Process for preparing cyantraniliprole via amino-cyano-benzene derivatives

Abstract

The present invention relates to the preparation of cyantraniliprole, comprising the preparation of a key intermediate of 8-methyl-2, 4-dioxo-1, 4-dihydro-2H-benzo [d] [1, 3] oxazine-6-formonitrile by means of 2-amino-5-((hydroxyimino) methyl)-3-methylbenzoic acid, in particular to the preparation of cyantraniliprole, comprising the preparation of a key intermediate of 8-methyl-2, 4-dioxo-1, 4-dihydro-2H-benzo [d] [1, 3] oxazine-6-carbonitrile. Wherein the hydroxylamine attacks the benzylformyl group to obtain 2-amino-5-((hydroxyimino) methyl)-3-methylbenzoic acid, which is dehydrogenated and cyclized simultaneously or by successive steps to obtain the desired product benzo [d] [1, 3] oxazine group and cyano group. In addition, an improved process for the synthesis of benzylformyl groups is also shown.

Description

Background Art:

[0001] Cyantraniliprole, a compound having the formula (VIII)

[0002]

[0003] is well known for its activity against pesticidal agents (i.e., insecticides). This insecticidal compound is known due to its unique mode of action (ryanoids) and thus its high importance in the agrochemical insecticide industry. Cyantraniliprole and its compound family were first described by E.I. Du Pont De Nemours and Co. in WO 2004 / 067528. In this patent, the innovator claimed protection for the compound, other corresponding compounds, possible compositions with other insecticides, and methods of use. In some cases, the synthesis of the compound involves the use and synthesis of one of the key intermediates, 2-amino-5-cyano-3-methylbenzoic acid. In most cases, the cyano group of this key intermediate is obtained by the coupling reaction of haloanthranilic acid with metal cyanide. In some cases, a palladium catalyst or metal halide is additionally required. This method is also described in the following patents CN 105367548, CN103450154, WO 2022058916, CN 104003976, WO 2006068669, WO 2008070158, WO2009111553, WO 2009085816, WO 2008082502, WO 2008070158, WO 2009006061. However, this method has many disadvantages, such as the use of heavy metals, low efficiency, low yield, high cost, and sometimes leads to metal contamination in the final product. The preparation method of this substance must be improved for economic commercial operation. In view of this, the present invention enables a convenient, cost-effective, and metal-free route for the preparation of 2-amino-5-cyano-3-methylbenzoic acid and its corresponding cyantraniliprole. Summary of the Invention:

[0004] The present invention relates to a method for preparing a compound having the formula (I) or a salt thereof

[0005]

[0006] The method comprises reacting a compound having the formula (II) or a salt thereof

[0007]

[0008] with hydroxylamine or a salt thereof, optionally in the presence of a solvent and optionally in the presence of a base.

[0009] In addition, the present invention relates to a method for preparing a compound of formula (IV) and its salts,

[0010]

[0011] which comprises dehydrating a compound of formula (I) optionally in the presence of a solvent.

[0012] Another aspect of the present invention relates to a method for preparing a compound of formula (II) and its salts,

[0013]

[0014] which comprises reacting a compound of formula (III) and its salts,

[0015]

[0016] with a formylating reagent selected from hexamethylenetetramine (HMTA), formaldehyde, paraformaldehyde, trioxane and / or methanediol and mixtures thereof, in the presence of an acid and optionally in the presence of a solvent.

[0017] The present invention also relates to a method for preparing a compound of formula (V) and its salts,

[0018]

[0019] which comprises a) reacting a compound of formula (I) or its salt with a compound of formula (A)

[0020]

[0021] wherein Z 1 and Z 2 are independently chloride, C1-C4-alkoxy, trichloromethoxy, C(O)Cl, C1-C6-alkoxycarbonate;

[0022] X is O;

[0023] in the presence of a solvent.

[0024] In addition, the present invention relates to a method for preparing a compound of formula (VII) and its salts,

[0025]

[0026]

[0027]

[0028]

[0028] Prepared by reacting with hydroxylamine or its salts, optionally in the presence of a solvent and optionally in the presence of a base.

[0029] With a compound of formula (A)

[0030]

[0031] wherein Z 1 and Z 2 are independently chloride, C1-C4-alkoxy, trichloromethoxy, C(O)Cl, C1-C6-alkoxycarbonate;

[0032] X is O;

[0033] Reacting in the presence of a solvent

[0034] and b) further reacting a compound of formula (V) with methylamine or its salts in the presence of a solvent and optionally in the presence of a base.

[0035] Furthermore, the present invention relates to a process for preparing a compound of formula (VII) and its salts,

[0036]

[0037] The process comprising a) reacting a compound of formula (IV) or its salts (prepared by dehydrating a compound of formula (I) optionally in the presence of a solvent) with a compound of formula (A)

[0038]

[0039] wherein Z 1 and Z 2 are independently chloride, C1-C4-alkoxy, trichloromethoxy, C(O)Cl, C1-C6-alkoxycarbonate;

[0040] X is O;

[0041] Reacting in the presence of a solvent, optionally in the presence of a base, optionally in the presence of a phase transfer catalyst to obtain a compound of formula (V),

[0042]

[0043] and b) reacting a compound of formula (V) with methylamine or its salts in the presence of a solvent and optionally in the presence of a base.

[0044] Furthermore, the present invention relates to a process for preparing a compound of formula (VII) and its salts,

[0045]

[0046] comprising a) reacting a compound of formula (IV) or a salt thereof, which is optionally prepared by dehydrating a compound of formula (I) in the presence of a solvent, 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 (DIC), 1-ethyl-(3-(3-dimethylaminopropyl))carbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and mixtures thereof, optionally in the presence of a base to form a compound of formula (VI)

[0047]

[0048] wherein R 1 is a halide, an optionally halogenated C1-C6-carboxylic acid, a carbodiimide, a hydroxytriazole;

[0049] and b) reacting the compound of formula (VI) with methylamine or a salt thereof in the presence of a solvent and optionally in the presence of a base.

[0050] The present invention further relates to a process for preparing a compound of formula (VIII) and salts thereof using a compound of formula (I) or a salt thereof,

[0051]

[0052] The present invention also relates to a process for preparing a compound of formula (VIII) and salts thereof using a compound of formula (IV) or a salt thereof,

[0053]

[0054] The compound of formula (IV) or a salt thereof is prepared by dehydrating a compound of formula (I) optionally in the presence of a solvent. Detailed Description:

[0055] Definition:

[0056] Before elaborating on the subject matter of the present invention, it may be helpful to provide definitions of certain terms used herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs.

[0057] Throughout this application, the description of different embodiments uses the term "comprising"; however, those skilled in the art will understand that in some specific cases, the language "consisting essentially of" or "consisting of" may alternatively be used to describe the embodiments.

[0058] Unless otherwise specifically stated, the term "a / an" as used herein includes the singular and the plural. Thus, the terms "a / an" or "at least one" may be used interchangeably in this application.

[0059] As used herein, the term "alkyl" refers to a branched, unbranched or cyclic carbon chain.

[0060] As used herein, the term "halogen" or "halo" refers to one or more halogen atoms, which are 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 and may vary depending upon the desired properties sought to be obtained. For a better understanding of the present teachings and without limiting their scope, all numbers expressing quantities, percentages or proportions, as well as other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about" unless otherwise indicated.

[0061] As used herein, the term "carbonyl" refers to the group -C=O.

[0062] As used herein, the term "alkoxy" refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.

[0063] As used herein, the term "alkoxycarbonyl" refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0064] As used herein, the term "trichloromethoxy" refers to a trichloromethyl group attached to the parent molecular moiety through an oxygen atom.

[0065] As used herein, the term "alkoxycarbonate" refers to an alkoxy group attached to the parent molecular moiety through a carbonate group.

[0066] As used herein, the term "telescopic process" refers to performing several reactions without separating the intermediate products. In particular, the telescopic process implies performing multiple transformations (including reaction quenching and other post-treatment operations) without directly separating the intermediate. The telescoped solution of the intermediate can be extracted, filtered (as long as the desired product remains in the filtrate), and solvent exchanged, but the intermediate ultimately remains in the solution and subsequent transformations are continued.

