Process for preparing amino-cyano-benzene derivatives

Abstract

The present invention relates to the process of preparation of cyano-benzene derivatives including cyantraniliprole, comprising the preparation of cyano-group via cyanation reagent, wherein the cyanation reagent reacts with benzene derivatives, to form the cyano-benzene derivatives. The present invention provides one-step, high yield, high efficiency, and low-cost cyanation synthesis of cyano substituted substances including common pesticides such as cyantraniliprole.

Description

[0001] TITLE: PROCESS FOR PREPARING AMINO-CYANO-BENZENE DERIVATIVES

[0002] FIELD OF INVENTION:

[0003] The present invention refers to a novel synthetic approach of cyano-benzene derivatives and particularly 2-amino-5-cyano-N-3-dimethylbenzamide by cyanation reagent, and its part in the manufacturing of pesticides, such as cyantraniliprole.

[0004] BACKGROUND:

[0005] Substituted compounds of the formula (I) and in particular 2-amino-5-cyano-N-3-dimethylbenzamide have a major part in the agriculture industry as a building block for various insecticides and in particular, cyantraniliprole.

[0006] The installation of cyano group can be done by reacting benzene halide derivatives with metal cyanide. This reaction has been extensively used due to its relatively, high selectivity and high yield. However, this synthetic approach possesses some drawbacks such as numerous synthetic steps due to the fact that halide group is required on the aromatic substrates, the use of metal cyanides, copper salts, and in some cases the addition of expensive iodide salts and ligands. Consequently, this approach has a high total cost, and time-consuming and therefore not ideal for commercial use. This kind of reaction is well described in W02008 / 082502, W02009 / 111553, and W02009 / 085816.

[0007] Another method to prepare cyano-benzene derivatives is by converting oxime group to cyano group in presence of triphosgene as described in WO2024038436. Yet, the main drawback in this approach is the numerous synthetic steps.

[0008] The more attractive method to install cyano group in terms of step economy is by reacting benzene derivatives with cyanogen reagent, such as cyanogen bromide (CNBr) (A. J. Simonsen, Tetrahedron Lett., 1995, 36, 7975, Y. Kita et al., Heterocycles, 1996, 42, 47) and cyanogen chloride (CNCI) (J. A. Nelson et al., J. Org. Chem., 1970, 35, 161) or dicyan. These cyanation reagents are the most common. Other cyanation reagents include N-cyano sulfonamides (F. Kurzer et al., J. Chem. Soc., 1949, 1034) and tosylcyanide (D. B. Collum et al., Tetrahedron Lett., 1981, 22, 5011, and M. Waser et al., Org. Chem. Front., 2016, 3, 1535-1540). This method was successfully applied on biphenyl compound as disclosed in W02003 / 037848. However, reacting substituted benzene derivatives with those cyanation reagents can suffer from the lack of selectivity.

[0009] Given the above, there is a need for new improved preparative methods for the cyanation of compounds such as compound of formula (I), and in particular for 2-amino-5-cyano-N-3- dimethylbenzamide.

[0010] SUMMARY:

[0011] The present invention relates to a process for the preparation of compound of formula (I) wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R2 is NO2, NH2, NCOR4, N(R4)2, -N=C(R4h, -NHN(R4)2; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; or R2 and R3 is connected together to form a 6-membered ring, comprising reacting a compound of formula (II) or its salts thereof wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R2 is NO2, NH2, NCOR4, N(R4)2, -N=C(R4h, -NHN(R4)2; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; or R2 and R3 is connected together to form a 6-membered ring, with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst. In addition, the present invention relates to a process for the preparation of compounds of formula (III) wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; comprising reacting a compound of formula (IV) or its salts thereof wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst.

[0012] The present invention also relates to a process for the preparation of compounds of formula (V)

[0013] wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; comprising reacting a compound of formula (VI) or its salts thereof wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst.

[0014] DESCRIPTION OF THE INVENTION:

[0015] Definitions:

[0016] 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".

[0017] 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.

[0018] 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.

[0019] The term "alkyl" as used herein refers to a branched, unbranched, or cyclic carbon chain, containing from one to six carbon atoms.

[0020] 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."

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

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

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

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

[0025] The term "one-pot" reaction as used herein, refers to the possibility to perform multiplechemical reactions in one step in a single reaction vessel without the need for isolation (e.g., purification) of the intermediates obtained in each chemical reaction. This process reduces the number of synthetic steps, and decreases waste materials, time, and cost.

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

[0027] The term "continued process" as used herein refers to a method of manufacturing where the production runs continuously, as opposed to batch processing where materials are processed in discrete batches. Continuous processes are characterized by a continuous flow of materials through the production line without interruptions.

[0028] The term "in situ" as used herein refers to a method wherein a reagent is generated by reaction that carried out in the same location where the reactants are formed. For example, a substance compound might be generated and used immediately in the next step of a reaction sequence without being isolated.

[0029] 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.

[0030] Any of the compounds described here as basic compound or intermediate in a process is intended also to include the compound salts such as HCI salts, HBr salts, acetic acid salts, no special meaning should be given to the fact that in some cases this is mentioned or not mention for specific compound in the text.

[0031] The salts of the compounds of the invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.

[0032] 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. According to 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.

