comprise from 5 to 15% of palladium.

 In the two cases in which the hydrogenation is continued after the end of the introduction of the nitrated benzene compound to make or perfect the dechlorination of the benzene compound, in the same enclosure or in another enclosure, the temperature of the reaction medium is advantageously from 80 to 1500C, preferably from 100 to 1500 C.

Likewise, after the end of the progressive introduction of the nitrated benzene compound, it is preferable to continue the hydrogenation under a partial hydrogen pressure of 1.5.1 or 5.106 Pa, in particular 2.106
Pa.

 All the variants set out above make it possible to achieve a quantitative conversion of the starting benzene compound with an almost quantitative yield of fluorinated aniline.

 The fluorinated aniline can be separated from the reaction medium at the end of the hydrogenation, in particular by distillation.

 At the end of the hydrogenation reaction, an amine concentration of up to 50% by weight of the reaction medium can be reached. Concentrations above 20% by weight are very easily reached.

 This possibility of obtaining very concentrated end products in the reaction medium makes it possible to improve the productivity of the tools, which represents an additional advantage of the inventlon process, adding to its high yield.

 As mentioned previously, the process according to the present invention can be applied to the preparation of 2,4-difluoroaniline by catalytic hydrogenation of 3-chloro 2,4difluoronitrobenzene, or of 5-chloro 2,4difluoronitrobenzene. These compounds can be obtained by reacting 2,3,4-trichloronitrobenzene, respectively 2,4,5-trichloro nitrobenzene with a source of fluorides.

 As a fluoride source, an alkaline fluoride, in particular a potassium or cesium fluoride, or a quaternary ammonium fluoride is conventionally used, in slight excess calculated relative to the two chlorine atoms in ortho and para to be substituted by fluorine.

 The reaction preferably takes place in a dry aprotic polar solvent such as sulfolane.

 Advantageously, 2,3,4-trichloro nitrobenzene, respectively 2,4,5-trichloronitlobenzene, is obtained by reaction of 1,2,3trichlorobenzene, respectively of 1,2,4-trichlorobenzene, with a reagent for nitration of compounds. aromatic, especially with nitric acid.

 The nitro function is introduced in position 6 at 96% on 1,2,3-trichlor benzene, and at 90% on 1,2,4-trichlorobenzene.

 Similarly, the method according to the present invention can be applied to the preparation of 3,5-difluoroaniline by catalytic hydrogenation of 2,4-dichloro 3,5-difluoronitrobenzene, 2,6-dichloro 3,5 difluoronitrobenzene, or 2,4,6-trichloro 3,5-difluoronitrobenzene.

 These compounds can be obtained by reacting 2-amino 4-chloro 3,5-difluoronitrobenzene, respectively of 2-amino 6 chloro 3,5-difluoronitrobenzene, respectively of 2-amino 4,6-dichloro 3,5-difluoronitrobenzene, cuprous chloride in the presence of a source of nitrite ions, in particular nitrous acid or sodium nitrite in an acid medium.

This reaction, known as the reaction of
Sandmeyer, diazotizes the nitrogen atom of the amine function, the azo group then being substituted by a chlorine atom.

 It has been found that this reaction is particularly effective with the compounds mentioned above and the present inventors have been able to observe very high reaction yields, much greater than 90%.

 2-amino 4-chloro 3,5-difluoronitrobenzene, respectively 2-amino 6-chloro 2,4-difluoronitrobenzene, respectively 2-amino 4,6-dichloro 3,5-difluoronitrobenzene, can be obtained by reaction of chloro 2,4-difluoroaniline, respectively of 5-chloro 2, difluoroaniline, respectively of 3,5-dichloro 2,4-difluoroaniline, with a reagent for the nitration of aromatic compounds, in particular with nitric acid.

 One of the best media for carrying out this nitration reaction is a medium which comprises nitric acid, sulfuric acid and a carboxylic acid.

