Process for the Production of Substituted Aromatic Hydrocarbons

Europaisches Patentamt (19) European Patent Office Office europeenpeen des brevets EP 0 663 379 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) intci.6: C07C 17/35, C07C 25/13 of the grant of the patent: 23.12.1998 Bulletin 1998/52

(21) Application number: 95300226.8

(22) Date of filing: 13.01.1995

(54) Process for the production of substituted aromatic hydrocarbons from corresponding anilines by dediazoniation Verfahren zur Herstellung von substituierten aromatischen Kohlenwasserstoffen durch Dediazonierung der ubereinstimmenden Anilinen Procede pour la production d'hydrocarbures aromatiques substitues par dediazonisation des anilines correspondantes

(84) Designated Contracting States: (74) Representative: AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL Ellis-Jones, Patrick George Armine et al PT SE J.A. KEMP & CO. 14 South Square (30) Priority: 13.01.1994 GB 9400569 Gray's Inn London WC1R 5LX (GB) (43) Date of publication of application: 19.07.1995 Bulletin 1995/29 (56) References cited: WO-A-93/19026 (73) Proprietor: RHODIA LIMITED Watford, Herts WD1 1QM (GB) • CHEMICAL ABSTRACTS, vol. 115, no. 15, 14 October 1991, Columbus, Ohio, US; abstract no. (72) Inventors: 158599, K AKIN AMI T ET AL 'Indirect synthesis • Mercier, Claude of bromo-substituted aromatic compounds' & Sneyd Park, Bristol BS9 1 RU (GB) UBE KOGYO KOTO SENMON GAKKO KENKYU • Scott, Graham Vaughan HOKOKU (UKKHDQ,03864359);91; VOL.37,; Chew-Magna, Avon BS18 8SX (GB) PP.43-7, UBE TECH. COLL.;UBE; JAPAN (JP) • PATENT ABSTRACTS OF JAPAN vol. 015, no. 163 (C-0826) 24 April 1991 & JP-A-03 034 944 (TOOKEMU PROD:KK) 14 February 1991

DO O) Is- CO CO CO CO Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice the Patent Office of the Notice of shall be filed in o to European opposition to European patent granted. opposition a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. a. 99(1) European Patent Convention). LU

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Description

This invention relates to the production of aromatic hydrocarbons. It is well known to replace aromatic primary amino groups by hydrogen by converting the amino group into a 5 corresponding diazonium salt group and then reducing the latter. For this purpose a number of reducing agents have been used, including hypophosphorous acid (H3P02) and primary alcohols. A metallic catalyst, e.g. copper or one of its salts, is usually included in the reaction mixture to promote the reduction. 1 ,3-Difluorobenzene is an important intermediate in the preparation of antifungal agents, and it has often been prepared from 2,4-difluoroaniline by diazotisation followed by reducing dediazoniation. Japanese Patent Application 10 91/34944 (Tokemu Product K.K., Chemical Abstracts 115: 28858c) describes the production of 1 ,3-difluorobenzene by diazotization of 2,4-difluoroaniline and reductive dediazoniation with hypophosphorous acid in the presence of more than 2 moles of acid (3 moles in the Examples). In another process, the reduction has been effected with isopropanol in the presence of a copper catalyst. Chemical Abstracts 1991 , 115 (15), 158599e describes reacting bromobenzamine derivatives with NaN02/H2S04 is in water and 30% phosphinic acid. These processes have significant disadvantages in practical use. Diazonium salts are unstable and can decompose violently in the solid or concentrated form. The handling of diazonium salts in substantial quantities on an industrial scale requires special precautions to prevent accident. Moreover, the known processes produce significant quantities of effluent which requires treatment (e.g. to reduce its copper content) before it can be discharged. There is therefore a need for a process which can be operated easily on an industrial scale with 20 reduced risk and reduced quantities of effluent. We have now devised a process in which the diazotization of substituted aromatic primary amines is carried out in the presence of hypophosphorous acid and a suitable metal catalyst so that the diazonium salt group formed is immediately replaced by hydrogen. The reaction mixture thus never contains any substantial quantity of diazonium salt. Moreover, reduced quantities of reagents, especially catalyst and mineral acid, are used, and this very considerably 25 simplifies the handling of the effluents produced by the process, and its volumic productivity is increased. An improved method for the isolation of the substituted aromatic hydrocarbon has also been devised which makes it possible to obtain a product of high purity in a very simple way. The process of the present invention for the production of a substituted aromatic hydrocarbon from a corresponding substituted aromatic primary amine comprises converting the said amine into a corresponding diazonium salt in the 30 presence of hypophosphorous acid or a hypophosphite salt and, optionally, a strong acid (i.e. an acid having a pKa less than or equal to O) in an amount not greater than that required to convert the amine into an acid addition salt thereof and to convert a said hypophosphite salt (if used) into hypophosphorous acid, and a metal catalyst that promotes reduction of the diazonium salt, e.g. a copper or iron catalyst (so that the diazonium group is replaced by hydrogen as it is formed). 35 The new process is especially useful for the production of substituted aromatic hydrocarbons such as the 1 ,3-difluorobenzene already mentioned. Thus, in its preferred operation, the new process involves the conversion of a starting material of formula:

