阅读说明：本技术 合成氨茴二酰胺化合物及其中间体的方法 (Method for synthesizing anthranilamide compound and intermediate thereof ) 是由 费南德拉赛·卡里 贾巴迪什·巴布 巴拉特·尤塔姆奥·申德 爱莫·德亚内什瓦·卡尔瓦格哈 卡姆 于 2020-02-20 设计创作，主要内容包括：本发明公开了一种合成式(I)的氨茴二酰胺化合物的方法,其中,其中,R～(1)、R～(2)、R～(3a)、R～(3b)、R～(3c)、R～(4)、R～(5)、R～(6)和Z如具体实施方式中所定义。所述方法包括如下步骤：得到式(IV)的单氰基或二氰基取代的苯胺化合物,然后将其转化为式(V)的氨茴酸化合物或式(Va)的氨茴酰胺化合物。此外,式(VI)化合物可以任选地由式(IV或V或Va)化合物合成。(The invention discloses a method for synthesizing an anthranilamide compound of a formula (I), wherein R is 1 、R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5 、R 6 And Z is as defined in the detailed description. The method comprises the following steps: to give a mono-or dicyano-substituted aniline compound of formula (IV) which is then converted into an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va). Furthermore, the compound of formula (VI) may optionally be synthesized from a compound of formula (IV or V or Va).)

1. a process for the synthesis of a compound of formula (I),

wherein the content of the first and second substances,

R¹is C₁-C₄Alkyl or halogen;

R²is hydrogen, halogen or cyano;

R^3aand R^3bIndependently of one another is hydrogen, C₁-C₄Alkyl or C₃-C₆cycloalkyl-C₁-C₄An alkyl group;

R^3cindependently is hydrogen or C₁-C₄An alkyl group;

R⁴is halogen, CF₃、OCF₂H、OCH₂CF₃Or

R⁵Is halogen;

R⁶hydrogen, halogen;

z is CR⁷Or N; and

R⁷is a hydrogen or a halogen, and the halogen,

the method comprises the following steps:

a) reacting an N-substituted anthranilamide compound of the formula (VI) with a pyrazole acid compound of the formula (VII) to give a compound of the formula (I),

wherein the content of the first and second substances,

R⁸is OH, Cl or O-C₁-C₄An alkyl group;

b) converting the anthranilamide compound of formula (Va) to the N-substituted anthranilamide compound of formula (VI) according to the reaction scheme shown below by any one of the following steps:

i. in the presence of a suitable base or a suitable acid and a suitable alkylating agent,

by using a suitable transamidation method:

or

According to the reaction scheme shown below, a suitable formula HN (R) is used^3a)(R^3b) Converting the anthranilic acid compound of formula (V) to an N-substituted anthranilamide compound of formula (VI):

c) converting a mono-or dicyano-substituted aniline compound of formula (IV) to an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va), optionally in the presence of a suitable base or a suitable acid, according to the reaction scheme shown below:

or

Converting a mono-or dicyano-substituted aniline compound of formula (IV) to an N-substituted anthranilamide compound of formula (VI) by any one of the following reaction steps, according to the reaction scheme shown below:

i) in the presence of a suitable base or a suitable acid and a suitable alkylating agent,

ii) use of the appropriate formula HN (R)^3a)(R^3b) The amine of (a) is subjected to ammonolysis:

d) optionally halogenating the compound in the presence of a suitable halogenating agent, wherein R¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) being hydrogen to give a compound wherein R is¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) which is a halogen.

e) The mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen is converted to a mono-or dicyano substituted aniline compound of formula (IV) using a suitable cyanating reagent according to the reaction scheme shown below:

f) converting a substituted aniline compound of formula (II) to a mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen, using a suitable halogenating agent according to the reaction scheme shown below:

2. a synthetic method for synthesizing a compound of formula (VI),

wherein the content of the first and second substances,

R¹is C₁-C₄Alkyl or halogen;

R²is hydrogen, halogen or cyano;

R^3aand R^3bIndependently of one another is hydrogen, C¹-C⁴Alkyl or C₃-C₆cycloalkyl-C₁-C₄An alkyl group;

R^3cis hydrogen or C₁-C₄An alkyl group;

the method comprises the following steps:

a) converting the anthranilamide compound of formula (Va) to the N-substituted anthranilamide compound of formula (VI) according to the reaction scheme shown below by any one of the following steps:

i. in the presence of a suitable base or a suitable acid and a suitable alkylating agent,

by using a suitable transamidation method:

or

According to the reaction scheme shown below, a suitable formula HN (R) is used^3a)(R^3b) Converting the anthranilic acid compound of formula (V) to an N-substituted anthranilamide compound of formula (VI):

b) converting a mono-or dicyano-substituted aniline compound of formula (IV) to an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va), optionally in the presence of a suitable base or a suitable acid, according to the reaction scheme shown below:

or

Converting the mono-or dicyano-substituted aniline compound of formula (IV) to an N-substituted anthranilamide compound of formula (VI) by any one of the following reaction steps, according to the reaction scheme shown below:

i) in the presence of a suitable base or a suitable acid and a suitable alkylating agent,

ii) use of the appropriate formula HN (R)^3a)(R^3b) The amine of (a) is subjected to ammonolysis:

c) optionally halogenating the compound in the presence of a suitable halogenating agent, wherein R¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) being hydrogen to give a compound wherein R is¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) which is halogen;

d) the mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen is converted to a mono-or dicyano substituted aniline compound of formula (IV) using a suitable cyanating reagent according to the reaction scheme shown below:

e) converting a substituted aniline compound of formula (II) to a mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen, using a suitable halogenating agent according to the reaction scheme shown below:

3. a method for synthesizing an anthranilic acid compound of the formula (V) or an anthranilamide compound of the formula (Va),

wherein the content of the first and second substances,

R¹is C₁-C₄Alkyl or halogen;

R²is hydrogen, halogen or cyano;

R^3cis hydrogen or C₁-C₄An alkyl group;

the method comprises the following steps:

a) converting a mono-or dicyano-substituted aniline compound of formula (IV) to an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va), optionally in the presence of a suitable base or a suitable acid, according to the reaction scheme shown below:

or

Converting the mono-or dicyano-substituted aniline compound of formula (IV) to an N-substituted anthranilamide compound of formula (VI) by any one of the following reaction steps, according to the reaction scheme shown below:

i) in the presence of a suitable base or a suitable acid and a suitable alkylating agent,

ii) use of the appropriate formula HN (R)^3a)(R^3b) The amine of (a) is subjected to ammonolysis:

b) optionally halogenating the compound in the presence of a suitable halogenating agent, wherein R¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) which is hydrogen, to give a compound in which R is¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) which is halogen;

c) the mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen is converted to a mono-or dicyano substituted aniline compound of formula (IV) using a suitable cyanating reagent according to the reaction scheme shown below:

d) converting a substituted aniline compound of formula (II) to a mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen, using a suitable halogenating agent according to the reaction scheme shown below:

4. a method as claimed in claim 1,2 or 3, wherein the method comprises: the mono-, di-or tri-haloaniline compound of formula (III) wherein X is Cl is converted to a mono-or dicyano substituted aniline compound of formula (IV) by using a suitable cyanating reagent according to the reaction scheme shown below:

5. the method of claim 1,2 or 3, the method comprising: converting the dicyano-substituted aniline compound of formula (IV-a) to an anthranilic acid compound of formula (V-a), or to an anthranilamide compound of formula (V-aa), or to a compound of formula (VI-a), according to the reaction scheme shown below:

6. the process of claim 1 or 2 or 3, wherein the suitable cyanating reagent is selected from alkali metal cyanides, tert-butyl isocyanate, ethyl cyanoacetate, 2-chlorobenzyl thiocyanate, benzyl thiocyanate, dimethyl malononitrile, p-toluenesulfonylmethyl isocyanate, trimethylcyanosilane, cyanohydrin, acetone cyanohydrin, diethyl cyanophosphonate, 1-cyano-4- (dimethylamino) -pyridyltetrafluoroborate or alkali metal hexacyanoferrate (II) acid salt.