 Advantageously, the reaction mixture can also comprise a significant proportion of water which can be introduced as such or by means of a solution of one of the abovementioned mineral acids.

 Advantageously, the water content of the reaction medium, of course without taking into account the starting product, is between 1110th and once the amount of pure nitric acid used.

 The amount of water introduced using a 65% nitric acid leads to satisfactory results.

 Preferably, before the nitration reaction, the amino group of the aniline can be deactivated by acylation. The acyl group can be installed in a conventional manner by reaction of the aniline with an anhydride or an acid halide, or with compounds derived from carbonic acid by mono-amidation.

 It is preferable, however, that the anilides remain stable under the conditions of the nitration reaction.

 The reaction of the cleavage of the anilide to restore the aniline can be carried out in the same reaction system as that of the nitration.

 It suffices to do this by heating to a temperature at least equal to 50 "C, preferably at least equal to 80" C, the reaction mixture resulting from the nitration after addition, optional, of a certain amount of water.

 The product of the nitration reaction, with or without passage through the anilide, leads to a final product in the form of the nitroaniline salt. This salt can be used in the Sandmeyer reaction in the same way as the nitro aniline itself.

 As a variant, 2,6-dichloro 3,5-difluoro nitrobenzene or 2,4,6-trichloro 3,5-difluoro nitrobenzene can be advantageously obtained by reversing the order of the nitration and Sandmeyer reactions, starting from 2,4difluoroaniline chloro, respectively 3,5-dichloro 2, difluoroaniline.

 Thus, 2,6-dichloro 3,5-difluoro nitrobenzene, respectively 2,4,6-trichloro 3,5-difluoro nitrobenzene, can be obtained by reaction of 1, 3dichloro 4,6-difluorobenzene, respectively of 1, 3,5trichloro 2,4difluorobenzene, with a reagent for the nitration of aromatic compounds, in particular with nitric acid. The ortho nitration of the two fluorine atoms is easily and regioselective.

 1,3-dichloro 4,6-difluorobenzene, respectively 1, 3,5-trichloro 2,4difluorobenzene, is preferably obtained by subjecting the Sandmeyer reaction to 5-chloro 2,4difluoroaniline, respectively 3.5 -dichloro 2,4-difluoroaniline.

 This variant is very advantageous compared to the reaction sequence explained above, since it makes it possible to avoid the stage of protection of the amine in the presence of the nitro group by passage through the anilide, which involves expensive reagents and which implies the need to treat effluents produced during the application of the Sandmeyer reaction to chlorofluoronitroaniline protected in the form of an anilide.

 3-chioro 2,4-difluoroaniline, respectively Schloro 2,4difluoroaniline, respectively 3,5-dichloro 2,4-difluoroaniline, can advantageously be obtained by hydrogenation of 3-chloro 2,4-difluoro nitrobenzene, respectively of 5 chloro 2,4-difluoronitrobenzene, respectively 3,5-dichloro 2,4-difluoro nitrobenzene, in particular according to a catalytic hydrogenation process according to the invention as described above.

 Any known method of reducing the nitro group to amino can be used provided that the latter does not affect the halogen substituents, and especially fluorine.

 In this regard, there may be mentioned a reduction by catalytic hydrogenalon at room temperature, the catalyst possibly being in particular Raney nickel or palladium.

 However, it is preferable to apply the reduction conditions according to the present invention, in particular by using a slightly poisoned reduction-selective catalyst which does not allow dechlorination.

 It is thus possible to prepare with good yield 2, and 3,5-difluoroaniline from simple precursors, namely 1,2,> and 1,2,4-trichlorobenzene. The sequence of reactions can be done by isolating each intermediate product at each step. The crude reaction mixture from the previous step can also be used in one step. For this, a universal solvent system will be used. The sulfolane is quite suitable. However, care should be taken that the reaction mixtures do not contain by-products, in particular sulfur products, capable of constituting or generating poisons for the catalyst or catalysts of the hydrogenation reactions.