[0033] According to an embodiment, the present invention provides a process for the preparation of compound of formula (I) wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R2 is NO2, NH2, NCOR4, N(R4)2, -N=C(R4h, -NHN(R4)2; R3 is halogen, OR4, NHR4, N(R4h; R4 is independently hydrogen, Cl-C4-alkyl; or R2 and R3 is connected together to form a 6-membered ring, comprising reacting a compound of formula (II) or its salts thereof wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R2 is NO2, NH2, NCOR4, N(R4)2, -N=C(R4h, -NHN(R4)2; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; or R2 and R3 is connected together to form a 6-membered ring, with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst.

[0034] According to an embodiment, the present invention provides a process for the preparation of compound of formula (I) wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R2 is NO2, NH2, NCOR4, N(R4)2, -N=C(R4h, -NHN(R4)2; R3 is halogen, OR4, NHR4, N(R4h; R4 is independently hydrogen, Cl-C4-alkyl; or R2 and R3 is connected together to form a 6-membered ring, comprising reacting a compound of formula (II) or its salts thereof wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R2 is NO2, NH2, NCOR4, N(R4)2, -N=C(R4h, -NHN(R4)2; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; or R2 and R3 is connected together to form a 6-membered ring, with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and in the presence of a catalyst.

[0035] According to an embodiment, the present invention provides a process for the preparation of compound of formula (I) wherein Ri is Me; R2 is NH2; and R3 is OH, OR4; wherein R4 is independently hydrogen, Cl-C4-alkyl, comprising reacting a compound of formula (II) or its salts thereof wherein Ri is Me; R2 is NH2; and R3 is OH, OR4; wherein R4 is independently hydrogen, Cl-C4-alkyl, with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst.

[0036] According to an embodiment, the present invention provides a process for the preparation of compound of formula (I) wherein Ri is Me; R2 is NH2; and R3 is OH, OR4; wherein R4 is independently hydrogen, Cl-C4-alkyl, comprising reacting a compound of formula (II) or its salts thereof with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and in the presence of a catalyst. According to an embodiment, the present invention provides a process for the preparation of compound of formula (I) wherein Ri is Me; R2 is NH2; and R3 is NHMe, NH2, comprising reacting a compound of formula (II) or its salts thereof wherein Ri is Me; R2 is NH2; and R3 is NHMe, NH2, with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst.

[0037] According to an embodiment, the present invention provides a process for the preparation of compound of formula (I) wherein Ri is Me; R2 is NH2; and R3 is NHMe, NH2, comprising reacting a compound of formula (II) or its salts thereof wherein Ri is Me; R2 is NH2; and R3 is NHMe, NH2, with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and in the presence of a catalyst.

[0038] According to an embodiment, the cyanation reagent in the process for the preparation of compound of formula (I), is selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), and the mixtures thereof.

[0039] According to an embodiment, the weight ratio between the compound of formula (II) and the cyanation reagent is from 1:1 to 1:20.

[0040] According to an embodiment, the weight ratio between the compound of formula (II) and the cyanation reagent is from 1:1 to 1:10.

[0041] According to an embodiment, the weight ratio between the compound of formula (II) and the cyanation reagent is from 1:1 to 1:5.

[0042] According to an embodiment, the amount of compound (II) in the mixture of the process for the preparation of compounds of formula (I) is from 1 % to 90 % by weight, more preferably 5 % to 50 % by weight, most preferably from 10 % to 30 % by weight, based on the weight of total mixture.

[0043] According to an embodiment, the amount of the cyanation reagent in the mixture of the process for the preparation of compounds of formula (I) is from 10 % to 90 % by weight, more preferably 20 % to 70 % by weight, most preferably from 30 % to 50 % by weight, based on the weight of total mixture.

[0044] According to an embodiment, the catalyst in the process for the preparation of compound of formula (I), is selected from Lewis acids, organo-metallic complexes and nucleophilic activators or mixture thereof.

[0045] According to an embodiment, the catalyst in the process for the preparation of compound of formula (I), is Lewis acid optionally selected from the group comprising aluminum chloride, ethylaluminum dichloride, diethylaluminum chloride, triethylaluminium, methylaluminium dichloride, dimethylaluminium chloride, trimethylaluminium, ferric chloride, ferric bromide, boron trihydride, boron trichloride, boron tribromide, boron trifluoride, zinc chloride, zinc bromide, titanium tetrachloride, titanium isopropoxide, magnesium chloride, magnesium bromide, and the mixtures thereof.

[0046] According to an embodiment, the catalyst in the process for the preparation of compound of formula (I), is organo-metallic complex optionally selected from the group comprising n- butyllithium, ethyllithium, methyllithium, diethylzinc, tributyltin hydride, triethylborane ethylaluminum dichloride, diethylaluminum chloride, triethylaluminium, methylaluminium dichloride, dimethylaluminium chloride, trimethylaluminium, methylmagnesium chloride, methylmagnesium bromide, dimethylmagnesium, and the mixtures thereof.

[0047] According to an embodiment, the catalyst in the process for the preparation of compound of formula (I), is nucleophilic activator optionally selected from the group comprising triethylamine, dimethylamine, tributylamine, aniline, indole, piperidine, pyridine, pyrimidine, pyrrolidine, pyrrole, imidazole, methylimidazole, 2-picoline, diisopropyl ethyl amine (DIPEA), pyridine, 4- (Dimethylamino)pyridine (DMAP), l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4- diazabicyclo[2.2.2]octane (DABCO), and the mixtures thereof.

[0048] According to an embodiment, the weight ratio between the compound of formula (II) and the catalyst is from 100:1 to 1:100. According to an embodiment, the weight ratio between the compound of formula (II) and the catalyst is from 20:1 to 1:20.

[0049] According to an embodiment, the weight ratio between the compound of formula (II) and the catalyst is from 20:1 to 1:1.1.

[0050] According to an embodiment, the weight ratio between the compound of formula (II) and the catalyst is from 1.1:1 to 1:20.

[0051] According to an embodiment, the amount of compound (II) in the mixture of the process for the preparation of compounds of formula (I) is from 0.1 % to 50 % by weight based on the weight of total mixture.

[0052] According to an embodiment, the amount of compound (II) in the mixture of the process for the preparation of compounds of formula (I) is from 1 % to 30 % by weight based on the weight of total mixture.

[0053] According to an embodiment, the amount of compound (II) in the mixture of the process for the preparation of compounds of formula (I) is from 5 % to 20 % by weight based on the weight of total mixture.

[0054] According to an embodiment the organic solvent in the process for the preparation of compounds of formula (I) is optionally selected from a group comprising aliphatic cyclic and acyclic hydrocarbons, such as octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether, halogenated aliphatic cyclic and acyclic hydrocarbons such as, carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, halogenated aromatic hydrocarbons such as chlorobenzene, dichlorobenzene, trichlorobenzene, aliphatic cyclic ethers such as diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t- butyl ether (MTBE), isopropylmethyl ether, tetra hydrofuran (THF), methyl-tetrahydrofuran (Me- THF), cyclopentylmethyl ether, aliphatic and cyclic esters such as ethyl acetate, nitriles such as acetonitrile, benzonitrile, ketones such as acetone, 2-butanone, C1-C4 carboxylic acids such as acetic acid, propionic acid, benzylic acid, polar protic and aprotic solvents such as formic acid, N- methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, water, and a mixture thereof.

[0055] According to an embodiment, the organic solvent in the process for the preparation of compounds of formula (I) is optionally selected from a group comprising, octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether, chloroform, dichloromethane, chlorobenzene, aliphatic ethers such as diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), isopropylmethyl ether, tetrahydrofuran (TH F), methyl-tetrahydrofuran (Me-THF), aliphatic esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone, 2-butanone, polar protic and aprotic solvents such as formic acid, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and a mixture thereof.

[0056] According to an embodiment, the organic solvent in the process for the preparation of compounds of formula (I) is optionally selected from a group comprising, hexane, pentane, cyclohexane, petroleum ether, dichloromethane, chlorobenzene, 1,4-dioxane, methyl t- butyl ether (MTBE), tetra hydrofuran (THF), methyl-tetrahydrofuran (Me-THF), ethyl acetate, nitriles such as acetonitrile, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and a mixture thereof.

[0057] According to an embodiment, the weight ratio between the compound of formula (II) and the organic solvent is from 1:20 to 10:1, preferably from about 1:0.5 to 1:5, most preferably from about 1:1 to 1:4.

[0058] According to an embodiment, the amount of the organic solvent in the mixture of the process for the preparation of compounds of formula (I) is from 10% to 90 % by weight, more preferably from 20% to 70 % by weight, most preferably from 30% to 50 %, by weight based on the weight of total mixture.

[0059] According to an embodiment, the compound of formula (II) is contacted with the cyanation reagent at the temperature interval of from -20 to 100°C, more preferably from about 0 to 50°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%. In particular, the process should be terminated when no more than 5% of compound of formula (II) remains in the reaction media.

[0060] According to an embodiment, the reaction mixture is monitored by HPLC analytical method, and the process ends when concentration of formula (II) is between 0-40%, preferably from 0-10%. In particular, the process should be terminated when no more than 1% of compound of formula (II) remains in the reaction media.

[0061] According to an embodiment, any residue of non-reacted compound of formula (II) is recycled according to common and known methods for anyone skilled in the art and can be reused in the next preparation process of formula (I).

[0062] According to an embodiment, the process for the preparation of compound of formula (I), is performed as a common batch process in which a specific amount of reactants is combined in a vessel or reactor, and the reaction is allowed to proceed under controlled conditions such as temperature, pressure, and reaction time according to any of the preceding embodiments. Once the reaction is complete, the products are isolated, and the reactor is cleaned before starting a new batch.

[0063] According to an embodiment, the process for the preparation of compound of formula (I), is performed in a continuous process, also known as continuous flow chemistry, wherein the reaction occurs continuously in a flowing stream of the reactants, without the need for discrete batch operations. Reactants are continuously fed into the reactor system, where they mixed, reacting, and form the compound of formula (I) as they flow through various reaction zones. The compound of formula (I) is then continuously removed from the reactor system, while unreacted starting materials or by-products are either recycled or purged from the system.

[0064] According to an embodiment, the process for the preparation of compound of formula (I), is performed as a telescopic process in which multiple reactions are carried out sequentially in the same reaction vessel, without the need for intermediate isolation and purification steps. According to an embodiment, the process for the preparation of compound of formula (I), comprising addition of the cyanation reagent to the reaction mixture and further mixing the reaction mixture.

[0065] In yet another embodiment, the process for the preparation of compound of formula (I), comprising the generation of a cyanation reagent in situ and further mixing the reaction mixture.

[0066] The reaction mixture containing the resulting a compound of formula (I) is optionally worked up or proceed as in telescopic / one-pot reaction without workup to the next step of process. 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.

[0067] According to another embodiment, the present invention is related to a process for the preparation of a compound of formula (III), and its salt thereof, wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; comprising reacting a compound of formula (IV) or its salts thereof wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst.

[0068] According to an embodiment, the present invention is related to a process for the preparation of a compound of formula (III), and its salt thereof, wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; comprising reacting a compound of formula (IV) or its salts thereof wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and in the presence of a catalyst.

[0069] According to another embodiment, the present invention is related to a process for the preparation of a compound of formula (III), and its salt thereof, wherein Ri is Ri is Me; comprising reacting a compound of formula (IV) or its salts thereof wherein Ri is Ri is Me; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst.

[0070] According to an embodiment, the present invention is related to a process for the preparation of a compound of formula (III), and its salt thereof, wherein Ri is Ri is Me; comprising reacting a compound of formula (IV) or its salts thereof with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and in the presence of a catalyst.

[0071] According to an embodiment, the cyanation reagent in the process for the preparation of compound of formula (III), is selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), and the mixtures thereof.

[0072] According to an embodiment, the weight ratio between the compound of formula (IV) and the cyanation reagent is from 1:1 to 1:20.

[0073] According to an embodiment, the weight ratio between the compound of formula (IV) and the cyanation reagent is from 1:1 to 1:10.

[0074] According to an embodiment, the weight ratio between the compound of formula (IV) and the cyanation reagent is from 1:1 to 1:5.

[0075] According to an embodiment, the amount of compound (IV) in the mixture of the process for the preparation of compounds of formula (III) is from 1 % to 90 % by weight, more preferably 5 % to 50 % by weight, most preferably from 10 % to 30 % by weight, based on the weight of total mixture.

[0076] According to an embodiment, the amount of the cyanation reagent in the mixture of the process for the preparation of compounds of formula (III) is from 10 % to 90 % by weight, more preferably 20 % to 70 % by weight, most preferably from 30 % to 50 % by weight, based on the weight of total mixture.

[0077] According to an embodiment, the catalyst in the process for the preparation of compound of formula (III), is selected from Lewis acids, organo-metallic complexes and nucleophilic activators or mixture thereof.

[0078] According to an embodiment, the catalyst in the process for the preparation of compound of formula (III), is Lewis acid optionally selected from the group comprising aluminum chloride, ethylaluminum dichloride, diethylaluminum chloride, triethylaluminium, methylaluminium dichloride, dimethylaluminium chloride, trimethylaluminium, ferric chloride, ferric bromide, boron trihydride, boron trichloride, boron tribromide, boron trifluoride, zinc chloride, zinc bromide, titanium tetrachloride, titanium isopropoxide, magnesium chloride, magnesium bromide, and the mixtures thereof.

[0079] According to an embodiment, the catalyst in the process for the preparation of compound of formula (III), is organo-metallic complex optionally selected from the group comprising n- butyllithium, ethyllithium, methyllithium, diethylzinc, tributyltin hydride, triethylborane ethylaluminum dichloride, diethylaluminum chloride, triethylaluminium, methylaluminium dichloride, dimethylaluminium chloride, trimethylaluminium, methylmagnesium chloride, methylmagnesium bromide, dimethylmagnesium, and the mixtures thereof.

[0080] According to an embodiment, the catalyst in the process for the preparation of compound of formula (III), is nucleophilic activator optionally selected from the group comprising triethylamine, dimethylamine, tributylamine, aniline, indole, piperidine, pyridine, pyrimidine, pyrrolidine, pyrrole, imidazole, methylimidazole, 2-picoline, diisopropyl ethyl amine (DIPEA), pyridine, 4-(Dimethylamino)pyridine (DMAP), l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4- diazabicyclo[2.2.2]octane (DABCO), and the mixtures thereof.

[0081] According to an embodiment, the weight ratio between the compound of formula (IV) and the catalyst is from 100:1 to 1:100.

[0082] According to an embodiment, the weight ratio between the compound of formula (IV) and the catalyst is from 20:1 to 1:20.

[0083] According to an embodiment, the weight ratio between the compound of formula (IV) and the catalyst is from 20:1 to 1:1.1.

[0084] According to an embodiment, the weight ratio between the compound of formula (IV) and the catalyst is from 1.1:1 to 1:20. According to an embodiment, the amount of compound (IV) in the mixture of the process for the preparation of compounds of formula (III) is from 0.1 % to 50 % by weight based on the weight of total mixture.

[0085] According to an embodiment, the amount of compound (IV) in the mixture of the process for the preparation of compounds of formula (III) is from 1 % to 30 % by weight based on the weight of total mixture.

[0086] According to an embodiment, the amount of compound (IV) in the mixture of the process for the preparation of compounds of formula (III) is from 5 % to 20 % by weight based on the weight of total mixture.

[0087] According to an embodiment, the organic solvent in the process for the preparation of compounds of formula (III) is optionally selected from a group comprising aliphatic cyclic and acyclic hydrocarbons, such as octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether, halogenated aliphatic cyclic and acyclic hydrocarbons such as, carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, halogenated aromatic hydrocarbons such as chlorobenzene, dichlorobenzene, trichlorobenzene, aliphatic cyclic ethers such as diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t- butyl ether (MTBE), isopropylmethyl ether, tetrahydrofuran (THF), methyl-tetrahydrofuran (Me- THF), cyclopentylmethyl ether, aliphatic and cyclic esters such as ethyl acetate, nitriles such as acetonitrile, benzonitrile, ketones such as acetone, 2-butanone, C1-C4 carboxylic acids such as acetic acid, propionic acid, benzylic acid, polar protic and aprotic solvents such as formic acid, N- methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, water, and a mixture thereof.

[0088] According to an embodiment, the organic solvent in the process for the preparation of compounds of formula (III) is optionally selected from a group comprising, octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether, chloroform, dichloromethane, chlorobenzene, aliphatic ethers such as diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), isopropylmethyl ether, tetrahydrofuran (THF), methyl-tetrahydrofuran (Me-THF), aliphatic esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone, 2-butanone, polar protic and aprotic solvents such as formic acid, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and a mixture thereof.

[0089] According to an embodiment, the organic solvent in the process for the preparation of compounds of formula (III) is optionally selected from a group comprising, hexane, pentane, cyclohexane, petroleum ether, dichloromethane, chlorobenzene, 1,4-dioxane, methyl t- butyl ether (MTBE), tetra hydrofuran (THF), methyl-tetrahydrofuran (Me-THF), ethyl acetate, nitriles such as acetonitrile, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and a mixture thereof.

[0090] According to an embodiment, the weight ratio between the compound of formula (VI) and the organic solvent is from 1:20 to 10:1, preferably from about 1:0.5 to 1:5, most preferably from about 1:1 to 1:4.

[0091] According to an embodiment, the amount of the organic solvent in the mixture of the process for the preparation of compounds of formula (III) is from 10% to 90 % by weight, more preferably from 20% to 70 % by weight, most preferably from 30% to 50 %, by weight based on the weight of total mixture.

[0092] According to an embodiment, the compound of formula (IV) is contacted with the cyanation reagent at the temperature interval of from -20 to 100°C, more preferably from about 0 to 50°C.

[0093] According to an embodiment, the reaction mixture is monitored by HPLC analytical method, and the process ends when concentration of formula (IV) is between 0-99%, preferably from 0-50%. In particular, the process should be terminated when no more than 5% of compound of formula (IV) remains in the reaction media.

[0094] According to an embodiment, the reaction mixture is monitored by HPLC analytical method, and the process ends when concentration of formula (IV) is between 0-40%, preferably from 0-10%. In particular, the process should be terminated when no more than 1% of compound of formula (IV) remains in the reaction media. According to an embodiment, any residue of non-reacted compound of formula (IV) is recycled according to common and known methods for anyone skilled in the art and can be reused in the next preparation process of formula (III).

[0095] According to an embodiment, the process for the preparation of compound of formula (I II), is performed as a common batch process in which a specific amount of reactants is combined in a vessel or reactor, and the reaction is allowed to proceed under controlled conditions such as temperature, pressure, and reaction time according to any of the preceding embodiments. Once the reaction is complete, the products are isolated, and the reactor is cleaned before starting a new batch.

[0096] According to an embodiment, the process for the preparation of compound of formula (I II), is performed in a continuous process, also known as continuous flow chemistry, wherein the reaction occurs continuously in a flowing stream of the reactants, without the need for discrete batch operations. Reactants are continuously fed into the reactor system, where they mixed, reacting, and form the compound of formula (III) as they flow through various reaction zones. The compound of formula (III) is then continuously removed from the reactor system, while unreacted starting materials or by-products are either recycled or purged from the system.

[0097] According to an embodiment, the process for the preparation of compound of formula (III), is performed as a telescopic process in which multiple reactions are carried out sequentially in the same reaction vessel, without the need for intermediate isolation and purification steps.

[0098] According to an embodiment, the process for the preparation of compound of formula (III), comprising addition of the cyanation reagent to the reaction mixture and further mixing the reaction mixture.

[0099] In yet another embodiment, the process for the preparation of compound of formula (III), comprising the generation of a cyanation reagent in in situ and further mixing the reaction mixture.

[0100] The reaction mixture containing the resulting a compound of formula (III) is optionally worked up or proceed as in telescopic / one-pot reaction without workup to the next step of process. 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.

[0101] According to another embodiment, the present invention is related to a process for the preparation of compounds of formula (V) wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; comprising reacting a compound of formula (VI) or its salts thereof wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen, p- tolylsu Ifonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent and optionally in the presence of a catalyst.

[0102] According to an embodiment, the present invention is related to a process for the preparation of compounds of formula (V)

[0103] wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; comprising reacting a compound of formula (VI) or its salts thereof wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen, p- tolylsu Ifonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent and in the presence of a catalyst.

[0104] According to another embodiment, the present invention is related to a process for the preparation of compounds of formula (V) comprising reacting a compound of formula (VI) or its salts thereof wherein Ri is Me; and R3 is NHMe, NH2, OR4; wherein R4 is independently hydrogen, Cl-C4-alkyl; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen, p- tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent and optionally in the presence of a catalyst.

[0105] According to an embodiment, the present invention is related to a process for the preparation of compounds of formula (V) wherein Ri is Me; and R3 is NHMe, NH2, OR4; wherein R4 is independently hydrogen, Cl-C4-alkyl; comprising reacting a compound of formula (VI) or its salts thereof with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen, p- tolylsu Ifonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent and in the presence of a catalyst.

[0106] According to an embodiment, the cyanation reagent in the process for the preparation of compound of formula (V), is selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), and the mixtures thereof.

[0107] According to an embodiment, the weight ratio between the compound of formula (VI) and the cyanation reagent is from 1:1 to 1:20.

[0108] According to an embodiment, the weight ratio between the compound of formula (VI) and the cyanation reagent is from 1:1 to 1:10.

[0109] According to an embodiment, the weight ratio between the compound of formula (VI) and the cyanation reagent is from 1:1 to 1:5.

[0110] According to an embodiment, the amount of compound (VI) in the mixture of the process for the preparation of compounds of formula (V) is from 1 % to 90 % by weight, more preferably 5 % to 50 % by weight, most preferably from 10 % to 30 % by weight, based on the weight of total mixture.

[0111] According to an embodiment, the amount of the cyanation reagent in the mixture of the process for the preparation of compounds of formula (V) is from 10 % to 90 % by weight, more preferably 20 % to 70 % by weight, most preferably from 30 % to 50 % by weight, based on the weight of total mixture.

[0112] According to an embodiment, the catalyst in the process for the preparation of compound of formula (V), is selected from Lewis acids, organo-metallic complexes and nucleophilic activators or mixture thereof.

[0113] According to an embodiment, the catalyst in the process for the preparation of compound of formula (V), is Lewis acid optionally selected from the group comprising aluminum chloride, ethylaluminum dichloride, diethylaluminum chloride, triethylaluminium, methylaluminium dichloride, dimethylaluminium chloride, trimethylaluminium, ferric chloride, ferric bromide, boron trihydride, boron trichloride, boron tribromide, boron trifluoride, zinc chloride, zinc bromide, titanium tetrachloride, titanium isopropoxide, magnesium chloride, magnesium bromide, and the mixtures thereof.

[0114] According to an embodiment, the catalyst in the process for the preparation of compound of formula (V), is organo-metallic complex optionally selected from the group comprising n- butyllithium, ethyllithium, methyllithium, diethylzinc, tributyltin hydride, triethylborane ethylaluminum dichloride, diethylaluminum chloride, triethylaluminium, methylaluminium dichloride, dimethylaluminium chloride, trimethylaluminium, methylmagnesium chloride, methylmagnesium bromide, dimethylmagnesium, and the mixtures thereof.

[0115] According to an embodiment, the catalyst in the process for the preparation of compound of formula (V), is nucleophilic activator optionally selected from the group comprising triethylamine, dimethylamine, tributylamine, aniline, indole, piperidine, pyridine, pyrimidine, pyrrolidine, pyrrole, imidazole, methylimidazole, 2-picoline, diisopropyl ethyl amine (DIPEA), pyridine, 4-(Dimethylamino)pyridine (DMAP), l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4- diazabicyclo[2.2.2]octane (DABCO), and the mixtures thereof.

[0116] According to an embodiment, the weight ratio between the compound of formula (VI) and the catalyst is from 100:1 to 1:100.

[0117] According to an embodiment, the weight ratio between the compound of formula (VI) and the catalyst is from 20:1 to 1:20.

[0118] According to an embodiment, the weight ratio between the compound of formula (VI) and the catalyst is from 20:1 to 1:1.1.

[0119] According to an embodiment, the weight ratio between the compound of formula (VI) and the catalyst is from 1.1:1 to 1:20. According to an embodiment, the amount of compound (VI) in the mixture of the process for the preparation of compounds of formula (V) is from 0.1 % to 50 % by weight based on the weight of total mixture.

[0120] According to an embodiment, the amount of compound (VI) in the mixture of the process for the preparation of compounds of formula (V) is from 1 % to 30 % by weight based on the weight of total mixture.

[0121] According to an embodiment, the amount of compound (VI) in the mixture of the process for the preparation of compounds of formula (V) is from 5 % to 20 % by weight based on the weight of total mixture.

[0122] According to an embodiment, the organic solvent in the process for the preparation of compounds of formula (V) is optionally selected from a group comprising aliphatic cyclic and acyclic hydrocarbons, such as octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether, halogenated aliphatic cyclic and acyclic hydrocarbons such as, carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, halogenated aromatic hydrocarbons such as chlorobenzene, dichlorobenzene, trichlorobenzene, aliphatic cyclic ethers such as diethyl ether, diglyme (diethyleneglycol dimethyl ether), 1,4-dioxane, methyl t- butyl ether (MTBE), isopropylmethyl ether, tetrahydrofuran (THF), methyl-tetrahydrofuran (Me- THF), cyclopentylmethyl ether, aliphatic and cyclic esters such as ethyl acetate, nitriles such as acetonitrile, benzonitrile, ketones such as acetone, 2-butanone, C1-C4 carboxylic acids such as acetic acid, propionic acid, benzylic acid, polar protic and aprotic solvents such as formic acid, N- methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, water, and a mixture thereof.

[0123] According to an embodiment, the organic solvent in the process for the preparation of compounds of formula (V) is optionally selected from a group comprising, octane, heptane, hexane, pentane, cyclooctane, cyclohexane, cyclopentane, petroleum ether, chloroform, dichloromethane, chlorobenzene, aliphatic ethers such as diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl t-butyl ether (MTBE), isopropylmethyl ether, tetrahydrofuran (THF), methyl-tetrahydrofuran (Me-THF), aliphatic esters such as ethyl acetate, nitriles such as acetonitrile, ketones such as acetone, 2-butanone, polar protic and aprotic solvents such as formic acid, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and a mixture thereof.

[0124] According to an embodiment, the organic solvent in the process for the preparation of compounds of formula (V) is optionally selected from a group comprising, hexane, pentane, cyclohexane, petroleum ether, dichloromethane, chlorobenzene, 1,4-dioxane, methyl t- butyl ether (MTBE), tetra hydrofuran (THF), methyl-tetrahydrofuran (Me-THF), ethyl acetate, nitriles such as acetonitrile, N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethylsulfoxide, and a mixture thereof.

[0125] According to an embodiment, the weight ratio between the compound of formula (VI) and the organic solvent is from 1:20 to 10:1, preferably from about 1:0.5 to 1:5, most preferably from about 1:1 to 1:4.

[0126] According to an embodiment, the amount of the organic solvent in the mixture of the process for the preparation of compounds of formula (V) is from 10% to 90 % by weight, more preferably from 20% to 70 % by weight, most preferably from 30% to 50 %, by weight based on the weight of total mixture.

[0127] According to an embodiment, the compound of formula (VI) is contacted with the cyanation reagent at the temperature interval of from -20 to 100°C, more preferably from about 0 to 50°C.

[0128] According to an embodiment, the reaction mixture is monitored by HPLC analytical method, and the process ends when concentration of formula (VI) is between 0-99%, preferably from 0-50%. In particular, the process should be terminated when no more than 5% of compound of formula (VI) remains in the reaction media.

[0129] According to an embodiment, the reaction mixture is monitored by HPLC analytical method, and the process ends when concentration of formula (VI) is between 0-40%, preferably from 0-10%. In particular, the process should be terminated when no more than 1% of compound of formula (VI) remains in the reaction media. According to an embodiment, any residue of non-reacted compound of formula (VI) is recycled according to common and known methods for anyone skilled in the art and can be reused in the next preparation process of formula (V).

[0130] According to an embodiment, the process for the preparation of compound of formula (V), is performed as a common batch process in which a specific amount of reactants is combined in a vessel or reactor, and the reaction is allowed to proceed under controlled conditions such as temperature, pressure, and reaction time according to any of the preceding embodiments. Once the reaction is complete, the products are isolated, and the reactor is cleaned before starting a new batch.

[0131] According to an embodiment, the process for the preparation of compound of formula (V), is performed in a continuous process, also known as continuous flow chemistry, wherein the reaction occurs continuously in a flowing stream of the reactants, without the need for discrete batch operations. Reactants are continuously fed into the reactor system, where they mixed, reacting, and form the compound of formula (V) as they flow through various reaction zones. The compound of formula (V) is then continuously removed from the reactor system, while unreacted starting materials or by-products are either recycled or purged from the system.

[0132] According to an embodiment, the process for the preparation of compound of formula (V), comprising addition of the cyanation reagent to the reaction mixture and further mixing the reaction mixture.

[0133] In yet another embodiment, the process for the preparation of compound of formula (V), comprising the generation of a cyanation reagent in situ and further mixing the reaction mixture.

[0134] The reaction mixture containing the resulting a compound of formula (V) is optionally worked up or proceed without workup to the next step of process. 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. According to an embodiment, the process for the preparation of compound of formula (V), is performed as a telescopic process in which multiple reactions are carried out sequentially in the same reaction vessel, without the need for intermediate isolation and purification steps.

[0135] In another aspect of this invention, the compounds of formula (I) and formula (III), according to any of the preceding embodiments in this present invention, can be used as an intermediates for the preparation of cyantraniliprole. As non-limiting example of preparation of cyantraniliprole, the compound of formula (I) can be at first transformed to intermediates of formula (III) and then reacted with the corresponding pyrazole carboxylic acid or its derivates by the methods such as but not limited to those disclosed in W02006 / 068669, WO 2004 / 067528, WO 2006 / 062978, W02008 / 082502, W02009 / 111553, W02009 / 085816 and WO2024038436.

[0136] 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.

[0137] EXPERIMENTAL PART:

[0138] 1: Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide from 2-amino-N,3- dimethylbenzamide:

[0139] To a 100 mL flask, 2-amino-N,3-dimethylbenzamide (0.5gr, 3.05 mmol) was dissolved in dichloromethane (5mL). FeCh (1 gr, 2 eq, 6.10 mmol) was added slowly at 25 °C and the mixture was stirred for 15 min under nitrogen atmosphere. Then, CNBr (0.65 gr, 2 eq, 6.10 mmol) was added at 25 °C and the mixture was stirred for an additional 12 h at 40 °C. 0.21 gr of 2-amino-5- cyano-N,3-dimethylbenzamide was obtained as solid product.

Claims

CLAIMS:

1. A process for the preparation of compound of formula (I)wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R2 is NO2, NH2, NCOR4, N(R4)2, -N=C(R4h, -NHN(R4)2; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; or R2 and R3 is connected together to form a 6-membered ring, comprising reacting a compound of formula (II) or its salts thereofwherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R2 is NO2, NH2, NCOR4, N(R4)2, -N=C(R4h, -NHN(R4)2; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; or R2 and R3 is connected together to form a 6-membered ring, with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst.

2. A process for the preparation of compound of formula (I)wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R2 is NO2, NH2, NCOR4, N(R4)2, -N=C(R4h, -NHN(R4)2; R3 is halogen, OR4, NHR4, N(R4h; R4 is independently hydrogen, Cl-C4-alkyl; or R2 and R3 is connected together to form a 6-membered ring, comprising reacting a compound of formula (II) or its salts thereofwherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R2 is NO2, NH2, NCOR4, N(R4)2, -N=C(R4h, -NHN(R4)2; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; or R2 and R3 is connected together to form a 6-membered ring, with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and in the presence of a catalyst.

3. The process according to any of claims 1-2, wherein Ri is Me; R2 is NH2; and R3 is OH, OR4; wherein R4 is independently hydrogen, Cl-C4-alkyl.

4. The process according to any of claims 1-3, wherein Ri is Me; R2 is NH2; and R3 is NHMe, NH2.

5. The process according to any of claims 1-4, wherein the weight ratio between the compound of formula (II) and the cyanation reagent is from 1:1 to 1:20.

6. The process according to any of claims 1-5, wherein the weight ratio between the compound of formula (II) and the catalyst is from 100:1 to 1:100.

7. The process according to any of claims 1-6, wherein the weight ratio between the compound of formula (II) and the organic solvent is from 1:20 to 10:1.

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

9. A process for the preparation of compounds of formula (III)wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; comprising reacting a compound of formula (IV) or its salts thereofwherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst.

10. A process for the preparation of compounds of formula (III)wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; comprising reacting a compound of formula (IV) or its salts thereofwherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide, and the mixtures thereof, in the presence of organic solvent, and in the presence of a catalyst.

11. The process according to any of claims 9-10, wherein Ri is Me.

12. The process according to any of claims 9-11, wherein the weight ratio between the compound of formula (IV) and the cyanation reagent is from 1:1 to 1:

20.

13. The process according to any of claims 9-12, wherein the weight ratio between the compound of formula (IV) and the catalyst is from 100:1 to 1:100.

14. The process according to any of claims 9-13, wherein the weight ratio between the compound of formula (IV) and the organic solvent is from 1:20 to 10:1.

15. The process according to any of claims 9-14, wherein the compound of formula (III) is isolated from the reaction mixture or transferred to the next step without isolation.

16. A process for the preparation of compounds of formula (V)wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R3 is halogen, OR4, NHR4, N(R4h; R4 is independently hydrogen, Cl-C4-alkyl; comprising reacting a compound of formula (VI) or its salts thereofwherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide and the mixtures thereof, in the presence of organic solvent, and optionally in the presence of a catalyst.

17. A process for the preparation of compounds of formula (V)wherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; comprising reacting a compound of formula (VI) or its salts thereofwherein Ri is hydrogen, halogen, Cl-C4-alkyl, Cl-C4-haloalkyl, Cl-C4-alkoxy; R3 is halogen, OR4, NHR4, N(R4)2; R4 is independently hydrogen, Cl-C4-alkyl; with cyanation reagent selected from cyanogen chloride, cyanogen bromide, cyanogen (CNCN), p-tolylsulfonyl cyanide, methyl thiocyanate, trimethylsilyl cyanide, N-cyano-N-phenyl-p-toluene sulfonamide and the mixtures thereof, in the presence of organic solvent, and in the presence of a catalyst.

18. The process according to any of claims 17-18, wherein Ri is Me; and R3 is NHMe, NH2, OR4; wherein R4 is independently hydrogen, Cl-C4-alkyl.

19. The process according to any of claims 17-18, wherein the weight ratio between the compound of formula (VI) and the cyanation reagent is from 1:1 to 1:20.

20. The process according to any of claims 17-19, wherein the weight ratio between the compound of formula (VI) and the catalyst is from 100:1 to 1:100.

21. The process according to any of claims 17-20, wherein the weight ratio between the compound of formula (VI) and the organic solvent is from 1:20 to 10:1.

22. The process according to any of claims 1-21, wherein the cyanation reagent is selected from the group comprising cyanogen chloride, cyanogen bromide, p-tolylsulfonyl cyanide and the mixtures thereof.

23. The process according to any of claims 1-22, wherein the catalyst is selected from the group of Lewis acids, organo-metallic complexes, nucleophilic activators, and the mixtures thereof.

24. The process according to claim 23, wherein the catalyst is Lewis acid selected from the group comprising aluminum chloride, ferric chloride, ferric bromide, boron trihydride, borontrichloride, boron tribromide, boron trifluoride, zinc chloride, zinc bromide, titanium tetrachloride, titanium isopropoxide, magnesium chloride, magnesium bromide, and the mixtures thereof.

25. The process according to claim 23, wherein the catalyst is organo-metallic complex selected from the group comprising n-butyllithium, ethyllithium, methyllithium, diethylzinc, tributyltin hydride, triethylborane ethylaluminum dichloride, diethylaluminum chloride, triethylaluminium, methylaluminium dichloride, dimethylaluminium chloride, trimethylaluminium, methylmagnesium chloride, methylmagnesium bromide, dimethylmagnesium, and the mixtures thereof.

26. The process according to claim 23, wherein the catalyst is nucleophilic activator selected from the group comprising triethylamine, dimethylamine, tributylamine, aniline, indole, piperidine, pyridine, pyrimidine, pyrrolidine, pyrrole, imidazole, methylimidazole, 2-picoline, diisopropyl ethyl amine (DIPEA), pyridine, 4-(Dimethylamino)pyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec- 7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO), and the mixtures thereof.

27. The process according to any of claims 1-26, wherein the organic solvent is selected from the group comprising carbon tetrachloride, dichloromethane, dichloroethane, chloroform, hexane, cyclohexane, cyclopentene, n-heptane, pentene, chlorobenzene, diisopropyl ether, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl-tetrahydrofuran, 1,4-dioxane, dimethoxy ethane, sulfolane, N-methylpyrrolidone, dimethylsulfoxide, dimethylacetamide, dimethyl carbonate, diethyl carbonate, propylene carbonate, acetonitrile and the mixtures thereof.

28. The process according to any of claims 1-27, wherein the process is carried out at a temperature of from -20°C to 130 °C.

29. The process according to claims 1-28, comprising the addition of the electrophilic cyanogen agent to the reaction mixture.

30. The process according to any of claims 1-28, comprising the generation of a cyanation reagent in situ.

31. The process according to any of claims 1-27, wherein the process is telescopic process.

32. The process according to any of claims 1-28, wherein the process is continued process.

33. The process of preparation of a cyantraniliprole of formula (VIII), and its salt thereof,using a compound of formula (I) prepared according to any of claims 1-8 or compound of formula (III) prepared according to any of claims 9-15.

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