7. The process of claim 6, wherein the suitable cyanating reagent is selected from the group consisting of sodium cyanide, cuprous cyanide, zinc cyanide, nickel cyanide, iron (III) cyanide, potassium cyanide, sodium hexacyanoferrate (II), potassium hexacyanoferrate (II), and acetone cyanohydrin.

8. A process as claimed in claim 1,2 or 3, wherein the suitable halogenating agent is selected from HX, NaX, KX, CuX₂、MgX₂、CsX、ZnX₂、SOCl₂、SO₂Cl₂、COCl₂、X₂、C(＝O)(OCl₃)₂t-BuOCl, NaOCl, chloramine-T, N-Halosuccinamide, POX₃、PX₃、PX₅Or a metal halide; wherein X is Cl, Br, I or F.

9. The process as claimed in claim 1 or 2 or 3, wherein the suitable solvent is selected from chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane, trichloroethane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, anisole, acetonitrile, propionitrile, N-or isobutyronitrile, benzonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, dimethyl sulfoxide, sulfone, sulfolane, methanol, ethanol, isopropanol, water or mixtures thereof.

10. A process according to claim 1 or 2 or 3, wherein the suitable alkylating agent is selected from alkyl halides, alkyl sulfates, alkyl peroxides, alkyl silyl peroxides, trialkyl phosphates, alkyl aldehydes (by reductive N-alkylation), halomethyl dialkyl silyl halides, metal complexes or triethyloxonium tetrafluoroborates.

11. The method of claim 10, wherein the alkyl halide is selected from alkyl chloride, alkyl bromide, alkyl iodide, alkyl fluoride, or mixtures thereof.

12. The method of claim 11, wherein the alkyl halide is an alkyl iodide selected from methyl iodide, ethyl iodide, or propyl iodide.

13. The method of claim 1, wherein the suitable coupling agent is selected from the group consisting of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), Dicyclohexylcarbodiimide (DCC), 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide, 1, 3-di-tert-butylcarbodiimide, 1- (dimethylaminopropyl) -3-ethylcarbodiimide iodomethane salt, 1-tert-butyl-3- (1-diphenylmethyl) -carbodiimide, 1, 3-diisopropylcarbodiimide, bis- (diphenylmethyl) -carbodiimide, 1-tert-butyl-3-ethylcarbodiimide, 1-methyl-2-chloropyridinium iodide, bis- (diphenylmethyl) -carbodiimide, bis- (N-methyl) -3-ethylcarbodiimide, bis- (N-methyl) -2-chloropyridinium iodide, bis- (N-methyl) -carbodiimide, N-methyl-3-ethyl-methyl-3-methyl-ethyl-carbodiimide, bis- (N-methyl-2-methyl-2-pyridinium iodide, bis (C-methyl-ethyl-bis- (N-methyl-ethyl-methyl-bis- (N-ethyl-methyl-ethyl-2-methyl-bis (C-methyl-2-ethyl-methyl-bis (C-2-ethyl-bis (S-N-, 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), BOP-chloride or isobutyl chloroformate.

14. The method of claim 1 or 2 or 3, wherein R of the suitable amine^3aAnd R^3bIndependently selected from hydrogen, C₁-C₄Alkyl or C₃-C₆cycloalkyl-C₁-C₄An alkyl group.

15. A process according to claim 1 or 2 or 3 wherein the suitable acid is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, acidic ion exchange resins or mixtures thereof.

16. A process according to claim 1 or 2 or 3, wherein the suitable base is selected from ammonia, alkali or alkaline earth metal hydroxides or carbonates or bicarbonates, methylamine, dimethylamine, diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, alkylated and dialkylated pyridines, dimethylaminopyridine, piperidine or mixtures thereof.

17. The method of claim 16, wherein the alkali or alkaline earth metal is selected from lithium, sodium, potassium, rubidium, cesium, calcium, magnesium, barium, or mixtures thereof.

18. The method of claim 1, wherein, in the compound of formula (I), R¹Is CH₃Br or Cl; r²CN, Br or Cl; r^3aIs H; r^3bIs methyl or 1-cyclopropylethyl; r^3cIs H; r⁴Is Br orR⁵Is Cl; r⁶Is H or Cl; z is N.

19. A process as claimed in claim 1,2 or 3, wherein, in the anthranilic diamides of the formula (VI), R¹Is CH₃Br or Cl; r²CN, Br or Cl; r^3aIs H; r^3bIs methyl or 1-cyclopropylethyl; r^3cIs H.

Technical Field

The invention relates to a method for synthesizing anthranilic diamide compounds. More specifically, the present invention relates to a method for synthesizing an anthranilamide compound of formula (I) from a substituted aniline compound of formula (II). The invention further relates to a process for the synthesis of intermediates useful in the synthesis of compounds of formula (I) from substituted aniline compounds of formula (II).

Background

Anthranilamides are a commercially important class of synthetic insecticides that bind to the ryanodine (ryanodine) receptor with selective potency against the insect form of the receptor relative to the mammalian form of the receptor. The first commercial anthranilamide of this class of synthetic insecticides was chlorantraniliprole, which has extraordinary activity against lepidopteran pests. The second anthranilamide product of this same class is cyantraniliprole, which has excellent trans-spectrum (cross-spectrum) activity against a range of insect orders, including lepidopteran and hemipteran pests. PCT publications WO2003015518, WO2003015519, WO2004067528, WO2005077934 and WO20100069502 disclose the use of anthranilamide for controlling invertebrate pests (such as arthropods).

These anthranilamide compounds can be prepared from 3, 5-substituted 2-amino-N-alkylbenzamide compounds as intermediates. PCT publication WO2013007603 discloses a process for preparing 2-amino-5-cyano-3-methyl (N-methyl) benzamide compounds from 2-amino-5-cyano-3-methylbenzoate. Furthermore, the synthesis of certain 3, 5-substituted 2-amino-N-alkyl-benzamide compounds and their use as intermediates for the preparation of the corresponding insecticidal anthranilamide compounds are disclosed in WO2004067528, WO2006068669, WO2006062978 and WO 2012103436. Further, methods of synthesizing cyano derivatives of anthranilamide compounds or intermediates containing cyano functionality thereof are disclosed in PCT publications WO2008010897, WO2008070158, WO2009085816, WO2009061991, WO2009006061, and WO 2008082502.

However, the methods described in the above documents are laborious and there is still a need to find a simple, efficient, industrially economical method for producing anthranilamide compounds. Therefore, the present invention provides a simple, environment-friendly and cost-effective method for preparing an anthranilamide compound and an intermediate thereof.

Disclosure of Invention

Object of the Invention

The main object of the present invention is to provide a simple, environmentally friendly and cost effective method for the synthesis of anthranilamide compounds of formula (I).

It is another object of the present invention to provide a method for synthesizing anthranilic acid (anthranilic acid) compounds of formula (V) and anthranilamide compounds of formula (Va).

It is still another object of the present invention to provide a method for synthesizing an N-substituted anthranilamide compound of the formula (VI).