Thus, the present invention also relates to a process for the preparation of 2,4-difluoroaniline by
(i) reacting 1,2,3-trichlorobenzene with a nitration reagent, in particular nitric acid, to give 2,3,4-trichloro nitrobenzene (A),
(ii) bringing (A) into contact with potassium fluoride to form 3-chioro 2,4-difluoronitrobenzene (B),
(iii) catalytic hydrogenation of (B) according to a process as described above.

Furthermore, the invention also relates to a process for the preparation of 3,5-difluoroaniline by
(i) reacting 1,2,3-trichlorobenzene with a nitration reagent, in particular nitric acid, to give 2,3,4-trichloro nitrobenzene (A),
(ii) bringing (A) into contact with potassium fluoride to form 3-chloro 2,4-difluoronitrobenzene (B),
(iii ′) catalytic hydrogenation of (B) under conditions which do not affect the chlorine atom, in particular according to a process as described above, to lead to 3-chioro 2,4-difluoroaniline (C),
(iv) reaction of (C) with a nitration reagent, leading to 3-chioro 2,4-difluoro Snitroaniline (D),
(v) bringing (D) into contact with cuprous chloride and a source of nitrite ions, in particular nitrous acid to form 2,4dichloro 3,5-difluoro nitrobenzene (E), and finally
(vi) catalytic hydrogenation of (E) according to a process as described above.

 This process leads to 3,5-difluoroaniline with a high yield. In addition, compared to known methods, it has the advantage of not requiring a chlorodenitration reaction which releases NO2CI as a by-product. This explosive by-product has so far limited the possibilities of industrial synthesis and 3,5-difluoroaniline. The process described above offers a cost-effective and safe solution to the problem of industrial synthesis of 3,5-difluoroaniline.

 The subject of the invention is also a process for the preparation of 3,5-difluoroaniline by: (i) reaction of 1,2,4-trichlorobenzene, respectively of 1,2,3,4-tetrachlo robenzene, with a nitration reagent , in particular nitric acid, to give 2,3,5-trichloronitrobenzene, respectively 2,3,4,5 tetrachloronitrobenzene, (ii) bringing together 2,3,5-trichloronitrobenzene, respectively 2,3, 4,5-tetrachloronitrobenzene, with potassium fluoride to form Schloro 2,4-difluoronitrobenzene, respectively 3,5-dichloro 2, difluoronitrobenzene, (iii) catalytic hydrogenation of 5-chloro 2,4-difluoronitrobenzene, respectively of 3, 5-dichloro 2,4-difluoronitrobenzene, under conditions which do not affect the chlorine atom, in particular according to a process as described above, to lead to 5-chioro 2,4-difluoro aniline, respectively 3,5 -dichloro 2,4-difluoro aniline, (iv) reaction of 5-chloro 2,4-difluoro aniline, respe ctively the 3,> dichloro 2,4-difluoro aniline, with cuprous chloride in the presence of a source of nitrite ions, in particular nitrous acid, to form 1,3dichloro 4,6-difluoro benzene, respectively 1, 3,5-trichloro 2,4difluoro benzene, (v) bringing together 1, 3-dichloro 4,6-difluoro benzene, respectively 1, 3,5-trichloro 2,4-difluoro benzene, with a reagent nitration, in particular nitric acid, to yield 2,6-dichloro 3,5-difluoro nitrobenzene, respectively 2,4,6-trichloro 3,5-difluoro nitrobenzene, and (vi) catalytic hydrogenation of 2, 6-dichloro 3,5-difluoro nitrobenzene, respectively 2,4,6-trichloro 3,5-difluoro nitrobenzene, according to a process as described above.

 This process, which only involves reactions with very high regioselectivity, makes it possible to achieve 3,5-difluoroaniline with a very good yield and a production cost compatible with an industrial application.

 The present invention will now be illustrated by means of the following examples.

EXAMPLES
Examples 1 to 4: Reduction of 3-chloro 2,4-difluoro nitrobenzene to chloro 2,4-difluoroaniline.

