Process for production of alkyl-pyridine n-oxides

Abstract

The invention relates to a method for producing an alkylpyridine N-oxide of formula (I) from the corresponding unsubstituted 3-alkylpyridine or the corresponding 5-alkylpyridine substituted in the 2-position of formula (II) in the presence of at least an oxidizing agent, water, an organic solvent and a catalyst.

Description

Field of the Invention

[0001] The present invention relates to a process for preparing an alkylpyridine N-oxide of formula (I) from the corresponding unsubstituted 3-alkylpyridine or 5-alkylpyridine substituted in the 2-position of formula (II) in the presence of at least an oxidizing agent, water, an organic solvent and a catalyst.

[0002] Alkylpyridine N-oxides of formula (I) are reactants for the synthesis of pharmaceutical and agrochemical active ingredients. Such structural elements are found, for example, in the acetyl-CoA carboxylase inhibitors in WO 2014 / 114578 A2, which can be used to treat, for example, diabetes or obesity. In addition, WO 2014 / 124230 A2 discloses 5-alkyl-2-halopyridine N-oxides of formula (I) as reactants in the preparation of active ingredients from the class of ERK kinase inhibitors, which are active ingredients that can be used to treat cancer. Background Art

[0003] Processes for preparing such compounds are known from the literature, but these processes have disadvantages when carried out on an industrial scale. For example, it is known to oxidize substituted pyridines with organic peroxides such as meta-chloroperbenzoic acid (MCPBA). The disadvantage here is a certain amount of meta-chlorobenzoic acid produced as waste, which may have to be laboriously separated from the product. In addition, organic peroxides require high safety measures, especially when storing them on an industrial scale.

[0004] For oxidation, hydrogen peroxide is a popular oxidizing agent in organic synthesis because the reaction products produced from it are only gaseous oxygen and water, and they do not have to be laboriously disposed of as waste. For example, it is known to use hydrogen peroxide-urea salt as an oxidizing agent. However, this procedure has the disadvantage of producing stoichiometric amounts of waste.

[0005] In contrast, using an aqueous hydrogen peroxide solution would be advantageous because this does not produce any waste. It has been found that several documents describe the preparation of 5-alkyl-2-halopyridine N-oxides using hydrogen peroxide in an uncatalyzed manner or in the presence of sodium tungstate (Na2WO4) (as described, for example, in CN103193704A) or trifluoroacetic anhydride. However, internal studies have shown that in this procedure, some 5-alkyl-2-halopyridines or 5-alkyl-2-cyanopyridines are not completely converted even after long reaction times. Apart from this, carrying out the reaction on an industrial scale in the presence of sodium tungstate and trifluoroacetic anhydride produces waste and / or deactivated catalysts, which have to be laboriously disposed of or reprocessed.

[0006] For example, in the case of acetic acid as the solvent, WO 2005 / 085248 A1 describes the reaction of 2-chloro-5-methylpyridine with an aqueous hydrogen peroxide solution, where 2-chloro-5-methylpyridine N-oxide is obtained in gram scale after a reaction time of 8 hours with a yield of 82%. When transferring this method to an industrial scale, the disadvantages are that the reaction time will increase to 24 hours or longer, and a large amount of acetic acid has to be laboriously separated from the product and disposed of as waste in an expensive way. In the case of such reactions, a long reaction time also always means an increased safety risk.

[0007] Methods for the oxidation of various monosubstituted pyridines with hydrogen peroxide in the presence of a catalyst are also known. For example, M.R. Prasad, Mol. Cat. A: Chemical 2002, 186, 109 - 120 describes the oxidation of 2-chloropyridine in water and methanol with hydrogen peroxide as a 30% aqueous solution at a temperature of 60 °C in the presence of a TS-1 catalyst with yields of 91% and 98%, respectively. In the case of water as the solvent, the reaction time is 24 hours, while in the case of methanol, a reaction time of only 2 hours is sufficient. Similarly, for example, 2-, 3-, and 4-methylpyridine are obtained in water with yields of only 29% to 32% within 24 hours at a temperature of 60 °C in the presence of a TS-1 catalyst with hydrogen peroxide as a 30% aqueous solution. In the case of methanol as the solvent, methyl-substituted pyridine N-oxides can be obtained in high yields of 93% to 95% within 5 to 6 hours at 60 °C in the presence of a Ti-ZSM-5(30) catalyst. Halogens act as electron-withdrawing substituents on the pyridine ring, while alkyl substituents are electron-donating substituents. According to this document, in the case of TS-1 as the catalyst, pyridine N-oxides with electron-donating substituents can only be obtained in relatively low yields using this method. All reactions according to this document were carried out using 2 molar equivalents of hydrogen peroxide based on the pyridine used and only in milliliter scale.

