NO324408B1 - Process for the preparation of 4-bromo-aniline derivatives - Google Patents

Abstract

A process for the preparation of 4-bromoaniline derivatives of formula I wherein: R 1 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -alkoxy, C 2 -haloalkoxy, C 2 -cycloalkyl, halogen R e C 1 -alkyl, C 4 -alkoxy, C -cycloalkyl, CC-alkenyl, cyano or a heterocyclic radical are described.

Description

The present invention provides a method for the production of 4-bromoaniline derivatives.

4-bromoaniline derivatives are useful compounds that are used as intermediates in the chemical industry. They are suitable, for example, for the production of active compounds used in the field of crop protection or for the production of pharmaceutical active compounds. WO 99/58509 describes, for example, methods for the production of isoxazolin-3-yl acylbenzenes where 4-bromoaniline derivatives are used as intermediates for the production of 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 only possible with difficulty (Houben-Weyl 5/4,241,274 ff). In general, bromination with elemental bromine is not selective, but is often associated with the formation of considerable amounts of dibromine compounds. According to experience, the selectivities for monobromo to dibromo compounds are in the order of magnitude of approx. 9:1, i.e. the proportion of undesired dibromo compounds is approx. 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 approx. 50% (see WO 99/58509).

It is an object of the present invention to provide an alternative

process for the production of 4-bromoaniline derivatives. The production 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. Consequently, the method described in WO 99/58509 has only limited application for the industrial production of such compounds.

We have found that this objective is achieved by a process for the preparation of 4-bromoaniline derivatives of formula I

where:

R<1> is C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, d -C 6 -haloalkyl, C 3 -C 8 - 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 ene

heterocyclic residue,

which involves the reaction of a compound of formula II

where R<5> and R<2> are as defined above with a brominating agent in a solvent containing at least 55% by weight of pyridine.

With the aid of the method according to the invention, it is possible to obtain the aniline derivatives of formula I in higher yields than with the previously known production processes. Thus, for example, the compound 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline can be obtained by the method described in WO 99/58509 (cf. Example 10 therein) in a yield of only 47%, while the yield in the method according to the invention is at least 60%, preferably at least 70% or 80% and especially at least 90%.

Furthermore, the compounds of 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, especially at least 95:5. Surprisingly, the proportion of impurities, such as for example dibromides (these dibromides are derivatives of formula I which are substituted in the 5- or 6-position with an additional bromide atom) is difficult to remove from the resulting reaction mixture or whose removal requires relatively high technical efforts, less than 5%. Consequently, the number of additional purification steps for isolating and working up the compounds I produced by the method 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 produced.

Due to the high selectivity and the small proportion of dibromo compounds, it is possible, if appropriate, to use the reaction product itself without further purification for the next process step for further conversion to suitable end products.

C 1 -C 6 alkyl is a straight chain or branched alkyl group having 1 to 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl; it is preferably C1-C4-alkyl, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.

Ci-C6 Halogenalkyl is a straight-chain or branched Ci-C6 alkyl group as mentioned above which is partially or completely substituted with 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-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, l-( fluoromethyl)-2-fluoroethyl, l-(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 yl or dodecafluorohexyl;

preferably C1-C4 haloalkyl, such as 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, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromoethyl)-2-bromomethyl, 4-fluorobutyl, 4-chlorobutyl, 4-brbmbutyl or nonafluorobutyl;

C1-C6-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;

Ci-C6-halogeno-alkoxy is a straight-chain or branched Ci-C6-alkoxy group as mentioned above which is partially or completely substituted with 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, l-( chloromethyl)-2-chloroethoxy, l-(bromomethyl)-2-bromomethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, nonafluorobutoxy, 5-fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy, undecafluoropentoxy, 6 -fluorohexoxy, 6- chlorohexoxy, 6-bromohexoxy, 6-iodohexoxy or dodecafluorohexoxy; preferably C 1 -C 4 -halo methoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromomethoxy, 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, l-(chloromethyl)-2-chloroethoxy, l-(bromomethyl)-2-bromomethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy ;

Ca-Cs-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 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen;

it is preferably unsubstituted C3-C6 cycloalkyl, such as, for example, cyclopropyl, cyclopentyl or cyclohexyl;