Example 1
Reduction of 3-chloro 2,4-difluoronitrobenzene to chloro 2,4-difluoroaniline.

 In a 300 ml stainless steel reactor stirred at 1000 rpm, fitted with a pump for injection under pressure and with a capacity (reserve and pressure regulator) allowing to control the pressure in the reactor and to measure the quantity of 'hydrogen consumed, 0.18 g of Raney nickel is placed in 100 ml of methanol.

 The reactor is purged three times with nitrogen then three times with hydrogen.

 The temperature of the reactor is brought to 50 ° C. and a hydrogen pressure of 1.5 × 10 6 Pa is installed. When these conditions are established, 50 ml of a solution of 18 g (0.093 mol) of chloro 2,4difluoronitrobenzene in methanol are injected at the rate of 28 ml / h.

 The temperature and pressure conditions are kept constant throughout the injection, the S chloro 2,4-difluoronitrobenzene concentration being maintained by the injection flow rate at a value of less than 500 ppm.

 After the end of the introduction of 3-chloro 2,4-di uoro nitrobenzene, the hydrogenation conditions are maintained for one hour without observing any additional hydrogen uptake, indicating that the reaction is complete.

 15.3 g of a very light product containing 99.5% of 3-chloro 2,4-difluoro aniline, containing only 0.02% of 2,4-difluoroaniline, are separated by simple distillation of the solvent. .

 The conversion rate of 3-chloro 2,4-difluoro nitrobenzene is 100% and the yield of 3-chloro 2,4-difluoroaniline is 99.6%.

 The speed of the reaction (disappearance of the starting product) was approximately 0.2 ml.h ~ '.g ~ of catalyst.

Example 2
The operation is carried out in a 300 ml reactor stirred by a turbine ensuring excellent gas-liquid transfer, so that the medium is always saturated with hydrogen under the conditions of the reaction.

 120 ml of ethyl acetate and 0.18 g of Raney nickel, previously washed with etaanol and ethyl acetate, are loaded into the reactor. After removing the air with nitrogen and then nitrogen with hydrogen, the reactor is pressurized to 1.5.106 Pa absolute with hydrogen at a temperature of 50 C. It is injected in 225 min, a solution of 0.093 mole of 3-chloro 2,4-difluoronitrobenzene dissolved in 80 ml of ethyl acetate.

 The consumption of hydrogen constantly corresponds to the stoichiometry of 3 moles per mole of nitro derivative.

It is checked by appropriate analytical means (continuous potential measurement and control by gas chromatography
CPG) that the concentration of nitro derivative remains less than or equal to 500 ppm.

 After stopping the injection of nitro derivative, the temperature and pressure conditions are maintained for another 15 min without observing hydrogen consumption.

The yield of Schloro 2,4-difluoroaniline (dosed by
CPG) is 99.6%. There is also 0.4% formation of 2,4-difluoroaniline resulting from the hydrodechlorination of the 3-chloro 2,4-difluoroaniline produced.

Example 3
The procedure is as in Example 2 but in a water-methanol mixture (10-90 by volume) as solvent and with palladium on carbon containing 10% Pd as catalyst.

 100 ml of the ethanol mixture and 200 mg of catalyst are placed in the reactor.

 The reactor is pressurized to 4.105 Pa with hydrogen and heated to 60 ° C. The 3-chloro 2,4difluoronitrobenzene (0.18 mole) is dissolved in 70 ml of methanol and injected into the reactor in 150 min.

 The concentration of nitro derivative is less than 500 ppm throughout the duration of the hydrogenation.

The yield of 3-chloro 2,4-difluoroaniline (dosed by
CPG) is 88.5%. There are also 10.2 9G of 2,4-difluoroaniline resulting from the hydrodechlorination of the chloro 2,4-difluoroaniline produced.