[0008] Accordingly, there is a need for a method for preparing alkylpyridine N-oxides of formula (I) which enables the efficient and safe preparation of these pyridine derivatives on an industrial scale.

[0009] Surprisingly, a simple and safe method for preparing alkylpyridine N-oxides of formula (I), preferably 3-alkylpyridine N-oxides or 5-alkyl-2-halopyridine N-oxides or 5-alkyl-2-cyanopyridine N-oxides, has been found, which method comprises reacting an alkylpyridine of formula (II), preferably 3-alkylpyridine, 5-alkyl-2-halopyridine or 5-alkyl-2-cyanopyridine, with an oxidizing agent in the presence of a catalyst, water and an organic solvent to obtain these products in good yield and high purity on an industrial scale. In this method, the solid catalyst can be easily separated from the reaction mixture and optionally reused in the method. Furthermore, the method according to the invention does not produce any critical waste that has to be disposed of with difficulty. SUMMARY OF THE INVENTION

[0010] Accordingly, the present invention provides a method for preparing a compound of formula (I),

[0011]

[0012] wherein R 1 is a straight-chain or branched C1-C 10 alkyl group, preferably a straight-chain or branched C1-C6 alkyl group, which may be unsubstituted, monosubstituted or polysubstituted, preferably monosubstituted or polysubstituted by a halogen group or an alkoxy group,

[0013] or wherein R 1 is a C3-C8 cycloalkyl group, which may be unsubstituted, monosubstituted or polysubstituted,

[0014] or wherein R 1 is an aralkyl group, which may be unsubstituted, monosubstituted or polysubstituted, preferably monosubstituted or polysubstituted by a halogen group or an alkoxy group,

[0015] and wherein R 2 is hydrogen, chlorine, bromine, fluorine or cyano,

[0016] The method comprises at least reacting a compound of formula (II)

[0017]

[0018] wherein the groups R 1 and R 2 have the definitions given for formula (I),

[0019] in the presence of at least an oxidizing agent, water, an organic solvent and a catalyst.

[0020] According to the straight-chain C1-C of R 1 and 10The alkyl group is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-decyl.

[0021] Preferably, according to the group R 1 The unsubstituted straight-chain or branched C1-C 10 alkyl group is methyl, ethyl or n-propyl. Preferably, according to the group R 1 The substituted straight-chain alkyl group is cyclopropylmethyl or 1,1-difluoroethyl.

[0022] According to R 1 The straight-chain or branched C1-C6 alkyl group is, 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.

[0023] The straight-chain or branched C1-C 10 alkyl group or C1-C6 alkyl group may be unsubstituted. It may also be mono-substituted or multi-substituted, preferably mono-substituted or multi-substituted by a halogen group or an alkoxy group. Examples of the mono-substituted C1-C6 alkyl group 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.

[0024] According to R 1 The C3-C8 cycloalkyl group is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

[0025] The C3-C8 cycloalkyl group can be unsubstituted, monosubstituted or polysubstituted. Examples of monosubstituted C3-C8 cycloalkyl groups 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.

[0026] Particularly preferably, R 1 is methyl, ethyl and n-propyl, and R 2 is hydrogen. Also particularly preferably, R 1 is methyl, ethyl and n-propyl, and R 2 is chlorine. Also particularly preferably, R 1 is methyl, ethyl and n-propyl, and R 2 is bromine. Also particularly preferably, R 1 is methyl, ethyl and n-propyl, and R 2 is fluorine. Also particularly preferably, R 1 is methyl, ethyl and n-propyl, and R 2 is cyano.

[0027] According to the present invention, "a method for preparing a compound having the formula (I) by reacting a compound having the formula (II) in the presence of at least an oxidizing agent, water, an organic solvent and a catalyst" means oxidizing a compound having the formula (II) with an oxidizing agent by contacting them with a catalyst in water and an organic solvent to obtain a compound having the formula (I).

