ZA200300816B

ZA200300816B - Method for producing 4-bromine-aniline derivatives.

Info

Publication number: ZA200300816B
Application number: ZA200300816A
Authority: ZA
Inventors: Joachim Gerhardt; Michael Keil; Rene Lochtman; Michael Rack; Wolfgang Von Deyn
Original assignee: Basf Ag
Priority date: 2000-06-30
Filing date: 2003-01-29
Publication date: 2004-03-10
Also published as: JP2004502680A; MXPA02012483A; SK285627B6; EA006293B1; DK1296965T3; CN1438995A; AU6911101A; NZ523825A; WO2002002537A1; ATE305928T1; AU2001269111B2; EP1296965A1; CZ20024177A3; NO20026201L; EP1296965B1; NO20026201D0; KR20030014393A; IL153412A0; CA2413723C; PL359155A1

Description

0050/51533 AMENDED SHEET ' ® Preparation of 4-bromoaniline derivatives

The present invention provides a process for preparing 4-bromoaniline derivatives. 4~-Bromoaniline derivatives are useful compounds which are used as intermediates in chemical industry. They are suitable, for example, for preparing active compounds used in the field of crop protection, or for preparing pharmaceutically active compounds.

WO 99/58509, for example, describes processes for preparing isoxazolin-3-ylacylbenzenes in which 4-bromoaniline derivatives are employed as intermediates for preparing herbicidally active compounds. WO 98/31681 describes these active compounds (2-alkyl-3-(4,5-dihydroisoxazol-3-yl)acylbenzenes) as herbicidally active compounds.

It is known from the literature that the selective bromination of anilines in the para position is impossible, or possible only with difficulty (Houben-Weyl 5/4, 241, 274 ff). In general, bromination with elemental bromine is not selective, but frequently associated with the formation of considerable amounts of dibromo compounds. According to experience, the selectivities for monobromo to dibromo compounds are in an order of magnitude of about 9:1, i.e. the proportion of undesired dibromo compounds is about 10%. Thus, only with expensive reagents, such as tetrabutylammonium tribromide, the compound 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline, for example, was obtained at -30_C in a yield of about 50% (cf.

WO 99/58509) .

A need exists to provide an alternative process for preparing 4- bromoaniline derivatives. The preparation process described in WO 99/58509 for the 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline derivatives gives unsatisfactory yields and an unsatisfactory purity of the products. Accordingly, the process described in WO 99/58509 is only of limited use for the industrial preparation of such compounds. 40

We have found that this need is fulfilled by a process for preparing 4-bromoaniline derivatives of the formula I

0050/51533 ® A

Br Re

I

NH, where: rR! is C;-Cg-alkyl, C;-Cg¢-haloalkyl, C;~Cg-alkoxy,

C;-C¢-haloalkoxy, C3-Cg-cycloalkyl, halogen

R? is C;-Cg¢-alkyl, C;-Cg-alkoxy, C3-Cg-cycloalkyl, C,-Cg-alkenyl, cyano or a heterocyclic radical, which comprises reacting a compound of the formula II

R!

R2

IT

. NH, in which R! and R? are as defined above with a brominating agent in the solvent pyridine or in a solvent mixture comprising at least 55% by weight of pyridine.

With the aid of the process according to the invention, it is possible to obtain the aniline derivatives of the formula I in : higher yields than with the prior-art preparation processes.

Thus, for example, the compound 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline can be obtained by the process described in WO 99/58509 (cf. Example 10 therein) in a yield of only 47%, whereas the yield in the process according to the invention is at least 60%, preferably at least 70% or 80%, and in particular at least 90%. )

Moreover, the compounds of the formula I are obtained in higher purity. Here, the bromination takes place with high selectivity in the 4-position of the phenyl ring. The selectivity (ratio of 40 monobromo to dibromo compound) is at least 92:8, in particular at least 95:5. Surprisingly, the proportion of impurities, such as, for example, dibromides (these dibromides are derivatives of the formula I which are substituted in the 5— or 6—position by a further bromine atom) which are difficult to remove from the 45 resulting reaction mixture, or whose removal requires relatively high technical expenditure, is less than 5%. Accordingly, the number of further additional purification steps for isolation and

0050/51533

C work-up of the compounds I prepared by the process according to . the invention can be reduced. This is particularly advantageous for the industrial production of the compounds I, since an efficient and cost-effective process can be provided.

