Method for preparing anthranilic acid diamide

Abstract

The present invention provides a novel process for preparing anthranilic acid diamides of Formula 1, intermediates, N-oxides or salts thereof, and intermediates thereof, preferably compounds of Formula 3, intermediates, N-oxides or salts thereof, on a commercial scale in good yield. In the formula 1 and the formula 3, R1, R2, R3, R4 and n are as defined in the specification.

Description

TECHNICAL FIELD

[0001] The present invention relates to a process for preparing a substituted 1-pyridylpyrazole-5-carboxylic acid of formula 3, an intermediate, an N-oxide or a salt thereof.

[0002]

[0003] wherein n is as described herein.

[0004] Further, the present invention relates to a process for preparing an anthranilic diamide compound of formula 1, an intermediate, an N-oxide or a salt thereof.

[0005]

[0006] wherein, n, R 1 , R 2 , R 3 and R 4 are as described herein. BACKGROUND

[0007] 1-pyridylpyrazole-5-carboxylic acids are known to be important intermediates in the agrochemical industry, for example for the synthesis of anthranilic diamides used to protect crops from pests. Various processes for preparing these intermediates have been disclosed.

[0008] WO 2019150220 discloses anthranilic diamides of formula (I) and their use as insecticides,

[0009]

[0010] wherein,

[0011] D represents D4; Z 1 independently a direct bond, CR 6 R 7 , NR c , O or S(O) 0-2 ; E represents a 4-membered heterocyclic ring. The application also provides a process for preparing a compound of formula (I).

[0012] WO 2022254395 discloses a process for preparing an anthranilic diamide of formula (I),

[0013]

[0014] wherein,

[0015] R a , R b , R 1 , R 2 , R 3 , R4 and n is as defined in the specification.

[0016] The processes described in the prior art have drawbacks such as longer synthetic route, use of additional reagents such as halogenating agent, oxidizing agent and catalyst etc. Hence, the processes are not economically viable and are not suitable for commercial scale preparation of anthranilic acid diamide compound of formula 1 and intermediates thereof. Further, the processes described in the prior art i.e. WO 2019150220 and WO 2022254395 involve Mitsunobu reaction for preparation of etherified product from ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-1H-pyrazole-5-carboxylate with either sulfolidine-3-ol or 3-hydroxy-sulfolidine-1,1-dioxide. Hence, these processes disclosed in the prior art have some drawbacks such as requirement of anhydrous conditions, dry solvents and expensive reagents such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) and triphenyl phosphine which are essential for Mitsunobu reaction.

[0017] Hence, there is a need for a simple, efficient, economically viable scalable process which overcomes at least one of the drawbacks of the known processes.

[0018] The present application provides a novel process for the preparation of anthranilic acid diamide of formula 1, intermediates, N-oxides or salts thereof, preferably compound of formula 3, intermediates, N-oxides or salts thereof on commercial scale with good yield, wherein the process is shorter, more efficient and avoids use of additional reagents such as halogenating agent, oxidizing agent and specific catalysts and Mitsunobu reaction itself. SUMMARY

[0019] OBJECT OF THE INVENTION

[0020] It is an object of the present application to provide a simple, economically viable commercial scale process for the preparation of compound of formula 3, intermediates, N-oxides or salts thereof.

[0021] It is another object of the present application to provide a simple, efficient, economically viable commercial scale process for the preparation of anthranilic acid diamide compound of formula 1, intermediates, N-oxides or salts thereof.

[0022] The present application provides a high yield and economical process for the preparation of anthranilic acid diamide compound of formula 1 and / or key intermediate i.e. compound of formula 3 to prepare the anthranilic acid diamide compound of formula 1, thereby providing a solution to these objectives and overcoming at least one of the drawbacks of the processes described in the prior art.

[0023] SUMMARY

[0024] The present invention relates to a novel, efficient and economically viable process for the preparation of a compound of formula 3, an intermediate, an N-oxide or a salt thereof,

[0025]

[0026] wherein n is an integer selected from 0-2,

[0027] The process comprises the steps of:

[0028] a. preparing a compound of formula 5 from a compound of formula 6 in the presence of a suitable reagent and a suitable solvent (A);

[0029]

[0030] b. reacting a compound of formula 5 with a compound of formula 10 in the presence of a suitable base (I), a suitable solvent (B) and optionally a phase transfer catalyst to obtain a compound of formula 4, wherein the compound of formula 4 is optionally isolated; and

[0031]

[0032] c. hydrolyzing a compound of formula 4 in the presence of a hydrolyzing agent to obtain a compound of formula 3,

[0033]

[0034] The present invention also provides a process for the preparation of a anthranilic acid diamide compound of formula 1, an intermediate, an N-oxide or a salt thereof,

[0035]

[0036] wherein,

[0037] R 1 selected from hydrogen or Ci-C6alkyl;

[0038] R 2 selected from Ci-C6alkyl or C3-C6cycloalkyl, wherein said Ci-C6alkyl and C3-C6cycloalkyl are optionally substituted with one or more substituents selected from halogen and C3-C6cycloalkyl;

[0039] R 3 selected from hydrogen, halogen or cyano;

[0040] R 4 selected from halogen, Ci-C6alkyl, Ci-C6alkoxy or Ci-C6haloalkyl;

[0041] n is an integer selected from 0-2,

[0042] The process comprises the steps of:

[0043] a. preparing a compound of Formula 5 from a compound of Formula 6 in the presence of a suitable reagent and a suitable solvent (A);

[0044]

[0045] b. reacting a compound of Formula 5 with a compound of Formula 10 in the presence of a suitable base (I), a suitable solvent (B), and optionally a phase transfer catalyst to give a compound of Formula 4, wherein the compound of Formula 4 is optionally isolated;

[0046]

[0047] c. hydrolyzing a compound of Formula 4 in the presence of a hydrolyzing agent to give a compound of Formula 3;

[0048] and

[0049] d. reacting a compound of Formula 3 with an acid chloride in a suitable solvent (C) and a suitable base (II) to give an anthranilic acid diamide compound of Formula 1, an intermediate, an N-oxide, or a salt thereof. DETAILED DESCRIPTION

[0050] The terms "comprises", "comprising", "includes", "including", "contains", "containing" or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises, includes or contains a list of elements does not include only those elements but can include other elements not expressly listed or inherent to such process or method.

[0051] In addition, the indefinite articles "a" and "an" preceding an element or component of the application are intended to be non-limiting regarding the number of instances of such element or component. For example, the indefinite articles "a" and "an" are understood to mean one or at least one, and the singular form of an element or component is understood to include the plural unless the number of instances is clearly specified as one.

[0052] The compounds of the present disclosure can exist in pure form or as a mixture of the different possible isomers (e.g., stereoisomers or structural isomers). Various stereoisomers include enantiomers, diastereomers, chiral isomers, atropisomers, conformational isomers, rotational isomers, tautomers, optical isomers, polymorphs, and geometric isomers. Any desired mixture of these isomers falls within the scope of the claims of the present disclosure. Those skilled in the art will appreciate that one stereoisomer can have higher activity and / or can exhibit beneficial effects when enriched relative to other isomers or when separated from other isomers. Furthermore, processes, methods, or techniques for separating, enriching, and / or selectively preparing the isomers are known to those skilled in the art.

[0053] The compounds of the present disclosure can exist in the form of an N-oxide or a salt. The compounds of the present invention can be acid addition salts or base addition salts. Acid addition salts include inorganic acids or organic acids, preferably hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid. Base addition salts include inorganic bases or organic bases, preferably alkali metal salts or alkaline earth metal salts.

[0054] The term "C1-C6alkyl" as used herein refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms, which can be optionally substituted with one or more substituents. Examples of C1-C6alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.

[0055] The term "C1-C6alkoxy" as used herein refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms, which is attached to the rest of the molecule through an oxygen linkage, which can be optionally substituted with one or more substituents. Examples of C1-C6alkoxy include, but are not limited to, methoxy, ethoxy, and the like.

[0056] Halogen as used herein refers to fluorine, chlorine, bromine, or iodine.

[0057] The term "C1-C6haloalkyl" as used herein refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms, which is substituted with one or more halogens, which can be optionally substituted with one or more substituents. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, trifluoroethyl, perfluoroethyl.

[0058] The term "C3-C6cycloalkyl" as used herein refers to a saturated non-aromatic carbocyclic ring having from 3 to 6 carbon atoms, which can be optionally substituted with one or more substituents. Examples of C3-C6cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0059] The term "optionally" or "optional" as used in the context of the present invention is intended to mean that any element, intermediate, reagent or condition (including any process step, such as the isolation of an intermediate) is optional and can or can not be employed in the practice of the invention. Similarly, this definition also applies to the use of reagents or reaction conditions.

[0060] The present description is explained with non-limiting examples in the specification. The description of known components and processing techniques may be omitted so as not to unnecessarily obscure the embodiments being set forth herein. The examples used herein are intended merely to facilitate an understanding of ways in which the present description can be practiced and to further enable a person of ordinary skill in the art to practice the present description. Accordingly, these examples should not limit the scope of the present description.

[0061] The description of the specific embodiments will sufficiently reveal the general nature of the herein implementations, so that others can, by applying current knowledge, readily modify and / or adapt for various applications the specific embodiments, without departing from the general concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the equivalent of the disclosed implementations. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, although the implementations have been described in terms of preferred embodiments, one skilled in the art will readily recognize that the implementations can be practiced with modifications within the spirit and scope of the implementations as described herein.

[0062] Any discussion of documents, acts, materials, devices, articles or the like that has been included in the present specification is solely for the purpose of providing a context for the disclosure. Such discussion should in no way be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure prior to the priority date of this application.

[0063] Accordingly, the present application provides a process for preparing a compound of formula 3, an intermediate, an N-oxide or a salt thereof,

[0064]

[0065] wherein n is an integer selected from 0-2,

[0066] The process comprises the steps of:

[0067] a. preparing a compound of formula 5 from a compound of formula 6 in the presence of a suitable reagent and a suitable solvent (A);

[0068]

[0069] b. reacting the compound of formula 5 with a compound of formula 10 in the presence of a suitable base (I), a suitable solvent (B) and optionally a phase transfer catalyst to give a compound of formula 4, wherein the compound of formula 4 is optionally isolated; and

[0070]

[0071] c. hydrolyzing the compound of formula 4 in the presence of a hydrolyzing agent to give a compound of formula 3.

[0072]

[0073] The present application also provides a process for preparing an anthranilic acid diamide of formula 1, an intermediate, an N-oxide or a salt thereof,

[0074]

[0075] wherein,

[0076] R 1 is selected from hydrogen or Ci-C6alkyl;

[0077] R 2 is selected from Ci-C6alkyl or C3-C6cycloalkyl, wherein said Ci-C6alkyl and C3-C6cycloalkyl are optionally substituted with one or more substituents selected from halogen and C3-C6cycloalkyl;

[0078] R 3 is selected from hydrogen, halogen or cyano;

[0079] R 4 is selected from halogen, Ci-C6alkyl, Ci-C6alkoxy or Ci-C6haloalkyl; and

[0080] n is an integer selected from 0-2,

[0081] The method comprises the following steps:

[0082] a. preparing a compound of formula 5 from a compound of formula 6 in the presence of a suitable reagent and a suitable solvent (A);

[0083]

[0084] b. reacting a compound of formula 5 with a compound of formula 10 in the presence of a suitable base (I), a suitable solvent (B) and optionally a phase transfer catalyst to give a compound of formula 4, wherein the compound of formula 4 is optionally isolated;

[0085]

[0086] c. hydrolyzing a compound of formula 4 in the presence of a hydrolysis agent to give a compound of formula 3; and

[0087]

[0088] d. reacting a compound of formula 3 with an acid chloride in a suitable solvent (C) and a suitable base (II) to give an anthranilic acid diamide of formula 1, an intermediate thereof, an N-oxide, or a salt thereof.

[0089] The present application also provides a method of preparing an anthranilic acid diamide compound of formula 1,

[0090]

[0091] wherein,

[0092] R 1 is selected from hydrogen or Ci-C6alkyl;

[0093] R 2 selected from C1-C6alkyl or C3-C6cycloalkyl, wherein said C1-C6alkyl and C3-C6cycloalkyl are optionally substituted with one or more substituents selected from halogen and C3-C6cycloalkyl;

[0094] R 3 selected from hydrogen, halogen or cyano;

[0095] R 4 selected from halogen, C1-C6alkyl, C1-C6alkoxy or C1-C6haloalkyl;

[0096] n is an integer selected from 0-2,

[0097] The process comprises the following steps:

[0098] a. preparing a compound of formula 5 from a compound of formula 6 in the presence of a suitable reagent and a suitable solvent (A);

[0099]

[0100] b. reacting a compound of formula 5 with a compound of formula 10 in the presence of a suitable base (I), a suitable solvent (B) and optionally a phase transfer catalyst to give a compound of formula 4, wherein the compound of formula 4 is optionally isolated;

[0101]

[0102] c. hydrolyzing a compound of formula 4 in the presence of a hydrolyzing agent to give a compound of formula 3; and

[0103]

[0104] d. (i). reacting a compound of formula 3 with an acid chloride in a suitable solvent (C) to form an acid chloride of formula 3A, which is then coupled with a compound of formula 9 using a suitable base (II) and a suitable solvent (D) to give an anthranilic acid diamide of formula 1, an intermediate thereof, an N-oxide, or a salt thereof.

[0105]

[0106] The present application also provides a process for preparing an anthranilic acid diamide compound of formula 1,

[0107]

[0108] wherein,

[0109] R 1 selected from hydrogen or C1-C6alkyl;

[0110] R2 selected from halogen, C1-C6alkyl, C1-C6alkoxy or C1-C6haloalkyl;

[0111] R 3 selected from hydrogen, halogen or cyano;

[0112] R 4 selected from halogen, C1-C6alkyl, C1-C6alkoxy or C1-C6haloalkyl;

[0113] n is an integer selected from 0-2,

[0114] The method comprises the following steps:

[0115] a. preparing a compound of formula 5 from a compound of formula 6 in the presence of a suitable reagent and a suitable solvent (A);

[0116]

[0117] b. reacting a compound of formula 5 with a compound of formula 10 in the presence of a suitable base (I), a suitable solvent (B) and optionally a phase transfer catalyst to give a compound of formula 4, wherein the compound of formula 4 is optionally isolated;

[0118]

[0119] c. hydrolyzing a compound of formula 4 in the presence of a hydrolyzing agent to give a compound of formula 3;

[0120]

[0121] d. (ii). reacting a compound of formula 3 with a compound of formula 7 in the presence of a suitable base (II) and an acid chloride to form a compound of formula 2, wherein the compound of formula 2 is optionally isolated; and ring opening a compound of formula 2 with a compound of formula 8 in the presence of a suitable base (III) in a suitable solvent (C) to give an anthranilic acid diamide of formula 1, an intermediate, an N-oxide or a salt thereof.

[0122]

[0123] The present application also provides a process for preparing an anthranilic acid diamide compound of formula 1,

[0124]

[0125] wherein,

[0126] R 1 selected from hydrogen or C1-C6alkyl;

[0127] R 2 selected from C1-C6alkyl or C3-C6cycloalkyl, wherein said C1-C6alkyl and C3-C6cycloalkyl are optionally substituted with one or more substituents selected from halogen and C3-C6cycloalkyl;

[0128] R 3 selected from hydrogen, halogen or cyano;

[0129] R 4 selected from halogen, C1-C6alkyl, C1-C6alkoxy or C1-C6haloalkyl;

[0130] n is an integer selected from 0-2,

[0131] The process comprises the following steps:

[0132] a. preparing a compound of formula 5 from a compound of formula 6 in the presence of a suitable reagent and a suitable solvent (A);

[0133]

[0134] b. reacting a compound of formula 5 with a compound of formula 10 in the presence of a suitable base (I), a suitable solvent (B) and optionally a phase transfer catalyst to give a compound of formula 4, wherein the compound of formula 4 is optionally isolated;

[0135]

[0136] c. hydrolyzing a compound of formula 4 in the presence of a hydrolyzing agent to give a compound of formula 3; and

[0137]

[0138] d. (i) reacting a compound of formula 3 with an acid chloride in a suitable solvent (C) to form an acid chloride of formula 3A, which is then coupled with a compound of formula 9 using a suitable base (II) and a suitable solvent (D) to give an anthranilic acid diamide of formula 1, an intermediate thereof, an N-oxide, or a salt thereof;

[0139]

[0140] or

[0141] d. (ii) reacting a compound of formula 3 with a compound of formula 7 in the presence of a suitable base (II) and an acid chloride to form a compound of formula 2, wherein the compound of formula 2 is optionally isolated; and ring opening a compound of formula 2 with a compound of formula 8 in the presence of a suitable base (III) in a suitable solvent (C) to give an anthranilic acid diamide of formula 1, an intermediate thereof, an N-oxide, or a salt thereof.

[0142]

[0143] In one embodiment, n = 2 for Formula 1, Formula 2, Formula 3, Formula 4 and Formula 10 in the methods of the present application.

[0144] In one embodiment, the present application provides a method of making an anthranilic acid diamide compound of Formula 1, wherein R 1 is H or C1-C2 alkyl; R 2 is C1-C4 alkyl; R 3 is fluoro or chloro; and R 4 is chloro or C1-C2 alkyl.

[0145] In one preferred embodiment, the present application provides a method of making an anthranilic acid diamide compound of Formula 1, wherein R 1 is H; R 2 is isopropyl or t-butyl; R 3 is chloro; and R 4 is methyl.

[0146] In one preferred embodiment, the compound of Formula 3 is made from a compound of Formula 5 without isolating the compound of Formula 4.

[0147] According to one embodiment of the present application, the conversion of the compound of Formula 5 to the compound of Formula 3 is accomplished in one step without isolating the compound of Formula 4.

[0148] In one embodiment of the present application, the compound of Formula 3 is converted in situ to the compound of Formula 3A in the presence of a suitable acyl chloride and a suitable solvent (C).

[0149]

[0150] In another embodiment of the present application, the acyl chloride of Formula 3A in step d can be isolated prior to reaction with the compound of Formula 9.

[0151]

[0152] wherein R 1 , R 2 , R 3 , R 4 and n are as described above.

[0153] In one embodiment, the present application provides an acyl chloride of the compound of Formula 3, which is represented as a compound of Formula 3A,

[0154]

[0155] wherein n is an integer selected from 0-2, preferably n is 2.

[0156] In another embodiment, the present application provides a process for preparing a compound of formula 4, comprising the step (step b):

[0157] reacting a compound of formula 5 with a compound of formula 10 in the presence of a suitable base (I), a suitable solvent (B) and optionally a phase transfer catalyst to obtain a compound of formula 4, wherein the compound of formula 4 is optionally isolated.

[0158]

[0159] Alternatively, the acyl chloride of the compound of formula 3 can be generated in situ and then reacted with the compound of formula 9 to obtain the anthranilic acid diamide compound of formula 1, an intermediate, an N-oxide or a salt thereof.

[0160] The compound of formula 10 can be obtained from a commercial source or can be synthesized according to the known methods as described in PCT application PCT / IN2023 / 051201, following the reaction scheme:

[0161]

[0162] The suitable base selected from base (I), base (II) or base (III) used in the present application can be independently selected from an organic base or an inorganic base.

