Process for preparing 2-amino-5-cyanobenzoic acid derivatives

Abstract

The present invention provides a process for the preparation of 2-amino-5- cyanobenzoic acid derivatives of formula (I) and particularly, provides a process of preparation of 2-amino-5-cyano-N,3-dimethylbenzamide. The method of the present invention further provides a process for the preparation of compounds of formula (III) as disclosed herein.

Description

[0001] PROCESS FOR PREPARING 2-AMINO-5-CYANOBENZOIC ACID DERIVATIVES

[0002] FIELD OF THE INVENTION

[0003] The present invention pertains to a method for the preparation of 2-amino-5-cyanobenzoic acid derivatives of formula (I). Particularly, relates to preparation of 2-amino-5-cyano-N,3-dimethylbenzamide.

[0004] O NC. A.

[0005] Y

[0006] R2

[0007] (I)

[0008] BACKGROUND OF THE INVENTION

[0009] Anthranilic diamides are a commercially important class of synthetic insecticides that bind to the ryanodine receptor with selective potency against insect versus mammalian forms of the receptor. The first commercialized anthranilic diamide of this class, chlorantraniliprole, has exceptional activity against lepidopteran pests. The second anthranilic diamide product of the same class, cyantraniliprole, has excellent crossspectrum activity against a range of insect orders, including both lepidopteran and hemipteran pests. The PCT publications W02003015518, W02003015519, W02004067528, W02005077934 and WO2010069502 disclose the use of anthranilic diamides for controlling invertebrate pests such as arthropods.

[0010] Preparation processes for the compound of formula (I) are already described in the literature for example: W02006068669, W02006062978, W02008082502, W02009006061, W02009061991, W02009085816, W02009111553, and W02013007603. W02006068669, discloses a cyanation reaction in the presence of Cu(I)Iodide, and N, N ’-dimethylenediamine, in chlorobenzene as solvent in the presence of potassium iodide.

[0011] 115 °C, 18 h NaCN, solvent, PhCI,

[0012] KI, Cu(l) Iodide,

[0013]

[0014] N. N'-dimethylethylene- diamine

[0015]

[0016] It is evident that the cyanation reaction can only occur in the presence of KI, Cu(I)iodide, and the ligand N, N ’-dimethylenediamine. Further, said process is not so cost effective at the production scale due to use of iodide reagents, and the ligand N, N’-dimethylenediamine.

[0017] W02006062978, W02009006061 and W02009061991 disclose the preparation of 2-amino-5-cyano-N,3-dimethylbenzamide from 2-amino-5-bromo-V,3-dimethylbenzamide using catalyst like palladium and Nickel in the presence of triphosphine ligands and cyanide source e.g. W02006062978, discloses reaction with Palladium (II) acetate, l,4-bis(diphenylphosphino)butane as ligand, zinc powder, and zinc(II) cyanide; W02009006061 discloses reaction with KI, triphenylphosphine, chloronaphthalenylbis(triphenylphosphine)nickel as a ligand, and KCN; W02009061991 discloses reaction with NaCN, Zn, and [1,1'-bis(diphenylphosphino)ferrocene][(l,2,5,6)-l,5-cyclooctadiene]nickel as a ligand. All these conditions are not environmentally friendly and produce environmental hazard on large scale.

[0018] W02008082502, W02009085816 and W02009111553 discloses a process for preparing 2-amino-5-cyano-N,3-dimethylbenzamide from 2-amino-5-bromo-N,3-dimethylbenzamide using cyanation source e.g. NaCN, iodine source, catalyst e.g. Cu(I)I and in the presence of ligand such as N, N’- Di methyl ethylenedi amine, picoline derivative and imidazole derivatives respectively. The prior art describes that for the conversion of bromo to cyano it requires, Cu(I)Iodide as catalyst (as well as iodine source) along with the ligands as described above which make the process expensive. From the above discussion, it is evident that prior art methods for the cyanation of anthranilamides utilize expensive reagents such as palladium catalysts, N-containing ligands, complexes of Ni or Fe, KI, and Cu(I) salts.

[0019] WO2013007603 discloses a process for preparing 2-amino-5-cyanobenzoic acid derivatives using Cu(I)CN as disclosed in the scheme below:

[0020]

[0021] One of the shortcomings associated with the above disclosed process is low yields of the product.

[0022] As per the processes disclosed in the prior art, cyanation is carried out in the presence of an iodine source, essentially in the form of KI or Cu(I) iodide. Apart from this, other catalyst like Pd or nickel-based reagents and N-containing ligands are used to get the desired conversion. All these reagents used are undesirable due to their high costs, challenges in effluent management and other disadvantages like stability, sensitivity to light, toxicity etc. The processes disclosed in the prior art also suffer in terms of yield and purity.

[0023] Thus, there is a need for a method that obviates at least one of the shortcomings associated with the known processes and find a simple, environment friendly, efficient and industrially economical process for the preparation of anthranilic acid / amides of formula (I). This need is addressed by the present invention.

[0024] The present invention provides a process for the preparation of compounds of formula (I) (2-amino-5-cyanobenzoic acid derivatives) using a Cu (II) salt which is cost effective, environment friendly, and enabling good yields on a commercial scale.

[0025] OBJECTIVE OF THE INVENTION: The main objective of the present invention is to provide a simple, environmentfriendly, and cost-effective process for the synthesis of anthranilic acid / amide compounds of formula (I).

[0026] Another objective of the present invention is to provide a process for the synthesis of anthranilic diamide compounds of formula (III).

[0027] SUMMARY OF THE INVENTION

[0028] The present invention provides a method for preparing compounds of formula (I),

[0029]

[0030] wherein

[0031] R1is selected from NR3R4, or OR5;

[0032] R2is selected from C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;

[0033] R3is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl are unsubstituted or substituted with a group selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkoxyl;

[0034] R4is selected from H, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0035] or

[0036] R3and R4together with the nitrogen atom to which they are attached may form a 5- or 6- membered heterocyclic ring optionally substituted with halogen or C1-C6 alkyl; and

[0037] R5is H, or C1-C6 alkyl;

[0038] comprising contacting:

[0039] (1) a compound of formula (II)

[0040]

[0041] wherein X is Br, or Cl; R1and R2are same as defined above

[0042] with

[0043] (2) a metal cyanide,

[0044] (3) a copper (II) salt, and

[0045] (4) optionally a suitable organic solvent.

