SK17972002A3 - Method for producing 4-bromine-aniline derivatives - Google Patents

Abstract

The invention relates to a method for producing 4-bromine-aniline derivatives of formula (I), wherein the substituents have the following meanings: R<1>: C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogen-alkoxy, C3-C8-cycloalkyl, halogen; R<2>: C1-C6-alkyl, C1-C6-alkoxy, C3-C8-cycloalkyl, C2-C6-alkenyl, cyano or a heterocyclic radical.

Description

Technical field

The present invention provides a process for the preparation of 4-bromoaniline derivatives.

BACKGROUND OF THE INVENTION

4-Bromoaniline derivatives are preferred compounds which are used as intermediates in the chemical industry. They are suitable, for example, for the preparation of active compounds which are used in the field of crop protection or for the preparation of pharmaceutically active compounds. For example, International Patent Document WO 99/58509 describes processes for the preparation of isoxazolin-3-ylacylbenzenes in which 4-bromoaniline derivatives are used as intermediates for the preparation of herbicidally active compounds. International patent document WO 98/31681 discloses these active compounds (2-alkyl-3- (4,5-dihydroisoxazol-3-yl) acylbenzenes) as herbicidally active compounds.

It is known in the literature that selective bromination of the anilines in para-position is not possible, or is only possible with great difficulty (Houben-Weyl 5/4, 241, 274 et seq.). Generally, bromination with elemental bromine is not selective, but is often associated with the formation of significant amounts of dibromo compounds. Based on experience, selectivities for monobrominated compounds to dibrominated compounds are characterized by a value of approximately 9: 1, i. the proportion of undesirable dibromo compounds is approximately 10%. Thus, only using expensive reagents such as tetrabutylammonium tribromide will give 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline, for example prepared at -30 ° C in about 50% yield. (cf. WO 99/58509).

It is an object of the present invention to provide an alternative process for the preparation of 4-bromoaniline derivatives. The preparation process disclosed in WO 99/58509 for the preparation of 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline derivatives does not provide satisfactory yields and sufficient product purity. Similarly, the process described in International Patent Document WO 99/58509 has only limited use in the industrial preparation of such compounds.

SUMMARY OF THE INVENTION

We have found that this object can be achieved by a process for the preparation of 4-bromoaniline derivatives of the general formula I

in which

R ¹ is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, Cr

C ₆ -alkoxy, C 1 -C ₆ -haloalkoxy, C ₃ -C ₈ -cycloalkyl, halogen;

R ² represents a C 1 -C ₆ -alkyl group, a C 1 -C 6 -alkoxy group, a C ₃ -C ₈ cycloalkyl group, a C ₂ -C ₆ -alkenyl group, a cyano group or a heterocyclic radical, the process comprising reacting a compound of formula II

wherein R ¹ and R ² are as defined above, with a brominating agent in a solvent such as pyridine or in a solvent mixture containing at least wt% pyridine.

Using the process of the present invention, it is possible to prepare the aniline derivatives of formula I in higher yields than using the prior art methods of preparation. Thus, for example, 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline can be prepared by the method described in International Patent Document WO 99/58509 (cf. Example 10 herein) in a yield of only 47%. %, while in the process of the present invention the yield is at least 60%, preferably at least 70% or 80%, and particularly preferably at least 90%.

In addition, the compounds of formula I can be prepared with higher purity. The bromination is carried out here with high selectivity at the 4-position of the phenyl ring. The selectivity (ratio of monobrominated compound to dibrominated compound) is at least 92: 8, in particular at least 95: 5. Surprisingly, the proportion of impurities such as dibromides (these dibromides are derivatives of the compound of formula I which are substituted at the 5 or 6 position by another bromine atom) ), which is difficult to remove from the resulting reaction mixture, or whose removal requires relatively high technical costs, is less than 5%. Accordingly, the number of additional additional purification steps in the isolation and processing of the compounds of Formula I prepared using the method of the present invention can be reduced. This is particularly advantageous in the industrial production of the compounds of formula I, since a usable and efficient preparation process can be provided.