Summary of The Invention

Accordingly, the present invention provides a process for the synthesis of an anthranilamide compound of formula (I) from a substituted aniline compound of formula (II),

wherein the content of the first and second substances,

R¹is C₁-C₄Alkyl or halogen;

R²is hydrogen, halogen or cyano;

R^3aand R^3bIndependently of one another is hydrogen, C₁-C₄Alkyl or C₃-C₆cycloalkyl-C₁-C₄An alkyl group;

R^3cindependently is hydrogen or C₁-C₄An alkyl group;

R⁴is halogen, CF₃、OCF₂H、OCH₂CF₃Or

R⁵Is halogen;

R⁶hydrogen, halogen;

z is CR⁷Or N; and

R⁷is a hydrogen or a halogen, and the halogen,

wherein R is¹、R²And R^3cHaving the above definition.

The synthesis method of the anthranilamide compound shown as the formula (I) comprises the following steps: to give a mono-or dicyano-substituted aniline compound of formula (IV) which is then converted into an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va). Finally, the compound of formula (VI) may optionally be synthesized from a compound of formula (IV or V or Va).

In one embodiment, the present invention provides a method of synthesizing an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va) from a substituted aniline compound of formula (II).

In another embodiment, the present invention provides a method for synthesizing an N-substituted anthranilamide compound of formula (VI) from a substituted aniline compound of formula (II).

Detailed Description

The definitions of terms used in the present disclosure provided herein are for illustrative purposes only and do not limit the scope of the present invention disclosed in the present disclosure in any way.

As used herein, the terms "comprises," "comprising," "includes" or "including," "has or" having, "" contains or "containing," "characterized by" or any other variation thereof, are intended to cover a non-exclusive inclusion, with any limitation explicitly stated.

The transitional phrase "consisting of … …" does not include any elements, steps, or components not specified. If in the claims, this is to be understood as excluding the claims from inclusion of materials other than those listed as being commonly associated with the claim. When the word "consisting of … …" appears in the clause of the body of the claims, rather than immediately after the preamble, it only limits the elements specified in the clause; other elements are not excluded from the claims as a whole.

The transitional phrase "consisting essentially of … …" is used to define that a composition or method includes materials, steps, features, components or elements in addition to those which are literally disclosed, provided that such additional materials, steps, features, components or elements do not materially affect the basic and novel characteristics of the claimed invention. The term "consisting essentially of … …" is intermediate between "comprising" and "consisting of … …".

Further, unless expressly stated otherwise, "or" refers to an inclusive "or" and not to an exclusive "or". For example, condition a "or" B "satisfies either of the following conditions: 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).

In addition, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be understood to include one or at least one and the singular forms of stated elements or components also include the plural unless the number is obviously singular.

A carbon-based group refers to a monovalent molecular moiety that comprises a carbon atom that connects the group to the remainder of the chemical structure by a single bond. The carbon-based groups may optionally contain saturated, unsaturated, and aromatic groups, chains, rings, and ring systems, and heteroatoms. Although the size of the carbon-based groups is not subject to any particular limitation, in the context of the present invention they typically comprise 1 to 16 carbon atoms and 0 to 3 heteroatoms. It is noteworthy that the carbon-based group is selected from C₁-C₆Alkyl radical, C₁-C₆Haloalkyl and phenyl, optionally substituted by 1-3 substituents selected from C₁-C₃Alkyl, halogen and nitro.

The meanings of various terms used in the specification will now be described.

The term "alkyl", used alone or in compound words such as "alkylthio" or "haloalkyl" or-N (alkyl) or alkylcarbonylalkyl or alkylsulfonylamino, includes straight or branched C₁To C₂₄Alkyl, preferably C₁To C₁₅Alkyl, more preferably C₁To C₁₀Alkyl, most preferably C₁To C₆An alkyl group. Representative examples of alkyl groups include methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, hexyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-methylpentyl, 2-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, hexyl, 2-ethylbutyl, or a, 1,1, 2-trimethylpropanes1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl or different isomers. If the alkyl group is at the terminus of a complex substituent (e.g., in an alkylcycloalkyl), the initial moiety of the complex substituent (e.g., a cycloalkyl) may be mono-or polysubstituted, identically or differently and independently, by alkyl groups. The same applies to complex substituents in which other groups (e.g., alkenyl, alkynyl, hydroxy, halogen, carbonyl, carbonyloxy, etc.) are terminal.

The term "cycloalkyl" refers to an alkyl group that is closed to form a ring. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. This definition also applies to cycloalkyl groups that are part of a complex substituent (e.g., cycloalkylalkyl, etc.), unless specifically defined otherwise.

The term "cycloalkyl" refers to an alkyl group that is closed to form a ring. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "cycloalkylalkyl" refers to a cycloalkyl substituent on an alkyl group, such as cyclopropyl or cyclobutyl or cyclopentyl substituted at C₁-C₆On any carbon of the alkyl group. Representative examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclopropylethyl.

As used herein, the term "combination" refers to the act of "mixing", "intermixing", or "bringing together" two or more compounds for the purpose of bringing the two or more compounds into intimate contact to facilitate a chemical reaction. For example, certain substrates, reagents or ingredients, reagents described in the summary of the invention, are "associated" with each other in a suitable vessel, container or device in such a way that the substrates, reagents or ingredients can chemically react with each other to form a new product.

To achieve at least one of the above objects, the present invention provides a method for synthesizing an anthranilamide compound of the formula (I),

wherein the content of the first and second substances,

R¹is C₁-C₄Alkyl or halogen;

R²is hydrogen, halogen or cyano;

R^3aand R^3bIndependently of one another is hydrogen, C₁-C₄Alkyl or C₃-C₆cycloalkyl-C₁-C₄An alkyl group;

R^3cindependently is hydrogen or C₁-C₄An alkyl group;

R⁴is halogen, CF₃、OCF₂H、OCH₂CF₃Or

R⁵Is halogen;

R⁶hydrogen, halogen;

z is CR⁷Or N; and

R⁷is a hydrogen or a halogen, and the halogen,

the method comprises the following steps:

a) reacting an N-substituted anthranilamide compound of the formula (VI) with a pyrazole acid compound of the formula (VII) to give a compound of the formula (I),

wherein the content of the first and second substances,

R⁸is OH, Cl or O-C₁-C₄An alkyl group;

b) converting the anthranilamide compound of formula (Va) to the N-substituted anthranilamide compound of formula (VI) according to the reaction scheme shown below by any one of the following steps:

i. in the presence of a suitable base or a suitable acid and a suitable alkylating agent,

by using a suitable transamidation method:

or

According to the reaction scheme shown below, a suitable formula HN (R) is used^3a)(R^3b) Converting the anthranilic acid compound of formula (V) to an N-substituted anthranilamide compound of formula (VI):

c) converting a mono-or dicyano-substituted aniline compound of formula (IV) to an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va), optionally in the presence of a suitable base or a suitable acid, according to the reaction scheme shown below:

or

Converting a mono-or dicyano-substituted aniline compound of formula (IV) to an N-substituted anthranilamide compound of formula (VI) by any one of the following reaction steps, according to the reaction scheme shown below:

i) in the presence of a suitable base or a suitable acid and a suitable alkylating agent,

ii) use of the appropriate formula HN (R)^3a)(R^3b) The amine of (a) is subjected to ammonolysis:

d) optionally halogenating the compound in the presence of a suitable halogenating agent, wherein R¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) being hydrogen to give a compound wherein R is¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) which is a halogen.

e) The mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen is converted to a mono-or dicyano substituted aniline compound of formula (IV) using a suitable cyanating reagent according to the reaction scheme shown below:

f) converting a substituted aniline compound of formula (II) to a mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen, using a suitable halogenating agent according to the reaction scheme shown below:

the compound of formula (VII) may be synthesized using any method known in the art. Synthetic methods for compounds of formula (VII) are disclosed, for example, in documents WO2003015518, WO20030155519, WO2011157664 and WO 2013030100.