[0067] As used herein, the term "salt" refers to organic salts such as chlorides, bromides, fluorides, iodides, acetates, bisulfates, phosphates, formates, nitrates, carbonates, etc., or alkali metal salts (if applicable), such as sodium, potassium, calcium, lithium, cesium, magnesium, barium, etc.

[0068] Any compound described herein as an intermediate in an alkaline compound or method is also intended to include compound salts such as HCl salts, acetate salts, etc., and no special meaning should be attributed to the mention or non-mention of this in some cases herein with respect to a particular compound.

[0069] Salts of the compounds of the present invention include acid addition salts with inorganic or organic acids such as hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, acetic acid, butyric acid, fumaric acid, lactic acid, maleic acid, malonic acid, oxalic acid, propionic acid, salicylic acid, tartaric acid, 4-toluenesulfonic acid or valeric acid.

[0070] At a minimum, each numerical parameter should be interpreted at least in accordance with the number of significant figures reported and by application of ordinary rounding techniques. In the examples, the term "about" as used herein specifically includes ±10% of the indicated value within the range. Additionally, all endpoints of all ranges involving the same component or property herein include the endpoints, are combinable independently, and include all intermediate points and ranges.

[0071] In an embodiment, the present invention provides a method for preparing a compound of formula (I) or a salt thereof

[0072]

[0073] The method comprises reacting a compound of formula (II) or a salt thereof

[0074]

[0075] with hydroxylamine or a salt thereof, optionally in the presence of a solvent and optionally in the presence of a base.

[0076] According to an embodiment, the hydroxylamine salt is selected from the group consisting of 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 mixtures thereof.

[0077] According to an embodiment, the hydroxylamine salt is selected from the group consisting of hydroxylamine hydrochloride, hydroxylamine acetate, hydroxylamine sulfate, hydroxylamine phosphate, hydroxylamine nitrate, and mixtures thereof.

[0078] According to an embodiment, the hydroxylamine salt is hydroxylamine hydrochloride.

[0079] According to an embodiment, the molar ratio between the compound of formula (II) and hydroxylamine or a hydroxylamine salt can be from about 1:10 to 10:1, preferably from about 1:5 to 1:1, and most preferably from about 1:1.2 to 1:1.

[0080] According to an embodiment, the molar ratio between the compound of formula (II) and hydroxylamine or a hydroxylamine salt can be from about 1:5 to 1:0.9, preferably from about 1:3 to 1:1, and most preferably from about 1:1.15 to 1:1.05.

[0081] According to an embodiment, the base is selected from the group consisting of: triethylamine, dimethylamine, aniline, indole, piperidine, pyridine, pyrimidine, pyrrolidine, pyrrole, imidazole, methylimidazole, 2-methylpyridine, 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 mixtures thereof.

[0082] According to an embodiment, the molar ratio between the compound of formula (II) and the base can be from about 1:10 to 10:1, preferably from about 1:5 to 1:1, and most preferably from about 1:1.2 to 1:1.

[0083] According to an embodiment, the molar ratio between the compound of formula (II) and the base can be from about 1:5 to 1:0.9, preferably from about 1:3 to 1:1, and most preferably from about 1:1.2 to 1:1.05.

[0084] According to an embodiment, the solvent is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons (such as octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether), halogenated aliphatic cyclic and acyclic hydrocarbons (such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane), aromatic hydrocarbons (such as benzene, toluene, xylene, ethylbenzene), halogenated aromatic hydrocarbons (such as chlorobenzene, dichlorobenzene, trichlorobenzene), aliphatic cyclic ethers (such as diethyl ether, diethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), cyclopentyl methyl ether), aliphatic esters and cyclic esters (such as ethyl acetate), nitriles (such as acetonitrile, benzonitrile), ketones (such as acetone, 2-butanone), C1-C6 alcohols (such as methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, tert-butanol, diethylene glycol, glycerol, ethylene glycol, propylene glycol), C1-C4 carboxylic acids (such as acetic acid, propionic acid, benzoic acid), polar protic and aprotic solvents (such as formic acid, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide), water, and mixtures thereof.

[0085] According to an embodiment, the solvent is selected from the group comprising: halogenated aliphatic cyclic and acyclic hydrocarbons (such as chloroform, dichloromethane), aliphatic ethers (such as diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF)), aliphatic esters (such as ethyl acetate), nitriles (such as acetonitrile), ketones (such as acetone, 2-butanone), polar protic and aprotic solvents (such as formic acid, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide), water and mixtures thereof.

[0086] According to an embodiment, the w / w ratio between the compound of formula (II) and the organic solvent can be from about 1:20 to 10:1, preferably from about 1:5 to 1:0.5, and most preferably from about 1:5 to 1:3.

[0087] According to an embodiment, the w / w ratio between the compound of formula (II) and the organic solvent can be from about 1:10 to 1:1, preferably from about 1:5 to 1:1, and most preferably from about 1:5 to 1:4.

[0088] According to an embodiment, the compound of formula (II) is contacted with hydroxylamine or its salt in a temperature range of about 10 °C to 130 °C. The preferred temperature range is about 50 °C to 100 °C, more preferably about 80 °C to 90 °C.

[0089] According to an embodiment, the compound of formula (II) is contacted with hydroxylamine or its salt in a temperature range of about 50 °C to 100 °C. The preferred temperature range is about 70 °C to 90 °C, more preferably about 80 °C to 85 °C.

[0090] According to an embodiment, the reaction mixture is monitored by HPLC analysis method, and the process ends when the concentration of formula (II) is between 0 - 99%, preferably 0 - 50%. In particular, the process should be terminated when no more than 5% of the compound of formula (II) remains in the reaction medium.

[0091] According to an embodiment, the reaction mixture is monitored by HPLC analysis method, and the process ends when the concentration of formula (II) is between 0 - 40%, preferably 0 - 10%. In particular, the process should be terminated when no more than 1% of the compound of formula (II) remains in the reaction medium.

[0092] Finally, optionally, the reaction mixture containing the obtained compound of formula (I) is post-treated, or without post-treatment, it proceeds to the next dehydration step as in a condensation / one-pot reaction. This stage may include processes such as addition of water, addition of organic solvent, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction and drying.

[0093] In a further embodiment, the present invention provides a method for preparing a compound of formula (IV) and its salts,

[0094]

[0095] which method comprises dehydrating a compound of formula (I) optionally in the presence of a dehydrating agent and optionally in the presence of a solvent.

[0096] According to an embodiment, the method for preparing a compound of formula (IV) comprises two routes, wherein the first route is the direct synthesis of a compound of formula (IV) from a compound of formula (I), and the second route is the synthesis of a compound of formula (IV) from a compound of formula (II) via the formation of a compound of formula (I), which can be done as a separate method or as a combined method, such as a one-pot reaction, a tandem reaction, preferably done as a one-pot reaction method. The intermediate formed in the above process can be separated from the reaction mixture, or the process can be continued without separating the intermediate.

[0097] According to an embodiment, the dehydration of the compound of formula (I) can be carried out in the presence of a dehydrating agent selected from the group consisting of: p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, trimethylsilyl trifluoromethanesulfonate, calcium chloride, iron(III) chloride, alumina, silica, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonyl chloride, acetic acid, oxalic acid, dimethyl sulfoxide and mixtures thereof.

[0098] According to an embodiment, the dehydration of the compound of formula (I) can be carried out in the presence of a dehydrating agent selected from the group consisting of: p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, calcium chloride, dimethyl sulfoxide and mixtures thereof.

[0099] According to an embodiment, the molar ratio between the compound of formula (I) and the dehydrating agent can be from about 1:20 to 10:1, preferably from about 1:1 to 1:5, most preferably from about 1:3 to 1:5.

[0100] According to an embodiment, the molar ratio between the compound of formula (I) and the dehydrating agent can be from about 1:10 to 5:1, preferably from about 1:2 to 1:5, most preferably from about 1:4 to 1:5.