Because of the high selectivity and the low proportion of dibromo compounds, it is also possible, if necessary, to use the reaction product even without further purification in the subsequent process steps to further convert to suitable end products.

C 1 -C ₆ -alkyl is a linear or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl; a C 1 -C 4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl is preferred.

C 1 -C ₆ -Haloalkyl is a linear or branched C 1 -C ₆ -alkyl group as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and / or iodine, ie, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl , trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromomethyl, 2-iodoethyl,

2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3, 3-trichloropropyl, 2,2,3,3,3pentafluoropropyl, heptafluoropropyl, 1- (fluoromethyl) -2-fluoroethyl, 1- (chloromethyl) -2-chloroethyl, 1- (bromomethyl) -2-bromomethyl, 4-fluorobutyl, 4- chlorobutyl, 4-bromobutyl, nonafluorobutyl, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl; preferably a C 1 -C ₄ -haloalkyl group such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-bromoethyl, 2-bromoethyl, 2-bromoethyl, 2-bromoethyl,

2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3, 3-trichloropropyl, 2,2,3,3,3pentafluoropropyl, heptafluoropropyl, 1- (fluoromethyl) -2-fluoroethyl, 1- (chloromethyl) -2-chloroethyl, 1- (bromomethyl) -2-bromomethyl, 4-fluorobutyl, 4- chlorobutyl, 4-bromobutyl or nonafluorobutyl;

C 1 -C ₆ -alkoxy is a straight or branched chain alkyl group having 1 to 6 carbon atoms such as methoxy, ethoxy, npropyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy or nhexyloxy; preferably a C 1 -C ₄ -alkoxy group such as methoxy, ethoxy, npropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy;

C 1 -C ₆ -haloalkoxy is a linear or branched C 1 -C 6 -alkoxy group as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and / or iodine, ie, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, 2-fluoroethoxy,

2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-

2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2,3-dichloropropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, 2,2,3,3-pentafluoropropoxy, heptafluoropropoxy, 1- (fluoromethyl) -2-fluoroethoxy, 1- (chloromethyl) -2-chloroethoxy,

1- (bromomethyl) -2-bromomethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, nonafluorobutoxy, 5-fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy, undecafluoropentoxy, 6-fluorohexoxy, 6-fluorohexoxy, 6-fluorohexoxy, 6-bromohexoxy, 6-iodohexoxy or dodecafluorohexoxy; preferably C ₁ -C ₄ -haloalkoxy such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy,

2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2, difluoroethoxy, 2,2- dichloro-2-fluoroethoxy,

2,2,2-trichloroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2-chloropropoxy,

3-chloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2,3-dichloropropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy,

2,2,3,3-pentafluoropropoxy, heptafluoropropoxy, 1- (fluoromethyl) -2-fluoroethoxy, 1 (chloromethyl) -2-chloroethoxy, 1- (bromomethyl) -2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy,

4-bromobutoxy or nonafluorobutoxy;

C 3 -C 8 -cycloalkyl is an unsubstituted or substituted cycloalkyl ring of 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Suitable substituents are, for example: C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or halogen;

an unsubstituted C ₃ -C 6 -cycloalkyl group such as cyclopropyl, cyclopentyl or cyclohexyl is preferred;

C 2 -C 6 -alkenyl is a linear or branched alkenyl group having 2 to 6 carbon atoms wherein the double bond is at the point of attachment, such as ethenyl, prop-1-en-1-yl, 1-methyletenyl, buten-1-yl, 1-methylprop-1-en-1-yl, 2-methylprop-1-en-1-yl, penten-1-yl, 1-methylbut-1-en-1-yl,

2-methylbut-1-en-1-yl, 3-methylbut-1-en-1-yl, 1,2-dimethylprop-1-en-1-yl, hex-1-en-1-yl,

1-methylpent-1-en-1-yl, 2-methylpent-1-en-1-yl, 3-methylpent-1-en-1-yl, 4-methylpent-16 en-1-yl, 1,2 -dimethylbut-1-en-1-yl, 1,3-dimethylbut-1-en-1-yl, 2,3-dimethylbut-1-en-1-yl,

3,3-dimethylbut-1-en-1-yl, 1-ethylbut-1-en-1-yl, 2-ethylbut-1-en-1-yl or 1-ethyl-2-methylprop-1-en-yl;

Halogen is fluorine, chlorine, bromine, preferably chlorine or bromine.