[0163] The inorganic base is selected from the group consisting of bicarbonates of alkali metals, such as lithium bicarbonate (LiHC03), sodium bicarbonate (NaHC03), potassium bicarbonate (KHC03) and cesium bicarbonate (CsHC03); carbonates of alkali / alkaline earth metals, such as sodium carbonate (Na2C03), calcium carbonate (CaC03), cesium carbonate (Cs2C03), lithium carbonate (Li2C03), potassium carbonate (K2C03); hydroxides of alkali / alkaline earth metals, such as lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium hydroxide (CsOH), calcium hydroxide (Ca(OH)2), phosphates of alkali metals, such as disodium hydrogen phosphate (Na2HP04), sodium phosphate (Na3P04), dipotassium hydrogen phosphate (K2HP04), potassium phosphate (K3P04); halides of alkali metals, such as sodium fluoride (NaF), potassium fluoride (KF) and cesium fluoride (CsF); hydrides of alkali metals, such as lithium hydride (LiH), sodium hydride (NaH) and potassium hydride (KH); and alkoxides of alkali metals, such as sodium methoxide (NaOCH3), sodium ethoxide (NaOCH2CH3), sodium tert-butoxide and potassium tert-butoxide, and the like, in a non-limiting manner.

[0164] The organic base is selected, in a non-limiting manner, from amines such as ethylamine, triethylamine, isopropylamine, diisopropylamine, triisopropylamine, pyridine, picoline, piperidine, methylmorpholine, N-methylpiperidine, N,N-(dimethylamino)pyridine (DMAP), dimethylpyridine, trimethylpyridine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide and choline hydroxide; amidines, which include, but are not limited to, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepine (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,4-diazabicyclo[2.2.2]octane (DABCO, triethylenediamine). 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,4-diazabicyclo[2.2.2]octane (DABCO, triethylenediamine).

[0165] The suitable solvent selected from solvent (A), solvent (B), solvent (C) or solvent (D) used in the present application can be independently selected from aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, ethers, cyclic ethers, nitriles, amides, ketones, acids, alcohols, water or mixtures thereof. Preferably, the solvent employed in the present process can be selected, in a non-limiting manner, from acetonitrile, acetic acid, acetone, hexane, heptane, octane, nonane, decane, dodecane, cycloalkanes (such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane); N,N-dimethylformamide, dichloroethane, ethyl acetate, toluene, xylene, mesitylene, benzene, halogenated benzene, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methoxy methane, methoxy ethane, ethoxy ethane, dimethoxy ethane, diethoxy ethane, dichloromethane, chloroform, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, hexamethylphosphoramide, 1,3-dimethyl-2-imidazolinone or combinations thereof.

[0166] The process for preparing a compound of formula 3 or formula 1, wherein the process step a, step b, step c and step d are carried out at a temperature ranging from 0 to 150 °C.

[0167] The suitable reagent for step a of the process for preparing a compound of formula 3 or formula 1 disclosed herein is selected from, but not limited to, nitric acid (HN03), sulfuric acid, acetic acid, hydrochloric acid or mixtures thereof. In a preferred embodiment, the suitable reagent used in step (a) is nitric acid (HN03), preferably 70% HN03.

[0168] In a preferred embodiment, the suitable solvent (A) in step (a) of the process for preparing a compound of formula 3 or formula 1 disclosed herein is selected from dichloromethane, dichloroethane or acetonitrile, preferably dichloroethane.

[0169] In a preferred embodiment, step (a) of the process for preparing the compounds of formula 3 or formula 1 as disclosed herein is generally carried out at a temperature in the range of 0 to 100 °C, preferably at a temperature in the range of 0 to 40 °C.

[0170] In another preferred embodiment, step a of the process for preparing the compounds of formula 3 or formula 1 as disclosed herein, wherein

[0171] i. the suitable reagent in method step a is selected from nitric acid (HN03), sulfuric acid, acetic acid, hydrochloric acid or mixtures thereof;

[0172] ii. the suitable solvent (A) in method step a is selected from dichloromethane, dichloroethane or acetonitrile;

[0173] iii. method step a is carried out at a temperature in the range of 0 to 100 °C.

[0174] In a preferred embodiment, the suitable base (I) in step (b) of the process for preparing the compounds of formula 3 or formula 1 as disclosed herein is selected from, but not limited to, alkali or alkaline earth metal carbonates or bicarbonates, alkali / alkaline earth metal hydroxides, alkali metal phosphates, alkali metal alkoxides or alkali metal hydrides; preferably K2C03, Na2C03, NaOH, KOH or K3P04; more preferably K2C03, KOH or K3P04.

[0175] In a preferred embodiment, the suitable solvent (B) of step (b) of the process for preparing the compounds of formula 3 or formula 1 as disclosed herein is selected from, but not limited to, dichloroethane, toluene, xylene, chlorinated benzene, acetonitrile and dioxane, dimethoxyethane; preferably monochloro / dichloro / chlorobenzene.

[0176] In a preferred embodiment, if a phase transfer catalyst is used in step (b) of the process of the present application, it is selected from tetraalkylammonium halides, preferably tetrabutylammonium bromide.

[0177] In a preferred embodiment, the suitable temperature of step (b) of the process for preparing the compounds of formula 3 or formula 1 as disclosed herein is in the range of 25 to 130 °C, preferably between 25 to 105 °C.

[0178] In another preferred embodiment, step b of the process for preparing the compounds of formula 3 or formula 1 as disclosed herein, wherein

[0179] i. the suitable base (I) in method step b is selected from K2C03, Na2C03, NaOH, KOH or K3P04;

[0180] ii. Suitable solvents (B) in method step b are selected from the group consisting of dichloroethane, toluene, xylene, chlorinated benzene, acetonitrile, dimethoxyethane and dioxane;

[0181] iii. The optional phase transfer catalyst is selected from the group consisting of tetraalkylammonium halides;

[0182] iv. Method step b is carried out at a temperature range of 25 to 130 °C.

[0183] The suitable hydrolyzing agent used in step (c) of the process for preparing the compound of formula 3 or formula 1 disclosed herein is an acid. In a preferred embodiment, the acid used for hydrolysis of the ester in step (c) is selected from the group consisting of, but not limited to, aqueous sulfuric acid (H2SO4) and hydrochloric acid (HC1). In a more preferred embodiment, the hydrolyzing agent used in step (c) of the present application is 10-50% aqueous sulfuric acid; preferably 20% aqueous H2SO4.

[0184] The suitable solvent for hydrolysis in step (c) of the process for preparing the compound of formula 3 or formula 1 disclosed herein is selected from the group consisting of, but not limited to, acetic acid (AcOH), water or acetonitrile; preferably acetic acid (AcOH).