The compound of formula (VI) may be converted to the compound of formula (I) by using any suitable method known in the art. For example, methods for converting compounds of formula (VI) to compounds of formula (I) are disclosed in PCT patent applications WO2012103436, WO2008010897 and WO 2006062978.

Any suitable method known in the art may be used to convert the compound of formula (V) to the compound of formula (VI). For example, methods for converting compounds of formula (V) to compounds of formula (VI) are disclosed in prior art documents CN106146414A, WO2016131098, ACS Med. chem. Lett.,2017,8(6), pp 678-681 and chem. Comm.,2018,54, 12766-12769.

In one embodiment, the anthranilamide compound of formula (Va) is converted to the N-substituted anthranilamide compound of formula (VI) by reacting the anthranilamide compound of formula (Va) with a suitable alkylating agent in a suitable solvent in the presence of a suitable base at a temperature in the range of 20 ℃ to 100 ℃ for 1 to 5 hours to give the N-substituted anthranilamide compound of formula (VI).

Suitable alkylating agents for the alkylation of the anthranilamide compounds of formula (Va) are selected from the group consisting of alkyl halides, alkyl sulfates (e.g. methyl sulfate), alkyl peroxides, alkyl silyl peroxides, trialkyl phosphates, alkyl aldehydes (by reductive N-alkylation), halomethyl dialkylsilyl halides, metal complexes or triethyloxonium tetrafluoroborate. Optionally, the alkylation reaction may be carried out by a reductive amination/alkylation process or by any other prior art means.

Non-limiting examples of alkyl halides for alkylation are selected from alkyl chlorides, bromides, iodides, fluorides or mixtures thereof. In one embodiment, the alkyl halide is selected from the group consisting of alkyl chlorides, alkyl bromides, alkyl iodides, and mixtures thereof. Preferably, the alkyl halide is an alkyl iodide selected from methyl iodide, ethyl iodide or propyl iodide.

In another embodiment, the anthranilamide compound of formula (Va) is converted to an N-substituted anthranilamide compound of formula (VI) by using a suitable transamidation method known in the art; for example, by using the methods described in J.Am.chem.Soc.,2006,128(50), pp 16406-16409; advanced Synthesis & Catalysis,2017,359(2), pp 302-; the transamidation methods disclosed in RSC adv, 2016,6, pp 52724-.

In yet another embodiment, the anthranilic acid compound of formula (V) is prepared by reacting the anthranilic acid compound of formula (V) with a compound of formula HN (R) in the presence of a suitable coupling agent^3a)(R^3b) Is converted to an N-substituted anthranilamide compound of the formula (VI) in which R is^3aAnd R^3bIndependently of one another is hydrogen, C₁-C₄Alkyl or C₃-C₆cycloalkyl-C₁-C₄An alkyl group.

In a preferred embodiment, the suitable coupling agent is selected from, but is not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), Dicyclohexylcarbodiimide (DCC), 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide, 1, 3-di-tert-butylcarbodiimide, 1- (dimethylaminopropyl) -3-ethylcarbodiimide iodomethane salt, 1-tert-butyl-3- (1-diphenylmethyl) -carbodiimide, 1, 3-diisopropylcarbodiimide, bis- (diphenylmethyl) -carbodiimide, 1-tert-butyl-3-ethylcarbodiimide, 1-methyl-2-chloropyridinium iodide, bis (N-methyl-N-phenyl) -carbodiimide, bis (N-methyl-ethyl-carbodiimide), bis (N-methyl-phenyl-ethyl-carbodiimide), bis (N-methyl-ethyl-3-carbodiimide), bis (N-methyl-2-chloropyridinium iodide), bis (N-methyl-bis (N-phenyl-methyl-3-methyl-bis (N-methyl-ethyl-methyl-3-methyl-carbodiimide), 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), BOP-chloride or isobutyl chloroformate.

The hydrolysis reaction is carried out by reacting the mono-or dicyano-substituted aniline compound of formula (IV) with a suitable base in a suitable solvent at a temperature in the range of 20 ℃ to 120 ℃ for 8 to 18 hours to obtain an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va).

Suitable bases for converting the mono-or dicyano-substituted aniline compound of formula (IV) to the anthranilic acid compound of formula (V) or the anthranilamide compound of formula (Va) include, but are not limited to, inorganic or organic bases. The inorganic base is preferably selected from ammonia, alkali or alkaline earth metal hydroxides, carbonates, bicarbonates and the like, wherein the alkali and alkaline earth metals are selected from lithium, sodium, potassium, rubidium, cesium, calcium, magnesium, barium and the like or mixtures thereof. The organic base is preferably selected from amines such as methylamine, dimethylamine, diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, alkylated and dialkylated pyridines, dimethylaminopyridine, piperidine and the like or mixtures thereof.

Suitable acids for converting the mono-or dicyano-substituted aniline compound of formula (IV) into the anthranilic acid compound of formula (V) or the anthranilic acid amide compound of formula (Va) include, but are not limited to, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), organic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), acidic ion exchange resins, and the like.

In one embodiment, by using the mono-or dicyano-substituted aniline compound of formula (IV) with a compound of formula HN (R)^3a)(R^3b) Converting the mono-or dicyano-substituted aniline compound of formula (IV) to an N-substituted anthranilamide compound of formula (VI), wherein R is^3aAnd R^3bIndependently selected from hydrogen, C₁-C₄Alkyl or C₃-C₆cycloalkyl-C₁-C₄An alkyl group.

In one embodiment, the cyanation reaction is carried out by reacting the mono-, di-or tri-haloaniline compound of formula (III) with a suitable cyanating reagent for 4 to 16 hours at a temperature in the range of 80 ℃ to 170 ℃ by classical nucleophilic substitution reaction or by coupling reaction using a suitable metal catalyst, preferably a palladium catalyst, and a suitable ligand to yield a mono-or dicyano-substituted aniline compound of formula (IV).

Suitable metal catalysts are selected from, but not limited to, copper (0), copper (I) acetate, copper (I) bromide, copper (I) chloride, copper (I) iodide, copper (I) oxide, copper (II) triflate, copper (II) acetate, copper (II) bromide, copper (II) chloride, copper (II) iodide, copper (II) oxide, NaX, KX, CuX₂、MgX₂CsX or ZnX₂(ii) a Wherein X is Cl, Br, I or F.

In another embodiment, a suitable metal catalyst is a palladium catalyst selected from, but not limited to, palladium (II) acetate, palladium chloride, palladium bromide, palladium iodide, dichlorobis (benzonitrile) palladium (II), dichlorobis (acetonitrile) palladium (II), palladium (II) chloride (pi-cinnamyl) dimer, and the like; palladium metal; palladium on carbon; zero-valent palladium such as bis (benzalacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and the like; complexes of divalent to zero-valent palladium with a ligand described later (for example, tetrakis (triphenylphosphine) palladium, bis (tri-tert-butylphosphino) palladium, bis (triphenylphosphine) palladium dichloride, 1' -bis (diphenylphosphino) ferrocene palladium dichloride-dichloromethane complex, 1, 2-bis (diphenylphosphino) ethane palladium dichloride), and the like.

Suitable ligands used are selected from, but not limited to, alkyl phosphine ligands such as trimethyl phosphine, triethyl phosphine, tri-n-butyl phosphine, di-t-butyl methyl phosphine, tri-t-butyl phosphine, tricyclohexyl phosphine, butyl-di-1-adamantyl phosphine, benzyl-di-1-adamantyl phosphine, and the like; alkyl phosphonium ligands such as tri-n-butyl phosphonium tetrafluoroborate, tri-t-butyl phosphonium tetrafluoroborate, di-t-butyl methyl phosphonium tetrafluoroborate, tricyclohexyl phosphonium tetrafluoroborate and the like; arylphosphine ligands such as triphenylphosphine, tri-o-tolylphosphine, tri-p-tolylphosphine, tri (2-furyl) phosphine, tri (2-thienyl) phosphine, etc.; bidentate phosphine ligands such as 1, 2-bis (diphenylphosphino) ethane, 1, 2-bis (diphenylphosphino) propane, 1, 2-bis (diphenylphosphino) butane, α' -bis (di-t-butylphosphino) -o-xylene, etc.; ferrocene-type phosphine ligands such as 1,1 '-bis (diphenylphosphino) ferrocene, 1' -bis (di-t-butylphosphino) ferrocene, 1 '-bis (diisopropylphosphino) ferrocene, 1,2,3,4, 5-pentaphenyl-1' - (di-t-butylphosphino) ferrocene, etc.; diaryl-type phosphine ligands, such as 2,2' -bis (diphenylphosphino) -1,1' -binaphthyl, 2' -bis (di-p-tolylphosphino) -1, V-binaphthyl, 2, ' -bis [ di (3, 5-xylyl) phosphino ] -1,1' -binaphthyl, 2' -bis (diphenylphosphino) -1,1' -biphenyl, 2-di-t-butylphosphino-1, 1' -binaphthyl, 2- (di-t-butylphosphino) -1,1' -biphenyl, 2-di-t-butylphosphino-2 ' - (N, N-dimethylamino) biphenyl, 2-di-t-butylphosphino-2 ' -methylbiphenyl, 2- (dicyclohexylphosphino) biphenyl, 2' -di-t-butylphosphino-1, 1' -biphenyl, 2' -di-t-butylphosphino-1 ' -biphenyl, 2' -dinaphthyl, 2' -dimethyldinaphthyl, 2' -biphenylyl, 2' -di-t-butylphosphino-1, 1' -binaphthyl, 2' -binaphthyl, 2- (dicyclohexylphosphino) -2,6' -dimethoxy-1, 1' -biphenyl, 2- (dicyclohexylphosphino) -2' - (N, N-dimethylamino) biphenyl, 2- (dicyclohexylphosphino) -2' -methylbiphenyl, 2- (dicyclohexylphosphino) -2',4',6' -triisopropyl-1, 1' -biphenyl, 2- (diphenylphosphino) -2' - (N, N-dimethylamino) biphenyl, etc.; pyrrole type phosphine ligands such as N-phenyl-2- (di-t-butylphosphino) pyrrole, N-phenyl-2- (dicyclohexylphosphino) pyrrole, etc.; diphenyl ether type phosphine ligands such as 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene, bis (2-diphenylphosphinophenyl) ether and the like; carbene ligands such as 1, 3-bis (2, 6-diisopropylphenyl) -4, 5-dihydroimidazolium tetrafluoroborate, 1, 3-bis (2, β -diisopropylphenyl) -4, 5-dihydroimidazolium chloride, 1, 3-bis (2,4, 6-trimethylphenyl) -4, 5-dihydroimidazolium chloride and the like.

In a preferred embodiment, the cyanation reaction is carried out by reacting the mono-, di-or tri-halogenated aniline compound of formula (III) with a suitable cyanating reagent in a suitable solvent at a temperature in the range of 110 ℃ to 170 ℃ for 4 to 8 hours to give the mono-or dicyano-substituted aniline compound of formula (IV).

Suitable cyanating reagents for converting the mono-, di-or tri-haloaniline compounds of formula (III) to the mono-or dicyano-substituted aniline compounds of formula (IV) include, but are not limited to, alkali metal cyanides, t-butyl isocyanate, ethyl cyanoacetate, 2-chlorobenzyl thiocyanate, benzyl thiocyanate, dimethyl malononitrile, p-toluenesulfonylmethyl isocyanate, trimethylcyanosilane, cyanohydrin, acetone cyanohydrin, diethyl cyanophosphonate, 1-cyano-4 (dimethylamino) -pyridinotetrafluoroborate, and alkali metal hexacyanoferrate (II) acid salts. Preferably, the metal cyanide reagent is selected from the group consisting of sodium cyanide, cuprous cyanide, zinc cyanide, nickel cyanide, iron (III) cyanide, potassium cyanide, acetone cyanohydrin, sodium hexacyanoferrate (II) and potassium hexacyanoferrate (II). More preferably, the metal cyanide reagent is selected from sodium cyanide or cuprous cyanide.

The halogenation reaction is carried out by reacting the substituted aniline compound of formula (II) with bromine, chlorine or iodine in a suitable solvent in the presence or absence of sodium bromide or calcium bromide at a temperature in the range of 0 ℃ to 50 ℃ for 30 minutes to 2 hours to give the mono-, di-or tri-halogenated aniline compound of formula (III).

Halogenation as described herein is carried out in the presence of suitable halogenating agents including, but not limited to, HX, NaX, KX, CuX₂、MgX₂、CsX、ZnX₂、SOCl₂、SO₂Cl₂、COCl₂、X₂、C(＝O)(OCl₃)₂t-BuOCl, NaOCl, chloramine-T, N-Halosuccinamide, POX₃、PX₃、PX₅Or a metal halide; wherein X is Cl, Br, I or F.

Suitable solvents for use in any of the process steps of the present invention are selected from aliphatic, alicyclic or aromatic halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane or trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane or anisole; nitriles, such as acetonitrile, propionitrile, n-or isobutyronitrile or benzonitrile; amides, such as N, N-dimethylformamide, Ν -dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; sulfoxides such as dimethyl sulfoxide or sulfones such as sulfolane; alcohols such as methanol, ethanol, isopropanol, polyethylene glycol, and the like; water or mixtures thereof.

In one embodiment, the anthranilic acid compound of formula (V) or the anthranilic acid amide compound of formula (Va) may be isolated.

In another embodiment of the invention, the anthranilic acid compound of formula (V) is reacted with a compound of formula (VII) to give a compound of formula (VIII), which is then reacted with an amine to give an anthranilic diamide compound of formula (I).

Wherein R is¹、R²、R^3a、R^3b、R^3c、R⁴、R⁵、R⁶、R⁸And Z is as defined above.

In another embodiment of the present invention, the present invention provides a method for synthesizing an N-substituted anthranilic acid compound of formula (VI),

wherein R is¹、R²、R^3aAnd R^3bAs defined above, in the above-mentioned manner,

the method comprises the following steps:

a) converting the anthranilamide compound of formula (Va) to the N-substituted anthranilamide compound of formula (VI) according to the reaction scheme shown below by any one of the following steps:

in the presence of a suitable base or a suitable acid and a suitable alkylating agent,

by using a suitable transamidation method:

or

According to the reaction scheme shown below, a suitable formula HN (R) is used^3a)(R^3b) And suitable couplingsAn agent that converts an anthranilic acid compound of formula (V) to an N-substituted anthranilic acid amide compound of formula (VI):

b) converting a mono-or dicyano-substituted aniline compound of formula (IV) to an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va), optionally in the presence of a suitable base or a suitable acid, according to the reaction scheme shown below:

or

Converting the mono-or dicyano-substituted aniline compound of formula (IV) to an N-substituted anthranilamide compound of formula (VI) by any one of the following reaction steps, according to the reaction scheme shown below:

i) in the presence of a suitable base or a suitable acid and a suitable alkylating agent,

ii) use of the appropriate formula HN (R)^3a)(R^3b) The amine of (a) is subjected to ammonolysis:

c) according to the reaction scheme shown below, optionally in the presence of a suitable halogenating agent, halogenating the compound in which R is¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) being hydrogen to give a compound wherein R is¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) which is halogen;