 This example shows that palladium on carbon is a catalyst capable of catalyzing both the reduction of the nitro group and the substitution of the chlorine atoms by hydrogen.

 Analysis of the fluorides in the liquid medium and in the catalyst shows that the hydrodefluorination is less than 0.1% relative to the nitro derivative used.

Example 4
The procedure is as in Example 2 with different loads and conditions.

180 ml of a methanol-water mixture (in a volume ratio 66/34) and 300 mg of Raney nickel are placed in the reactor. The reactor is pressurized to 2.106 Pa with hydrogen and heated to 60
C. The pressure is then kept constant at 2.2.106 Pa.

 A solution of 0.155 mol of S chloro 2,4-difluoro nitrobenzene in 70 ml of methanol is injected over 270 min.

 The yield of 3-chloro 2,4-difluoroaniline is 87% and the yield of 2,4-difluoroaniline is 13%.

Comparative examples 1 to 3
The hydrogenation of 2,4-difluoro nitrobenzene chloro is carried out by placing all of the nitrated benzene compound in the reactor at the start of the reaction.

Comparative example 1
10 g of 95% pure chloro 2,4-difluoronitrobenzene (10% chloro 2,4-difluoronitrobenzene) 0.049 mol) in 38 ml of methanol, with 13 ml of chlorobenzene, 0.8 ml of water and 0.08 g of platinum carbon 5% platinum. Chlorobenzene is used to avoid dechlorination of 3-chloro 2,4-difluoronitrobenzene, by acting in competition with 3-chloro 2,4-difluoronitrobenzene with respect to this reaction.

 The autoclave is purged three times with nitrogen then three times with hydrogen.

 The temperature of the autoclave is brought to 35 ° C. and a hydrogen pressure of 4.2.1 os Pa is installed. The pressure is maintained at this value by continuously introducing hydrogen, while the temperature rises to 500 ° C. because of the exothermicity of the reaction. The reaction is completed in 45 minutes.

 After this period, it is verified that the conversion rate of the starting chloro 2,4difluoronitrobenzene is 100%. The rate of formation of 3-chloro 2,4-difluoroaniline, which is equal to 81%, is likewise measured, the rest of the transformation product being constituted by various products including nitrogen-containing halogenated benzene compounds with azo or azoxy functions, possibly having lost chlorine and fluorine. 3-chloro 2,4-difluoroaniline can be isolated by distillation, then subjected to salification in the form of the hydrochloride and further distillation. These purification operations, however, drop the yield to about 50%.

 The reaction rate was 0.83 mol.h'l.g- 'of catalyst.

Comparative example 2
3.7 g of 95% pure S chloro 2,4difluoronitrobenzene are placed in a shaking-stirred stainless steel autoclave equipped with a capacity for controlling the pressure in the auXbve and measuring the quantity of hydrogen consumed. (0.018 mol) in 100 ml of ethanol at 4% water, with 30 mg of palladium-on-carbon at 10% Pd.

 The temperature of the autoclave is brought to 35 ° C. and a hydrogen pressure of 1.105 Pa is installed. The pressure and the temperature are maintained for 400 minutes.

 After this heating period, it is verified that the conversion rate of the starting 3-chloro 2,4-difiuoronitrobenzene is 100%. The rate of formation of 3-chloro 2,4-difluoroaniline, which is 84%, is likewise measured, the rest of the transformation product consisting of the same products as in Comparative Example 1.

 The reaction rate was 0.1 to 0.2 mol.h-1.g-1 of catalyst.

Comparative example 3
Repeat the comparative example 2 with 90 mg of catalyst and 14.8 g of chloro 2,4-difluoronitrobenzene.

 The reaction time is 400 min. The conversion rate of the nitro derivative is 100%. The yield of 3-chloro 2,4difluoroaniline is 57%. The rest is always made up of the same by-products as in Comparative Examples 1 and 2.

