Process for preparing substituted benzamides

Abstract

The present invention relates innovative process conditions for the preparation of formula (I) and, in particular, N-(diphenylmethylene)-2-(3-chloro-5-triflnoromethyl-2-pyridvl) glycinate via the contact of benzophenone glycine imine ethyl ester and substituted halo pyridine in the presence of novel solvent system and base. In addition, the present invention provides one-pot reaction for preparation of pyridylbenzamides using preparative method for compound of formula (I).

Description

[0001] Title: PROCESS FOR PREPARING SUBSTITUTED BENZAMIDES

[0002] FIELD OF INVENTION:

[0003] The present invention refers to improved reaction for the synthesis of key intermediate of formula (I) for manufacturing of pyridylmethylbenzamides, and to one-pot reaction of preparing of pyridylbenzamides, in particular, of fluopicolide.

[0004] BACKGROUND:

[0005] Substituted pyridylmethylbenzamide derivatives of formula (VI) wherein

[0006] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0007] Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 q is 0-5 are well known for their activity against phytopathogenic fungi and are extensively used in the agriculture industry as pesticide. Bayer Ltd were the first to describe fluopicolide, (2,6-Dichloro- N-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]methyl}benzamide), and its family of compounds of formula (V) in EP1056723. In this patent, compounds, and the synthesis via substituted 2- (aminomethyl)pyridine substances, a key intermediate in the synthesis, were disclosed. WO 1999 / 042447 and WO 2004 / 065359, display a process for the preparation of 2- aminomethylpyridine via benzophenone imine derivatives. However, this method has low economic efficiency, low yields, and high cost. In particular, the preparation of ethyl N- (diphenylmethylene)-2-(3-chloro-5-triflnoromethyl-2-pyridyl)glycinate substance required the use of high volume of propionitrile which is costly, toxic and highly flammable. In this specific process the use of polluting tetrabutylammonium bromide (TBAB) is also required.

[0008] Other processes as describe in patents WO 2002 / 016322, and WO 2004 / 046114 display the preparation of substituted 2-(aminomethyl)pyridine derivatives by hydrogenation of the corresponding substituted 2-cyanopyridine substance in the presence of metal catalyst. However, this method results in low yield of the hydrogenation step, the formation of dehalogenated side products and the formation of secondary and tertiary amines that contaminate the desired primary desired amine. In addition, this method is costly, inefficient, and occasionally leads to metal contamination in the final product.

[0009] In view of the above, there is a need for new improved preparative methods for these compounds, and specifically for N-(diphenylmethylene)-2-(3-chloro-5-triflnoromethyl-2- pyridyl )glycinate.

[0010] Summary

[0011] The present invention is directed to a process for preparing a compound of formula (I) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0012] Z is halogen, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of a compound of formula (II) or its salts thereof wherein

[0013] Z is halogen, substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; with compound of formula (III) or its salts thereof wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0014] U is Cl, Br, F, I; p is 0-4 in the presence of: a) at least one solvent (a) selected from the group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and halogenated acyclic hydrocarbons, aromatic hydrocarbons and halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and the mixtures thereof, b) at least one polar aprotic solvent (b) selected from the group comprising N-methyl-2- pyrrolidinone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetra hydrofuran, acetone, ehtylacetate, dichloromethane and the mixtures thereof, c) at least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium C1-C4 alkoxide, potassium C1-C4 alkoxide, and the mixtures thereof; and d) optionally a catalyst (d) selected from the group comprising 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and the mixtures thereof.

[0015] Another aspect of the present invention is related to the method of preparing compound of formula (VI) wherein

[0016] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0017] Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 q is 0-5 using a compound of formula (I) prepared by reaction of a compound of formula (II) or its salts thereof wherein

[0018] Z is halogen, substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; with compound of formula (III) or its salts thereof (X)p ci

[0019] N^U (HI) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0020] U is Cl, Br, F, I; p is 0-4 in the presence of: a) at least one solvent (a) selected from the group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and halogenated acyclic hydrocarbons, aromatic hydrocarbons and halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and the mixtures thereof, b) at least one polar aprotic solvent (b) selected from the group comprising N-methyl-2- pyrrolidinone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetra hydrofuran, acetone, ehtylacetate, dichloromethane and the mixtures thereof; and c) at least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium C1-C4 alkoxide, potassium C1-C4 alkoxide, and the mixtures thereof; and d) optionally a catalyst (d) selected from the group comprising 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and the mixtures thereof.

[0021] DESCRIPTION OF THE INVENTION:

[0022] Definitions: 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.

[0023] 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".

[0024] 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.

[0025] 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. For purposes of better understanding the present teachings and in no way limiting the scope of the teachings, unless otherwise indicated, all numbers expressing quantities, percentages, or proportions, and other numerical values used in the specification and claims, are to be understood as being modified in all instances by the term "about."

