MXPA00011047A - Method for producing isoxazoline-3-yl-acyl benzene - Google Patents

Abstract

The invention relates to a method for producing isoxazolene of the formula (I), where the substituents have the following meanings:R1 is hydrogen, C1-C6 alkyl, R2 is C1-C6 alkyl, R3, R4, R5 are hydrogen, C1-C6 alkyl or R4 and R5 together form a linkage, R6 is a heterocyclic ring, and n is 0, 1 or 2. Said method comprises the production of an intermediate compound of the formula (VI) where R1, R3, R4 and R5 have the meanings given above. This step is followed by halogenation, thiomethylation, oxidation and acylation to yield compounds of formula (I). The invention also relates to new intermediate products for producing compounds of formula (I) and new methods for producing the intermediate products.

Description

PREPARATION OF ISOXAZOLIN-3-ILACILBENCENOS The present invention provides a process for preparing isoxazolin-3-yl-cyclobenzenes, novel intermediates and novel processes for preparing these intermediates. Isoxazolin-3-ylcylbenzenes are useful compounds that can be used in the field of crop protection. WO 98/31681, for example, describes 2-alkyl-3- (4,5-dihydroisoxazol-3-yl) acylbenzenes as compounds as active herbicides. An object of the present invention is to provide an alternative process for preparing benzoyl derivatives substituted with 3-heterocyclyl. The preparation process described in WO 98/31681 for 2-alkyl-3- (4,5-dihydroisoxazol-3-yl) acylbenzenes or precursors thereof (2-alkyl-3- (4,5-dihydroisoxazole- 3-yl) bromobenzene) is not particularly suitable for the industrial preparation of these compounds, since the synthesis involves a plurality of steps and the yield of the final product in question, based on the starting materials used in the first step of the invention. synthesis, it is relatively low. The preparation of compounds or intermediates with a structure similar to that of the compounds of the formula I is known from the literature: WO 96/26206 describes a process for preparing 4- [3- (4,5-dihydroisoxazol-3-yl) benzoyl] -5-hydroxypyrazoles where, in the last step, a 5-hydroxypyrazole is reacted with a 3- (4,5-dihydroisoxazol-3-yl) benzoic acid derivative. The 3- (4,5-dihydroisoxazol-3-yl) benzoic acid derivative required for this process can only be obtained with difficulty, by a large number of steps. Consequently, the process is relatively expensive and is not economically optimal. DE 197 09 118 describes a process for preparing 3- (4,5-dihydroisoxazol-3-yl) benzoic acid from 3-bromo- (4,5-dihydroisoxazol-3-yl) benzene, Grignard reagents and dioxide carbon. Surprisingly, we have found that the number of steps within the process in the preparation of benzoyl derivatives substituted with 3-heterocyclyl can be reduced compared to the process described in WO 98/31681 if the synthesis is carried out by means of the selection of intermediaries. On the other hand, the process according to the invention has the advantage of the total yield of the final products of the formula I and also of the intermediates X, based on the starting materials used, is greater than the performance of the processes described in WO 98/31681. In addition, the respective intermediaries of the individual process steps can be obtained with good performance. On the other hand, some of the individual steps of the process are advantageous for the industrial preparation of the intermediaries, since these allow a preparation at a cost effective and economic of the latter. Furthermore, it is advantageous that the starting materials used are basic chemicals which are easy to prepare and which can be obtained by several independent suppliers of raw materials, even in relatively large quantities. In total, the process according to the invention provides an industrial process at a more effective, economic and safe cost to prepare active compounds as herbicides of the formula I. We have found that the object of the invention is achieved by a process for preparing compounds of the formula I wherein the substituents are defined below: R is hydrogen, Ci-Cß alkyl, is Ci-Cß alkyl R, R, R are hydrogen, Ci-Cß alkyl or R and R together form a bond, R is a heterocyclic ring, n is 0, 1 or 2; which is to prepare an intermediary of formula VI: 1 3 5 in which R and R -R are as defined above. In subsequent reaction steps, the compounds of the formula VI are converted into the corresponding 3-bromo substituted compounds (bromobenzene derivatives), and the amino group on the phenyl ring is converted to a sulfonyl group, giving the compounds of the Formula X: The compounds of the formula X (3- (4,5-dihydroisoxazol-3-yl) bromobenzenes) are useful intermediates for preparing active compounds of the formula I. In particular, the process according to the invention provides the compounds I in the Last step of reaction in good performance. The compounds I are suitable, for example, for use as crop protection agents, in particular as herbicides, as described in WO 96/26206 and WO 97/35850. According to the invention, the compounds of the formula I and the intermediates required, in particular the compounds of the formula VI or X, can advantageously be prepared by combining one or more of the following steps of process a) -g): a) reaction of a nitro-o-methylphenyl compound of the formula II: wherein the radical R is as defined above with an organic nitrite R-ONO in the presence of a base, to give an oxime of formula III: wherein the radical R is as defined above; b) cyclization of the oxime of formula III with an alkene of formula IV: wherein R 3 to R 5 are as defined in claim 1, in the presence of a base to give the isoxazole of formula V: wherein R 1 and R 3 to R 5 are as defined in claim 1; c) reduction of the nitro group in the presence of a catalyst to give the aniline of formula IV: wherein R 1 and R 3 to R 5 are as defined in claim 1; d) • reaction of the aniline of the formula VI with a dialkyl disulfide of the formula VII: R '-S-S-R VII in the presence of an organic R-ONO nitrite and, if appropriate, a catalyst to give the thioether of the formula VIII: VIII wherein R1 to R5 are as defined in claim 1; e) bromination of the thioether of the formula VIII with a brominating agent to give the bromothioether of the formula IX. wherein R to R are as defined in claim 1; f) oxidation of the bromothioether of the formula IX with an oxidizing agent to give the isoxazoles of the formula X. where n is the numbers 1 or 2, g) If the reaction of the isoxazoline of the formula X with a compound of the formula R -OH (XI) in the presence of carbon monoxide, a catalyst and a base, is appropriate, give the compounds of formula I.

Essentially, the process according to the invention for preparing compounds X comprises one or more of the steps of process a) -f) or, in the case of compounds I, one or more of process steps a) -g ). Preference is given to those reaction sequences comprising one of the steps of process a) or d) or both steps a) and d). The C 1 -C 4 alkyl and C 1 -C 4 alkyl groups are straight or branched chain alkyl groups having 1-6 and 1-4 carbon atoms, respectively, for example, methyl, ethyl, n-propyl, isopropyl, n -butyl, isobutyl, n-pentyl or n-hexyl in all cases. This applies analogously to the C?-Cg alkoxy group. R is preferably an alkyl group, in particular a methyl, ethyl, isopropyl, n-propyl or n-butyl group [sic]. R3, R4 and R5 are preferably hydrogen. R and R together can also indicate a bond, giving rise to the 3 corresponding isoxazole derivatives. In this case, R is preferably hydrogen. In the definition of R, "heterocyclic ring" means a saturated, unsaturated or partially unsaturated heterocycle having 1, 2 or 3 oxygen atoms, sulfur or nitrogen. Preference is given to heterocycles having 2 nitrogen atoms. In particular, R is a pyrazole radical, as described in more detail in WO 98/31681. This is preferably a pyrazole which is attached in the 4-position and which may be substituted or unsubstituted by additional chemically inert radicals under the chosen reaction conditions. Suitable pyrazole substituents of this type are, for example, the following groups: hydroxyl, oxo, sulfonyloxy, Ci-Cß alkyl or Ci- alco alkoxy, in particular C alquilo-C4 alkyl at position 1. Particularly Preference R is the l-alkyl-5-hydroxypyrazol-4-yl group, in particular l-methyl-5-hydroxypyrazol-4-yl; l-ethyl-5-hydroxypyrazol-4-yl. The process according to the invention is particularly suitable for preparing the following compounds of the formula I: l-methyl-4- (3- (4,5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonylbenzoyl) - 5-hydroxypyrazole, l-ethyl-4- (3- (4,5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonylbenzoyl) -5-hydroxypyrazole, l-methyl-4- (3- (4, 5-dihydroisoxazol-3-yl) -2-ethyl-4-methylsulfonylbenzoyl) -5-hydroxypyrazole, l-methyl-4- (3- (4,5-dihydroisoxazol-3-yl) -2-propyl-4-methylsulfonylbenzoyl ) -5-hydroxypyrazole, l-methyl-4- (3- (4,5-dihydroisoxazol-3-yl) -2-butyl-4-methylsulfonylbenzoyl) -5-hydroxypyrazole.

