AU2001269111B2

AU2001269111B2 - Method for producing 4-bromine-aniline derivatives

Info

Publication number: AU2001269111B2
Application number: AU2001269111A
Authority: AU
Inventors: Joachim Gebhardt; Michael Keil; Rene Lochtman; Michael Rack; Wolfgang Von Deyn
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 2000-06-30
Filing date: 2001-06-29
Publication date: 2006-12-14
Anticipated expiration: 2021-06-29
Also published as: JP2004502680A; CA2413723A1; ZA200300816B; PL359155A1; SK17972002A3; DE50107619D1; NZ523825A; PL206026B1; CN1438995A; BRPI0112121B1; HUP0301741A2; DK1296965T3; EP1296965B1; BR0112121A; CA2413723C; EA006293B1; SK285627B6; CZ301413B6; JP4937485B2; ATE305928T1

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

ID

p Preparation of 4-bromoaniline derivatives The present invention provides a process for preparing 0 5 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 10 protection, or for preparing pharmaceutically active compounds.

WO 99/58509, for example, describes processes for preparing isoxazolin-3-ylacylbenzenes in which 4-bromoaniline derivatives C( are employed as intermediates for preparing herbicidally active compounds. WO 98/31681 describes these active compounds S 15 (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 0 C in a yield of about 50% (cf.

WO 99/58509).

It is an object of the present invention 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.

According to the invention, there is provided a process for preparing 4-bromoaniline derivatives of the formula I.

0050/51533 2

R

1 Br 2

NH

where:

R

1 is C 1

-C

6 -alkyl, Ci-C 6 -haloalkyl, C 1

-C

6 -alkoxy, Ci-C 6 -haloalkoxy, C 3

-C

8 -cycloalkyl, halogen

R

2 is C 1

-C

6 -alkyl, Ci-C 6 -alkoxy, C 3

-C

8 -cycloalkyl, C 2

-C

6 -alkenyl, cyano or a heterocyclic radical, which comprises reacting a compound of the formula II Ri R2

NH

2 in which R 1 and R 2 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 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 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 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 resulting reaction mixture, or whose removal requires relatively high technical expenditure, is less than Accordingly, the number of further additional purification steps for isolation and 0050/51533 3 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.

C

1

-C

6 -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 1

-C

4 -alkyl, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

C

1

-C

6 -Haloalkyl is a straight-chain or branched C 1

-C

6 -alkyl group as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 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, 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, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, nonafluorobutyl, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, undecafluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl or dodecafluorohexyl; preferably C 1

-C

4 -haloalkyl, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 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, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 0050/5 153 3 4 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, fluoromethyl luoroethyl, 1- (chioromethyl) -2-chioroethyl, 1-(bromomethyl)-2-bromoethyl, 4-f luorobutyl, 4-chiorobutyl, 4-bromobutyl or nonafluorobutyl; Cl-C 6 -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 1

-C

4 -alkoxy such as, for example, methoxy, ethoxy, n-propyloxy, n-butyloxy, isobutyloxy or tert-butyloxy; Cl-C 6 -haloalkoxy is a straight-chain or branched Cl-C 6 -alkoxy group as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, 2-f luoroethoxy, 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-f luoropropoxy, 3-f luoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2 -bromopropoxy, 3-bromopropoxy, 2,2 -dif luoropropoxy, 2, 3-difluoropropoxy, 2, 3-dichloropropoxy, 3,3, 3-trifluoropropoxy, 3, 3,3-trichloropropoxy, 2,2,3, 3-pentafluoropropoxy, heptafluoropropoxy, 1- (fluoromethyl luoroethoxy, 1-(chloromethyl)-2-chloroethoxy, 1-(bromomethyl) -2-bromoethoxy, 4-f luorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, nonafluorobutoxy, luoropentoxy, 5-chloropentoxy, 5-bromopentoxy, undecafluoropentoxy, 6-f luorohexoxy, 6-chlorohexoxy, 6-bromohexoxy, 6-iodohexoxy or dodecafluorohexoxy; preferably Cl-C 4 -haloalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, 2-f luoroethoxy, 2-chioroethoxy, 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-f luoropropoxy, 3-f luoropropoxy, 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, fluoromethyl)-2-fluoroethoxy, 1-(chloromethyl) -2-chloroethoxy, 1-(bromomethyl) -2-bromoethoxy, 4-f luorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy; 0050/51533

C

3

-C

8 -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: Cl-C 6 -alkyl,

C

1

-C

6 -alkoxy or halogen; preference is given to unsubstituted C 3

-C

6 -cycloalkyl, such as, for example, cyclopropyl, cyclopentyl or cyclohexyl;

C

2

-C

6 -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-1-en-1-yl, 1-methylethenyl, 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-1-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, 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

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, etc.

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

0050/51533 6 The process according to the invention is preferably suitable for preparing compounds of the formula I where the substituents are as 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 1

-C

6 -alkyl, C 1

-C

6 -alkoxy, C 3

-C

8 -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 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 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 pyridine-containing solvent mixture, as solution or suspension.