[0026] 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 the term "about" 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.

[0027] The term "carbonyl" as used herein refers to the group -C=O The term "alkoxy," as used herein, refers to optionally substituted alkyl group attached to the parent molecular moiety through an oxygen atom.

[0028] The term "aryloxy" refers to optionally substituted aryl group attached to the parent molecular moiety through an oxygen atom.

[0029] The term "alkoxycarbonyl," as used herein, refers to optionally substituted alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0030] The term "benzyloxy", as used herein, refers to a benzyl group C6H5CH2- attached to the parent molecular moiety through an oxygen atom.

[0031] The term "alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to six carbon atoms.

[0032] The term "one-pot" reaction as used herein, refers to the possibility to perform a multiplechemical 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.

[0033] 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.

[0034] The term "salts", as used herein, refers to organic salts such as chloride, bromide, fluoride, iodide, acetate, hydrogen sulfates, phosphates, formats, nitrate, carbonate etc., or, if applicable, alkaline metal salts such as sodium, potassium, calcium, lithium, cesium, magnesium, barium and the like.

[0035] As used herein, the verb "comprise" as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. As used herein the term "granules" broadly refers to grains, particles, pellets or crumbs.

[0036] The present invention relates to the process of preparation of a compound of formula (I) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is halogen, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of a compound of formula (II) or its salts thereof wherein

[0037] Z is halogen, substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; with compound of formula (III) or its salts thereof wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0038] U is Cl, Br, F, I; p is 0-4 in the presence of: a) at least one solvent (a) selected from the group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and halogenated acyclic hydrocarbons, aromatic hydrocarbons and halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and the mixtures thereof, b) at least one polar aprotic solvent (b) selected from the group comprising N-methyl-2- pyrrolidinone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetra hydrofuran, acetone, ehtylacetate, dichloromethane and the mixtures thereof; and c) at least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium C1-C4 alkoxide, potassium C1-C4 alkoxide, and the mixtures thereof; and d) optionally a catalyst (d) selected from the group comprising 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and the mixtures thereof.

[0039] Compounds covered by formula (II) are known and can be prepared for example according to the procedures disclosed in WO 2004 / 065359.

[0040] Compounds covered by formula (III) are known and can be purchase from multiple chemical suppliers.

[0041] The present invention also, relates to the process of preparation of a compound of formula (I) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0042] Z is halogen, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of a compound of formula (II) or its salts thereof wherein Z is halogen, substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; with compound of formula (III) or its salts thereof wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; U is Cl, Br, F, I; p is 0-4 in the presence of the solvent system comprising: a) at least one solvent (a) selected from the group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and halogenated acyclic hydrocarbons, aromatic hydrocarbons and halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and the mixtures thereof, b) at least one polar aprotic solvent (b) selected from the group comprising N-methyl-2- pyrrolidinone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetra hydrofuran, acetone, ehtylacetate, dichloromethane and the mixtures thereof; and c) at least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium C1-C4 alkoxide, potassium C1-C4 alkoxide, and the mixtures thereof; and d) a catalyst (d) selected from the group comprising 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p- chloroaniline, and the mixtures thereof.

[0043] According to an embodiment, the molar ratio between compound (II) to compound (III) is from 1:5 to 5:1.

[0044] According to an embodiment, the molar ratio between compound (II) to compound (III) is from 1:2 to 2:1.

[0045] According to an embodiment, the molar ratio between compound (II) to compound (III) is from 1:1.1 to 1:1.

[0046] According to an embodiment the solvent (a) is selected from the group comprising aliphatic hydrocarbons (acyclic and cyclic), selected from octane, heptane, hexane, pentane, cyclooctane, cyclopentane, petroleum ether, cyclohexane, cyclopentane, and chlorinated hydrocarbons selected from, carbon tetrachloride, chloroform, 1,2-dichloroethane, methylene chloride and aromatic hydrocarbons selected from toluene, benzene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, and ethers (acyclic and cyclic) selected from diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), tetra hydrofuran (THF), methyl-tetrahydrofuran (Me-THF), cyclopentylmethyl ether, methyl-tert- butyl ether, and aliphatic and aromatic esters selected from ethyl acetate, propyl acetate, butyl acetate, and ketones selected from acetone, 2-butanone, cyclohexanone, and alcohols selected from methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol t-butyl alcohol, diethylene glycol, glycerin, ethylene glycol, and the mixture

[0047] According to an embodiment the solvent (b) is selected from the group comprising N-methyl-2- pyrrolidinone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetra hydrofuran, acetone, ethyl acetate, dichloromethane, and the mixtures thereof. According to an embodiment the solvent (a) is selected from the group comprising aromatic hydrocarbons solvents and halogenated aromatic hydrocarbons solvents selected from toluene, benzene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene and the mixtures thereof.

[0048] According to an embodiment the solvent (b) is selected from the group comprising dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methyl pyrrolidone and the mixtures thereof.

[0049] According to an embodiment the solvent (a) is toluene.

[0050] According to an embodiment the solvent (a) is xylene.

[0051] According to an embodiment the solvent (a) monochlorobenzene.

[0052] According to an embodiment the solvent (b) is dimethylacetamide.

[0053] According to an embodiment the solvent (b) is dimethylformamide.

[0054] According to an embodiment the solvent (b) is N-methyl pyrrolidone.

[0055] According to an embodiment the solvent (b) is dimethylsulfoxide.

[0056] According to an embodiment, the weight ratio between the solvent (a) and the solvent (b) is from 100:1 to 1:100.

[0057] According to an embodiment, the weight ratio between the solvent (a) and the solvent (b) is from 50:1 to 1:1.

[0058] According to an embodiment, the weight ratio between the solvent (a) and the solvent (b) is from 50:1 to 30:1.

[0059] According to an embodiment, the weight ratio between the solvent (a) and the solvent (b) is 40:1 w / w.

[0060] According to an embodiment, the weight ratio between compound (I) and the solvent system is from 1:10 to 1:0.5. According to an embodiment, the weight ratio between compound (I) and the solvent system is from 1:5 to 1:1.

[0061] According to an embodiment, the weight ratio between compound (I) and the solvent system is from 1:3 to 1:2.

[0062] According to an embodiment the base (c) is selected from the group comprising aluminum hydroxide, calcium hydroxide, calcium hydroxide, iron(ll) hydroxide, lithium hydroxide, potassium hydroxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, butyl lithium, sodium hydride, potassium hydride, sodium methoxide, potassium hydroxide, potassium tert- butoxide and the mixtures thereof.

[0063] According to an embodiment the base (c) is selected from the group comprising potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the mixtures thereof.

[0064] According to an embodiment the base (c) is potassium carbonate.

[0065] According to an embodiment the base (c) is potassium hydroxide.

[0066] According to an embodiment the base (c) is sodium carbonate.

[0067] According to an embodiment the base (c) is sodium bicarbonate.

[0068] According to an embodiment the base (c) is sodium hydroxide.

[0069] According to an embodiment the base (c) is optionally in the form of granules, flakes, powder, and the mixtures thereof.

[0070] According to an embodiment the base (c) is in the form of powder.

[0071] According to an embodiment, the weight ratio between compound (I) and the base is from 1:5 to 1:1.

[0072] According to an embodiment, the weight ratio between compound (I) and the base is from 1:3 to 1:1. According to an embodiment, the weight ratio between compound (I) and the base is from 1:2 to 1:1.

[0073] According to an embodiment the catalyst (d) is selected from the group comprising trimethylamine, tributylamine, diisopropylamine, 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.

[0074] According to an embodiment the catalyst (d) is selected from the group comprising trimethylamine, tributylamine, diisopropylamine, tetramethylethylendiamine, pyridine, 4- dimethylaminopyridine and the mixtures thereof.

[0075] According to an embodiment the catalyst (d) is 4-dimethylaminopyridine.

[0076] According to an embodiment the catalyst (d) is proline or L-proline.

[0077] According to an embodiment the catalyst is (d) morpholine.

[0078] According to an embodiment the catalyst is (d) piperidine.

[0079] According to an embodiment, the weight ratio between compound (I) and the catalyst is from 1:0.01 to 1:0.2.

[0080] According to an embodiment, the weight ratio between compound (I) and the catalyst is from 1:0.02 to 1:0.1.

[0081] According to an embodiment, the weight ratio between compound (I) and the catalyst is from 1:0.04 to 1:0.06.

[0082] According to an embodiment, the molar ratio between the base (c) and the catalyst (d) is from 100:1 to 1:100.

[0083] According to an embodiment, the molar ratio between the base (c) and the catalyst (d) is from 50:1 to 1:1. According to an embodiment, the molar ratio between the base (c) and the catalyst (d) is from 25:1 to 10:1.

[0084] According to an embodiment, the weight ratio between the base (c) and the catalyst (d) is 20:1.

[0085] According to an embodiment, compound (II) is contacted with compound (III) at the temperature interval from 10 to 130°C.

[0086] According to an embodiment, compound (II) is contacted with compound (III) at the temperature interval from 60 to 130°C.

[0087] According to an embodiment, compound (II) is contacted with compound (III) at the temperature interval from 100 to 120°C.

[0088] According to an embodiment the reaction mixture is monitored by HPLC analytical method, and the process ends when the concentration of formula (II) is between 0-99%, preferably from 0- 50%, most preferably, in particular, when no more than 1% of compound of formula (II) remains in the reaction media.

[0089] Finally, the reaction mixture containing the resulting a compound of formula (I) 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.

[0090] According to an embodiment the next step in the process can be performed as separate processes wherein the compound (I) is isolated and purified or as combined process, such as one- pot reaction, telescopic-reaction wherein the compound (I) is not separated from the process mixture.

[0091] According to an embodiment the next step in the process is performed as one-pot reaction.

[0092] According to an embodiment, the reaction can be performed in the presence of a phase transfer catalyst selected from the group comprises of pyridinium hydrochloride, pyridinium acetate, pyridinium triflate, pyridinium hydrobromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, tetraethylammonium bromide, tetraethylammonium chloride, tetraethylammonium hydrogen sulfate, tetraethylammonium iodide, tetramethylammonium bromide, tetramethylammonium chloride, tetramethylammonium hydrogen sulfate, tetramethylammonium iodide, tetrapropylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium hydrogen sulfate, tetrapropylammonium iodide, tetraoctylammonium bromide, tetraoctylammonium chloride, tetraoctylammonium hydrogen sulfate, tetraoctylammonium iodide, crown ethers, polyethylene glycol, and the mixtures thereof, preferably, tetrabutylammonium bromide and the mixtures thereof.

[0093] According to an embodiment, a molar ratio between compound (I) to the phase transfer catalyst is from 1:1 to 1:0.0001, preferably from 1:0.01 to 1:0.1, most preferably from 1:0.05 to 1:0.01.

[0094] According to another embodiment, the compound of formula (VI), wherein

[0095] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0096] Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 q is 0-5 is prepared by a process comprising step a) preparation of compound (I) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0097] Z is halogen, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 prepared by reaction of a compound of formula (II) or its salts thereof wherein

[0098] Z is halogen, substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3; with compound of formula (III) or its salts thereof wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0099] U is Cl, Br, F, I; p is 0-4 in the presence of: a) at least one solvent (a) selected from the group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and halogenated acyclic hydrocarbons, aromatic hydrocarbons and halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and the mixtures thereof, b) at least one polar aprotic solvent (b) selected from the group comprising N-methyl-2- pyrrolidinone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetra hydrofuran, acetone, ehtylacetate, dichloromethane and the mixtures thereof; and c) at least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium C1-C4 alkoxide, potassium C1-C4 alkoxide, and the mixtures thereof; and d) optionally a catalyst (d) selected from the group comprising 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and the mixtures thereof. step b) preparation of compound (IV) wherein

[0100] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 by mixing compound (I) in the presence of an acid and optionally organic solvent, and step c) contacting compound (IV) or its salt thereof with compound (V) wherein q is an integer equal to 1, 2, 3 or 4,

[0101] Y is halogen and q is 0-5 L is a leaving group selected from C1-C6 alkoxy, OH, halogens, halide, OSfO^R; wherein R is -CH3, -C6H5-CH3; in the presence of organic solvent and optionally in the presence of a base.

[0102] Compounds covered by formula (V) are known and can be purchase from multiple chemical suppliers.

[0103] According to an embodiment the acid in step b) is selected from the group comprises sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydrochloric acid, hydrobromic acid, nitric acid, and the mixture thereof, preferably, hydrochloric acid.

[0104] According to an embodiment, the molar ratio between compound (I) to the acid in step b) is from about 1:10 to 1:0.5, preferably, from about 1:2 to 1:4.

[0105] According to an embodiment the organic solvent in step b) is selected from the group comprises water, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, dimethylformamide, 1,4-dioxane, ethyl acetate, acetonitrile, tetrahydrofuran, acetic acid, toluene, benzene, hexane, cyclohexane, dimethylsulfoxide, pyridine, piperidine, morpholine, diethyl ether, chloroform, 1,2-dichloroethane, acetone, isopropyl acetate, anisole, A / -methyl-2- pyrrolidone, 4-methylmorpholine, nitromethane and the mixtures thereof, preferably, toluene.

[0106] According to an embodiment, the weight ratio in step b) between compound (I) to the organic solvent can be from about 1:10 to 10:1, preferably from 1:1 to 1:5, most preferably from about 1:2 to 1:4.

[0107] According to an embodiment, in step b), compound (IV) is produced by mixing the compound of formula (I), acid, and organic solvent, and heating the resulting mixture to temperature of from 20 to 130°C, preferably from 50 to 100°C, most preferably from 60 to 70°C.

[0108] According to an embodiment the reaction mixture in step b) is allowed to stir between 10 minutes to 5 hours according to the reaction progress, preferably from 0.5 to 3 hours, most preferably from 1 to 2 hours. According to an embodiment the reaction mixture in step b) is monitored by HPLC analytical method, and the reaction ends when concentration of formula (I) is 0-99%, preferably 0-50%, in particular, when no more than 2.5% of compound of formula (I) remains in the reaction media.

[0109] Finally, according to an embodiment, the reaction mixture in step b) containing the resulting a compound of formula (IV) is worked up. This stage may include, cooling, adding water, adding organic solvent, stirring, heating, phases separation, distillation, precipitation, recrystallization, concentration, filtration, washing, purification, pH adjustment, extraction, and drying processes.

[0110] According to an embodiment, the molar ratio between compound (IV) to compound (V) in step c) is from 1:5 to 5:1.

[0111] According to an embodiment, the molar ratio between compound (IV) to compound (V) in step c) is from 1:2 to 2:1.

[0112] According to an embodiment, the molar ratio between compound (IV) to compound (V) in step c) is from 1:1.1 to 1:1.

[0113] According to an embodiment, the base in step c) is selected from the group comprises alkali and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates and organic primary, secondary and tertiary amines, such as triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, aniline, chloroaniline and the mixture thereof, preferably sodium hydroxide.

[0114] According to an embodiment, the molar ratio between compound (IV) to the base in step c) is from about 1:10 to 1:0.5, preferably 1:1 to 1:5, most preferably from about 1:2 to 1:3.

[0115] According to an embodiment, the organic solvent in step c) is selected from the group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, ethers, aliphatic and aromatic esters, nitriles, ketones, C1-C4 alcohols, n-alkyls protic and aprotic polar solvents such as, dichloromethane, chloroform, pyridine, tetrahydrofuran, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, pyrrolidones, dimethylformamide, dimethylacetamide, dimethylsulfoxide, water and the mixtures thereof, preferably toluene.

[0116] According to an embodiment, weight ratio between compound (IV) to the solvent in step c) is from about 1:1 to 1:20, preferably 1:1 to 1:5, most preferably from about 1:2 to 1:3.

[0117] According to an embodiment, the base in step c) can be added as solid or as an aqueous solution of between 1% to 60% w / w, preferably as aqueous solution of about 2 to 20% w / w, most preferably 5 to 10% w / w.

[0118] According to an embodiment, weight ratio between compound (IV) to aqueous base solution in step c) can be from about 1:001 to 1:1, preferably from about 1:0.01 to 1:0.5, most preferably from about 1:0.05 to 1:0.15.

[0119] According to an embodiment, the compound of formula (IV) preferably contacted with the compound of formula (V) in step c), at raised temperature. A preferred temperature interval is from 0 to 130°C, preferably from 0 to 50°C, most preferably from 10 to 20°C.

[0120] According to an embodiment the reaction mixture in step c) is allowed to stir for 1 minute to 10 hours after completion of the addition, preferably for 10 minutes to 5 hours, most preferably for 1 to 2 hours.

[0121] According to an embodiment the reaction temperature interval of the stirring phase in step c) is from 0 to 130°C, preferably from 10 to 50°C, most preferably from 20 to 30°C.

[0122] According to an embodiment the reaction mixture in step c) is monitored by HPLC analytical method and ends when concentration of formula (IV) is between 0-99%, preferably from 0-50%, in particular, when no more than 0.5% of compound of formula (IV) remains in the reaction media.

[0123] Finally, according to an embodiment, the reaction mixture in step c) containing the resulting a compound of formula (VI) 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. 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.

[0124] EXAMPLES:

[0125] Example 1: Preparation of ethyl 2-((diphenylmethylene)amino)acetate (compound II) from glycine ethyl ester hydrochloride and Benzophenone:

[0126] To a 2L reactor equipped with dean-stark condenser, toluene (400 mL), glycine ethyl ester hydrochloride (100 gr), benzophenone (264.24 mL), were charged at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 1 hour under azeotropic reflux. N,N- Diisopropylethylamine (DIPEA) (102.37 gr) was dissolved in toluene (lOOmL) and the solution was added dropwise through 2 hours under azeotropic reflux at 125°C and water extraction. Mixture was allowed to swirl for additional 3 hours and the reaction progress was monitored by HPLC and ended when glycine ethyl ester hydrochloride was less than 0.5% in the reaction mixture. The mixture was cooled to 25°C and water (300 mL) was added. Mixture was stirred, settled and organic layer was separated. The organic toluene layer (810gr, 20%) with the desired ethyl 2-

[0127] ((diphenylmethylene)amino)acetate (85% yield) was transfer to the next step without further action.

[0128] Example 2: Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro-5-triflnoromethyl-2- pyridyl)glycinate (compound I) from ethyl 2-((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0129] To a IL reactor equipped with dean-stark condenser, toluene solution (783gr,) of ethyl 2- ((diphenylmethylene)amino)acetate (20%, 162 gr), dimethylacetamide (DMAc) (12.5 mL), potassium carbonate (100 gr), dimethylaminopyridine (DMAP) (4.34 gr) and 2,3-dichloro-5- (trifluoromethyl)pyridine (127.3 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 16 hours under azeotropic reflux. Water was extracted and the reaction progress was monitored by HPLC and ended when compound (III) was less than 0.2% in the reaction mixture. The mixture was cooled to 25°C and water (200 mL) was added. Mixture was stirred, settled and the organic layer was separated. The organic toluene layer (883 gr,26.8%) with the desired product (236.64 gr, 91.4% yield) was transfer to the next step without further action.

[0130] Example 3: Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro-5- triflnoromethyl-2-pyridyl) glycinate (compound I) from ethyl 2-((diphenylmethylene)amino)acetate (compound II) and 2,3- dichloro-5-(trifluoromethyl)pyridine (compound III):

[0131] To a 5L reactor equipped with dean-stark condenser, toluene solution (1410 mL) of ethyl 2- ((diphenylmethylene)amino)acetate (18.3%, 315.84 gr), dimethylacetamide (DMAc) (25.0 mL), potassium carbonate (200 gr), dimethylaminopyridine (DMAP) (8.85 gr, 0.06 eq) and 2,3-dichloro-5- (trifluoromethyl)pyridine (258 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 16 hours. Water was extracted and the reaction progress was monitored by HPLC and ended when compound (III) was less than 0.2% in the reaction mixture. The mixture was cooled to 25°C and water (1000 mL) was added. Mixture was stirred, settled and organic layer was separated. The organic toluene layer (1590 gr) with the desired product (478.6 gr, 90.76% yield) was transfer to the next step without further action.

[0132] Example 4: Preparation of (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methanamine (compound IV) from ethyl N-(diphenylmethylene)-2-(3-chloro-5- triflnoromethyl-2-pyridyl)glycinate (compound I):

[0133] To a IL reactor equipped with dean-stark condenser, toluene layer with ethyl N-(diphenylmethylene)- 2-(3-chloro-5- triflnoromethyl-2-pyridyl)glycinate (compound I) from the previous step (883 gr) was charged. To this mixture Con. HCI (250 ml, 2.5 Vol) was charged at 25°C and the mixture was stirred for 5 minutes. The reaction was then heated to 85°C for 4 hours. The reaction progress was monitored by HPLC and ended when compound (I) was less than 0.5% in the reaction mixture. The mixture was then heated to azeotropic reflux at 110°C under azeotropic reflux and water was extracted. The mixture was cooled to 65°C and methanol (50mL) was added. The mixture was stirred for 30 minutes at 65°C, and then at 25°C for another 30 minutes. Th solid precipitant was filtered and washed with 20% methanol in toluene (200mL). The solid was dried under vacuum at 65°C to obtain the desire product (112.5 gr, 62% yield from Glycine ethyl ester hydrochloride) at 99% purity. Example 5: Preparation of 2,6-dichloro-N-((3-chloro-5-(trifluoromethyl)pyridin-2- yl)methyl)benzamide (compound V) by 2,6-dichlorobenzoyl chloride (compound VI) and (3-chloro- 5(trifluoromethyl)pyridin-2-yl)methanamine (compound IV)

[0134] To a IL reactor, water (400 mL) and sodium hydroxide (34.7 gr) were charged, the resulting mixture was cooled to 15°C and 3-chloro-5-(trifluoromethyl)pyridine-2-yl)methanamine hydrogen chloride salt (1033.95 gr) was charged. Then, 2,6-dichlorobenzoyl chloride (91.31 gr) was charged dropwise, maintaining the temperature between 15°C to 20°C. Mixture was allowed to stir at 25°C for 2 hours. The reaction progress was monitored by HPLC and ended when compound (VI) was less than 0.5% in the reaction mixture. Precipitant was filtered, washed with water (200 mL) and dried under vacuum. Solid was dissolved in toluene (200 mL) and washed with water (200 mL) at 25°C. Mixture was heated to 90°C for 30 minutes and cooled to 5°C for 1 hour. Solid was precipitated and filtered. The solid was washed with toluene (50 mL) at 5°C and dried under vacuum to give the desire product (143.6 gr, 92% yield).

[0135] Comparative examples:

