Preparation of substituted pyrazole compounds and their use as precursors of o-aminobenzamide

Abstract

A method for preparing a pyrazole derivative 3-bromo-5-methyl-1-H-pyrazole-N-2-chloropyridine (compound of formula I) is disclosed, wherein the method is by reacting a compound of formula II with a halogen-substituted pyridine, or by decarboxylating a pyrazole carboxylic acid of formula XI in the presence of an acid, optionally in the presence of a base and an organic solvent. In addition, a method for preparing a synthetic precursor of formula II, formula IV, formula V, formula VI, formula XI, and a method for preparing a compound of formula VII are provided, including reacting a compound of formula I with an oxidant, optionally in the presence of a catalyst. A compound of formula I as a useful synthetic precursor for preparing an o-aminobenzamide of formula VIII is also disclosed.

Description

[0001] Related Applications

[0002] This application claims priority to Chinese Patent Application No. 201910317694.4 filed on April 19, 2019, the contents of which are incorporated herein by reference in their entirety. Field of the Invention

[0003] The present invention relates to the preparation of substituted pyrazole derivatives and their further conversion into pesticidally active anthranilamide compounds, in particular chloranthraniliprole. Background of the Invention

[0005] Pyrazoles are nitrogen-containing five-membered heterocycles that constitute a class of compounds widely used in organic synthesis. They are one of the most studied groups of compounds among nitrogen-containing heterocycles, as they exist in different structures with various applications, especially in agriculture. In fact, a large number of synthetic methods for the generation of active pesticides have been reported over the years.

[0006] Active pesticides of particular interest are the anthranilamide insecticides disclosed previously, for example, in PCT patent publications WO 2001 / 070671, WO 2003 / 015519 and WO 2003 / 015518, particularly chlorantraniliprole. A variety of pyrazole precursors leading to the preparation of the anthranilamide compounds and a general method for their preparation are disclosed, for example, in PCT patent publications WO 2001 / 070671, WO 2006 / 062978, WO 2003 / 016283, WO 2004 / 011447 and WO 2003 / 015519. In addition, the preparation of some pyrazole precursors that can be used for further preparing anthranilamide compounds is disclosed, for example, in WO 1998 / 040358, EP0333131, EP 0151866 and US3254093. However, all described methods are of only limited use in batch syntheses on an industrial scale.

[0007] In addition, PCT patent publications WO 2001 / 070671 and WO 2003 / 016300 disclose in a general manner the alkylation of substituted methyl pyrazoles and further oxidation of the methyl group by potassium permanganate to produce pyrazole carboxylic acid compounds as precursors for preparing o-aminobenzamide compounds. However, the above-mentioned type of conversion only records the alkyl and / or haloalkyl substituents on the pyrazole ring, and does not provide an industrial scale method for preparing the starting methyl pyrazole compounds. Therefore, there is still a need for an effective industrial scale method for producing the starting methyl pyrazole compounds and further converting them into the pyrazole carboxylic acid precursor of chlorantraniliprole by the alkylation of the methyl pyrazole compounds substituted by halogen and the effective oxidation of the methyl group thereafter. Generally, it is necessary to have an additional cost-effective large-scale industrial method for preparing the pyrazole carboxylic acid precursor of chlorantraniliprole. Summary of the invention

[0008] The present invention relates to the preparation of a pyrazole derivative 3-bromo-5-methyl-1-H-pyrazole-N-2-chloropyridine (compound of formula I) by reacting a compound of formula II with a halogen-substituted pyridine, optionally in the presence of a base and an organic solvent.

[0009]

[0010] According to the present invention, there is also provided a method for preparing a compound of formula II, which comprises contacting a compound of formula IV with a base to obtain a compound of formula V, and further decarboxylating the compound of formula V in the presence of an acid, or contacting a compound of formula IV with an acid to obtain a compound of formula II.

[0011]

[0012] Furthermore, the present invention relates to a process for preparing a compound of formula IV, which comprises contacting a compound of formula VI with a brominating agent, optionally in the presence of a base and an organic solvent,

[0013]

[0014] Furthermore, the present invention relates to a process for preparing a compound of formula I, which comprises decarboxylating a compound of formula XI in the presence of an acid,

[0015]

[0016] Furthermore, the present invention relates to a process for preparing a compound of formula XI, comprising: a) contacting a compound of formula XII with a brominating agent, optionally in the presence of a base and an organic solvent, to obtain a compound of formula XIII; and b) contacting a compound of formula XIII with an acid

[0017]

[0018] Furthermore, the present invention relates to a process for preparing a compound of formula XI, comprising: a) contacting a compound of formula IV with a base to obtain a compound of formula V,

[0019]

[0020] wherein R is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, optionally substituted phenyl or optionally substituted benzyl;

[0021]

[0022] and b) reacting a compound of formula V with a compound of formula III in the presence of a base and an organic solvent, optionally in the presence of a catalyst The pyridine contact

[0023] Wherein L is a leaving group.

[0024] Furthermore, the present invention relates to a process for preparing a compound of formula I from a compound of formula XI prepared as described above.

[0025] In addition, the present invention provides compounds of formula I:

[0026]

[0027] Furthermore, the present invention provides a process for preparing a compound of formula VII,

[0028]

[0029] This involves reacting a compound of formula I with an oxidizing agent, optionally in the presence of a catalyst.

[0030] The present invention also relates to a method for preparing a compound of formula VIII using a compound of formula I,

[0031]

[0032] The present invention also relates to a process for preparing a compound of formula VIII,

[0033]

[0034] It comprises the following steps: optionally reacting a compound of formula I with an oxidizing agent in the presence of a catalyst to obtain a compound of formula VII; then reacting the compound of formula VII with an ortho-aminoaromatic carboxylic acid IX

[0035]

[0036] Reaction to give the corresponding benzoxazinone X

[0037]

[0038] The resulting benzoxazinone X is then reacted with methylamine to provide the compound of formula VIII.

[0039] Furthermore, the present invention provides a process for preparing a compound of formula VIII,

[0040]

[0041] The process is carried out by reacting a compound of formula I with an oxidizing agent, optionally in the presence of a catalyst, to obtain a compound of formula VII, and then reacting the compound of formula VII with an o-aminobenzamide XIV to obtain a compound of formula VIII,

[0042]

[0043] Another aspect of the present invention relates to a process for preparing a compound of formula VIII using a compound of formula I prepared as described above.