d) the mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen is converted to a mono-or dicyano substituted aniline compound of formula (IV) using a suitable cyanating reagent according to the reaction scheme shown below:

e) converting a substituted aniline compound of formula (II) to a mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen, using a suitable halogenating agent according to the reaction scheme shown below:

in yet another embodiment, the present invention provides a method of synthesizing an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va),

wherein, R is¹、R²、R^3aAnd R^3bAs defined above, in the above-mentioned manner,

the method comprises the following steps:

a) converting a mono-or dicyano-substituted aniline compound of formula (IV) to an anthranilic acid compound of formula (V) or an anthranilic acid amide compound of formula (Va), optionally in the presence of a suitable base or a suitable acid, according to the reaction scheme shown below:

or

Converting the mono-or dicyano-substituted aniline compound of formula (IV) to an N-substituted anthranilamide compound of formula (VI) by any one of the following reaction steps, according to the reaction scheme shown below:

i) in the presence of a suitable base or a suitable acid and a suitable alkylating agent,

ii) use of the appropriate formula HN (R)^3a)(R^3b) The amine of (a) is subjected to ammonolysis:

b) optionally halogenating the compound in the presence of a suitable halogenating agent, wherein R¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) which is hydrogen, to give a compound in which R is¹And/or R²A mono-or dicyano-substituted aniline compound of formula (IV) which is halogen;

c) the mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen is converted to a mono-or dicyano substituted aniline compound of formula (IV) using a suitable cyanating reagent according to the reaction scheme shown below:

d) converting a substituted aniline compound of formula (II) to a mono-, di-or tri-halogenated aniline compound of formula (III) wherein X is halogen, using a suitable halogenating agent according to the reaction scheme shown below:

in yet another embodiment, the present invention provides a process for converting a mono-, di-or tri-haloaniline compound of formula (III) wherein X is Cl to a mono-or dicyano-substituted aniline compound of formula (IV) using a suitable cyanating reagent and a suitable metal catalyst according to the reaction scheme shown below:

in yet another embodiment, the present invention provides a process for converting a dicyano-substituted aniline compound of formula (IV-a) to an anthranilic acid compound of formula (V-a), or to an anthranilic acid amide compound of formula (V-aa), or to a compound of formula (VI-a), by using a suitable reagent, such as a suitable alkylating reagent or a suitable amine, according to the reaction scheme shown below:

the method disclosed in the present invention for synthesizing the anthranilamide compound of formula (I) is shown in scheme 1 below:

wherein R is¹、R²、R^3a、R^3b、R^3c、R⁴、R⁵、R⁶、R⁷、R⁸And Z is as defined above.

In a preferred embodiment, the present invention provides a process for preparing anthranilic diamides of the formula I

Wherein the content of the first and second substances,

R¹is CH₃Br or Cl;

R²CN, Br or Cl;

R^3ais H and R^3bIs methyl or 1-cyclopropylethyl;

R^3cis H;

R⁴is Br or

R⁵Is Cl;

r6 is H or Cl;

z is N.

In another embodiment, the present invention provides a process for preparing a compound of formula VI

Wherein the content of the first and second substances,

R¹is CH₃Br or Cl;

R²CN, Br or Cl;

R^3ais H and R^3bIs methyl or 1-cyclopropylethyl;

R^3cis H.

The process disclosed herein is preferably carried out batchwise. However, continuous reaction channels are also possible.

The disclosed process may be carried out in the absence of a solvent or in the presence of one or more suitable solvents. The optional solvent should be oxidation resistant (i.e. preferably a solvent having an oxidation rate significantly slower than the oxidation rate of the compounds of formulae I to VII) and suitable for suspending or preferably dissolving the reactants.

The optimum work-up of the reaction mixture after the end of the respective reaction is known to any person skilled in the art. In one embodiment, the work-up is generally carried out by isolating the product by filtration and optionally washing with a solvent, optionally further drying the product if desired.

The process steps according to the invention are generally carried out at atmospheric pressure. Alternatively, however, it is also possible to work under vacuum or pressure.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Accordingly, the following examples are to be construed as merely illustrative, and not limitative of the disclosure in any way whatsoever.

Example (b):

the compound of formula (V) may be converted to the compound of formula (VI) by any of the methods known in the art and disclosed in prior art documents such as CN106146414A, WO2016131098, ACS Med. chem. Lett.,2017,8(6), pp 678-.

The compound of formula (VI) is converted to the compound of formula (I) by using any method known in the art and as disclosed in PCT patent applications WO2012103436, WO2008010897 and WO 2006062978.

Example 1: synthesis of 2-amino-3-bromo-5-chlorobenzoic acid

a) Step 1: synthesis of 2, 6-dibromo-4-chloroaniline

To a stirred solution of sodium bromide (1.7g, 16.5mmol) in water (10mL) at 25 deg.C was added bromine (0.9mL, 16.5 mmol). The resulting solution was added dropwise to 4-chloroaniline (1g, 7.8mmol) at 25 ℃. After completion of the reaction, the reaction mixture was filtered, and the resulting solid was washed with water (50mL) and a 10% aqueous solution of sodium thiosulfate (20mL) in this order, and dried under reduced pressure to give 2, 6-dibromo-4-chloroaniline (2.2g, 7.9mmol, yield 100%).¹H-NMR(400MHz,DMSO-d6)δ7.54(s,2H),5.49(s,2H)。

b) Step 2: synthesis of 2-amino-3-bromo-5-chlorobenzonitrile

To a stirred solution of 2, 6-dibromo-4-chloroaniline (1.0g,3.5mmol) in N-methylpyrrolidinone (1.6mL) was added cuprous cyanide (0.3g,3.8mmol) and the reaction mixture was stirred at 150 ℃ for 1 hour. After completion of the reaction, the reaction mixture was diluted with a mixture of ethyl acetate (10mL) and water (10mL) and filtered through a celite bed. The resulting filtrate was diluted with ice water (10mL) and extracted twice with ethyl acetate (20 mL). The combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography using ethyl acetate and hexane as eluent to obtain 2-amino-3-bromo-5-chlorobenzonitrile (0.52g, 2.2mmol, 64% yield).¹H-NMR (400MHz, chloroform-D) δ 7.81(D, J ═ 2.4Hz,1H),7.68(D, J ═ 2.4Hz,1H),6.26(s, 2H).

c) And step 3: synthesis of 2-amino-3-bromo-5-chlorobenzoic acid

A solution of 2-amino-3-bromo-5-chlorobenzonitrile (0.2g,0.9mmol) in ethanol (2mL) was added to aqueous sodium hydroxide (0.1g,2.6mmol) and stirred at 100 ℃ for 16 h. After completion of the reaction, the volatiles were removed from the reaction and the reaction mixture was washedDiluted with water and acidified to pH 3.0 using 2M aqueous hydrochloric acid. The precipitated material was filtered and dried to give 2-amino-3-bromo-5-chlorobenzoic acid (160mg, 0.6mmol, 74% yield).¹H-NMR(400MHz,DMSO-d6)δ13.33(bs,1H),7.75(d,J＝2.4Hz,1H),7.72(d,J＝2.4Hz,1H),6.83(s,2H),LCMS：[249.85]^M-H。

Example 2: synthesis of 2-amino-5-cyano-N, 3-dimethylbenzamide:

a) step-1: synthesis of 2, 4-dibromo-6-methylaniline:

to a solution of sodium bromide (19.2g,187mmol) in water (50mL) at 25 deg.C was added bromine. The resulting solution was added dropwise to o-toluidine (10.3ml, 93mmol) at 10 ℃. The reaction mixture was stirred at 10 ℃ for 30 minutes. After completion of the reaction, the reaction mixture was diluted with water (50mL), filtered, and the resulting solid was washed successively with water and a 10% aqueous solution of sodium thiosulfate, and dried under reduced pressure to give 2, 4-dibromo-6-methylaniline (23g, 87mmol, yield 93%).¹H-NMR(400MHz,DMSO-d6)δ7.44-7.34(1H),7.20-7.11(1H),4.46-4.20(bs,2H)。

b) Step-2: synthesis of 4-amino-5-methylisophthalamide:

i) to a stirred solution of 2, 4-dibromo-6-methylaniline (20g,75mmol) in N-methylpyrrolidinone (60mL) was added cuprous cyanide (20g,151mmol) and the reaction mixture was stirred at 150 ℃ for 6 hours. After completion of the reaction, the reaction mixture was diluted with a mixture of 30% aqueous ammonium hydroxide (50mL) and ethyl acetate (100mL) and stirred for 1 hour. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed sequentially with water (50mL) and brine solution (50 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-amino-5-methylisobenzodicarbonitrile (8.7g, 55.4mmol, 73% yield). LCMS: [156]^M-H,¹H-NMR(400MHz,DMSO-d6)δ7.87(d,J＝1.8Hz,1H),7.56(d,J＝0.9Hz,1H),6.75(s,2H),2.10(s,3H)。

ii) to a stirred mixture of 2, 4-dibromo-6-methylaniline (1.0g,3.77mmol), potassium iodide (0.25g,1.510mmol), copper (I) iodide (0.14g,0.755mmol) and potassium ferricyanide (1.243g, 3.77mmol) in polyethylene glycol (PEG) (10mL) under a nitrogen atmosphere was added a solution of N, N' -dimethylethylenediamine (1.016mL, 9.44mmol) in polyethylene glycol (PEG) (5 mL). The reaction mixture was heated at 175 ℃ for 4 hours. After completion of the reaction, the reaction mixture was diluted in ethyl acetate (80mL) and washed with water (2X 70mL) and a saturated solution of ammonium chloride (3X 70 mL). The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to give the crude product, which was crystallized from ethanol to give the pure product 4-amino-5-methylisophthalamide (350mg, 2.227mmol, 67% yield).

iii) A reaction mixture of 2, 4-dibromo-6-methylaniline (50g,189mmol), N-dimethylformamide (100mL), potassium ferrocyanide (27.8g,75mmol), sodium carbonate (20g,189mmol), 2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl (9g,18.87mmol), and bis (dibenzylideneacetone) palladium (5.43g,9.44mmol) was heated to 130 ℃ for 6 hours. After completion of the reaction, the reaction mixture was cooled to 25 ℃, filtered through a celite bed and washed with dichloromethane. The filtrate was concentrated under reduced pressure to give a crude product, which was then dissolved in dichloromethane, t-butyl methyl ether was added to the mixture and the mixture was stirred at 25 ℃ for 2 hours. The mixture was filtered and the solid residue was stirred in ethanol (30mL) at 10-15 ℃ for 5 hours and filtered to obtain 17g of pure product. The two filtrates were then mixed together, concentrated and purified by flash column chromatography to give a small amount of impure second crop which was again stirred in ethanol (7mL) for 16 h to give 6g of pure product. (HPLC purity 89%), 4-amino-5-methylisobenzodinitrile 23g, 146mmol, 78% yield). MS: 156.00[ M-H ] M/z]。¹H-NMR(400MHz,CDCl₃)δ7.85(d,J＝2.0Hz,1H),7.53(d,J＝0.8Hz,1H),6.73(s,2H),2.07(s,3H)。

iv) A reaction mixture of 2, 4-dibromo-6-methylaniline (10g,37.7mmol), potassium ferrocyanide (6.38g,15.10mmol), palladium II acetate (1.729g,3.77mmol) and sodium acetate (6.19g,75mmol) in N, N-dimethylformamide (70mL) was heated at 150 ℃ for 18 hours. After the reaction is finished, removing the solvent under reduced pressure; the crude product was diluted in ethyl acetate (500mL), filtered through celite and washed with ethyl acetate and water (300 mL). The filtrate was washed with saturated sodium bicarbonate solution (2x200mL) and brine (2x200mL), dried over sodium sulfate, and concentrated to obtain crude compound (15 g). Ethanol (100mL) was added to the crude compound and the mixture was stirred for 16 hours. The mixture was cooled to 0 ℃ and filtered to obtain the pure product 4-amino-5-methyl-isophthalonitrile (4.6 g; 29.3mmol, 78% yield).

v) to a stirred mixture of 2, 4-dibromo-6-methylaniline (0.600g,2.265mmol), sodium cyanide (NaCN) (0.222g,4.53mmol), copper (I) iodide (0.129g,0.679mmol), potassium iodide (0.226g, 1.359mmol) in xylene (3mL) under a nitrogen atmosphere was added a solution of N, N' -dimethylethylenediamine (0.600g,2.265mmol) in xylene (0.5 mL). The reaction was heated at 175 ℃ for 16 h, then the mixture was diluted in ethyl acetate (70mL) and water (75mL), and the separated organic layer was washed with saturated ammonium chloride solution (50mL), saturated sodium bicarbonate solution (50mL) and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated to give a crude material (0.685g), which was purified by flash column chromatography to give the pure product 4-amino-5-methyl isophthalonitrile (0.085g, 0.541mmol, 24% yield).

vi) to a stirred solution of 2, 4-dibromo-6-methylaniline (0.500g,1.887mmol) in N-methyl-2-pyrrolidone (5mL) was added copper (I) cyanide (0.340g,3.79 mmol). The reaction mixture was stirred at 160 ℃ for 16 hours. After completion of the reaction, the reaction mixture was diluted with 30% aqueous ammonia (50mL) and ethyl acetate (300mL) and further stirred for 1 hour. The reaction mixture was extracted with ethyl acetate (50mL), washed with water (30mL) and brine (30mL) and evaporated to dryness to give the desired product which was purified with dichloromethane and ether to give 4-amino-5-methyl isophthalonitrile (0.200g,1.272mmol, 67% yield).

c) Step-3: synthesis of 2-amino-5-cyano-3-methylbenzamide:

a reaction mixture of aqueous sodium hydroxide (0.5g, 12.7mmol) and 4-amino-5-methylisobenzodinitrile (2g, 12.7mmol) in ethanol (15mL) was stirred at 70 ℃ for 4 hours. After completion of the reaction, the reaction mixture was diluted with ice water (30mL), and the resulting precipitate was filtered and washed with water (20mL)And dried under reduced pressure to give 2-amino-5-cyano-3-methylbenzamide (1.6g, 9.13mmol, yield 72%) as an off-white solid.¹H-NMR(400MHz,DMSO-d6)δ7.97-7.90(bs,1H),7.89-7.84(m,1H),7.45-7.37(m,1H),7.36-7.22(bs,3H),2.08(s,3H),LCMS:[363.8]^M-H。

d) Step-4: 2-amino-5-cyano-N, 3-dimethylbenzamide

To a mixture of 2-amino-5-cyano-3-methylbenzamide (200mg, 1.1mmol) and cesium carbonate (446mg, 1.4mmol) in dimethylformamide (2mL) was added methyl iodide and the reaction mixture was stirred in a sealed tube at 60 ℃ for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20mL) and washed twice with brine solution (20 mL). The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by flash chromatography using ethyl acetate and hexane as eluents to give 2-amino-5-cyano-N, 3-dimethylbenzamide (86mg, 0.5mmol, yield 40%).¹H-NMR(400MHz,DMSO-d6)δ8.50-8.35(1H),7.89-7.75(1H),7.51-7.37(1H),7.25-7.09(2H),2.79-2.68(3H),2.15-2.05(3H),LCMS:[463.8]^M-H。