Preferred intermediates of the formula VI are the following compounds: • 2- (4,5-dihydroisoxazol-3-yl) aniline, 2- (4,5-dihydroisoxazol-3-yl) aniline, 2- (4,5) -dihydroisoxazol-3-yl) -3-methylaniline, 2- (4,5-dihydroisoxazol-3-yl) -3-ethylaniline, 2- (isoxazol-3-yl) -aniline, 2- (isoxazol-3-yl) ) -3-methylaniline, g. 2- (isoxazol-3-yl) -3-ethylaniline. The preferred intermediates of formula X are the following compounds: 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4,5-dihydroisoxazole, 3- (3-chloro-2-methyl-6-methylsulfonylphenyl) - 4,5-dihydroisoxazole, 3- (3-bromo-6-methylsulfonylphenyl) -4,5-dihydroisoxazole, 3- (3-bromo-2-ethyl-6-methylsulfonylphenyl) -4,5-dihydroisoxazole, 3- (3-bromo-2-isopropyl-6-methylsulfonylphenyl) -4,5-dihydroisoxazole, 3- (3-bromo-2-methyl-6-ethylsulfonylphenyl) -4,5-dihydroisoxazole, 3- (3-bromo-2) - methyl-6-propylsulfonylphenyl) -4,5-dihydroisoxazole, 3- (3-bromo-2-methyl-6-butylsulfonylphenyl) -4,5-dihydroisoxazole, 3- (3-bromo-2-methyl-6-) pentylsulfonylphenyl) -4,5-dihydroisoxazole, 3- (3-bromo-2-methyl-6-hexylsulfonylphenyl) -4,5-dihydroisoxazole. A possible reaction sequence for the preparation of compounds X is summarized in the following diagram: The individual steps of the reaction are illustrated in more detail below: 1 . Step a) II III The reaction is carried out, for example, under the following conditions: the solvents used are dipolar aprotic solvents, for example N, N-dialkylformamide, N, N-dialkylacetamide, N-methylpyrrolidone (NMP), preferably: dimethylformamide (DMF) ) or NMP. The temperature is from -60 ° C to room temperature; preferably from -50 to -20 ° C. To achieve a sufficiently low melting point of the solvent system, it is also possible to use mixtures of solvents, for example with THF. The organic R-ONO nitrites used are alkyl nitrites (R = alkyl), preferably n-butyl nitrite or (iso) amyl nitrite. Suitable bases are: MO alkyl, MOH, RMgX (M = alkali metal); preferably potassium methoxide (KOMe), sodium methoxide (NaOMe), or potassium tert-butoxide (KOt butylate). When sodium bases are used, it is possible to add 1-10 mole% of amyl alcohol. The stoichiometric ratios are, for example, as follows: 1-4 equivalents of base, 1-2 equivalents of R-ONO; preferably: 1.5-2.5 base equivalents and 1-1.3 equivalents of R-ONO. 5 The addition, for example, is carried out in the following order: a) nitro-o-xylene and nitrite are initially charged and the base dosed, b) To avoid the addition of a solid base, the base may initially be charged in DMF, and the nitro-o-xylene / butyl nitrite can be added } 10 simultaneously. The speed at which the base is dosed is relatively slow, so that the required cooling is reduced to a minimum. The treatment is carried out by one of the following methods: a) precipitation of the product by agitation in water. b) Precipitation of product by adding a sufficient amount of water to the reaction mixture. The purification of the product is carried out by trituration with toluene at 0-110 ° C, preferably at room temperature. twenty 2. Step b) ITEM? The reaction is carried out, for example, by the following mechanical intermediates: conversion of the oxime III to an activated hydroxamic acid derivative, for example, hydroxamic acid chloride, by chlorination with a chlorinating agent, conversion of the hydroxamic acid derivative activated in the nitrile oxide, for example conversion of the hydroxamic acid chloride in the presence of a base in the nitrile oxide, and subsequent cycloaddition of the alkene IV in the nitrile oxide. This reaction is a new process for preparing isoxazole derivatives of formula V. Surprisingly, this process provides the isoxazolines in very good yields. In addition, only some products are formed, and these can also be separated relatively easily. In correspondence, on an industrial scale, it is easy to isolate and purify the final products, so that the isoxazolines can be prepared with high purity and at low cost. The use of the known processes for preparing isoxazolines to date has been disadvantageous, since isoxazolines could only be obtained in unsatisfactory yields starting from the reaction of benzaldoximes. In addition, the processes known from the prior art frequently use solutions containing alkali metal hypohalide which lead to the formation of very poorly soluble and unfavorable by-products for the environment. The process according to the invention is characterized in that the use of solutions containing alkali metal hypohalide can be avoided, the process in this way being essentially free of alkali metal hypohalides. The isoxazolines are prepared, for example, by the following method: initially, a hydroxamic acid chloride is formed which, in a second step, is cyclized with an alkene with measured addition of base, and if appropriate, under superatmospheric pressure. Advantageously, these individual steps can be combined in a reaction in "a kettle". For this purpose, the reaction is carried out in a solvent suitable for both partial steps, for example, a carboxylic ester, such as ethyl acetate, chlorobenzene or acetonitrile. The preparation of hydroxamic acid chlorides with N-chlorosuccinimide in DMF is known from the literature (Liu et al., J. Org. Chem. 1980; 45: 3916-3918). However, it is also mentioned that the conversion of o-nitrobenzaldoximes into hydroxamic acid chlorides by chlorination is possible only in poor yields (Chag J. Org, Chem. 1971, 36: 2146-2155). An expected side reaction is the formation of benzal chloride. Surprisingly, in the process described above, conditions were found that allow the preparation of the desired hydroxamic acid chlorides in excellent ! 10 returns. It is particularly advantageous if economic chlorine is used. The reaction is carried out, for example, under the following conditions: solvent: haloalkanes, such as 1,2-dichloroethane or methylene chloride; aromatic compounds, such as benzene, toluene, chlorobenzene, nitrobenzene or xylene; polar aprotic solvents, for example, N, N-dialkylformamides, acetamides, N-methylpyrrolidone, dimethylpropyleneurea; tetramethylurea, acetonitrile, propionitrile; alcohols, such as methanol, ethanol, n-propanol or isopropanol; carboxylic acids, such as acetic acid or propionic acid; carboxylic esters, such as ethyl acetate. Preference is given to the use of the following solvents: acetic acid, methanol, ethanol, 1,2-dichloroethane, methylene chloride, chlorobenzene or ethyl acetate. The reaction carried out at from -40 ° C to 100 ° C, preferably from -10 to 40 ° C or from 0 to 30 ° C. Suitable for use as halogenating agents are: N-chlorosuccinimide, elemental chlorine, preferably chlorine. The stoichiometric ratios are, for example, 1-3 equivalents of halogenating agent, preferably 1-1.5 equivalents. In the case of chlorine, the metered addition is carried out by the introduction of chlorine gas and N-chlorosuccinimide (NCS) is measured as a solid, if appropriate, in a suitable solvent. I 10 The treatment is carried out, for example, according to the following scheme: a) no purification. The solution is used directly additionally; b) exchange of solvent by distillative separation of the solvent; c) addition of water and extraction of hydroxamic acid chloride with a adequate solvent. By base addition, the hydroxamic acid chlorides are converted to the nitrile oxides. Since the latter compounds are unstable, the problem that had to be solved was to find conditions under which the nitrile oxides are stabilized and converted into the desired products. Surprisingly, this problem was solved by the selection of the following reaction conditions: the solvents used were: halogenated alkanes, such as 1,2-dichloroethane or methylene chloride; compounds Aromatics, such as benzene, toluene, chlorobenzene, nitrobenzene or xylene; polar aprotic solvents, for example: N, N-dialkylformamides, acetamides, N- • methylpyrrolidone, dimethylpropyleneurea; tetramethylurea, acetonitrile, propionitrile, carboxylic esters, such as ethyl acetate. Preference is given to using: 1,2-dichloroethane, methylene chloride, toluene, xylene, ethyl acetate or chlorobenzene. The temperatures for the reaction are from 0 ° C to 100 ° C, preferably 0-50 ° C or 0-30 ° C. • The bases used are: tertiary amines, for example: triethylamine, cyclic amines, such as N-methylpiperidine or N, N '-dimethylpiperazine, pyridine, alkali metal carbonates, for example sodium carbonate or potassium carbonate, metal bicarbonates alkaline, for example Sodium bicarbonate or potassium bicarbonate, alkaline earth metal carbonates, for example calcium carbonate, alkali metal hydroxides, for example sodium hydroxide or potassium hydroxide. Preference is given to using triethylamine, sodium carbonate, sodium bicarbonate or sodium hydroxide. The stoichiometric ratios are, for example, 1-3 equivalents of base, preferably 1-1.5 equivalents; 1-5 equivalents of alkene, preferably 1-2 equivalents. The dosed addition is preferably carried out under a superatmospheric alkene pressure, by slow addition of the base. The reaction is carried out, a, from atmospheric pressure to 10 atm, preferably at a pressure of 1-6 atm atmospheric pressure [sic].

Step c) V VI This reaction is a novel chemoselective hydrogenation, hitherto unknown, of a nitro group in the presence of an isoxazoline. Surprisingly, it was found that, under the chosen reaction conditions, the N-0 bond of the isoxazoline ring does not dissociate. The catalytic hydrogenation of aromatic nitro compounds to give the anilines has been conformed for a long time (see Houben-Weyl, vol IV / lc, p.506 ff). On the other hand, it is also known that NO bond of isoxazoline can be dissociated by catalytic hydrogenation, for example using Raney nickel (Curran et al., Synthesis 1986, 312-315) or palladium (Auricchio et al., Tetrahedron, 43, 3983-3986, 1987) as a catalyst.

The reaction is carried out, for example, under the following conditions: the aromatic compounds are suitable solvents, such as benzene, toluene, xylene; aprotic polar solvents, for example N, N-5 dialkylformamides, acetamides, N-methylpyrrolidone, dimethylpropyleneurea; tetramethylurea, carboxylic esters, such as ethyl acetate, ethers, such as diethyl ether or methyl tertiary butyl ether, cyclic ethers, such as tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol, n-propanol or | 10 isopropanol, carboxylic acids, such as acetic acid or propionic acid. Preference is given to using the following solvents: ethyl acetate, toluene, xylene, methanol. The reaction is carried out at temperatures from -20 ° C to 100 ° C; preferably from 0 to 50 ° C, particularly from preference from 0 to 30 ° C. The catalyst used is a palladium or platinum catalyst supported on activated carbon, with a content of 0.1 to 15% by weight, based on activated carbon as support. If a palladium catalyst is used, it can be impurified with sulfur or selenium to achieve better selectivity. Preference is given to using activated carbon / platinum or activated carbon / palladium having a Pt or Pd content of 0.5-10% by weight. The stoichiometric ratios for the reaction are, for example, as follows: from 0.001 to 1% by weight of platinum or palladium, based on the nitro compounds: preferably from 0.01 to 1% by weight of platinum. The hydrogen is dosed continuously or batchwise, preferably batchwise, at a pressure from atmospheric pressure to 50 atm, preferably from atmospheric pressure to 10 atm. 5 The reaction mixture is worked to remove the catalyst by filtration. If appropriate, the catalyst can be reused. The solvent is distilled. For the next reaction in the next step of the process, the product can be used directly without purification I 10 additional. If required, the product can also be further purified. The product is purified, for example, according to the following scheme: if required, the aniline can be purified by stirring it in a dilute mineral acid, for example acid Aqueous hydrochloric or dilute sulfuric acid, and extraction with a suitable organic extractant, for example halogenated alkanes, such as 1,2-dichloroethane or methylene chloride, aromatic compounds, such as benzene, toluene, chlorobenzene or xylene, ethers, such as diethyl ether or methyl tert-butyl ether or carboxylic esters, such as ethyl acetate and can be released again using a base.

Step d) VI VIII The reaction is carried out under the following conditions: the solvents used are, for example: halogenated alkanes, such as 1,2-dichloroethane or methylene chloride, aromatic compounds, such as benzene, toluene, chlorobenzene, nitrobenzene, or an excess of the disulfide of dialkyl as solvent. Preference is given to using excess dialkyl disulfide as the solvent. The temperature of the reaction is from 40 ° C to 150 ° C, preferably from 50 to 100 ° C, particularly preferably from 60 to 90 ° C. The reagents used are organic nitrites (R-ONO), such as, for example, alkyl nitrites, preferably n-butyl nitrite, nitrite (iso) amyl or tert-butyl nitrite. In this case, R is any chemically inert organic radical that has no effect on the actual reaction. R is, for example, an alkyl group of Ci-Cβ or alkenyl of C-Cg. In the reaction of the compounds, the stoichiometric ratios are, for example, as follows: 1-3 equivalents of alkyl nitrite, preferably 1-1.5 equivalents of alkyl nitrite. It is possible to use the following catalysts: copper powder, elemental copper in a different form, for example, chips, wires, granules, beads, rods; copper (I) salts, for example copper (I) chloride, copper (I) bromide or copper (I) salt iodide or elemental iodine, particularly preferably copper powder. When the reaction is carried out in the solvent, 1-3 equivalents of dialkyl disulfide, preferably 1-2 equivalents, are employed. In a preferred embodiment, an excess of dialkyl disulfide is used as the solvent and then recovered by distillation. For further reactions, the product can be used without further purification. If appropriate, it is also possible to purify the product beforehand by distillation or crystallization using suitable solvents, for example diisopropyl ether.

. IX The bromination is carried out as the method described in WO 98/31676. Acetic acid is an advantageous solvent. 6. Step f) IX The oxidation is carried out in the same way as the method described in WO 98/31676 (see p, line 32 to page 11, line 25).

Step g) The optional subsequent conversion of the compound of the formula X into compounds of the formula I is carried out by addition of R -OH (XI) in the presence of carbon monoxide and a suitable catalyst and base. If R is a substituted or unsubstituted pyrazole or pyrazolone ring, the reaction is preferably carried out using palladium-containing catalysts, such as, for example, Pd (0) catalyst or bis (triphenylphosphine) palladium (II) chloride. The process mentioned in step g) is a new and advantageous process for preparing compounds of the formula I which are obtained from halophenyl derivatives X by acylation or carboxylation with hydroxy-substituted heterocycles of the formula R6-OH (XI). EP-A 344 775 describes a process for preparing 4-benzoyl-5-hydroxypyrazoles in one step, where the synthesis is carried out starting from bromobenzenes and 5-1-hydroxypyrazoles in the presence of carbon monoxide, base and catalyst. The benzoyl radical of the target molecules can carry the following substituents in the 3-position: alkoxycarbonyl, alkoxy, alkoxymethyl. These substituents are considered to be relatively stable or inert chemically and allow the use of the drastic reaction conditions of the working examples. In contrast, the preparation of benzoyl-5-hydroxypyrazoles bearing less stable substituents at position 3, as is the case, for example, for the isoxazole or isoxazoline radical, is not described in EP 344 775, with respect to the drastic reaction conditions. In particular, due to its redox properties, the isoxazole or isoxazoline radical is considered a highly sensitive radical. A further disadvantage of the process known as EP-A 344 775 is the fact that 5-hydroxypyrazole is always used in a large excess. The process is illustrated below in more detail, using the example where R = pyrazole (XI.a) as a heterocycle. However, in principle, it is also possible to use other heterocyclic compounds, as defined at the beginning. The process is preferably carried out by reaction of a hydroxypyrazole of the formula XI. to: ? wherein R is C? -C? alkyl and M is hydrogen or an alkali metal atom, preferably sodium or potassium, and a bromobenzene of formula X: wherein R 1 to R 5 are as defined above, in the presence of carbon monoxide, a palladium catalyst, if at least one molar equivalent of a potassium salt and, if appropriate, at least one molar equivalent of a tertiary amine of formula XIII: N (Ra) 3 XIII wherein one of the Ra radicals can represent phenyl or naphthyl and the other Ra radicals are C? -C6 alkyl, at temperatures from 100 to 140 ° C at a pressure of from 1 to 40 kg / cm. In a preferred embodiment of the process, 5-hydroxypyrazole XI. a and the bromobenzene derivative X are used in a molar ratio from 1 to 2. Preference is given to use, as 5-hydroxypyrazole XI. a, 7 compounds, wherein R is Ci-Cß alkyl, in particular methyl or ethyl. The 5-hydroxypyrazoles (or pyrazolinones) of the formula XI. used as starting materials are known and can be prepared by processes known per se (see EP-A 240 001, WO 96/26206 and J. Prakt. Chem. 315 (1973), 382). In general, 5-hydroxypyrazole XI. a is used in equimolar or excess amounts, based on the bromobenzene derivative X. For reasons of economy, it makes sense to avoid a relatively large excess of 5-hydroxypyrazole. Under the reaction conditions, according to the invention, the stoichiometric reaction gives the same yields as those obtained if an excess of 5-hydroxypyrazole was used. This was surprising, since a large excess of 5-hydroxypyrazole is used in all the examples of the processes described in EP-A 344 775. In the process according to the invention, the molar ratio of 5-hydroxypyrazole to bromobenzene is preferably adjusted to 1 -2 and particularly preferably up to 1.0-1.2. Above 140 ° C decomposition occurs, and below 100 ° C, the reaction is interrupted. The reaction, in this way, is generally carried out in a temperature range from 100 to 140 ° C, preferably from 110 to 130 ° C. Surprisingly, it has been found that high pressure in the range of up to 150 kg / m normally required for the reaction (cf. details in EP 344 775) can be reduced to a value no greater than 40 kg / cm, preference of up to 20 kg / cm 2 or even up to 10 kg / cm2, without this having an adverse effect on the reaction conditions, such as reaction temperature or reaction time, or causing a loss of performance. The reaction pressure is preferably at least 3 kg / cm, in particular at least 5 kg / cm. Suitable pressure ranges are, for example: 1-40 kg / cm 2, 5-20 kg / cm2 or 10-20 2 kg / cm, in particular 3-10 and particularly preferably 5-8 kg / cm2.

This reduction in pressure is particularly advantageous if the preparation process is carried out on an industrial scale, since the safety requirements that have to be met with respect to the used pressure vessels 5 are less severe. In this way, the cost of using the high pressure vessels can be dispensed with this. Accordingly, the preparation process described in g) is safe and more economical. In addition, surprisingly it was found that the compounds The palladium materials used as catalysts are, under the chosen reaction conditions, mainly obtained as elemental palladium and can be removed from the reaction mixture in a simple manner by filtration. In this way, the concentration of the reaction solution that contains palladium for subsequent disposal, which is complicated and expensive, and any incineration of the waste can be substantially omitted. This reduces recycling costs. The pore size of the palladium precipitate is 1-10 μ, in particular 1-4 μ. Palladium Filtering in this way can be worked at a lower cost to give the corresponding palladium compounds such as palladium chloride, since the recycling costs depend on the concentration of the palladium. Suitable solvents for the reaction in step g) of the process are nitriles, such as benzonitrile and acetonitrile, amides, such as dimethylformamide, dimethylacetamide, tetraalkylureas of C? -C- or N-methylpyrrolidone, and preferably ethers, such as tetrahydrofuran and methyl ter -butyl ether. Particularly preferable solvents are ethers such as 1,4-dioxane and dimethoxyethane. The. Suitable catalysts are ligand-palladium complexes in which palladium is present in the oxidation state 0, palladium metal, if suitable in a support, and preferably palladium salts (I) (II). The reaction with palladium (I) (II) salts and metallic palladium is preferably carried out in the presence of complex ligands. A suitable palladium (I) (0) ligand complex is, for example, tetrakis (triphenylphosphane) palladium. The metal palladium is preferably absorbed in an inert carrier material, for example, activated carbon, silica, alumina, barium sulfate or calcium carbonate. The reaction is preferably carried out in the presence of complex ligands, for example triphenylphosphane. Suitable palladium (II) salts are, for example, palladium acetate and palladium chloride. The reaction is preferably carried out in the presence of complex ligands, for example, triphenylphosphane. Suitable complex ligands for ligand-palladium complexes, or those in which the reaction with palladium metal or palladium (I) (II) salts is preferably carried out, are tertiary phosphates whose structure is represented by the following formulas: wherein n is a number from 1 to 4 and the radicals R to R are C 1 -C 6 alkyl, C 1 -C 2 arylalkyl or, preferably, aryl. Aryl is, for example, naphthyl and substituted or unsubstituted phenyl, such as, for example, 2-tolyl and, in particular, unsubstituted phenyl. The complex palladium salts can be prepared in a manner known per se from commercially available palladium salts, such as palladium chloride or palladium acetate, and the corresponding phosphanes, for example: triphenylphosphane or 1,2-bis (diphenylphosphane) ethane Many complex palladium salts are also commercially available. Preferred palladium salts are [(R) (+) 2, 2-bis (diphenylphosphane) -1,1-biphenyl] palladium (II) chloride, bis (triphenylphosphane) palladium (II) acetate, and in particular , bis (triphenylphosphane) palladium (II) chloride. In general, the palladium catalyst is used in a concentration from 0.05 to 5 mol%, preferably from 1 to 3 mol%. The amines N (Ra) 3 of structure XIII which are suitable for the processes are tertiary amines, for example N-methylpiperidine, ethyldiisopropylamine or 1,8- 5-bisdimethylaminonaphthalene or, in particular, triethylamine. Suitable potassium salts are, for example, potassium phosphate, potassium cyanide and, in particular, potassium carbonate. Advantageously, the water content of the potassium salt should be low. For this reason, carbonate I 10 potassium was, before use, generally dried at at least 150 ° C. The amount of potassium salt used is advantageously at least one molar equivalent. Otherwise, the reaction speed will be reduced, or the rearrangement of Fries intermediary will not proceed completely, and O-acylated pyrazole derivatives will be obtained. Preferably, in each case from 2 to 4 molar equivalents and particularly preferably 2 molar equivalents of potassium salt are employed, based on bromobenzene III. In addition to the potassium salt, the reaction mixture is preferably also mixed with an amine N (Ra) 3 of the formula XIII in which one of the radicals Ra can be phenyl or naphthyl and the other radicals Ra are alkyl C ? ~ Cß. Preferably, 1 to 4 molar equivalents, Particularly preferably 2 molar equivalents of amine XIII are used, based on bromobenzene X. To work, the reaction solution is usually introduced into water. If the reaction is carried out in a water-miscible solvent, such as 1,4-dioxane, it may be advantageous to remove in advance some or all of the solvent from the reaction mixture, if appropriate, under reduced pressure. Any of the solid components is then removed from the aqueous alkaline reaction mixture, and a pH from 2.5 to 4.5, preferably 3.5, is established by acidification with a mineral acid, for example, hydrochloric acid, causing almost complete precipitation of the product of value. The isoxazoline radical, in particular, is sensitive to hydrolysis. In processes for preparing benzoylpyrazoles containing this radical, preferably a pH of less than 2 should be avoided. Acylation in process step g) is preferably carried out under the following process conditions: solvent: dioxane or mixtures of dioxane and acetonitrile . Temperature: 110-130 ° C. Pressure: 5-8, preferably approximately 6 kg / cm. Catalyst: palladium chloride (II). The molar ratio of the heterocyclic hydroxy compounds (such as, for example, 5-hydroxypyrazole) to the bromobenzene derivatives: from 1 to 2 and particularly preferably from 1.0 to 1.2. Alternatively to the synthesis route shown in Scheme 1, the compounds of formula X can also be prepared according to Schemes 2 and 3 below. • Scheme 2 shows a possible synthesis route for bromobenzene derivatives of the type of formula X using the synthesis of 3- [3-bromo-2-methyl-6- (methylsulfonyl) phenyl] -4,5-dihydro-isoxazole as an example. The individual steps of the process can be carried out following the usual standard methods. • 10 Scheme 2 Scheme 3 shows another possible synthesis route for bromobenzene derivatives of the type of formula X.

Scheme 3: The bromination of compounds of the formula VI is carried out similarly to the direct bromination of anilines. If the reagent used is tetrabutylammonium tribromide, in some cases it is possible to achieve selective monobromination at the position of the amine function (Berthelot et al., Synth.

Commun. 1986, 16: 1641). However, a general problem in such brominations is the formation of polybrominated products (Bull, Chem. Soc. Jpn. 1988, 61: 597-599). Thus, for example, the reaction of VI with tetrabutylammonium tribromide in a methanol / water mixture with calcium carbonate as a base gives a product mixture containing approximately 25% by-product dibromide. The separation of the product mixture is critical in particular when the substituents include isoxazole or isoxazoline radicals, which, taking into account their redox properties, are considered as labile under the chosen reaction conditions. Now we have found conditions that allow the desired product XIV to be prepared with good yields, without forming more highly brominated byproducts. In accordance with the reaction conditions of the invention, the preferred reagent is tetrabutylammonium tribromide. The solvents used are haloalkanes, such as 1,2-dichloroethane or methylene chloride, alcohols, such as methanol, ethanol, n-propanol, isopropanol or aliphatic nitriles, such as acetonitrile, preferably acetonitrile. The preferred base [sic] is potassium carbonate. The brominated intermediates XIV can then be converted to the isoxazol-2-ylbromobenzenes X according to the invention by different routes. Intermediates for preparing compounds IX from XIV or compounds X from IX can be prepared by the aforementioned processes. However, it is alternatively also possible to convert the anilines initially to the sulfonyl chlorides X.c (see Houben-Weyl, vol.9, pp. 575-580). The sulfonyl chlorides can be converted by reduction, for example, using sodium sulphide, by the sulfinic acid step (see Houben-Weyl, vol.9, pp. 306-307), and subsequent alkylation (see Houben-Weyl, vol IX, pp. 231-233), in the alkyl sulfones. The two steps can advantageously be combined in a "reaction vessel". This synthesis has the advantage that favorable raw materials are used to introduce the alkylsulfonyl groups. The oximation of the substituted toluenes, used in the step of process a) of the process according to the invention, is a new and advantageous method for converting toluene derivatives to benzaldoximes. In principle, this method is suitable for preparing benzaldoximes of the formula XV wherein the radicals are as defined below: X is N02, S (0) nRy, Rx is any inert radical Ry is any inert radical m is 0, 1, 2, 3 or 4, n is 0, 1 or 2. Rx and Ry are any organic radical that can be identical or different and are inert under the chosen reaction conditions. Rx can, for example, be: halogen, such as, for example, chlorine, bromine or iodine; carboxyl; carboxamide; N-alkylcarboxamides and N, N-f) dialkylcarboxamides; phenyl; C -C6 alkyl, such as, for example, methyl, ethyl; C6-C6 alkoxy; alkylthio of C? -Cg u other radicals. If m > l, Rx can in each case be identical or different. Rx preferably has the same meaning as R and is located ortho for the oxime group -CH = N0H. m is, in particular, the number 2, one of the Rx substituents ^^ has the same meaning as R and the second substituent Rx being a halogen atom that is preferably located meta for the oxime group. Ry is preferably C? -Cg alkyl, for example methyl, ethyl, propyl. Preferred compounds XV are those in which X is the group S02-Ry and m is the number 2. In this case, one of the radicals Rx is preferably halogen (for example bromine or chlorine) and is located meta for the oxime group. The second radical Rx is preferably C 1 -C 6 alkyl (for example methyl, ethyl) and is located ortho to the oxime group. According to the invention, the compounds of the formula XVI (o-nitrotoluene or o-alkylsulfonyl toluene) Wherein the substituents are as defined above are reacted with an organic nitrite of the formula R-ONO, as already defined, in the presence of a base. The nitrosation of o-nitrotoluene has been described in the literature (Lapworth, J. Chem. Soc. 79 (1901), 1265). However, even in this first work, a dimeric byproduct is mentioned. Subsequent work only describes the preparation of dimeric products under similar reaction conditions (Das et al., J. Med. Chem. 13 (1970), 979). The repetition of the experiment described in the literature using o-nitrotoluene shows that, indeed, 2-nitrobenzaldoxime is formed in small amounts. When the described conditions were applied to 3-nitro-o-xylene, only dimer XVIII was formed.

XVII XVIII By additions of Michael, which proceed under similar conditions, the literature similarly mentions that this does not happen with 3-nitro-o-xylene (Li, Thottathil, Murphy, Tetrahedron Lett 36 (1994), 6591). From what has been described, therefore, it would not be expected that the benzaldoximes can be prepared in excellent yields from 2-nitrotoluene substituted in the 6-position. Furthermore, surprisingly it was found that the alkyl sulfonates (X = S02Ry) can , under comparable conditions, likewise be oximedas in the methyl group in the position o. The compounds prepared by the process according to the invention are important intermediates in the production of active compounds for crop protection agents (WO 98/31681). The reaction is preferably carried out under the following conditions: The solvents used are: dipolar aprotic solvents, for example: N, N-dialkylformamide, N, N-dialkylacetamide, N-methylpyrrolidone, preferably DMF, NMP. The temperature is from -60 ° C to room temperature; preferably from -50 to -20 ° C. The preferred nitrite or alkyl nitrite is n-butylnitrite and (iso) amyl nitrite. Suitable bases are: (M = alkali metal): MOalkyl, MOH, RMgX; preferably KOMe, NaOMe, KOt-butoxide. If sodium bases are used, preference is given to adding 1-10 mole% of amyl alcohol. The stoichiometry is as follows: 1-4 base equivalents, 1-2 equivalents of ROCIO; preferably: 1.5-2.5 base equivalents, 1-1.3 equivalents of ROCK (ie, an organic nitrite). The order of addition: a) nitro-o-xylene and nitrite are initially charged and the base is introduced, b) To avoid having to dose the base as a solid, it is possible to initially load the base in DMF and add nitro-o- 5 xylene / butyl nitrite simultaneously. It is advantageous to introduce the base for a relatively long period of time, in order to reduce the required cooling. The work is carried out, for example, as follows: a) precipitation by agitation of the mixture in water / acid. B) ! 10 Precipitation by addition of a sufficient amount of water / acid. Suitable acids are mineral acids, such as sulfuric acid, hydrochloric acid or phosphoric acid, or even other carboxylic acids, such as acetic acid. The purification of the product: by trituration with toluene, a from 0 to 110 ° C, preferably at room temperature. If the reaction is carried out at a relatively high temperature (from -10 to 0 ° C), followed by further stirring at room temperature, the treatment provides the benzonitriles directly. In addition, it is It is possible to release the aldehyde function from the benzaldoximes of the formula XV in the presence of an acid catalyst and an aliphatic aldehyde, for example an aqueous formaldehyde solution. Suitable solvents are halogenated alkanes, such as 1,2-dichloroethane or methylene chloride, Aromatic compounds, such as benzene, toluene, chlorobenzene, nitrobenzene or xylene, polar aprotic solvents, for example N, N-dialkylformamides, -acetamides such as N-methylpyrrolidone, dimethylpropyleneurea; tetramethylurea, tetrahydrofuran, acetonitrile, propionitrile or acetone, if appropriate with addition of water. Particularly advantageous are aqueous acetone (1 to 20% water), dioxane / water mixtures and tetrahydrofuran / water mixtures. The reaction is carried out at temperatures from room temperature to the reflux temperature of the solvent, preferably from 30 to I 10 70 ° C. Suitable acids are mineral acids such as aqueous hydrochloric acid, sulfuric acid or phosphoric acid, and acidic ion exchangers, such as Amberlyst 15 or Dowex 50W x 8. In the case of the compounds of the formula XV, the group The oxime -CH = NOH can then be converted to the corresponding aldehydes (-CHO) or even to the corresponding nitriles (-CN). These compounds are important building blocks of synthesis for preparing active compounds of the formula I (see WO 98/31681). The step of thioalkylation employed in process step d) of the process according to the invention is a new and advantageous method for converting aniline derivatives to thioether derivatives (thioalkylation of aniline derivatives). In principle, the method is generally adequate for Prepare thioethers of the formula XIX wherein R x is any inert radical, m is a number from 0 to 5 and R is an alkyl group of C? -C g, which consists in reacting an aniline of the formula XX with a dialkyl disulfide of the formula VII R2 - R 'VII in the presence of a catalyst. Preferred catalysts are copper powder, in particular copper powder with a particle size of less than 70 μ or elemental copper in another form, such as, for example, chips, wire, granules, beads or rods. In the compounds of the formula XIX and XX, Rx is any chemically inert radical under the reaction conditions chosen during the reaction with the compounds of the formula VII. In this sense, suitable groups Rx are, for example: hydrogen, alkyl, haloalkyl, halogen, cyano, nitro, alkoxy, haloalkoxy, alkylthio or heterocyclic radicals as mentioned in the beginning, in the definition of R. A heterocyclic radical is, in particular, a 5-membered heterocyclic ring substituted with saturated, partially saturated or aromatic alkyl of the group of isoxazolines, isoxazoles, thiazolines, thiazoles, oxazoles and pyrazoles. The compounds of formula XIX and XX may carry one or more, preferably one, two or three I 10 Rx substituents which may be identical or different. Rx is preferably an alkyl group of C? -Cg, for example methyl, ethyl or propyl, m is preferably the number 1 or 2. If m is the number 1, Rx is preferably 2 ortho or meta with the group -SR (in the casp of compounds XIX) 15 or towards the amino group (in the case of compounds XX). If m is the number 2, the second radical Rx is preferably ortho and meta with the group -S-R or with the amino group. The thioethers of the formula XIX are useful intermediates for preparing active compounds in the chemical industry, for example for preparing crop protection agents (for example, WO 96/11906; WO 98/31676) or for the preparation of medicaments. A process that is frequently used to introduce alkylthio functions is the exchange of a halogen (EP 0 711 754). However, the process described in this publication has the disadvantage that it is limited to aromatic compounds that are substituted by radicals that are strong electron acceptors. In addition, the preparation often requires high temperatures. Under these reaction conditions, other sensitive functional groups are chemically modified, resulting in complex reaction mixtures that are difficult and expensive to purify, or where, in certain cases, the separation of the impurities is not possible at all. In addition, suitable precursors do not I »10 are always available in the trade. The methods for preparing arylalkyl sulfides from aniline are known, but these methods have serious disadvantages. Sandmeyer's reaction, for example, requires the use of equimolar amounts of alkylthiolate of copper (Baleja, Synth, Commun. 14 (1984), 215-218). The yields that are usually obtained are only in the range from 2 up to One more method that has been described is the reaction of aromatic amines with alkyl nitrites in sulfur Excess alkyl (Giam et al., J. Chem. Soc., Chem. Commun 1980, 756-757). Here, it is a problem that, in some cases to a considerable degree, side reactions occur, causing low yields and a high cost in the purification of the product. In addition, it was noted that, if the The reaction is carried out in an inert diluent, a vigorous reaction which was difficult to control is established after the induction phase, thus excluding its use on an industrial scale. It is an object of the present invention to provide an alternative process for the preparation of thioethers. Using the preparation process according to the invention, it is possible to prepare alkylaromatic thioethers advantageously from aniline. Using the process, it is possible to carry out the preparation in a simple way, at a low cost and efficiently, taking into account ecological and economically advantageous aspects. According to the invention, the reaction of the aniline with a dialkyl disulfide and an organic R-ONO nitrite is carried out according to the reaction shown in the above reaction scheme, in the presence of a catalyst, preferably elemental copper. Comparative experiments have shown that, under the conditions according to the invention, considerably better yields are obtained and less byproducts are formed than when catalyst is used. In addition, the reaction is easy to control and suitable for use on an industrial scale. The reaction is carried out under reaction conditions specified in more detail as follows: suitable solvents are halogenated alkanes, such as 1,2-dichloroethane or methylene chloride, or aromatics, such as benzene, toluene, chlorobenzene or nitrobenzene. Alternatively, it is also possible to use an excess of dialkyl disulfide itself as a solvent. This variant is particularly advantageous. The temperatures for the reaction are from 40 ° C to 150 ° C, preferably from 60 to 100 ° C and, in particular, from 70 to 90 ° C. In the reaction, it is advantageous to add a C n-Cg alkyl nitrite reagent. Suitable for this purpose are, for example, n-butyl nitrite, (iso) amyl nitrite and tert-butyl nitrite. In this case, the stoichiometry is, for example: 1-3 equivalents of alkyl nitrite, preferably 1-1.5 equivalents of alkyl nitrite. Suitable catalysts are copper or elemental copper powder in another form, copper (I) salts, for example copper (I) chloride, copper (I) bromide or copper (I) iodide, copper (II) salts , or elemental iodine, preferably copper powder or elemental copper in another form. The reaction, for example, is carried out under the following stoichiometric ratios: if the reaction is carried out in a solvent: 1-3 equivalents of dialkyl disulfide, preferably 1-2 equivalents. If the reaction is carried out without additional solvent, that is, if the dialkyl disulfide is used as a solvent: an excess of dialkyl disulfide or a mixture of dialkyl disulfide is used, the distillative recovery being possible. The product is purified, for example, by distillation or crystallization (for example from diisopropyl ether). The present invention further provides a process for preparing compounds X using the process described above for the oximation of substituted toluenes XVI (cf process step a)) and / or using the process described above for the thioalkylation of aniline derivatives XX (cf. process step d)). In the reaction scheme 4 below, a suitable preparation process is described using the example of a compound X wherein R 1 = CH 3, R 2 = CH 3, R 3 = R 4 = R 5 = H. In principle, the process is also suitable for preparing compounds X, wherein the radicals R -R are as defined.

Scheme 4 step a) The invention is illustrated in more detail in the following working examples. Examples 1-9 refer to process steps a) -g). Examples 10-26 relate to the preparation of the raw materials or intermediates, or are corresponding comparative examples. Example 27 refers to the reaction sequence for preparing compounds X, shown in scheme 4.

Example 1 Preparation of 2-methyl-6-nitrobenzaldoxime (process step a) - variant A) A solution of 274 g (2.6 mol) of n-butyl nitrite (97%) and 300 g (2.0 mol) of 3- Nitro-o-xylene (97%) in 750 ml of dimethylformamide is cooled to -55 to -60 ° C, and a solution of 522 g (4.56 mol) of potassium tert-butoxide in 750 ml of dimethylformamide is added. drop at this temperature for a period of 2.5 hours. During the addition, the color of the solution changes from yellow to dark red and the solution becomes viscous. The reaction is verified by HPLC. For the treatment, initially 300 ml of water and then approximately 300 ml of glacial acetic acid are added, until the pH reaches 5-6. During the addition, the temperature increases to -10 ° C, and a yellow suspension forms. The reaction mixture is then poured into 6 kg of ice water and the residue which is formed is filtered off with suction, washed with 5 l of water and dried in a drying cabinet at 30 ° C overnight. This gives 339 g of a light beige crude product that is released from the impurities by suspension in about 3 hours. 1 of toluene at 80-90 ° C for two hours. After cooling, the product is filtered with suction and dried. This gives 276 g of 2-nitro-6-methyl-benzaldoxime. Yield: 77%, m.p .: 190-192 ° C, purity (according to HPLC): 98%.

Example 2: Preparation of 2-methyl-6-nitrobenzaldoxime (process step a) - variant B) 1200 ml of anhydrous DMF are initially charged to a 4 1 reaction vessel and cooled to -40 ° C. At this temperature, 336.5 g (4.56 mol) of potassium methoxide (95%) are added and suspended with stirring. Then a mixture of 300 g (1.92 mol) of 3-nitro-o-xylene (97%) and 274 g (2.52 mol) of n-butyl nitrite (95%) is added dropwise at -40 ° C by a period of 7 hours (if the mixture cools accordingly, the duration of this addition can be reduced as desired, a longer period of addition has not yet been tested, temperature variations between -35 and -45 ° C are tolerated ). The complete conversion of the raw material is verified by HPLC. The reaction discharge is then added with stirring, from -5 to 0 ° C, to a mixture of 300 ml of water and 300 ml of glacial acetic acid. The reaction mixture is then poured into 6 kg of ice water and the solid is separated by filtration (without any problem, the filtrate resistance has not yet been determined) and washed twice in each case with 500 ml of water (care : the raw product has an intense smell). The crude product (HPLC: 96% area) is purified by suspending the wet solid in 800 ml of toluene for 1.5 h. The solid is filtered (without any problem, the filter resistance has not yet been determined) and it is dried at 50 ° C in a vacuum drying cabinet. Yield: 306 g (HPLC: area 99.4% product, E / Z mixture), corresponds to 85% theoretical.

Example 3 Preparation of 3- (2-methyl-6-nitrophenyl) -4,5-dihydroisoxazole (process step b)) a) At 60 ° C, a small amount of a solution of 3.71 g (28 mmol) of N Chlorosuccinimide in 30 ml of acetonitrile is added to a solution of 5 g (28 mmol) of 2-methyl-6-nitrobenzaldoxime in 50 ml of acetonitrile. Once the reaction has begun, the rest of the solution is slowly added dropwise at 40-50 ° C. The mixture is stirred for another 20 minutes until the conversion is complete by HPLC. This gives an orange solution that is carefully concentrated. The residue is suspended in 50 ml of toluene for about 1.5 hours and the solution is separated from the succinimide. The filtrate is still orange-red. The solution is loaded in a mini autoclave, and an ethylene pressure of 30 bar is applied. Then, for a period of 5 hours, a solution of 4.7 g of sodium bicarbonate in 50 ml of water is metered in, and the mixture is stirred at an ethylene pressure of 30 bar for another 5 hours. For the treatment, the phases are separated and the toluene phase is washed 2x with NaHC03 solution and lx with water, dried and concentrated. Yield: 4.9 g (86%), brownish brown crystals, m.p .: 100-105 ° C. 1H-NMR (CDC13): d = 8.00 (d, 1H); 7.57 (d, 1H), 7.49 (t, 1H); 4.60 (t, 2H); 3.32 (t, 2H); 2.41 (s, 3H). b) 100 g of 2-methyl-6-nitrobenzaldoxime are dissolved in 750 ml of glacial acetic acid, and then chlorine is introduced for two hours. The excess chlorine is washed with nitrogen. The glacial acetic acid is then distilled and the residue is suspended in 1000 ml of toluene. The reaction mixture is charged in the autoclave, and an ethylene pressure of 6 bar is applied. For a period of one hour, 55.6 g of triethylamine (1 equivalent) in 300 ml of toluene are metered in, and the mixture is stirred at room temperature and under 6 bar of ethylene for 10 h. The mixture is washed once with saturated aqueous NaHCO 3 solution and once with water. The organic phase is dried over sodium sulfate, filtered and concentrated using a rotary evaporator. Yield: 96.3 g (87% theoretical).

Example 4 Preparation of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline (process step c)) a) A solution of 117 g (0.57 mol) of 3- (2-methyl-6-nitrophenyl) ) -4,5-dihydroisoxazole in 1.2 1 ethyl acetate and 11.7 g of a catalyst containing 5% by weight of platinum on carbon are added to an autoclave for hydrogenation. Then the autoclave is washed twice with nitrogen. At a hydrogen pressure of 20 bar, the mixture is then hydrogenated at 25-30 ° C during 48 hours, with vigorous agitation. The reaction discharge is suction filtered through silica gel and the solvent is removed under reduced pressure. Is all 94 g of a brown solid which is taken in methyl tert-butyl ether and water and extracted with ÍM hydrochloric acid. The aqueous phase is adjusted to pH 10-11 and extracted with methylene chloride. The methylene chloride phase is dried over magnesium sulfate and the solvent is removed.

Yield 87 g (87%) of an orange solid, m.p.:86-88 ° C, purity according to HPLC 97%. The product can be further purified by stirring with refluxing methyl tert-butyl ether: mp: 90-91 ° C, purity according to 100% HPLC. b) A solution of 1000 g (4.85 mol) of 3- (2-methyl-6-nitrophenyl) -4,5-dihydroisoxazole in 5.5 1 of methanol and 4.6 g of a catalyst containing 10% by weight of palladium on carbon they are added to a hydrogenation autoclave. The autoclave is then washed twice with nitrogen. At a hydrogen pressure of 2.5 bar, the mixture is then hydrogenated at 25-30 ° C for 17 hours, with vigorous stirring. The reaction is filtered off with suction through silica gel and the solvent is removed under reduced pressure. This gives 781.8 g of a light brown solid. Yield 781.7 g (85%) (content according to 93% HPLC).

Example 5 Preparation of 3- (2-methyl-6-methylthiophenyl) -4,5-dihydroisoxazole (process step d)) 19.5 g (170 mmol) of tert-butyl nitrite and 20 g of copper powder are lightly charged in 30 ml of dimethyl disulfide, and a solution of 20 g (114 mmol) of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline in 100 ml of dimethyl disulphide are added dropwise to, from 50 to 55 ° C. The mixture is then stirred at 60 ° C for 1.5 hours. For treatment, the solid is filtered with suction and the solution is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with saturated aqueous NaHCO 3 solution, dried over sodium sulfate, filtered and concentrated. The excess dimethyl disulfide is removed under vacuum with an oil pump. This gives 23.4 g (99%) of a dark oil that solidifies after a while. (Content according to HPLC 100%). The product can be further purified by stirring in methyl tert-butyl ether, m.p .: 66-67 ° C.

Example 6 Preparation of 3- (3-bromo-2-methyl-6-methylthiophenyl) -4,5-dihydroisoxazole (process step e)) At 0 ° C, 10 g (48 mmol) of 3- (2-methyl) -6-methylthiophenyl) -4,5-dihydroisoxazole is added a little at a time to 120 ml of conc. Sulfuric acid, and the mixture is stirred for about 30 minutes. 3.7 g (23 mmol) of bromine are then added dropwise, the mixture is stirred at 0 ° C for 2.5 hours. The mixture is then allowed to warm to room temperature for a period of about 45 minutes. A homogeneous solution is formed. For the treatment, the reaction mixture is poured into cold water and extracted three times with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried with magnesium sulfate and concentrated. This gave 11.4 g of crude product which is used for the next step without further purification.

Example 7 Preparation of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4,5-dihydroisoxazole (process step f)) At not more than 45 ° C, 11.3 g (100 mmol) of hydrogen peroxide 30% concentration is added dropwise to a solution of 11.4 g (40 mmol) of 3- (3-bromo-2-methyl-6-methylthiophenyl) -4,5-dihydroisoxazole and 400 mg of sodium tungstate hydrate in 100 ml of glacial acetic acid. The reaction mixture is stirred at room temperature overnight. For the treatment, the mixture is poured onto cold water and extracted with methylene chloride, and the organic phase is washed with aqueous sodium sulfite solution, dried over magnesium sulfate and concentrated. Yield: 9.6 g. For purification, the product can be recrystallized from 65 ml of isopropanol. Yield: 7.7 g (50% in two steps), m.p .: 137-139 ° C.

Example 8 l-Methyl-4- (3- (4,5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonylbenzoyl) -5-hydroxypyrazole (process step g) - variant A) 2.2 1 of 1, 4-dioxane, 100 g (0.315 mol) of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4,5-dihydroisoxazole, 30.82 g (0.315 mol) of l-methyl-5-hydroxypyrazole, 87 g (0.63 mol) of potassium carbonate, 63.5 g (0.63 mol) of triethylamine and 11.2 g (0.016 mol) of bis (triphenylphosphine) -palladium dihydrochloride were added to an autoclave of 3.5 1. The autoclave was then washed twice with nitrogen, a pressure of 10 kg / cm of carbon monoxide was applied and the mixture was heated with stirring to 130 ° C. The carbon monoxide pressure was increased to 20 kg / cm and the mixture was stirred at 130 ° C for 24 h. The mixture was then concentrated under reduced pressure and the residue was received in water. The aqueous phase of pH 11 was extracted with dichloromethane. The organic phase is discarded. The aqueous phase is adjusted to pH 4 using hydrochloric acid 18% concentration. The precipitate was filtered, washed three times with water and dried at 40 ° C under reduced pressure. This gives 85 g of product. The filtrate is extracted with dichloromethane. The organic phase is dried with sodium sulfate, and the solvent is then removed under reduced pressure, giving others 12.7 g of product.

Yield 97.7 g (85.6%), m.p .: 215-219 ° C, XH-NMR (CDC13): d = 2.38 (s); 3.23 (s); 3.41 (bs); 3.74 (s); 4.61 (t); 7.37 (s); 7.64 (d); 8.16 (d).

Example 9 l-Methyl-4- (3- (4,5-dihydroisoxazol-3-yl) -2-methyl-4-methyl-sulfonylbenzoyl) -5-hydroxypyrazole (process step g) - variant B) 2 1 1,4-dioxane, 250 g (0.77 mol) of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4,5-dihydroisoxazole, 77 g (0.77 mol) of l-methyl-5-hydroxypyrazole, 269 g (1.93 mol) of potassium carbonate, 197 g (1.93 mol) of triethylamine, 1.39 g (0.0077 mol) of palladium chloride (II) and 4.12 g (0.0154 mol) of triphenylphosphine were added to an autoclave of 3.5 1 The autoclave was washed twice with nitrogen, the mixture was heated with stirring to 130 ° C and a carbon monoxide pressure of 6 kg / cm was applied. By continuous addition of carbon monoxide, the carbon monoxide pressure was kept constant at 6 kg / cm and the mixture was stirred at 130 ° C for 36 h. The mixture was then mixed with 1 1 of demineralized water and the precipitated palladium was filtered on a blue band filter. (pore size 2 to 3 μ) and washed with water. Dioxane, triethylamine and some of the water were then distilled in a single pass (150 mbar or atmospheric pressure). The aqueous phase was adjusted to pH 2.5 using 20% strength sulfuric acid and stirred at 5 ° C for 12 h, while the pH was being readjusted. The precipitate was filtered, washed three times with water and dried at 70 ° C under reduced pressure. This gave 227 g of product (100% heat). Yield 227 g (81%), m.p .: 215-219 ° C, 1 H-NMR (CDC13): d = 2.38 (s); 3.23 (s); 3.41 (bs); 3.74 (s); 4.61 (t); 7.37 (s); 7.64 (d); 8.16 (d). Palladium recovery speed in the filter: 85-98% Palladium elemental analysis that was filtered (dry): 48% Pd, 22%, 11% C, 1.3% H, 0.2% P, 0.2% S, Br < 0.5%, Cl < 0.5%, N < 0.5% Example 10 Preparation of 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline 30 g (170 mmol) of 2- (4,5-dihydroisoxazol-3-yl) -3-methylaniline was dissolve in 400 ml of acetonitrile, and 94 g (0.68 mol) of potassium carbonate are added. At a temperature < 30 ° C, 84 g (174 mmol) of tetrabutylammonium tribromide are then added a little at a time, with vigorous stirring. For treatment the solid is filtered with suction and the solution is diluted with methylene chloride and extracted with water. The solvent is removed from the residue and then taken up again in methyl tert-butyl ether and washed twice with water. The organic phase is dried and concentrated. Yield 20.4 g (47%) of a brown solid, m.p .: 126-130 ° C, purity according to HPLC 97%.

Example 11 Preparation of 4-bromo-2- (4,5-dihydroisoxazol-3-yl) -3-methyl-benzenesulfonyl chloride At 15 ° C, a solution of 9 g (35 mmol) of 4-bromo-2- (4,5-Dihydro-isoxazol-3-yl) -3-methylaniline in 50 ml of glacial acetic acid is added to 15 ml of concentrated hydrochloric acid. At 5-10 ° C, a solution of 2.44 g (35 mmol) of sodium nitrite in 10 ml of water is then added dropwise, and the mixture is stirred at 5 ° C for one hour. This solution is then added dropwise at room temperature to a mixture of a solution of 47 g (0.74 mol) of sulfur dioxide in 100 ml of glacial acetic acid and a solution 2. 23 g (13 mmol) of copper (II) chloride in 5 ml of water, the mixture is stirred at room temperature for one hour and then poured into 300 ml of cold water and extracted with methylene chloride. The organic phase is washed with water, dried with magnesium sulfate and concentrated. Yield 11.8 g (99%), purity according to HPLC 96% In the following working examples, the preparation of benzaldoximes of formula XV (process step a)) are described in more detail.

Example 12 Preparation of 2-methyl-6-nitrobenzaldoxime (variant A) A solution of 274 g (2.6 mol) of n-butyl nitrite (97%) and 300 g (2.0 mol) of 3-nitro-o-xylene ( 97%) in 750 ml of dimethylformamide is cooled from -55 to -60 ° C, and a solution of 522 g (4.56 mol) of potassium tert-butoxide in 750 ml of dimethylformamide is added dropwise at this temperature for a period of 2.5 hour period. During the addition, the color of the solution changes from yellow to dark red and the solution becomes viscous. The reaction is checked by HPLC. For the treatment, initially 300 ml of water and then approximately 300 ml of glacial acetic acid are added, until the pH reaches 5-6. During the addition, the temperature increases to -10 ° C, and a yellow suspension forms. The reaction mixture is then poured into 6 kg of cold water and the residue that forms is filtered off with suction, washed with 5 l of water and dried in a drying cabinet at 30 ° C overnight. This gives 339 g of a light beige crude product that is released from the impurities by suspension in about 3 1 of toluene at 80-90 ° C for two hours. After cooling, the product is filtered with suction and dried. This gives 276 g of 2-nitro-6-methyl-benzaldoxime.

Yield: 77%, m.p .: 190-192 ° C, purity (according to HPLC): 98%.

Example 13 Preparation of 2-methyl-6-nitrobenzaldoxime (variant B) 1200 ml of anhydrous DMF are initially charged to a 4 1 reaction vessel and cooled to -40 ° C. At this temperature, 336.5 g (4.56 mol) of potassium methoxide (95%) are added and suspended with stirring. A mixture of 300 g (1.92 mol) of 3-nitro-o-xylene (97%) and 274 g (2.52 mol) of n-butyl nitrite (95%) is then added dropwise at -40 ° C during 7 hours (if the mixture is cooled accordingly, the duration of this addition can be reduced as desired). The complete conversion of the raw material is checked by HPLC. The reaction discharge is then added with stirring, at -5 to 0 ° C, to a mixture of 300 ml of water and 300 ml of glacial acetic acid. The reaction mixture is then poured into 6 kg of cold water and the solid is filtered off and washed twice with 500 ml of water each time. The crude product (HPLC: 96% area) is purified by suspending the wet solid in 800 ml of toluene for 1.5 h. The solid is filtered and dried at 50 ° C in a vacuum drying cabinet. Yield: 306 g (HPLC: area 99.4% of product, E / Z mixture), corresponds to 85% of theory.

Example 14 Preparation of 2-chloro-6-nitrobenzaldoxime A solution of 4.1 g (40 mmol) of n-butyl nitrite (97%) and 5 g (29 mmol) of 2-chloro-6-nitrotoluene in 50 ml of dimethylformamide it is cooled to -55 ° to -60 ° C, and a solution of 3.3 g (29.5 mmol) of potassium tert-butoxide in 30 ml of dimethylformamide is added dropwise at this temperature, over a period of 20 minutes. The reaction is checked by HPLC. For the treatment, water is initially added, and the solution is then adjusted to pH 5-6 using glacial acetic acid. The product is isolated by extraction with ethyl acetate. This gives 5.7 g of 2-chloro-6-nitrobenzaldoxime. 1 H-NMR (CDC13): d = 8.00 (d, 1H); 7.84 (s, 1H); 7.76 (d, 1H); 7.52 (t, 1H).

Example 15 Preparation of 3-chloro-2-methyl-6-methylsulfonylbenzaldoxime A solution of 12.7 g (119 mmol) of n-butyl nitrite (97%) and 20 g (92 mmol) of 2,3-dimethyl-4- Methylsulfonylchlorobenzene in 100 ml of dimethylformamide is cooled from -55 to -60 ° C, and a solution of 16.8 g (147 mmol) of potassium tert-butoxide in 70 ml of dimethylformamide is added dropwise at this temperature, over a period of 30 minutes. The reaction is checked by HPLC. For the treatment, initially 50 ml of water are added, and the mixture is then adjusted to pH 5-6 using about 30 ml of glacial acetic acid. The mixture is then poured into 0.7 kg of cold water and the aqueous phase is extracted with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 18.4 g of a light beige crude product which is purified by recrystallization from about 30 ml of toluene. Yield: 6.15 g (27%) of white crystals, m.p .: 164-168 ° C, purity (according to HPLC): 100%.