[0044] Another aspect of the present invention relates to a process for preparing a compound of formula VIII using a compound of formula VII prepared as described above.

[0045] Yet another aspect of the present invention relates to a process for preparing a compound of formula VIII using a compound of formula II prepared as described above.

[0046] Yet another aspect of the present invention relates to a process for preparing a compound of formula VIII using a compound of formula XI prepared as described above. DETAILED DESCRIPTION

[0047] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any other variation thereof, are intended to cover a non-exclusive inclusion without expressly indicating any limitation. For example, a composition, mixture, process, or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method.

[0048] The transitional phrase "consisting of" excludes any element, step, or ingredient not specified. If in a claim, such a phrase would render the claim exclusive of materials other than those recited, except for impurities normally associated therewith. When the phrase "consisting of" appears in a clause of a claim body, rather than immediately following a preamble, it is limited only to the elements specified in that clause; other elements are not excluded from the claim as a whole.

[0049] The transitional phrase "consisting essentially of is used to define a composition or method that also includes materials, steps, features, components, or elements in addition to those literally disclosed, provided that such additional materials, steps, features, components, or elements do not materially affect the basic and novel characteristics of the claimed invention. The term "consisting essentially of occupies a middle ground between "comprising" and "consisting of."

[0050] If the applicant has defined an invention or a portion thereof using open-ended terms such as "comprising," it should be readily understood that (unless otherwise indicated) the description should be interpreted as also describing such an invention using the terms "consisting essentially of" or "consisting of."

[0051] In addition, unless expressly stated to the contrary, "or" refers to an inclusive or, not an exclusive or. For example, condition A or B satisfies any of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and both A and B are true (or exist).

[0052] Moreover, the indefinite articles "a" and "an" before an element or component of the present invention are intended to be non-restrictive to the number of instances (i.e., occurrences) of the element or component. Therefore, "a" or "an" should be understood to include one or at least one, and the singular word form of an element or component also includes the plural, unless the number obviously represents the singular.

[0053] Certain compounds of the present invention may exist as one or more stereoisomers. Various stereoisomers include enantiomers, diastereomers and geometric isomers. It will be appreciated by those skilled in the art that one stereoisomer may be more active and / or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). In addition, the skilled artisan knows how to separate, enrich and / or selectively prepare the stereoisomers.

[0054] Therefore, the compounds of the present invention may exist as a mixture of stereoisomers, as individual stereoisomers or as optically active forms.

[0055] The term "halogen", alone or in a compound word such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. In addition, when used in a compound word such as "haloalkyl", the alkyl group may be partially or completely substituted by a halogen atom, which may be the same or different. Examples of "haloalkyl" include F3C, ClCH2, CF3CH2 and CF3CCl2. The term "haloalkoxy" includes CF3O, CCl3CH2O, HCF2CH2CH2O and CF3CH2O.

[0056] According to one embodiment, the compound of formula I is prepared by reacting a compound of formula II with a pyridine of formula III (wherein L is a leaving group) in the presence of a base and an organic solvent, optionally in the presence of a catalyst, as shown in Scheme 1:

[0057]

[0058] Option 1.

[0059] L may be any leaving group compatible with the reaction conditions. For example, L may be a halogen or an optionally halogenated sulfonyl group.

[0060] According to one embodiment, the suitable base used in the above reaction is selected from hydroxides, hydrides, alkoxides, and sulfates, sulfonates, sulfinates, phosphates, phosphonates, formates, oxalates, carbonates, acetates, propionates, benzoates and citrates of alkali metals and alkaline earth metals. More preferably, the suitable base can be an alkali metal carbonate and / or an alkali metal hydroxide.

[0061] Suitable bases used in the abovementioned process steps are generally used in amounts of 0.01 to 100.0 mol, more preferably 0.1 to 10.0 mol, in particular 1.0 to 5.0 mol and especially 1.2 to 2.0 mol, based in each case on 1 mol of the compound of the formula II.

[0062] According to another embodiment, organic solvent can be selected from polar or non-polar organic solvents, such as C1-C6 alcohol, ketone, ester, aromatic solvent, heteroaromatic solvent, aliphatic solvent, amide, sulfone, sulfoxide, halogenated solvent, nitrile, carbonate, urea and mixture thereof.Suitable polar solvent can be, for example but not limited to, alcohol (preferably C1-C4 alcohol), acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylethanolamine or their mixture.In one embodiment, suitable solvent is made up of N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, n-butanol, ethanol or its mixture.In a preferred embodiment, suitable polar solvent is made up of N,N-dimethylacetamide, dimethyl sulfoxide or its mixture. Suitable non-polar solvents may be, for example but not limited to, C1-C6 alkanes, C1-C6 halogenated alkanes, aromatic solvents such as benzene, xylene, nitrobenzene, and / or ethers such as 1,4-dioxane, or mixtures thereof.

[0063] Suitable catalysts are selected from alkali metal fluorides such as CsF, KF, NaF, quaternary ammonium salts such as tetraethylammonium hydrogen sulfate, triethylbenzylammonium chloride, phosphonium salts such as tetraphenylphosphonium bromide, PEG, crown ethers and mixtures thereof.

[0064] A suitable molar ratio of the catalyst to the pyrazole compound of formula II is from 0.001 to 100 mol / mol, in particular from 0.01 to 10.0 mol / mol.

[0065] In principle, the reactants can be contacted with each other in any desired order. For example, each of the compound of formula II and the pyridine of formula III can be first charged, optionally dissolved in a solvent or in dispersed form, and then the base, optionally in dissolved or dispersed form, can be added, or conversely the base, optionally dissolved or dispersed in a solvent, can be first charged and mixed with compound II. Alternatively, the two reactants can also be added to the reaction vessel simultaneously.

[0066] According to one embodiment, the compound of formula II is prepared as shown in Scheme 2. The method comprises contacting a compound of formula IV (wherein R is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, optionally substituted phenyl or optionally substituted benzyl) with a base to obtain a compound of formula V, and further decarboxylating the compound of formula V in the presence of an acid, or by contacting the compound of formula IV with an acid to obtain a compound of formula II.

[0067]

[0068] Solution 2. Preparation of compounds of formula II.

[0069] According to one embodiment, the compound of formula IV is heated with a base, preferably to a temperature of 90° C. to 120° C., more preferably to a temperature of 100° C. After the reaction mixture is cooled to a temperature of 5 to 10° C. and further quenched with an acid, the resulting compound of formula V is isolated. Suitable bases are selected from alkali metal and alkaline earth metal hydroxides, hydrides, alkoxides, and sulfates, sulfonates, sulfinates, phosphates, phosphonates, formates, oxalates, carbonates, acetates, propionates, benzoates and citrates, preferably from alkali metal hydroxides or alkoxides, such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and the like.

[0070] According to one embodiment, the acid is selected from hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid and mixtures thereof.

[0071] According to another embodiment, the obtained compound of formula V is converted into a compound of formula II by heating the compound of formula V with 30-60% by volume of an acid, preferably to a temperature of 90°C to 120°C, more preferably to a temperature of 100-105°C, wherein the acid is, for example, hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid and mixtures thereof.

[0072] According to another embodiment, the above-mentioned conversion of the compound of formula IV into the compound of formula II can be carried out in a one-pot-process without isolating the compound of formula V.

[0073] According to another embodiment, the compound of formula II is obtained by a one-step process comprising heating the compound of formula IV with 30-60% by volume of an acid, preferably to a temperature of 90°C to 120°C, more preferably to 100-110°C, wherein the acid is, for example, hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid and mixtures thereof.

[0074] According to one embodiment, the compound of formula IV is prepared by brominating a compound of formula VI, wherein R is as defined above, comprising contacting the compound of formula VI with a brominating agent, optionally in the presence of a base and an organic solvent, as shown in Scheme 3.

[0075] According to one embodiment, suitable bases are selected from alkali metal and alkaline earth metal hydroxides, hydrides, alkoxides, and sulfates, sulfonates, sulfinates, phosphates, phosphonates, formates, oxalates, carbonates, acetates, propionates, benzoates and citrates.

[0076] According to another embodiment, suitable organic solvents are selected from C1-C6 alcohols, ketones, esters, aromatic solvents, heteroaromatic solvents, aliphatic solvents, amides, sulfones, sulfoxides, halogenated solvents, nitriles, carbonates, ureas and mixtures thereof.

[0077] Any brominating agent capable of generating an electrophilic bromide ion (Br+) can be used in the bromination process. Non-limiting examples of such agents include bromine (Br2), N-bromosuccinimide (NBS), dibromodimethylhydantoin, N-bromophthalimide, N-bromosaccharin, monosodium bromoisocyanurate hydrate, dibromoisocyanuric acid (=DBI), dimethyl bromide, 5,5-dibromomeldrum's acid CAS No.: 66131-14-4, bis(2,4,6-trimethylpyridinium)-bromonium hexafluorophosphate and BrCl and mixtures thereof.

[0078] According to one embodiment, a suitable brominating agent is selected from bromine (Br2), N-bromosuccinimide (NBS) and / or N-bromophthalimide.

[0079] According to one embodiment, the process employed is one in which the amount of brominating agent is selected from a value ranging from 0.01 to 10.0 molar equivalents relative to the starting compound of formula VI.

[0080] According to one embodiment, the process is used in the presence of a base.

[0081] In a class of this embodiment are processes wherein the amount of base used is selected from a value of 0.01 to 10.0 molar equivalents relative to the starting compound of formula VI.

[0082]

[0083] Solution 3. Preparation of compounds of formula IV

[0084] According to one embodiment, the bromination process can be carried out in the presence of an organic solvent. Suitable organic solvents include acetonitrile, propionitrile and halogenated saturated aliphatic hydrocarbons, such as lower alkyl halides, such as dichloromethane, carbon tetrachloride, chloroform, bromochloromethane, 1,1,2-trichloroethane, 1,2-dibromoethane, dibromomethane, dichloroethane, etc. Liquid saturated hydrocarbon diluents are also suitable, and are typically such substances, such as cyclohexane, methylcyclohexane, 1,3-dimethylcyclohexane, 1,4-dimethylcyclohexane, isopropylcyclohexane.

[0085] According to another embodiment, the process is used in the presence of a base and an organic solvent.

[0086] In the practice of the present invention, the reaction temperature is maintained in the range of 0 to 50° C., preferably in the range of 15 to 30° C., for substantially the entire reaction period, i.e., at least until all of the brominating agent and the compound of formula VI have been mixed together. Since the bromination reaction is exothermic, it is preferred to maintain temperature control by gradually adding the brominating agent to the compound of formula VI substrate.

[0087] The compounds of formula VI can be prepared by known methods, for example as generally disclosed in Journal of Heterocyclic Chemistry, Vol. 46, No. 5, pp. 801-827. Specifically, Scheme 4 shows the preparation of compound VIa by reaction of dimethylformamide dimethyl acetal and ethyl acetoacetate via formylation of the active methylene group and further reaction with hydrazine hydrate.

[0088]

[0089] Solution 4 : Preparation of the compound of formula VIa.

[0090] According to the present invention, the compound of formula VII is prepared by reacting the compound of formula I with an oxidizing agent, optionally in the presence of a catalyst, as shown in Scheme 5.

[0091]

[0092] Solution 5 . Preparation of the compound of formula VII.

[0093] The compound of formula VII includes various methods of preparation previously disclosed, for example, in WO 2003 / 015519 and WO 2003 / 015518.

[0094] According to one embodiment, the aforementioned oxidation reaction includes a solvent selected from water, inert alcohols, carboxylic acids and esters thereof, chlorinated hydrocarbons, sulfoxides, sulfones, amides, ethers, ketones, pyridines and mixtures thereof. When selecting a solvent, it is necessary to partially or completely dissolve the starting compound of formula I.

[0095] According to one embodiment, the oxidizing agent is chosen from permanganates, such as potassium permanganate, sodium permanganate, or from organic and inorganic peroxides, such as benzoyl peroxide, tert-butyl peroxide, sodium peroxide, hydrogen peroxide, oxygen (diluted or undiluted O2, O3), or mixtures thereof.

[0096] According to another embodiment, the oxidation reaction is used in the presence of a catalyst. Suitable catalysts are selected from N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, quaternary ammonium salts such as tetraethylammonium hydrogen sulfate, triethylbenzylammonium chloride, phosphonium salts such as tetraphenylphosphonium bromide, PEG, crown ethers, sodium nitrite, tert-butyl nitrite, cobalt (II) acetate, manganese (II) acetate and mixtures thereof.

[0097] According to another embodiment, the oxidation reaction may be used in the presence of a catalyst selected from N-hydroxysuccinimide, N-hydroxyphthalimide and sodium nitrite, tert-butyl nitrite, cobalt (II) acetate, manganese (II) acetate and mixtures thereof.

[0098] According to another embodiment, the oxidation reaction may be used in the presence of a solvent selected from C1-C6 alcohols such as tert-butanol, organic nitriles such as acetonitrile, carboxylic acids such as acetic acid or halogenated derivatives thereof.

[0099] A suitable molar ratio of the catalyst to the pyrazole compound of formula I is from 0.001 to 100 mol / mol, in particular from 0.01 to 10.0 mol / mol.

[0100] The oxidation proceeds particularly smoothly if the molar ratio of oxidant to pyrazole compound of the formula I is from 0.1 to 100 mol / mol, in particular from 1.0 to 10.0 mol / mol.

[0101] Finally, the reaction mixture containing the oxidation product is post-processed. This stage may include filtration, purification, acidification (pH < 4), extraction, concentration and recrystallization. Optimization of these steps can result in a purity of more than 90%.

[0102] According to the present invention, the compound of formula I is preferably contacted with the oxidizing agent at an elevated temperature, i.e. above room temperature (20° C.). The preferred temperature interval is 50 to 120° C., most preferably 70 to 120° C. Without limiting the scope of protection, the elevated temperature most likely promotes the dissolution of the compound of formula I for more effective oxidation.

[0103] According to another aspect of the present invention, the compound of formula I is prepared by decarboxylating the compound of formula XI in the presence of an acid, as shown in Scheme 6:

[0104]

[0105] Solution 6 : Preparation of compounds of formula I from compounds of formula XI.

[0106] Suitable acids are selected from hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid and mixtures thereof.

[0107] In the practice of the present invention, the decarboxylation reaction temperature is maintained in the range of 10 to 130°C, preferably in the range of 100 to 120°C.

[0108] For the reaction, catalytic amounts of acid are generally sufficient. Typically, the acid is used in an amount of 0.1 to 1000 mol, in particular 1.0 to 10.0 mol, per mole of the compound of the formula XI.

[0109] Typically, the decarboxylation reaction is used in the presence of an organic solvent or solvent mixture. Suitable organic solvents are protic polar solvents, for example aliphatic alcohols preferably having 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol, or carboxylic acids, such as acetic acid, or aromatic polar solvents, such as aromatic hydrocarbons, such as benzene, toluene, xylene, isopropylbenzene, chlorobenzene, nitrobenzene or tert-butylbenzene, aprotic polar solvents, for example cyclic ethers or acyclic ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether (MTBE), tert-butyl ethyl ether, tetrahydrofuran (THF) or dioxane, cyclic or acyclic amides, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone or tetramethylurea, or aliphatic nitriles, such as acetonitrile or propionitrile, and mixtures thereof.

[0110] According to another aspect of the present invention, the compound of formula XI can be prepared by: a) contacting the compound of formula XII with a brominating agent, optionally in the presence of a base and an organic solvent, to obtain the compound of formula XIII; and b) contacting the compound of formula XIII with an acid, as shown in Scheme 7.

[0111]

[0112] Solution 7 . Preparation of compounds of formula XI.

[0113] According to one embodiment, a suitable brominating agent is selected from bromine (Br2), N-bromosuccinimide (NBS), dibromodimethylhydantoin, N-bromophthalimide, N-bromosaccharin, monosodium bromoisocyanurate hydrate, dibromoisocyanuric acid (=DBI), dimethyl bromide, 5,5-dibromomalberylic acid CAS No.: 66131-14-4, bis(2,4,6-trimethylpyridinium)-bromonium hexafluorophosphate and BrCl and mixtures thereof, preferably selected from bromine (Br2), N-bromosuccinimide (NBS) and / or N-bromophthalimide.

[0114] Suitable acids are selected from hydrochloric acid, hydrobromic acid, tetrafluoroboric acid, hexafluorophosphoric acid, trifluoroacetic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid, phosphonic acid and mixtures thereof.

[0115] According to one embodiment, the compound of formula XI is prepared in the presence of an organic solvent. Suitable organic solvents are selected from C1-C6 alcohols, ketones, esters, aromatic solvents, heteroaromatic solvents, aliphatic solvents, amides, sulfones, sulfoxides, halogenated solvents, nitriles, carbonates, ureas and mixtures thereof.

[0116] According to another embodiment, the bromination of the compound of formula XII is carried out in the presence of a base. Suitable bases are selected from alkali metal and alkaline earth metal hydroxides, hydrides, alkoxides, and sulfates, sulfonates, sulfinates, phosphates, phosphonates, formates, oxalates, carbonates, acetates, propionates, benzoates and citrates.

[0117] According to a preferred embodiment, the compound of formula XI is prepared in the presence of a base and an organic solvent.

[0118] According to another aspect of the present invention, the compound of formula I can be prepared from the compound of formula XI, which is prepared by: a) contacting the compound of formula XII with a brominating agent, optionally in the presence of a base and an organic solvent, to obtain the compound of formula XIII; and b) contacting the compound of formula XIII with an acid, as shown in Scheme 7.

[0119] According to another aspect of the present invention, the compound of formula XI is prepared by: a) contacting a compound of formula IV (wherein R is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, optionally substituted phenyl or optionally substituted benzyl) with a base to obtain a compound of formula V, and b) contacting the compound of formula V with a pyridine of formula III (wherein L is a leaving group as defined above) in the presence of a base and an organic solvent, optionally in the presence of a catalyst, as shown in Scheme 8.

[0120]

[0121] Solution 8 . Preparation of the compound of formula XI from the compound of formula IV.

[0122] Suitable bases are selected from alkali metal and alkaline earth metal hydroxides, hydrides, alkoxides, and sulfates, sulfonates, sulfinates, phosphates, phosphonates, formates, oxalates, carbonates, acetates, propionates, benzoates and citrates.

[0123] Suitable organic solvents are selected from the group consisting of C1-C6 alcohols, ketones, esters, aromatic solvents, heteroaromatic solvents, aliphatic solvents, amides, sulfones, sulfoxides, halogenated solvents, nitriles, carbonates, ureas and mixtures thereof.

[0124] According to one embodiment, the above method is used in the presence of a catalyst selected from alkali metal fluorides such as CsF, KF, NaF, quaternary ammonium salts such as tetraethylammonium hydrogen sulfate, triethylbenzylammonium chloride, phosphonium salts such as tetraphenylphosphonium bromide, PEG, crown ethers and mixtures thereof.

[0125] Suitable molar ratios of the catalyst to the pyrazole compound of formula V are from 0.001 to 100 mol / mol, in particular from 0.01 to 10.0 mol / mol.

[0126] Another aspect of the present invention relates to the preparation of compounds of formula I from compounds of formula XI prepared as shown in the above embodiments.

[0127] According to one embodiment, the present invention relates to compounds of formula I, in particular 3-bromo-5-methyl-1-H-pyrazole-N-2-chloropyridine, stereoisomers, solvates and / or N-oxides thereof.

[0128] In another aspect of the invention, the compound of formula I prepared by the process of the invention can be used as an intermediate to prepare the compound of formula VIII (chlorantraniliprole) by methods known in WO 2001 / 070671, WO 2006062978, WO 2003 / 015519 and WO 2003 / 015518.

[0129] According to another embodiment of the present invention, the compound of formula VIII is prepared using the compound of formula II, which is formed by: contacting the compound of formula IV with a base to obtain the compound of formula V, and further decarboxylating the compound of formula V in the presence of an acid; or b) contacting the compound of formula IV with an acid, as disclosed above.

[0130] Another aspect of the present invention is the preparation of a compound of formula VIII using a compound of formula XI, which is formed by contacting a compound of formula VI with a brominating agent, optionally in the presence of a base and an organic solvent, as disclosed above.

[0131] Another aspect of the present invention is the use of a compound of formula XI to prepare a compound of formula VIII, which is formed by: a) contacting a compound of formula IV (wherein R is C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, optionally substituted phenyl or optionally substituted benzyl) with a base to obtain a compound of formula V, and b) contacting the compound of formula V with a pyridine of formula III (wherein L is a leaving group as defined above) in the presence of a base and an organic solvent, optionally in the presence of a catalyst, as disclosed in the previous embodiments.

[0132] Another aspect of the present invention is the use of a compound of formula I prepared by a process disclosed above to prepare a compound of formula VII.

[0133] Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent.Therefore, the following examples are to be construed as illustrative only, and are not intended to limit the present disclosure in any way whatsoever.

[0134] Example

[0135] Example 1. Preparation of ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (A)

[0136] A 500 mL four-necked flask equipped with a mechanical stirrer and a thermometer was charged with 152.7 g (1.20 mol) of 99% dimethyl sulfate and heated to 80° C. At 80 to 90° C., 92.9 g (1.26 mol) of DMF was added dropwise to the reaction over 1 hour. The mixture was maintained at 80-85° C. for 3 h and then cooled to 20-30° C. to obtain a DMF-DMS solution.

[0137] 131.3g (1.0mol) 99% ethyl acetoacetate and 122.4g (1.20mol) triethylamine were charged into a 1L four-necked flask equipped with a mechanical stirrer, a thermometer and a dropping funnel. The DMF-DMS solution prepared above was added dropwise to the mixture over 30 minutes, and the temperature was maintained at less than 20°C. After the addition was complete, the reaction mixture was warmed to 25-30°C and stirred for another 1h. Then 1L DCM and 0.5L water were added to the mixture and stirred for another 10min. The aqueous layer was separated and extracted with 2×200mL DCM again. The combined (Z)-2-((dimethylamino)methylene)-3-oxobutanoic acid ethyl ester / DCM solution was used without further purification (yield: 99%).

[0138] Example 2. Preparation of ethyl 3-methyl-1H-pyrazole-4-carboxylate (VI)

[0139] A 1L four-necked flask equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with (Z)-2-((dimethylamino)methylene)-3-oxobutanoic acid ethyl ester / DCM solution (1.0 mol). 65.6 g (1.05 mol) of 80% hydrazine hydrate was added dropwise to the DCM solution over 2 h, and the temperature was maintained at less than 20 ° C. The mixture was then warmed to 25-30 ° C and stirred for another 1 h. The resulting DCM layer was separated and washed with 0.5% HCl aqueous solution until the pH of the aqueous phase reached 7 or less. The DCM phase was concentrated to obtain 143 g of ethyl 3-methyl-1H-pyrazole-4-carboxylate as a yellow liquid (yield: 93%).

[0140] Example 3. Preparation of 5-bromo-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (IV)

[0141] 143g (0.93mol) 3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester, 250mL EtOH, 270g water and 77.0g (0.93mol) NaOAc were loaded into a 2L four-necked flask equipped with a mechanical stirrer, a thermometer, a pH meter and a dropping funnel, and the reaction mixture was stirred at room temperature for 0.5h. 203g (1.26mol) Br was added dropwise to the reaction mixture within 2h, and a 20% NaOH aqueous solution was added to keep the pH between 6 and 8. The mixture was then stirred for another 1h at 20 to 30°C. The resulting mixture was then filtered, and the filtrate was concentrated under vacuum (-0.1MP) at 40°C, and then filtered again. The combined filter cake was stirred for 0.5h in 500mL water. The mixture was filtered and washed with 500 mL of water, and the filter cake was dried to give ethyl 5-bromo-3-methyl-1H-pyrazole-4-carboxylate 216.0 g as a white solid (98% yield).

[0142] Example 4. Preparation of 5-bromo-3-methyl-1H-pyrazole-4-carboxylic acid (V)

[0143] Into the 100mL four-necked flask equipped with mechanical stirrer, thermometer and condenser, 3.2g (80mmol) NaOH and 46mL H o are loaded.After NaOH dissolves, 9.3g (40mmol) 5-bromo-3-methyl-1H-pyrazole-4-ethyl formate is added and suspended in the solution.The mixture is heated to 100 ℃ and kept at this temperature for 4h.Then the mixture is cooled to 5 to 10 ℃ and quenched with 10mL concentrated HCl.The obtained mixture is separated by filtration, and the filter cake is washed with 10mL water and dried to obtain 5-bromo-3-methyl-1H-pyrazole-4-formic acid 8.2g, which is a pale white solid (100% yield).

[0144] Example 5. Preparation of 5-bromo-3-methyl-1H-pyrazole (II)

[0145] 5-bromo-3-methyl-1H-pyrazole-4-carboxylic acid 8.2g (40mmol) and concentrated hydrochloric acid 67mL (0.8mol) were loaded into a 100mL four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser. The mixture was heated to 105°C and kept at this temperature for 6h. After the reaction was completed, it was cooled to room temperature and concentrated to dryness. The residue was dissolved in 40mL water and neutralized with a 6mol / L NaOH aqueous solution until the pH reached 7 to 8. The resulting mixture was separated by filtration, and the filter cake was washed with 5mL water and dried to obtain 5-bromo-3-methyl-1H-pyrazole 5.9g, which was a pale white solid (92% yield).

[0146] Example 6. Preparation of 5-bromo-3-methyl-1H-pyrazole (II)

[0147] A 2L four-necked flask equipped with a mechanical stirrer, a thermometer and a dropping funnel was charged with 216.0 g (0.91 mol) of 98% 5-bromo-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester and 557 g (2.27 mol) of 40% H2SO4. The mixture was stirred at 100 to 110°C for 22 h and then cooled to 20 to 30°C. Thereafter, 606 g of 30% NaOH aqueous solution was added to neutralize the mixture until the pH reached 7 to 8. The resulting mixture was filtered between 40 and 50°C, the filter cake was washed with 250 mL of water, and then dried to obtain 5-bromo-3-methyl-1H-pyrazole 139.6 g as a light yellow solid (93% yield).

[0148] Example 7. Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole (I)

[0149] A 100 mL three-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser was charged with 14.5 g (87.6 mmol) of 97% 3-bromo-5-methyl-1H-pyrazole, 13.2 g (87.6 mmol) of 98% 2,3-dichloropyridine, 24.5 g (175.1 mmol) of potassium carbonate powder, 0.51 g (8.76 mmol) of 99% anhydrous potassium fluoride, 2.34 g (8.76 mmol) of 99% 1,4,7,10,13,16-hexaoxacyclooctadecane, and 44 mL of N,N-dimethylacetamide. The reaction was heated to 150 °C and stirred vigorously for 13 hours. The reaction was cooled to ambient temperature and filtered through a celite pad to remove undissolved solids. The solids were washed with 10 mL of N,N-dimethylacetamide. The obtained brown solution was distilled under reduced pressure, and the fractions were collected at 45° C. 40 mL of water and 20 mL of hexane were added to the residue, and the mixture was vigorously stirred at 50° C. for 1 hour and then cooled to room temperature. The product was isolated by filtration and then air-dried for 12 hours to obtain 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole 20.1 g as a brown solid (79% yield).

[0150] Example 8. Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (VII)

[0151] A 250 mL four-necked flask equipped with a mechanical stirrer, a thermometer, a condenser and an oxygen inlet was charged with 2-(3-bromo-5-methyl-1H-pyrazol-1-yl)-3-chloropyridine 13.6 g (50 mmol), N-hydroxysuccinimide 5.8 g (50 mmol) and acetic acid 136 mL. The mixture was heated to 120 ° C, while oxygen was bubbled in and HNO3 (1 mL) was added dropwise. The reaction was maintained at 120 ° C for 6 h. After the reaction was completed, it was cooled to room temperature and concentrated to dryness. The residue was dissolved in a 2 mol / L NaOH aqueous solution and washed with 30 mL of ethyl acetate. The pH of the aqueous solution was adjusted to 1-2 with 32% HCl. The resulting mixture was separated by filtration, and the filter cake was washed with 20 mL of water and dried to obtain 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid 9.8 g as an off-white solid (65% yield).

[0152] Example 9. Preparation of 5-bromo-2-(3-chloro-2-pyridyl)-2H-pyrazole-3-carboxylic acid (VII)

[0153] A 100 mL four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser was charged with 2.2 g (8 mmol) of 99% 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole, 91 mg (0.4 mmol) of 99% tetraethylammonium hydrogen sulfate, 16 mL of tert-butyl alcohol, and 64 mL of water. The mixture was heated to 80°C, and 3.8 g (24 mmol) of KMnO4 was added to the reaction at 80°C within 4 h. The reaction was stirred vigorously at 80°C for another 6 h, and then cooled to ambient temperature. Then 2 mL of saturated sodium sulfite was added, and the reaction mixture was filtered. The filter cake was washed with 5 mL of water and 10 mL of dichloromethane. The filtrate was extracted with dichloromethane (10 mL×3). The organic phase was concentrated to dryness to recover 0.55 g of raw material 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole. The pH value of the aqueous layer was adjusted to 1 with concentrated hydrochloric acid, and the crude product was collected by filtration and then air-dried for 2 hours to give 1.01 g of 5-bromo-2-(3-chloro-2-pyridinyl)-2H-pyrazole-3-carboxylic acid as a white product (40% yield).

[0154] Example 10. Preparation of 5-bromo-2-(3-chloro-2-pyridyl)-2H-pyrazole-3-carboxylic acid (VII)

[0155] 109 g of acetic acid, 6 g (22 mmol) of 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole, 4.3 g (37.1 mmol) of N-hydroxysuccinimide, 0.4 g (2.2 mmol) of cobalt (II) acetate and 0.2 g (1.1 mmol) of manganese (II) acetate were added to a 250 mL pressure reactor. Oxygen was introduced into the reactor to reach 20 bar at room temperature. The mixture was heated for 30 min under stirring. When the temperature of the mixture reached 100 ° C, the reactor was pressurized to 40 bar with oxygen and the temperature was set to 110 ° C. The reaction was carried out for more than 6 h. After the reaction was completed, the mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in a 2 mol / L NaOH aqueous solution and washed with 30 mL of ethyl acetate. The pH value of the aqueous solution was adjusted to 1-2 with a concentrated HCl solution. The resulting mixture was isolated by filtration, the filter cake was washed with 20 mL of water and dried to give 4.7 g of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid as an off-white solid (70% yield).

[0156] Example 11. Preparation of 5-bromo-2-(3-chloro-2-pyridyl)-2H-pyrazole-3-carboxylic acid (VII)

[0157] 10g M-272 (0.037mol), 8.45g N-hydroxysuccinimide (0.073mol) and 100ml acetic acid (10 volume equivalents) were loaded into a 250mL 4-neck RBF equipped with a magnetic stirrer, a thermometer, a condenser and an oxygen inlet. The reaction mixture was stirred at room temperature for 15-20min and then heated to 110°C. The oxygen purge was started with 5mL / min. At this time, 7.6g NaNO2 was added to the reaction mass in small portions (5 to 10 portions) (immediately releasing a reddish gas). The oxygen purge was continued and the reaction mass was stirred at 110°C for 2h. After the reaction was completed, the oxygen was stopped, the reaction mass was cooled to room temperature and the acetic acid was evaporated under reduced pressure. The residual material was dissolved in 110mL 2NNaOH solution and stirred at room temperature for 0.5h. The water layer was extracted twice with 50mL ethyl acetate and the organic layer was separated. The organic phase was concentrated to dryness to recover 5.0 g of raw material 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole. The pH of the aqueous layer was adjusted to 1 with concentrated hydrochloric acid, and the crude product was collected by filtration and then air-dried for 2 hours to obtain 4.33 g of 5-bromo-2-(3-chloro-2-pyridyl)-2H-pyrazole-3-carboxylic acid as a white product (39% yield).

[0158] Example 12. Preparation of 3-bromo-1-(3-chloro-2-pyridinyl)-5-methyl-1H-pyrazole (I)

[0159] A 100 mL three-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser was charged with 10 g (60.2 mmol) of 97% 3-bromo-5-methyl-1H-pyrazole, 9.09 g (60.2 mmol) of 98% 2,3-dichloropyridine, 16.6 g (120.4 mmol) of potassium carbonate powder, and 30 mL of N,N-dimethylacetamide. The reaction was heated to 150°C and stirred vigorously for 13 hours. The reaction was cooled to ambient temperature, filtered through a celite pad to remove undissolved solids and washed with 10 mL of N,N-dimethylacetamide. The resulting brown solution was distilled under reduced pressure, and the fractions were collected at 45°C. 40 mL of water and 20 mL of hexane were added to the residue, and the mixture was stirred vigorously at 50°C for 1 hour, and then cooled to room temperature. The product was isolated by filtration and then air dried for 12 hours to give 3-bromo-1-(3-chloro-2-pyridinyl)-5-methyl-1H-pyrazole 12.3 g as a brown solid (75% yield).

[0160] Example 13. Preparation of 5-bromo-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (IV)

[0161] 100g (0.65mol) 3-methyl-1H-pyrazole-4-ethyl formate, 200mL EtOH and 250g water are added to the 1L four-necked flask equipped with mechanical stirrer, thermometer and dropping funnel, reaction mixture is stirred at room temperature for 0.5h, and in 2h, 160g (1.0mol) Br is added dropwise in reaction mixture.Then, mixture is stirred for 1h at 20 to 30 ℃.Gained mixture is concentrated at 40 ℃ under reduced pressure.Filter cake is stirred for 0.5h in 500mL water.Mixture is filtered and washed with 500mL water and dried filter cake, to obtain 5-bromo-3-methyl-1H-pyrazole-4-ethyl formate 75.7g, is white solid (50% yield).

[0162] Example 14. Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-5-methyl-1H-pyrazole (I)

[0163] 113.9 g (0.36 mol) of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid and 353 g (1.44 mol) of 40% H2SO4 were added to a 1L four-necked flask equipped with a mechanical stirrer, a thermometer and a dropping funnel. The mixture was stirred at 100 to 110°C for 22 h and then cooled to 20 to 30°C. 380 g of 30% aqueous NaOH solution was added to neutralize the mixture until the pH reached 7 to 8. The resulting mixture was filtered between 40 and 50°C, and the filter cake was washed with 250 mL of water and then dried to obtain 63.6 g of a light yellow solid.

[0164] Example 15. Preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate (XIII)

[0165] 66.4 g (0.25 mol) of ethyl 1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate, 50 mL of EtOH, 70 g of water and 20.7 g (0.25 mol) of sodium acetate were added to a 500 mL four-necked flask equipped with a mechanical stirrer, a thermometer, a pH meter and a dropping funnel, and the reaction mixture was stirred at room temperature for 0.5 h. 50.4 g (0.32 mol) of Br2 was added dropwise to the reaction mixture over 2 h, and then a 20% aqueous NaOH solution was added to keep the pH between 6 and 8. The mixture was then stirred for another 1 h at 20 to 30 ° C. The resulting mixture was then filtered, and the filtrate was concentrated under reduced pressure at 40 ° C, and then filtered again. The combined filter cake was stirred in 100 mL of water for 0.5 h. The mixture was filtered and washed with 100 mL of water, and the filter cake was dried to give ethyl 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate 84.4 g as a white solid.

[0166] Example 16. Preparation of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate (XIII)

[0167] 66.4g (0.25mol) 1- (3-chloropyridin-2-yl) -5-methyl -1H- pyrazole -4- carboxylic acid ethyl ester, 50mL EtOH, 70g water were added to a 500mL four-necked flask equipped with a mechanical stirrer, a thermometer and a dropping funnel, and the reaction mixture was stirred at room temperature for 0.5h. 40g (0.25mol) Br2 was added dropwise to the reaction mixture over 2 hours, and the mixture was then stirred for another 1h at 20 to 30°C. The resulting mixture was concentrated at 40°C under reduced pressure. The filter cake was stirred in 100mL water for 0.5h. The mixture was filtered and washed with 100mL water, and the filter cake was dried to obtain 3-bromo-1- (3-chloropyridin-2-yl) -5-methyl -1H- pyrazole -4- carboxylic acid ethyl ester 63.8g as a white solid.

[0168] Example 17. Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (XI)

[0169] 50 g (0.15 mol) of ethyl 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylate and 0.75 L of 1 M HCl solution were added to a 1 L four-necked flask equipped with a mechanical stirrer, a thermometer and a dropping funnel, and the mixture was heated to 110 ° C and maintained for 5 h. After the reaction was completed, the product was collected by filtration. Drying was performed to obtain 42.7 g of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid as a white solid.

[0170] Example 18. Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (XI)

[0171] A 100 mL three-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser was charged with 5 g (24.4 mmol) of 3-bromo-5-methyl-1H-pyrazole-4-carboxylic acid, 3.61 g (24.4 mmol) of 98% 2,3-dichloropyridine, 6.77 g (49 mmol) of potassium carbonate powder, 0.14 g (2.44 mmol) of 99% anhydrous potassium fluoride, 0.65 g (2.44 mmol) of 99% 1,4,7,10,13,16-hexaoxacyclooctadecane, and 20 mL of N,N-dimethylacetamide. The reaction was heated to 150 °C and stirred vigorously for 13 hours. The reaction was cooled to ambient temperature and filtered through a celite pad to remove undissolved solids. The solids were washed with 10 mL of N,N-dimethylacetamide. The resulting brown solution was distilled under reduced pressure, and fractions were collected at 45°C and stirred with 20 mL of water and 10 mL of hexane at 50°C for 1 hour, then cooled to room temperature. The product was isolated by filtration and then air-dried for 12 hours to give 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid 6.18 g as a brown solid.

[0172] Example 19. Preparation of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (XI)

[0173] A 100 mL three-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser was charged with 5 g (24.4 mmol) of 3-bromo-5-methyl-1H-pyrazole-4-carboxylic acid, 3.61 g (24.4 mmol) of 98% 2,3-dichloropyridine, 6.77 g (49 mmol) of potassium carbonate powder, and 20 mL of N,N-dimethylacetamide. The reaction was heated to 150°C and stirred vigorously for 13 hours. The reaction was cooled to ambient temperature and filtered through a celite pad to remove undissolved solids. The solids were washed with 10 mL of N,N-dimethylacetamide. The resulting brown solution was distilled under reduced pressure, and the fractions were collected at 45°C. 20 mL of water and 10 mL of hexane were added to the residue, and the mixture was stirred vigorously at 50°C for 1 hour and then cooled to room temperature. The product was isolated by filtration and then air dried for 12 hours to give 4.94 g of 3-bromo-1-(3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid as a brown solid.

[0174] Furthermore, the entire contents of any priority documents of this application are incorporated herein by reference.

Claims

1. Compounds of formula I:

2. A method for preparing a compound of formula I: The method comprises reacting a compound of formula II in the presence of a base and an organic solvent, optionally in the presence of a catalyst. Reaction with pyridine of formula III is carried out: wherein L is a leaving group selected from Cl, Br, I and a halogenated or unhalogenated sulfonyl group: Wherein R, R' is C1-C4 alkyl, phenyl, which is optionally substituted by halogen, The catalyst is selected from alkali metal fluorides, quaternary ammonium salts, phosphonium salts, PEG, crown ethers and mixtures thereof.

3. The process according to claim 2, wherein the base is selected from the group consisting of hydroxides, hydrides, alkoxides, and sulfates, sulfonates, sulfinates, phosphates, phosphonates, formates, oxalates, carbonates, acetates, propionates, benzoates and citrates of alkali metals and alkaline earth metals.

4. The method according to claim 2, wherein the organic solvent is selected from the group consisting of C1-C6 alcohols, ketones, esters, aromatic solvents, heteroaromatic solvents, aliphatic solvents, amides, sulfones, sulfoxides, halogenated solvents, nitriles, carbonates, ureas, and mixtures thereof.

5. The process according to claim 2, wherein the compound of formula I is prepared in the presence of a catalyst.

6. The method of claim 5, wherein the catalyst is selected from the group consisting of alkali metal fluorides, quaternary ammonium salts, phosphonium salts, PEG, crown ethers, and mixtures thereof.

7. The process according to claim 5, wherein the catalyst is selected from the group consisting of cesium fluoride, potassium fluoride, sodium fluoride, tetraethylammonium hydrogen sulfate, triethylbenzylammonium chloride, tetraphenylphosphonium bromide and mixtures thereof.

8. A method for preparing a compound of formula VIII The method comprises the following steps: a) optionally in the presence of a catalyst, reacting a compound of formula I according to claim 1 Reaction with an oxidizing agent to obtain a compound of formula VII The oxidant is selected from oxygen, air, ozone, hydrogen peroxide, benzoyl peroxide, tert-butyl peroxide, m-chloroperbenzoic acid, peracetic acid, peroxybenzoic acid, magnesium monoperoxyphthalate, potassium peroxymonosulfate, sodium permanganate, potassium permanganate and mixtures thereof, The catalyst is selected from N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, tetraethylammonium hydrogen sulfate, triethylbenzylammonium chloride, tetraphenylphosphonium bromide, PEG, crown ether, sodium nitrite, tert-butyl nitrite, cobalt (II) acetate, manganese (II) acetate and mixtures thereof, b) reacting the compound of formula VII with an o-aminoaromatic carboxylic acid IX To obtain the corresponding benzoxazinone X and c) reacting the obtained benzoxazinone X with methylamine to obtain the compound of formula VIII.

9. A method for preparing a compound of formula VIII The method comprises the following steps: a) reacting a compound of formula I with an oxidizing agent, optionally in the presence of a catalyst, To obtain the compound of formula VII The oxidant is selected from oxygen, air, ozone, hydrogen peroxide, benzoyl peroxide, tert-butyl peroxide, m-chloroperbenzoic acid, peracetic acid, peroxybenzoic acid, magnesium monoperoxyphthalate, potassium peroxymonosulfate, sodium permanganate, potassium permanganate and mixtures thereof, The catalyst is selected from N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxybenzotriazole, tetraethylammonium hydrogen sulfate, triethylbenzylammonium chloride, tetraphenylphosphonium bromide, PEG, crown ether, sodium nitrite, tert-butyl nitrite, cobalt (II) acetate, manganese (II) acetate and mixtures thereof, b) reacting the compound of formula VII with anthranilamide XI to obtain a compound of formula VIII

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