EXAMPLE 3 Synthesis of 2-amino-3-bromo-5-chlorobenzonitrile

a) Step 1: synthesis of 2-amino-5-chlorobenzonitrile

To a stirred solution of 2-bromo-4-chloroaniline (20g, 97mmol) in N-methyl-2-pyrrolidone (70mL) was added cuprous cyanide (19.14g, 145 mmol). The resulting reaction mixture was stirred at 140 ℃ for 5 hours. After completion of the reaction, the reaction mixture was cooled to 25 ℃ and poured into water (250 mL). The resulting solid was filtered and washed with water and aqueous sodium bicarbonate. The crude product was dissolved in ethyl acetate (100mL) and washed with water (30mL), aqueous ammonium hydroxide (30mL) and brine solution (30 mL). The ethyl acetate layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was triturated with hexane and dried under reduced pressure to obtain 2-amino-5-chlorobenzonitrile (11.8g, 77mmol, yield 80)％)。¹HNMR(400MHz,DMSO-d6)δ7.47(d,J＝2.4Hz,1H),7.31(dd,J＝9.2,2.4Hz,1H),6.77-6.79(m,1H),6.22(s,2H),GCMS:[206.9]。

b) Step 2: synthesis of 2-amino-3-bromo-5-chlorobenzonitrile

To a stirred solution of sodium bromide (0.7g, 7.2mmol) in water (10mL) was added dropwise bromine (0.4mL, 7.2mmol) at 25 ℃. To the solution was added 2-amino-5-chlorobenzonitrile (1g,6.55mmol) and stirred at 25 ℃ for 30 minutes. After completion of the reaction, the reaction mixture was filtered, washed with water and 10% aqueous sodium thiosulfate (20mL), and dried under reduced pressure to give 2-amino-3-bromo-5-chlorobenzonitrile (1.4g, 6.05mmol, 92% yield).¹HNMR(400MHz,DMSO-D6)δ7.82(d,J＝2.4Hz,1H),7.66(d,J＝2.4Hz,1H),6.27(s,2H),GCMS:[231.8]。

c) And step 3: synthesis of 2-amino-3-bromo-5-chlorobenzonitrile

To a stirred suspension of 2-amino-3-bromo-5-chlorobenzonitrile (1.4g,6mmol) in ethanol (8mL) was added a solution of sodium hydroxide (0.7g,18.1mmol) in water (8mL) and stirred at 100 ℃ for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give a semi-solid, which was diluted with water and acidified with 10% aqueous hydrochloric acid to give the desired crude product as a solid, which was filtered and dried to give 2-amino-3-bromo-5-chlorobenzoic acid (1.48g,5.9mmol, 98% yield).¹HNMR(400MHz,DMSO-d6)δ13.28(s,1H),7.74(d,J＝2.4Hz,1H),7.72(d,J＝2.4Hz,1H),6.77(s,2H),LCMS:[249.85]^M+2。

Example 4: synthesis of 4-amino-5-methylisophthalamide:

i) to 2, 4-dichloro-6-methylaniline (2.0g,11.36mmol), [ (cinnamyl) PdCl under an argon atmosphere]₂To a mixture of (0.063g,0.11mmol), 2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl (0.162g, 0.34mmol) and N, N-diisopropylethylamine (9.92mL, 56.81 mmol) was added N-butanol (20 mL). The reaction mixture was purged with argon for 10 minutes. The reaction mixture was then heated at 80 ℃ and acetone cyanohydrin (2.079mL,22.72mmol) diluted in n-butanol (20mL) was added over 3 hours. After completion of the reaction, the reaction mixture was cooled to 25 ℃, concentrated under reduced pressure to give a crude product, which was then purified with iceWashed with cold water (20mL), and the resulting precipitate was filtered and dried to give 4-amino-5-methylisobenzodinitrile (1.5g, 9.54mmol, 84% yield).¹H-NMR(400MHz,DMSO-d6)δ:7.89(d,J＝1.7Hz,1H),7.57(d,J＝1.7Hz,1H),6.76(s,2H),2.10(s,3H)。GCMS：157.1。

ii) to 2, 4-dichloro-6-methylaniline (10g,56.8mmol), [ (cinnamyl) PdCl under an argon atmosphere]₂To a mixture of (0.31g,0.56mmol), 2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl (0.81g,1.7mmol) and N, N-Diisopropylethylamine (DIPEA) (49.6mL,284mmol) was added N-butyl-1-ol (100 mL). The reaction mixture was purged with argon for 10 minutes. The reaction mixture was then heated at 85 ℃ and acetone cyanohydrin (8.32mL,91mmol) diluted in n-butanol (100mL) was added over 5 hours. After completion of the reaction, the reaction mixture was cooled to 25 ℃ and concentrated under reduced pressure to give crude product, which was purified by Combi Flash chromatography using 0-60% ethyl acetate in hexane as eluent to give 2-amino-5-chloro-3-methylbenzonitrile (2.6g, 15.61mmol, yield 27%) and 4-amino-5-methyl-m-phthalonitrile (4.5g, 28.6mmol, yield 50%).

2-amino-5-chloro-3-methylbenzonitrile:¹H-NMR(400MHz,DMSO-d6)δ7.39(d,J＝1.6Hz,1H),7.27(d,J＝2.0Hz,1H),5.93(s,2H),2.11(s,3H)。GCMS:166.1；

4-amino-5-methylisobenzodinitrile:¹H-NMR(400MHz,DMSO-d6)δ:7.89(d,J＝1.7Hz,1H),7.57(d,J＝1.7Hz,1H),6.76(s,2H)2.10(s,3H)。GCMS:157.1。

iii) to 2, 4-dichloro-6-methylaniline (100g,568mmol), [ (cinnamyl) PdCl under nitrogen]₂To a mixture of (1.57g,2.84mmol), 2-dicyclohexylphosphino-2 ',4',6 '-tri-isopropyl-1, 1' -biphenyl (1.57,2.84mmol) and N, N-Diisopropylethylamine (DIPEA) (496mL,2.84mol) was added N-butanol (1000 mL). The reaction mixture was then purged with nitrogen for 10 minutes. The reaction mixture was heated to 85 ℃ and acetone cyanohydrin (83mL,909mmol) in n-butanol (500mL) was added over 5 hours. After completion of the reaction, the reaction mixture was cooled to 25 ℃. The solvent was evaporated under reduced pressure to give a crude residue, which was then washed with ice-cold water (2000 mL). Filtering and drying the obtained solid to obtainObtaining a crude product. The resulting crude product was dissolved in hot ethanol (1000mL), cooled, the solid precipitate filtered, dried to give 4-amino-5-methyl-isophthalonitrile (28g, 178mmol, 31% yield), the filtrate concentrated under reduced pressure and redissolved in hot ethanol (500mL), cooled and filtered to give the product mixture as a solid (20 g). The filtrate was concentrated to obtain 2-amino-5-chloro-3-methylbenzonitrile (37g, 222mmol, yield 39%).

2-amino-5-chloro-3-methylbenzonitrile:¹H-NMR(400MHz,DMSO-d6)δ:7.39(d,J＝1.6Hz,1H),7.27(d,J＝2.0Hz,1H),5.93(s,2H),2.11(s,3H)。GCMS:166.1；

4-amino-5-methylisobenzodinitrile:¹H-NMR(400MHz,DMSO-d6)δ:7.89(d,J＝1.7Hz,1H),7.57(d,J＝1.7Hz,1H),6.76(s,2H),2.10(s,3H).GCMS:157.1。