Example 16 Preparation of 3-bromo-2-methyl-6-methylsulfonylbenzaldoxime A solution of 2.1 g (20 mmol) of n-butyl nitrite (97%) and 4 g (15 mmol) of 2,3-dimethyl-4-methylsulfonylbromobenzene in 50 ml of dimethylformamide is cooled from -55 to -60 ° C, and a solution of 2.8 g (25 mmol) of ter- Potassium butoxide in 35 ml of dimethylformamide is added dropwise at this temperature, for a period of 20 minutes. The reaction is checked by HPLC. For the treatment, initially 10 ml of water are added, the mixture is then adjusted to pH 5-6 using about 9 ml of glacial acetic acid. The mixture is then poured into 100 ml of cold water and the aqueous phase is extracted with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 3.6 g of an oily crude product (90% by HPLC) which can be purified by recrystallization from toluene. Yield: 1.22 g (27%) m, m.p .: 192-194 ° C, purity (according to HPLC): 99%.

Example 17 Preparation of N, N-diphenyl-3-hydroxyamino-2-methyl-4-methylsulfonylbenzamide a) Preparation of the precursor g (3 mmol) of 2,3-dimethylthioanisole and 7.6 g (33 mmol) of diphenylcarbamoyl chloride are dissolved in 50 ml of 1,2-dichloroethane and, at room temperature, are mixed with 4.8 g (36 mmol) of anhydrous aluminum chloride. The reaction mixture is refluxed for 3 hours and then poured onto a mixture of ice and concentrated hydrochloric acid, and the aqueous phase is extracted twice with methylene chloride. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 10.8 of crude product which is purified by chromatography on silica gel using the mobile phase toluene / ethyl acetate. Yield: 7.8 g of N, N-diphenyl-2,3-dimethyl-4-methylthiobenzamide. At not more than 45 ° C, 5.7 g (50 mmol) of hydrogen peroxide 30% concentration are added dropwise to a solution of 7 g (20 mmol) of N, N-diphenyl-2,3-dimethyl- 4-methylthiobenzamide and 200 mg of sodium tungstate hydrate in 50 ml of glacial acetic acid. The mixture is stirred at room temperature overnight. For the treatment, the mixture is poured onto cold water and extracted with methylene chloride, the organic phase is washed with aqueous sodium sulfite solution, dried over magnesium sulfate and concentrated. Yield: 7.4 g of N, N-diphenyl-2,3-dimethyl-4-methylsulfonylbenzamide, m.p .: 155-165 ° C. b) Preparation of N, N-diphenyl-3-hydroxyimino-2-methyl-4-methylsulfonyl-benzamide A solution of 0.7 g (6.9 mmol) of n-butyl nitrite (97%) and 2 g (5.3 mmol) of N, N-diphenyl-2,3-dimethyl-4-methylsulfonylbenzamide in 30 ml of dimethylformamide is cooled to -55 to -60 ° C, and a solution of 1.4 g (12 mmol) of potassium tert-butoxide in 10 ml of dimethylformamide is added dropwise at this temperature for a period of 20 minutes. The reaction is checked by HPLC. For the treatment, initially 10 ml of water are added, and the mixture is then adjusted to pH 5-6 using glacial acetic acid. The mixture is then poured over 100 ml of water | The mixture was cooled and the aqueous phase was extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This gives 3.0 g of a partially crystalline crude product, which is purified by chromatography on silica gel using the phase mobile toluene / acetone. Yield: 1.0 g (46%), m.p .: 208-211 ° C.

Example 18 Preparation of 3-bromo-2-methyl-6-methylsulfonylbezaldehyde 7.1 g of 3-bromo-2-methyl-6-methylsulphonylbenzaldoxime (23 mmol) are stirred at 65 ° C in a mixture of 17 g of 5% strength hydrochloric acid, 2 g of 37% formaldehyde solution of concentration, 15 ml of water and 30 ml of tetrahydrofuran for 32 hours. During this time, another 3.5 g of formaldehyde solution at 37% concentration were added in 0.5 g portions. The mixture is then cooled to room temperature and the product is filtered with suction. This gives 5.1 g 79%) of the product, purity 94% (according to CG).

Example 19 Preparation of 2-methyl-6-nitrobenzaldehyde At 65 ° C, 14 g of 2-methyl-6-nitrobenzaldoxime (80 mmol) are stirred in a mixture of 55 ml of 5% strength hydrochloric acid, 37 g of 37% concentration formaldehyde solution, 50 ml of water and 100 ml of tetrahydrofuran for 24 hours. The phases are then separated and the dark phase is extracted with methylene chloride / water. The organic phase is dried with sodium sulfate and concentrated. This gives 10.1 g of the crude product, which is purified by filtration through silica gel using the toluene mobile phase. Yield: 7.2 g (54%) Example 20 Preparation of 2-methyl-6-nitrobenzonitrile A solution of 16 g (150 mmol) of n-butyl nitrite (97%) and 7.7 g (50 mmol) of 3-nitro-o-xylene (97%) in 50 ml of dimethylformamide is cooled to -5 to -10 ° C and, a solution of 100 g (100 mmol) of potassium tert-butoxide in 50 ml of dimethylformamide is added at this temperature, for a period of 1.5 hours. The reaction mixture is stirred at room temperature for another 6 days. For the treatment, the mixture is poured onto cold water and adjusted to pH 1 using hydrochloric acid, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated. This gives 8.2 g of product. The 2-methyl-6-nitrobenzonitrile can be purified by chromatography on silica gel using the mobile phase toluene. p.f. 101-103 ° C. In the above working examples, the preparation of thioethers of the formula Villa (process step d) are described in more detail: Example 21 a) Comparative example The reaction of 2,3-dimethylaniline with dimethyl disulfide and tert-butyl nitrite in the methylene chloride solvent gives only a small amount of the desired product C. According to a CG analysis, the main products were the products of dimerization A and B. Dimer A is also formed if the reaction is carried out in excess dimethyl disulfide. b) Process according to the invention The reaction of 2,3-dimethylaniline with dimethyl disulphide and tert-butyl nitrite is carried out similarly to the method described in a) using the solvent methylene chloride, but added as a catalyst. Cu. The reaction proceeds uniformly to give the desired dimethylthioanisole C. It was not possible to identify the dimerization product A and B [sic] by CG analysis.

Example 22 a) Comparative example In the reaction of 2- (4,5-dihydroisoxazol-3-yl) -3-methyl-aniline with dimethyl disulfide and tert-butyl nitrite without catalyst, by-products were formed. A mixture of A and B is obtained in a ratio of 2: 1 according to the percent area by HPLC. b) Process according to the invention The reaction is carried out in a manner similar to the method described in a), but in the presence of Cu powder. In this case, subproduct A can not be detected.

Example 23 Preparation of 2,3-dimethylthioanisole 355 g (3.44 mmol) of tert-butyl nitrite and 250 g of copper powder (3.9 mmol) are initially charged in 1250 ml of dimethyl disulfide, and a solution of 250 g (2.07 mol) of 2,3-dimethylaniline in 1000 ml of dimethyl disulfide is added dropwise at 50-52 ° C. The mixture is then added at 75-80 ° C for 1.5 hours. For the treatment, the mixture is cooled, filtered with suction through kieselguhr, and the filtrate is washed with saturated aqueous solution of NaHCO 3. For the purification of the product, the organic phase is separated by distillation. Initially, the excess dimethyl disulfide is removed at atmospheric pressure. 1446 g of dimethyl disulfide (purity> 97% according to CG) are recovered. The residue is then subjected to fractional distillation under reduced pressure (0.1 mbar). Yield: 261.3 g (83%), purity according to CG 97.5% b) 14.2 g (124 mmol) of tert-butyl nitrite and 2.5 g (40 mmol) of copper powder are charged initially to 50 ml of dimethyl disulfide and a solution of 10 g (81 mmol) of 2 is added, 3-dimethylaniline in 50 ml of dimethyl disulfide dropwise at 50-52 ° C. The mixture is then stirred at 75-80 ° C for 1.5 hours. According to a GC analysis, 100% of the aniline has been converted to the desired 2, 3-dimethylthioanisole.

Example 24 Preparation of 2-methyl-6-nitrothioanisole 226 g (1.97 mmol) of tert-butyl nitrite and 100 g of copper powder are initially charged to 300 ml of dimethyl disulfide, and a solution of 200 g is added. (1.32 mol) of 2-methyl-6-nitroaniline in 700 ml of dimethyl disulfide dropwise at 50-55 ° C. The mixture is then stirred at 75 ° C for 8 hours. For the treatment, the solid is filter with suction and the solution is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with an aqueous solution, saturated with NaHCO 3, dried over sodium sulfate, filtered and concentrated using a rotary evaporator. The excess of dimethyl disulfide is I 10 removes empty with an oil pump. This gives 271 g (99%) of a dark red oil, purity according to HPLC 87%.

Example 25 15 Preparation of 2-methyl-3, 4-dimethylthiobromobenzene 14. 8 g (129 mmol) of tert-butyl nitrite and 20 g of copper powder are charged initially to 50 ml of dimethyl disulfide, and a solution of 20 g (86 mol) of 4- 20 bromo-3-methyl is added. -2-methylthioaniline in 100 ml of dimethyl disulfide dropwise at 50-55 ° C. The mixture is then stirred at 50 ° C for 4 hours. For treatment, the solid is filtered with suction and the solution is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase Wash with saturated aqueous NaHCO 3 solution, dry over sodium sulfate, filter and concentrate using a rotary evaporator. The excess dimethyl disulfide is removed in vacuum with an oil pump. This gives 19.7 g of a dark oil. The product can be purified by trituration in methyl tertiary butyl ether. Yield 9.32 g (41%), m.p .: 70-73 ° C.

Example 26 Preparation of 2,3-dimethyl-4-methylthiobromobenzene 603 g (5.85 mmol) of tert-butyl nitrite and 375 g of copper powder (5.9 mol) are initially charged to 3000 ml of dimethyl disulfide, and 761 g (3.75 mol) of 4-bromo-2,3- Dimethylaniline is added dropwise at 50-58 ° C. The mixture is then stirred at 75-80 ° C for 9 hours. For the treatment, the mixture is cooled, the residue is filtered and the filtrate is washed with saturated aqueous solution of NaHCO 3. For the purification of the product, the organic phase is separated by distillation. Initially, the excess dimethyl disulfide is removed under atmospheric pressure. 1870 g of dimethyl disulfide (purity >)97% according to CG) are recovered. The residue is then subjected to fractional distillation under reduced pressure (0.1 mbar). Yield: 523 g (60%), purity according to CG 99% Example 27 (Sequence of the reaction according to Scheme 4) a) Preparation of 2,3-dimethylthioanisole 5 355 g (3.44 mol) of tert-butyl nitrite and 250 g of copper powder (3.9 mol) are initially charged in 1250 ml of dimethyl disulfide, and a solution of 250 g (2.07 mol) of 2,3-dimethylaniline in 1000 ml of | 10 dimethyl disulfide by dripping at 50-52 ° C. The mixture is then stirred at 75-80 ° C for 1.5 hours. For the treatment, the mixture is cooled, filtered with suction through kieselguhr, and the filtrate is washed with saturated aqueous solution of NaHCO 3. For purification of the product, the organic phase is separated by distillation. Initially, the excess dimethyl disulfide is removed at atmospheric pressure. 1446 g of dimethyl disulfide (purity> 97% according to CG) are recovered. The residue is then subjected to distillation fractionated under reduced pressure (0.1 mbar). Yield: 261.3 g (83%), purity (according to CG) 97.5% b) Preparation of 2,3-dimethyl-4-methylthiobromobenzene 25 510 g (3.33 mol) of 2,3-dimethylthioanisole are initially charged in 3 1 glacial acetic acid, and a solution of 592 g (7.4 mol) of bromine in 1 1 glacial acetic acid per drops at room temperature for a period of 3 hours. The reaction is slightly exothermic. The reaction mixture is stirred at room temperature for another 3.5 hours. The precipitate is then filtered off with suction and the filtrate is mixed with 270 g of sodium acetate and concentrated. The residue is taken up in 2% dichloromethane and washed twice with 10 ml of sodium bicarbonate solution and 2 times with sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated. Yield: 615 g (79%), purity (according to CG) 99.2%. c) Preparation of 2,3-dimethyl-4-methylsulfonylbromobenzene A at least 100 ° C (slight reflux), 266 g (2.35 mol) of hydrogen peroxide at 30% concentration add by dripping for a period of 45 minutes to a solution of 182 g (0.78 mol) of 2,3-dimethyl-4-methylthiobromobenzene and 5.24 g of sodium tungstate hydrate in 1 1 of glacial acetic acid. The reaction mixture is stirred at room temperature by other 2 hours For the treatment, the mixture is poured into 7.8 1 of cold water and stirred for another 30 minutes. The white residue is then filtered with suction and washed 3 times with water. The crystals are dried at 70 ° C under reduced pressure overnight. 5 Yield: 195 g (94%), purity (according to CG) 100%. d) Preparation of 3-bromo-2-methyl-6- ^ methylsulfonylbenzaldoxime 10 272.6 g of sodium ethoxide (3.8 mol) are dissolved in 0.4 1 of DMF, and a solution of 400 g of 2,3-dimethyl-4- methylsulfonylbromobenzene (1.52 mol) and 214.6 g (1977 mol) of n-butyl nitrite in 0.8 1 of DMF are added to -20 ° C to -15 ° C. Then, another 100 g of sodium ethoxide is added. The reaction mixture is stirred from -20 ° C to -15 ° C for a total of 5.5 hours. The mixture is poured over 4 1 of cold water and 0.4 1 of glacial acetic acid and extracted with a total of 4 1 of MtBE. The MtBE phase is washed with 1 liter of sodium bicarbonate solution and twice with water. The aqueous phases are combined. The MtBE phase is concentrated using a rotary evaporator and dried. The solution is concentrated and the residue is dried using an oil pump.

Yield: 331 g (75%) of yellowish brown crystals, purity (according to HPLC) 96.6%. e) Preparation of 3- (3-bromo-2-methyl-6-methylsulfonylphenyl) -4,5-dihydro-isoxazole At 60 ° C, a small amount of N-chlorosuccinamide is added to a solution of 50 g (171 mmol) of 3-bromo-2-methyl-6-methylsulphonylbenzaldoxime in 200 ml of dimethylformamide. Once the reaction has begun, a total of 23.3 g (171 mmol) of N-chlorosuccinimide are dosed at 40-50 ° C. The reaction mixture is stirred for another 30 minutes, until the reaction is complete according to HPLC. The reaction mixture is then poured into cold water and the solid is filtered with suction, washed 3 times with water and 3 times with N-pentane. The hydroxamic acid chloride is used wet and without further purification for the next reaction. The solid is dissolved in 250 ml of dichloromethane, and the ethylene is passed through the solution. With continuous introduction of ethylene, 20.3 g (200 mmol) of triethylamine are added dropwise. The reaction mixture is stirred at room temperature for about 72 hours, with repeated introduction of more ethylene gas.

For the treatment, the reaction mixture is washed 3 times with water, and the solvent is removed. This gives 49 g of brownish brown crystals which, according to HPLC, contain 90.6% of product. The product can be purified by recrystallization from 200 ml of isopropanol. Yield: 31 g (57%) of white crystals, m.p. 133-136 ° C, purity (according to HPLC) 99.5%.

Claims (23)

1. A process for preparing isoxazoles of the formula I wherein the substituents are defined below: R "is hydrogen, C -C6 alkyl, R * is C? -Cg alkyl, R3, R4, R5 are hydrogen, C? -C6 alkyl, or R4 and R5 together they form a bond, Rc is a heterocyclic ring, n is 0, 1 or 2, which comprises preparing an intermediate of the formula VI SAW wherein R, R, R and R are as above, and the subsequent reaction to give compounds of formula I.

The process as mentioned in claim 1, comprises one or more of the following process steps: a) reaction of a nitro-o-methylphenyl compound of the formula II wherein the radical R is as already defined with an organic R-ONO nitrite in the presence of a base to give an oxime of formula III. wherein the radical R is as defined above; b) cyclization of the oxime of formula III with an alkene of formula IV. wherein R 3 to R 5 are as defined in claim 1, in the presence of a base to give the 4,5-dihydroisoxazole of the formula V wherein R 1 and R 3 to R 5 are as defined in claim 1; c) reduction of the nitro group in the presence of a catalyst to give the aniline of formula VI SAW 1 3 5 in which R and R up to R are as defined in claim 1; d) reduction of the aniline of the formula VI with a dialkyl disulfide of the formula VII R -S-S-R VII in the presence of an organic nitrite and, if appropriate, a catalyst to give the thioether of formula VIII wherein R to R are as defined in claim 1; bromination of the thioether of the formula VIII with a brominating agent to give the bromothioether of the formula IX. wherein R to R are as defined in claim 1; 10 f) oxidation of the bromothioether of the formula IX with an oxidizing agent to give the isoxazoles of the formula X wherein n are the numbers 1 or 2, g) carboxylation of isoxazole of formula X in the presence 20 of a compound R -OH (XI) and carbon monoxide and a catalyst to give a compound of formula I.

3. The process as recited in claim 2, wherein the carboxylation in step g) of the process is carried out in the presence of carbon monoxide, 25 palladium catalyst, if appropriate, at least one molar equivalent of a potassium salt and, if appropriate, at least one molar equivalent of a • tertiary amine of the formula XIII N (Ra) 3 XIII In which one of the radicals Ra can be phenyl or naphthyl and the other radicals Ra are C? -Cg alkyl, they are reacted with each other [sic] at 100-140 ° C and at a • 10 pressure of 1-40 kg / cm 2 '

4. The process as mentioned in claim 3, wherein the reaction is carried out at a pressure of 5-8 kg / cm.

5. The process as recited in claim 3 or 4, wherein the reaction is carried out at 110-130 ° C.

The process as mentioned in any of claims 3 to 5, wherein the catalyst used is a palladium (I) (II) salt.

7. The process as recited in claim 6, wherein the catalyst used is bis (triphenylphosphane) palladium (I) (II) chloride.

The process as mentioned in any of claims 3 to 5, wherein the catalyst used is tetrakistriphenylphosphanopalladium (I) (0).

9. The process as recited in any of claims 3 to 8, wherein the potassium salt used is potassium carbonate, and furthermore, an amine of the formula XIII (N (Ra) 3) is used.

The process as mentioned in any of claims 3 to 9, wherein the compound XI and the compound X are employed in a molar ratio from 1 to 2.

The process as mentioned in any of claims 2 -10, where, in step g) of The process of the heterocyclic compound XI used is a pyrazole derivative of the formula X (.a ? and [sic] R is C 1 -C 4 alkyl and M is hydrogen or an alkali metal atom.

12. The process as recited in any of claims 1-11, wherein the substituents are as defined below: R is hydrogen C?-C4 alkyl, R 2 is C alquilo-C alkyl, R, R, R are hydrogen or C -C alkyl, R is pyrazol-4-yl which can be substituted by alkyl groups and / or a hydroxyl group.

13. A compound of formula III wherein R is C? -C6 alkyl.

14 A compound of formula XII wherein the radicals are as defined in the following: A is nitro, amino or an SR 2 group XR is hydrogen, C?-Cg alkyl, 2 R is C?-C6 alkyl, R 3, R 4, R 5 are hydrogen, C? -Cg alkyl, or R4 and R5 together form a bond.

15. A compound of formula X wherein the radicals are as defined in the following: R is hydrogen, C 1 -C 6 alkyl, R 2 is C 1 -Cg alkyl, 3 4 5 4 5 R, R, R are hydrogen, alkyl C? -C6, or R and R together form a bond, n is the number 0, 1 or 2.

16. A process for preparing compounds as mentioned in claim 15, comprises one or more of steps a) - f) of the process set forth in claim 2.

17. The use of the compounds as recited in any of claims 13, 14 or 15 for preparing compounds of the formula I.

18. The process for preparing compounds of the formula XV XV wherein the radicals are as defined below: X is N02, S (0) nRy, Rx, R y are in each case any inert radical; m is 0, 1, 2, 3 or 4; n is 2; comprising the reaction of the compounds of formula XVI XVI wherein the substituents are as defined above with an organic nitrite of the formula RO-NO, wherein R is an aliphatic or aromatic radical, in the presence of a base, the reaction being carried out at a lower temperature of - 20 ° C in the presence of a dipolar aprotic solvent followed, if appropriate, by conversion of the oxime group -CH = NOH in formula XV into the corresponding aldehydes -CHO, nitriles (-CN) or nitrile oxides (-CNO).

19. The process as recited in claim 18, wherein the solvent used is DMF.

20. A process for preparing thioethers of formula XIX. XIX wherein the substituents are as defined in the following: Rx is an inert radical, m is a number from 0 to 5, R2 is an alkyl of C] .- C6, which comprises the reaction of an aniline of the formula XX with a dialkyl disulfide of the formula VII R S S R VII 20 in the presence of a catalyst.

21. A process as recited in claim 20, wherein the catalyst used is copper powder or elemental copper.

22. The compound of formula XV. wherein the radicals as defined below: X is S (0) nR and R is hydrogen, C? -Cg alkyl, halogen, C? ~ 10 C6 alkoxy, C? -C6 alkylthio, Rx [sic] is an inert radical, Ry [sic] is a radical selected from the group consisting of hydrogen, chlorine and bromine and located on the phenyl ring in the para position with group X, 15 m is 1, n is 0, 1 or 2.

23 A process for preparing compounds IX or X using one of the processes as mentioned in claim 18 and 20. 20