[0185] In a preferred embodiment, the suitable temperature for step (c) of the process for preparing the compound of formula 3 or formula 1 disclosed herein is 50 to 130 °C, preferably 70 to 105 °C.

[0186] In another preferred embodiment, step c of the process for preparing the compound of formula 3 or formula 1 disclosed herein, wherein

[0187] i. The hydrolyzing agent in method step c is selected from the group consisting of acids;

[0188] ii. The suitable solvent in method step c is selected from the group consisting of acetic acid (AcOH), water or acetonitrile;

[0189] iii. Method step c is carried out at a temperature range of 50 to 130 °C.

[0190] The acyl chloride used in step (d), step (d(i)) or step (d(ii)) of the process for preparing the compound of formula 1 disclosed herein is selected from the group consisting of, but not limited to, thionyl chloride (SOCl2), methylsulfonyl chloride (MsCl, methanesulfonyl chloride), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), oxalyl chloride, triphosgene and phosgene. In a preferred embodiment, the acyl chloride is selected from thionyl chloride (SOCl2), methylsulfonyl chloride (MsCl) or phosgene (COCl2).

[0191] In a preferred embodiment, the base (II) and base (III) used in step (d), step (d(i)) or step (d(ii)) of the process for preparing the compounds of formula 1 disclosed herein are independently selected from, but not limited to, inorganic bases, such as carbonates, bicarbonates, hydroxides, hydrides or alkoxides of alkali or alkaline earth metals; organic bases, such as isopropylamine, triethylamine, diisopropylethylamine, triisopropylamine, pyridine, picoline, N-methylmorpholine, N-methylpiperidine, N,N-(dimethylamino)pyridine (DMAP), lutidine, collidine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide; amidines, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). In a more preferred embodiment, the base (II) and base (III) are independently selected from triethylamine, isopropylamine, pyridine, picoline or mixtures thereof.

[0192] In a preferred embodiment, suitable solvent (C) and solvent (D) in step (d), step (d(i)) or step (d(ii)) of the process for preparing the compounds of formula 1 disclosed herein are independently selected from dichloroethane, acetonitrile (ACN), N,N-dimethylformamide (DMF), ethyl acetate, pyridine, picoline or mixtures thereof.

[0193] The reaction temperature of step (d), step (d(i)) and step (d(ii)) of the process for preparing the compounds of formula 1 disclosed herein is between 0 and 80 °C.

[0194] In another preferred embodiment, step d, step (d(i)) or step (d(ii)) of the process for preparing the compounds of formula 1 disclosed herein, wherein

[0195] i. the acid chloride in method step d, step (d(i)) or step (d(ii)) is selected from thionyl chloride (SOCl2), methylsulfonyl chloride (MsCl), phosphorus pentachloride (PCI5), phosphorus trichloride (PCI3), oxalyl chloride, triphosgene or

[0196] phosgene;

[0197] ii. suitable solvent (C) and solvent (D) in method step d, step (d(i)) or step (d(ii)) are independently selected from dichloroethane, acetonitrile (ACN), N,N-dimethylformamide (DMF), ethyl acetate, pyridine, picoline or mixtures thereof;

[0198] lutidine, collidine or mixtures thereof;

[0199] iii. The suitable base (II) and base (III) in method step d, step (d(i)) or step (d(ii)) are independently selected from the group consisting of alkali metal or alkaline earth metal carbonates, bicarbonates, hydroxides, hydrides or alkoxides, isopropylamine, triethylamine, diisopropylethylamine, triisopropylamine, pyridine, picoline, N-methylmorpholine, N-methylpiperidine, N,N-(dimethylamino)pyridine (DMAP), lutidine, collidine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5,7-triazabicyclo[4.4.0]

[0200] dec-5-ene (TBD) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN);

[0201] iv. Method step d, step (d(i)) or step (d(ii)) is carried out at a temperature in the range of 0 to 80 °C.

[0202] The reaction time is not critical and depends on the batch size, temperature, reaction type, solvent and reagents used and is typically in the range of a few minutes to several hours.

[0203] The process for preparing the anthranilic acid diamides of the above formula 1, the intermediates of formula 3, the intermediates of formula 4 or the respective N-oxides or salts thereof according to the present disclosure employs simple transformation procedures, readily available starting materials, reagents and reaction conditions, making it suitable for commercial scale applications. Furthermore, the process according to the present disclosure provides the desired intermediates and end compounds in high yield and chemical purity.

[0204] The person skilled in the art is aware of methods for the optimal work-up of the reaction mixture after the respective reaction has ended. The work-up is typically performed by isolating the product and, optionally, washing with a solvent, and, further optionally, drying the product, if necessary or desired.

[0205] According to the process of the present disclosure, the products obtained in the individual steps can be isolated from the reaction mixture or used directly in the subsequent reaction step without isolation. The isolation of the reaction products can be performed by techniques including, but not limited to, decanting, filtering, centrifuging, evaporating, liquid-liquid extraction, distilling, recrystallizing, chromatography or a combination thereof.

[0206] The reaction steps according to the present disclosure are typically carried out at atmospheric pressure. However, it is also possible to choose to carry out the reaction steps of the present process under reduced or elevated pressure.

[0207] The following examples will further illustrate the present application, which are only for illustrating the present application and do not limit the scope of the present application. Although the present application has been described in accordance with the embodiments thereof, variations and modifications are possible to those skilled in the art, and are intended to fall within the scope of the present application.

[0208] The present application provides a process for preparing an anthranilic acid diamide of Formula 1, an intermediate of Formula 3, an intermediate of Formula 4, or their respective N-oxides or salts, wherein the steps can be carried out in batch, semi-continuous or continuous reaction mode, in particular also under semi-continuous flow or continuous flow reaction conditions.

[0209] Although the subject matter has been described in considerable detail with specific reference to certain embodiments and implementations thereof, other implementations are possible.

[0210] Embodiments

[0211] The present disclosure will now be described with respect to Examples, which are intended to illustrate embodiments of the present disclosure and are not intended to limit the scope of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the disclosed methods and compositions, exemplary methods, devices, and materials are described herein. It is to be understood that this disclosure is not limited to the particular methodology, protocols, and reagents described, as these can vary.

[0212] Experimental Examples:

[0213]

[0214] Scheme 1: Preparation of anthranilic acid diamide compounds of Formula 1

[0215] All solvents and reagents used in the present application are from commercial sources. Reactants such as 2-(3-chloro-2-pyridyl)-5-oxo-3-pyrazolidinecarboxylic acid ethyl ester (compound of Formula 6), o-aminobenzoic acid based reactants (compound of Formula 7) and amines of Formula 8 are either available from commercial suppliers or prepared according to known literature procedures. Amines of Formula 9 are prepared according to literature procedures or methods described in prior art such as WO 2020170092 and WO 2022064454.