[0136] Example 6 (with DMSO and DMAP O.leq): Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro- 5- triflnoromethyl-2-pyridvl)glycinate (compound I) from ethyl 2- ((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0137] To a 2L reactor equipped with dean-stark condenser, toluene solution (498 mL) of ethyl 2- ((diphenylmethylene)amino)acetate (21.3%, 106 gr), dimethylsulfoxide (DMSO) (70 mL), potassium carbonate (70.7 gr), dimethylaminopyridine (DMAP) (6.1 gr) and 2,3-dichloro-5- (trifluoromethyl)pyridine (87.5 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 6 hours. Water was extracted and the reaction progress was monitored by HPLC and ended when compound (III) was less than 0.2% in the reaction mixture. The mixture was cooled to 25°C and water (350 mL) was added. Mixture was stirred, settled and the organic layer was separated. The organic toluene layer (593 gr) with the desired product (148.8 gr, 85.32% yield) was transfer to the next step without further action. Example 7 (with DMSO and DMAP 0.05eq): Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro- 5- triflnoromethyl-2-pyridyl)glycinate (compound I) from ethyl 2- ((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0138] To a 2L reactor equipped with dean-stark condenser, toluene solution (542 mL) of ethyl 2- ((diphenylmethylene)amino)acetate (19.8%, 104.3gr), dimethylsulfoxide (DMSO) (70 mL), potassium carbonate (70.7 gr), dimethylaminopyridine (DMAP) (3.0 gr) and 2,3-dichloro-5- (trifluoromethyl)pyridine (87.5 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 12 hours. Water was extracted and the reaction progress was monitored by HPLC and ended when compound (III) was less than 0.2% in the reaction mixture. The mixture was cooled to 25°C and water (350 mL) was added. Mixture was stirred, settled and organic layer was separated. The organic toluene layer (653.6 gr) with the desired product (157.5 gr, 87.44% yield) was transfer to the next step without further action.

[0139] Example 8 (without DMAP): Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro-5- triflnoromethyl-2-pyridyl)glycinate (compound I) from ethyl 2-((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0140] To a 2L reactor equipped with dean-stark condenser, toluene solution (462.8 mL) of ethyl 2- ((diphenylmethylene)amino)acetate (22.0%, 101.8 gr), dimethylsulfoxide (DMSO) (70 mL), potassium carbonate (70.7 gr), and 2,3-dichloro-5-(trifluoromethyl)pyridine (87.5 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 24 hours. Water was extracted and the reaction progress was monitored by HPLC and ended when compound (III) was less than 0.2% in the reaction mixture. The mixture was cooled to 25°C and water (350 mL) was added. Mixture was stirred, settled and organic layer was separated. The organic toluene layer (655.8 gr) with the desired product (148.2 gr, 84.40% yield) was transfer to the next step without further action. Example 9 (without DMAP and DMAc): Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro-5- triflnoromethyl-2-pyridyl)glycinate (compound I) from ethyl 2-((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0141] To a 500mL reactor equipped with dean-stark condenser, 2-((diphenylmethylene)amino)acetate (25 gr), toluene (125 mL), potassium carbonate (26.37 gr), and 2,3-dichloro-5-(trifluoromethyl)pyridine (20.40 gr) were charged at 25°C and stirred for 5 minutes. Water was extracted and the reaction was then heated to azeotropic reflux at 125°C for 12 hours. Reaction conditions led to poor yield of only 0.25% desired product.

[0142] Example 10 (with MCB): Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro-5- triflnoromethyl- 2-pyridyl)glycinate (compound I) from ethyl 2-((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0143] To a IL reactor equipped with dean-stark condenser, monochlorobenzene (MCB) solution (397 mL) of ethyl 2-((diphenylmethylene)amino)acetate (14.3%, 56.7 gr), potassium carbonate (50.51 gr), dimethylaminopyridine (DMAP) (1.14 gr) and 2,3-dichloro-5-(trifluoromethyl)pyridine (78.15 gr) were charged at 25°C and stirred for 5 minutes. Water was extraxted and the reaction was then heated to azeotropic reflux at 135°C for 12 hours. The reaction progress was monitored by HPLC. Reaction conditions led to poor yield of only 18.98% desired product.

[0144] Example 11 (with MCB and DMSO): Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro-5- triflnoromethyl-2-pyridyl)glycinate (compound I) from ethyl 2-((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0145] To a IL reactor equipped with dean-stark condenser, monochlorobenzene (MCB) solution (397 mL) of ethyl 2-((diphenylmethylene)amino)acetate (14.3%, 56.7 gr), dimethylsulfoxide (DMSO) (25 mL), potassium carbonate (50.51 gr), dimethylaminopyridine (DMAP) (1.14 gr), and 2,3-dichloro-5- (trifluoromethyl)pyridine (78.15 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 135°C for 6 hours. Water was extracted and the reaction progress was monitored by HPLC. The mixture was cooled to 25°C and water (250 mL) was added. Mixture was stirred, settled and organic layer was separated. The organic toluene layer (571 gr) with the desired product (102.78 gr, 78.92% yield) was transfer to the next step without further action.

[0146] Example 12 (with NaOH and toluene): Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro-5- triflnoromethyl-2-pyridyl)glycinate (compound I) from ethyl 2-((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0147] To a 500 mL reactor equipped with dean-stark condenser, toluene (125 mL), ethyl 2- ((diphenylmethylene)amino)acetate (25 gr), sodium hydroxide (4.06 gr), and 2,3-dichloro-5- (trifluoromethyl)pyridine (20.40 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 6 hours. Water was extracted and the reaction progress was monitored by HPLC. Reaction conditions led to poor yield of only 27.0% desired product.

[0148] Example 13 (with NaOH and DMF): Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro-5- triflnoromethyl-2-pyridyl)glycinate (compound I) from ethyl 2-((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0149] To a 500 mL reactor, dimethylformamide (DMF) (150 mL), and ethyl 2- ((diphenylmethylene)amino)acetate (191.5 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then cooled to 2°C and sodium hydroxide (25.3 gr) was added. Reaction was stirred for 2 minutes and 2,3-dichloro-5-(trifluoromethyl)pyridine (131.55 gr) was charged and the mixture was heated to 10°C. Mixture was spontaneous heated to 17°C and stirred for 6 hours. The reaction progress was monitored by HPLC. Reaction conditions led to moderate yield of only 51.95% desired product.

[0150] Example 14 (with NaOH and NMP): Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro-5- triflnoromethyl-2-pyridyl)glycinate (compound I) from ethyl 2-((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0151] To a 250 mL reactor, N-methylpyrrolidone (NMP) (75 mL), and ethyl 2- ((diphenylmethylene)amino)acetate (96.0 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then cooled to 2°C and sodium hydroxide (12.65 gr) was added. Reaction was stirred for 2 minutes and 2,3-dichloro-5-(trifluoromethyl)pyridine (65.77 gr) was charged and the mixture was heated to 10°C. Mixture was then spontaneous heated to 17°C and stirred for 6 hours.The reaction progress was monitored by HPLC. Reaction conditions led to moderate yield of only 57.43% desired product.

[0152] Example 15 (with NaOH and DMSO): Preparation of ethyl N-(diphenylmethylene)-2-(3-chloro-5- triflnoromethyl-2-pyridyl)glycinate (compound I) from ethyl 2-((diphenylmethylene)amino)acetate (compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (compound III):

[0153] To a 250 mL reactor, dimethylsulfoxide (DMSO) (75 mL), and ethyl 2- ((diphenylmethylene)amino)acetate (96.0 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then cooled to 2°C and sodium hydroxide (12.65 gr) was added. Reaction was stirred for 2 minutes and 2,3-dichloro-5-(trifluoromethyl)pyridine (65.77 gr) was charged and the mixture was heated to 10°C. Mixture was then spontaneous heated to 17°C and stirred for 6 hours. The reaction progress was monitored by HPLC. Reaction conditions led to moderate yield of only 55.97% desired product.

Claims

CLAIMS:

1. A process for preparing of a compound of formula (I)wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is halogen, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of a compound of formula (II) or its salts thereofwhereinZ is halogen, substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; with compound of formula (III) or its salts thereofwherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;U is Cl, Br, F, I;in the presence of: a) at least one solvent (a) selected from the group comprising aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and halogenated acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and the mixtures thereof, and b) at least one polar aprotic solvent (b) selected from the group comprising N-methyl-2- pyrrolidinone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetra hydrofuran, acetone, ethyl acetate, dichloromethane and the mixtures thereof; and c) at least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium C1-C4 alkoxide, potassium C1-C4 alkoxide, and the mixtures thereof; and d) optionally a catalyst (d) selected from the group comprising 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and the mixtures thereof.

2. The process according to claim 1 wherein the solvent (a) is selected from the group comprising pentane, hexane, cyclohexane, benzene, toluene, chlorobenzene, dichlorobenzene, trichlorobenzene, dichloromethane, chloroform, tetrachloromethane, acetone, methyl ethyl ketone, cyclohexanone, methanol, ethanol, propanol, butanol, pentanol, hexanol, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane and the solvent (b) is selected from the group comprising N-methyl-2-pyrrolidinone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetra hydrofuran, acetone, ethyl acetate, dichloromethane and the mixtures thereof.

3. The process according to any of claims 1-2, wherein the ratio between the solvent (a) and the solvent (b) is from 100:1 to 1:100.

4. The process according to any of claims 1-3, wherein the weight ratio between compound (I) and the solvent system is from 10:1 to 1:0.5.

5. The process according to any of claims 1-4, wherein the base (c) is selected from the group comprising potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide and the mixtures thereof.

6. The process according to any of claims 1-5, wherein the weight ratio between compound (I) and the base (c) is from 1:5 to 1:1.

7. The process according to any of claims 1-6, wherein the catalyst (d) is selected from the group comprising 4-dimethylaminopyridine (DMAP), triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and the mixtures thereof.

8. The process according to any of claims 1-7, wherein the weight ratio between compound (I) and the catalyst (d) is from 1:0.01 to 1:0.2.

9. A process of preparing a compound of formula (VI)whereinX is halogen, C1-C4 alkyl or C1-C4 haloalkyl;Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 q is 0-5 using a compound of formula (I) prepared by the process according to any of claims 1-8.

10. The process of preparation of compound of formula (VI) according to claim 9, performed as a one-pot reaction.

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