Synthesis of cyano-anthranilic acid

Abstract

The present invention relates to the preparation of cyano-anthranilic acid derivatives from 2-amino-5-formyl-3-methylbenzoic acid derivatives, including 2-amino-5-cyano-3- methylbenzoic acid, in the presence of N-methylpyrrolidone (NMP), N,N- dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof, used as a dehydration agent. The present invention discloses an efficient, high yield process to obtain cyano-anthranilic acid intermediate further leading to the manufacturing of diamides, in particular, cyantraniliprole.

Description

[0001] TITLE: SYNTHESIS OF CYANO-ANTHRANILIC ACID

[0002] FIELD OF INVENTION:

[0003] The present invention relates to the preparation of cyano-anthranilic acid derivatives, including 2-amino-5-cyano-3-methylbenzoic acid from 2-amino-5-formyl-3-methylbenzoic acid derivatives, in the presence of solvent which acts as a dehydration agent.

[0004] BACKGROUND:

[0005] Cyantraniliprole, a compound of formula (VIII) is well known for its activity against pesticides i.e., insecticide. This insecticide compound is known for its unique mode of action, the ryanoid class, and thus its highly importance in the agrochemical insecticide industry. E.L Du Pont De Nemours and Co. were the first to describe Cyantraniliprole, and its family of compounds in WO 2004 / 067528. In this patent the innovator claims the compound, other corresponding compounds, possible mixtures with other insecticides and methods of use. The synthesis of this compound comprises, in certain cases, the use and synthesis of one of the key intermediates, 2-amino-5-cyano-3-methylbenzoic acid. The cyano group of this key intermediate is obtained, in most cases, by a coupling reaction of a haloanthranilic acid with a metal cyanide. In some cases, a palladium catalyst or a metal halide is additionally required. This approach is also described in the following patents: CN105367548, CN103450154, WO2022058916, CN104003976, W02006068669, W02008070158,

[0006] W02009111553, W02009085816, W02008082502, W02008070158, W02009006061. In recent publication WO2024116197 the hydrogenation of nitro group, also conducted by metal catalyst to obtain the required amino group, was disclosed. WO2024186513 publication discloses the synthesis of this substance under photochemical conditions. These methods have many drawbacks such as low efficiency, low yields, high cost, and use heavy metals that also occasionally leads to metal contamination in the final product. Recently, a new approach for the synthesis of anthranilic acid derivatives was published by ADAMA MACHTESIM LTD., WO2024038436, comprising the preparation of anthranilic acid derivatives via the synthesis of the corresponding hydroxyimino-derivative followed by a dehydration of said hydroxyiminoderivative in the presence of a base.

[0007] Preparative methods for this substance must be improved for economic commercial operation. In view of that, the present invention makes available a convenient, cost-effective route, free of metals way to prepare a 2-amino-5-cyano-3-methylbenzoic acid and use it for the preparation of Cyantraniliprole.

[0008] SUMMARY:

[0009] The present invention is related to the process for the preparation of a compound of formula (I), or its salts thereof, comprising reaction of a compound of formula (II) or its salts thereof with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof. The present invention is also related to the process for the preparation of a compound of formula (III), or its salt thereof, comprising a) reacting a compound of formula (I) or its salt thereof, prepared by reacting a compound of formula (II) or its salts thereof with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof, with a compound of formula (A)

[0010] 0

[0011] JI

[0012] Z1 Z2(A) wherein Z1and Z2, are independently, chloride, Cl-C4-alkoxy, trichloromethyloxy, C(O)CI, C1-C6- alkyloxycarbonate; in the presence of a solvent to obtain a compound of formula (IV) and b) further reacting the compound of formula (IV) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base.

[0013] Furthermore, the present invention is related to the process for the preparation of a compound of formula (III) or its salt thereof, comprising a) reacting a compound of formula (I) or its salt thereof, prepared by reacting a compound of formula (II) or its salts thereof with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof, with thionyl chloride, sulfuryl chloride, phthaloyl chloride, phosphorus pentachloride, phosphorus trichloride, cyanuric chloride, acetic anhydride, propionic anhydride, butyric anhydride, hexanoic anhydride, benzoic anhydride, trichloroacetic anhydride, isopropenyl acetate, acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIG), ethyl-(N',N'- dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), or a mixture thereof, optionally in the presence of a base to obtain a compound of formula (V) wherein R1, is halide, optionally halogenated Cl-C6-carboxylic acid, carbodiimide, hydroxytriazoles; and b) reacting the compound of formula (V) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base. The present invention further directed to the process for the preparation of a compound of formula (VI), and its salt thereof, comprising a) preparation of a compound of formula (I), or its salts thereof comprising reaction of a compound of formula (II) or its salts thereof with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof b) contacting of a compound of formula (I) and a compound of formula (A) 0z1Z2(A) wherein Z1 and Z2, are independently, chloride, Cl-C4-alkoxy, trichloromethyloxy, C(O)CI, C1-C6- alkyloxycarbonate; in the presence of a solvent to obtain a compound of formula (IV) c) contacting the compound of formula (IV) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base, to obtain a compound of formula (III), and d) contacting the compound of formula (III) with a compound of formula (VII) or its salt thereof, wherein Y is halide or hydroxy group; in the presence of a solvent and optionally in the presence of a base, wherein the base is inorganic base, organic base, and the mixtures thereof. of the invention:

[0014] Definitions:

[0015] Prior to setting forth the present subject matter in detail, it may be helpful to provide definitions of certain terms to be used herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this subject matter pertains.

[0016] Throughout the application, descriptions of various embodiments use the term "comprising"; however, it will be understood by one skilled in the art, that in some specific instances, an embodiment can alternatively be described using the language "consisting essentially of" or "consisting of".

[0017] The term "a" or "an" as used herein includes the singular and the plural, unless specifically stated otherwise. Therefore, the terms "a," "an" or "at least one" can be used interchangeably in this application.

[0018] The term "alkyl" as used herein refers to a branched, unbranched, or cyclic carbon chain.

[0019] The term "halogen" or "halo" as used herein refers to one or more halogen atoms, defined as F, Cl, Br, and I. Unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained.

[0020] As used herein, numerical values include ±10% from the indicated value. In addition, all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges. It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention.

[0021] The term "carbonyl" as used herein refers to the group -C=O.

[0022] The term "alkoxy," as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom. The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0023] The term " trichloromethyloxy," as used herein, refers to a trichloromethyl group attached to the parent molecular moiety through an oxygen atom.

[0024] The term "alkyloxycarbonate" as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonate group.

[0025] The term "dehydration agent" in purpose of the present invention is referred to a substance that removes water molecules from another compound. The dehydration agent is used to drive dehydration reaction, which involves the elimination of water (H2O) from reactants to form a product.

[0026] The term "telescopic process" as used herein refers to carrying out several reactions without isolating the intermediate products. In particular, the telescopic process suggests the execution of multiple transformations (including reaction quenches and other workup operations) without the direct isolation of intermediates. Telescoped solutions of intermediates can be extracted, filtered (as long as the desired product remains in the filtrate), and solvent exchanged, but the intermediate is ultimately held in solution and carried forward to the subsequent transformation.

[0027] The term "one-pot synthesis process" as used herein, refers to the possibility to perform multiple chemical reactions in one step in a single reaction vessel without the need of isolation (e.g., purification) of the intermediates obtained in each chemical reaction. This method reduces the number of the synthetic steps, decreases waste materials, time, and cost.

[0028] The term "salts", as used herein, refers to organic salts as chloride, bromide, fluoride, iodide, acetate, hydrogen sulfates, phosphates, formats, nitrate, carbonate, or, if applicable, alkaline metal salts as sodium, potassium, calcium, lithium, cesium, magnesium, barium.

[0029] Any of the compounds described here as basic compound or intermediate in a process is intended also to include the compound salts as hydrogen chloride salts, acetic acid salts, no special meaning should be given to the fact that in some cases this is mentioned or not mention for specific compound in the text. The salts of the compounds of the invention include acid-addition salts with inorganic or organic acids as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.

[0030] At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. In an embodiment, use of numerical parameter herein specifically includes ±10% from the indicated values in the range. In addition, the endpoints of all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges.

[0031] According to one aspect, the present invention relates to a process for the preparation of a compound of formula (I), or its salts thereof, comprising reacting a compound of formula (II) or its salts thereof with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof.

[0032] According to an embodiment, the compound of formula (II) is at a concentration of from 10% to 90% by weight, based on the total weight of the mixture.

[0033] According to an embodiment, the compound of formula (II) is at a concentration of from 15% to 50% by weight, based on the total weight of the mixture. According to an embodiment, the compound of formula (II) is at a concentration of from 20% to 40% by weight, based on the total weight of the mixture.

[0034] According to an embodiment, the solvent is A / -methylpyrrolidone (NMP).

[0035] According to an embodiment, the solvent is A / ,A / -dimethylformamide (DMF).

[0036] According to an embodiment, the solvent is dimethylacetamide.

[0037] According to an embodiment, the solvent is dimethylsulfoxide (DMSO).

[0038] According to an embodiment, the solvent serves not only to solvate the substances in the reaction mixture, but also as dehydration agent which removes a water molecule from the intermediate substance that is generated in the process between the reactant (a compound of formula (II)) and the final product (a compound of formula (I)). Therefore, the process described in this invention redundant the need for the presence of a base in the reaction, and significantly improves this method of preparation of a compound of formula (I) in terms of yield, sustainability, large-scale feasibility, cost, and time efficiency.

[0039] According to an embodiment, the solvent in the reaction is pre-hydrated from water content prior to the reaction process.

[0040] According to an embodiment, the solvent in the reaction process may have water content in amount of from 0.01% to 30%, more preferably from 0.01% to 10%, most preferably from 0.01% to 1%.

[0041] According to an embodiment, a distillation is done through the reaction to remove the excess of water in the process.

[0042] According to an embodiment, the hydroxylamine salt is selected from a group comprising hydroxylamine hydrochloride, hydroxylamine hydrobromide, hydroxylamine acetate, hydroxylamine fluoride, hydroxylamine iodide, hydroxylamine sulfate, hydroxylamine disulfate, hydroxylamine phosphate, hydroxylamine nitrate, hydroxylamine perchlorate, Hydroxylamine- O-sulfonic acid, hydroxylamine carbonate and the mixtures thereof. According to an embodiment, the hydroxylamine salt is selected from a group comprising hydroxylamine hydrochloride, hydroxylamine acetate, hydroxylamine sulfate, hydroxylamine phosphate, hydroxylamine nitrate, and the mixtures thereof.

[0043] According to an embodiment, the hydroxylamine salt is hydroxylamine hydrochloride.

[0044] According to an embodiment, the hydroxylamine salt is at a concentration of from 1% to 50% by weight, based on the total weight of the mixture.

[0045] According to an embodiment, the hydroxylamine salt is at a concentration of from 5% to 25% by weight, based on the total weight of the mixture.

[0046] According to an embodiment, the hydroxylamine salt is at a concentration of from 10% to 20% by weight, based on the total weight of the mixture.

[0047] According to an embodiment, the molar ratio between the compound of formula (II) to hydroxylamine or hydroxylamine salt can be from 1:5 to 1:0.9, preferably from 1:3 to 1:1, most preferably from 1:1.15 to 1:1.05.

[0048] According to an embodiment, the weight ratio between the compound of formula (II) to the solvent can be from 1:20 to 10:1, preferably from 1:5 to 1:0.5, most preferably from 1:3 to 1:1.

[0049] According to an embodiment, the compound of formula (II) contacted with the hydroxylamine or its salt thereof at the temperature interval of from 30 to 130°C. A preferred temperature interval is from 70 to 120°C, more preferably from 100 to 120°C.

[0050] According to an embodiment, the reaction mixture is monitored by HPLC analytical method, and the process ends when concentration of formula (II) is between 0-99%, preferably from 0-50%. In particular, the process should be terminated when no more than 5% of compound of formula (II) remains in the reaction media.

[0051] According to an embodiment, the reaction mixture is monitored by HPLC analytical method, and the process ends when concentration of formula (II) is between 0-40%, preferably from 0-10%. In particular, the process should be terminated when no more than 1% of compound of formula (II) remains in the reaction media. According to an embodiment, the reaction mixture containing the resulting compound of formula (I) is optionally worked up or proceed as in telescopic / one-pot synthesis process without workup to the next step. This stage may include adding water, adding organic solvent, stirring, cooling, heating, phases separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying processes.

[0052] According to an embodiment, the reaction mixture containing the resulting compound of formula (I) is isolated from the reaction mixture by adding water, filtrate the precipitant and washing the solid product with water or organic solvent and dry the solid product by air or vacuum at temperature between 30 to 100 °C.

[0053] According to an embodiment, the reaction mixture containing the resulting compound of formula (I) is transferred by metering to the next step in the manufacturing process without any additional operation.

[0054] In yet another embodiment, the present invention provides a process for the preparation of a compound of formula (III), and its salt thereof, comprising step a) reacting a compound of formula (I) or its salt thereof, prepared by reacting of a compound of formula (II) or its salts thereof, NH2

[0055] \|X^^C°2H

[0056] CHO (||) with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof, according to any of the preceding embodiments, with a compound of formula (A)

[0057] 0

[0058] JI

[0059] Z1 Z2(A) wherein Z1and Z2, are independently, chloride, Cl-C4-alkoxy, trichloromethyloxy, C(O)CI, C1-C6- alkyloxycarbonate; in the presence of a solvent to obtain a compound of formula (IV) and step b) further reacting the compound of formula (IV) with methylamine or its salts thereof, in the presence of a solvent, and optionally in the presence of a base.

[0060] According to an embodiment, the solvent in the process for the preparation of a compound of formula (IV) (step a), is selected from a group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons halogenated aromatic hydrocarbons, aliphatic and cyclic ethers diethyl ether, aliphatic and cyclic esters, nitriles, ketones, C1-C6 alcohols, polar protic and aprotic solvents, water, and a mixture thereof. According to an embodiment, the solvent in the process for the preparation of a compound of formula (IV) (step a), is selected from a group comprising octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane petroleum ether, carbontetrachloride, chloroform, methylenechloride, 1,2-dichloroethane, benzene, toluene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), isopropylmethyl ether, tetra hydrofuran (THF), methyltetrahydrofuran (Me-THF), cyclopentylmethyl ether, ethyl acetate, dimethyl carbonate, diethyl carbonate, acetonitrile, benzonitrile, acetone, 2-butanone, methanol, ethanol, 1-butanol, 2- butanol, 1-propanol, 2-propanol, t-butyl alcohol, diethylene glycol, glycerin, ethylene glycol, propylene glycol l-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetic acid, water, and a mixture thereof.

[0061] According to an embodiment the solvent in the process for the preparation of a compound of formula (IV) (step a), is selected from a group comprising halogenated aliphatic acyclic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic and cyclic ethers, aliphatic esters, nitriles, ketones, C1-C6 alcohols, polar protic and aprotic solvents, water, and a mixture thereof.

[0062] According to an embodiment the solvent in the process for the preparation of a compound of formula (IV) (step a), is selected from a group comprising ethers diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), isopropylmethyl ether, tetrahydrofuran (THF), methyl-tetrahydrofuran (Me-THF), dimethyl carbonate, diethyl carbonate, and a mixture thereof.

[0063] According to an embodiment, the weight ratio between the compound of formula (I) to the solvent in the process for the preparation of a compound of formula (IV) can be from 1:20 to 10:1, preferably from 1:1 to 1:10, most preferably from 1:3 to 1:5.

[0064] According to an embodiment the compound of formula (A) in the process for the preparation of a compound of formula (IV) is selected form a group comprises of phosgene, diphosgene, triphosgene, methyl chloroformate, ethyl chloroformate, dimethylcarbamoyl chloride, oxalyl chloride, di-t-butyl dicarbonate, dimethyl dicarbonate, diethyl dicarbonate or a mixture thereof. According to an embodiment the compound of formula (A) in the process for the preparation of a compound of formula (IV) is selected form a group comprises of triphosgene, phosgene, oxalyl chloride, or a mixture thereof.

[0065] According to an embodiment, the molar ratio between the compound of formula (I) to the compound of formula (A) in the process for the preparation of a compound of formula (IV) (step a), is from 1:20 to 10:1, preferably from 1:1 to 1:10, most preferably from 1:1 to 1:2.

[0066] According to an embodiment, the molar ratio between the compound of formula (I) to the compound of formula (A) in the process for the preparation of a compound of formula (IV) (step a), is from 1:1 to 1:10, preferably from 1:1 to 1:5, most preferably from 1:1.05 to 1:1.2.

[0067] According to an embodiment, compound of formula (I) contacted with compound of formula (A) in the process for the preparation of a compound of formula (IV) (step a), is performed between the temperature interval of from 0 to 100°C. A preferred temperature interval is from 0 to 60°C, more preferably from 20 to 40°C.

[0068] According to an embodiment, compound of formula (I) contacted with compound of formula (A) in the process for the preparation of a compound of formula (IV) (step a), is performed between the temperature interval of from 0 to 60°C. A preferred temperature interval is from 20 to 40°C, more preferably from 25 to 30°C.

[0069] According to an embodiment the reaction mixture in the process for the preparation of a compound of formula (IV) (step a), is monitored by HPLC analytical method, and the process ends when concentration of formula (I) is between 0-99%, preferably from 0-50%, most preferably, in particular, when no more than 1% of compound of formula (I) remains in the reaction media.

[0070] According to an embodiment the reaction mixture is monitored by HPLC analytical method, and the process ends when concentration of formula (I) is between 0-40%, preferably from 0-10%. In particular the process ends when no more than 1% of compound of formula (I) remains in the reaction media.

[0071] According to an embodiment, the reaction mixture containing the resulting a compound of formula (IV) is worked up. This stage may include adding water, adding organic solvent, stirring, cooling, heating, phases separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying processes.

[0072] According to an embodiment, the reaction mixture containing the resulting compound of formula (IV) is optionally worked up or proceed as in telescopic / one-pot synthesis process without workup to the next step. This stage may include adding water, adding organic solvent, stirring, cooling, heating, phases separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying processes.

[0073] According to an embodiment, the reaction mixture containing the resulting compound of formula (IV) is isolated from the reaction mixture by adding water, filtrate the precipitant and washing the solid product with water or organic solvent and dry the solid product by air or vacuum at temperature between 30 to 100 °C.

[0074] According to an embodiment, the reaction mixture containing the resulting compound of formula (IV) is transferred by metering to the next step in the manufacturing process without any additional operation.

[0075] According to an embodiment, the solvent in the process for the preparation of a compound of formula (III) (step b), is selected from a group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic and cyclic esters, nitriles, ketones, C1-C6 alcohols, polar protic and aprotic solvents, water, and a mixture thereof.

[0076] According to an embodiment, the solvent in the process for the preparation of a compound of formula (III) (step b), is selected from a group comprising octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane petroleum ether, carbontetrachloride, chloroform, methylenechloride, 1,2-dichloroethane, benzene, toluene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, aliphatic and cyclic ethers diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), isopropylmethyl ether, tetrahydrofuran (THF), methyl-tetrahydrofuran (Me-THF), cyclopentylmethyl ether, ethyl acetate, acetonitrile, benzonitrile, acetone, 2-butanone, methanol, ethanol, 1-butanol, 2- butanol, 1-propanol, 2-propanol, t-butyl alcohol, diethylene glycol, glycerin, ethylene glycol, propylene glycol, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetic acid, water, and a mixture thereof.

[0077] According to an embodiment the solvent in the process for the preparation of a compound of formula (III) (step b), is selected from a group comprising diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), isopropylmethyl ether, tetra hydrofuran (THF), methyl-tetrahydrofuran (Me-THF), and a mixture thereof.

[0078] According to an embodiment, the methylamine salt is selected from a group comprising of methylammonium chloride, methylammonium bromide, methylammonium iodide, methylammonium nitrate, methylammonium format, methylammonium sulfate, methylammonium tetrafluoroborate, methylammonium acetate, methylammonium hydroxide, methylammonium perchlorate and a mixture thereof.

[0079] According to an embodiment, the methylamine salt is selected from a group comprising of methylammonium chloride, methylammonium nitrate, methylammonium acetate, methylammonium hydroxide and a mixture thereof.

[0080] According to an embodiment, the methylamine salt is methylammonium chloride.

[0081] According to an embodiment, the methylamine, or its salt thereof in the process for the preparation of a compound of formula (III) (step b), is at a concentration of from 1% to 50% by weight, based on the total weight of the mixture.

[0082] According to an embodiment, the methylamine, or its salt thereof in the process for the preparation of a compound of formula (III) (step b), is at a concentration of from 5% to 25% by weight, based on the total weight of the mixture.

[0083] According to an embodiment, the methylamine, or its salt thereof in the process for the preparation of a compound of formula (III) (step b), is at a concentration of from 10% to 20% by weight, based on the total weight of the mixture. According to an embodiment, a molar ratio between compound (IV) to the methylamine or its salt thereof can be from about 1:20 to 1:0.1, preferably from about 1:10 to 1:1, most preferably from about 1:5 to 1:3.

[0084] According to an embodiment, a molar ratio between compound (IV) to the methylamine or its salt thereof can be from about 1:10 to 1:1, preferably from about 1:5 to 1:2, most preferably from about 1:3 to 1:2.

[0085] According to an embodiment, the weight ratio between the compound of formula (IV) to the solvent in the process for the preparation of a compound of formula (III) (step b), is from 1:20 to 10:1, preferably from 1:5 to 1:0.5, most preferably from 1:3 to 1:1.

[0086] According to an embodiment, the compound of formula (IV) contacted with the methylamine or its salt thereof in the process for the preparation of a compound of formula (III) (step b), at the temperature interval of from 30 to 130°C. A preferred temperature interval is from 70 to 120°C, more preferably from 100 to 120°C.

[0087] According to an embodiment, the reaction mixture of the process for the preparation of a compound of formula (III) (step b), is monitored by HPLC analytical method, and the process ends when concentration of formula (IV) is between 0-99%, preferably from 0-50%. In particular, the process should be terminated when no more than 5% of compound of formula (IV) remains in the reaction media.

[0088] According to an embodiment, the reaction mixture of the process for the preparation of a compound of formula (III) (step b), is monitored by HPLC analytical method, and the process ends when concentration of formula (IV) is between 0-40%, preferably from 0-10%. In particular, the process should be terminated when no more than 1% of compound of formula (IV) remains in the reaction media.

[0089] According to an embodiment, the reaction mixture of the process for the preparation of a compound of formula (III) (step b), containingthe resulting compound of formula (III) is optionally worked up or proceed as in telescopic / one-pot synthesis process without workup to the next step. This stage may include adding water, adding organic solvent, stirring, cooling, heating, phases separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying processes.

[0090] According to an embodiment, the reaction mixture of the process for the preparation of a compound of formula (III) (step b), containing the resulting compound of formula (III) is isolated from the reaction mixture by adding water, filtrate the precipitant and washing the solid product with water or organic solvent and dry the solid product by air or vacuum at temperature between

[0091] 30 to 100 °C.

[0092] According to an embodiment, the reaction mixture of the process for the preparation of a compound of formula (III) (step b), containing the resulting compound of formula (III) is transferred by metering to the next step in the manufacturing process without any additional operation.

[0093] According to an embodiment, the present invention is directed to a process for the preparation of a compound of formula (III), and its salt thereof, comprising a) preparation of a compound of formula (I), or its salts thereof comprising reaction of a compound of formula (II) or its salts thereof with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof b) contacting of a compound of formula (I) and a compound of formula (A)

[0094] 0

[0095] JJ Z Z2(A) wherein Z1and Z2, are independently, chloride, Cl-C4-alkoxy, trichloromethyloxy, C(O)CI, C1-C6- alkyloxycarbonate; in the presence of a solvent to obtain a compound of formula (IV) and c) further contacting the compound of formula (IV) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base.

[0096] In yet another embodiment, the present invention provides a method for the preparation of a compound of formula (III), and its salt thereof, comprising step a) reacting a compound of formula (I) or its salt thereof, prepared by reacting of a compound of formula (II) or its salts thereof, with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof, according to any of the preceding embodiment, with thionyl chloride, sulfuryl chloride, phthaloyl chloride, phosphorus pentachloride, phosphorus trichloride, cyanuric chloride, acetic anhydride, propionic anhydride, butyric anhydride, hexanoic anhydride, benzoic anhydride, trichloroacetic anhydride, isopropenyl acetate, acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIG), ethyl-(N',N'- dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), and a mixture thereof, optionally in the presence of a base to form a compound of formula (V) wherein R1, is halide, optionally halogenated Cl-C6-carboxylic acid, carbodiimide, hydroxytriazoles; and step b) reacting the compound of formula (V) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base.

[0097] According to an embodiment the base in the process for the preparation of a compound of formula (V) (step a), and in the process for the preparation of a compound of formula (III) (step b) is selected from a group comprising triethylamine, dimethylamine, aniline, indole, piperidine, pyridine, pyrimidine, pyrrolidine, pyrrole, imidazole, methylimidazole, 2-picoline, 4- methylmorpholine, dimethylaminopyridine, N,N-diisopropylethylamine, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, potassium carbonate, potassium bicarbonate, potassium hydroxide, aluminum hydroxide, calcium hydroxide, iron hydroxide, lithium hydroxide, ammonium hydroxide, ammonium acetate, and a mixture thereof.

[0098] According to an embodiment the base in the process for the preparation of a compound of formula (V) (step a), and in the process for the preparation of a compound of formula (III) (step b) is selected from a group comprising triethylamine, imidazole, sodium carbonate, sodium bicarbonate, sodium acetate, potassium carbonate, potassium bicarbonate, and a mixture thereof.

[0099] According to an embodiment, the molar ratio between compound (I) to the base in the process for the preparation of a compound of formula (V) (step a), is from 1:20 to 1:0.1, preferably from 1:10 to 1:1, most preferably from 1:1.5 to 1:1.

[0100] According to an embodiment, the molar ratio between compound (I) to the base in the process for the preparation of a compound of formula (V) (step a), is from 1:10 to 1:1, preferably from 1:5 to 1:1, most preferably from 1:1.3 to 1:1.1.

[0101] According to an embodiment, the solvent in the process for the preparation of a compound of formula (V) (step a), and in the process for the preparation of a compound of formula (III) (step b) is selected from a group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic and cyclic ethers, aliphatic esters, nitriles, ketones, C1-C6 alcohols, polar protic and aprotic solvents, water, and a mixture thereof. According to an embodiment, the solvent in the process for the preparation of a compound of formula (V) (step a), and in the process for the preparation of a compound of formula (III) (step b) is selected from a group comprising octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane petroleum ether, carbontetrachloride, chloroform, methylenechloride, 1,2-dichloroethane, benzene, toluene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), isopropylmethyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), cyclopentylmethyl ether, ethyl acetate, acetonitrile, benzonitrile, acetone, 2-butanone, methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, t-butyl alcohol, diethylene glycol, glycerin, ethylene glycol, propylene glycol, A / -methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, water, and a mixture thereof.

[0102] According to an embodiment, a weight ratio between the compound of formula (I) in the process for the preparation of a compound of formula (V) (step a) to the solvent in step a) can be from 1:20 to 10:1, preferably from 1:0.5 to 1:5, most preferably from 1:3 to 1:5.

[0103] According to an embodiment, a weight ratio between the compound of formula (I) in the process for the preparation of a compound of formula (V) (step a) to the solvent in step a) can be from 1:10 to 1:1, preferably from 1:5 to 1:1, most preferably from 1:3 to 1:4.

[0104] According to an embodiment, the molar ratio between compound (V) to the base in the process for the preparation of a compound of formula (III) (step b) is from 1:20 to 1:0.1, preferably from 1:10 to 1:1, most preferably from 1:1.5 to 1:1.

[0105] According to an embodiment, the molar ratio between compound (V) to the base in the process for the preparation of a compound of formula (III) (step b) is from 1:10 to 1:1, preferably from 1:5 to 1:1, most preferably from 1:1.3 to 1:1.1.

[0106] According to an embodiment, a weight ratio between the compound of formula (V) to the solvent in the process for the preparation of a compound of formula (III) (step b) is from 1:20 to 10:1, preferably from 1:0.5 to 1:5, most preferably from 1:3 to 1:5. According to an embodiment, a weight ratio between the compound of formula (V) to the solvent in the process for the preparation of a compound of formula (III) (step b) is from 1:10 to 1:1, preferably from 1:5 to 1:1, most preferably from 1:3 to 1:4.

[0107] According to an embodiment, the methylamine salt is selected from a group comprising of methylammonium chloride, methylammonium bromide, methylammonium iodide, methylammonium nitrate, methylammonium format, methylammonium sulfate, methylammonium tetrafluoroborate, methylammonium acetate, methylammonium hydroxide, methylammonium perchlorate and a mixture thereof.

[0108] According to an embodiment, the methylamine salt is selected from a group comprising of methylammonium chloride, methylammonium nitrate, methylammonium acetate, methylammonium hydroxide and a mixture thereof.

[0109] According to an embodiment, the methylamine salt is methylammonium chloride.

[0110] According to an embodiment, the methylamine, or its salt thereof in the process for the preparation of a compound of formula (III) (step b), is at a concentration of from 1% to 50% by weight, based on the total weight of the mixture.

[0111] According to an embodiment, the methylamine, or its salt thereof in the process for the preparation of a compound of formula (III) (step b), is at a concentration of from 5% to 25% by weight, based on the total weight of the mixture.

[0112] According to an embodiment, the methylamine, or its salt thereof in the process for the preparation of a compound of formula (III) (step b), is at a concentration of from 10% to 20% by weight, based on the total weight of the mixture.

[0113] According to an embodiment, a molar ratio between compound (V) to the methylamine or its salt thereof can be from about 1:20 to 1:0.1, preferably from about 1:10 to 1:1, most preferably from about 1:5 to 1:3. According to an embodiment, a molar ratio between compound (V) to the methylamine or its salt thereof can be from about 1:10 to 1:1, preferably from about 1:5 to 1:2, most preferably from about 1:3 to 1:2.

[0114] According to an embodiment, the weight ratio between the compound of formula (V) to the solvent in the process for the preparation of a compound of formula (III) (step b), is from 1:20 to 10:1, preferably from 1:5 to 1:0.5, most preferably from 1:3 to 1:1.

[0115] According to an embodiment, the compound of formula (V) contacted with the methylamine or its salt thereof in the process for the preparation of a compound of formula (III) (step b), at the temperature interval of from 30 to 130°C. A preferred temperature interval is from 70 to 120°C, more preferably from 100 to 120°C.

[0116] According to an embodiment, compound of formula (I) in the process for the preparation of a compound of formula (V) (step a), contacted with any of thionyl chloride, sulfuryl chloride, phthaloyl chloride, phosphorus pentachloride, phosphorus trichloride, cyanuric chloride, acetic anhydride, propionic anhydride, butyric anhydride, hexanoic anhydride, benzoic anhydride, trichloroacetic anhydride, isopropenyl acetate, acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride and a mixture thereof, is performed between the temperature interval of from 0 to 120°C. A preferred temperature interval is from 70 to 120°C, more preferably from 70 to 100°C.

[0117] According to an embodiment, a weight ratio between the compound of formula (I) in the process for the preparation of a compound of formula (V) (step a), to any of thionyl chloride, sulfuryl chloride, phthaloyl chloride, phosphorus pentachloride, phosphorus trichloride, cyanuric chloride, acetic anhydride, propionic anhydride, butyric anhydride, hexanoic anhydride, benzoic anhydride, trichloroacetic anhydride, isopropenyl acetate, acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride and a mixture thereof, can be from 1:1 to 1:10, preferably from 1:1 to 1:5, most preferably from 1:1.5 to 1:4.

[0118] According to an embodiment, the compound of formula (I) in the process for the preparation of a compound of formula (V) (step a), contacted with any of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBt) and a mixture thereof, is performed between the temperature interval of from 0 to 120°C. A preferred temperature interval is from 0 to 50°C, more preferably from 0 to 30°C.

[0119] According to an embodiment, a weight ratio between the compound of formula (I) in the process for the preparation of a compound of formula (V) (step a), to any of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBt) and a mixture thereof, can be from 1:1 to 1:10, preferably from 1:1 to 1:3, most preferably from 1:1.1 to 1:1.5.

[0120] According to an embodiment, the compound of formula (I) in the process for the preparation of a compound of formula (V) (step a), contacted with methylamine, or its salt thereof is performed between the temperature interval of from 0 to 120°C, more preferably from 10 to 70°C.

[0121] According to an embodiment, the compound of formula (I) in the process for the preparation of a compound of formula (V) (step a), contacted with methylamine, or its salt thereof is performed between the temperature interval of from 0 to 60°C.

[0122] According to an embodiment, the reaction mixture of the process for the preparation of a compound of formula (V) (step a) is monitored by HPLC analytical method, and the process ends when concentration of formula (I) is between 0-99%, preferably from 0-50%. In particular, the process should be terminated when no more than 1% of compound of formula (I) remains in the reaction media.

[0123] According to an embodiment the reaction mixture of the process for the preparation of a compound of formula (V) (step a) is monitored by HPLC analytical method, and the process ends when concentration of formula (I) is between 0-20%, preferably from 0-10%. In particular, the process should be terminated when no more than 1% of compound of formula (I) remains in the reaction media.

[0124] According to an embodiment the reaction mixture of the process for the preparation of a compound of formula (III) (step b) is monitored by HPLC analytical method, and the process ends when concentration of formula (V) is between 0-99%, preferably from 0-50%. In particular, the process should be terminated when no more than 1% of compound of formula (V) remains in the reaction media.

[0125] According to an embodiment the reaction mixture of the process for the preparation of a compound of formula (III) (step b) is monitored by HPLC analytical method, and the process ends when concentration of formula (V) is between 0-20%, preferably from 0-10%. In particular, the process should be terminated when no more than 1% of compound of formula (V) remains in the reaction media.

[0126] According to an embodiment, the reaction mixture containing the resulting a compound of formula (III) is worked up. This stage may include adding water, adding organic solvent, stirring, cooling, heating, phases separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying processes.

[0127] According to an embodiment, the reaction mixture containing the resulting compound of formula (III) is optionally worked up or proceed as in telescopic / one-pot reaction without workup to the next step. This stage may include adding water, adding organic solvent, stirring, cooling, heating, phases separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying processes.

[0128] According to an embodiment, the reaction mixture containing the resulting compound of formula (III) is isolated from the reaction mixture by adding water, filtrate the precipitant and washing the solid product with water or organic solvent and dry the solid product by air or vacuum at temperature between 30 to 100 °C.

[0129] According to an embodiment, the present invention is directed to a process for the preparation of a compound of formula (III), and its salt thereof, comprising a) preparation of a compound of formula (I), or its salts thereof comprising reaction of a compound of formula (II) or its salts thereof with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof, b) contacting a compound of formula (I) or its salt thereof, with thionyl chloride, sulfuryl chloride, phthaloyl chloride, phosphorus pentachloride, phosphorus trichloride, cyanuric chloride, acetic anhydride, propionic anhydride, butyric anhydride, hexanoic anhydride, benzoic anhydride, trichloroacetic anhydride, isopropenyl acetate, acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIG), ethyl- (N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), and a mixture thereof, optionally in the presence of a base to obtain a compound of formula (V) wherein R1, is halide, optionally halogenated Cl-C6-carboxylic acid, carbodiimide, hydroxytriazoles; and c) further contacting the compound of formula (V) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base. In another aspect of this invention, the compound of formula (I) prepared by reacting of a compound of formula (II) or its salts thereof, with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), N,N- dimethylformamide (DMF), A / ,A / -dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof, according to any of the preceding embodiments, can be used as an intermediate for preparation of cyantraniliprole. As non-limiting example of preparation of cyantraniliprole, the compound of formula (I) can be at first transformed to intermediates of formula (IV) and / or (V) as disclosed in the present invention, and then reacted with the corresponding pyrazole carboxylic acid or its derivates by the methods such as but not limited to those disclosed in W02006068669, W02004067528, W02006062978 and WO2024038436.

[0130] In another embodiment, the compounds of formula (I), (III), (IV) and (V) are prepared according to the present invention can be used for preparation of cyantraniliprole using different methods such as, but not limited to those disclosed in W02006068669, W02004067528, W02006062978 and WO2024038436.

[0131] According to an embodiment, the present invention is directed to A process for the preparation of a compound of formula (VI), and its salt thereof, from a compound of formula (I), or its salts thereof, prepared by contacting of a compound of formula (II) or its salts thereof, NH2

[0132] \|X^^C°2H

[0133] CHO (||) with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof. According to an embodiment, the present invention is directed to the process for the preparation of a compound of formula (VI), and its salt thereof, comprising a) preparation of a compound of formula (I), or its salts thereof comprising reaction of a compound of formula (II) or its salts thereof

[0134] NH2

[0135] ^^ / CO2H

[0136] CHO (||) with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof b) contacting of a compound of formula (I) and a compound of formula (A)

[0137] 0

[0138] JI

[0139] Z1 Z2(A) wherein Z1 and Z2, are independently, chloride, Cl-C4-alkoxy, trichloromethyloxy, C(O)CI, C1-C6- alkyloxycarbonate; in the presence of a solvent to obtain a compound of formula (IV) c) contacting the compound of formula (IV) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base, to obtain a compound of formula (III) and d) contacting the compound of formula (III) with a compound of formula (VII) or its salt thereof, wherein Y is halide or hydroxy group; in the presence of a solvent and optionally in the presence of a base wherein the base is inorganic base, organic base, and the mixtures thereof. According to an embodiment, the inorganic base is selected from the group comprising potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the mixtures thereof.

[0140] According to an embodiment, the organic base is selected from the group comprising trimethylamine, triethylamine, tributylamine, diisopropylamine, diethylamine, tetramethylethylendiamine, pyridine, piperidine, morpholine, proline, L-proline, 4- dimethylaminopyridine, dimethylbenzylamine, quinoline, aniline, imidazole, pyrrole, pyrrolidine, pyrimidine, piperazine, morpholine, N-methyl morpholine, N-ethyl pyrrolidine, diisopropylmehtylamine, diisopropylethylamine, triallyl amine, diallyl amine, indole, and the mixtures thereof.

[0141] According to an embodiment, the present invention is directed to the process for the preparation of a compound of formula (VI), and its salt thereof, comprising a) preparation of a compound of formula (I), or its salts thereof comprising reaction of a compound of formula (II) or its salts thereof with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof b) contacting a compound of formula (I) or its salt thereof, with thionyl chloride, sulfuryl chloride, phthaloyl chloride, phosphorus pentachloride, phosphorus trichloride, cyanuric chloride, acetic anhydride, propionic anhydride, butyric anhydride, hexanoic anhydride, benzoic anhydride, trichloroacetic anhydride, isopropenyl acetate, acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIG), ethyl- (N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), and a mixture thereof, optionally in the presence of a base to obtain a compound of formula (V) wherein Rl, is halide, optionally halogenated Cl-C6-carboxylic acid, carbodiimide, hydroxytriazoles; c) contacting the compound of formula (V) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base, to obtain a compound of formula (III), and d) contacting the compound of formula (III) with a compound of formula (VII) or its salt thereof, wherein Y is halide, hydroxy group; in the presence of a solvent and optionally in the presence of a base wherein the base is inorganic base, organic base, and the mixtures thereof.

[0142] According to an embodiment, the inorganic base is selected from the group comprising potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the mixtures thereof.

[0143] According to an embodiment, the organic base is selected from the group comprising trimethylamine, triethylamine, tributylamine, diisopropylamine, diethylamine, tetramethylethylendiamine, pyridine, piperidine, morpholine, proline, L-proline, 4- dimethylaminopyridine, dimethylbenzylamine, quinoline, aniline, imidazole, pyrrole, pyrrolidine, pyrimidine, piperazine, morpholine, N-methyl morpholine, N-ethyl pyrrolidine, diisopropylmehtylamine, diisopropylethylamine, triallyl amine, diallyl amine, indole, and the mixtures thereof.

[0144] Without further elaboration, it is believed that one skilled in the art using the preceding description is able to utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever.

[0145] EXPERIMENTAL PART:

[0146] Example 1: Preparation of 2-amino-5-cyano-3-methylbenzoic acid from 2-amino-5-formyl-3- methyl benzoic acid: To a IL reactor, 2-amino-5-formyl-3-methylbenzoic acid (70 gr), hydroxylamine hydrochloride (30.6 gr), and N-methylpyrrolidone (NMP) (210 mL) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to 110°C and the mixture was allowed to stir for 2 hours. The reaction progress was monitored by HPLC and ended when the starting material was less than 1% in the reaction mixture. The mixture was cooled to 20°C and water (420 mL) was added dropwise. The participant was filtered, washed three times with water (420 mL) and dried under vacuum at 90°C for 12 hours to obtain 70 gr of solid product with purity of 90.2% (92% yield). Preparation of 2-amino-5-cyano-3-methylbenzoic acid from 2-amino-5-formyl-3- methyl benzoic acid:

[0147] To a IL reactor, 2-amino-5-formyl-3-methylbenzoic acid (70 gr), hydroxylamine hydrochloride (30.6 gr), and N,N-Dimethylformamide (DMF) (210 mL) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to 130°C and the mixture was allowed to stir for 2 hours. The reaction progress was monitored by HPLC and ended when the starting material was less than 1% in the reaction mixture. The mixture was cooled to 20°C and water (420 mL) was added dropwise. The participant was filtered, washed with water (420 mL) and dried under vacuum at 90°C for 12 hours to obtain 66 gr of solid product with purity of 90.7% (88% yield). Preparation of 2-amino-5-cyano-3-methylbenzoic acid from 2-amino-5-formyl-3- methyl benzoic acid:

[0148] To a IL reactor, 2-amino-5-formyl-3-methylbenzoic acid (70 gr), hydroxylamine hydrochloride (30.6 gr), and N,N-Dimethylacetamide (DMA) (210 mL) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to 110°C and the mixture was allowed to stir for 3 hours. The reaction progress was monitored by HPLC and ended when the starting material was less than 1% in the reaction mixture. The mixture was cooled to 20°C and water (420 mL) was added dropwise. The participant was filtered, washed with water (420 mL), and dried under vacuum at 90°C for 12 hours to obtain 76 gr of solid product with purity of 80.5% (89% yield). Preparation of 2-amino-5-cyano-3-methylbenzoic acid from 2-amino-5-formyl-3- methyl benzoic acid:

[0149] To a IL reactor, 2-amino-5-formyl-3-methylbenzoic acid (70 gr), hydroxylamine hydrochloride (30.6 gr), and N,N-methylpyrrolidone (NMP) (210 mL) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to 110°C and the mixture was allowed to stir for 2 hours. The reaction progress was monitored by HPLC and ended when the starting material was less than 1% in the reaction mixture. The mixture was cooled to 20°C and water (210 mL) was added dropwise. The participant was filtered, washed with water (420 mL), and dried under vacuum at 90°C for 12 hours to obtain 70 gr of solid product with purity of 83.8% (88% yield). Preparation of 2-amino-5-cyano-3-methylbenzoic acid from 2-amino-5-formyl-3- methylbenzoic acid: (NMP with 10wt% water)

[0150] To a IL reactor, 2-amino-5-formyl-3-methylbenzoic acid (70 gr), hydroxylamine hydrochloride (30.6 gr), N,N-methylpyrrolidone (NMP) (203 mL) and water (7 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to 110°C and the mixture was allowed to stir for 3 hours.

[0151] The reaction progress was monitored by HPLC and ended when the starting material was less than 1% in the reaction mixture. The mixture was cooled to 20°C and water (196 mL) was added dropwise. The participant was filtered, washed with water (420 mL), and dried under vacuum at 90°C for 12 hours to obtain 66.5 gr of solid product with purity of 92.4% (90% yield). Preparation of 2-amino-5-cyano-3-methylbenzoic acid from 2-amino-5-formyl-3- methylbenzoic acid: (NMP with 30wt% water)

[0152] To a IL reactor, 2-amino-5-formyl-3-methylbenzoic acid (70 gr), hydroxylamine hydrochloride (30.6 gr), N,N-methylpyrrolidone (NMP) (189 mL) and water (21 gr) were charged at 25°C and stirred for

[0153] 5 minutes. The reaction was then heated to 110°C and the mixture was allowed to stir for 5 hours.

[0154] The reaction progress was monitored by HPLC and ended when the starting material was less than 1% in the reaction mixture. The mixture was cooled to 20°C and water (168 mL) was added dropwise. The participant was filtered, washed with water (420 mL), and dried under vacuum at 90°C for 12 hours to obtain 67 gr of solid product with purity of 88.1% (86% yield). Preparation of 2-amino-5-cyano-3-methylbenzoic acid from 2-amino-5-formyl-3- methyl benzoic acid:

[0155] To a 0.1L reactor, 2-amino-5-formyl-3-methylbenzoic acid (2.0 gr), hydroxylamine hydrochloride

[0156] (0.85 gr), and dimethylsulfoxide (DMSO) (10 mL) were charged at 25°C and stirred for 5 minutes.

[0157] The reaction was then heated to 90°C and the mixture was allowed to stir for 4 hours. The reaction progress was monitored by HPLC and ended when the starting material was less than 1% in the reaction mixture. The mixture was cooled to 40°C and water (100 mL) was added dropwise. The mixture was cooled to 10°C and the participant was filtered. The solid filtrate was washed three times with water (50 mL) and dried to obtain 1.55 gr of solid product (63% yield).

[0158] Preparation of 8 methyl 2,4-dioxo-l,4-dihydro-2H-benzo[d][l,3]oxazine-6-carbonitrile from 2-amino-5-cyano-3-methylbenzoic acid:

[0159] To a 0.1L reactor, 2-amino-5-cyano-3-methylbenzoic acid (5.0 gr), toluene (50 mL), tetrabutylammonium bromide (0.26 gr) and 30% aqueous solution of sodium hydroxide (10.1 mL) was charged at 25°C and stirred for 5 minutes. To the mixture, triphosgene (3.7 gr) in toluene (24 gr) was added portion-wise maintaining the temperature at 25°C and the mixture was allowed to stir for 1.5 hours. The reaction progress was monitored by HPLC and ended when the starting material was less than 1% in the reaction mixture. The precipitant was filtered and washed twice with water and dried to obtain 6.0 gr of solid product (91% yield).

[0160] Preparation of 8 methyl-2,4-dioxo-l,4-dihydro-2H-benzo[d][l,3]oxazine-6-carbonitrile from 2-amino-5-cyano-3-methylbenzoic acid:

[0161] To a 0.1L reactor, 2-amino-5-((hydroxyimino)methyl)-3-methylbenzoic acid (8.0 gr), triphosgene (24.0 gr), and THF (80.0 mL) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to 66°C and the mixture was allowed to stir for 2 hours. The reaction progress was monitored by HPLC and ended when the starting material was less than 1% in the reaction mixture. The reaction mixture was then concentrated to obtain 7.1 gr of the desired product (Yield: 85%). 10: Preparation of cyantraniliprole from 2 amino-5-cyano N,3-dimethyl benzamide:

[0162] To a 5L reactor, toluene (2200 gr) and 2-amino-5-cyano-N,3-dimethylbenzamide (215 gr) were charged at 25°C and stirred for 5 minutes. The mixture was heated to 90°C and vacuum was applied at 380 mbar. Then, 3-bromo-5-(3-chloropyridin-2-yl)cyclopenta-l,3-diene-l-carbonyl chloride (350 gr) in toluene (1140 gr) was added dropwise while extracting hydrogen chloride and toluene from the reaction. At the end of the addition, reaction mixture was allowed to stir for additional 3 h while toluene was added to maintain the reaction mixture volume at 800 gr. Then, vacuum was stopped, and the mixture was allowed to stir for additional lh while purging with nitrogen. The reaction progress was monitored by HPLC and ended when the starting material was less than 1% in the reaction mixture. The mixture was cooled to 0°C and solid precipitant was filtered. The solid was washed with toluene and vacuum dried at 70°C. The solid was then dissolved in methanol (1600 gr) and mixture was heated to 65°C for 4h. Mixture was cooled to 5°C for 2h and the precipitant solid was filtered and washed with fresh methanol. The solid was dried under vacuum at 70°C for 2 hours to obtain 470 gr product (91% yield).

Claims

CLAIMS:

1. A process for the preparation of a compound of formula (I), or its salts thereofcomprising reaction of a compound of formula (II) or its salts thereofNH2\|X^ / CO2HCHO (||) with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), A / ,A / - dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof.

2. The process according to claim 1, wherein the solvent is / V-methylpyrrolidone (NMP).

3. The process according to any of claims 1-2, wherein the weight ratio between the compound of formula (II) and the organic solvent is from 1:20 to 10:1.

4. The process according to any of claims 1-3, wherein the hydroxylamine salt is selected from a group comprising hydroxylamine hydrochloride, hydroxylamine hydrobromide, hydroxylamine acetate, hydroxylamine fluoride, hydroxylamine iodide, hydroxylamine sulfate, hydroxylamine disulfate, hydroxylamine phosphate, hydroxylamine nitrate, hydroxylamine perchlorate, hydroxylamine-O-sulfonic acid, hydroxylamine carbonate and the mixtures thereof.

5. The process according to any of claims 1-4, wherein the molar ratio between the compound of formula (II) to hydroxylamine or hydroxylamine salt is from 1:5 to 1:0.9.

6. The process according to any of claims 1-5, wherein the process is carried out at a temperature of from 30°C to 130 °C.

7. The process according to any of claims 1-6, wherein the compound of formula (I) is isolated from the reaction mixture or transferred to the next step without isolation.

8. A process for the preparation of a compound of formula (III), and its salt thereof,comprising a) preparation of a compound of formula (I), or its salts thereofcomprising reaction of a compound of formula (II) or its salts thereofNH2\^J^CO2HCHO (||) with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), N,N- dimethylacetamide (DMA),, dimethylsulfoxide (DMSO), and the mixtures thereof b) contacting of a compound of formula (I) and a compound of formula (A)wherein Z1and Z2, are independently, chloride, Cl-C4-alkoxy, trichloromethyloxy, C(O)CI, Cl-C6-alkyloxycarbonate; in the presence of a solvent to obtain a compound of formula (IV)and c) further contacting the compound of formula (IV) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base.

9. The process according to claim 8, wherein the solvent in step c) is selected from a group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic and cyclic ethers, aliphatic esters, nitriles, ketones, dimethyl carbonate, dimethylformamide, pyridine, dimethylsulfoxide, A / -alkylpyrrolidones, Cl-C6-alkoxy, Cl- C4-carboxylic acid, water, and a mixture thereof.

10. The process according to any of claims 8-9, wherein the base is selected from a group comprising triethylamine, pyridine, 2-picoline, 4-methylmorpholine, dimethyl aminopyridine, A / ,A / -diisopropylethylamine, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, ammonium hydroxide and a mixture thereof.

11. A process for the preparation of a compound of formula (III), and its salt thereof,comprising a) preparation of a compound of formula (I), or its salts thereofcomprising reaction of a compound of formula (II) or its salts thereofwith hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), A / ,A / - dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof, b) contacting a compound of formula (I) or its salt thereof, with thionyl chloride, sulfuryl chloride, phthaloyl chloride, phosphorus pentachloride, phosphorus trichloride, cyanuric chloride, acetic anhydride, propionic anhydride, butyric anhydride, hexanoic anhydride, benzoic anhydride, trichloroacetic anhydride, isopropenyl acetate, acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIG), ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), and a mixture thereof, optionally in the presence of a base to obtain a compound of formula (V)wherein R1, is halide, optionally halogenated Cl-C6-carboxylic acid, carbodiimide, hydroxytriazoles; and c) further contacting the compound of formula (V) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base.

12. The process according to claim 11, wherein the solvent in step c) is selected from a group comprising cyclic and acyclic aliphatic carbohydrates, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons,aliphatic and cyclic ethers, aliphatic, nitriles, ketones, C1-C6 alcohols, A / -alkylpyrrolidones, dimethylformamide, pyridine, dimethylsulfoxide, 1,2-dimethoxyethane, ethylene glycol, water, and a mixture thereof.

13. The process according to any of claims 11-12, wherein the base is selected from a group comprising triethylamine, pyridine, 2-picoline, 4-methylmorpholine, dimethyl aminopyridine, A / ,A / -diisopropylethylamine, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, ammonium hydroxide and a mixture thereof.

14. A process for the preparation of a compound of formula (VI), and its salt thereof,from a compound of formula (I), or its salts thereof,prepared by contacting of a compound of formula (II) or its salts thereof,with hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of A / -methylpyrrolidone (NMP), A / ,A / -dimethylformamide (DMF), A / ,A / - dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof.

15. A process for the preparation of a compound of formula (VI), and its salt thereof,comprising a) preparation of a compound of formula (I), or its salts thereofcomprising reaction of a compound of formula (II) or its salts thereofwith hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof b) contacting of a compound of formula (I) and a compound of formula (A)wherein Z1 and Z2, are independently, chloride, Cl-C4-alkoxy, trichloromethyloxy, C(O)CI, Cl-C6-alkyloxycarbonate; in the presence of a solvent to obtain a compound of formula (IV)c) contacting the compound of formula (IV) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base, to obtain a compound of formula (III), and d) contacting the compound of formula (III)with a compound of formula (VII) or its salt thereof,wherein Y is halide or hydroxy group; in the presence of a solvent and optionally in the presence of a base, wherein the base is inorganic base, organic base, and the mixtures thereof.

16. A process for the preparation of a compound of formula (VI), and its salt thereof,comprising a) preparation of a compound of formula (I), or its salts thereofcomprising reaction of a compound of formula (II) or its salts thereofwith hydroxylamine or its salts thereof, in the presence of a solvent selected from the group consisting of N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), and the mixtures thereof b) contacting a compound of formula (I) or its salt thereof, with thionyl chloride, sulfuryl chloride, phthaloyl chloride, phosphorus pentachloride, phosphorus trichloride, cyanuric chloride, acetic anhydride, propionic anhydride, butyric anhydride, hexanoic anhydride, benzoic anhydride, trichloroacetic anhydride, isopropenyl acetate, acetyl chloride, propionyl chloride, isobutyryl chloride, benzoyl chloride, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIG), ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), and a mixture thereof, optionally in the presence of a base to obtain a compound of formula (V)wherein Rl, is halide, optionally halogenated Cl-C6-carboxylic acid, carbodiimide, hydroxytriazoles; c) contacting the compound of formula (V) with methylamine or its salts thereof, in the presence of a solvent and optionally in the presence of a base, to obtain a compound of formula (III),and d) contacting the compound of formula (III) ormula (VII) or its salt thereof,wherein Y is halide, hydroxy group; in the presence of a solvent and optionally in the presence of a base wherein the base is inorganic base, organic base, and the mixtures thereof.

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