Owing to the high selectivity and the small proportion of dibromo compounds, it is possible, if appropriate, to use the reaction product even without additional purification for the next process steps for further conversion into suitable end products.

C1-C¢-Alkyl is a straight-chain or branched alkyl group having 1 - 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl; preference is given to C;-Cs-alkyl, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

Ci-C¢-Haloalkyl is a straight-chain or branched C;-Cg-alkyl group as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, i.e., for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-jiodoethyl, 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, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1l-(fluoromethyl)-2-fluoroethyl, l-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, nonafluorobutyl, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl or dodecafluorohexyl; preferably C;-Cy-haloalkyl, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 40 chlorfluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 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, 45 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2~-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl,

0050/51533 o 3,3,3-trichloropropyl, 2,2,3,3, 3-pentafluoropropyl, , heptafluoropropyl, 1-(fluoromethyl)-2-fluoroethyl, l-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl;

C1-Ce¢-alkoxy is a straight-chain or branched alkyl group having 1 - 6 carbon atoms, such as, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy or n-hexyloxy; preferably C;-Cs-alkoxy such as, for example, methoxy, ethoxy, n-propyloxy, n-butyloxy, isobutyloxy or tert-butyloxy;

C1-Cg-haloalkoxy is a straight-chain or branched C;-Cg-alkoxy group as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, i.e., 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, l-(fluoromethyl)-2-fluoroethoxy, 1-(chloromethyl)-2-chloroethoxy, 1l-(bromomethyl)-2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, nonafluorobutoxy,

S5-fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy, undecafluoropentoxy, 6-fluorohexoxy, 6-chlorohexoxy, 6-bromohexoxy, 6-iodohexoxy or dodecafluorohexoxy; preferably

C;-C4-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, 40 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, l-(chloromethyl)-2-chloroethoxy, 1- (bromomethyl)-2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 45 4-bromobutoxy or nonafluorobutoxy;

0050/51533 ® C3-Cg-cycloalkyl is an unsubstituted or substituted cycloalkyl . ring having 3 - 8 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Suitable substituents are, for example: C;-Cg¢-alkyl,

C;-Cg-alkoxy or halogen; preference is given to unsubstituted C3-Cg-cycloalkyl, such as, for example, cyclopropyl, cyclopentyl or cyclohexyl;

C;-Cg-alkenyl is a straight-chain or branched alkenyl group having 2 - 6 carbon atoms, where the double bond is at the point of attachment, such as, for example, ethenyl, prop-l-en-1-yl, l-methylethenyl, buten-1-yl, l-methylprop-l-en-1-yl, 2-methylprop-l-en-l-yl, penten-1l-yl, l-methylbut-l-en-1-yl, . 2-methylbut-l-en-1-yl, 3-methylbut-l-en-1-yl, 1,2-dimethylprop-l-en-1-yl, hex-l-en-1-yl, l-methylpent-l-en-1-yl, 2-methylpent-l-en-1-yl, 3-methylpent-l-en-1-yl, 4-methylpent-l-en-1-yl, 1,2-dimethylbut-l-en-1-yl, 1,3-dimethylbut-l-en-1-yl, 2,3-dimethylbut-l1-en-1-yl, 3,3-dimethylbut-l-en-1-yl, l-ethylbut-l-en-1-yl, 2-ethylbut-l-en-1-yl or l-ethyl-2-methylprop-1l-en-yl;

Halogen is fluorine, chlorine, bromine, in particular chlorine or bromine. "Heterocyclic ring” is a saturated, unsaturated or partially unsaturated heterocycle having 3 — 8 ring atoms and one, two or three oxygen, sulfur or nitrogen atoms. Preference is given to heterocycles which contain at least one oxygen and/or one nitrogen atom. Preference is furthermore given to heterocycles having 5 or 6 ring atoms. The heterocycle can be attached to the phenyl ring at any site of the heterocycle, for example via a heterocylic nitrogen ring atom or a carbon ring atom. The heterocycles are unsubstituted or mono-, di- or trisubstituted.

Suitable substituents are radicals which are chemically inert under the chosen reaction conditions, such as, for example,

C;-Cg-alkyl, C;-Cg-alkoxy or halogen. Suitable heterocyclic rings in the context of the present invention are, for example, the 40 following heterocycles: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, piperidinyl, morpholinyl, oxazinyl, isoxazolinyl, isoxazolidinyl, etc.

Preference is given to the following heterocycles: isoxazolyl, isoxazolinyl or isoxazolidinyl, in particular 45 4,5-dihydroisoxazol-3-yl or 4,5-dihydroisoxazol-5-yl.

0050/51533

C The process according to the invention is preferably suitable for . preparing compounds of the formula I where the substituents are as defined below:

R! is C;-Cg-alkyl, C;-Cg¢-alkoxy, C3-Cg-cycloalkyl, halogen,

RZ? is C;-Cg-alkyl, C;-Cg-alkoxy, C3-Cg-cycloalkyl, cyano or a heterocyclic radical. ) The process according to the invention is furthermore preferably suitable for preparing the following compounds of the formula I: 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline, 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-ethylaniline, 4-bromo-2-(4,5-dihydroisoxazol-3-yl-)3-methoxyaniline, 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-ethoxyaniline, 4-bromo-2-(3-methyl-4,5-dihydroisoxazol-5-yl)-3-methylaniline, 4-bromo-2-(3-methyl-4,5-dihydroisoxazol-5-yl)-3-ethylaniline, 4-bromo-2-(3-methyl-4,5-dihydroisoxazol-5-yl-)3-methoxyaniline, 4-bromo-2-(3-methyl-4,5-dihydroisoxazol-5-yl)-3-ethoxyaniline, 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-ethoxyaniline, 4-bromo-2-(5-methylisoxazol-3-yl)-3-methylaniline, 4-bromo-2-(5-methylisoxazol-3-yl)-3-ethylaniline, 4-bromo-2-(5-methylisoxazol-3-yl-)3-methoxyaniline, 4-bromo-2-(5-methylisoxazol-3-yl)-3-ethoxyaniline, 4-bromo-2-cyano-3-methylaniline, 4-brom-2-cyano-3-methoxyaniline.

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

According to the invention, the reaction is carried out in the solvent pyridine, or in solvent mixtures comprising at least 55% by weight, preferably 80% by weight of pyridine. In the case of solvent mixtures, suitable additional solvents in the mixture with pyridine are, for example, alcohols, such as methanol or ethanol, in particular methanol; esters, such as ethyl acetate or 40 butyl acetate, in particular ethyl acetate or butyl acetate; amides, such as, for example, N,N-dimethylformamide or

N,N-dimethylacetamide; or water.

Initially, the compound II is charged in pyridine or a 45 pyridine-containing solvent mixture, as solution or suspension.

The brominating agent is then added over a period of 5 minutes —

0050/51533 o 5 hours. The brominating agent is added either directly, i.e. without solvent, or together with a suitable solvent.

Preferred brominating agents are elemental bromine or a mixture of HBr and hydrogen peroxide. In the case of bromine, the bromine is preferably added together with a suitable solvent, such as, for example, pyridine, with formation of pyridinium perbromide.

In this case, a particularly high selectivity in the ratio of monobromo to dibromo compound is achieved.

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

The reaction is carried out at temperatures of 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 of from 50°C to 100°C, preferably in the range from 80°C to 100°C, with particular preference at about 100°C.

The reaction time is 1 - 24 hours, preferably 2 - 12 hours, in particular 5 — 8 hours. In a further preferred embodiment, the reaction time is 30 min - 10 h, preferably 30 min - 5 hours.

If the brominating agent used is a mixture of HBr and hydrogen peroxide, the brominating agent is added to the solution of II over a period of preferably from 10 minutes to 3 hours. The molar ratio of HBr to compound II is preferably in the range from 1:1 to 1.5:1. The addition is carried out at temperatures of 0 — 50°C, preferably 20 — 40°C. The hydrogen peroxide is then added. The molar ratio of H;0, to HBr is from 1:1 to 1.5:1. The addition is carried out at temperatures of from 10°C to the boiling point of the solvent, preferably from 50°C to 120°C, with preference from 80°C to 100°C, with particular preference at about 100°C; in a further preferred embodiment, the addition is preferably carried out at from 60°C to 85°C. The solution is then stirred for a period of 10 min - 36 hours, preferably 10 min - 8 hours. In a further embodiment, the solution is stirred for a period of 1 =~ 40 36 hours, preferably 2 - 8 hours. In a further embodiment, the solution is stirred for a period of from 10 min to 3 hours, preferably from 10 min to 2 hours. Subsequently, the product is worked up and purified. To this end, the solution is concentrated. The crude product is dissolved in a suitable 45 solvent, preferably pyridine or a solvent mixture comprising at least 50% pyridine, and water is added. Filtration and washing of

0050/51533 ® the residue or crystallization using a suitable solvent (for

A example water) gives the product in good yield and high purity.

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

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

The ratio of the compound of the formula II to pyridine or : pyridine/water is chosen such that a 5 - 25% strength solution, preferably a 10 - 15% strength solution, is formed. Above 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 added to the solution that remains over a period of 1 - 3 hours, preferably 1.5 - 2.5 hours, at 50 - 120°C, preferably 80 - 110°C, in particular at about 100°C. The hydrogen peroxide is usually employed in a 20% strength to 50% strength, preferably 30 to 50% strength, aqueous solution.

The mixture is then stirred for about 10 min to 2 h, preferably : 30 min to 1 h.

This is followed by work-up of the product. To this end, the reaction solution is cooled to about room temperature and, if required, washed with aqueous sodium sulfite solution, and the organic phase is concentrated. The resulting product can be used without further purification for subsequent reactions. However, ’ it is also possible to take up the residue in dimethyl disulfide, to wash the resulting solution with water or aqueous sodium hydroxide solution and to use the resulting organic phase for subsequent reactions. 40

In a further embodiment, it is possible to add HBr to the pyridine which, if appropriate, comprises up to 10% of water, and then to remove the water azeotropically. The compound of the formula II is then dissolved in the reaction mixture and the 45 hydrogen peroxide is added dropwise. Both the quantitative ratios

0050/51533 ® of the substances employed and time and temperature conditions ] correspond to the conditions mentioned above.

In a further embodiment, it is also possible to use pyridinium hydrobromide instead of pyridine and HBr.

If the brominating agent used is elemental bromine, the brominating agent is preferably added to the solution of II a little at a time or continuously over a period of from about 30 minutes to 6 hours. The molar ratio of bromine to the compound II is preferably in the range from 1:1 to 1.5:1. The addition is carried out at temperatures of 0 — 50°C, preferably at room temperature. The solution is then stirred for a period of 1 — 24 hours, preferably 2 — 8 hours. Subsequently, the product is worked up 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 comprising at least 50% pyridine, and admixed with water. Filtration and washing of the residue or crystallization using a suitable solvent (for example water) gives the product in good yield and high purity.

Furthermore, the product can also be obtained from the reaction solution by extraction. To this end, the reaction solution is initially concentrated and the residue is taken up in a suitable solvent or solvent mixture, the components being selected, for example, from water, ethyl acetate and dimethyl disulfide (DMDS), in particular water, ethyl acetate, water/ethyl acetate or water/DMDS. Suitable for the extraction are water-immiscible solvents or the corresponding solvent mixtures, such as, for example, 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. Suitable for washing are, for example, water and aqueous solvents. Suitable for recrystallization are, for example, toluene and benzene.

In principle, in the context of further reaction for preparing 40 active compounds, the crude product obtained can also be used for the next reaction step without further purification of the reaction solution. To this end, the reaction solution which contains the compounds of the formula I can be diluted with further solvents and thus be employed as crude solution for the 45 next process step. Alternatively, it is also possible to

0050/51533

C concentrate the reaction solution and to transfer the resulting . residue directly or as a melt into the next process step.

The compounds of the formula II to be used as starting materials are known from the literature and/or commercially available. They can be prepared by processes known per se, such as, for example, described in more detail in WO 98/31681 or WO 99/58509.

The invention is illustrated in more detail in the working examples below.

Example 1 4-Bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline

Brominating agent: HBr/H,0, 100.5 g of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline are initially charged in 2000 g of pyridine, and 98.2 g of HBr are added dropwise at 20-35°C. At 78-84°C, 64.6 g of hydrogen peroxide are then added dropwise over 0.5 h. The mixture is stirred at 25°C for a further 12 hours and then concentrated until an oily residue remains. The crude product is, at 50°C, dissolved in 100 ml of pyridine and admixed with 1000 ml of water. The mixture is stirred at 0°C for 1 h and then filtered off, and the filter residue is washed twice with 200 ml of water and dried.

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

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

Brominating agent: bromine 100 g of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline are 40 initially charged in 1000 g of pyridine, and a solution of altogether 96.19 g of bromine in 1000 g of pyridine is added dropwise at 20°C in five freshly prepared portions, over 3 hours.

The mixture is stirred for a further 12 hours. Pyridine is distilled off at 150 mbar and a bath temperature of 75°C. The 45 residue is dissolved in 2 1 of water and extracted repeatedly with in each case 250 ml of ethyl acetate. Concentration gives 122.1 g of product (yield 81.6%; GC: 93.2% of

Claims

J 0050/51533 AMENDED SHEET We claim:

1. A process for preparing 4-bromocaniline derivatives of the formula I R! [=] Br 1 NH, where: R® is C,-C4-alkyl, C,-Cs-haloalkyl, C,-C.-alkoxy, C,-C,.- haloalkoxy, C;-Cs-cycloalkyl, halogen R® is C,-C4-alkyl, C,-C¢-alkoxy, C,-C,-cycloalkyl, C,-C,- alkenyl, cyano or a heterocyclic radical, which comprises reacting a compound of the formula II Rt Re? II NH, in which R' and R® are as defined above with a brominating agent in the solvent pyridine or a solvent mixture comprising at least 55% by weight pyridine.

2. A process as claimed in claim 1, wherein the brominating agent used is bromine.

3. A process as claimed in claim 1, wherein the brominating agent used is hydrogen bromide and hydrogen peroxide.

4. A process as claimed in any one of claims 1 to 3, wherein the solvent used is pyridine. 40

5. A process as claimed in any one of claims 1 to 4, where R! ig C,-Cgs-alkyl.

6. A process as claimed in claim 5, where R' is methyl or ethyl. 45

7. A process as claimed in any one of claims 1 to 6, where R® ig a heterocyclic ring.

0050/51533 AMENDED SHEET

C

8. A process as claimed in claim 7, where R?® is an isoxazole, isoxazoline or isoxazolidine ring.

9. A process as claimed in claim 8, where R® is 4,5- dihydroisoxazol-3-yl or 4,5-dihydroisoxazol-5-yl.

10. A process as claimed in any one of claims 1 to 8 for preparing 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline.

11. A process according to the invention for preparing a compound of the formula I, substantially as hereinbefore described and exemplified.

12. A process for preparing a compound of the formula I, including any new and inventive integer or combination of integers, substantially as herein described.