40 NH2

(Hal). 45

where R is alkyl, alkoxy or alkylthio each of which has up to 4 carbon atoms and is unsubstituted or substituted by halogen, e.g. methyl, trifluoromethyl, trifluoromethoxy, or trifluoromethylthio, Hal is fluorine, chlorine or bromine, m is so 0 to 4, and n is 1 to 5, the Hal radicals being the same or different when n is 2 to 5, and the sum of m and n being 1 to 5, into a product of the formula:

(Hal)n

2 EP 0 663 379 B1

where Hal, m and n are as hereinbefore defined. The diazotisation of the aromatic amine is carried out with reagents of known kind. Thus the amine, in the presence of a suitable strong mineral acid, preferably an oxygen-containing acid such as sulphuric acid, may be treated with an alkali metal nitrite, e.g. sodium nitrite. Since, in the process of the invention, the diazotisation is carried out in the 5 presence of hypophosphorous acid (H3P02), the latter may be used to convert the alkali metal nitrite into nitrous acid. The reduction of the diazonium salt to replace the diazonium group by hydrogen requires 1 mole of hypophosphorous acid per mole of starting amine (i.e. per amino group to be replaced by hydrogen). In principle, therefore, 1 mole of hypophosphorous acid per mole of starting amine can be used both to convert the required amount of alkali metal nitrite into nitrous acid, and to reduce the diazonium group. However, in practice, a moderate excess of acid (preferably 10 not more than 1 .33 mole per amino group to be replaced) should be used. If hypophosphorous acid is used as the sole mineral acid, 1 to 2 moles per mole of starting amine are used, while if a strong mineral acid is also included in the reaction mixture, then the proportion of hypophosphorous acid may be reduced, but not below 1 molar proportion per amino group to be replaced, and the amount of the strong acid may be 0 to 1 equivalent per mole of starting amine. It is to be noted in this connection that sulphuric acid behaves in the context of the present invention as a monobasic is acid as its second dissociation constant is not that of a strong acid as defined above. If the hypophosphorous acid is introduced in the form of a salt, e.g. NaH2P02, 1 equivalent of strong mineral acid is required to convert this salt into hypophosphorous acid, and one equivalent of the strong acid is also required to convert the alkali metal nitrite into nitrous acid. In no case are more than 2 equivalents of total acids used per mole of amine. 20 The reaction may be operated at a temperature in the range of 10 to 80°C. At temperatures below about 10°C, the reaction proceeds only slowly even in the presence of the catalyst. At above 80°C, the reaction may be difficult to control. A preferred temperature range is 20 to 50°C. A metal catalyst based on, for example, iron or preferably copper is included in the reaction mixture. The proportion of copper catalyst required is only 0.001 to 0.1 moles of copper, preferably about 0.005 moles, per mole of the aromatic amine starting material. The copper catalyst is conveniently 25 added in the form of a cupric salt, e.g. cupric sulphate, but can, if desired, be added in other forms, e.g. as cuprous oxide (Cu20) or even finely divided metallic copper. The reaction is preferably operated by forming a reaction mixture comprising aqueous hypophosphorous acid (as such or as a salt), e.g. in a proportion of 1 .00 to 1 .3 moles per mole of the amine to be used, and sulphuric acid in a proportion of 0.25 to 0.5 moles per mole of amine (plus any amount required to convert a salt of hypophosphorous 30 acid into the free acid). To this mixture, the copper catalyst, e.g. cupric sulphate, is added in a proportion of 0.002 to 0.01 moles per mole of amine. The total amount of water included in the mixture should be enough for a readily stirrable reaction mixture to be obtained, but is preferably not much greater than this. It may be, more particularly, about 30 to 50% of the total weight of the acids used. Typically 100 to 400 g, preferably 150 to 300 g, of water are used per mole of amine starting material. This mixture is adjusted to the required temperature, e.g. 25°C. 35 The aromatic primary amine starting material, e.g. 2,4-difluoroaniline, preferably as the free base, but if desired as a salt (preferably with a strong mineral acid), and the sodium nitrite, as a concentrated aqueous solution (containing e.g. 30 to 70% by weight of the nitrite), in an amount from 1 to 1.1 moles per mole of the amine, are then added alternately in portions not exceeding 50%, preferably 10% to 33%, by weight of the whole. Continuous simultaneous addition of the solutions is also possible the rates being adjusted so that a small excess of the amine (relative to the 40 nitrite) is maintained in the reaction mixture. In the reaction mixture the amine is present in the form of a salt having only limited solubility, and the concentration of the amine is preferably as high as possible consistent with obtaining a stirrable reaction mixture. The rate of mixing of the solutions is adjusted-so that there is no build up of diazonium salt in the reaction mixture and substantially immediate reduction of the diazonium salt promoted by the presence of the catalyst. Desirably, the 45 detectable concentration of diazonium salt in the reaction mixture is maintained below about 0.05 moles per litre, and preferably at 0.001-0.005 moles per litre. The mixture obtained after the reaction consists of an organic phase containing the desired substituted aromatic hydrocarbon which is substantially insoluble in water, and an aqueous phase containing the residues of the acids and inorganic compounds used. If desired, and if its boiling point permits it, the substituted aromatic hydrocarbon product so may be distilled from the reaction mixture as it is formed. According to a feature of the invention, the reaction product is conveniently worked up by adding thereto a water- immiscible aliphatic alcohol having a boiling point above 150°C, e.g. 2-ethyl-1-hexanol (b.p. 183°C), preferably after the non-aqueous phase (containing most of the desired product) has been separated. The water-immiscible phase containing the desired substituted aromatic hydrocarbon and the alcohol is then separated from the aqueous residue 55 of the reaction medium and optionally washed to remove residual acid. This organic phase (which may then be recom- bined with the non-aqueous phase from the reaction mixture) is then fractionally distilled in the presence of a small amount of water. The substituted aromatic hydrocarbon forms an azeotrope with water and this azeotrope is collected. Since the substituted aromatic hydrocarbon is substantially insoluble in water, the azeotrope separates into two phases,

3 EP 0 663 379 B1

and of these the organic phase is the desired product in substantially pure form. It may if desired, be dried and redistilled before use. The aliphatic alcohol can be recovered from the distillation residue and reused. When the process is operated in glass vessels, a hydrofluoric acid trap such as boric acid may be included in the 5 reaction mixture to trap fluoride ions and prevent corrosion of the apparatus. The following Examples illustrate the invention. The stated molar proportions are in relation to the amine starting material.

EXAMPLES 10 Example 1 (0.875 mole DFA with 1 molar proportion H3P02 + 0.5 molar proportion H2S04.)

Into a 500 ml flask fitted with an addition funnel, thermometer, mechanical stirrer and a 4' column fractionation apparatus fitted on top with a gas counter, hypophosphorous acid (50% w/w aqueous, 115.2g, 1 .0 molar proportion), is copper sulphate pentahydrate (1 .12g, 0.005 molar proportion) and boric acid (0.54g, 0.001 molar proportions) were introduced. To the pale blue solution at 25°C, 77% H2S04 (56g, 0.5 molar proportion) was added. The reaction was moderately exothermic. The temperature was maintained <50°C with ice cooling. 1/3 of the 2,4-difluoroaniline (total weight 2,4 DFA= 113g = 87 ml, i.e. 1/3 = ~ 29ml.) was added dropwise, while maintaining vigorous stirring at temperature < 30°C. A mobile slurry was obtained. To the mixture, at 20-30°C, a solution of one third of the total amount of 20 sodium nitrite [total required is: 63g NaN02, i.e. 1.05 molar proportion, in 105 g of water, for 125 ml total volume, so 1/3 portion is ~ 40 ml.] was added, while maintaining vigorous stirring and a temperature between 20-30°C (ice bath). Typical addition time was ~ 30 mn. Nitrogen was evolved immediately (and measured with a gas counter). At the end of the addition of the first portion of sodium nitrite, the reaction mixture was kept for a few minutes until the end of gas evolution and the second portion of 2,4-difluoroaniline was then added followed by the second part of the sodium nitrite 25 solution. Finally the last portions of the 2,4-DFA and the sodium nitrite were added. At the end of the addition, the top organic phase (brown) was separated from the bottom aqueous layer. The aqueous layer was extracted with 2 x 1 0 ml of 2-ethyl-1 -hexanol (d=0.8). All the organic phases (1 07. 1 g) were combined and washed with a 10% ammonium chloride solution until neutral. After atmospheric pressure distillation (b.p. of 1 ,3-difluorobenzene azeotrope with water = 72°C/760 mmHg) and decantation to separate the aqueous phase from 1 ,3-DFB, 30 81 .9g of pure 1 ,3 DFB (purity S 99.8% by GC) were obtained, i.e. a yield of 82%.

Example 2: (1 .2 molar proportion H3P02 + 0.5 molar proportion H2S04)

The reaction was carried out as in Example 1 but using 1.2 molar proportion H3P02 (138.25g, 50% aqueous 35 solution). After addition in 3 portions of the DFA and the sodium nitrite, the decantation/extraction gave 1 07. 5g of crude organics. After azeotropic distillation 82. 3g of colourless pure 1 ,3-DFB (99.8% by GC) were obtained, (yield ~ 82.5%).

Example 3: (0.4 molar proportion NaH2P02 + 0.6 molar proportion H3P02 + 1 .0 molar proportion H2S04)

40 The reaction was carried out as in Example 1 but with partial in situ generation of H3P02 (from NaH2P02 and H2S04). After addition in 3 portions of the 2,4-DFA and the sodium nitrite solutions, 21.1 I of gas evolved. The decantation/extraction gave 101 .1g of crude organics. After azeotropic distillation, 75.1gof pure 1 ,3-DFB were obtained (yield ~ 75.2%).

45 Example 4: (1 .0 molar proportion NaH2P02 + 1 .5 molar proportion H2S04)

The reaction was carried out as in Example 1 but with total in situ generation of H3P02. After addition of the starting materials in 3 portions, 20.4 1 of gas evolved. The decantation/extraction gave 104.4g of crude organics. After azeotropic distillation, 70. 2g of pure 1,3-DFB were obtained. (Yield ~ 70.4%). 50 Example 5:

The reaction was carried out as in Example 1 but with a reaction temperature of 50°C + 5°C. 21 .9 L of gas were evolved in 1 hour 30 minutes. The decantation/extraction gave 104.95 g of crude organics. After azeotropic distillation, 55 74.3 g of colourless 1 ,3-DFB (74.5% yield) were obtained.

4 EP 0 663 379 B1

Comparative Example

2,4 Difluoroaniline sulfate was prepared by mixing 62.6 g (2.5 molar proportions) of 98% sulphuric acid with 32.3 g (0.25 mole) of 2,4-difluoroaniline in a three neck flask. 66 g (2.0 molar proportions) of 50% H3P02 aqueous solution 5 were added and the slurry was allowed to warm to 50°C + 5°C. Then 18.3 g (1.1 molar proportion) of sodium nitrite dissolved into 30 g of water were added drop by drop, while the temperature was kept at 50°C + 5°C. After 1 hour 30 minutes for the complete addition, only 3.2 liter of gas had been evolved (Theory [~ 6.3 I). The reaction mixture was worked up as in Example 1 (decantation, extraction, distillation). Only 7.7 g of 1 ,3-difluorobenzene (yield = 27%) were obtained. 10 Example 6

The reaction was carried out as in Example 1 but using different anilines as starting materials. The Table below summarises the yields obtained after isolation by decantation, extraction and distillation : (not optimised). 15 Substrate Product Yield (isolated - Pure) Bromo-6-difluoro-2,4-aniline Bromo-1-difluoro-3,5-benzene 72% m.Trifluoromethylaniline Trifluoromethyl benzene 79% 4-Chloro-2-fluoroaniline 3-Chlorofluorobenzene 81% 2,6-Difluoroaniline 1 ,3-Difluorobenzene 77% 2,4-Difluoroaniline (80%) + 2,6-Difluoroaniline (20%) 1 ,3-Difluorobenzene 78% Trifluoro-2,3,4-aniline Trifluoro-1 ,2,3-benzene 82% Pentafluoroaniline Pentafluorobenzene 83% p.Trifluoromethoxy aniline Trifluoromethoxy benzene 70% 2-Fluoro-5-methyl aniline 4-Fluorotoluene 84%

Example 7: (Industrial production)

In a 1.3 m3 glass lined reactor under nitrogen, 335 kg 50% H3P02 and 160.5 kg H2S04 (77%) were charged on a mixture containing 104 kg of a 2% w/w boric acid aqueous solution and 22.5 kg of a 15% w/w copper sulphate aqueous solution. 324 kg of 2,4-difluoroaniline was added (in 3 steps) alternatively with 487 kg of 40% w/w sodium nitrite aqueous solution at a temperature controlled to be 25-30°C whilst controlling instantaneous decomposition of the diazonium salt by nitrogen evolution. At the end of the nitrite addition (63 kg of nitrogen evolved), decantation and extraction of the aqueous phase by 30 kg of ethyl hexanol gave 352 kg of crude 1 ,3DFB. The aqueous phase (1040 kg) contained only 0.6 kg of 1 ,3DF (GC analysis). Distillation at atmosphere pressure of the crudes gave a 82.3% yield on grade 1 ,3DFB. (99.8% Purity by GC - 500 ppm water).

Claims

1. Process for the production of a substituted aromatic hydrocarbon from a corresponding substituted aromatic primary amine which comprises converting the said amine into a corresponding diazonium salt in the presence of hypophosphorous acid or a hypophosphite salt and, optionally, an acid having a PKa less than or equal to 0, in an amount not greater than that required to convert the amine into an acid addition salt thereof and to convert a said hypophosphite salt (if used) into hypophosphorous acid, and a metal catalyst that promotes reduction of the diazonium salt.

2. Process according to claim 1 wherein the starting material has the formula:

5 EP 0 663 379 B1

NH2

(R) m (Hal)„

where R is alkyl, alkoxy or alkylthio, each of which has up to 4 carbon atoms and is unsubstituted or substituted by halogen, Hal is fluorine, chlorine or bromine, m is 0 to 4 and n is 1 to 5, the Hal radicals being the same or different when n is 2 to 5, and the sum of m and n being 1 to 5 and the product has the formula:

where R, Hal, m and n, are as hereinbefore defined.

3. Process according to claim 2 wherein the aromatic amine starting material is 2,4-difluoroaniline.

4. Process according to any one of claims 1 to 3 wherein the said amine is converted into a corresponding diazonium salt by reaction in aqueous medium with a source of nitrite ion in the presence of hypophosphorous acid and optionally a mineral acid having a PKa less than or equal to 0.

5. Process according to claim 4 wherein the said amine is reacted with an alkali metal nitrite in substantially equimolar amount in the presence of 1 to 2 molar proportions of hypophosphorous acid and 0 to 2 equivalents of the mineral acid, the total proportion of acid being not more than 2 equivalents per mole of said amine.

6. Process according to claim 4 or 5, wherein the said mineral acid is sulphuric acid.

7. Process according to claim 4, 5 or 6 wherein the amine and the nitrite are added either alternately to the reaction mixture in portions each of which constitutes 1 0 to 33% by weight of the whole or simultaneously and continuously in proportions such that a small excess of the amine is maintained in the reaction mixture.

8. Process according to any one of claims 1 to 7 wherein the metal catalyst is a copper catalyst.

9. Process according to claim 8 wherein the proportion of the catalyst is 0.001 to 0.1 moles of copper per mole of the aromatic amine.

10. Process according to any one of claims 1 to 9 wherein the reaction is performed at 10° to 80°C.

11. Process according to claim 10 wherein the reaction is performed at 20° to 50°C.

12. Process according to anyone of claims 1 to 11 wherein the substituted aromatic hydrocarbon product is separated from the reaction mixture by (i) extracting the aqueous phase of the reaction mixture with a water-immiscible aliphatic alcohol having a boiling point above 1 50°C, (ii) separating the extract obtained and, if desired, combining it with the previously separated water-immiscible phase of the reaction mixture, (iii) fractionally distilling the separated water-immiscible phase obtained in the presence of a small amount of water and collecting a fraction comprising an azeotropic mixture of water and the desired substituted aromatic hydrocarbon, and (iv) separating the substituted aromatic hydrocarbon from the said azeotropic mixture.

13. Process according to claim 12 wherein the said alcohol is 2-ethyl-1-hexanol. EP 0 663 379 B1

Patentanspriiche

1. Verfahren zur Herstellung eines substituierten aromatischen Kohlenwasserstoffs ausgehend von einem entsprechenden substituierten, aromatischen primaren Amin, wobei man das Amin in Gegenwart hypophosphoriger Saure 5 oder eines Hypophosphitsalzes und gegebenenfalls einer Saure mit einem pka-wert von 0 oder weniger in einer Menge, die nicht groBer ist als die Menge, die benotigt wird, urn das Amin in sein Saureadditionssalz zu uberfuhren und das Hypophosphitsalz (falls verwendet) zu hypophosphoriger Saure umzusetzen, und in Gegenwart eines Metallkatalysators, derdie Reduktion des Diazoniumsalzes begunstigt, zu einem entsprechenden Diazoniumsalz umsetzt. 10 2. Verfahren nach Anspruch 1 , wobei das Ausgangsmaterial die Formel

20 aufweist, in der R eine Alkyl-, Alkoxy- oder Alkylthiogruppe darstellt, die jeweils bis zu 4 Kohlenstoffatome aufweist und gegebenenfalls mit einem Halogen substituiert ist; Hal Fluor, Chlor oder Brom darstellt; m 0 bis 4 betragt; und n 1 bis 5 ist, wobei die Halogenreste Hal identisch oder verschieden sind, wenn n 2 bis 5 betragt, die Summe aus m und n 1 bis 5 betragt und das Produkt die folgende Formel aufweist:

30 wobei R, Hal, m und n die zuvor angegebene Bedeutung haben.

3. Verfahren nach Anspruch 2, wobei das aromatische Aminausgangsmaterial 2,4-Difluoranilin ist.

35 4. Verfahren nach einem der Anspruche 1 bis 3, wobei das Amin durch Reaktion in waBrigem Medium mit einer Nitritionenquelle in Gegenwart von hypophosphoriger Saure und gegebenenfalls einer Mineralsaure (anorgani- schen Saure) mit einem pKa-Wert von 0 oder weniger zu einem entsprechenden Diazoniumsalz umgesetzt wird.

5. Verfahren nach Anspruch 4, wobei man das Amin mit einem Alkalimetallnitrit in im wesentlichen aquimolarer Menge 40 in Gegenwart der 1- bis 2fachen molaren Menge hypophosphoriger Saure und 0 bis 2 Aquivalenten der Mineral- saure reagieren Ial3t, wobei die Gesamtmenge an Saure nicht mehr als 2 Aquivalente pro Mol Amin betragt.

6. Verfahren nach Anspruch 4 oder 5, wobei die Mineralsaure Schwefelsaure ist.

45 7. Verfahren nach Anspruch 4, 5 oder 6, wobei das Amin und das Nitrat entweder abwechselnd zu dem Reaktions- gemisch zugegeben werden, wobei die jeweiligen Zugabemengen 10 bis 33 Gew.-% des Gesamtgemisches dar- stellen, oder gleichzeitig und kontinuierlich in solchen Mengen, dal3 ein geringfugiger UberschuB an Amin in der Reaktionsmischung beibehalten wird. so 8. Verfahren nach einem der Anspruche 1 bis 7, wobei der Metallkatalysator ein Kupferkatalysator ist.

9. Verfahren nach Anspruch 8, wobei die Menge an Katalysator 0.001 bis 0. 1 mol Kupfer pro Mol aromatisches Amin betragt.

55 10. Verfahren nach einem der Anspruche 1 bis 9, wobei die Reaktion bei Temperaturen von 10 °C bis 80 °C durchgefuhrt wird.

11. Verfahren nach Anspruch 10, wobei die Reaktion bei Temperaturen von 20 °C bis 50 °C durchgefuhrt wird.

7 EP 0 663 379 B1

!. Verfahren nach einem der Anspruche bis 11 , wobei das substituierte aromatische Kohlenwasserstoffprodukt von der Reaktionsmischung abgetrennt wird durch (i) Extraktion der waBrigen Phase der Reaktionsmischung mit einem nicht wassermischbaren aliphatischen Alkohol mit einem Siedepunkt oberhalb von 150°C, (ii) Abtrennung des erhaltenen Extraktes und gegebenenfalls Vereinigen mit der zuvor abgetrennten, nicht wassermischbaren Phase der Reaktionsmischung, (iii) f raktionierte Destination der erhaltenen, abgetrennten, nicht wassermischbaren Phase in Gegenwart einer geringfugigen Menge Wasser und Auffangen einer Fraktion, die eine azeotrope Mischung aus Wasser und dem gewunschten, substituierten aromatischen Kohlenwasserstoff umfaBt, und (iv) Abtrennung des substituierten aromatischen Kohlenwasserstoffs von der azeotropen Mischung.

i. Verfahren nach Anspruch 12, wobei der Alkohol 2-Ethyl-1-hexanol ist.

15 1. Procede pour la production d'un hydrocarbure aromatique substitue, a partir d'une amine aromatique primaire substitute correspondante, qui comporte I'etape consistant a convertir ladite amine en un sel diazonium corres- pondent en presence d'acide hypophosphoreux ou d'un sel hyposphosphite et facultativement d'un acide presentant un pKa, inferieur ou egal a 0, en quantite non superieure a celle requise pour convertir I'amine en un sel d'addition d'acide de celle-ci, et pour convertir en acide hypophosphoreux ledit sel hypophosphite eventuellement 20 utilise, et d'un catalyseur metallique qui favorise la reduction du sel diazonium.

2. Procede selon la revendication 1 , dans lequel le materiau de depart presente la formule:

dans laquelle R est un alkyle, un alcoxy ou un alkylthio, dont chacun compte jusqu'a 4 atomes de carbone et est non substitue ou substitue par un halogene, Hal est le fluor, le chlore ou le brome, m est de 0 a 4 et n est de 1 a 35 5, les radicaux Hal etant identiques ou differents lorsque n vaut 2 a 5, et la somme de m et n est de 1 a 5 et le produit presente la formule:

45 dans laquelle R, Hal, m et n sont comme definis plus haut.

3. Procede selon la revendication 2, dans lequel le materiau de depart amine aromatique est la 2,4-difluoroaniline.

4. Procede selon I'une quelconque des revendications 1 a 3, dans lequel ladite amine est convertie en un sel diazo- 50 nium correspondant par reaction en milieu aqueux avec une source d'ion nitrite en presence d'acide hypophosphoreux et facultativement d'un acide mineral presentant un pKa inferieur ou egal a 0.

5. Procede selon la revendication 4, dans lequel on fait reagir ladite amine avec un nitrite de metal alcalin en quantite essentiellement equimolaire en presence de 1 a 2 proportions molaires d'acide hypophosphoreux et de 0 a 2 55 equivalents de I'acide mineral, la proportion totale d'acide n'etant pas superieure a 2 equivalents par mole de ladite amine.

6. Procede selon les revendications 4 ou 5, dans lequel ledit acide mineral est I'acide sulfurique.

8 EP 0 663 379 B1

7. Procede selon les revendications 4, 5 ou 6, dans lequel I'amine et le nitrite sont ajoutes au melange de reaction soit en alternance, par portions qui constituent chacune de 10 a 33% en poids de la totalite, soit simultanement et en continu, en proportions telles qu'un petit exces de I'amine soit maintenu dans le melange de reaction.

8. Procede selon I'une quelconque des revendications 1 a 7, dans lequel le catalyseur metallique est un catalyseur de cuivre.

9. Procede selon la revendication 8, dans lequel la proportion du catalyseur est de 0,001 a 0,1 mole de cuivre par mole de I'amine aromatique.

10. Procede selon I'une quelconque des revendications 1 a 9, dans lequel la reaction est conduite entre 10° et 80° C.

11. Procede selon la revendication 10, dans lequel la reaction est conduite entre 20° et 50° C.

12. Procede selon I'une quelconque des revendications 1 a 11 , dans lequel le produit hydrocarbure aromatique substitue est separe du melange de reaction, (i) en extrayant la phase aqueuse du melange de reaction avec un alcool aliphatique non miscible avec I'eau et presentant un point d'ebullition superieur a 150° C, (ii) en separant I'extrait obtenu et, si on le souhaite, en le combinant avec la phase du melange de reaction, non miscible avec I'eau et precedemment separee, (iii) par distillation fractionnee de la phase non miscible avec I'eau, obtenue en presence d'une petite quantite d'eau et par collecte d'une fraction comportant un melange azeotropique d'eau et de I'hydrocarbure aromatique substitue recherche, et (iv) par separation de I'hydrocarbure aromatique substitue dudit melange azeotropique.

13. Procede selon la revendication 12, dans lequel ledit alcool est le 2-ethyl-1-hexanol.