C2-C6-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 ethenyl, prop-l-en-1-yl, 1-methylethenyl, buten-l-yl, 1-methylprop-l-en-l-yl, 2-methylprop-l-en-l-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-l-yl, hex-1-en-1-yl, 1-methylpent-l-en-l- yl, 2-methylpent-l-en-l-yl, 3-methylpent-l-en-l-yl, 4-methylpent-l-en-l-yl, 1,2-dimethylbut-l-en-l- yl, 1,3-dimethylbut-l-en-l-yl, 2,3-dimethylbut-1-en-l-yl, 3,3-dimethylbut-l-en-l-yl, 1-ethylbut-l- en-1-yl, 2-ethylbut-1-en-1-yl or 1-ethyl-2-methylprop-1-en-yl;

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

"Heterocyclic ring" is a saturated, unsaturated or partially unsaturated heterocyclic group having 3 - 8 ring atoms and one, two or three oxygen, sulfur or nitrogen atoms. Preferred are heterocyclic groups containing at least one oxygen and/or one

nitrogen atom. Furthermore, the heterocyclic groups preferred which have 5 or 6 ring atoms. The heterocyclic group may be attached to the phenyl ring at any point in the heterocyclic group, for example through a heterocyclic nitrogen ring atom or a carbon ring atom. The heterocyclic groups are unsubstituted or mono-, di- or tri-substituted. Suitable substituents are residues which are chemically inert under the chosen reaction conditions, such as, for example, C1-C6 alkyl, C1-C6 alkoxy or halogen. Suitable heterocyclic rings in the context of the present invention are, for example, the following heterocyclic groups: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, piperidinyl, morpholinyl, oxazinyl, isoxazolinyl,

isoxazolidinyl, etc. The following heterocyclic groups are preferred: isoxazolyl, isoxazolinyl or isoxazolidinyl, especially 4,5-dihydroisoxazol-3-yl or 4,5-dihydroisoxazol-5-yl.

The method according to the invention is preferably suitable for the preparation of compounds of formula I where the substituents are as defined below:

R<1> is C1-C6-alkyl, C1-C6-alkoxy, C3-C8-cycloalkyl, halogen,

R<2> is C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, cyano or a heterocyclic radical.

The method according to the invention is furthermore preferably suitable for the production of the following compounds of 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-Bromo-2-cyano-3-methoxyaniline.

The reaction of compounds II with a brominating agent is preferably carried out in 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 further solvents in the mixture with pyridine are, for example, alcohols, such as methanol or ethanol, especially methanol; esters, such as ethyl acetate or butyl acetate, especially ethyl acetate or butyl acetate; amides, such as for example N,N-dimethylformamide or N,N-dimethylacetamide; or water.

First, compound II is added to pyridine or a pyridine-containing solvent mixture as a solution or suspension. The brominating agent is then added over a period of 5 minutes - 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 to form 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 method, the brominating agent and the compound 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 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 from 50°C to 100°C, preferably in the range from 80°C to 100°C, with particular preference at approx. 100°C.

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

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 H2O2 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 approx. 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 - 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. The product is then processed and cleaned. For this purpose, the solution is concentrated. The raw product becomes

dissolved in a suitable solvent, preferably pyridine or a solvent mixture comprising at least 50% pyridine, and water is added. Filtration and washing of the residue after 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 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 formula II is first added to pyridine or 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 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 chosen so that a 5-25% strong solution, preferably a 10-15% strong solution, is formed. Over 0.8 to 1.1 molar equivalents, preferably 0.9 to 1.0 molar equivalents, of HBr is then added to the resulting solution. The water is removed by azeotropic distillation and hydrogen peroxide is added to the solution which is kept over a period of 1 - 3 hours, preferably 1.5 - 2.5 hours, at 50 - 120°C, preferably 80 - 110°C, especially at approx. . 100°C. The hydrogen peroxide is usually used in a 20% to 50% strength, preferably 30 to 50% strength, aqueous solution.

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

This is followed by processing of the product. For this purpose, the reaction solution is cooled to about room temperature and, if necessary, 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, contains up to 10% of water and then remove the water azeotropically. The compound of formula II is then dissolved in the reaction mixture, and hydrogen peroxide is added dropwise. Both the quantitative ratio of the substances used and the 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 approx. 30 minutes to 6 hours. The molar ratio of bromine 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 at room temperature. The solution is then stirred for a period of 1-24 hours, preferably 2-8 hours. The product is then processed and cleaned. For this purpose, 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 mixed with water. Filtration and washing of the residue after 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. For this purpose, the reaction solution is first 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), especially water, ethyl acetate, water/ethyl acetate or water/DMDS. Suitable for the extraction are non-water-miscible 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 obtained residue 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 the production of active compounds, the crude product obtained can also be used for the next reaction step without further purification of the reaction solution. For this purpose, the reaction solution containing the compounds of formula I can be diluted with further solvents and thus used as a crude solution for the next process step. Alternatively, it is also possible to concentrate the reaction solution and transfer the resulting residue directly or as a melt to the next process step.

The compounds of formula II to be used as starting materials are known from the literature and/or are commercially available. They can be produced 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 embodiment examples below.

Example 1

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

Brominating agent: HBT/ H2O2

100.5 g of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline is first added to 2000 g of pyridine, and 98.2 g of HBr is added dropwise at 20-35 °C. At 78-84 °C, 64.6 g of hydrogen peroxide are then added dropwise over 0.5 hours. The mixture is stirred at 25°C for a further 12 hours and then concentrated until an oily residue remains. The crude product is dissolved at 50°C in 100 ml of pyridine and mixed with 1000 ml of water. The mixture is stirred at 0°C for 1 hour and then filtered off, and the filter cake 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 is first added to 1000 g of pyridine, and a solution of a total of 96.19 g of bromine in 1000 g of pyridine is added dropwise at 20°C for 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 residue is dissolved in water and extracted repeatedly with 250 ml of ethyl acetate in each case. Concentration gives 122.1 g of product (yield 81.6%; GC: 93.2% of 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

5 g of the compound 2-(4,5-dihydroisoxazoi-3-yl)-3-methylanirine is first added to 50 g of pyridine, and a solution of a total of 4.89 g of bromine in 50 g of pyridine (the mixture must be prepared at 0°C ) is added dropwise at 20°C over 5 hours. The mixture is stirred at 25°C for a further 12 hours. The batch is poured into 250 ml of water and extracted three times with 100 ml of MTBE in each case. The combined organic phases are washed twice with 100 ml of water in each case, dried over sodium sulfate and evaporated.

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-dihydroisoxazol-3-yl)-3-methylaniline

Brominating agent: HBr, H2O2

500.0 g of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline is first added to 4500 g of pyridine, and at 25 - 35°C 467.4 g of 47% strong HBr is added dropwise. During reflux, the water is distilled off azeotropically at atmospheric pressure. At 100°C, 199.2 g of 50% strength H 2 O 2 is 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 sulphite solution, and the solvent is then distilled off (T<100°C). The residue is taken up in 3,220 g of dimethyl disulphide and washed at 60°C with 1,500 g of water. The resulting solution is used for the subsequent reaction.

This gives approx. 83% of the desired product.

Claims (10)

1. Process for the preparation of 4-bromoaniline derivatives of formula I where: R<1> is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl Cs-Cs-cycloalkyl, halogen R<2> is C1-C6-alkyl, C1-C6-alkoxy, C3-C8-cycloalkyl, C2-C6-alkenyl, cyano or a heterocyclic residue, which comprises reacting a compound of formula II where R<1> and R<2> are as defined above with a brominating agent in a solvent containing at least 55% by weight of pyridine. 2. Method according to claim 1, where the brominating agent used is bromine. 3. Process according to claim 1, where the brominating agent used is hydrogen bromide and hydrogen peroxide. 4. Method according to any one of claims 1 - 3, where the solvent used is pyridine. 5. Method according to any one of claims 1-4, where R<1> is C1-Q-alkyl. 6. Process according to claim 5, where R<1> is methyl or ethyl. 7. A method according to any one of claims 1-6, wherein R<2> is a heterocyclic ring. 8. Method according to claim 7, where R 2 is an isoxazole, isoxaisoline or isoxazolidine ring. 9. Process according to claim 8, where R 2 is 4,5-dihydroisoxazol-3-yl or 4,5-dihydroisoxazol-5-yl. 10. Process according to any one of claims 1-8 for the production of 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline.