Process for the production of alkyl-pyridine n-oxides

Abstract

The present invention relates to a process for producing alkyl-pyridine N-oxides of formula (I) from the corresponding unsubstituted 3-alkyl pyridines or the 5-alkyl pyridines of formula (II) correspondingly substituted in 2-position, in the presence of at least one oxidant, water, organic solvent and catalyst.

Description

[0001] Process for the preparation of alkylpyridine N-oxides

[0002] The present invention relates to a process for the preparation of alkylpyridine N-oxides of the formula (I) from the corresponding unsubstituted 3-alkylpyridines or the correspondingly 2-substituted 5-alkylpyridines of the formula (II) in the presence of at least oxidizing agent, water, organic solvent and catalyst.

[0003] Alkylpyridine N-oxides of formula (I) are starting materials for the synthesis of pharmaceutical and agrochemical active ingredients. Such structural elements are found, for example, in acetyl-CoA carboxylase inhibitors in WO 2014 / 114578 A2, which can be used to treat, for example, diabetes or obesity. Furthermore, 5-alkyl-2-haloylpyridine N-oxides of formula (I) are disclosed as starting materials in the preparation of active ingredients from the group of ERK kinase inhibitors, which can be used to treat cancer, in WO 2014 / 124230 A2.

[0004] State of the art

[0005] Processes for the production of such compounds are known from the literature, but they have disadvantages when carried out on an industrial scale. Oxidations of substituted pyridines with organic peroxides, such as m-chloroperbenzoic acid (MCPBA), are known. A disadvantage is the resulting amount of m-chlorobenzoic acid as a waste product, which may have to be separated from the product at great expense. In addition, organic peroxides require stringent safety measures, especially when stored on an industrial scale.

[0006] In organic synthesis, hydrogen peroxide is a popular oxidizing agent because its reaction products are only gaseous oxygen and water, which do not require complex disposal as waste products. For example, the use of hydrogen peroxide urea salts as oxidizing agents is well known. However, this approach has the disadvantage of producing stoichiometric amounts of waste.

[0007] The use of an aqueous hydrogen peroxide solution would be advantageous, as this does not generate any waste. Several documents were found that describe the preparation of 5-alkyl-2-halopyridine N-oxides with hydrogen peroxide, either uncatalyzed or in the presence of sodium tungstate (Na2WO4)—as described, for example, in CN103193704A—or trifluoroacetic anhydride. Our own investigations have shown that complete conversion of some 5-alkyl-2-halopyridines or 5-alkyl-2-cyanopyridines does not occur with this procedure, even with long reaction times. Irrespective of this, the reaction in the presence of sodium tungstate and trifluoroacetic anhydride on an industrial scale generates waste and / or used catalysts, which must be laboriously disposed of or recycled.For example, using acetic acid as the solvent, W02005 / 085248 A1 describes the reaction of 2-chloro-5-methylpyridine with aqueous hydrogen peroxide solution, whereby 2-chloro-5-methylpyridine N-oxide was obtained on a gram scale after a reaction time of 8 hours in yields of 82 percent. The disadvantage of this process, if scaled up to an industrial scale, is that the reaction times would increase to 24 hours or more, and large quantities of acetic acid would have to be laboriously separated from the product and disposed of as waste at great expense. Long reaction times in such reactions always pose an increased safety risk.

[0008] Processes for the oxidation of various monosubstituted pyridines with hydrogen peroxide in the presence of catalysts are also known. For example, MR Prasad, Mol. Cat. A: Chemical 2002, 186, 109-120, describes the oxidation of 2-chloropyridine in water and methanol in yields of 91 and 98%, respectively, using hydrogen peroxide as a 30% aqueous solution in the presence of a TS-1 catalyst at a temperature of 60 °C. With water as the solvent, the reaction time was 24 hours, whereas with methanol, a reaction time of only 2 hours was sufficient. Analogously, for example, 2-, 3-, and 4-methylpyridine were obtained in water in yields of only 29 to 32% using hydrogen peroxide as a 30% aqueous solution in the presence of a TS-1 catalyst at a temperature of 60 °C within 24 hours.Using methanol as the solvent, the methyl-substituted pyridine N-oxides are obtainable within 5 to 6 hours at 60 °C in high yields of 93 to 95% in the presence of a Ti-ZSM-5 (30) catalyst. While halogens act as electron-withdrawing substituents on the pyridine ring, alkyl substituents represent electron-donating substituents. According to this literature, pyridine N-oxides with electron-donating substituents are only obtainable in lower yields using this method with TS-1 as the catalyst. All reactions according to this literature were carried out with 2 molar equivalents of hydrogen peroxide based on the pyridine used and only on a milliliter scale.

[0009] There was therefore a need for a process for the preparation of alkyl pyridine N-oxides of formula (I) by which these pyridine derivatives can be produced efficiently and safely on an industrial scale.

[0010] Surprisingly, a simple and safe process for the preparation of alkylpyridine N-oxides, preferably 3-alkylpyridine N-oxides or 5-alkyl-2-halopyridine N-oxides or 5-alkyl-2-cyanopyridine N-oxides, of formula (I) has been found, which comprises the reaction of alkylpyridines, preferably 3-alkylpyridines, 5-alkyl-2-halopyridines or 5-alkyl-2-cyanopyridines, of formula (II) with oxidizing agents in the presence of catalysts, water, and organic solvents to give these products on an industrial scale in good yields and high purities. In this process, the solid catalyst can be easily separated from the reaction mixture and, if necessary, reused in the process. Furthermore, the process according to the invention does not produce any critical waste materials that would require complex disposal. The invention therefore relates to a process for the preparation of compounds of formula (I), in the R 1represents linear or branched Ci-Cio-alkyl, preferably linear or branched Ci-Ce-alkyl, which may be unsubstituted, mono- or polysubstituted, preferably by halogenyl or alkoxy radicals, or in which R 1 represents Ce-Ce-cycloalkyl, which may be unsubstituted, mono- or polysubstituted, or in which R 1 represents aralkyl which may be unsubstituted, mono- or polysubstituted, preferably with halogenyl or alkoxy radicals, and in which R 2 represents hydrogen, chlorine, bromine, fluorine or cyano, comprising at least the reaction of compounds of formula (II),

[0011] (II), in which the residue R 1 and R 2 which have the meaning given for formula (I), in the presence of at least oxidizing agent, water, organic solvent and catalyst.

[0012] Linear Ci-Cio-alkyl according to R 1is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.

[0013] Preferably, unsubstituted linear or branched Ci-Cio-alkyl according to radical R 1 represents methyl, ethyl, or n-propyl. Preferred is substituted linear alkyl according to the radical R 1 Cyclopropylmethyl or 1,1-difluoroethyl.

[0014] Linear or branched Ci-Ce-alkyl according to R 1 represents, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methylbutyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-Methyl-1-pentyl, 2-Methyl-2-pentyl, 3-Methyl-2-pentyl, 4-Methyl-2-pentyl, 2-Methyl-3-pentyl, 3-Methyl-3-pentyl, 2,2-Dimethyl-1-butyl, 2,3-Dimethyl-1-butyl, 3,3-Dimethyl-1-butyl, 2,3-Dimethyl-2-butyl, 3,3-Dimethyl-2-butyl or 3-Ethyl-1-butyl.

[0015] The linear or branched Ci-C10-alkyl or Ci-C8-alkyl may be unsubstituted. It may also be mono- or polysubstituted, preferably with halogenyl or alkoxy radicals. Examples of monosubstituted Ci-C8-alkyl are 2-methoxy-1-ethyl, 2-ethoxy-1-ethyl, 3-methoxy-1-propyl, 3-ethoxy-1-propyl or 1-cyclopropylmethyl, 1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 1,1-difluoroethyl or 2,2-difluorocyclopropylmethyl.

[0016] Ce-Ce-cycloalkyl according to R 1 is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,

[0017] Ce-Ce-cycloalkyl can be unsubstituted, mono- or polysubstituted. Examples of monosubstituted Ce-Ce-cycloalkyl are 2-methylcyclobutyl, 3-methylcyclobutyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2-methylcycloheptyl, 3-methylcycloheptyl, 4-methylcycloheptyl, 2-ethylcyclobutyl, 3-ethylcyclobutyl, 2-ethylcyclopentyl, 3-ethylcyclopentyl, 2-ethylcyclohexyl, 3-ethylcyclohexyl, 4-ethylcyclohexyl, 2-propylcyclobutyl, 3-propylcyclobutyl, 2-Propylcyclopentyl, 3-Propylcyclopentyl, 2-Butylcyclobutyl, 3-Butylcyclobutyl, 2-Hydroxycyclopropyl, 2-Fluorocyclopropyl stands.

[0018] Particularly preferred are R 1 for methyl, ethyl and n-propyl and R 2 represents hydrogen. R 1 for methyl, ethyl and n-propyl and R 2 represents chlorine. R 1for methyl, ethyl and n-propyl and R 2 represents bromine. R 1 for methyl, ethyl and n-propyl and R 2 represents fluorine. R 1 for methyl, ethyl and n-propyl and R 2 for cyano.

[0019] According to the invention, “process for preparing compounds of formula (I) by reacting compounds of formula (II) in the presence of at least oxidizing agent, water, organic solvent and catalyst” means that compounds of formula (II) are oxidized with the oxidizing agent by contacting with catalyst in water and organic solvent to give compounds of formula (I).

[0020] In the process according to the invention, the catalyst is, for example, a microporous solid, preferably a titanium silicalite, particularly preferably titanium silicalite-1, also called TS-1. TS-1 is commercially available from various manufacturers.

[0021] Examples of microporous solids include molecular sieves such as ZSM5. ZSM5 is an aluminosilicate zeolite belonging to the pentasil family. It is composed of silicon, aluminum, oxygen, and optionally other countercations.

[0022] Titanium-containing silicalites have the general chemical formula Sh-xTixO2 and are produced, for example, in a hydrothermal reaction of tetraethyl silicate (TES) as the SiO2 source with tetraethyl titanate (TET) as the TiO2 source in the presence of tetrapropylammonium hydroxide as the base. After the reaction, calcination is typically carried out to remove ammonium salts from the solid. This produces porous solids in which tetravalent Si(IV) species are isomorphically replaced by tetravalent Ti(IV) species.

[0023] The titanium silicalite most commonly used on an industrial scale is titanium silicalite-1, also commonly abbreviated to TS-1. This typically has a molar SiO2 / TiO2 ratio of at least 25 and a BET surface area of ​​360 to 420 g / m 2 and a pore diameter of approximately 0.5 nanometers. Titanium silicalite-1 or TS-1 is particularly preferred as a catalyst for the process according to the invention.

[0024] The process according to the invention very particularly preferably takes place in the presence of 7 to 15 grams of catalyst per mole of compound of formula (II) used in the process. In particular, the process according to the invention takes place in the presence of 11 to 13 grams of catalyst per mole of compound of formula (II) used in the process. "In the presence of catalyst" means according to the invention that the reaction mixture comprising compound of formula (II), oxidizing agent, water and organic solvent is brought into contact with catalyst in the liquid phase, so that the reaction mixture is in the form of a suspension. This suspension is usually mixed mechanically or hydraulically in order to increase the interaction of the liquid phase with the suspended catalyst.

[0025] In the process according to the invention, the oxidizing agent is preferably hydrogen peroxide. Hydrogen peroxide is typically used as an oxidizing agent in the form of aqueous solutions. In the process according to the invention, the oxidizing agent is particularly preferably a 30 to 70 percent (by weight) aqueous solution of hydrogen peroxide. Particular preference is given to using from 0.9 to 2.0 mol, in particular from 1.0 to 1.3 mol, of oxidizing agent per mole of compound of formula (II) used in the process according to the invention.

[0026] The process according to the invention is also carried out in the presence of water. In addition to the water present in the aqueous hydrogen peroxide solution, further water can also be added to the reaction mixture. However, it is preferred that no additional water besides the water present in the oxidizing agent, preferably hydrogen peroxide, be added to the reaction mixture.

[0027] The process according to the invention is furthermore carried out in the presence of at least one organic solvent. The catalyst is present in the reaction mixture as a solid, while the compounds of formula (I) and formula (II) are usually partially or completely dissolved in the solvent. Preferred organic solvents are linear aliphatic alcohols, particularly preferably methanol, ethanol, 1-propanol or 1-butanol, or any mixtures thereof. Methanol is particularly preferred as the solvent for the process according to the invention. This has the advantage that the temperature of the reaction mixture is limited by the boiling point of the methanol at the respective pressure in the reaction vessel, whereby decomposition of the oxidation product can be avoided. In an alternative preferred embodiment, the process according to the invention is furthermore carried out in the presence of organic acids, for example acetic acid.The presence of organic acids, for example acetic acid, in addition to the presence of oxidizing agent, water, organic solvent and catalyst has the advantage that, on the one hand, the reaction proceeds more rapidly and, on the other hand, the acetic acid stabilizes the pyridine N-oxide during workup, which involves thermal stress. The process according to the invention is particularly preferably carried out in the presence of 1.0 to 3.0 mol of acetic acid per mole of compound of formula (II) used, in particular in the presence of 1.0 to 1.2 mol of acetic acid per mole of compound of formula (II) used.

[0028] In a further preferred embodiment, the process according to the invention is further carried out in the presence of at least one inorganic base. The presence of an inorganic base has the advantage that the formation of alkylcarboxylic acid esters, e.g., from acetic acid and methanol, is largely suppressed by increasing the pH.

[0029] The inorganic base is preferably selected from alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates or alkaline earth metal carbonates, alkali metal bicarbonates or alkaline earth metal bicarbonates. The inorganic base is particularly preferably sodium hydroxide and sodium bicarbonate. The base can be used in the process according to the invention in solid or liquid form, in pure form, or dissolved or suspended in liquid media.

[0030] The process according to the invention is particularly preferably carried out in the presence of 0.001 to 0.1 mol of inorganic base per mol of compound of formula (II) used, in particular in the presence of 0.005 to 0.05 mol of inorganic base per mol of compound of formula (II) used.

[0031] The reaction of the compounds of formula (II) in the process according to the invention takes place, for example, at temperatures of 60 to 90 °C, preferably of 70 to 85 °C.

[0032] The process according to the invention is preferably carried out in such a way that a) at least the compound of formula (II) and optionally organic solvent are initially charged, and b) the mixture from step a) is heated to a temperature of 60 to 90 °C, preferably of 70 to 85 °C, and c) the oxidizing agent is added to the mixture from step b) within 1 to 7 hours, preferably 1 to 5 hours.

[0033] In this case, the starting materials - except for the oxidizing agent - i.e. compound of formula (II), catalyst, organic solvent, optionally water, optionally acetic acid, optionally inorganic base, can preferably be mixed initially individually or together, both in pure substance and dissolved or suspended at ambient temperature.

[0034] Likewise preferably, the process according to the invention is carried out in such a way that a) at least the compound of formula (II), optionally oxidizing agent and optionally organic solvent are initially introduced, and b) the mixture from step a) is heated to a temperature of 60 to 90 °C, preferably of 70 to 85 °C, and c) the oxidizing agent is added to the mixture from step b) within 1 to 7 hours, preferably 1 to 5 hours.

[0035] Likewise preferably, the starting materials, i.e. compound of formula (II), catalyst, organic solvent, optionally water, optionally acetic acid, optionally inorganic base, and a portion of the oxidizing agent required for the reaction, can first be mixed individually or together, both in pure substance and dissolved or suspended at ambient temperature.

[0036] The reaction mixture is then preferably heated to the required reaction temperature. The reaction mixture is also preferably heated to boiling point under reflux. The oxidizing agent, preferably hydrogen peroxide, is then added to the mixture of starting materials brought to reaction temperature.

[0037] If part of the oxidizing agent has already been added to the reaction in step a), the remainder of the oxidizing agent required for the reaction and not yet added in step a) is added in step c) within 1 to 7 hours, preferably within 1 to 5 hours.

[0038] The oxidizing agent is preferably added under temperature control, as the reaction is exothermic. If necessary, the reaction mixture is cooled during the addition. Particularly preferably, the oxidizing agent is added continuously. The oxidizing agent is typically added to the mixture of starting materials within 1 to 10 hours, preferably 2 to 5 hours. Dosing the oxidizing agent into the reaction mixture, which contains, among other things, the catalyst, also has the advantage that no temporary excesses of hydrogen peroxide are required in the reaction mixture. This allows the reaction to be handled safely even on a large scale, since an accumulation of peroxide in the reaction mixture is never to be expected.

[0039] After the addition of the oxidizing agent has ended, the reaction mixture is preferably kept at a temperature of 60 to 90 °C, preferably 70 to 85 °C, until no further reaction takes place. The chemical reaction is typically monitored by gas chromatography, thin-layer chromatography, infrared spectroscopy, or HPLC. The process according to the invention is typically carried out at ambient pressure or at a pressure of up to 0.6 megapascals under an inert gas, for example nitrogen or argon. The process according to the invention produces molecular oxygen, which escapes from the reaction mixture in gaseous form due to the reaction temperature and can be removed from the reaction circuit for safety reasons.

[0040] If the reaction temperature is above the boiling point of the reaction mixture or of the individual components of the reaction mixture at ambient pressure, the reaction is usually carried out in pressure-tight apparatus, for example in autoclaves, under increased autogenous pressure or under pressure, for example with nitrogen.

[0041] After completion of the reaction of the compound of formula (II), the reaction product, i.e. the compounds of formula (I), is obtained from the reaction mixture, for example, by i) filtering the reaction mixture, which has been cooled to ambient temperature, preferably to from 30 °C to 50 °C, to separate the catalyst from the filtrate, and ii) optionally washing the filtered-off catalyst with organic solvent to obtain a wash liquor, and iii) mixing the filtrate from step a) and the wash liquor from step b), and iv) isolating the reaction product, i.e. the compound of formula (I), by separating it from the organic solvent, optionally from water and / or acetic acid, for example by distillation, and v) optionally drying the filtered-off catalyst with a stream of inert gas and optionally reusing it in a subsequent reaction.

[0042] The compound of formula (I) can be stored in pure form or as a solution in organic solvents or acetic acid and / or used as a starting material in a subsequent process. It should be noted that pyridine N-oxides can be thermally unstable substances. Therefore, appropriate safety tests and precautions must be taken when handling them on an industrial scale.

[0043] Surprisingly, a safe, rapid, and economical process for the preparation of compounds of formula (I) has been discovered that overcomes the disadvantages of the prior art processes. The yield of compound of formula (I) based on the compound of formula (II) used in the process according to the invention is between 90 and 99 percent of theory, even on an industrial scale, for example, with 1000 to 2000 kg of compound of formula (II) as feedstock, with reaction times of less than 10 hours. The compound of formula (I) is formed with a high purity, for example, with less than 0.5 wt. % of reactant and / or secondary components. Used catalyst can optionally be reused in a subsequent reaction. Furthermore, the process according to the invention produces significantly less waste than the prior art processes. Examples

[0044] Example 1: Preparation of 2-chloro-5-methyl-pyridine-1-oxide (comparative example)

[0045] A mixture of 50 g (0.39 mol) of 2-chloro-5-methylpyridine, 70 g of water, and 2.5 g of titanium silicalite TS-1 was heated to 60 °C. At 60 °C, 53 g (0.78 mol) of hydrogen peroxide (aqueous solution, 50 wt.% H2O2) were added over 1 hour. Stirring was then continued at 60 °C for 24 hours, after which approximately 50% conversion was achieved.

[0046] Example 2: Preparation of 3-methylpyridine-1-oxide (according to the invention)

[0047] A mixture of 150 g (1.61 mol) of 3-methylpyridine, 200 g of methanol, 75 g (1.25 mol) of acetic acid, and 20 g of titanium silicalite TS-1 was heated to reflux. 130 g (1.91 mol) of hydrogen peroxide (aqueous solution, 50 wt.% H2O2) were added over a period of 2 hours under reflux. After cooling to ambient temperature, the solid was filtered off and washed with methanol. The combined mother and wash liquors were concentrated in vacuo at approximately 40 °C. The distillation residue was 246 g of a light beige solution (content 66.8 wt.% 3-methylpyridine-

[0048] 1-oxide, yield 93.5% of theory).

[0049] Example 3: Preparation of 2-chloro-5-methylpyridine 1-oxide (according to the invention)

[0050] A mixture of 50 g (0.4 mol) of 2-chloro-5-methylpyridine, 100 g of methanol, and 5 g of titanium silicalite TS-1 was heated to reflux. Under reflux, 30 g (0.4 mol) of hydrogen peroxide (aqueous solution, 50 wt.% H2O2) were added over 1 hour. The mixture was then stirred under reflux for 5 hours. After cooling to ambient temperature, the solid was filtered off and washed with 25 g of methanol. The combined filtrates gave 185 g of a light beige solution (content 28 wt.% 2-chloro-5-methylpyridine 1-oxide, yield 92.1% of theory).

[0051] Example 4 Preparation of 2-chloro-5-methylpyridine 1-oxide (according to the invention)

[0052] A mixture of 50 g (0.39 mol) of 2-chloro-5-methylpyridine, 100 g of methanol, and 5 g of titanium silicalite TS-1 was treated with 0.1 g of 50% sodium hydroxide solution (0.13 mol) and then heated to reflux. Under reflux, 30 g (0.44 mol) of hydrogen peroxide (aqueous solution, 50 wt.% H2O2) were added over 1 hour. The mixture was then stirred under reflux for 3 hours. After cooling to ambient temperature, the solid was filtered off and washed with 25 g of methanol. The combined filtrates yielded 190 g of a light beige solution (content 27 wt.%).

[0053] 2-chloro-5-methyl-pyridine-1-oxide, yield 91.2% of theory).

[0054] Example 5: Preparation of 2-chloro-5-methylpyridine 1-oxide (according to the invention)

[0055] A mixture of 188 g (1.5 mol) of 2-chloro-5-methylpyridine, 244 g of methanol, 94 g of acetic acid, and 17 g of titanium silicalite TS-1 was heated to reflux. Under reflux, 107 g (1.6 mol) of hydrogen peroxide (aqueous solution, 50 wt.% H2O2) were added over 2 hours. The mixture was then stirred under reflux for 2 hours. After cooling to ambient temperature, the solid was filtered off and washed with methanol. The combined mother and wash liquors were concentrated under vacuum at approximately 40 °C. The distillation residue yielded 242 g of a yellow solution (content 82.7 wt.% 2-chloro-5-methylpyridine 1-oxide, yield 94.6% of theory).

[0056] Example 6: Preparation of 2-chloro-5-methylpyridine 1-oxide (according to the invention)

[0057] A mixture of 1155 g (9.06 mol) of 2-chloro-5-methylpyridine, 1502 g of methanol, 578 g (9.62 mol) of acetic acid, 5.8 g (0.07 mol) of sodium bicarbonate, and 105 g of titanium silicalite TS-1 was heated to 76 to 78 °C under nitrogen. 659 g (9.68 mol) of hydrogen peroxide (aqueous solution, 50 wt.% H2O2) were added over 4 hours under reflux. The mixture was then stirred under reflux for 4 hours. After cooling to 50 °C, the solid was filtered off and washed with 115 g of methanol heated to 50 °C. The combined mother liquors and wash liquors were concentrated in vacuo at approximately 40 °C. The distillation residue obtained was 1719 g of a red-brown solution (content 72.6% 2-chloro-5-methyl-pyridine-1-oxide, yield 96.0% of theory).

Claims

Process for the preparation of compounds of formula (I), in the R 1 represents linear or branched Ci-Cio-alkyl, preferably linear or branched Ci-Ce-alkyl, which may be unsubstituted, mono- or polysubstituted, or in which R 1 represents Ce-Ce-cycloalkyl, which may be unsubstituted, mono- or polysubstituted, or in which R 1 represents aralkyl, which may be unsubstituted, mono- or polysubstituted, and in which R 2 represents hydrogen, chlorine, bromine, fluorine or cyano, comprising at least the reaction of compounds of formula (II), in which the remainder R 1 and R 2 which have the meaning given for formula (I), in the presence of at least oxidizing agent, water, organic solvent and catalyst.

2. The method according to claim 1, wherein R 1 for methyl, ethyl and n-propyl and R2 for hydrogen, R 1 for methyl, ethyl and n-propyl and R 2 for chlorine, or R 1 for methyl, ethyl and n-propyl and R 2 for bromine, or R 1 for methyl, ethyl and n-propyl and R 2 for fluorine, or R 1 for methyl, ethyl and n-propyl and R 2 stand for cyano.

3. The process according to claim 1, wherein substituted Ci-Ce-alkyl according to R 1 stands for cyclopropylmethyl or 1,1-difluoroethyl.

4. Process according to one of claims 1 to 3, characterized in that the catalyst is a titanium silicalite.

5. Process according to claim 4, characterized in that the catalyst is titanium silicalite-1 or TS-1.

6. Process according to one of claims 1 to 5, characterized in that the reaction is carried out in the presence of 7 to 15 g of catalyst per mole of compound of formula (II) used, preferably 11 to 13 g of catalyst per mole of compound of formula (II) used.

7. Process according to one of claims 1 to 6, characterized in that the oxidizing agent is hydrogen peroxide, preferably in the form of aqueous solutions.

8. Process according to one of claims 1 to 7, characterized in that from 0.9 to 2.0 mol, preferably from 1.0 to 1.3 mol, of oxidizing agent are used per mol of compound of formula (II) used.

9. Process according to one of claims 1 to 8, characterized in that it is carried out in the presence of organic solvents, preferably in the presence of methanol, ethanol, 1-propanol, 1-butanol, or mixtures thereof.

10. The process according to any one of claims 1 to 9, characterized in that it is carried out in the presence of acetic acid, preferably in the presence of 1.0 to 3.0 mol of acetic acid per mol of compound of formula (II) used, particularly preferably in the presence of 1.0 to 1.2 mol of acetic acid per mol of compound of formula (II) used.

11. Process according to one of claims 1 to 10, characterized in that it is carried out in the presence of inorganic base, preferably in the presence of 0.001 to 0.1 mol of inorganic base per mol of compound of formula (II) used, in particular in the presence of 0.005 to 0.05 mol of inorganic base per mol of compound of formula (II) used.

12. Process according to one of claims 1 to 11, characterized in that the inorganic base is selected from alkali hydroxides, alkaline earth hydroxides, alkali carbonates or alkaline earth carbonates, alkali hydrogen carbonates or alkaline earth hydrogen carbonates.

13. Process according to one of claims 1 to 12, characterized in that the inorganic base is sodium hydroxide or sodium bicarbonate.

14. Process according to one of claims 1 to 13, characterized in that the reaction takes place at temperatures of 60 to 90 °C, preferably of 70 to 85 °C.

15. The process according to any one of claims 1 to 14, characterized in that a) at least the compound of formula (II) and optionally organic solvent are initially introduced, and b) the mixture from step a) is heated to a temperature of 60 to 90 °C, preferably of 70 to 85 °C, and c) the oxidizing agent is added to the mixture from step b) within 1 to 7 hours, preferably 1 to 5 hours.

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