[0216] Example 1: Preparation of anthranilic acid diamide compounds of Formula 1

[0217] Step a: Synthesis of 1-(3-chloropyridin-2-yl)-3-hydroxy-1H-pyrazole-5-carboxylic acid ethyl ester

[0218]

[0219] To a stirred suspension of ethyl 2-(3-chloropyridin-2-yl)-5-oxopyrazolidine-3- carboxylate (compound of formula 6, 100 g, 371 mmol) in dichloroethane (500 mL) was added 70% aqueous nitric acid (16.7 g, 185 mmol) at 0-5 °C. The temperature of the reaction mass was raised to 20-30 °C and stirring was continued. After completion of the reaction, the reaction mass was cooled to 0-5 °C. The solid obtained was filtered, washed with water (500 mL) and dried to get ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-1H-pyrazole-5-carboxylate (formula 5) (68 g, yield 68%).

[0220] 1 H NMR (DMSO-d6, 400 MHz): δ 8.12-8.10 (dd, J = 1.6 Hz, 1H), 7.84-7.82 (dd, J = 1.6 Hz, 1H), 6.98-6.95 (dd, J = 4.8 Hz, 1H), 5.28-5.23 (m, 1H), 4.11 (q, 2H), 3.67 (s, 3H), 3.54-3.47 (.m, 1H), 3.20-3.16 (m, 1H), 1.14 (t, 3H), 3.31 (m, 1H), 2.93 (m, 1H), 1.15 (t, 3H)

[0221] MS: m / z = 348.0 [M+H] + .

[0222] Step b: Synthesis of ethyl 1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H- pyrazole-5-carboxylate

[0223] Method 1: Reaction with potassium carbonate as base

[0224]

[0225] To a stirred suspension of ethyl 1-(3-chloropyridin-2-yl)-3-hydroxy-1H-pyrazole-5- carboxylate (86 g, 300 mmol) in chlorobenzene (172 mL) was added potassium carbonate (2.0 eq, 85 g, 600 mmol) at 25-30 °C. The reaction mass temperature was raised to 70-75 °C and stirring was continued for 45 min. To this reaction mass was added a solution of 3-chlorothietan-1,1-dioxide (Formula 10) (2.0 eq, 89 g, 600 mmol) in chlorobenzene (172 mL) at 70-75 °C. The reaction mass temperature was raised to 80-85 °C and stirring was continued for 3 h. After completion of the reaction, the reaction mass was cooled to 60-65 °C and filtered. The filtrate was concentrated under reduced pressure to get ethyl 1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H-pyrazole-5-carboxylate (Formula 4) (135.7 g) as crude which was used as such in step c.

[0226] HPLC purity (%) - 86.6; MS - m / z 371 [M+H] + .

[0227] Method 2: Reaction with potassium phosphate as base

[0228] To a stirred suspension of ethyl 2-(3-chloropyridin-2-yl)-5-oxopyrazolidine-3-carboxylate (5 g, 18.7 mmol) in chlorobenzene (50 mL) was added 3-chlorothietan-1,1-dioxide (15.01 g, 37.4 mmol), tetrabutylammonium bromide (1.5 g, 4.7 mmol) and potassium phosphate tribasic (13.9 g, 65.4 mmol) at 25-30 °C. The reaction mass temperature was raised to 80-85 °C and stirring was continued for 30 h. After completion of the reaction, the reaction mass was cooled to 60-65 °C and filtered. The filtrate was concentrated under reduced pressure to get ethyl 1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H-pyrazole-5-carboxylate (Formula 4) (11.9 g, 77% yield).

[0229] Method 3: Reaction with potassium hydroxide as base

[0230] To a stirred suspension of 2-(3-chloropyridin-2-yl)-5-oxopyrazolidine-3-carboxylic acid ethyl ester (0.5 g, 1.868 mmol) in chlorobenzene (5 mL) was added 3-chlorothietan-l,l-dioxide (0.52 g, 3.74 mmol), tetrabutylammonium bromide (0.15 g, 0.47 mmol) and potassium hydroxide (0.26 g, 4.67 mmol) at 25-30 °C. The reaction mass was allowed to warm to 80-85 °C and stirring was continued for 24 h. After completion of the reaction, the reaction mass was cooled to 60-65 °C and filtered. The filtrate was concentrated under reduced pressure to get crude 1-(3-chloropyridin-2-yl)-3-((l,l-dioxidothietan-3-yl)oxy)-lH-pyrazole-5-carboxylic acid ethyl ester (Formula 4) which was used as such for the next step.

[0231] Step c: Synthesis of 1-(3-chloropyridin-2-yl)-3-((l,l-dioxidothietan-3-yl)oxy)-lH- pyrazole-5-carboxylic acid (Formula 3):

[0232]

[0233] To a stirred suspension of 2-(3-chloropyridin-2-yl)-5-oxopyrazolidine-3-carboxylic acid ethyl ester (0.5 g, 1.868 mmol) in chlorobenzene (5 mL) was added 3-chlorothietan-l,l-dioxide (0.52 g, 3.74 mmol), tetrabutylammonium bromide (0.15 g, 0.47 mmol) and potassium hydroxide (0.26 g, 4.67 mmol) at 25-30 °C. The reaction mass was allowed to warm to 80-85 °C and stirring was continued for 24 h. After completion of the reaction, the reaction mass was cooled to 60-65 °C and filtered. The filtrate was concentrated under reduced pressure to get crude 1-(3-chloropyridin-2-yl)-3-((l,l-dioxidothietan-3-yl)oxy)-lH-pyrazole-5-carboxylic acid ethyl ester (Formula 4) which was used as such for the next step.

[0234] 1 H-NMR (400 MHz, Chloroform-D) δ 8.48 (dd, J = 4.7, 1.7 Hz, 1H), 7.93 (dd, J = 8.3, 1.5 Hz, 1H), 7.44 (dd, J = 8.1, 4.7 Hz, 1H), 6.58 (s, 1H), 5.38-5.32 (m, 1H), 4.61-4.55 (m, 2H), 4.37-4.31 (m, 2H).

[0235] MS: m / z = 343.0 [M+H] + .

