WO2024013736A1

WO2024013736A1 - Process for preparing substituted benzamides

Info

Publication number: WO2024013736A1
Application number: PCT/IL2023/050715
Authority: WO
Inventors: Bhavinkumar HAMIRANI; Gandham MAHESH; Mannam Sreedevi; Bijukumar Gopinathan Pillai
Original assignee: Adama Makhteshim Ltd.
Priority date: 2022-07-12
Filing date: 2023-07-10
Publication date: 2024-01-18

Abstract

The present invention relates to new intermediates for the preparation of pyridylmethylbenzamides via substituted hydroxyiminopyridines or acetamidopyridines, and their innovative preparation processes. The invention discloses, in particular, the total synthesis of fluopicolide fungicide. The preparation of the main substances of the fluopicolide synthesis, specifically, substituted pyridine-2-ylmethanamine or its salt, is disclosed via two different synthesis routes, comprises two novel substances.

Description

Title: Process for preparing substituted benzamides

FIELD OF INVENTION:

The present invention refers to new key intermediates for the preparation of pyridylmethylbenzamides, and corresponded preparation processes thereof. In general, the invention directed to a novel approach for the preparation of pyridylmethylbenzamides, in particular, Fluopicolide.

BACKGROUND:

Background of invention

Substituted pyridylmethylbenzamide derivatives of formula (VIII)

wherein

X 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 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 (VIII) in EP1056723. In this patent, compounds, and the synthesis via substituted 2- (aminomethyl)pyridine derivatives, 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.

WO 2002/016322, and WO 2004/046114 display the preparation of substituted 2- (aminomethyl)pyridine derivatives by hydrogenation of the corresponding substituted 2- cyanopyridine derivatives 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 which contaminate the desired primary amine. In addition, this method is costly, inefficient, and occasionally leads to metal contamination in the final product. Preparative methods for these compounds must be improved for economic commercial operation. In view of that, the present invention makes available a convenient, cost-effective route, to prepare substituted 2-(aminomethyl)pyridine derivatives and its corresponded pyridylmethylbenzamides. Summary

The present invention is directed to a compound of formula (I),

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is optionally halogen substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 and more specifically to a compound of formula (la) also, related to the method of preparing of a compound of formula (I)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is optionally halogen substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, 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 X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is optionally halogen substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 with nitrite salt selected from the group comprising sodium nitrite, potassium nitrite, ammonium nitrite and the mixture thereof, in the presence of acid, optionally in the presence of a solvent, optionally in the presence of phase transfer catalyst.

Another aspect of the present invention is related to the method of preparing of a compound of formula (II) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

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

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 in the presence of an acid selected form the group consisting of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonic acid, para-toluene sulfonic acid, phosphoric acid. And/or a with an alkaline metal halides selected from a group comprising sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, lithium bromide, In addition, the present invention is related to the method of preparing of a compound of formula

(III) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of a compound of formula (IV)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 with a compound of formula A

₍A,

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; in the presence of a base and a phase transfer catalyst.

The present invention is also related to the method of preparing of a compound of formula (II) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is optionally halogen substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising heating of a compound of formula (III) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 at 60-180°C under pressure of 1-32 bars.

The present invention further provides a process of preparing of a compound of formula (V) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of compound of a formula (I)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 with hydrogen in the presence of metal catalyst, optionally in the presence of acid.

Another aspect of the present invention is related to the method of preparing a compound of formula (VI) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 comprising a) preparing a compound of formula (V) according to above methods and b) further reaction of resulting a compound of formula (V) with an acid, optionally in the presence of organic solvent.

The present invention, additionally provides a method of preparing of a compound of formula (VIII)

wherein

X 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 comprising reaction of a compound of formula (VI) prepared according to the above method with a compound of formula (VII)

wherein q is an integer equal to 1, 2, 3 or 4, Y is halogen and

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

The present invention is further related to the method of preparing of a compound of formula (VIII)

wherein

X 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 the compound of formula (I)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH₃, -CeHs-CHs; p is 0-4

Another aspect of the present invention is related to a compound of formula (XI),

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 and more specifically to a compound of formula (Xia),

The present invention further provides a method for preparing a compound of formula (XI),

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of a compound of formula (IX)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 with a compound of formula (X)

wherein Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; in the presence of organic solvent, optionally in the presence of base and optionally in the presence of phase transfer catalyst.

In addition, the present invention provides the method for the preparing a compound of formula (VI), or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 comprising preparing a compound of formula (XI) according to above method with an acid, optionally in the presence of organic solvent.

Another aspect of the present invention is related to the method of preparing a compound of formula (VIII)

wherein

X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

wherein q is an integer equal to 1, 2, 3 or 4,

Y is halogen and

L is a leaving group selected from C1-C6 alkoxy, OH, halogens, hydrogen, OSfO^R; wherein R is - CH₃, -C₆H₅-CH₃; q is 0-5

In the presence of organic solvent, optionally in the presence of base.

Specifically, the present invention is correlated to the method of preparing of a compound of formula (VIII)

wherein

X 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 the compound of formula (XI)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; wherein Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3; p is 0-4

Description of the invention:

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.

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".

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.

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."

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.

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.

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

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

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

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.

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. 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.

The term "E/Z isomer", as used herein, refers to chemical compound that have the same chemical formulas, yet are different from one another, geometrically.

The present invention relates to a new compound of general formula (I):

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3; p is 0-4

The compound of formula (I) according to the invention can exist in both E/Z form and in any mixture thereof.

In an embodiment, the present invention represents a new compound of formula (la):

The compound of formula (la) according to the invention can exist in both E/Z form and in any mixture thereof

In another embodiment, the present invention provides a method for preparing a compound of formula (I)

by reaction of a compound of formula (II) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3; p is 0-4 with nitrite salt, optionally in the presence of solvent, optionally in the presence of an acid, optionally in the presence of phase transfer catalyst.

According to an embodiment, nitrite salt can be selected from the group comprising sodium nitrite, potassium nitrite, calcium nitrite, lithium nitrite, ammonium nitrite and the mixture thereof, preferably sodium nitrite.

According to an embodiment, a molar ratio between compound (II) to nitrite salt can be from about 1:10 to 10:1, preferably from about 1:1 to 1:5, most preferably from 1:1 to 1:1.5.

According to an embodiment the organic solvent is selected from the group consisting of aliphatic hydrocarbons (acyclic and cyclic), such as octane, heptane, hexane, pentane, cyclooctane, cyclopentane, petroleum ether, cyclohexane, cyclopentane, chlorinated hydrocarbons such as, carbon tetrachloride, chloroform, 1,2-dichloroethane, methylene chloride, optionally substituted aromatic hydrocarbons such as toluene, benzene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, ethers (acyclic and cyclic) such as, diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), tetrahydrofuran (THF), methyltetrahydrofuran (Me-THF), cyclopentylmethyl ether, methyl-tert- butyl ether), aliphatic and aromatic esters, such as ethyl acetate , nitriles, such as acetonitrile, benzonitrile, ketones, such as acetone, 2-butanone , alcohols, such as methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol t-butyl alcohol, diethylene glycol, glycerin, ethylene glycol polar aprotic solvents like dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, water and the mixture thereof.

According to an embodiment, a molar ratio between compound (II) to organic solvent can be from about 1:20 to 10:1, preferably from 1:0.5 to 1:5, most preferably from about 1:3 to 1:5.

According to an embodiment the acid is selected from the group consisting of organic acid, Cl- C6 carboxylic acid, acetic acid, propionic acid, formic acid, benzoic acid, citric acid, glutamic acid, malonic acid, tartaric acid, phthalic acid, barbituric acid, cinnamic acid, glutaric acid, hexanoic acid, malic acid, folic acid, trifluoroacetic acid, ascorbic acid, glutamic acid, benzylic acid, lactic acid, para-toluene sulfonic acid, inorganic acid, such as sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydrochloric acid, hydrobromic acid, nitric acid, and the mixture thereof.

According to an embodiment, a molar ratio between compound (II) to acid 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.

According to an embodiment the phase transfer catalyst selected from the group consisting of ammonium salt or polyethers selected from the group consisting 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.

According to an embodiment, a molar ratio between compound (II) to phase transfer catalyst can be from about 1:1 to 1:0.0001, preferably from about 1:0.01 to 1:0.1, most preferably from about 1:0.05 to 1:0.01.

According to an embodiment, the compound of formula (II) contacted with the nitrite salt at the temperature interval of from 10 to 130°C. A preferred temperature interval is from 15 to 50°C., more preferably from 15 to 25°C.

According to an embodiment, the nitrite salt can be added to the mixture of compound (II), as a solid or as an aqueous solution. In case of that the nitrite salt is added as an aqueous solution to the compound (II) mixture, a weight ratio between the aqueous solution and the compound (II) mixture, can be of from 10:1 and 1:10 w/w, preferably from 0.5:1 to 2:1, most preferably a 1:1 w/w.

According to an embodiment the reaction mixture is allowed to stir between 1 minute to 10 hours according to the reaction progress, preferably from 1 to 2 hours. According to an embodiment the reaction temperature interval is from 0 to 130°C, preferably from 0 to 50°C, most preferably from 10 to 20°C.

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

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.

In another embodiment, the present invention provides a method of preparing a compound of formula (II) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 by two-step reaction, which can be performed as separated processes or as combined processes, such as one-pot reaction, telescopic-reaction, preferably, in one-pot reaction process. The intermediates formed in the above process can be isolated from the reaction mixture or the process can be continued without isolation of said intermediates.

According to the embodiment the first step provides the method of preparing a compound of formula (III), or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3;; p is 0-4 by reaction of a compound of formula (IV)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 with compound of formula A

O O

Z¹^^Z² (A)

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3;; in the presence of base, organic solvent, and phase transfer catalyst

According to an embodiment the compound (A) is selected from the group consisting of methyl malonate, ethyl malonate, propyl malonate, hexyl malonate, cyclohexyl malonate, benzyl malonate, chloromethyl malonate, chloroethyl malonate, chloropropyl malonate, chlorohexyl malonate, chlorocyclohexyl malonate, chlororbenzyl malonate, bromomethyl malonate, bromoethyl malonate, bromopropyl malonate, bromohexyl malonate, bromocyclohexyl malonate, bromorbenzyl malonate, malonic acid and the mixtures thereof, preferably, methyl malonate or ethyl malonate.

According to an embodiment, a molar ratio between compound (IV) to malonic acid or alkyl malonate can be from about 1:10 to 10:1, preferably from 2:1 to 1:2, most preferably from about 1:1 to 1:1.5

According to an embodiment the base is selected from the group consisting of 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, trimethylamine, tributylamine, diisopropylamine, tetrmethylethylendiamine, pyridine, dimethylbenzylamine, quinoline, aniline, imidazole, pyrrole, pyrrolidine, pyrimidine, piperidine, piperazine, morpholine, N-methyl morpholine, N-ethyl pyrrolidine, diisopropylmehtylamine, diisopropylethylamine, triallyl amine, diallyl amine, indole, butyl lithium, sodium hydride, potassium hydride, and the mixtures thereof, preferably, potassium bicarbonate.

According to an embodiment, the molar ratio between compound (IV) to the base can be from about 1:10 to 10:1, preferably from 2:1 to 1:5, most preferably from about 1:1 to 1:3.

According to an embodiment the organic solvent is selected from the group consisting of aliphatic hydrocarbons (acyclic and cyclic) such as, octane, heptane, hexane, pentane, cyclooctane, cyclopentane, petroleum ether, cyclohexane, cyclopentane, chlorinated hydrocarbons such as, carbon tetrachloride, chloroform, 1,2-dichloroethane, methylene chloride, aromatic hydrocarbons with or without substitution such as, toluene, benzene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene), all ethers (acyclic and cyclic) such as, diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), tetrahydrofuran (THF), methyl- tetrahydrofuran (Me-THF), cyclopentylmethyl ether, methyl-tert- butyl ether), all aliphatic and aromatic esters such as, ethyl acetate , nitriles such as, acetonitrile, benzonitrile, ketones such as, acetone, 2-butanone , alcohols such as, methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol t-butyl alcohol, diethylene glycol, glycerin, ethylene glycol, polar aprotic solvents like dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, water and the mixture thereof, preferably, a mixture of dimethyl sulfoxide and toluene.

According to an embodiment, a w/w ratio between compound (IV) to organic solvent can be from about 1:20 to 20:1, preferably from about 1:1 to 1:10, most preferably from about 1:3 to 1:5.

According to an embodiment, a molar ratio between compound (IV) to phase transfer catalyst can be from about 1:1 to 1:0.0001, preferably from about 1:0.1 to 1:0.001, most preferably from about 1:0.05 to 1:0.01

According to an embodiment, compound (III) is produced by mixing of a compound of formula (IV), malonic acid or malonate derivative, and base in organic solvent, and heating the mixture to temperature interval from 20 to 130°C, preferably from 50 to 110°C, most preferably from 80 to 100°C.

According to an embodiment the reaction mixture is allowed to stir between 1 to 10 hours according to the reaction progress, preferably from to 10 hours, most preferably from 5 to 7 hours.

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

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

According to the embodiment a second step, which is completed as in one-pot process, comprising the method of preparing a compound of formula (II) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

According to the embodiment a compound of formula (II) is prepared by the process provide the reaction of a compound of formula (III) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl,

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfOhR; wherein R is -CH3, -C6H5-CH3; p is 0-4 in the presence of an acid, and/or, with an alkaline metal halides

According to an embodiment the acid in the above process is selected from the group consisting of sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydrochloric acid, hydrobromic acid, nitric acid, and the mixture thereof, preferably, hydrochloric acid.

According to an embodiment, a w/w ratio between compound (III) to the acid can be from about 1:0.5 to 1:10, preferably from 1:0.5 to 1:5, most preferably from about 1:1 to 1:2

According to an embodiment the alkaline metal halides is selected from a group consisting of sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, lithium bromide, most preferably sodium chloride or potassium chloride According to an embodiment, a w/w ratio between compound (III) to the alkaline metal halides can be from about 1:0.1 to 1:10, preferably from 1:0.5 to 1:5, most preferably from about 1:1.5 to 1:2.5

According to an embodiment, compound (II) is produced by mixing of a compound of formula (III), and acid, and heating the mixture to temperature interval from 20 to 130°C, preferably from 100 to 130°C, most preferably from 120 to 130°C.

According to an embodiment the reaction mixture is allowed to stir between 1 to 10 hours according to the reaction progress, preferably from 5 to 10 hours, most preferably from 8 to 9 hours.

According to an embodiment the reaction mixture is monitored by HPLC analytical method and ends when concentration of formula (III) is between 0-99%, preferably from 0-50%, in particular, when no more than 2.5% of compound of formula (III) remains in the reaction media.

Finally, the reaction mixture containing the resulting a compound of formula (II) is worked up. This stage may include cooling, adding water, adding organic solvent, stirring, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, decantation, washing, purification, pH adjustment, extraction, and drying processes.

According to alternative embodiment of a method of preparing a compound of formula (II) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising heating of a compound of formula (III) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 at high temperature of between 60 to 200°C, preferably from 120 to 180°C, most preferably from 140 to 160°C, and under pressure of between 1 to 32 bars, preferably from 15-25 bars, most preferably from 19-23 bars.

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

In another embodiment, of this present invention, a method of preparing a compound of formula (VI), or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 via two steps reaction which can be performed as separate processes or as combine process, such as one-pot reaction, telescopic-reaction, preferably, in one-pot reaction process, is described.

According to the embodiment, the first step provides the method of preparing a compound of formula (V) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of a compound of formula (I)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 with hydrogen in the presence of metal catalyst, optionally in the presence of acid.

According to an embodiment, the metal catalyst is selected form the group comprising zinc, iridium, nickel, palladium, platinum, rhodium, or ruthenium, cobalt, tin, iron, Raney Ni, or metal salts selected form the group of iron chlorides, iron nitrates, nickel chlorides, nickel bromides, Grubs catalysts, and the mixtures thereof.

According to an embodiment, a w/w ratio between compound (I) to catalyst can be from about 1:1 to 1:0.0001, preferably from 1:0.005 to 1:0.5, most preferably from about 1:0.05 to 1:0.15

According to an embodiment, optionally in the presence of C1-C4 carboxylic acid selected form the group comprising acetic acid, propionic acid, butyric acid, lactic acid, formic acid, citric acid, oxalic acid, malic acid, tartaric acid, and a mixture thereof, preferably, acetic acid.

According to an embodiment, a w/w ratio between compound (I) to C1-C4 carboxylic acid can be from about 1:10 to 1:0.5, preferably from 1:10 to 1:1, most preferably from about 1:8 to 1:2

According to an embodiment, optionally in the presence of hydrogen gas at a pressure of between 4-20bar, preferably from 8 to 16 bar, most preferably from about 10-15 bar.

According to an embodiment, compound (V) is produced by mixing of a compound of formula (I), and optionally acid, and optionally hydrogen gas and at temperature interval of from 20 to 130°C, preferably from 50 to 100°C, most preferably from 70 to 80°C.

According to an embodiment, the reaction mixture is allowed to stir between 1 to 10 hours according to the reaction progress, preferably from 5 to 10 hours, most preferably from 5 to 8 hours.

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

Finally, the reaction mixture containing the resulting a compound of formula (V) 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.

According to the embodiment, the second step comprising the method of preparing a compound of formula (VI), or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 comprising reaction of a compound of formula (V)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3; p is 0-4 in the presence of an acid, optionally in the presence of organic solvent.

According to an embodiment the acid is selected from the group consisting of sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydrochloric acid, hydrobromic acid, nitric acid, and the mixture thereof, preferably, hydrochloric acid.

According to an embodiment, molar ratio between compound (V) to acid can be from about 1:10 to 1:0.5, preferably, from about 1:2 to 1:4.

According to an embodiment the organic solvent is selected from water, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, dimethylformamide, 1,4- dioxane, ethyl acetate, acetonitrile, tetrahydrofuran, acetic acid, toluene, benzene, hexane, cyclohexane, dimethyl sulfoxide, pyridine, diethyl ether, chloroform, 1,2-dichloroethane, acetone, isopropyl acetate, anisole, A/-methyl-2-pyrrolidone, 4-methylmorpholine, nitromethane and the mixtures thereof, preferably, toluene.

According to an embodiment, a w/w ratio between compound (V) to 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. According to an embodiment, compound (VI) is produced by mixing of a compound of formula (V), 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.

According to an embodiment the reaction mixture 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 is monitored by HPLC analytical method, and the reaction ends when concentration of formula (V) is 0-99%, preferably 0-50%, in particular, when no more than 2.5% of compound of formula (V) remains in the reaction media.

Finally, the reaction mixture containing the resulting a compound of formula (VI) 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.

According to another embodiment, the compound of formula (VIII), which is a well-known fungicide compound of the fluopicolide of formula:

wherein

X 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 is prepared by a process provides the steps of a) preparation of compound (VI) as described above via compound of formula (I), b) reaction of compound (VI) with compound of formula (VII) in the presence of organic solvent, optionally in the presence of base.

wherein q is an integer equal to 1, 2, 3 or 4,

Y is halogen and L is a leaving group selected from C1-C6 alkoxy, OH, halogens, halide, OSfOhR; wherein R is -CH3, -C₆H₅-CH₃; q is 0-5

According to an embodiment, the base is selected from the group comprising of alkali and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates and organic primary, secondary and tertiary amines, such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, aniline, chloroaniline and the mixture thereof, preferably sodium hydroxide.

According to an embodiment, molar ratio between compound (VI) to base can be from about 1:10 to 1:0.5, preferably 1:1 to 1:5, most preferably from about 1:2 to 1:3

According to an embodiment, the organic solvent 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, dimethyl sulfoxide, water and the mixtures thereof, preferably toluene.

According to an embodiment, w/w ratio between compound (VI) to solvent can be from about 1:1 to 1:20, preferably 1:1 to 1:5, most preferably from about 1:2 to 1:3

According to an embodiment, base 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.

According to an embodiment, w/w ratio between compound (VI) to aqueous base solution 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.

According to an embodiment, the compound of formula (VII) preferably contacted with the compound of formula (VI), 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.

According to an embodiment the reaction mixture 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.

According to an embodiment the reaction temperature interval of the stirring phase is from 0 to 130°C, preferably from 10 to 50°C, most preferably from 20 to 30°C. According to an embodiment the reaction mixture is monitored by HPLC analytical method and ends when concentration of formula (VI) is between 0-99%, preferably from 0-50%, in particular, when no more than 0.5% of compound of formula (VI) remains in the reaction media.

Finally, the reaction mixture containing the resulting a compound of formula (VIII) 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.

In additional embodiment, the present invention relates to a new derivative of general formula (XI)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

According to an embodiment, the present invention provides a method of preparing a compound of formula (VI) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 via two steps reaction which can be performed as separate processes or as combined process, such as one-pot reaction, telescopic-reaction, preferably, in one-pot reaction process, is displayed.

According to an embodiment, the first step comprising the method of preparing of a compound of formula (XI)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 by reaction of a compound of formula (IV)

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3; in the presence of organic solvent, optionally in the presence of base, and optionally in the presence of phase transfer catalyst.

According to an embodiment, a molar ratio between compound (IV) to compound (X) can be from about 1:10 to 10:1, preferably 1:0.5 to 1:5, most preferably from about 1:1 to 1:2.

According to an embodiment, base is selected from the group comprising of triethylamine, diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium alkoxide, potassium alkoxide, potassium tert-butoxide, sodium hydride, potassium hydride, butyl lithium, lithium diisopropyl amine, aniline, p-chloroaniline and the mixtures thereof, preferably potassium carbonate.

According to an embodiment, a molar ratio between compound (IV) to the base can be from about 1:5 to 0.5:1.0, preferably from about 1:1 to 1:5, most preferably from about 1:1.5 to 1:2.5.

According to an embodiment, organic solvent selected from dichloromethane, chloroform, pyridine, water, tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidone, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, dimethylacetamide and the mixtures thereof, preferably dimethyl sulfoxide.

According to an embodiment, a w/w ratio between compound (IV) to solvent can be from about 1:20 to 1:0.1, preferably from about 1:1 to 1:10, most preferably from about 1:3 to 1:5.

According to an embodiment, phase transfer catalyst selected from the group comprising of quaternary ammonium salts, phosphonium salts, polyether's and the mixtures thereof, such as benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride, tetra-n- butylammoniumchloride, tetra-n-butylammonium bromide tetra-n-butylammonium iodide tetra-n-butylammonium fluoride, crown ethers, polyethylene glycols and the mixture thereof, preferably, tetra-n-butylammonium bromide.

According to an embodiment, a molar ratio between compound (IV) to phase transfer catalyst can be from about 1:1 to 1:0.0001, preferably 1:0.25 to 1:0.025, most preferably from about 1:0.15 to 1:0.05

According to an embodiment, the second step provides the method of preparing of a compound of formula (VI) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 comprising reaction of a compound of formula (XI)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 in the presence of acid optionally in the presence of organic solvent.

According to an embodiment, molar ratio between compound (XI) to the acid can be from about 1:10 to 1:0.5, preferably from about 1:1 to 1:10, mot preferably from about 1:4 to 1:6.

According to an embodiment the organic solvent is selected organic solvent selected from water, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, dimethylformamide, 1,4- dioxane, ethyl acetate, acetonitrile, tetrahydrofuran, acetic acid, toluene, benzene, hexane, cyclohexane, dimethyl sulfoxide, pyridine, diethyl ether, chloroform, 1,2-dichloroethane, acetone, isopropyl acetate, anisole, A/-methyl-2-pyrrolidone, 4-methylmorpholine, nitromethane and the mixtures thereof, preferably, toluene.

According to an embodiment, a w/w ratio between compound (XI) to the organic solvent can be from about 1:10 to 10:0.1, preferably from ,1:10 to 1:1, most preferably from about 1:5 to 1:1.

According to an embodiment, compound (VI) is produced by mixing of a compound of formula (XI), acid, and organic solvent, and heating the mixture to temperature interval from 0 to 130°C, preferably from 50 to 120°C, most preferably from 100 to 115°C.

According to an embodiment, the reaction mixture is allowed to stir between 10 minutes to 20 hours according to the reaction progress, preferably from 5 to 15 hours, most preferably from 12 to 15 hours.

According to an embodiment, the reaction mixture is monitored by HPLC analytical method and ends when concentration of formula (XI) is 0-99%, preferably 0-50%, in particular, when no more than 2.0% of compound of formula (XI) remains in the reaction media.

Finally, the reaction mixture containing the resulting compound of formula (XI) 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.

According to another embodiment, the compound of formula (VIII),

wherein

X 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 is prepared by a process comprising the steps of: a) preparation of compound (VI) as described above via compound of formula (XI) b) reaction of compound (VI) with compound of formula (VII) in the presence of organic solvent, optionally in the presence of base.

wherein q is an integer equal to 1, 2, 3 or 4,

Y is halogen and

L is a leaving group selected from C1-C6 alkoxy, OH, halogens, halide, OSfO^R; wherein R is -CH3, -C₆H₅-CH₃; q is 0-5

According to an embodiment, base can be added as solid or as an aqueous solution of from 1% to 60% w/w, preferably as aqueous solution of from 2 to 20% w/w, most preferably from 5 to 10% w/w.

According to an embodiment the reaction temperature interval of the stirring phase is from 0 to 130°C, preferably from 10 to 50°C, most preferably from 20 to 30°C.

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

EXAMPLES:

Example 1: Preparation of Methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetate (compound II) from 2,3-Dichloro-5-(trifluoromethyl)pyridine (compound IV) via Dimethyl-2-(3-chloro-5- (trifluoromethyl)pyridine-2-yl)malonate (compound III):

To a IL reactor equipped with dean-stark condenser, toluene (180 mL), potassium carbonate (138 gr), dimethyl aminopyridine (2.82 gr) and tetra-n-butylammonium bromide (7.46 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 115°Cfor 30 minutes through 1 hour. 3 mL of water was collected, and the heating was continued until no water collection was detected. The mixture was cooled to 85°C and dimethyl malonate (77.7 gr), and dimethyl sulfoxide (120 mL) were added dropwise, followed by dropwise addition of compound (IV) (100 gr). The mixture was heated to 100°C through 6 hours. The reaction progress was monitored by HPLC and ended when compound (IV) was less than 1.5% in the reaction mixture. The mixture was cool to 25°C and the pH was adjusted by cone. HCI (160 mL). Solid particles were filtered and washed with Toluene (200 mL) twice. Toluene was distilled out to give compound (III) in dimethyl sulfoxide. The mixture was acidified by cone. HCI to adjust the pH to 2.5. The mixture was heated to 115°C through 16 hours. The reaction progress was monitored by HPLC and ended when compound (III) was less than 1.5% in the reaction mixture. The mixture was cooled to 25°C and water (400 mL) was added followed by Toluene (200 mL). Mixture was stirred, settled and organic layer was separated. Aqueous layer was washed again with toluene (200 mL) and organic phases were combined. Toluene was distillated to give (%w/w) 109 gr oily crude product containing compound (II), 75-77% yield.

Example 2: Preparation of Dimethyl-2-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)malonate (compound III) from 2,3-Dichloro-5-(trifluoromethyl)pyridine (compound IV):

To a IL reactor equipped with a condenser, N-methyl-2-pyrrolidone (300 mL), potassium carbonate (142 gr), were charged at 25°C and stirred for 5 minutes. 2,3-Dichloro-5- (trifluoromethyl)pyridine (100 gr) was charged to the reactor and mixture was stirred for 15 minutes. Dimethyl malonate (77.3 gr) was charged to the reactor and mixture was stirred for 15 minutes. The reaction was then heated to 75°C for 1 hour. Temperature was increased to 90°C for additional 9h. The reaction progress was monitored by HPLC and ended when compound (IV) was less than 1.5% in the reaction mixture. The mixture was cool to 25°C and the pH was adjusted by cone. HCI (160 mL). Solid particles were filtered and washed with N-methyl-2-pyrrolidone (200 mL) twice. N-Methyl-2-pyrrolidone was distilled out to give an oily crude product containing compound (III), 92% yield.

Example 3: Preparation of Dimethyl-2-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)malonate

(compound III) from 2,3-Dichloro-5-(trifluoromethyl)pyridine (compound IV): To a 2L reactor equipped with a condenser, toluene (700 mL), potassium carbonate (136 gr), dimethyl malonate (78.3 gr) tetra-n-butylammonium bromide (7.4 gr) and dimethyl aminopyridine (2.8 gr) were charged at 25°C and stirred for 5 minutes. 2,3-Dichloro-5- (trifluoromethyl)pyridine (103 gr) was charged to the reactor and mixture was stirred for 15 minutes. The reaction was then heated to 115°C for 14 hour. The reaction progress was monitored by HPLC and ended when compound (IV) was less than 1.5% in the reaction mixture. The mixture was cool to 25°C and the pH was adjusted by cone. HCI (160 mL). Solid particles were filtered and washed with toluene (200 mL) twice. Toluene was distilled out to give an oily crude product containing compound (III), 91% yield.

Example 4: Preparation of Dimethyl-2-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)malonate (compound III) from 2,3-Dichloro-5-(trifluoromethyl)pyridine (compound IV):

To a IL reactor equipped with a condenser, N,N-di methyl acetamide (150 mL), potassium carbonate (96 gr), dimethyl malonate (77.4 gr) tetra-n-butylammonium bromide (7.4 gr) and dimethyl aminopyridine (2.8 gr) were charged at 25°C and stirred for 5 minutes. 2,3-Dichloro-5- (trifluoromethyl)pyridine (100 gr) was charged to the reactor and mixture was stirred for 15 minutes. The reaction was then heated to 90°C for 8 hours. The reaction progress was monitored by HPLC and ended when compound (IV) was less than 1.5% in the reaction mixture. The mixture was cool to 25°C and the pH was adjusted by cone. HCI (160 mL). Solid particles were filtered and washed with N,N-dimethyl acetamide (200 mL) twice. N,N-dimethyl acetamide was distilled out to give an oily crude product containing compound (III), 93% yield.

Example 5: Preparation of Dimethyl-2-(3-chloro-5-(trifluoromethyl) pyridin-2-yl)malonate (compound III) from 2,3-Dichloro-5-(trifluoromethyl)pyridine (compound IV):

To a 0.25L reactor equipped with reflux condenser, compound (IV) (25 gr), dimethyl malonate (19.4 gr), potassium carbonate (34 gr), dimethyl aminopyridine (0.7 gr) and tetra-n- butylammonium bromide (1.88 gr) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 85°C for 3 hours. The reaction progress was monitored by HPLC and ended when compound (IV) was less than 1.5% in the reaction mixture. Viscous oily residue was obtained to give, 72% yield of compound (III). Example 6: Preparation of Methyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetate (compound II) from Dimethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (compound III):

To a 0.250L reactor equipped with reflux condenser, compound (III) (20 gr), dimethyl sulfoxide (40 mL) and 30% sodium chloride aqueous solution (25 mL) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to 110°C for 24 hours. The reaction progress was monitored by HPLC and ended when compound (III) was less than 2.0% in the reaction mixture. Mixture was cool to 25°C and water (100 mL) was added. The organic compound was extracted twice with toluene (100 mL). Toluene was distilled out to give a viscous oily residue with 80% of compound (II), 94% yield of compound (II).

Example 7: Preparation of Methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetate (compound II) from Dimethyl-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (compound III):

To a 0.250L autoclaved reactor, compound (III) (10 gr), and dimethyl sulfoxide (20 mL) were charged at 25°C and stirred for 5 minutes. The reaction was then heated to 145°C for 7 hours. The reaction progress was monitored by HPLC and ended when compound (III) was less than 1.5% in the reaction mixture. Viscous oily residue was obtained to give, 62% yield of compound (ID-

Example 8: Preparation of Methyl -2-(3-chloro-5-(trifluoromethyl) pyridine-2-yl)- (hydroxylimine)acetate (compound I) from Methyl 2-(3-chloro-5-(trifluoromethyl) pyridin-2-yl) acetate (compound II):

To a IL reactor, methyl 2-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)acetate (107 gr), acetic acid (100 mL) and water (30 mL) were charged at 25°C, and stirred for 5 minutes. The mixture was cooled to 10°C and solution of sodium nitrite (35.72 gr) in water (40 mL) was added dropwise, maintaining the temperature below 25°C. The mixture was allowed to stir for 2 hours at 15°C. The reaction progress was monitored by HPLC and ended when compound (II) was less than 1.5% in the reaction mixture. Water (350 mL) was added, and mixture was cooled to 5°C. Solid was filtered, washed with water (100 mL) and dried under vacuum, to give solid compound (I), 97% yield. Example 9: Preparation of Methyl-2-(3-chloro-5-(trifluoromethyl) pyridine-2-yl)- (hydroxylimine)acetate (compound I) from Methyl 2-(3-chloro-5-(trifluoromethyl) pyridin-2-yl) acetate (compound II):

To a IL reactor, methyl 2-(3-chloro-5-(trfluoromethyl)pyridine-2-yl)acetate (20 gr), acetic acid (100 mL), water (30 mL) and tetra-n-butylammonium bromide (2.54 gr) were charged at 25°C, and stirred for 5 minutes. The mixture was cooled to 10°C and solution of sodium nitrite (35.72 gr) in water (40 mL) was added dropwise, maintaining the temperature below 25°C. The mixture was allowed to stir for 2 hours at 15°C. The reaction progress was monitored by HPLC and ended when compound (II) was less than 1.5% in the reaction mixture. Water (350 mL) was added, and mixture was cooled to 5°C. Solid was filtered, washed with water (100 mL) and dried under vacuum, to give solid compound (I), 97% yield.

Example 10: Preparation of (3-Chloro-5-(trifluoromethyl)pyridin-2-yl)methanamine Hydrochloride (compound VI) from Methyl-2-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-(hydroxylimine)acetate (compound I) via methyl 2-amino-2-(3-chloro-5-trifluoromehtyl)pyridine-2-yl)acetate (compound V)

To a IL autoclave reactor, Methyl -2-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)- (hydroxylimine)acetate (20 gr), acetic acid (200 mL) and Raney Ni (2 gr) were charged. The autoclave was closed and heated to 75°C for 8 hours. The reaction progress was monitored by HPLC and ended when compound (I) was less than 1.5% in the reaction mixture. Mixture was filtered and washed with acetic acid (40 mL). Filtrate was d istil lated and to the residue cone. HCI (20 mL), water (10 mL) and toluene (30mL) were charged. Mixture was heated to 65°C and stirred for 2 hours. The mixture was cooled to 5°C and the solid precipitant was filtered, washed with toluene (20 mL) and dried under vacuum, to give 12 gr solid product of compound (VI), 85% yield.

Example 11: Preparation of (3-Chloro-5-(trifluoromethyl)pyridin-2-yl)methanamine Hydrochloride (compound VI) from Methyl-2-(3-chloro-5-(trifluoromethyl)pyridine-2-yl)-(hydroxylimine)acetate (compound I) via methyl 2-amino-2-(3-chloro-5-trifluoromehtyl)pyridine-2-yl)acetate (compound V)

To a IL autoclave reactor, Methyl-2-(3-chloro-5-(trifluoromethyl) pyridi ne-2-yl)- (hydroxylimine)acetate (70 gr), acetic acid (200 mL) were charged and stirred for 10 minutes at 10°C. Zinc dust (40.8 gr) was added at 10°C and mixture was stirred for 2 hours. The reaction progress was monitored by HPLC and ended when compound (I) was less than 0.5% in the reaction mixture. Mixture was filtered and washed with acetic acid (50 mL). Filtrate was distillated and to the residue, cone. HCI (20 mL), was charged. Mixture was heated to 100°C and stirred for 5 hours. The reaction progress was monitored by HPLC and ended when compound (V) was less than 0.5% in the reaction mixture. Water was distilled out from the solution and the oily residue was dissolved in toluene (150 mL). The mixture was cooled to 5°C and the solid precipitant was filtered. The solid residue was washed with toluene (50 mL) and dried under vacuum, to give 46.5 gr solid product of compound (VI), 83% yield.

Example 12: Preparation of (3-Chloro-5-(trifluoromethyl)pyridin-2-yl)methanamine Hydrochloride (compound VI) from 2,3-Dichloro-5-(trifluoro methyl)pyridine (compound IV) & Diethylacetamidomalonate (compound X) via Diethyl-2-acetamido-2-(3-chloro-5- (trifluoromethyl)pyridine-2-yl)malonate (compound XI)

To a 2L reactor, 2,3-dichloro-5-(trifluoromethyl)pyridine (100 gr), diethyl-2-acetamidomalonate (106.7 gr), potassium carbonate (130.6 gr), tetra-n-butylammonium bromide(14.8 gr) and dimethyl sulfoxide (400 mL) were charged and the resulting mixture was heated to 80°C for 13 hours. The reaction progress was monitored by HPLC and ended when compound (IV) was less than 2.0% in the reaction mixture. Mixture was cooled to 25°C and water (1000 mL) and toluene (500 mL) were charged. After that, the mixture was stirred for 20 minutes, and organic layer was separated. Aqueous layer was washed with toluene (200 mL) and organic phases were combined. Organic phases were washed with water (200 mL) and separated. Toluene was distillated to give oily residue. Cone. HCI (307 gr) was charged, and the mixture was heated to 105°C for 15 hours. The reaction progress was monitored by HPLC and ended when compound (XI) was less than 0.5% in the reaction mixture. The mixture was cooled to 65°C and distillated to lower volume. The mixture was further cooled to 25°C and toluene (200 mL) was charged. Mixture was heated to 70°C for 1 hour. Mixture was cooled to 5°C for 1 hour and solid was filtered, washed with toluene (100 mL) and vacuum dried to give 73 gr solid product of compound (VI), 63% yield.

Example 13: Preparation of 2,6-dichloro-N-((3-chloro-5-(trifluoromethyl)pyridin-2- yl)methyl)benzamide (compound VIII) by 2,6-dichlorobenzoyl chloride (compound VII) & (3-chloro- 5(trifluoromethyl)pyridin-2-yl)methanamine (compound VI) 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. Toluene (10 mL) was used to wash any solid remains to the reactor. 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. Solid 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 filtered, washed with toluene (50 mL) at 5°C and dried under vacuum to give 143.6 gr solid product of compound (VIII), 92% yield.

Claims

CLAIMS:

1. A compound of formula (I)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4

2. A compound of formula (la) g a compound of formula (I)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, 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 X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 with a nitrite salt selected from the group comprising sodium nitrite, potassium nitrite, ammonium nitrite and the mixture thereof, in the presence of solvent, optionally in the presence of an acid, and optionally in the presence of phase transfer catalyst.

4. A process according to claim 3 wherein the nitrite salt is sodium nitrite.

5. A process according to claim 3 wherein the solvent 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 pyrrolidones, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water, and the mixture thereof.

6. A process according to claim 3 performed in the presence of an acid selected from the group comprising acetic acid, formic acid, chloroacetic acid, dichloroacetic acid, trifluoroacetic acid, carboxylic acids, sulfuric acid, phosphoric acid, para-toluene sulfonic acid, hydrochloric acid, and the mixture thereof.

7. The process according to claim 3 performed in the presence of phase transfer catalyst selected from quaternary ammonium salts, phosphonium salts, crown ethers, polyether's and the mixtures thereof. Wherein the phase transfer catalyst selected from a group comprising benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride, tetra-n- butylammoniumchloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium fluoride, crown ethers, polyethylene glycols, polypropylene glycols, and the mixture thereof.

8. A process of preparing a compound of formula (II) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of compound of formula (III) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3. p is 0-4 with an acid selected form the group consisting of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonic acid, para-toluene sulfonic acid, phosphoric acid. And/or a with alkaline metal halides selected from a group consisting of sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, lithium bromide.

9. A process of preparing a compound of formula (III), or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of compound of formula (IV)

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; in the presence of a base and a phase transfer catalyst, optionally in the presence of solvent.

10. The process according to claim 9, wherein a base is selected from the group comprising of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium C1-C4 alkoxide, potassium C1-C4 alkoxide, potassium tert- butoxide, sodium hydride, potassium hydride, butyl lithium, lithium diisopropyl amine, aniline, p-chloroaniline and the mixtures thereof.

11. The process according to claim 9 performed in the presence of phase transfer catalyst selected from quaternary ammonium salts, phosphonium salts, crown ethers, polyether's and the mixtures thereof. Wherein the phase transfer catalyst selected from a group comprising benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride, tetra-n- butylammoniumchloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium fluoride, crown ethers, polyethylene glycols, polypropylene glycols, and the mixture thereof.

12. A process of preparing a compound of formula (II) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising heating of compound of formula (III) or its salts thereof

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 at 60-180°C under high pressure of 1-32 bars.

13. A process for preparing a compound of formula (V) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of compound of formula (I),

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3; p is 0-4 in the presence of metal catalyst, optionally in the presence of hydrogen, optionally in the presence of carboxylic acid.

14. The process according to claim 13, wherein metal catalyst is selected form the group comprising zinc, iridium, nickel, palladium, platinum, rhodium, or ruthenium, cobalt, tin, iron, Raney Ni, or the corresponding salts selected form the group of chlorides, bromide, iodide, nitrates, and the mixture thereof.

15. The process according to claim 13, performed in the presence of C1-C4 carboxylic acid selected form the group comprising acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoracetic acid, propionic acid, butyric acid, lactic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, tartaric acid, and a mixture thereof.

16. A process of preparing a compound of formula (VI) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 comprising a) preparing a compound of formula (V) according to any of claim of claims 13-15 and b) further reaction of resulting a compound of formula (V) with an acid, optionally in the presence of organic solvent.

17. The process according to claim 16 wherein an acid is selected from the group comprising of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonic acid, para-toluene sulfonic acid, phosphoric acid, and the mixture thereof.

18. The process according to claim 16 performed in the presence of organic solvent selected from water, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, dichloromethane, methanol, ethanol, isopropanol, tertbutanol, dimethylformamide, 1,4-dioxane, ethyl acetate, acetonitrile, tetrahydrofuran, acetic acid, toluene, benzene, hexane, cyclohexane, dimethyl sulfoxide, pyridine, diethyl ether, chloroform, 1,2-dichloroethane, 1-chlorobenzene, 1,2-dichlorobenzene, 1,3,5-trichlorobenzene, acetone, isopropyl acetate, anisole, A/-methyl-2-pyrrolidone, 4-methylmorpholine, nitromethane and the mixtures thereof.

19. A process of preparing a compound of formula (VIII)

wherein

X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 comprising reaction of compound of formula (VI) prepared according to claim 16 with a compound of formula (VII)

wherein q is an integer equal to 1, 2, 3 or 4,

Y is halogen and

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

20. The process according to claim 19 wherein a base is selected from the group comprising of alkali and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates and organic primary, secondary and tertiary amines, such as triethylamine, diisopropylethylamine, pyridine, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, aniline, p-chloroaniline and the mixture thereof.

21. The process according to claim 19 performed in the presence of organic solvent 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, water, tetrahydrofuran, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, pyrrolidones, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water and the mixtures thereof.

22. A process of preparing a compound of formula (VIII)

wherein

X 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)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z is, optionally halogen substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4.

23. A compound of formula (XI)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

Z¹, Z² are independently, optionally halogen substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4.

24. A compound of formula (Xia)

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO^R; wherein R is -CH3, -C6H5-CH3; p is 0-4 comprising reaction of compound of formula (IX)

Z¹, Z² are independently, optionally halogen substituted, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkyl amino, OSfO R; wherein R is -CH3, -C6H5-CH3;

In the presence of organic solvent, in the presence of base and optionally in the presence of phase transfer catalyst.

26. The process according to claim 25 wherein a base is selected from the group comprising of triethylamine, diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium alkoxide, potassium alkoxide, potassium tert-butoxide, sodium hydride, potassium hydride, butyl lithium, lithium diisopropyl amine, aniline, p-chloroaniline and the mixtures thereof.

27. The process according to claim 25 performed in the presence of organic solvent selected from dichloromethane, chloroform, pyridine, water, tetrahydrofuran, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, dimethylacetamide and the mixtures thereof.

28. The process according to claim 25 performed in the presence of phase transfer catalyst selected from the group comprising of quaternary ammonium salts, phosphonium salts, crown ethers polyether's and the mixtures thereof. Wherein the phase transfer catalyst selected from a group comprising benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and methyltrioctylammonium chloride, tetra-n- butylammoniumchloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium fluoride, crown ethers, polyethylene glycols and the mixture thereof.

29. A process of preparing a compound of formula (VI) or its salts thereof,

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 comprising preparing a compound of formula (XI) according to claim 25 and b) further reaction of resulting a compound of formula (XI) with an acid, optionally in the presence of organic solvent.

30. The process according to claim 29 wherein an acid is selected from the group comprising of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonic acid, para-toluene sulfonic acid, phosphoric acid, and the mixture thereof.

31. The process according to claim 29 performed in the presence of organic solvent selected from the group comprising of water, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, dichloromethane, methanol, ethanol, propanol, isopropanol, tert-butanol, dimethylformamide, 1,4- dioxane, ethyl acetate, acetonitrile, tetrahydrofuran, acetic acid, toluene, benzene, hexane, cyclohexane, dimethyl sulfoxide, pyridine, diethyl ether, chloroform, 1,2-dichloroethane, 1-chlorbenzen, 1,2-dichlorobenzene, 1,3,5-trichlorobenzene, acetone, isopropyl acetate, anisole, A/-methyl-2-pyrrolidone, 4-methylmorpholine, nitromethane and the mixtures thereof.

32. A process of preparing a compound of formula (VIII)

wherein

X 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 comprising reaction of compound of formula (VI) prepared according to claim 29 with compound of formula (VII)

wherein q is an integer equal to 1, 2, 3 or 4,

Y is halogen and

In the presence of organic solvent, optionally in the presence of base.

33. The process according to claim 32 wherein a base is selected from the group comprising of triethylamine, diisopropylethylamine, pyridine, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, aniline, chloroaniline and the mixture thereof.

34. The process according to claim 32 performed in the presence of organic solvent selected from dichloromethane, chloroform, pyridine, water, tetrahydrofuran, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, dimethylacetamide and the mixtures thereof.

35. A process of preparing a compound of formula (VIII)

wherein

X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;