[0028] In the method according to the present invention, the catalyst is, for example, a microporous solid, preferably a titanium silicalite, particularly preferably titanium silicalite-1 (also known as TS-1). TS-1 is commercially available from various manufacturers.

[0029] The microporous solid is, for example, a molecular sieve, such as ZSM5. ZSM5 is an aluminosilicate zeolite belonging to the pentasil family. It is constructed from silicon cations, aluminum cations, oxygen cations and optionally additional counter cations.

[0030] The titanium-containing silicalite has the chemical general formula Si 1-x Ti xO2 and is prepared, for example, in a hydrothermal reaction of tetraethyl orthosilicate (TES) as a SiO2 source and tetraethyl orthotitanate (TET) as a TiO2 source in the presence of tetrapropylammonium hydroxide as a base. This reaction is usually followed by calcination in order to remove the ammonium salts from the solid. This results in a porous solid in which the tetravalent Si(IV) species are isomorphously replaced by tetravalent Ti(IV) species.

[0031] The titanium silicalite most often used on an industrial scale is titanium silicalite-1 (also commonly abbreviated as TS-1). This generally has a SiO2 / TiO2 molar ratio of at least 25, a BET surface area of 360 to 420 g / m 2 and a pore diameter of about 0.5 nanometers. Titanium silicalite-1 or TS-1 is particularly preferred as a catalyst for the process according to the invention.

[0032] Very particularly preferably, the process according to the invention is carried out in the presence of 7 to 15 grams of catalyst per mole of the compound of formula (II) used in the process. In particular, the process according to the invention is carried out in the presence of 11 to 13 grams of catalyst per mole of the compound of formula (II) used in the process. According to the invention, "in the presence of a catalyst" means bringing a reaction mixture containing the compound of formula (II), an oxidizing agent, water and an organic solvent into contact with the catalyst in the liquid phase, with the result that the reaction mixture is in the form of a suspension. The suspension is usually mechanically or hydraulically mixed in order to increase the interaction between the liquid phase and the suspended catalyst.

[0033] In the process according to the invention, the oxidizing agent is preferably hydrogen peroxide. Hydrogen peroxide is usually used as an oxidizing agent in the form of an aqueous solution. In the process according to the invention, the oxidizing agent is particularly preferably an aqueous hydrogen peroxide solution of 30% to 70% (by weight %). Particularly preferably, in the process according to the invention, 0.9 to 2.0 mol, in particular 1.0 to 1.3 mol, of the oxidizing agent are used per mole of the compound of formula (II) used.

[0034] The process according to the invention is further carried out in the presence of water. In addition to the water present in the aqueous hydrogen peroxide solution, additional water can also be added, for example, to the reaction mixture here. However, it is preferred not to add any additional water to the reaction mixture in addition to the water present in the oxidizing agent, preferably hydrogen peroxide.

[0035] The method according to the invention is further carried out in the presence of at least one organic solvent. The catalyst is present as a solid in the reaction mixture, while the compounds of formula (I) and formula (II) are generally partially or completely dissolved in the solvent. Preferred organic solvents are straight-chain fatty alcohols, particularly preferably methanol, ethanol, 1-propanol or 1-butanol, or any desired mixture thereof. Methanol is particularly preferred as the solvent for the method according to the invention. This has the advantage that the temperature of the reaction mixture is limited by the boiling point of methanol in the reaction vessel at the corresponding pressure, which can prevent the decomposition of the oxidation product.

[0036] In an alternative preferred embodiment, the method according to the invention is further carried out in the presence of an organic acid (such as acetic acid). In addition to the presence of the oxidizing agent, water, organic solvent and catalyst, the presence of an organic acid (such as acetic acid) has the advantages that, firstly, the reaction proceeds faster, and secondly, acetic acid stabilizes the pyridine N-oxide during the post-treatment in which it is thermally stressed. Particularly preferably, the method according to the invention is carried out in the presence of 1.0 to 3.0 mol of acetic acid per mole of the compound of formula (II) used, especially in the presence of 1.0 to 1.2 mol of acetic acid per mole of the compound of formula (II) used.

[0037] In another preferred embodiment, the method according to the invention is further carried out in the presence of at least one inorganic base. The presence of the inorganic base has the advantage that the formation of alkyl carboxylates (such as from acetic acid and methanol) is largely inhibited by increasing the pH.

[0038] 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. Particularly preferably, the inorganic base is sodium hydroxide and sodium bicarbonate. In the method according to the invention, the base can be used in solid or liquid form, as a pure substance, or in the form of a suspension or dissolved in a liquid medium.

[0039] Particularly preferably, the method according to the invention is carried out in the presence of 0.001 to 0.1 mol of inorganic base per mole of the compound of formula (II) used, especially in the presence of 0.005 to 0.05 mol of inorganic base per mole of the compound of formula (II) used.

[0040] In the method according to the invention, the compound of formula (II) reacts, for example, at a temperature of 60 °C to 90 °C, preferably 70 °C to 85 °C.

[0041] Preferably, the method according to the invention is carried out in such a way

[0042] a) First, charge at least a compound of formula (II) and optionally an organic solvent, and

[0043] b) Heat the mixture from step a) to a temperature of 60 °C to 90 °C, preferably 70 °C to 85 °C, and

[0044] c) Add an oxidizing agent to the mixture from step b) over a period of 1 to 7 hours, preferably 1 to 5 hours.

[0045] Preferably, here, the starting materials (except for the oxidizing agent) - namely, the compound of formula (II), the catalyst, the organic solvent, optionally water, optionally acetic acid, optionally an inorganic base - in pure form or in dissolved or suspended form, initially separate or together, can first be mixed at ambient temperature.

[0046] Equally preferably, the process according to the invention is carried out in such a way that

[0047] a) First, charge at least a compound of formula (II), optionally an oxidizing agent and optionally an organic solvent, and

[0048] b) Heat the mixture from step a) to a temperature of 60 °C to 90 °C, preferably 70 °C to 85 °C, and

[0049] c) Add an oxidizing agent to the mixture from step b) over a period of 1 to 7 hours, preferably 1 to 5 hours.

[0050] Equally preferably, the starting materials - namely, the compound of formula (II), the catalyst, the organic solvent, optionally water, optionally acetic acid, optionally an inorganic base and a part of the oxidizing agent required for the reaction - in pure form or in dissolved or suspended form, initially separate or together, can first be mixed at ambient temperature.

[0051] Subsequently, preferably, the reaction mixture is heated to the required reaction temperature. Equally preferably, the reaction mixture is heated to boiling heat under reflux. Then, the oxidizing agent, preferably hydrogen peroxide, is added to the mixture of starting materials that has reached the reaction temperature.

[0052] If a part of the oxidizing agent has already been added to the reaction in step a), then in step c), the remaining part of the oxidizing agent required for the reaction and not added in step a) is added over a period of 1 to 7 hours, preferably over a period of 1 to 5 hours.

[0053] The oxidizing agent is preferably added under temperature control since the reaction proceeds exothermically. This may involve cooling the reaction mixture. Particularly preferably, the oxidizing agent is added continuously. The oxidizing agent is generally added to the mixture of starting materials over a period of 1 to 10 hours, preferably 2 to 5 hours. Metering the oxidizing agent into the reaction mixture, which particularly contains a catalyst, also has the advantage that no temporary excess of hydrogen peroxide is required in the reaction mixture. This allows the reaction to be safely handled even on a large scale since peroxide accumulation in the reaction mixture is not expected at any time.

[0054] Once the addition of the oxidizing agent is complete, the reaction mixture is preferably maintained at a temperature of 60 °C to 90 °C, preferably 70 °C to 85 °C, until no further reaction occurs. The chemical reaction is generally monitored by gas chromatography, thin layer chromatography, infrared spectroscopy or HPLC.

[0055] The process according to the invention is generally carried out at ambient pressure or at a pressure of up to 0.6 megapascals under an inert gas (such as 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 discharged from the reaction circuit for safety reasons.

[0056] If the reaction temperature is higher than the boiling point of the reaction mixture or of the individual components of the reaction mixture at ambient pressure, the reaction is generally carried out in a pressure-sealed device (such as an autoclave) at elevated autogenous pressure or at an applied pressure (such as nitrogen pressurization).

[0057] After completion of the reaction of the compound of formula (II), the reaction product is obtained from the reaction mixture, for example, in the following manner, namely the compound of formula (I)

[0058] i) filtering the reaction mixture which has been cooled to ambient temperature, preferably cooled to 30 °C to 50 °C, wherein the catalyst is separated from the filtrate, and

[0059] ii) optionally washing the filtered catalyst with an organic solvent, wherein a wash liquor is obtained, and

[0060] iii) mixing the filtrate from step a) and the wash liquor from step b), and

[0061] iv) separating the reaction product (i.e., the compound of formula (I)) from the organic solvent, optionally with water and / or acetic acid (for example by distillation), and

[0062] v) optionally drying the filtered catalyst with a stream of inert gas and optionally reusing it in a subsequent reaction.

[0063] Compounds of formula (I) can be stored in pure form or in the form of a solution in an organic solvent or acetic acid, and / or used as a reactant in subsequent processes. Generally, care should be taken that pyridine N-oxides may be thermally unstable substances. Therefore, appropriate safety investigations and precautions should be taken when handling them on an industrial scale.

[0064] Surprisingly, a safe, rapid and economical method for preparing compounds of formula (I) has now been found, which overcomes the disadvantages of the methods according to the prior art. Even on an industrial scale, for example in the case of 1000 to 2000 kg of a compound of formula (II) as starting material, with a reaction time of less than 10 hours, the yield of the compound of formula (I) according to the method of the invention (based on the compound of formula (II) used) is between 90% and 99% of theory. The compounds of formula (I) are formed here in high purity, for example with less than 0.5% by weight of reactants and / or secondary components. The spent catalyst can optionally be reused in subsequent reactions. In addition, significantly less waste is formed in the method according to the invention than in the methods according to the prior art. Detailed description

[0065] Examples

[0066] Example 1: Preparation of 2-chloro-5-methylpyridine 1-oxide (comparative example)

[0067] A mixture of 50 g (0.39 mol) of 2-chloro-5-methylpyridine, 70 g of water and 2.5 g of titanium silicate zeolite TS-1 was heated to 60 °C. 53 g (0.78 mol) of hydrogen peroxide (aqueous solution, 50% by weight H2O2) was metered in at 60 °C within 1 hour. Stirring was then continued at 60 °C for 24 hours, after which a conversion of approximately 50% was achieved.

[0068] Example 2: Preparation of 3-methylpyridine 1-oxide (invention)

[0069] 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 silicate zeolite TS-1 was heated to reflux. 130 g (1.91 mol) of hydrogen peroxide (aqueous solution, 50% by weight H2O2) was metered in at reflux within 2 hours. After cooling to ambient temperature, the solid was separated by filtration and washed with methanol. The combined mother liquor and washings were concentrated under reduced pressure at approximately 40 °C. 246 g of a light beige solution as a distillation residue was obtained (content of 3-methylpyridine 1-oxide 66.8% by weight, yield 93.5% of theory).

[0070] Example 3: Preparation of 2-chloro-5-methylpyridine 1-oxide (the present invention)

[0071] A mixture of 50 g (0.4 mol) of 2-chloro-5-methylpyridine, 100 g of methanol and 5 g of titanium silicate zeolite TS-1 was heated to reflux. 30 g (0.4 mol) of hydrogen peroxide (aqueous solution, 50% by weight of H2O2) was metered in over 1 hour under reflux. Then stirring was continued for 5 hours under reflux. After cooling to ambient temperature, the solid was separated by filtration and washed with 25 g of methanol. 185 g of a light beige solution as the combined filtrate was obtained (the content of 2-chloro-5-methylpyridine 1-oxide was 28% by weight, and the yield was 92.1% of theory).

[0072] Example 4: Preparation of 2-chloro-5-methylpyridine 1-oxide (the present invention)

[0073] A mixture of 50 g (0.39 mol) of 2-chloro-5-methylpyridine, 100 g of methanol and 5 g of titanium silicate zeolite TS-1 was admixed with 0.1 g of a 50% sodium hydroxide solution (0.13 mol), and then heated to reflux. 30 g (0.44 mol) of hydrogen peroxide (aqueous solution, 50% by weight of H2O2) was metered in over 1 hour under reflux. Then stirring was continued for 3 hours under reflux. After cooling to ambient temperature, the solid was separated by filtration and washed with 25 g of methanol. 190 g of a light beige solution as the combined filtrate was obtained (the content of 2-chloro-5-methylpyridine 1-oxide was 27% by weight, and the yield was 91.2% of theory).

[0074] Example 5: Preparation of 2-chloro-5-methylpyridine 1-oxide (the present invention)

[0075] 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 silicate zeolite TS-1 was heated to reflux. 107 g (1.6 mol) of hydrogen peroxide (aqueous solution, 50% by weight of H2O2) was metered in over 2 hours under reflux. Then stirring was continued for 2 hours under reflux. After cooling to ambient temperature, the solid was separated by filtration and washed with methanol. The combined mother liquor and washings were concentrated under reduced pressure at about 40 °C. 242 g of a yellow solution as the distillation residue was obtained (the content of 2-chloro-5-methylpyridine 1-oxide was 82.7% by weight, and the yield was 94.6% of theory).

[0076] Example 6: Preparation of 2-chloro-5-methylpyridine 1-oxide (the present invention)

[0077] In the case of introducing nitrogen, 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 silicate zeolite TS-1 was heated to 76 °C to 78 °C under reflux. 659 g (9.68 mol) of hydrogen peroxide (aqueous solution, 50% H2O2 by weight) was metered in over 4 hours under reflux. Then stirring was continued for 4 hours under reflux. After cooling to 50 °C, the solid was separated by filtration and washed with 115 g of methanol heated to 50 °C. The combined mother liquor and washings were concentrated under reduced pressure at about 40 °C. 1719 g of a red-brown solution as a distillation residue was obtained (the content of 2-chloro-5-methylpyridine 1-oxide was 72.6% by weight, and the yield was 96.0% of the theory).

Claims

1. A method for preparing a compound of formula (I), wherein R 1 is a straight-chain or branched C1-C 10 alkyl group, preferably a straight-chain or branched C1-C6 alkyl group, which may be unsubstituted, monosubstituted or polysubstituted, or wherein R 1 is a C3-C8 cycloalkyl group which may be unsubstituted, monosubstituted or polysubstituted, or wherein R 1 is an aralkyl group, which may be unsubstituted, monosubstituted or polysubstituted, and wherein R 2 is hydrogen, chlorine, bromine, fluorine or cyano, the method comprising at least reacting a compound of formula (II) wherein the group R 1 and R 2 have the definitions given for formula (I), in the presence of at least an oxidizing agent, water, an organic solvent, and a catalyst.

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

3. The method according to claim 1, wherein According to R 1 The substituted C1-C6 alkyl group is cyclopropylmethyl or 1,1-difluoroethyl.

4. The method according to any one of claims 1 to 3, characterized in that, The catalyst is a titanium silicate zeolite.

5. The method according to claim 4, wherein The catalyst is titanium silicate zeolite - 1 or TS - 1.

6. The method according to any 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 the compound of formula (II) used, preferably 11 to 13 g of catalyst per mole of the compound of formula (II) used.

7. The method according to any one of claims 1 to 6, characterized in that, The oxidizing agent is hydrogen peroxide, which is preferably in the form of an aqueous solution.

8. The method according to any one of claims 1 to 7, characterized in that, 0.9 to 2.0 mol, preferably 1.0 to 1.3 mol of the oxidizing agent is used per mole of the compound of formula (II) used.

9. The method according to any one of claims 1 to 8, characterized in that, The method is carried out in the presence of an organic solvent, preferably in the presence of methanol, ethanol, 1 - propanol, 1 - butanol, or a mixture thereof.

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

11. The method according to any one of claims 1 to 10, characterized in that, The method is carried out in the presence of an inorganic base, preferably in the presence of 0.001 to 0.1 mol of inorganic base per mole of the compound of formula (II) used, especially in the presence of 0.005 to 0.05 mol of inorganic base per mole of the compound of formula (II) used.

12. The method according to any one of claims 1 to 11, characterized in that, The inorganic base is 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.

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

14. The method according to any one of claims 1 to 13, characterized in that, The reaction is carried out at a temperature of 60 °C to 90 °C, preferably 70 °C to 85 °C.

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

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