Heterocyclic ring ”is a saturated, unsaturated or partially unsaturated heterocycle containing 3 to 8 ring atoms and one, two or three oxygen, sulfur or nitrogen atoms. Heterocycles containing at least one oxygen atom and / or one nitrogen atom are preferred. Also preferred are heterocycles having 5 or 6 ring atoms. The heterocyclic ring may be attached to the phenyl ring at any position in the heterocyclic ring, for example via a heterocyclic ring nitrogen atom or a ring carbon atom. The heterocyclic rings may be unsubstituted or mono-, dialkyl or trisubstituted. Suitable substituents are radicals that are chemically inert under selected reaction conditions, such as, for example, C 1 -C ₆ -alkyl, C 1 -C 6 -alkoxy or halogen. Suitable heterocyclic rings in the context of the present invention are, for example, the following heterocycles: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, piperidinyl, morpholinyl, oxazinyl, isoxazolinyl, isoxazolidinyl and the like. Preferred are the following heterocycles: isoxazolyl, isoxazolinyl or isoxazolidinyl, especially 4,5-dihydroisoxazol-3-yl or 4,5-dihydroisoxazol-5-yl.

The process of the present invention is particularly suitable for the preparation of compounds of formula I in which the substituents have the meanings defined below:

R ¹ is C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C ₃ -C ₈ -cycloalkyl, halogen,

R ² is C _r C ₆ alkyl group, CrCo alkoxy, C ₃ -C8cykloalkylovú group, a cyano group, or a heterocyclic radical.

In addition, the process of the present invention is particularly suitable for the preparation of the following compounds of formula I, such as:

4-bromo-2- (4,5-3-yl) -3-methylaniline,

4-bromo-2- (4,5-3-yl) -3-ethylaniline,

4-bromo-2- (4,5-3-yl) 3-methoxyaniline,

4-bromo-2- (4,5-3-yl) -3-methoxyaniline,

4-bromo-2- (3-methyl-4,5-5-yl) -3-methylaniline,

4-bromo-2- (3-methyl-4,5-5-yl) -3-ethylaniline,

4-bromo-2- (3-methyl-4,5-5-yl) 3-methoxyaniline,

4-bromo-2- (3-methyl-4,5-5-yl) -3-methoxyaniline,

4-bromo-2- (isoxazol-3-yl) -3-methylaniline,

4-bromo-2- (isoxazol-3-yl) -3-ethylaniline,

4-bromo-2- (isoxazol-3-yl) -3-methoxyaniline,

4-bromo-2- (isoxazol-3-yl) -3-methoxyaniline,

4-bromo-2- (5-methyl-isoxazol-3-yl) -3-methylaniline,

4-bromo-2- (5-methyl-isoxazol-3-yl) -3-ethylaniline,

4-bromo-2- (5-methyl-isoxazol-3-yl) 3-methoxyaniline,

4-bromo-2- (5-methyl-isoxazol-3-yl) -3-ethoxyaniline,

4-bromo-2-cyano-3-methylaniline,

4-bromo-2-cyano-3-methoxyaniline.

The reaction of the compounds of formula II with a brominating agent is preferably carried out using the following process steps:

According to the present invention, the reaction is carried out in a solvent such as pyridine or in a solvent mixture containing at least 55% by weight, preferably 80% by weight pyridine. In the case of a solvent mixture, suitable additional solvents in a mixture with pyridine are, for example, alcohols such as methanol or ethanol, particularly preferably methanol; esters such as ethyl acetate or butyl acetate, particularly preferably ethyl acetate or butyl acetate; amides such as Ν, Ν-dimethylformamide or Ν, Ν-dimethylacetamide; or water.