Comparative example 4
In this comparative example, the hydrogenation is carried out by introducing 3-chloro 2,4difluoronitrobenzene gradually but without respecting the condition that the content of Schloro 2, difluoronitrobenzene in the reaction medium remains below 1000 ppm.

 In a 300 ml stainless steel reactor stirred at 1000 rpm, fitted with a pump for injection under pressure and with a capacity (reserve and pressure regulator) allowing to control the pressure in the reactor and to measure the quantity of 'hydrogen consumed, 0.20 g of palladium on carbon containing 10% Pd are placed in 90 ml of methanol and 10 ml of water.

 The reactor is purged three times with nitrogen then three times with hydrogen.

 The temperature of the reactor is brought to 60 ° C. and a hydrogen pressure of 3.105 Pa is installed. When these conditions are established, 50 ml of a solution of 39 g (0.2 mol) of 3-chloro 2,4-difluoronitrobenzene in methanol are injected at the rate of 28 ml / hr.

 The temperature and pressure conditions are kept constant throughout the injection.

 After the end of the introduction of 3-chloro 2,4-difluoro nitrobenzene, the hydrogenation conditions are maintained for one hour without observing any additional hydrogen uptake, thus indicating that the reaction is complete.

 A clear product is separated by simple distillation of the solvent.

 We measure the aniline formation rate which is 88%.

 The conversion rate of 3-chloro 2,4-difluoronitrobenzene is always 100%.

 Example 1, compared with Comparative Examples 1, 2 and 3, clearly demonstrates the remarkable improvement in the yield of the reducing hydrogenation reaction thanks to the injection of the starting product in a gradual manner while maintaining a concentration of nitro compound. less than 1000 ppm.

 Examples 5 to 8: Hydrodehalogenation of Schbro 2, e difluoroaniline to form 2,4difluoroaniline.

Example 5
1.64 g of 3-chloro 2,4-difluoroaniline of Example 1, 0.05 g of palladium-on-charcoal are charged into a 125 ml stirred bomb (autoclave) marketed by the company PROLABO, shaken by shaking. 10% Pd in 22 ml of methanol, with 11 ml of a 1 mol soda solution (0.011 mol).

 The closed autoclave is purged three times with nitrogen at a pressure of 3.105 Pa and then three times with hydrogen at a pressure of 3.105 Pa.

 The pressure in the autoclave is brought to 2.106 Pa of hydrogen and the temperature is raised to 90 ° C. in 25 minutes. These conditions are maintained for 3 hours.

 At the end of this time1 the transformation rate of 3chloro 2,4-difluoroaniline is determined by gas chromatography at 98%.

 The yield of 2,4difluoroaniline is 97.5%.

 The reaction rate was 0.065 mol.h1.g-1 of catalyst.

 The overall yield of Examples 1 and 2 for the preparation of 2,4difluoroaniline by catalytic hydrogenation from 3-chlom 2,4-difluoronitrobenzene is 97.1%.

Example 6
88 ml of methanol, 44 ml of water, 0.2 g of hydrogen are charged into a reactor stirred by a turbine ensuring under the reaction conditions a transfer of hydrogen gas / liquid such that the medium is always saturated with hydrogen. carbon palladium on 10% Pd and 0.04 mol of 3-chloro 2,4 difluoro aniline.

 A hydrogen pressure is installed in the reactor which is heated to 90 C. The hydrogen pressure is kept constant at 1.9 × 10 6 Pa absolute at 90 C.

 After a period of 3 hours, the transformation rate of chloro 2,4difluom aniline is 100% and the yield of 2, difluoroaniline is 99%. The rest of the transformation product (1%) consists of 4-fluoro aniline and traces of aniline.

 EXAMPLE 7 Example 6 is repeated at 125 ° C. under 2.16 Pa of hydrogen.

After 2 hours, the yield of 2,4-difluoroaniline is 99.2% and that of 4-fluoroaniline is 0.8%.

Example 8
44 ml of methanol, 22 ml of water, 0.1 g of Raney nickel, 0.022 mole of sodium hydroxide and 0.02 mole of 3-chloro are charged into the same reactor as that of Example 6 2,4-difluoroaniline.