[0236] In situ step b and step c: Preparation of 1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H-pyrazole-5-carboxylic acid from 1-(3-chloropyridin-2-yl)-3-hydroxy-1H-pyrazole-5-carboxylic acid ethyl ester in situ

[0237]

[0238] To a stirred suspension of 1-(3-chloropyridin-2-yl)-3-hydroxy-1H-pyrazole-5-carboxylic acid ethyl ester, 3-chlorothietane-1,1-dioxide (2.0 eq, 26.3 g, 185 mmol) and potassium carbonate (1.2 eq, 15.65 g, 111 mmol) in chlorobenzene (50 mL) was added at 25-30 °C. The temperature of the reaction mass was raised to 70-80 °C and stirring was continued for 3 h. After completion of the reaction, the reaction mass was cooled to 25-30 °C. To the above suspension was added acetic acid (25 mL) and 20% aqueous sulphuric acid (125 mL). The temperature of the reaction mass was raised to 95-100 °C and the mixture was stirred for 24 h. After completion of the reaction, the reaction mass was cooled to 0-5 °C, stirred for 1-2 h and the solid obtained was filtered, washed with water (100 mL) and dried to get 1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H-pyrazole-5-carboxylic acid (Formula 3) (16.8 g, 48.9 mmol, yield 90.29%).

[0239] Step d: Synthesis of N-(2-(tert-butylcarbamoyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H-pyrazole-5-carboxamide (Formula 1)

[0240]

[0241] A suspension of 1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H- pyrazole-5-carboxylic acid (1.2 g, 3.09 mmol) and 2-amino-N-(tert-butyl)-5-chloro-3- methylbenzamide (Formula 9) (1.05 eq, 0.8 g, 3.24 mmol) in 6 mL of acetonitrile was cooled to 0-5 °C and stirred for 10-15 min. To this suspension was added dropwise 3- methylpyridine (2.301 g, 2.4 ml, 24.70 mmol) over a period of 5 min and stirring was continued for 10-15 min. Methanesulfonyl chloride (1.061 g, 0.717 ml, 9.26 mmol) was added dropwise over a period of 5 min. The reaction mass was slowly allowed to warm to 25-30 °C and stirring was continued for 5 h. After completion of the reaction, the reaction mass was concentrated under reduced pressure to remove acetonitrile to get a residue. To the residue was added acetone (3 mL) and water (5 mL) and the mixture was stirred at 0-5 °C. The solid obtained was filtered, washed with water (5 mL) and dried to get N-(2-(tert-butylcarbamoyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H-pyrazole-5-carboxamide (Formula 1) (1.4 g, 2.472 mmol, 80.04 % yield). MS: m / z = 566.0 [M+H] + .

[0242] Alternative to step d:

[0243] Synthesis of 6-chloro-2-(1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H- pyrazol-5-yl)-8-methyl-4H-benzo[d][1,3]oxazin-4-one

[0244] A stirred suspension of 1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H- pyrazole-5-carboxylic acid (Formula 3) (50.0 g, 131 mmol) and 2-amino-5-chloro-3- methylbenzoic acid (Formula 7) (25.6 g, 138 mmol) in acetonitrile (400 mL) was cooled to 0-10 °C and pyridine (83 g, 1052 mmol) was added at 0-10 °C. To this reaction mixture, methanesulfonyl chloride (45.2 g, 394 mmol) was added dropwise at 0-10 °C. The resulting reaction mixture was stirred at 25-30 °C for 1-2 h. After completion of the reaction, the reaction mixture was cooled to 0-5 °C and filtered. The filter cake was washed with water (125 g) and dried under reduced pressure to obtain 6-chloro-2-(1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H-pyrazol-5-yl)-8- methyl-4H-benzo[d][1,3]oxazin-4-one (Formula 2) (63 g, 97% yield).

[0245] Synthesis of N-(2-(tert-butylcarbamoyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H-pyrazole-5-carboxamide

[0246] To a stirred suspension of 6-chloro-2-(1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3- yl)oxy)-1H-pyrazol-5-yl)-8-methyl-4H-benzo[d][1,3]oxazin-4-one (43.5 g, 87 mmol) in N,N- dimethylformamide (87 mL) was added tert-butylamine (Formula 8) (9.58 g, 131 mmol) dropwise at 10-20 °C over a period of 30-40 min. The reaction mixture was stirred at 25-30 °C for 6-8 h. After completion of the reaction, excess tert-butylamine was distilled off from the reaction mixture under reduced pressure. To the residue, isopropyl alcohol (304.5 mL) was added and the resulting reaction mixture was stirred at 25-30 °C for 6-8 h. The resulting solid was filtered, the wet filter cake was washed with acetone (87 mL) and dried under reduced pressure to obtain N-(2-(tert-butylcarbamoyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-2-yl)-3-((1,1-dioxidothietan-3-yl)oxy)-1H-pyrazole-5-carboxamide (Formula 1) (43 g, 86% yield).

Claims

1. A process for preparing a compound of Formula 3, an intermediate, an N-oxide, or a salt thereof, wherein n is an integer selected from 0-2, the process comprising the steps of: a. preparing a compound of Formula 5 from a compound of Formula 6 in the presence of a suitable reagent and a suitable solvent (A), b. reacting a compound of Formula 5 with a compound of Formula 10 in the presence of a suitable base (I), a suitable solvent (B), and optionally a phase transfer catalyst to give a compound of Formula 4, wherein the compound of Formula 4 is optionally isolated, and c. hydrolyzing a compound of Formula 4 in the presence of a hydrolyzing agent to give a compound of Formula 3, 2. A process for preparing a compound of Formula 1, an intermediate, an N-oxide, or a salt thereof, wherein, R 1 selected from hydrogen or Ci-C6alkyl; R 2 selected from the group consisting of C1-C6alkyl and C3-C6cycloalkyl, wherein said C1-C6alkyl and C3-C6cycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen and C3-C6cycloalkyl; R 3 selected from hydrogen, halogen or cyano; R 4 selected from halogen, Ci-C6-alkyl, Ci-C6-alkoxy or Ci-C6-haloalkyl; and n is an integer selected from 0-2, the process comprising the steps of: a. preparing a compound of Formula 5 from a compound of Formula 6 in the presence of a suitable reagent and a suitable solvent (A); b. reacting a compound of Formula 5 with a compound of Formula 10 in the presence of a suitable base (I), a suitable solvent (B), and optionally a phase transfer catalyst to give a compound of Formula 4, wherein the compound of Formula 4 is optionally isolated, c. hydrolyzing a compound of Formula 4 in the presence of a hydrolyzing agent to give a compound of Formula 3, and d. reacting a compound of Formula 3 with an acid chloride in a suitable solvent (C) and a suitable base (II) to give a compound of Formula 1, an intermediate, an N-oxide, or a salt thereof.