First, the compound of formula II is presented in pyridine or in a solvent mixture containing pyridine, as a solution or suspension. The brominating agent is then added over a period of 5 minutes to 5 hours. The brominating agent is added either directly, i. without solvent, or together with a suitable solvent.

A preferred brominating agent is elemental bromine or a mixture of HBr and hydrogen peroxide. If bromine is used, it is preferably added together with a suitable solvent such as pyridine to form pyridinium bromide. In this case, in particular, a high selectivity of the ratio of the monobrominated compound to the dibrominated compound is achieved.

In a preferred embodiment of the process of the present invention the brominating agent and the compound of formula II are used in a molar ratio of from 1: 1 to 2: 1. The brominating agent is preferably used in equimolar amounts or in a slight excess.

The reaction is preferably carried out at temperatures from 20 ° C to the boiling point of the solvent, preferably in the range from 60 ° C to 85 ° C. In a further preferred embodiment, the reaction is carried out at temperatures from 50 ° C to 100 ° C, preferably in the range from 80 ° C to 100 ° C, particularly preferably at 100 ° C.

The reaction time is 1 to 24 hours, preferably 2 to 12 hours, particularly preferably 5 to 8 hours. In a preferred embodiment, the reaction time is 30 minutes to 10 hours, particularly preferably 30 minutes to 5 hours.

When a mixture of HBr and hydrogen peroxide is used as the brominating agent, the brominating agent is added to the solution of the compound of formula II over a period of time, preferably from 10 minutes to 3 hours. The molar ratio of HBr to the compound of formula II is preferably in the range from 1: 1 to 1.5: 1. The addition is carried out at temperatures from 0 to 50 ° C, preferably 20 to 40 ° C. Hydrogen peroxide is then added. The molar ratio of H ₂ O ₂ to HBr is from 1: 1 to 1.5: 1. ° C to 100 ° C, particularly preferably at a temperature of about 100 ° C; in another preferred embodiment, the addition is preferably carried out at a temperature of from 60 ° C to 85 ° C. The solution is then stirred for 10 minutes to 36 hours, preferably 10 minutes to 8 hours. In another embodiment, the solution is stirred for 1 hour to 36 hours, preferably 2 to 8 hours. In yet another embodiment, the solution is stirred for a period of from 10 minutes to 3 hours, preferably from 10 minutes to 2 hours. The product is then processed and purified. In this work-up, the solution is concentrated. The crude product is dissolved in a suitable solvent, preferably pyridine or a solvent mixture containing at least 50% pyridine, and water is added. Filtration and washing of the residue or crystallization using a suitable solvent (e.g. water) gives the product in good yield and high purity.

However, it is also possible to shake the crude product in dimethyl disulfide and wash the product with water and / or aqueous sodium hydroxide solution. The organic solution can then be used in the following steps.

In a preferred embodiment, the compound of formula II is first introduced in pyridine or a mixture of pyridine and water. In the latter case, the ratio of pyridine to water ranges from 80 to 98% by weight to 20 to 5% by weight, preferably from 90 to 95% by weight to 10 to 5% by weight.

The ratio of the compound of formula II to pyridine or pyridine / water is selected so as to form a 5 to 25% solution, preferably a 10 to 15% solution. More than 0.8 to 1.1 molar equivalents, preferably 0.9 to 1.0 molar equivalents of HBr are then added to the resulting solution. The water is removed by azeotropic distillation and hydrogen peroxide is then added to the remaining solution over a period of 1 to 3 hours, preferably 1.5 to 2.5 hours, at a temperature of 50 to 120 ° C, preferably 80 to 110 ° C, particularly preferably at at about 100 ° C. Hydrogen peroxide is usually used as an aqueous solution, at a concentration of 20% to 50%, preferably 30% to 50%.