 It is heated to 900 C under hydrogen pressure which is kept constant at 7.5 × 105 Pa absolute at 90 C.

 The final transformation rate of 3-chloro 2,4-difluoro aniline is 75.5%. The yield of 2,4-difluoroaniline is 80% relative to the transformation product and there is 20% aniline.

 Raney nickel is not very effective in carrying out the hydrodechlorination reaction and furthermore significantly catalyzes the hydrodé fluorination of 2,4difluoroaniline under these conditions.

Example 9
Hydrogenation of 3-chloro 2,4-difluoronitrobenzene to 2,4difluoroaniline in a single reactor linking the reduction and then hydrodechlorination reactions.

 160 ml of methanol and 30 ml of water are loaded into the reactor described in example 1, as well as 0.2 g of 10% Pd palladium-on-carbon. A solution of 0.207 mol of 3-chloro 2,4-difluoro nitrobenzene in 100 ml of methanol is injected over 5 hours. The reactor is pressurized at 2.106 Pa kept constant and its temperature is 60 ° C. The hydrogF nation being finished at the end of this period, 0.22 mol of sodium hydroxide is added in the form of a concentrated aqueous solution and the mixture is heated to 120 ° C. maintaining the pressure at 2.106 Pa of hydrogen.

 After 5 hours of reaction, it is measured by gas chromatography that the level of 3-chioro 2,4-difluoro nitrobenzene engaged and the level of 2,4-difluoro aniline is 95% compared to 3chloro 2,4- difluoro nitrobenzene used. 2,4-difluoro aniline can easily be isolated from the reaction medium by distillation.

Claims (21)