The brominating agent is then added over a period of 5 minutes 0050/51533 7 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 0 C. In a further preferred embodiment, the reaction is carried out at temperatures of from 50 0 C to 100 0 C, preferably in the range from 80 0 C to 100 0 C, with particular preference at about 100 0

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 0

C,

preferably 20 40 0 C. The hydrogen peroxide is then added. The molar ratio of H 2 0 2 to HBr is from 1:1 to 1.5:1. The addition is carried out at temperatures of from 10 0 C to the boiling point of the solvent, preferably from 50 0 C to 1200C, with preference from 80 0 C to 100oC, with particular preference at about 100OC; in a further preferred embodiment, the addition is preferably carried out at from 600C to 850C. 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 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 solvent, preferably pyridine or a solvent mixture comprising at least 50% pyridine, and water is added. Filtration and washing of 0050/51533 8 the residue or crystallization using a suitable solvent (for 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 1200C, preferably 80 1100C, in particular at about 1000C. The hydrogen peroxide is usually employed in a 20% strength to 50% strength, preferably 30 to strength, aqueous solution.

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

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 hydrogen peroxide is added dropwise. Both the quantitative ratios 0050/51533 9 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 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 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 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 next process step. Alternatively, it is also possible to 0050/51533 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 2 0 2 100.5 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 0 C. At 78-84 0 C, 64.6 g of hydrogen peroxide are then added dropwise over 0.5 h. The mixture is stirred at 25 0

C

for a further 12 hours and then concentrated until an oily residue remains. The crude product is, at 50 0 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 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 0 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 0 C. The 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 0050/51533 11 4 -bromo- 2 -(4,5-dihydroisoxazol-3-yl)-3-methylaniline, 2.7% of 6 -bromo- 2 -(4,5-dihydroisoxazol-3-yl)-3-methylaniline, 4.1% of 4, 6 -dibromo- 2 -(4,5-dihydroisoxazol-3-yl)-3-methylaniline).

Example 3 4-Bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline Brominating agent: bromine g of the compound 2 4 ,5-dihydroisoxazol-3-yl)-3-methylaniline are initially charged in 50 g of pyridine, and a solution of altogether 4.89 g of bromine in 50 g of pyridine (mixture to be prepared at 0°C) is added dropwise at 20 0 C over 5 h. The mixture is stirred at 250C for a further 12 hours. The batch is poured into 250 ml of water and extracted three times with in each case 100 ml of MTBE. The combined organic phases are washed twice with in each case 100'ml of water, dried over sodium sulfate and concentrated.

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

Example 4 4-Bromo-2-(4,5-dihydroisoxazole-3-yl)-3-methylaniline Brominating agent: HBr, H 2 0 2 500.0 g of 2 4 ,5-dihydroisoxazol-3-yl)-3-methylaniline are initially charged in 4 500 g of pyridine, and at 25 350C, 467.4 g of 47% strength HBr are added dropwise. Under reflux, the water is distilled off azeotropically at atmospheric pressure. At 1000C, 199.2 g of 50% strength H 2 0 2 are then added dropwise over a period of 2 hours. The reaction mixture is stirred for another hour and then cooled to room temperature and washed with sodium sulfite solution, and the solvent is then distilled off (T<1000C).

The residue is taken up in 3 220 g of dimethyl disulfide and, at 600C, washed with 1 500 g of water. The resulting solution is used for a subsequent reaction.

This gives about 83% of the desired product.

lla Comprises/comprising and grammatical variations thereof when Sused in this specification are to be taken to specify the presence of stated features, integers, steps or components or 0 groups thereof, but do not preclude the presence or addition of "Z 5 one or more other features, integers, steps, components or groups thereof.

Claims

1. A process for preparing 4-bromoaniline derivatives of the formula I Ri R 2 NH 2 where: R 1 is C 1 -C,-alkyl, C-C,-haloalkyl, C,-C,-alkoxy, C,-C 6 -haloalkoxy, C 3 -C-cycloalkyl, halogen R 2 is C 1 -C,-alkyl, C,-C 6 -alkoxy, C 3 -C,-cycloalkyl, C,-C 6 -alkenyl, cyano or heterocyclic radical, which comprises reacting a compound of the formula II R 2 NH 2 in which R' and R 2 are as defined above with a brominating agent in the solvent pyridine or a solvent mixture comprising at least 55% by weight of 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 3, wherein the solvent used is pyridine. A process as claimed in any one of claims 1 4, where R' is C,-C,-alkyl. S6. A process as claimed in claim 5, where R' is methyl or ethyl. (Nc

7. A process as claimed in any one of claims 1 6, where R 2 is a heterocyclic ring. 4\ 8. A process as claimed in claim 7, where R 2 is an isoxazole, isoxazoline or isoxazolidine ring. C 9. A process as claimed in claim 8, where R 2 is dihydroisoxazol-3-yl or 4,5-dihydroisoxazol-5-yl. A process as claimed in any one of claims 1 8 for preparing 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline.

11. A process for preparing 4-bromoaniline derivatives according to claim 1 substantially as herein described with reference to any one of the examples. DATED this 23rd day of November 2006 BASF AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P22249AU00