The mixture is then stirred for about 10 minutes to 2 hours, preferably 30 minutes to 1 hour.

This is followed by treatment of the product. For this purpose, the reaction solution is cooled to approximately room temperature and, if necessary, washed with aqueous sodium sulphite solution and the organic phase is concentrated. The resulting product can be used in the following reactions without further purification. However, the residue can also be taken up in dimethyl disulfide, the resulting solution washed with water or an aqueous sodium hydroxide solution, and the resulting organic phase can be used in subsequent reactions.

In another embodiment, HBr, which may optionally contain up to 10% water, may be added to the pyridine, and the water may then be removed azeotropically. The compound of formula II is then dissolved in the reaction mixture and hydrogen peroxide is added dropwise. The quantitative ratios of the substances used as well as the reaction time and the reaction temperature correspond to the above conditions.

In addition, pyridinium hydrobromide may also be used in an embodiment of the present invention instead of pyridine and HBr.

When elemental bromine is used as the brominating agent, the brominating agent is preferably added to the solution of the compound of formula II over a short period of time or added continuously over a period of about 30 minutes to 6 hours. The molar ratio of bromine to the compound of formula II is preferably in the range of 1: 1 to 1.5: 1. The addition is carried out at temperatures of 0 to 50 ° C, preferably at room temperature. The solution is then stirred for 1 to 24 hours, preferably 2 to 8 hours. The product is then processed and purified. To this end, the solution is concentrated and the crude product is dissolved in a suitable solvent, preferably pyridine or a solvent mixture containing at least 50% pyridine, and mixed with water. Filtration and washing of the residue or crystallization using a suitable solvent (e.g. water) yields the product in good yield and high purity.

In addition, the product can also be obtained from the reaction solution by extraction. To this end, the reaction solution is first concentrated and the residue is shaken in a suitable solvent or solvent mixture, the components being selected, for example, from the group consisting of water, ethyl acetate and dimethyl disulfide (DMDS), in particular water, ethyl acetate, water / ethyl acetate or water / DMDS. Suitable solvents for extraction are water-immiscible solvents or corresponding solvent mixtures such as ethyl acetate, butyl acetate, toluene or methyl tert-butyl ether (MTBE). Concentration of the solution gives the product in good yield and high purity.

The crude product is purified either by washing the residue obtained or by crystallization. For example, water and aqueous solvents are suitable for washing. For example, toluene and benzene are suitable for recrystallization.

In principle, as regards further reactions to prepare the active compounds, the crude product obtained can also be used in the next reaction step without further purification of the reaction solution. For this purpose, the reaction solution containing the compounds of the formula I can be diluted with other solvents and thus used as a crude solution in the next step of the process according to the invention. Alternatively, the reaction solution may also be concentrated and the remaining residue carried directly or in the form of a melt to the next step.

The compounds of formula II which are used as starting materials are known from the literature and / or are commercially available. They can be prepared using methods that are well known per se, such as those described in more detail in International Patent Documents WO 98/31681 or WO 99/58509.

The present invention is explained in more detail in the Examples below.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4-Bromo-2- (4,5-3-yl) -3-methylaniline

Brominating agent: HBr / H ₂ O ₂

First, 100.5 g of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline in 2000 g of pyridine were metered in and 98.2 g of HBr were added dropwise at 20-35 ° C. 64.6 g of hydrogen peroxide was then added dropwise over a period of 0.5 hours at 78-84 ° C. The mixture was stirred at 25 ° C for an additional 12 hours and then concentrated until an oily residue was obtained. The crude product was dissolved at 50 ° C in 100 ml of pyridine and mixed with 1000 ml of water. The mixture was stirred at 0 ° C for one hour and then filtered and the filter residue was washed twice with 200 ml of water and dried.