 1. Process for the preparation of a compound containing an aniline substituted by one or more halogen atoms of which at least one is a fluorine atom, in particular a fluoroaniline, comprising a step in which a catalytic hydrogenation is subjected to a compound containing a nitrobenzene substituted by one or more halogen atoms, at least one of which is a fluorine atom, in particular a chlorofluoronitrobenzene, so as to reduce the nitro group to the amino group by substituting with hydrogen atoms the atoms halogen other than fluorine atoms, step in which said nitrated benzene compound is introduced progressively into a chamber under hydrogen pressure containing a hydrogenation catalyst in a liquid medium so that the content of compound containing nitro function in the hydrogenation medium remains less than or equal to 1000 ppm (by mass).  2. Method according to claim 1 for the preparation of difluoroaniline by catalytic hydrogenation of chloro-difluoronitrobenzene or dichloro-difluoro-nitrobenzene.  3. Method according to claim 1 or 2, for the preparation of 2,4 - :: lifluoroaniline by catalytic hydrogenation of 3-chioro 2, difluoronitrobenzene or 5-chloro 2,4difluornnitrobenzene.  4. Method according to claim 1 or 2, for the preparation of 3,5-difluoroaniline by catalytic hydrogenation of 2,4-dichlorr> 3,5-difluoron itrobenzene or 2,6-dichloro 3,5-difluoronitrobenzene.  5. Method according to one of claims 1 to 4, wherein said benzene compound with nitro function is gradually introduced into said enclosure so that the content of nitrated benzene compound in the hydrogenation medium remains less than 500 ppm.  6. Method according to one of claims 1 to 5, wherein said benzene compound with nitro function is gradually introduced into said enclosure so that the content of nitric benzene compound in the hydrogenation medium remains in the range of 200 to 500 ppm.  7. Method according to one of claims 1 to 6, wherein said catalytic hydrogenation is carried out in a polar solvent, which may be protic or aprotic.  8. Method according to one of claims 1 to 7, wherein said catalytic hydrogenation with progressive introduction of nitro benzene compound is carried out at a temperature of 0 to 100 C, preferably from 50 to 80 C.  9. Method according to one of claims 1 to 8, wherein said catalytic hydrogenation with progressive introduction of nitrated benzene compound is carried out under a partial hydrogen pressure of 105 to 2.106 Pa.  10. Method according to one of claims 1 to 9, wherein said catalytic hydrogenation is carried out in the presence of a base, in particular an alkaline base.  11. Method according to one of claims 1 to 9, in which, after the end of the progressive introduction of the nitrated benzene compound, the hydrogenation is continued in the presence of a base, in particular an alkaline base.  12. Method according to one of claims 10 or 11, wherein the concentration of said base in the reaction medium is less than or equal to 1 ml / l, preferably 0.5 mol / l.  13. Method according to one of claims 1 to 12, wherein the hydrogenation is continued after the end of the progressive introduction of the nitro benzene compound, at a temperature of 80 to 150- C.  14. Method according to one of claims 1 to 13, wherein the hydrogenation is continued after the end of the gradual introduction of the nitric benzene compound, under a partial pressure of hydrogen from 1.5.106 to 5.106 Pa.  15. Process for the preparation of 2,4-difluoroaniline by catalytic hydrogenation according to one of claims 1 to 14 of 3-chloro 2,4difluoronitrobenzene, respectively of 5-chloro 2,4-difluoronitobenzene, obtained by reaction of 2, 3,4-trichloronitrobenzene, respectively 2,4,5-trichloronitrobenzene, with an alkaline fluoride, in particular potassium fluoride in a polar aprotic solvent.  16. The method of claim 15, wherein 2,3,4trichloronitrobenzene, respectively 2,4,5-trichloronitrobenzene, is obtained by reaction of 1,2,3-trichlorobenzene, respectively 1,2,4trichlorobenzene, with a reagent for nitration of aromatic compounds1 in particular with nitric acid.  17. Process for the preparation of 3,5-difluoroaniline by catalytic hydrogenation according to one of claims 1 to 14 of 2,4 dichloro 3,5-: lifluoronitrobenzene, respectively of 2,6-dichloro 3,5difluoronitrobenzene, obtained by reaction of 2-amino 4-chloro 3,5 difluoronitrobenzene, respectively of 2-amino 6chloro 3,5 - :: litiuoronitrobenzene, with cuprous chloride in the presence of nitrous acid.  18. The method of claim 17, wherein the 2amino 4-chloro 3,5-difluoronitrobenzene, respectively 2-amino 6 chloro 3,5-difluoronitrobenzene, is obtained by reaction of 3-chloro 2,4difluoroaniline, respectively of Schloro 2 , 4-difluoroaniline, with a reagent for the nitration of aromatic compounds, in particular with nitric acid.  19. A process for the preparation of 3,5-difluoro aniline by catalytic hydrogenation according to one of claims 1 to 14 of 2,6 dichloro 3,5-difluoro nitrobenzene, of 2,4,6-trichIoro 3,5difluoro nitrobenzene, respectively, obtained by reaction of 1,3-dichloro 4,6-difluoro benzene, respectively of 1,3,5-trichloro 2,4-difluoro benzene, with a reagent for the nitration of aromatic compounds, in particular with nitric acid.  20. The method of claim 19, wherein 1,3-dichloro 4,6-difluoro benzene, respectively 1,3,5-trichloro 2,4-difluorobenzene, is obtained by reaction of 5-chioro 2,4- difluoroaniline, respectively 3,5-dichloro 2,4difluoroaniline, with cuprous chloride in the presence of nitrous acid.  21. The method of claim 18 or 20, wherein the chloro 2,4-difluoroaniline, respectively 5-chloro 2,4-difluoroaniline, respectively 3,5-dichloro 2,4-difluoroaniline, is obtained by hydrogenation of 3-chloro 2,4-difluoronitrobenzene, respectively of 5 chloro 2,4-difluoronitrobenzene, respectively of 3,5-dichloro 2,4 difluoro nitrobenzene, in particular according to a process according to any one of claims 1 and 5 to 9.