3. The method of claim 2, wherein, In step d, a compound of Formula 3 is reacted with an acid chloride in a suitable solvent (C) to form an acid chloride of Formula 3A, which is then coupled with a compound of Formula 9 using a suitable base (II) and a suitable solvent (D) to give a compound of Formula 1, an intermediate, an N-oxide, or a salt thereof; wherein R 1 , R 2 , R 3 , R 4 and n are as defined in claim 2.

4. The method of claim 2, wherein, In step d, a compound of Formula 3 is reacted with a compound of Formula 7 in the presence of a suitable base (II) and an acid chloride to form a compound of Formula 2, wherein the compound of Formula 2 is optionally isolated; and a compound of Formula 2 is ring opened with a compound of Formula 8 in the presence of a suitable base (III) in a suitable solvent (C) to give a compound of Formula 1, an intermediate, an N-oxide, or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 and n are as defined in claim 2.

5. The method of any one of claims 2-4, wherein, R 1 is H or C1-C2alkyl; R 2 is C1-C4alkyl; R 3 is fluoro or chloro; and R 4 is chloro or C1-C2alkyl.

6. The method of claim 5, wherein, R 1 is H; R 2 is isopropyl or tert-butyl; R 3 is chloro; and R 4 is methyl.

7. The method of claim 1 or 2, wherein, a compound of Formula 3 is prepared from a compound of Formula 5 in one step without isolating a compound of Formula 4.

8. The method of claim 2 or 3, wherein, In step d, a compound of Formula 3 is converted to a compound of Formula 3A in situ in the presence of a suitable acid chloride and a suitable solvent (C):

9. The method of claim 2 or 3, wherein, In step d, a compound of Formula 3 is converted to a compound of Formula 3A in the presence of a suitable acid chloride and a suitable solvent (C), wherein the acid chloride of Formula 3A can be isolated:

10. A process for the preparation of a compound of formula 4, wherein, the process comprising the step (step b): reacting a compound of Formula 5 with a compound of Formula 10 in the presence of a suitable base (I), a suitable solvent (B), and optionally a phase transfer catalyst to give a compound of Formula 4, wherein the compound of Formula 4 is optionally isolated, 11. The method of any of the preceding claims, wherein, n＝2。 12. The method of any one of the preceding claims, wherein, the suitable base (I), base (II), or base (III) is independently selected from an inorganic base or an organic base.

13. The method according to claim 12, wherein: The inorganic base can be selected from lithium bicarbonate (LiHC03), sodium bicarbonate (NaHC03), potassium bicarbonate (KHC03), cesium bicarbonate (CsHC03), sodium carbonate (Na2C03), calcium carbonate (CaC03), cesium carbonate (Cs2C03), lithium carbonate (Li2C03), potassium carbonate (K2C03), lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium hydroxide (CsOH), calcium hydroxide (Ca(OH)2), disodium hydrogen phosphate (Na2HP04), sodium phosphate (Na3P04), dipotassium hydrogen phosphate (K2HP04), potassium phosphate (K3P04), sodium fluoride (NaF), potassium fluoride (KF), cesium fluoride (CsF), lithium hydride (LiH), sodium hydride (NaH), potassium hydride (KH), sodium methoxide (NaOCH3), sodium ethoxide (NaOCH2CH3), sodium tert-butoxide or potassium tert-butoxide.

14. The method of claim 12, wherein, The organic base can be selected from ethylamine, triethylamine, isopropylamine, diisopropylamine, triisopropylamine, pyridine, picoline, piperidine, methylmorpholine, N-methylpiperidine, N,N-dimethylaminopyridine (DMAP), lutidine, collidine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, choline hydroxide, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 2,3,4,6,7,8,9,10-octahydropyrimido[l,2-a]azepine 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,4-diazabicyclo[2.2.2]octane (DABCO).

15. The method of any one of claims 1-4 and 8-10, wherein, The suitable solvent (A), solvent (B), solvent (C) or solvent (D) is independently selected from acetonitrile, acetic acid, acetone, hexane, heptane, octane, nonane, decane, dodecane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, dimethylformamide, dichloroethane, ethyl acetate, toluene, xylene, mesitylene, benzene, halogenated benzene, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, methoxy methane, methoxy ethane, ethoxy ethane, dimethoxy ethane, diethoxy ethane, dichloromethane, chloroform, dichloroethane, N,N-dimethylformamide, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, hexamethylphosphoramide, 1,3-dimethyl-2-imidazolidinone or a combination thereof.

16. The method of any one of claims 1-4 and 8-10, wherein, The steps a, b, c and d of the process are carried out at a temperature range of 0 to 150 °C.

17. The process as claimed in claim 1 or 2, wherein i. the suitable reagent in step a is selected from nitric acid (HN03), sulfuric acid, acetic acid, hydrochloric acid or a mixture thereof; ii. the suitable solvent (A) in step a is selected from dichloromethane, dichloroethane or acetonitrile; iii. step a is carried out at a temperature range of 0 to 100 °C.

18. The process as claimed in claim 1 or 2 or 10, wherein i. the suitable base (I) in step b is selected from K2C03, Na2C03, NaOH, KOH or K3P04; ii. the suitable solvent (B) in step b is selected from dichloroethane, toluene, xylene, chlorinated benzene, acetonitrile, dioxane and dimethoxy ethane; iii. the optional phase transfer catalyst is selected from tetraalkylammonium halide; iv. step b is carried out at a temperature range of 25 to 130 °C.

19. The process as claimed in claim 1 or 2, wherein i. the hydrolyzing agent in step c is selected from an acid; ii. The suitable solvent in step c is selected from acetic acid (AcOH), water or acetonitrile; iii. Step c is carried out at a temperature range of 50 to 130 °C.

20. The process of any one of claims 2-4 and 8-9, wherein i. The acyl chloride in step d is selected from thionyl chloride (SOCl2), methylsulfonyl chloride (MsCl), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), oxalyl chloride, triphosgene or phosgene; ii. The suitable solvent (C) and solvent (D) in step d are independently selected from dichloroethane, acetonitrile (ACN), N,N-dimethylformamide (DMF), ethyl acetate, pyridine, picoline or mixtures thereof; iii. The suitable base (II) and base (III) in step d are independently selected from carbonates, bicarbonates, hydroxides, hydrides or alkoxides of alkali or alkaline earth metals, isopropylamine, triethylamine, diisopropylethylamine, triisopropylamine, pyridine, picoline, N-methylmorpholine, N-methylpiperidine, N,N-(dimethylamino)pyridine (DMAP), lutidine, collidine, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); iv. Step d is carried out at a temperature range of 0 to 80 °C.

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