[0046] The invention also provides a method for preparing compounds of formula (III)

[0047]

[0048] wherein,

[0049] R1is selected from NR3R4, or OR5;

[0050] R2is selected from C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0051] R3is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl are unsubstituted or substituted with a group selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkoxyl;

[0052] R4is selected from H, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0053] or R3and R4together with the nitrogen atom to which they are attached may form a 5- or 6- membered heterocyclic ring optionally substituted with halogen or C1-C6alkyl;

[0054] R5is H or C1-C6alkyl;

[0055] Z is CR9, or N;

[0056] R6is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy; OCF2H, OCH2CF3, or -A-C1-C5heterocyclyl; wherein -A- is selected from the group comprising of direct bond, CHR10, -O- or -S; and said heterocyclyl may optionally be substituted with one or more groups selected from hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl;

[0057] R7is selected from F, Cl or Br; R8is selected from H, F or Cl; R9is H or C1-C6 alkyl; and R10is H or C1-C6 alkyl;

[0058] using compounds of formula (I),

[0059]

[0060] wherein

[0061] R1and R2are same as defined above;

[0062] characterized by preparing said compounds of formula (I) by the method disclosed above.

[0063] DETAILED DESCRIPTION OF THE INVENTION

[0064] The definitions provided herein for the terminologies used in the present disclosure are for illustrative purposes only and in no manner limit the scope of the present invention disclosed in the present disclosure. As used herein, the terms “comprises”, “comprising”, “includes”, “including”, “has”, “having”, “contains”, “containing”, “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process, or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, or method.

[0065] The transitional phrase “consisting of’ excludes any element, step or ingredient not specified. If in the claim, such would close the claim to the inclusion of materials other than those recited except for impurities ordinarily associated therewith. When the phrase “consisting of’ appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole.

[0066] Further, unless expressly stated to the contrary, “or” refers to an inclusive “or” and not to an exclusive “or”. For example, a condition A “or” B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0067] Also, the indefinite articles “a” and “an” preceding an element or component of the present invention are intended to be non-restrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore “a” or “an” should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is meant to be singular.

[0068] As used herein, the term “condensing” or “contacting” or “subjecting” or “reacting” or “treating” refers to a process of combining reactant(s) in a suitable medium or in a solvent, wherein the reactant gets converted into the product under the reaction condition described. As used herein, the term “sufficient formation” refers to wherein, the conversion of reactant(s) into the product is 50 % or more under the reaction conditions described. Carbon-based radical refers to a monovalent molecular component comprising a carbon atom that connects the radical to the remainder of the chemical structure through a single bond. Carbon-based radicals can optionally comprise saturated, unsaturated, and aromatic groups, chains, rings and ring systems, and heteroatoms. Although carbon-based radicals are not subject to any particular limit in size, in the context of the present invention they typically comprise 1 to 16 carbon atoms and 0 to 3 heteroatoms. Of note are carbon-based radicals selected from C1-C6 alkyl, C1-C6 haloalkyl, and phenyl optionally substituted with 1-3 substituents selected from C1-C3 alkyl, halogen, and nitro.

[0069] The meaning of various terms used in the description shall now be illustrated.

[0070] The term “alkyl” used either alone or in compound words such as “alkylthio” or “haloalkyl” or -N(alkyl) or alkylcarbonylalkyl or alkylsuphonylamino includes straight-chain or branched C1 to C6 alkyl. Representative examples of alkyl include methyl, ethyl, propyl, 1 -methylethyl, butyl, 1 -methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3 -methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, hexyl, 1, 1 -dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 1,1 -dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3 -dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1 -ethyl- 1 -methylpropyl and l-ethyl-2-methylpropyl or the different isomers. If the alkyl is at the end of a composite substituent, as, for example, in alkylcycloalkyl, the part of the composite substituent at the start, for example the cycloalkyl, may be mono- or polysubstituted identically or differently and independently by alkyl. The same also applies to composite substituents in which other radicals, for example alkenyl, alkynyl, hydroxyl, halogen, carbonyl, carbonyloxy and the like, are at the end. The term “cycloalkyl” means alkyl closed to form a ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. This definition also applies to cycloalkyl as a part of a composite substituent, for example cycloalkylalkyl etc., unless specifically defined elsewhere.

[0071] The term "C3-C6 cycloalkoxyl" refers to a group of the general formula -OR, where R is a saturated hydrocarbon ring containing 3 to 6 carbon atoms. Non-limiting examples include -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, and -O-cyclohexyl.

[0072] The term “halogen”, either alone or in compound words such as “halomethyl”, or “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “halomethyl”, “haloalkyl”, said alkyl or methyl may be partially or fully substituted with halogen atoms which may be the same or different. Non-limiting examples of “haloalkyl” include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, di chlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1-bromoethyl, 1 -fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-tri chloroethyl, pentafluoroethyl, 1, 1 -dichloro-2,2,2-trifluoroethyl, and 1,1,1-trifluoroprop-2-yl.

[0073] The term "alkoxy" used either alone or in compound words included C1 to C6 alkoxy. Non limiting examples of alkoxy include methoxy, ethoxy, propoxy, 1 -methylethoxy, butoxy, 1 -methylpropoxy, 2-methylpropoxy, 1, 1 -dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3 -methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1, 1 -dimethylpropoxy, 1,2-dimethylpropoxy, 1 -methylpentoxy, 2-methylpentoxy, 3 -methylpentoxy, 4-methylpentoxy, 1, 1 -dimethylbutoxy, 1,2-dimethylbutoxy, 1,3 -dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1 -ethylbutoxy, 2-ethylbutoxy, 1, 1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1 -ethyl- 1 -methylpropoxy and l-ethyl-2-methylpropoxy and the different isomers. This definition also applies to alkoxy as a part of a composite substituent, for example haloalkoxy, alkynylalkoxy, etc., unless specifically defined elsewhere.

[0074] The term "hydroxy" means -OH.

[0075] The term “H” means hydrogen.

[0076] The term "heterocycle" or "heterocyclic" or "heterocyclyl" includes "aromatic heterocycle" or "heteroaryl bicyclic ring system" and "nonaromatic heterocycle " or polycyclic or bicyclic (spiro, fused, bridged, non-fused) ring compounds in which ring may be aromatic or non-aromatic, wherein the heterocycle ring contains at least one heteroatom selected from N, O, S(O)0-2, and / or C ring member of the heterocycle may be replaced by C(=O) and C(=S).

[0077] The term "non-aromatic heterocycle" or "non-aromatic heterocyclic" means three- to ten-membered, preferably three- to six-membered, saturated or partially unsaturated heterocycle containing one to four heteroatoms, selected from the group of oxygen, nitrogen and sulphur; mono, bi- or tricyclic heterocycles which contain, in addition to carbon ring members, one to three nitrogen atoms and / or one oxygen or sulphur atom or one or two oxygen and / or sulphur atoms; if the ring contains more than one oxygen atom, they are not directly adjacent; for example (but not limited to) oxetanyl, thietanyl, thietanyl 1 -oxide, thietanyl 1,1 -di oxi de, oxiranyl, aziridinyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxadiazolidinyl, thiadiazolidinyl, triazolidinyl, dihydrofuryl, dihydrothienyl, pyrrolinyl, isoxazolinyl, isothiazolinyl, dihydropyrazolyl, dihydrooxazolyl, dihydrothiazolyl, piperidinyl, pyrazynyl, morpholinyl, thiomorphlinyl, 1,3-dioxany, tetrahydropyranyl, tetrahydrothienyl; wherein these rings are attached to the skeleton via one of the carbon or nitrogen of said rings. This definition also applies to heterocyclyl as a part of a composite substituent, for example heterocyclylalkyl etc., unless specifically defined elsewhere.

[0078] The term "heteroaryl" or "aromatic heterocyclic" means 5-membered, fully unsaturated monocyclic ring system containing one to four heteroatoms selected from the group of oxygen, nitrogen and sulphur; if the ring contains more than one oxygen atom, they are not directly adjacent; 5-membered heteroaryl containing one to four nitrogen atoms or one to three nitrogen atoms and one sulphur or oxygen atom; 5 -membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulphur or oxygen atom as ring members, for example (but not limited thereto) furyl, thienyl, pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl; wherein these rings are attached to the skeleton via one of the carbon or nitrogen of said rings.

[0079] When a group contains a substituent which can be hydrogen, then, when this substituent is taken as hydrogen, it is recognized that said group is being un-substituted.

[0080] As used herein, the term “C1-C5heterocyclyl” refers to a saturated or unsaturated ring system containing 1 to 5 carbon atoms and one or more heteroatoms selected from O, N, or S(O)0-2. The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of the ways in which the embodiments herein may be practiced and to further enable those skilled in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

[0081] The description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and / or adapt for various applications of such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modifications within the spirit and scope of the embodiments as described herein. The numerical values mentioned in the description and the description / claims though might form a critical part of the present invention of the present disclosure, any deviation from such numerical values shall still fall within the scope of the present disclosure if that deviation follows the same scientific principle as that of the present invention disclosed in the present disclosure.

[0082] The compound of formula (I) or (III) and intermediates thereof is also read as including salts thereof. Exemplary salts include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, trifluoroacetate, and trifluoromethane sulfonate.

[0083] Embodiments of the present invention include:

[0084] Embodiment 1

[0085] The present invention is directed to a method for preparing compounds of formula (I) or salts thereof,

[0086]

[0087] wherein,

[0088] R1is selected from NR3R4, or OR5;

[0089] R2is selected from C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; R3is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl are unsubstituted or substituted with a group selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkoxyl;

[0090] R4is selected from H, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0091] or

[0092] R3and R4together with the nitrogen atom to which they are attached may form a 5- or 6- membered heterocyclic ring optionally substituted with halogen or C1-C6 alkyl; and

[0093] R5is H, or C1-C6 alkyl;

[0094] comprising the step of:

[0095] reacting,

[0096] (1) a compound of formula (II)

[0097]

[0098] wherein X is Br, or Cl; R1, R2, R3, R4, and R5are same as defined above; with

[0099] (2) a metal cyanide,

[0100] (3) a copper (II) salt, and

[0101] (4) optionally a suitable organic solvent.

[0102] Embodiment la.

[0103] The invention also provides a method for preparing a compound of formula (la), wherein R1is NHR3; R2R2

[0104]

[0105] Embodiment lb.

[0106] The invention also provides a method for preparing a compound of formula (lb), wherein R1is OR5, and wherein R5is H;

[0107]

[0108] Embodiment lc.

[0109] The invention also provides a method for preparing a compound of formula (Ic), wherein R1is OR5, and wherein R5is C1-C6alkyl;

[0110]

[0111] Embodiment 2

[0112] The method as disclosed in any of the above embodiments, wherein R3and R4together with the nitrogen atom to which they are attached may form a 5- or 6- membered heterocyclic ring.

[0113] Embodiment 3 The method as disclosed in any of the above embodiments, wherein R3is C1-C6alkyl, Ci-Ce haloalky 1, cyclopropyl, cyclopropyl-cyclopropyl, cyclopropylmethyl, cyclopropylethyl, or methylcyclopropyl and R4is selected from H, C1-C3 alkyl, or C3-Ce cycloalkyl.

[0114] Embodiment 4

[0115] The method of embodiment 3, wherein R3is C1-C4 alkyl, or cyclopropylethyl and R4is H.

[0116] Embodiment 5

[0117] The method of embodiment 4, wherein R3is methyl.

[0118] Embodiment 6

[0119] The method as disclosed in any of the above embodiments, wherein R2is methyl, or trifluoromethyl.

[0120] Embodiment 7

[0121] The method as disclosed in any of the above embodiments, wherein X is Br.

[0122] Embodiment 8

[0123] The method as disclosed in any of the above embodiments, wherein the compound of formula (II) is 2-amino-5-bromo- / V,3-dimethylbenzamide.

[0124] Embodiment 9

[0125] The method of any one of the embodiments 1 to 8, wherein the metal cyanide is selected from alkali metal cyanides, alkali metal hexacyanoferrates(II) and copper(I) cyanide.

[0126] Embodiment 10

[0127] The method of embodiment 9, wherein the metal cyanide is selected from the group consisting of alkali metal cyanides and alkali metal hexacyanoferrates(II). Embodiment 11

[0128] The method of embodiment 9, wherein the metal cyanide is selected from one or more of sodium cyanide, copper(I) cyanide, potassium hexacyanoferrate(II) and sodium hexacyanoferrate(II).

[0129] Embodiment 12

[0130] The method of embodiment 11, wherein the metal cyanide is selected from the group consisting of sodium cyanide, copper(I) cyanide, sodium hexacyanoferrate(II) and potassium hexacyanoferrate(II).

[0131] Embodiment 13

[0132] The method of embodiment 12, wherein the metal cyanide is selected from the group consisting of sodium cyanide, copper(I) cyanide and potassium hexacyanoferrate(II).

[0133] Embodiment 14

[0134] The method of embodiment 13, wherein the metal cyanide is copper(I) cyanide.

[0135] Embodiment 15

[0136] The method of any one of the embodiments 1 to 14, wherein the mole ratio between the metal cyanide to the compound of formula (II) ranges from 1: 6 to 100: 1.

[0137] Embodiment 16

[0138] The method of embodiment 15 wherein the mole ratio between the metal cyanide to the compound of formula (II) ranges from 1:6 to 50: 1.

[0139] Embodiment 17

[0140] The method of embodiment 16 wherein the mole ratio between the metal cyanide to the compound of formula (II) ranges from 1:6 to 25: 1. Embodiment 18

[0141] The method of embodiment 17 wherein the mole ratio between the metal cyanide to the compound of formula (II) ranges from 1:6 to 10: 1.

[0142] Embodiment 19

[0143] The method of any one of the embodiments 1 to 18, wherein the mole ratio between the metal cyanide to the compound of formula (II) ranges from 1:6 to 6: 1.

[0144] Embodiment 20

[0145] The method of embodiment 19 wherein the mole ratio between the metal cyanide to the compound of formula (II) ranges from 1:2.5 to 2.5:1.

[0146] Embodiment 21

[0147] The method of embodiment 20 wherein the mole ratio between the metal cyanide to the compound of formula (II) ranges from 1:2 to 2: 1.

[0148] Embodiment 22

[0149] The method of embodiment 21 wherein the mole ratio between the metal cyanide ion to the compound of formula (II) is 1:1.

[0150] Embodiment 23

[0151] The method as disclosed in any of the embodiments 1 to 22, wherein the copper(II) salt is Copper(II) acetate, Copper(II) borate, Copper(II) bromide, Copper(II) carbonate, Basic copper carbonate, Copper(II) chlorate, Copper(II) chloride, Copper(II) fluoride, Copper(II) hydroxide, Copper(II) oxide, Copper(II) phosphate, Copper(II) sulfate, Copper(II) tetrafluoroborate, Copper(II) triflate, or Copper(II) trifluoroacetate and hydrates thereof; preferably Copper(II) acetate. Embodiment 24

[0152] The method of any one of embodiments 1 to 23, wherein the mole ratio of the copper(II) salt to the compound of formula (II) ranges from 0.01: 1 to 1:1.

[0153] Embodiment 25

[0154] The method of any one of the embodiments 1 to 24, wherein the mole ratio of the copper(II) salt to the compound of formula (II) ranges from 0.1:1 to 0.9: 1.

[0155] Embodiment 26

[0156] The method of any one of the embodiments 1 to 25, wherein the mole ratio of the copper(II) salt to the compound of formula (II) ranges from 0.2: 1 to 0.8: 1.

[0157] Embodiment 27

[0158] The method of any one of the embodiments 1 to 26, wherein the mole ratio of the copper(II) salt to the compound of formula (II) ranges from 0.25: 1 to 0.5: 1.

[0159] Embodiment 28

[0160] The method of any one of the embodiments 1 to 27, wherein the mole ratio of the copper(II) salt to the compound of formula (II) ranges from 0.3:1 to 0.45: 1.

[0161] Embodiment 29

[0162] The method of any one of embodiments 1 to 28, wherein the compound of formula (II), the metal cyanide, and the Cu (II) salt are contacted in a suitable organic solvent. Embodiment 30

[0163] The method of any one of the embodiments 1 to 29, wherein the compound of formula (II) is contacted with a suitable organic solvent to form a mixture, and then the metal cyanide and the Cu (II) salt or the Cu (II) salt and metal cyanide are added to the mixture.

[0164] Embodiment 31 The method of any one of the embodiments 29 or 30, wherein the suitable organic solvent comprises one or more solvents selected from the group consisting of halogenated and non-halogenated aliphatic and aromatic hydrocarbons, and dipolar aprotic solvents.

[0165] Embodiment 32

[0166] The method of embodiment 31 wherein the suitable organic solvent comprises one or more solvents selected from the group consisting of xylenes, toluene, chlorobenzene, methoxybenzene (also known as anisole), 1,2,4-trimethylbenzene, 1,3,5-trimethylbenzene (also known as mesitylene), ethylbenzene, (l-methylethyl)benzene (also known as cumene), C1-C3 alkyl-substituted naphthalenes (e.g., 1-methylnaphthalene, 2-methylnaphthalene, 1,5-dimethylnaphthalene, 2,6-dimethylnaphthalene and 1,3-dimethylnaphthalene), mixture of C9-C10 aromatic hydrocarbons, mixture of C10-C11 aromatic hydrocarbons; N, N-dimethylacetamide, diglyme, tetraglyme, sulpholane, 5-ethyl-2-methylpyridine, N, N-dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone (NMP).

[0167] Embodiment 33

[0168] The method of embodiment 32 wherein the suitable organic solvent comprises one or more dipolar aprotic solvents selected from N,N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, 5-ethyl-2-methylpyridine, or N-methyl-2-pyrrolidone (NMP).

[0169] Embodiment 34

[0170] The method of embodiment 33, wherein the suitable organic solvent comprises 5-ethyl-2-methylpyridine, or N-methyl-2-pyrrolidone.

[0171] Embodiment 35 The method of any one of the embodiments 1 to 34, wherein the compound of formula (II), metal cyanide and Cu (II) salt are contacted with a suitable organic solvent at a temperature in the range of 80 to 200 °C.

[0172] Embodiment 36

[0173] The method of any one of the embodiments 1 to 35, wherein the compound of formula (II), metal cyanide and Cu (II) salt are contacted with a suitable organic solvent at a temperature in the range of 150 to 200 °C.

[0174] Embodiment 37

[0175] The method of any one of the embodiments 1 to 36, wherein the compound of formula (II), metal cyanide and Cu (II) salt are contacted with a suitable organic solvent at a temperature in the range of 160 to 195 °C.

[0176] Embodiment 38

[0177] The method of embodiment 1, wherein X is Br or Cl, comprising: contacting a compound of formula (II) with a suitable organic solvent to form a mixture, and then sequentially adding the metal cyanide, and the copper(II) salt, maintaining the temperature of the mixture between about 145 and 200 °C for about 2 to about 30 h, cooling the mixture to between about 0 and 75 °C, adding water to the mixture, optionally stirring for about 1 to about 8 h, and then recovering a compound of formula (I).

[0178] Embodiment 39

[0179] The method as disclosed in embodiment 38, wherein the compound of formula (I) is 2-amino-5-cyano- / V,3-dimethylbenzamide.

[0180] Embodiment 40 The method as disclosed in embodiment 39, suitable diluents in the workup of the reaction according to the invention are all inert organic solvents. These preferably include aliphatic, alicyclic or aromatic hydrocarbons such as, for example, petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; halogenated hydrocarbons such as, for example, chlorobenzene, dichlorobenzene, dichloromethane, dichloroethane or trichloroethane; ethers, such as diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-di ethoxy ethane or anisole; ketones, such as acetone, butanone, methyl isobutyl ketone or cyclohexanone; esters such as methyl acetate or ethyl acetate.

[0181] Embodiment 41

[0182] In an embodiment, there is provided a method for the preparation of a compound of formula (I) as disclosed in any of the embodiments 1 to 40, wherein the compound of formula (II) is prepared from a substituted aniline according to any of the method or process as described in the prior art references W02008 / 082502, W02020170092, WO2022058916, WO2022064454, and W02024105700.

[0183] Embodiment 42

[0184] A method for preparing a compound of formula (III) or salts thereof

[0185]

[0186] wherein,

[0187] R1is selected from NR3R4, or OR5;

[0188] R2is selected from C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; R3is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl are unsubstituted or substituted with a group selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkoxyl;

[0189] R4is selected from H, C1-C6 alkyl, or C3-C6 cycloalkyl;

[0190] or

[0191] R3and R4together with the nitrogen atom to which they are attached may form a 5- or 6- membered heterocyclic ring optionally substituted with halogen or C1-C6alkyl;

[0192] R5is H or C1-C6alkyl;

[0193] Z is CR9, or N;

[0194] R6is selected from the group comprising of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy; OCF2H, OCH2CF3, or -A-C1-C5heterocyclyl; wherein -A- is selected from the group comprising of direct bond, CHR10, -O- or -S-; and said heterocyclyl may optionally be substituted with one or more groups selected from hydrogen, halogen, cyano, C1-C4 alkyl or C1-C4 haloalkyl;

[0195] R7is selected from F, Cl or Br; R8is selected from H, F or Cl; R9is H or C1-C6 alkyl; and R10is H or C1-C6 alkyl;

[0196] using a compound of formula (I),

[0197]

[0198] wherein

[0199] R1and R2, are same as defined above;

[0200] characterized by: preparing said compound of formula (I) by the method disclosed in embodiment 1. Embodiment 43 The method as disclosed in embodiment 42, wherein R1is NR3H, and the compound obtained is referred to as compound of formula (Illa).

[0201]

[0202] Embodiment 44 The method as disclosed in embodiment 42, wherein R1is OR5, and R5= H, and the compound obtained is referred to as the compound of formula (Illb).

[0203]

[0204] Embodiment 45 The method as disclosed in embodiment 42, wherein R1is OR5, and R5= C1-C6alkyl, and the compound obtained is referred to as the compound of formula (IIIc).

[0205]

[0206] Embodiment 46 The method of any of embodiments 42 to 45, wherein Z is N. Embodiment 47

[0207] The method of any one of the embodiments 41 to 46, wherein R3and R4are independently, H, C1-C4 alkyl, cyclopropyl, cyclopropyl-cyclopropyl, cyclopropylmethyl, cyclopropylethyl or methylcyclopropyl.

[0208] Embodiment 48

[0209] The method of embodiment 47, wherein R3is methyl and R4is H.

[0210] Embodiment 49

[0211] The method of any one of embodiments 41 to 48, wherein R2is methyl.

[0212] Embodiment 50

[0213] The method of any one of the embodiments 41 to 49, wherein R6is selected from the

[0214] S(O)0.2

[0215] group comprising of bromo, chloro, O and

[0216]

[0217] Embodiment 51

[0218] The method of any one of the embodiments 41 to 50, wherein R7is Cl.

[0219] Embodiment 52

[0220] The method of any one of embodiments 41 to 51, wherein R8is H.

[0221] Embodiment 53

[0222] In one embodiment of the present invention, R1is selected from NR3R4, or OR5; R2is selected from C1-C3 alkyl;

[0223] R3is selected from C1-C3 alkyl;

[0224] R4is H;

[0225] and

[0226] R5is H, or C1-C3 alkyl. Embodiment 54

[0227] According to any of the above embodiment, the present invention provides the preparation of compound of formula (III) or salts thereof,

[0228]

[0229] wherein,

[0230] R1is selected from NR3R4, or OR5;

[0231] R2is C1-C6alkyl;

[0232] R3is selected from H, or C1-C6alkyl;

[0233] R4is selected from H, or C1-C6alkyl;

[0234] R5is H or C1-C6alkyl;

[0235] Z is N;

[0236] R6is selected from the group comprising of bromo, chloro, O S(O)0-2

[0237]

[0238] R8is selected from H, or Cl;

[0239] comprising the steps of:

[0240] step-A: reacting

[0241] (1) a compound of formula (II)

[0242]

[0243] wherein X is Br, or Cl; R1and R2are as defined above,

[0244] with

[0245] (2) a metal cyanide,

[0246] (3) a copper (II) salt, and

[0247] (4) optionally a suitable organic solvent;

[0248] to obtain compound of formula (I);

[0249] step-B: reacting the compound of formula (I) obtain in step A with a compound of formula (VII),

[0250]

[0251] to obtain compound of formula (III).

[0252] Embodiment 55

[0253] According to embodiment 54, said step-B is carried out in the presence of a suitable acid chloride, a suitable base and a suitable solvent, which are selected from:

[0254] i. the acid chloride in the step-B is selected from thionyl chloride (SOCh), mesityl chloride (MsCl), phosphorus pentachloride (PCI5), phosphorus trichloride (PCh), oxalyl chloride, triphosgene or phosgene; ii. the suitable solvent(s) in the step-B are independently selected from dichloroethane, acetonitrile (ACN), A, A-dimethylformamide (DMF), ethyl acetate, pyridine, picoline, or mixtures thereof;

[0255] iii. the suitable base(s) in the step-B are independently selected from alkali or alkaline earth metal carbonate, bicarbonate, hydroxide, hydrides or alkoxide, isopropyl amine, triethylamine, diisopropylethyl amine, triisopropylamine, pyridine, picoline, N-methylmorpholine, N- methylpiperidine, N, A-(dimethylamino)pyridine (DMAP), lutidine, collidine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4- diazabicyclo[2.2.2]octane (DABCO), l,5,7-triazabicyclo[4.4.0]dec-5- ene (TBD), or l,5-diazabicyclo[4.3.0]non-5-ene (DBN); iv. the step-B is performed at a temperature within a range of 0 to 80°C.

[0256] In the following schemes the definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Z in the compounds of the present invention are as defined above unless specifically defined otherwise.

[0257] Scheme 1

[0258] As shown in Scheme 1, compound of formula (I), is prepared by contacting a compound of formula (II) with at least one metal cyanide, at least one copper(II) salt, and optionally in the presence of a suitable solvent.

[0259] Metal cyanide,

[0260] Cu (II) salt Scheme 1

[0261]

[0262]

[0263] In the present method, the metal cyanide particularly comprises at least one compound selected from the group consisting of alkali metal cyanides, alkali metal hexacyanoferrates (II) and copper(I) cyanide. Suitable alkali metal cyanides include compounds with an alkali metal such as sodium or potassium. Suitable alkali metal hexacyanoferrates (II) include, for example, potassium hexacyanoferrate(II) and sodium hexacyanoferrate(II), both of which are commercially available at low cost, are non-toxic, easy to handle, and have six cyanide ions available for transfer to compounds of formula (II).

[0264] Typically, the mole ratio between the metal cyanide and the compound of formula (II) is from 1:6 to 100:1, 1:6 to 50:1, 1:6 to 25:1, 1:6 to 10:1, 1:6 to 6:1, 1:2.5 to 2.5:1, 1:2 to 2:1 or 1:1.

[0265] In the method of Scheme 1, the copper(II) salt reagent is believed to act as a source of a chemical species which catalyzes the conversion of formula (II) compounds to formula (I).

[0266] The mole ratio of the copper(II) salt to the compound of formula (II) ranges from 0.01:1 to 1:1, 0.1:1 to 0.9:1, 0.2:1 to 0.8:1, 0.25:1 to 0.5:1, 0.3:1 to 0.45:1.

[0267] The reaction of Scheme 1 is typically conducted in a suitable organic solvent. A variety of solvents can be used to form the suitable solvent system for this method. Typically, the method is most satisfactorily conducted using solvents in which compounds of formula (II), are preferably completely or at least substantially soluble.

[0268] Examples of suitable solvents include halogenated and nonhalogenated aliphatic and aromatic hydrocarbons such as xylenes, toluene, chlorobenzene, methoxybenzene (also known as anisole), 1,2,4-trimethylbenzene, 1,3, 5 -trimethylbenzene (also known as mesitylene), ethylbenzene, (l-methylethyl)benzene (also known as cumene), C1-C3 alkyl-substituted naphthalenes (e.g., 1 -methylnaphthalene, 2-methylnaphthalene, 1,5-dimethylnaphthalene, 2,6-dimethylnaphthalene and 1,3-dimethylnaphthalene) and aromatic solvent mixtures, such as mixture of C9-C10 aromatic hydrocarbons and mixture of C10-C11 aromatic hydrocarbons, and dipolar aprotic solvents such as N, N-dimethylacetamide, diglyme, tetraglyme, sulpholane, 5-ethyl-2-methylpyridine, N, N- dimethylformamide, dimethylsulfoxide, and N-methyl-2-pyrrolidone (NMP), including mixtures of the foregoing solvents.

[0269] The method is most satisfactorily conducted using a solvent that allows for reaction temperatures between about 80 and 200 °C, preferably between 150 to 200 °C, and more preferably between 160 to 195 °C. This can be accomplished by using a solvent with a normal boiling point (i.e. boiling point at 100 kPa pressure), such as 5-ethyl-2-methylpyridine, or V-methyl-2-pyrrolidone (NMP), within or above this range or by operating at elevated pressure with a lower boiling solvent such as xylenes or toluene. The method is also conveniently conducted using a solvent with a normal boiling point in the range of about 150 and 200 °C such as 1,3, 5 -trimethylbenzene, 1-methylnaphthalene, C9-C11 aromatic solvent mixtures, or mixtures thereof.

[0270] In the present method, the order in which reactants are combined is not critical to the outcome of the reaction. One order of combination, for example, involves combining the compound of formula (II) with the suitable organic solvent to form a mixture, and then sequentially adding the metal cyanide, and the copper(II) salt reagent. Alternatively, in some cases it is advantageous to dissolve the copper(II) salt in the suitable organic solvent and add this solution to a mixture comprising the compound of formula (II), metal cyanide and a suitable organic solvent. A variety of other orders of addition, such as mixing the compound of formula II, the metal cyanide, the Cu (II) salt and the suitable organic solvent together, are also useful for the present method.

[0271] Scheme 2:

[0272] Starting compounds of formula (II) can be made by a variety of methods known in the art. As shown in Scheme 2, according to one method, compounds of formula (II) are prepared by halogenation of a compound of formula (V) using a variety of reagents known in the literature including bromine, chlorine, sulfuryl chloride, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) and halogenating reagents such as mixtures comprising hydrogen peroxide and hydrogen halide. For leading references describing these methods, see PCT Patent Publications WO199816503 (Scheme 4 and Example 132), W02006068669 (Scheme 11), W02003015519 (Scheme 4 and Example 1, Step A) and W02006062978 (Scheme 15; Example 4, Step B and Example 5, Step B).

[0273]

[0274] Another method for preparing compounds of formula (II) wherein X is Br and R1is NHR3involves bromination of compounds of formula (V) by treatment with a gas containing bromine, as illustrated by the procedure of reference example 1 (Reference Example 1 is also found in PCT Patent Publication W02008082502).

[0275] Scheme 3:

[0276] Compounds of formula Ila (Formula II, wherein R1is NHR3) can also be prepared by contacting an isatoic anhydride of formula (VI) with an alkyl amine of formula (IV) in the presence of a carboxylic acid as illustrated in Scheme 3.

[0277]

[0278] Further, the compound of formula (II) or (Ila) as disclosed in any of the above embodiment, is prepared from a substituted aniline according to any of the method or process as described in the prior art references e.g. W02006062978, W02008082502, WO2012103436, WO2013117601, WO2021086957, W02020170092, WO2022058916, WO2022064454, or WO2024105700.

[0279] Scheme 4

[0280] In another aspect of the present invention, compounds of formula (I) prepared by the method of Scheme 1 are useful as intermediates for preparing compounds of formula (III). Compounds of Formula (III) are useful as insecticides, as described, for example in PCT Patent Publications W02003015518 and W02006055922.

[0281] Also see PCT Patent Publication WO 2004 / 067528, which teaches the general method shown in Scheme 4, including experimental examples relevant to Scheme 4.

[0282]

[0283] Scheme 5

[0284] Another method of preparing compounds of formula (Illa) is shown in Scheme 5. In this method a compound of formula (Illa) is prepared by combining a compound of formula (la) (formula (I), wherein R1is NHR3), a pyrazole of formula (VII) and sulfonyl chloride according to the general method taught in PCT Patent Publication WO 2006 / 062978, which is hereby incorporated herein in its entirety by reference.

[0285]

[0286]

[0287] As described in WO 2006 / 062978, a variety of reaction conditions are possible for this transformation. The method is described PCT Patent Publication WO 2003 / 016282. Conversion of the esters to acids can be done using the methods described above. Also, WO 2003 / 016282 provides a relevant experimental example for the conversion of an ester to an acid.

[0288] Scheme 6 Anthranilic amides of formula (la) can also be prepared from the corresponding acids of formula (lb) (formula (I), wherein R1is OR5and R5is H) or esters of Formula Ic (formula (I), wherein R1is OR5and R5is H or C1-C4 alkyl) as shown below in Scheme

[0289]

[0290] 4Ic: R = (C C alkyl) lb: R5= H

[0291] The preparation of an anthranilic amide is carried out using an anthranilic acid through an N-protected aniline intermediate or through a 4H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride) intermediate. A procedure useful for conversion of anthranilic esters to anthranilic amides is described in PCT Patent Publication WO 2006 / 062978. Also, E. B. Skibo et al., Journal of Medicinal Chemistry 2002, 45(25), 5543-5555 discloses preparation of an anthranilic amide from the corresponding anthranilic ester using sodium cyanide catalyst.

[0292] The product compounds of formula (Illa) can be isolated from the reaction mixtures by methods known to those skilled in the art, including crystallization, filtration, and extraction.

[0293] Any person skilled in the art knows the best work-up of the reaction mixtures after the end of the respective reactions. In one embodiment, the work-up is usually carried out by isolation of the product by filtration, and optionally washing with solvent, further optionally drying of the product if required.

[0294] Without further elaboration, it is believed that one skilled in the art using the preceding description can 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. The following examples illustrate synthesis procedures, and the starting material of each example may not have necessarily been prepared by a particular preparative run whose procedure is described in other examples.

[0295] Examples

[0296] General Method for Cyanation:

[0297] A reactor was charged with the solvent (1-2.0 vol.), the compound of formula (II) (1 eq), the copper (II) salt (0.01-0.5 equivalent) and the cyanating source (0.3-2 eq) at 25-30 °C. The reaction mixture was heated to 160-195 °C, and allowed to stir at this temperature for 2-16 hrs. After completion of the reaction, the reaction mixture was cooled, diluted with the diluent (6.0 vol.), and filtered through a Celite® bed. The obtained filtrate was then diluted with a mixture of water and 25 % aq. ammonia solution and filtered to obtain a wet cake. The wet cake was washed with water, and further dried in a vacuum tray drier to afford the compound of formula (I).

[0298] Example 1: Preparation of 2-amino-5-cyano-N,3-dimethylbenzamide:

[0299]

[0300] (lla-a) (la-a)

[0301] A reactor was charged with N-methyl-2-pyrrolidone (36 mL, 2.0 vol.), 2-amino-5-bromo-N,3-dimethylbenzamide (Ila-a, 18.0 g, 72.6 mmol, 98% assay), potassium ferrocyanide trihydrate (9.29 g, 21.77 mmol), and copper (II) acetate monohydrate (3.22 g, 16.12 mmol) at 25-30 °C. The reaction mixture was heated to 160-165 °C, and stirred at the same temperature for 28 h. After completion of the reaction, the mixture was cooled and filtered through a Celite® bed. The filtrate was diluted with a mixture of water (110 mL) and 25 % aq. ammonia solution (55 mL) and filtered. The filtered residue was washed with water and further dried to afford 2-amino-5-cyano-N,3-dimethylbenzamide (11.5 g, 82 % yield) as a light brown solid.

[0302] ¹H-NMR (400 MHz, DMSO-d6) δ 8.41 (bs, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.16 (bs, 2H), 2.72 (d, J= 4.8 Hz, 3H), 2.08 (s, 3H) MS: m / z 190.3 [M+l], 5 Following examples as shown in Table 1 were carried out in an analogous way by the variation of the reaction conditions mentioned in Example 1:

[0303] Table 1

[0304]

[0305] Example 6

[0306] 10 A reactor was charged with N-methyl-2-pyrrolidone (NMP) (4 mL, 2.0 vol.), 2-amino-5-bromo-N,3-dimethylbenzamide (Ila-a, 2 g, 8.10 mmol, 98.5% assay), CuCN (1.452 g, 8.1 mmol) and copper (II) acetate monohydrate (0.016 g, 0.081 mmol) at 25-30 °C. The reaction mixture was heated to 175-180 °C and stirred for 6 h. After completion of the reaction, the reaction mixture was cooled, diluted with ethyl acetate (6.0 vol.), 15 filtered through a Celite® bed, and the filtrate was then diluted with a mixture of water (20 mL) and 25 % aq. ammonia solution (10 mL), and filtered to obtain a wet cake. The wet cake was washed with water, and further dried in a vacuum tray drier to afford 2-amino-5-cyano-N,3-dimethylbenzamide (Ia-a,) as a light brown solid.

[0307] Following examples as shown in Table 2 were carried out in an analogous way by the variation of the reaction conditions mentioned in Example 6:

[0308] Table 2

[0309]

[0310] NMP: N-Methyl-2-pyrrolidone; EMP: 5-Ethyl-2-methylpyridine

[0311] *Compound (IIa-a): 2-amino-5-bromo-N,3-dimethylbenzamide

[0312] Comparative example disclosed in WO2013007603

[0313] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification.

Claims

WE CLAIM1. A method for preparing compounds of formula (I),wherein,R1is selected from NR3R4, or OR5;R2is selected from C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl;R3is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl; wherein said C1-C6 alkyl, C3-C6 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl are unsubstituted or substituted with a group selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkoxyl;R4is selected from H, C1-C6 alkyl, or C3-C6 cycloalkyl;orR3and R4together with the nitrogen atom to which they are attached may form a 5- or 6- membered heterocyclic ring optionally substituted with halogen or C1-C6 alkyl; andR5is H, or C1-C6 alkyl;comprising contacting:(1) a compound of formula (II)wherein X is Br, or Cl; R1and R2are as defined above,with(2) a metal cyanide,(3) a copper (II) salt, and(4) optionally a suitable organic solvent.

2. The method as claimed in claim 1, wherein R1is -NR3R4.

3. The method as claimed in claim 1, wherein R1is -OH.

4. The method as claimed in claim 1, wherein R1is -O-C1-C6alkyl.

5. The method for preparing the compound of formula (I) as claimed in claim 1 wherein the compound of formula (I) is represented by a compound of formula (la) or salts thereof,wherein, R2and R3are as defined in claim 1,comprising contacting:(1) a compound of formula (Ila)wherein X, R2and R3are as defined in claim 1;with(2) a metal cyanide,(3) a copper (II) salt, and(4) optionally a suitable organic solvent.

6. The method as claimed in claim 1, wherein the said method further comprises the preparation of compound of formula (III) or salts thereof,wherein,R1is selected from NR3R4, or OR5;R2is Ci-C6alkyl;R3is selected from H, or C1-C6alkyl;R4is selected from H, or C1-C6alkyl;R5is H or C1-C6alkyl;Z is N;S(O)0.2R6is selected from the group comprising of bromo, chloro, O orR7is Cl;R8is selected from H, or Cl;comprising the steps of:step-A: reacting(1) a compound of formula (II)wherein X is Br, or Cl; R1and R2are as defined above,with(2) a metal cyanide,(3) a copper (II) salt, and(4) optionally a suitable organic solvent;to obtain compound of formula (I);step-B: reacting the compound of formula (I) obtain in step A with a compound of formula (VII),to obtain compound of formula (III).

7. The method as claimed in any one of the preceding claims, wherein the metal cyanide is selected from the group consisting of alkali metal cyanides, alkali metal hexacyanoferrates(II) and copper(I) cyanide.

8. The method as claimed in any one of the preceding claims, wherein the metal cyanide is selected from the group consisting of sodium cyanide, copper(I) cyanide, potassium hexacyanoferrate(II) and sodium hexacyanoferrate(II).

9. The method as claimed in any one of the preceding claims, wherein the copper(II) salt is selected from Copper(II) acetate, Copper(II) borate, Copper(II) bromide, Copper(II) carbonate, Basic copper carbonate, Copper(II) chlorate, Copper(II) chloride, Copper(II) fluoride, Copper(II) hydroxide, Copper(II) oxide, Copper(II) phosphate, Copper(II) sulfate, Copper(II) tetrafluoroborate, Copper(II) triflate, or Copper(II) trifluoroacetate or hydrates thereof.

10. The method as claimed in claim 9, wherein the copper(II) salt is Copper(II) acetate or a hydrate thereof.

11. The method as claimed in any one of the preceding claims, wherein the suitable organic solvent comprises one or more solvents selected from the group consisting of halogenated and non-halogenated aliphatic and aromatic hydrocarbons, and dipolar aprotic solvents.

12. The method as claimed in claim 11, wherein one or more dipolar aprotic solvent(s) is(are) selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, 5-ethyl-2-methylpyridine, or N-methyl-2-pyrrolidone (NMP).

13. The method as claimed in any one of the preceding claims, wherein the mole ratio of the copper(II) salt to the compound of formula (II) ranges from 0.01:1 to 1:1.

14. The method as claimed in in any one of the preceding claims,, wherein the mole ratio between the metal cyanide to the compound of formula (II) ranges from 1:6 to 10:1.

15. The method as claimed in any one of the preceding claims, wherein the reaction is carried out at a temperature in the range of 80 to 200 °C.

16. The method as claimed in any one of the preceding claims, wherein R1is selected from NR3R4, or OR5;R2is C1-C3 alkyl;R3is C1-C3 alkyl;R4is H;andR5is H, or C1-C3 alkyl.

17. The method as claimed in claim 16, wherein R2and R3are independently methyl.

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