[0101] According to an embodiment, the solvent is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons (such as octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether), halogenated aliphatic cyclic and acyclic hydrocarbons (such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane), aromatic hydrocarbons (such as benzene, toluene, xylene, ethylbenzene), halogenated aromatic hydrocarbons (such as chlorobenzene, dichlorobenzene, trichlorobenzene), aliphatic and cyclic ethers (such as diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), cyclopentyl methyl ether), aliphatic and cyclic esters (such as ethyl acetate), nitriles (such as acetonitrile, benzonitrile), ketones (such as acetone, 2-butanone), C1-C6 alcohols (such as methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, tert-butanol, diethylene glycol, glycerol, ethylene glycol, propylene glycol), polar protic and aprotic solvents (N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide), water, and mixtures thereof.

[0102] According to an embodiment, the solvent is selected from the group consisting of: halogenated aliphatic cyclic and acyclic hydrocarbons (such as chloroform, dichloromethane), aliphatic ethers (such as diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF)), aliphatic esters (such as ethyl acetate), nitriles (such as acetonitrile), ketones (such as acetone, 2-butanone), polar protic and aprotic solvents (such as formic acid, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide), water, and mixtures thereof.

[0103] According to an embodiment, the w / w ratio between the compound of formula (I) and the organic solvent can be from about 1:20 to 10:1, preferably from about 1:5 to 1:0.5, and most preferably from about 1:5 to 1:3.

[0104] According to an embodiment, the w / w ratio between the compound of formula (I) and the organic solvent can be from about 1:10 to 1:1, preferably from 1:5 to 1:1, and most preferably from about 1:5 to 1:4.

[0105] According to an embodiment, the dehydration process of the compound of formula (I) can be carried out in a temperature range of about 10°C to 130°C. The preferred temperature range is about 50°C to 100°C, more preferably about 80°C to 90°C.

[0106] According to an embodiment, the dehydration process of the compound of formula (I) can be carried out in a temperature range of about 50°C to 110°C. The preferred temperature range is about 70°C to 90°C, more preferably about 85°C to 90°C.

[0107] According to an embodiment, the reaction mixture is monitored by HPLC analysis method, and the process ends when the concentration of formula (I) is between 0 - 99%, preferably 0 - 50%. In particular, the process should be terminated when no more than 5% of the compound having formula (I) remains in the reaction medium.

[0108] According to an embodiment, the reaction mixture is monitored by HPLC analysis method, and the process ends when the concentration of formula (I) is between 0 - 40%, preferably 0 - 10%. In particular, the process should be terminated when no more than 1% of the compound having formula (I) remains in the reaction medium.

[0109] Finally, the reaction mixture containing the obtained compound of formula (IV) is post - treated. This stage may include processes such as adding water, adding organic solvents, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying.

[0110] In another embodiment, the present invention provides a method for preparing a compound of formula (II) and its salts,

[0111]

[0112] The method includes reacting a compound of formula (III) and its salts,

[0113]

[0114] with a formylating reagent selected from hexamethylenetetramine (HMTA), formaldehyde, paraformaldehyde, trioxane, and / or methanediol and their mixtures, in the presence of an acid, optionally in the presence of a solvent.

[0115] The compound of formula (III) (3 - methyl - o - aminobenzoic acid, CAS No. [4389 - 45 - 1]) is a commercially available and known compound, which can be prepared according to many conventional methods.

[0116] According to an embodiment, the molar ratio between the compound of formula (III) and the formylating reagent can be about 1:20 to 1:0.3, preferably about 1:5 to 1:0.5, most preferably about 1:2 to 1:1.

[0117] According to an embodiment, the molar ratio between the compound of formula (III) and the formylating reagent can be about 1:5 to 1:0.3, preferably about 1:5 to 1:1, most preferably about 1:1.2 to 1:1.1.

[0118] According to an embodiment, the molar ratio between the compound having formula (III) and the formylating reagent may be from about 1:20 to 1:0.1, preferably from about 1:5 to 1:0.5, and most preferably from about 1:0.8 to 1:0.6.

[0119] According to an embodiment, the molar ratio between the compound having formula (III) and the formylating reagent may be from about 1:10 to 1:0.5, preferably from about 1:2 to 1:0.5, and most preferably from about 1:0.7 to 1:0.5.

[0120] According to an embodiment, the formylating reagent is selected from the group consisting of hexamethylenetetramine (HMTA), formaldehyde, paraformaldehyde, trioxane, methanediol, and mixtures thereof.

[0121] According to an embodiment, the formylating reagent is hexamethylenetetramine (HMTA).

[0122] According to an embodiment, the formylating reagent is formaldehyde.

[0123] According to an embodiment, the formylating reagent is paraformaldehyde.

[0124] According to an embodiment, the acid is selected from the group consisting of formic acid, trifluoromethanesulfonic acid, oxalic acid, carbonic acid, citric acid, tartaric acid, glutaric acid, lactic acid, malonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, boric acid, and mixtures thereof.

[0125] According to an embodiment, the acid is selected from the group consisting of methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, and mixtures thereof.

[0126] According to an embodiment, the molar ratio between the compound having formula (III) and the acid may be from about 1:20 to 1:0.1, preferably from about 1:10 to 1:0.5, and most preferably from about 1:5 to 1:1.

[0127] According to an embodiment, the molar ratio between the compound having formula (III) and the acid may be from about 1:10 to 1:1, preferably from about 1:3 to 1:1, and most preferably from about 1:1.9 to 1:1.5.

[0128] According to an embodiment, the solvent is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons (such as octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether), halogenated aliphatic cyclic and acyclic hydrocarbons (such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane), aromatic hydrocarbons (such as benzene, toluene, xylene, ethylbenzene), halogenated aromatic hydrocarbons (such as chlorobenzene, dichlorobenzene, trichlorobenzene), aliphatic and cyclic ethers (diethyl ether, diethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), cyclopentyl methyl ether), aliphatic esters and cyclic esters (such as ethyl acetate), nitriles (such as acetonitrile, benzonitrile), ketones (such as acetone, 2-butanone), C1-C6 alcohols (such as methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, tert-butanol, diethylene glycol, glycerol, ethylene glycol, propylene glycol), polar protic and aprotic solvents (such as N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide), acetic acid, water, and mixtures thereof.

[0129] According to an embodiment, the solvent is selected from the group consisting of: halogenated aliphatic acyclic hydrocarbons (such as dichloromethane), halogenated aromatic hydrocarbons (such as chlorobenzene, dichlorobenzene, trichlorobenzene), aliphatic ethers and cyclic ethers (diethylene glycol dimethyl ether, 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF)), aliphatic esters (such as ethyl acetate), nitriles (such as acetonitrile), ketones (such as acetone, 2-butanone), C1-C6 alcohols (such as methanol, ethanol, 1-butanol, 1-propanol, 2-propanol), polar protic and aprotic solvents (such as N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetic acid), water, and mixtures thereof.

[0130] According to an embodiment, the solvent is selected from the group consisting of: chlorobenzene, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetic acid, water, and mixtures thereof.

[0131] According to an embodiment, the w / w ratio between the compound of formula (III) and the organic solvent can be from about 1:20 to 10:1, preferably from about 1:5 to 1:1, and most preferably from about 1:3 to 1:1.

[0132] According to an embodiment, the w / w ratio between the compound of formula (III) and the organic solvent can be from about 1:10 to 1:1, preferably from about 1:5 to 1:1, and most preferably from about 1:2.2 to 1:2.

[0133] According to an embodiment, the contacting of the compound having formula (III) with the formylating reagent is carried out between a temperature range of about 10 °C to 130 °C. The preferred temperature range is about 70 °C to 120 °C.

[0134] According to an embodiment, the contacting of the compound having formula (III) with the formylating reagent is carried out between a temperature range of about 70 °C to 120 °C. The preferred temperature range is about 80 °C to 100 °C, more preferably about 85 °C to 95 °C.

[0135] According to an embodiment, the reaction mixture is monitored by an HPLC analysis method, and the process ends when the concentration of formula (III) is between 0 - 99%, preferably 0 - 50%. In particular, the process should be terminated when no more than 1% of the compound having formula (III) remains in the reaction medium.

[0136] According to an embodiment, the reaction mixture is monitored by an HPLC analysis method, and the process ends when the concentration of formula (III) is between 0 - 40%, preferably 0 - 10%. In particular, the process should be terminated when no more than 1% of the compound having formula (III) remains in the reaction medium.

[0137] Finally, the reaction mixture containing the resulting compound having formula (II) is worked up. This stage may include processes such as adding water, adding an organic solvent, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying.

[0138] In another embodiment, the present invention provides a method for preparing a compound having formula (V) and its salts,

[0139]

[0140] The method includes a) reacting a compound having formula (I) or its salt, which is prepared by reacting a compound having formula (II) or its salt

[0141]

[0142] with hydroxylamine or its salt, optionally in the presence of a solvent, optionally in the presence of a base.

[0143] with a compound having formula (A)

[0144]

[0145] wherein Z 1 and Z 2 are independently chloride, C1 - C4 - alkoxy, trichloromethoxy, C(O)Cl, C1 - C6 - alkoxycarbonate;

[0146] X is O;

[0147] The reaction is carried out in the presence of a solvent.

[0148] According to the embodiment, the solvent is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons (such as octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether), halogenated aliphatic cyclic and acyclic hydrocarbons (such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane), aromatic hydrocarbons (such as benzene, toluene, xylene, ethylbenzene), halogenated aromatic hydrocarbons (such as chlorobenzene, dichlorobenzene, trichlorobenzene), aliphatic and cyclic ethers (diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), cyclopentyl methyl ether), aliphatic esters and cyclic esters (such as ethyl acetate), nitriles (such as acetonitrile, benzonitrile), ketones (such as acetone, 2-butanone), C1-C6 alcohols (such as methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, tert-butanol, diethylene glycol, glycerol, ethylene glycol, propylene glycol), polar protic and aprotic solvents (such as N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide), acetic acid, water and mixtures thereof.

[0149] According to the embodiment, the solvent is selected from the group consisting of: halogenated aliphatic acyclic hydrocarbons (such as dichloromethane), halogenated aromatic hydrocarbons (such as chlorobenzene, dichlorobenzene, trichlorobenzene), aliphatic ethers and cyclic ethers (diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF)), aliphatic esters (such as ethyl acetate), nitriles (such as acetonitrile), ketones (such as acetone, 2-butanone), C1-C6 alcohols (such as methanol, ethanol, 1-butanol, 1-propanol, 2-propanol), polar protic and aprotic solvents (such as N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetic acid), water and mixtures thereof.

[0150] According to the embodiment, the solvent is selected from the group consisting of: aliphatic and cyclic ethers diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF) and mixtures thereof.

[0151] According to the embodiment, the w / w ratio between the compound of formula (I) and the solvent can be from about 1:20 to 10:1, preferably from about 1:1 to 1:10, and most preferably from about 1:3 to 1:5.

[0152] According to an embodiment, the w / w ratio between the compound of formula (I) and the solvent in step a) can be from about 1:1 to 1:10, preferably from about 1:1 to 1:5, and most preferably from about 1:3 to 1:4.

[0153] According to an embodiment, the compound of formula (A) is selected from the group consisting of: phosgene, diphosgene, triphosgene, methyl chloroformate, ethyl chloroformate, dimethylcarbamoyl chloride, oxalyl chloride, di-tert-butyl dicarbonate, dimethyl dicarbonate, diethyl dicarbonate, or a mixture thereof.

[0154] According to an embodiment, the compound of formula (A) is selected from the group consisting of: triphosgene, phosgene, oxalyl chloride, or a mixture thereof.

[0155] According to an embodiment, the w / w ratio between the compound of formula (I) and the compound of formula (A) can be from about 1:20 to 10:1, preferably from about 1:1 to 1:10, and most preferably from about 1:1 to 1:2.

[0156] According to an embodiment, the w / w ratio between the compound of formula (I) and the compound of formula (A) in step a) can be from about 1:1 to 1:10, preferably from about 1:1 to 1:5, and most preferably from about 1:1.05 to 1:1.2.

[0157] According to an embodiment, the contact between the compound of formula (I) and the compound of formula (A) is carried out in a temperature range of about 0°C to 100°C. The preferred temperature range is about 0°C to 60°C, more preferably about 20°C to 40°C.

[0158] According to an embodiment, the contact between the compound of formula (I) and the compound of formula (A) is carried out in a temperature range of about 0°C to 60°C. The preferred temperature range is about 20°C to 40°C, more preferably about 25°C to 30°C.

[0159] According to an embodiment, the reaction mixture is monitored by HPLC analysis method, and when the concentration of formula (I) is between 0 - 99%, preferably 0 - 50%, most preferably, especially when no more than 1% of the compound of formula (I) remains in the reaction medium, the process ends.

[0160] According to an embodiment, the reaction mixture is monitored by HPLC analysis method, and when the concentration of formula (I) is between 0 - 40%, preferably 0 - 10%, the process ends. In particular, when no more than 1% of the compound of formula (I) remains in the reaction medium, the process ends.

[0161] Finally, the reaction mixture containing the obtained compound of formula (I) is worked up. This stage can include processes such as adding water, adding an organic solvent, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying.

[0162] In another embodiment, the present invention provides a method for preparing a compound of formula (VII) and its salts,

[0163]

[0164] which method comprises a) reacting a compound of formula (IV) or its salt prepared according to the present invention with a compound of formula (A)

[0165]

[0166] wherein Z 1 and Z 2 are independently chloride, C1-C4-alkoxy, trichloromethoxy, C(O)Cl, C1-C6-alkoxycarbonate;

[0167] X is O;

[0168] in the presence of a solvent, optionally in the presence of a base, and optionally in the presence of a phase transfer catalyst to obtain a compound of formula (V),

[0169]

[0170] and b) reacting the compound of formula (V) with methylamine or its salt in the presence of a solvent and optionally in the presence of a base.

[0171] According to an embodiment, the compound of formula (A) is selected from the group consisting of: phosgene, diphosgene, triphosgene, methyl chloroformate, ethyl chloroformate, dimethylcarbamoyl chloride, oxalyl chloride, di-tert-butyl dicarbonate, dimethyl carbonate, diethyl carbonate, or a mixture thereof.

[0172] According to an embodiment, the compound of formula (A) is selected from the group consisting of: triphosgene, phosgene, oxalyl chloride, or a mixture thereof.

[0173] According to an embodiment, the molar ratio between the compound of formula (IV) and the compound of formula (A) is from about 1:20 to 1:0.1, preferably from about 1:5 to 1:0.2, and most preferably from about 1:1 to 1:0.4.

[0174] According to an embodiment, the molar ratio between the compound of formula (IV) and the compound of formula (A) is from about 1:10 to 1:0.1, preferably from about 1:1 to 1:0.2, and most preferably from about 1:0.6 to 1:0.4.

[0175] According to an embodiment, the base is selected from the group consisting of: triethylamine, dimethylamine, aniline, indole, piperidine, pyridine, pyrimidine, pyrrolidine, pyrrole, imidazole, methylimidazole, 2-methylpyridine, 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 mixtures thereof.

[0176] According to an embodiment, the base is selected from the group consisting of: triethylamine, imidazole, sodium hydroxide, potassium hydroxide, and mixtures thereof.

[0177] According to an embodiment, the molar ratio between the compound of formula (IV) and the base can be from about 1:20 to 1:1, preferably from about 1:10 to 1:1.2, and most preferably from about 1:5 to 1:2.

[0178] According to an embodiment, the molar ratio between the compound of formula (IV) and the base can be from about 1:10 to 1:1, preferably from about 1:5 to 1:1.2, and most preferably from about 1:3 to 1:2.

[0179] According to an embodiment, the phase transfer catalyst is selected from the group consisting of ammonium salts or polyethers, and these ammonium salts or polyethers are selected from the group consisting of pyridinium hydrochloride, pyridinium acetate, pyridinium trifluoromethanesulfonate, pyridinium hydrobromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, crown ethers, polyethylene glycol, and mixtures thereof.

[0180] According to an embodiment, the phase transfer catalyst is selected from the group consisting of ammonium salts or polyethers, and these ammonium salts or polyethers are selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, polyethylene glycol, and mixtures thereof.

[0181] According to an embodiment, the molar ratio between the compound of formula (IV) and the phase transfer catalyst can be from about 1:1 to 1:0.0001, preferably from about 1:0.1 to 1:0.001, and most preferably from about 1:0.05 to 1:0.005.

[0182] According to an embodiment, the molar ratio between the compound of formula (IV) and the phase transfer catalyst can be from about 1:0.1 to 1:0.001, preferably from about 1:0.05 to 1:0.01, and most preferably from about 1:0.04 to 1:0.02.

[0183] According to an embodiment, the solvent in step a) is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons (such as octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether), halogenated aliphatic cyclic and acyclic hydrocarbons (such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane), aromatic hydrocarbons (benzene, toluene, xylene, ethylbenzene), halogenated aromatic hydrocarbons (such as chlorobenzene, dichlorobenzene, trichlorobenzene), aliphatic ethers and cyclic ethers (such as diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), cyclopentyl methyl ether), aliphatic esters (such as ethyl acetate), nitriles (such as acetonitrile, benzonitrile), ketones (such as acetone, 2-butanone), dimethyl carbonate, polar protic and aprotic solvents (such as dimethylformamide, pyridine, dimethyl sulfoxide, n-alkylpyrrolidone) and mixtures thereof.

[0184] According to an embodiment, the solvent in step a) is selected from the group consisting of: halogenated aliphatic acyclic hydrocarbons (such as dichloromethane), aromatic hydrocarbons (such as toluene), halogenated aromatic hydrocarbons (such as chlorobenzene, dichlorobenzene, trichlorobenzene), aliphatic ethers and cyclic ethers (such as 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF)), aliphatic esters (such as ethyl acetate), nitriles (such as acetonitrile), polar protic and aprotic solvents (such as dimethylformamide, pyridine, dimethyl sulfoxide, n-alkylpyrrolidone) and mixtures thereof.

[0185] According to an embodiment, the w / w ratio between the compound of formula (IV) and the solvent in step a) can be from about 1:20 to 10:1, preferably from about 1:0.5 to 1:5, and most preferably from about 1:3 to 1:5.

[0186] According to an embodiment, the w / w ratio between the compound of formula (IV) and the solvent in step a) can be from about 1:10 to 1:1, preferably from about 1:5 to 1:1, and most preferably from about 1:3 to 1:4.

[0187] According to an embodiment, the contact between the compound of formula (IV) and the compound of formula (A) is carried out in a temperature range of about 0 °C to 100 °C. The preferred temperature range is about 10 °C to 60 °C, more preferably about 20 °C to 30 °C.

[0188] According to an embodiment, the contact between the compound of formula (IV) and the compound of formula (A) is carried out in a temperature range of about 5 °C to 60 °C. The preferred temperature range is about 10 °C to 40 °C, more preferably about 20 °C to 30 °C.

[0189] According to an embodiment, the contact of the compound of formula (IV) with triphosgene is carried out in a temperature range of about 5 °C to 60 °C. The preferred temperature range is about 10 °C to 40 °C, more preferably about 20 °C to 30 °C.

[0190] According to an embodiment, the reaction mixture is monitored by HPLC analysis method, and when the concentration of formula (IV) is between 0-99%, preferably 0-50%, most preferably, especially when no more than 1% of the compound of formula (IV) remains in the reaction medium, the process ends.

[0191] According to an embodiment, the reaction mixture is monitored by HPLC analysis method, and when the concentration of formula (IV) is between 0-40%, preferably 0-10%, the process ends. In particular, when no more than 1% of the compound of formula (IV) remains in the reaction medium, the process ends.

[0192] Finally, the reaction mixture containing the obtained compound of formula (IV) is post-treated. This stage may include processes such as adding water, adding organic solvents, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction and drying.

[0193] According to an embodiment, the methylamine salt is selected from the group consisting of: methylammonium chloride, methylammonium bromide, methylammonium iodide, methylammonium nitrate, methylammonium form, methylammonium sulfate, methylammonium tetrafluoroborate, methylammonium acetate, methylammonium hydroxide, methylammonium perchlorate and mixtures thereof.

[0194] According to an embodiment, the methylamine salt is selected from the group consisting of: methylammonium chloride, methylammonium nitrate, methylammonium acetate, methylammonium hydroxide and mixtures thereof.

[0195] According to an embodiment, the molar ratio between compound (V) and methylamine or its salt can be about 1:20 to 1:0.1, preferably about 1:10 to 1:1, most preferably about 1:5 to 1:3.

[0196] According to an embodiment, the molar ratio between compound (V) and methylamine or its salt can be about 1:10 to 1:1, preferably about 1:5 to 1:2, most preferably about 1:3 to 1:2.

[0197] According to the embodiment, the solvent in step b) is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons (such as octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether), halogenated aliphatic cyclic and acyclic hydrocarbons (such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane), aromatic hydrocarbons (such as benzene, toluene, xylene, ethylbenzene), halogenated aromatic hydrocarbons (such as chlorobenzene, dichlorobenzene, trichlorobenzene), aliphatic ethers and cyclic ethers (such as diethyl ether, diethylene glycol dimethyl ether (diglyme), 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), cyclopentyl methyl ether), aliphatic esters (such as ethyl acetate), nitriles (such as acetonitrile, benzonitrile), ketones (such as acetone, 2-butanone), C1-C6 alcohols (such as methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, tert-butanol, diethylene glycol, glycerol, ethylene glycol, propylene glycol), polar protic and aprotic solvents (N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide), water and mixtures thereof.

[0198] According to the embodiment, the solvent in step b) is selected from the group consisting of: halogenated aliphatic hydrocarbons (such as dichloromethane), aliphatic ethers and cyclic ethers (such as 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF)), aliphatic esters (such as ethyl acetate), nitriles (such as acetonitrile), C1-C6 alcohols (such as methanol, ethanol, 1-butanol, 2-propanol), polar protic and aprotic solvents (such as N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide), water and mixtures thereof.

[0199] According to the embodiment, the w / w ratio between the compound of formula (V) and the solvent in step a) can be from about 1:20 to 10:1, preferably from about 1:0.5 to 1:5, and most preferably from about 1:3 to 1:5.

[0200] According to the embodiment, the w / w ratio between the compound of formula (V) and the solvent in step a) can be from about 1:10 to 1:1, preferably from about 1:5 to 1:1, and most preferably from about 1:3 to 1:4.

[0201] According to the embodiment, the contact between the compound of formula (V) and methylamine or its salt is carried out in a temperature range of about -10°C to 100°C. The preferred temperature range is about 5°C to 30°C, more preferably about 20°C to 30°C.

[0202] According to the embodiment, the contact between the compound of formula (V) and methylamine or its salt is carried out in a temperature range of about 0°C to 50°C. The preferred temperature range is about 10°C to 40°C, more preferably about 25°C to 30°C.

[0203] According to an embodiment, the reaction mixture is monitored by HPLC analysis method, and the process ends when the concentration of formula (V) is between 0-99%, preferably 0-50%. In particular, the process should be terminated when no more than 1% of the compound having formula (V) remains in the reaction medium.

[0204] According to an embodiment, the reaction mixture is monitored by HPLC analysis method, and the process ends when the concentration of formula (V) is between 0-20%, preferably 0-10%. In particular, the process should be terminated when no more than 1% of the compound having formula (IV) remains in the reaction medium.

[0205] In another embodiment, the present invention provides a method for preparing a compound of formula (VII) and its salts,

[0206]

[0207] The method comprises a) reacting a compound of formula (IV) or its salt (which is optionally prepared by dehydrating a compound of formula (I) in the presence of a solvent according to the present invention) with thionyl chloride, sulfonyl 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 (DIC), ethyl-(N’,N’-dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and mixtures thereof, optionally in the presence of a base to form a compound of formula (VI)

[0208]

[0209] wherein R 1 is a halide, an optionally halogenated C1-C6-carboxylic acid, a carbodiimide, a hydroxytriazole;

[0210] and b) reacting the compound of formula (VI) with methylamine or its salt in the presence of a solvent and optionally in the presence of a base.

[0211] According to an embodiment, the bases in steps a) and b) are selected from the group consisting of: triethylamine, dimethylamine, aniline, indole, piperidine, pyridine, pyrimidine, pyrrolidine, pyrrole, imidazole, methylimidazole, 2-methylpyridine, 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 mixtures thereof.

[0212] According to the embodiment, the base in steps a) and b) is selected from the group consisting of: triethylamine, imidazole, sodium carbonate, sodium bicarbonate, sodium acetate, potassium carbonate, potassium bicarbonate, and mixtures thereof.

[0213] According to the embodiment, the molar ratio between compound (IV) and the base in step a) can be from about 1:20 to 1:0.1, preferably from 1:10 to 1:1, and most preferably from about 1:1.5 to 1:1.

[0214] According to the embodiment, the molar ratio between compound (IV) and the base in step a) can be from about 1:10 to 1:1, preferably from 1:5 to 1:1, and most preferably from about 1:1.3 to 1:1.1.

[0215] According to the embodiment, the molar ratio between compound (IV) and the base in step b) can be from about 1:20 to 1:0.1, preferably from 1:10 to 1:1, and most preferably from about 1:1.5 to 1:1.

[0216] According to the embodiment, the molar ratio between compound (IV) and the base in step b) can be from about 1:10 to 1:1, preferably from 1:5 to 1:1, and most preferably from about 1:1.3 to 1:1.1.

[0217] According to the embodiment, the solvents in steps a) and b) are selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons (such as octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether), halogenated aliphatic cyclic and acyclic hydrocarbons (such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane), aromatic hydrocarbons (such as benzene, toluene, xylene, ethylbenzene), halogenated aromatic hydrocarbons (such as chlorobenzene, dichlorobenzene, trichlorobenzene), aliphatic ethers and cyclic ethers (such as diethyl ether, diethylene glycol dimethyl ether (diglyme), 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), cyclopentyl methyl ether), aliphatic esters (such as ethyl acetate), nitriles (such as acetonitrile, benzonitrile), ketones (such as acetone, 2-butanone), C1-C6 alcohols (such as methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, tert-butanol, diethylene glycol, glycerol, ethylene glycol, propylene glycol), polar protic and aprotic solvents (such as N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide), water, and mixtures thereof.

[0218] According to the embodiment, the solvent in steps a) and b) is selected from the group including the following: halogenated aliphatic hydrocarbons (such as carbon tetrachloride), aliphatic ethers and cyclic ethers (such as 1,4-dioxane, methyl tert-butyl ether (MTBE), isopropyl methyl ether, tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF)), nitriles (such as acetonitrile), ketones (such as acetone, 2-butanone), C1-C6 alcohols (such as methanol, ethanol, 1-butanol, 2-propanol), polar protic and aprotic solvents (such as N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide), water and mixtures thereof.

[0219] According to the embodiment, the w / w ratio between the compound of formula (IV) and the solvent in step a) can be from about 1:20 to 10:1, preferably from about 1:0.5 to 1:5, and most preferably from about 1:3 to 1:5.

[0220] According to the embodiment, the w / w ratio between the compound of formula (IV) and the solvent in step a) can be from about 1:10 to 1:1, preferably from about 1:5 to 1:1, and most preferably from about 1:3 to 1:4.

[0221] According to the embodiment, the w / w ratio between the compound of formula (VI) and the solvent in step b) can be from about 1:20 to 10:1, preferably from about 1:0.5 to 1:5, and most preferably from about 1:3 to 1:5.

[0222] According to the embodiment, the w / w ratio between the compound of formula (VI) and the solvent in step b) can be from about 1:10 to 1:1, preferably from about 1:5 to 1:1, and most preferably from about 1:3 to 1:4.

[0223] According to the embodiment, the contact of the compound of formula (IV) with any one of thionyl chloride, sulfonyl 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 mixtures thereof is carried out in a temperature range of about 0 °C to 120 °C. The preferred temperature range is about 70 °C to 120 °C, more preferably about 70 °C to 100 °C.

[0224] According to the embodiment, the w / w ratio between the compound of formula (VI) and any one of thionyl chloride, sulfonyl 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 mixtures thereof can be from about 1:1 to 1:10, preferably from about 1:1 to 1:5, and most preferably from about 1:1.5 to 1:4.

[0225] According to an embodiment, the contact of the compound having formula (IV) with any one of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBt), and mixtures thereof is carried out between a temperature range of about 0 °C to 120 °C. The preferred temperature range is about 0 °C to 50 °C, more preferably about 0 °C to 30 °C.

[0226] According to an embodiment, the w / w ratio between the compound having formula (VI) and any one of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-hydroxybenzotriazole (HOBt), and mixtures thereof can be about 1:1 to 1:10, preferably about 1:1 to 1:3, and most preferably about 1:1.1 to 1:1.5.

[0227] According to an embodiment, the contact of the compound having formula (VI) with methylamine or its salt is carried out between a temperature range of about 0 °C to 120 °C, more preferably about 10 °C to 70 °C.

[0228] According to an embodiment, the contact of the compound having formula (VI) with methylamine or its salt is carried out between a temperature range of about 0 °C to 60 °C.

[0229] According to an embodiment, the reaction mixture of step a) is monitored by an HPLC analysis method, and the process ends when the concentration of formula (IV) is between 0 - 99%, preferably 0 - 50%. In particular, the process should be terminated when no more than 1% of the compound having formula (IV) remains in the reaction medium.

[0230] According to an embodiment, the reaction mixture of step a) is monitored by an HPLC analysis method, and the process ends when the concentration of formula (IV) is between 0 - 20%, preferably 0 - 10%. In particular, the process should be terminated when no more than 1% of the compound having formula (IV) remains in the reaction medium.

[0231] According to an embodiment, the reaction mixture of step b) is monitored by an HPLC analysis method, and the process ends when the concentration of formula (VI) is between 0 - 99%, preferably 0 - 50%. In particular, the process should be terminated when no more than 1% of the compound having formula (VI) remains in the reaction medium.

[0232] According to an embodiment, the reaction mixture of step b) is monitored by an HPLC analysis method, and the process ends when the concentration of formula (VI) is between 0 - 20%, preferably 0 - 10%. In particular, the process should be terminated when no more than 1% of the compound having formula (VI) remains in the reaction medium.

[0233] In another aspect of the present invention, the compound having formula (I) can be used as an intermediate for the preparation of cyantraniliprole. As a non-limiting example for the preparation of cyantraniliprole, as disclosed in the present invention, the compound having formula (I) can first be converted into an intermediate having formula (IV) and / or (VII), and then reacted with the corresponding pyrazole carboxylic acid or its derivative by methods (such as but not limited to those disclosed in WO2006068669, WO 2004 / 067528, WO 2006 / 062978).

[0234] In another aspect of the present invention, the compound having formula (II) prepared according to the present invention can be used as an intermediate for the preparation of cyantraniliprole. For the preparation of cyantraniliprole, as disclosed in the present invention, the compound having formula (II) can first be converted into an intermediate having formula (IV) and / or (VII), and then reacted with the corresponding pyrazole carboxylic acid or its derivative by methods (such as but not limited to those disclosed in WO2006068669, WO 2004 / 067528, WO 2006 / 062978).

[0235] In another embodiment, the compounds having formula (II), (IV) and (VII) prepared according to the present invention can be used to prepare cyantraniliprole using different methods (such as but not limited to those disclosed in WO 2006068669, WO 2004 / 067528, WO 2006 / 062978).

[0236] Without further elaboration, it is believed that those skilled in the art can utilize the present invention to its fullest extent using the foregoing description. Accordingly, the following examples are to be construed as merely illustrative and in no way limiting of the disclosure.

[0237] Experimental section:

[0238] Example 1: Preparation of 2-amino-5-formyl-3-methylbenzoic acid from 2-amino-3-methylbenzoic acid:

[0239] At 25 °C, 2-amino-3-methylbenzoic acid (15.1 g), acetic acid (30 mL), and methanesulfonic acid (28 mL) were charged into a 1 L reactor and stirred for 5 minutes. Then the reaction was heated to 50 °C, and hexamethylenetetramine (HMTA) (30.8 g) was added in portions. The reaction was further heated to 90 °C, and the reaction mixture was stirred for 3.5 hours. The reaction progress was monitored by HPLC and ended when the starting material in the reaction mixture was less than 1%. The reaction mixture was cooled to 25 °C and 32% hydrochloric acid (54 mL) was added, followed by water (500 mL), and the mixture was stirred for 2 hours. 40% aqueous sodium hydroxide solution (97.5 g) was added to obtain a pH of 5-6, followed by water (100 mL). The precipitate was filtered and washed twice with water (100 mL). The filtered precipitate was transferred to water (300 mL), and the mixture was heated to 60 °C for 1 hour. The mixture was cooled to 30 °C, and the precipitate was filtered. The solid precipitate was washed twice with water (50 mL) and transferred to acetonitrile (40 mL). The mixture was stirred for 0.5 hour, and the solid was filtered and dried to obtain 11.8 g of a solid product with 83% purity (55% yield).

[0240] Example 2: Preparation of 2-amino-5-formyl-3-methylbenzoic acid from 2-amino-3-methylbenzoic acid:

[0241] In a 1 L reactor, 2-amino-3-methylbenzoic acid (40 g), hexamethylenetetramine (HMTA) (80 g), and acetic acid (120 mL) were mixed at 25 °C for 10 minutes. Then, methanesulfonic acid (76 mL) was added dropwise while maintaining the temperature at 50 °C. The reaction was further heated to 85 °C, and the reaction mixture was stirred for 2 hours. The reaction progress was monitored by HPLC and ended when the starting material in the reaction mixture was less than 1%. Water (500 mL) was added to the hot reaction mixture, and the mixture was stirred at 80 °C for 20 minutes. Then, 40% aqueous sodium hydroxide solution (170 g) was added to the solution to obtain a pH of 5, and the mixture was stirred at 30 °C for 12 hours. The solid precipitate was filtered and washed with water, and the product was dried to obtain 42.6 g of a solid product with 92% purity (83% yield).

[0242] Example 3 (comparison): Preparation of 2-amino-5-formyl-3-methylbenzoic acid from 2-amino-3-methylbenzoic acid:

[0243] At 25 °C, a 1 L reactor was charged with 2-amino-3-methylbenzoic acid (10 g), acetic acid (18.3 mL), paraformaldehyde (3.27 g), and hexamethylenetetramine (HMTA) (10.19 g), and stirred for 5 minutes. The reaction was then heated to 100 °C, and the reaction mixture was stirred for 2 hours. The reaction progress was monitored by HPLC and ended when the starting material in the reaction mixture was less than 1%. Hot water (75 mL) at 60 °C was added to the reaction mixture, followed by hydrochloric acid (58 mL), and the mixture was stirred at 90 °C for an additional 0.5 hour. The mixture was cooled to 25 °C, and 1 M aqueous sodium hydroxide was added to obtain a pH of 4. After 24 hours, the precipitate was filtered and washed twice with water (100 mL). The filtered precipitate was dissolved in hot acetonitrile (50 mL) at 60 °C. The acetonitrile was evaporated, and the solid was dried to obtain 3.4 g of a pale yellow solid product (29% yield).

[0244] As shown in Comparative Example 3, the reaction carried out without an additional acid (e.g., methanesulfonic acid) resulted in a significant decrease in yield.

[0245] Example 4: Preparation of 2-amino-5-((hydroxyimino)methyl)-3-methylbenzoic acid from 2-amino-5-formyl-3-methylbenzoic acid:

[0246] At 25 °C, a 0.1 L reactor was charged with 2-amino-5-formyl-3-methylbenzoic acid (2.0 g), hydroxylamine hydrochloride (0.85 g), and acetonitrile (20 mL), and stirred for 5 minutes. The reaction was then heated to 80 °C, and the mixture was stirred for 4 hours. The reaction progress was monitored by HPLC and ended when the starting material in the reaction mixture was less than 1%. The mixture was cooled to 40 °C, and water (100 mL) was added dropwise. The mixture was cooled to 10 °C, and the precipitate was filtered. The solid filtrate was washed three times with water (50 mL) and dried to obtain 1.95 g of a solid product (90% yield).

[0247] Example 5: Preparation of 2-amino-5-cyano-3-methylbenzoic acid from 2-amino-5-formyl-3-methylbenzoic acid:

[0248] At 25 °C, a 0.1 L reactor was charged with 2-amino-5-formyl-3-methylbenzoic acid (2.0 g), hydroxylamine hydrochloride (0.85 g), and dimethyl sulfoxide (10 mL), and stirred for 5 minutes. The reaction was then heated to 90 °C and the mixture was stirred for 4 hours. The reaction progress was monitored by HPLC and ended when the starting material in the reaction mixture was less than 1%. The mixture was cooled to 40 °C and water (100 mL) was added dropwise. The mixture was cooled to 10 °C and the precipitate was filtered. The solid filtrate was washed three times with water (50 mL) and dried to obtain 1.55 g of the solid product (63% yield).

[0249] Example 6: Preparation of 8-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile from 2-amino-5-cyano-3-methylbenzoic acid:

[0250] At 25 °C, a 0.1 L reactor was charged with 2-amino-5-cyano-3-methylbenzoic acid (5.0 g), toluene (50 mL), tetrabutylammonium bromide (0.26 g), and 30% aqueous sodium hydroxide solution (10.1 mL), and stirred for 5 minutes. Triphosgene (3.7 g) in toluene (24 g) was added to the mixture in portions, the temperature was maintained at 25 °C, and the mixture was stirred for 1.5 hours. The reaction progress was monitored by HPLC and ended when the starting material in the reaction mixture was less than 1%. The precipitate was filtered, washed twice with water, and dried to obtain 6.0 g of the solid product (91% yield).

[0251] Example 7: Preparation of 8-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile from 2-amino-5-((hydroxyimino)methyl)-3-methylbenzoic acid:

[0252] At 25 °C, a 0.1 L reactor was charged with 2-amino-5-((hydroxyimino)methyl)-3-methylbenzoic acid (8.0 g), triphosgene (24.0 g), and THF (80.0 mL), and stirred for 5 minutes. The reaction was then heated to 66 °C and the mixture was stirred for 2 hours. The reaction progress was monitored by HPLC and ended when the starting material in the reaction mixture was less than 1%. The reaction mixture was then concentrated to obtain 7.1 g of the desired product (yield: 85%).

[0253] Example 8: Preparation of 8-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile from 2-amino-5-((hydroxyimino)methyl)-3-methylbenzoic acid:

[0254] At 25 °C, a 0.1 L reactor was charged with 2-amino-5-((hydroxyimino)methyl)-3-methylbenzoic acid (1.0 g), triphosgene (3.0 g) and Me-THF (10.0 mL), and stirred for 5 minutes. The reaction was stirred at 25 °C for 2 hours. The reaction progress was monitored by HPLC and ended when the starting material in the reaction mixture was less than 1%. The reaction mixture was then concentrated to obtain 0.8 g of the desired product (yield: 80%).

[0255] Example 9: Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide from 8-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile:

[0256] At 25 °C, a 0.1 L reactor was charged with 8-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile (2.0 g), 2-propanol (20 mL) and sodium bicarbonate (2.83 g), and stirred for 5 minutes. Methylammonium chloride (1.7 g) was added to the mixture in portions, the temperature was maintained at 0 °C, and the mixture was stirred for 2.5 hours. The reaction progress was monitored by HPLC and ended when the starting material in the reaction mixture was less than 1%. The crude product was filtered out, washed in water and dried to obtain 1.5 g of the product (yield: 80%).

[0257] Example 10: Preparation of cyantraniliprole from 2-amino-5-cyano-N,3-dimethylbenzamide:

[0258] At 25 °C, a 5 L reactor was charged with toluene (2200 g) and 2-amino-5-cyano-N,3-dimethylbenzamide (215 g) and stirred for 5 minutes. The mixture was heated to 90 °C and a vacuum was applied at 380 mbar. Then, 3-bromo-5-(3-chloropyridin-2-yl)cyclopent-1,3-diene-1-carbonyl chloride (350 g) in toluene (1140 g) was added dropwise while extracting hydrogen chloride and toluene from the reaction. At the end of the addition, the reaction mixture was stirred for an additional 3 h while adding toluene to maintain the volume of the reaction mixture at 800 g. Then, the vacuum was stopped and the mixture was stirred for an additional 1 h while purging with nitrogen. The reaction progress was monitored by HPLC and ended when the starting material in the reaction mixture was less than 1%. The mixture was cooled to 0 °C and the solid precipitate was filtered. The solid was washed with toluene and dried under vacuum at 70 °C. The solid was then dissolved in methanol (1600 g) and the mixture was heated to 65 °C for 4 h. The mixture was cooled to 5 °C for 2 h and the precipitate solid was filtered and washed with fresh methanol. The solid was dried under vacuum at 70 °C for 2 hours to obtain 470 g of the product (91% yield).

Claims

1. A method for preparing a compound of formula (I) or a salt thereof The method comprises reacting a compound of formula (II) or a salt thereof with hydroxylamine or a salt thereof, optionally in the presence of a solvent and optionally in the presence of a base.

2. The method according to claim 1, wherein The base is selected from the group consisting of: triethylamine, dimethylamine, pyridine, 2-methylpyridine, 4-methylmorpholine, dimethylaminopyridine, N,N-diisopropylethylamine, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, potassium carbonate, potassium bicarbonate, potassium hydroxide, ammonium hydroxide, ammonium acetate and mixtures thereof.

3. The method according to claim 1, wherein, The solvent is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic ethers and cyclic ethers, aliphatic esters, nitriles, ketones, C1-C6 alcohols, C1-C4 carboxylic acids, formic acid, pyridine, ethylene glycol, propylene glycol, n-alkylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water and mixtures thereof.

4. A method for preparing a compound of formula (IV) and a salt thereof, The method comprises dehydrating the compound of formula (I) optionally in the presence of a solvent.

5. The method according to claim 4, wherein The solvent is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic ethers and cyclic ethers, aliphatic esters, nitriles, ketones, C1-C6 alcohols, C1-C4 carboxylic acids, acetonitrile, pyridine, ethylene glycol, propylene glycol, n-alkylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water and mixtures thereof.

6. A method for preparing a compound of formula (II) and a salt thereof, The method comprises reacting a compound of formula (III) and a salt thereof, with a formylating reagent selected from hexamethylenetetramine (HMTA), formaldehyde, paraformaldehyde, trioxane and / or methanediol and mixtures thereof, in the presence of an acid and optionally in the presence of a solvent.

7. The method according to claim 6, wherein The acid is selected from the group consisting of: formic acid, trifluoromethanesulfonic acid, monochloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, boric acid and mixtures thereof.

8. The method according to claim 6, wherein The solvent is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic ethers and cyclic ethers, aliphatic esters, nitriles, ketones, C1-C6 alcohols, n-alkyl protonic and aprotic polar solvents such as pyridine, ethylene glycol, propylene glycol, n-alkylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water and mixtures thereof.

9. A method for preparing a compound of formula (V) and a salt thereof, The method comprises a) reacting the compound of formula (I) or a salt thereof prepared according to claim 1 with a compound of formula (A) wherein Z 1 and Z 2 independently are chloride, C1-C4-alkoxy, trichloromethoxy, C(O)Cl, C1-C6-alkoxycarbonate; X is O; in the presence of a solvent, optionally in the presence of a base and optionally in the presence of a phase transfer catalyst.

10. The method according to claim 9, wherein, The solvent is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic ethers and cyclic ethers, aliphatic esters, nitriles, ketones, C1-C6 alcohols, n-alkyl protonic and aprotic polar solvents such as pyridine, ethylene glycol, propylene glycol, n-alkylpyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water and mixtures thereof.

11. A method for preparing a compound of formula (VII) and salts thereof, The method comprising a) reacting a compound of formula (I) or a salt thereof prepared according to claim 1 with a compound of formula (A) wherein Z 1 and Z 2 independently are chloride, C1-C4-alkoxy, trichloromethoxy, C(O)Cl, C1-C6-alkoxycarbonate; X is O; in the presence of a solvent and b) further reacting a compound of formula (V) with methylamine or a salt thereof in the presence of a solvent and optionally in the presence of a base.

12. The method according to claim 11, wherein, The solvent is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic ethers and cyclic ethers, aliphatic esters, nitriles, ketones, dimethyl carbonate, dimethylformamide, pyridine, dimethyl sulfoxide, n-alkylpyrrolidone, C1-C6-alkoxy, C1-C4-carboxylic acid, water and mixtures thereof.

13. The method according to claim 11, wherein The base is selected from the group consisting of: triethylamine, pyridine, 2-methylpyridine, 4-methylmorpholine, dimethylaminopyridine, N,N-diisopropylethylamine, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, ammonium hydroxide and mixtures thereof.

14. A method for preparing a compound of formula (VII) and salts thereof, The method comprising a) reacting a compound of formula (IV) or a salt thereof prepared according to claim 4 with a compound of formula (A) wherein Z 1 and Z 2 are independently chloride, C1-C4-alkoxy, trichloromethoxy, C(O)Cl, C1-C6-alkoxycarbonate; X is O; in the presence of a solvent, optionally in the presence of a base, optionally in the presence of a phase transfer catalyst to obtain a compound of formula (V), and b) reacting a compound of formula (V) with methylamine or a salt thereof in the presence of a solvent and optionally in the presence of a base.

15. The method according to claim 14, wherein, The base is selected from the group consisting of: triethylamine, pyridine, 2-methylpyridine, 4-methylmorpholine, dimethylaminopyridine, N,N-diisopropylethylamine, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, ammonium hydroxide and mixtures thereof.

16. The method according to claim 14, wherein the method is carried out in the presence of a phase transfer catalyst selected from quaternary ammonium salts, phosphonium salts, crown ethers, polyethers and mixtures thereof.

17. The method according to claim 14, wherein, The phase transfer catalyst is selected from the group consisting of: benzyltriethylammonium chloride, methyltricaprylylammonium chloride, methyltributylammonium chloride and methyltrioctylammonium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium fluoride, crown ethers, polyethylene glycol, polypropylene glycol and mixtures thereof.

18. The method according to claim 14, wherein The solvent in step a) is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic ethers and cyclic ethers, aliphatic esters, nitriles, ketones, dimethyl carbonate, dimethylformamide, pyridine, dimethyl sulfoxide, n-alkylpyrrolidone and mixtures thereof.

19. The method according to claim 14, wherein, The solvent in step b) is selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic ethers and cyclic ethers, aliphatic esters, nitriles, ketones, dimethyl carbonate, dimethylformamide, pyridine, dimethyl sulfoxide, n-alkylpyrrolidone, C1-C6-alkoxy, C1-C4-carboxylic acids, water and mixtures thereof.

20. A process for preparing a compound of formula (VII) and salts thereof, said process comprising a) reacting a compound of formula (IV) or a salt thereof prepared according to claim 4 with thionyl chloride, sulfonyl 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 (DIC), ethyl-(N’,N’-dimethylamino)propylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and mixtures thereof, optionally in the presence of a base to form a compound of formula (VI) wherein R 1 is a halide, an optionally halogenated C1-C6-carboxylic acid, a carbodiimide, a hydroxytriazole; and b) reacting the compound of formula (VI) with methylamine or a salt thereof in the presence of a solvent and optionally in the presence of a base.

21. The method according to claim 20, wherein The solvent is selected from the group consisting of: cyclic and acyclic aliphatic carbohydrates, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, aliphatic ethers and cyclic ethers, aliphatics, nitriles, ketones, C1-C6 alcohols, n-alkylpyrrolidone, dimethylformamide, pyridine, dimethyl sulfoxide, 1,2-dimethoxyethane, ethylene glycol, water and mixtures thereof.

22. The method according to claim 20, wherein, The base is selected from the group consisting of: triethylamine, pyridine, 2-methylpyridine, 4-methylmorpholine, dimethylaminopyridine, N,N-diisopropylethylamine, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, ammonium hydroxide and mixtures thereof.

23. A process for preparing a compound of formula (VIII) and salts thereof using a compound of formula (I).

24. A process for preparing a compound of formula (VIII) and salts thereof using a compound of formula (II) prepared according to claims 6-8.

25. A process for preparing a compound of formula (VIII) and salts thereof using a compound of formula (IV) prepared according to claims 4-5.

26. A process for preparing a compound of formula (VIII) and salts thereof using a compound of formula (V) prepared according to any one of claims 9-10.

27. A process for preparing a compound of formula (VIII) and salts thereof using a compound of formula (VII) prepared according to any one of claims 11-13, or 14-19 or 20-22.

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