141 g (yield: 92%) of a yellow solid are thus obtained (HPLC: 94.6% 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline, 1.8% 6-bromo-2). - (4,5-dihydroisoxazol-3-yl) -3-methylaniline, 3.4% 4,6-dibromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline).

Example 2

4-Bromo-2- (4,5-3-yl) -3-methylaniline

Brominating agent: bromine

First, 100 g of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline in 1000 g of pyridine was metered in, and a solution of a total of 96.19 g of bromine in 1000 g of pyridine was added dropwise at 20 ° C over 3 hours. , in five freshly prepared proportions. The mixture was stirred for an additional 12 hours. The pyridine was distilled off at a pressure of 150 mbar and a bath temperature of 75 ° C. The residue was dissolved in 2 L of water and extracted repeatedly with 250 ml of ethyl acetate each time. Concentration gave 122.1 g of the product (yield 81.6%; GC: 93.2% 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline, 2.7% 6-bromo) -2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline, 4.1% 4,6-dibromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline).

Example 3

4-Bromo-2- (4,5-3-yl) -3-methylaniline

Brominating agent: bromine

First, 5 g of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline in 50 g of pyridine was metered in, and a solution of a total of 4.89 g of bromine in 50 g of pyridine was added dropwise at 20 ° C over 5 hours. (prepared at 0 ° C). The mixture was stirred at 25 ° C for an additional 12 hours. The batch was poured into 250 ml of water and extracted three times with 100 ml of MTBE each. The combined organic phases were washed twice with 100 ml of water each time, dried over sodium sulphate and concentrated.

Thus, 6.0 g of the product were obtained (yield 79.8%; 94.3% 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline, 1.8% 6-bromo-2- ( 4,5-dihydroisoxazol-3-yl) -3-methylaniline, 3.5% 4,6-dibromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline).

Example 4

4-Bromo-2- (4,5-3-yl) -3-methylaniline

Brominating agent: HBr, H2O2

First, 500.0 g of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline in 4,500 g of pyridine were metered in, and 467.4 g of 47% HBr were added dropwise at 25-35 ° C. Under reflux, water was distilled off azeotropically at atmospheric pressure. At 100 ° C, 199.2 g of 50% Η2Ο2 were then added dropwise over 2 hours. The reaction mixture was stirred for an additional hour and then cooled to room temperature and washed with sodium sulfite solution and the solvent was subsequently distilled off (T < 100 ° C). The residue was taken up in 3220 g of dimethyl disulfide and washed with 1500 g of water at 60 ° C. The resulting solution was used in the next reaction.

Thus, approximately 83% of the desired product was obtained.

Claims (10)

Process for the preparation of 4-bromoaniline derivatives of the general formula I (d) in which: R ¹ represents C 1 -C ₆ -alkyl, C 1 -C ₆ -haloalkyl, C 1 -C ₆ -alkoxy, C 1 -C ₆ -haloalkoxy, C 3 -C 6 -cycloalkyl, halogen; R ² is C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 8 -cycloalkyl, C 2 -C 6 -alkenyl, cyano or a heterocyclic radical comprising the reaction of a compound of formula II wherein R ¹ and R ² are as defined above, with a brominating agent in a solvent such as pyridine. The process according to claim 1, wherein the brominating agent used is bromine. The process according to claim 1, wherein the brominating agent used is hydrogen bromide and hydrogen peroxide. Process according to any one of claims 1 to 3, characterized in that the solvent used is pyridine. Process according to any one of claims 1 to 4, characterized in that R ¹ represents a C 1 -C ₆ -alkyl group. The process according to claim 5, wherein R ¹ is methyl or ethyl. 7. A method according to any one of claims 1 to 6, characterized in that R ² is a heterocyclic ring. 8. The method of claim 7, characterized in that R ² is an isoxazole, isoxazoline or isoxazolidine ring. A process according to claim 8 wherein R ² is 4,5-dihydroisoxazole- 3-yl or 4,5-dihydroisoxazol-5-yl. A process according to any one of claims 1 to 8, wherein the derivative is 4-Bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline.