Process for the synthesis of anthranilic acid/amide compounds and intermediates thereof

1 . A process for the preparation of a compound of formula (Z) or a salt thereof:

wherein,

R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 3 -C 6 cycloalkyl;

R 3 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 haloalkyl and C 3 -C 6 cycloalkyl;

R is selected from the group consisting of hydrogen or COR 11 ;

wherein, R 11 is selected from the group consisting of C 1 -C 4 alkoxy, O-benzyl and O-phenyl;

R 10 is selected from the group consisting of CX 3 , OR 9 , and NR 4a R 4b ;

wherein, X represents halogen;

R 9 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

R 4a and R 4b are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl; and NR 4a R 4b represent —N═S(R 7 R 8 )═(O) n ;

n represents an integer from 0-1;

R 7 and R 8 are independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl;

comprising step a) and one or more of steps b) to f):

a) reacting a substituted aniline of formula (II) with a trihaloacetonitrile of formula (IX) to obtain a compound of formula (Z), wherein R 10 is CX 3 ;

or

i. reacting a substituted aniline of formula (II) with acetonitrile to obtain a substituted 2-aminoacetophenone of formula (III),

 and

ii. halogenating the compound of formula (III) using a halogenating reagent to obtain a compound of formula (Z), wherein R 10 is CX 3 ;

b) hydrolyzing the compound of formula (Z), wherein R 10 is CX 3 , with a base or an acid to obtain a compound of formula (Z), wherein R 10 is OR 9 and R 9 is hydrogen;

or

converting the compound of formula (III) to a compound of formula (Z), wherein R 10 is OR 9 and R 9 is hydrogen, without isolation of the compound of formula (Z) wherein R 10 is CX 3 ;

c) converting the compound of formula (Z), wherein R 10 is CX 3 , to a compound of formula (Z), wherein R 10 is OR 9 and R 9 is alkyl; with a base or an acid and in the presence of an alcoholic solvent;

d) reacting the compound of formula (Z), wherein R 10 is CX 3 , with a substituted amine of formula (VIII) to obtain a compound of formula (Z), wherein R 10 is NR 4a R 4b ;

e) reacting the compound of formula (Z), wherein R 10 is OR 9 and R 9 is hydrogen; with a substituted amine of formula (VIII) and a coupling reagent or a halogenating reagents and optionally in the presence of a base to obtain a compound of formula (Z), wherein R 10 is NR 4a R 4b ;

or

i. reacting the compound of formula (Z), wherein R 10 is OR 9 and R 9 is hydrogen; with an acid to obtain a compound of formula (IVa),

 and

ii. reacting the compound of formula (IVa) with a substituted amine of formula (VIII) to obtain compound of formula (Z), wherein R 10 is NR 4a R 4b ;

f) reacting the compound of formula (Z), wherein R 10 is OR 9 and R 9 is C 1 -C 4 alkyl; with a substituted amine of formula (VIII) in the presence of a base to obtain a compound of formula (Z), wherein R 10 is NR 4a R 4b ;

wherein R, R 1 , R 2 , R 3 , R 4a and R 4b are as defined above.

2 . The process according to claim 1 , wherein said process further comprises the step of:

reacting the compound of formula (Z) wherein R 10 is NR 4a R 4b , with a compound of formula (VII), to obtain a compound of formula (I),

wherein, W is OH, Cl, O—C 1 -C 4 alkyl, O—C(O) C 1 -C 4 alkyl or imidazolyl;

R 5 is selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, CHF 2 , CF 3 , C 1 -C 4 alkoxy, OCF 2 H, OCH 2 CF 3 , and -A-C 3 -C 5 heterocyclyl;

wherein -A- is selected from the group consisting of direct bond, CHR 6 , —O— or —S—; and said heterocyclyl may optionally be substituted with one or more group selected from hydrogen, halogen, cyano, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;

R 6 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;

X is halogen;

and R, R 1 , R 2 , R 3 , R 4a and R 4b are as defined in claim 1

or

i. reacting the compound of formula (Z) wherein R 10 represent OR 9 and R 9 is hydrogen with a compound of formula (VII), to obtain the compound of formula (IA),

ii. reacting the compound of formula (IA) with a substituted amine of formula (VIII) to obtain compound of formula (I);

3 . A process for the preparation of a compound of formula (Z) or a salt thereof,

wherein,

R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 3 -C 6 cycloalkyl;

R 3 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 haloalkyl and C 3 -C 6 cycloalkyl;

R is selected from the group consisting of hydrogen or COR 11 ;

wherein, R 11 is selected from the group consisting of C 1 -C 4 alkoxy, O-benzyl and O-phenyl;

R 10 is selected from the group consisting of CX 3 , OR 9 , and NR 4a R 4b ;

wherein, X represents halogen;

R 9 is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

R 4a and R 4b are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl; and NR 4a R 4b represent —N═S(R 7 R 8 )═(O) n ;

n represents an integer from 0-1;

R 7 and R 8 are independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl;

comprising:

a) reacting a substituted aniline of formula (II) with a trihaloacetonitrile of formula (IX) to obtain a compound of formula (Z), wherein R 10 is CX 3 ;

or

i. reacting a substituted aniline of formula (II) with acetonitrile to obtain a substituted 2-aminoacetophenone compound of formula (III),

 and

ii. halogenating the compound of formula (III) using a halogenating reagent to obtain a compound of formula (Z), wherein R 10 is CX 3 ;

4 . The process according to claim 1 , wherein, said process for the synthesis of a compound of formula (Z), wherein R 10 is OR 9 and R 9 is hydrogen; comprises steps of:

b) hydrolyzing the compound of formula (Z), wherein R 10 is CX 3 , with a base or an acid to obtain a compound of formula (Z), wherein R 10 is OR 9 and R 9 is hydrogen;

or

converting the compound of formula (III) to a compound of formula (Z), wherein R 10 is OR 9 , and R 9 is hydrogen, without isolation of the compound of formula (Z) wherein R 10 is CX 3 ;

5 . The process according to claim 1 , wherein, said process for the synthesis of a compound of formula (Z), wherein R 10 is NR 4a R 4b ; comprises steps of

d) reacting the compound of formula (Z), wherein R 10 is CX 3 , with a substituted amine of formula (VIII) to obtain a compound of formula (Z), wherein R 10 is NR 4a R 4b ;

e) reacting the compound of formula (Z), wherein R 10 is OR 9 and R 9 is hydrogen; with a substituted amine of formula (VIII) with coupling reagent or a halogenating reagents and optionally in the presence of a base to obtain a compound of formula (Z), wherein R 10 is NR 4a R 4b ;

or

i. reacting the compound of formula (Z), wherein R 10 is OR 9 and R 9 is hydrogen; with an acid to obtain a compound of formula (IVa),

 and

ii. reacting the compound of formula (IVa) with a substituted amine of formula (VIII) to obtain compound of formula (Z), wherein R 10 is NR 4a R 4b ;

f) reacting the compound of formula (Z), where in R 10 is OR 9 and R 9 is C 1 -C 4 alkyl; with a substituted amine of formula (VIII) in the presence of a base to obtain a compound of formula (Z), wherein R 10 is NR 4a R 4b ;

wherein R, R 1 , R 2 , R 3 R 4a , R 4b and X are as defined above.

6 . The process according to claim 1 , wherein, said process for the synthesis of a compound of (Z), wherein R 10 is CX 3 , and R 3 is halogen, from compound of formula (III), wherein R 3 is hydrogen, and all other variables are defined as in claim 1 ;

comprising, halogenating the compound of formula (III), wherein R 3 is hydrogen, using a halogenating reagent to obtain a compound of formula (Z), wherein R 10 is CX 3 and R 3 is halogen;

7 . The process according to claim 2 , wherein said compound of formula (I) is chlorantraniliprole, cyantraniliprole, cyclaniliprole, tetraniliprole, tetra-chlorantraniliprole, bromantraniliprole, dichlorantraniliprole or fluchlordiniliprole.

8 . The process according to claim 1 , wherein,

R 1 is methyl or halogen;

R 2 is hydrogen or halogen;

R 3 is halogen or cyano;

R 10 is CX 3 , OR 9 or NR 4a R 4b ;

R 9 is hydrogen, methyl, ethyl n-propyl, iso-propyl, iso-butyl, or tert-butyl,

R 4a is methyl, ethyl, n-propyl, iso-propyl, cyclopropyl methylcyclopropyl, ethylcyclopropyl, iso-butyl, tert-butyl;

R 4b is hydrogen or methyl,

X is halogen.

9 . The process according to claim 1 , wherein,

R 1 is methyl, chloro or bromo;

R 2 is hydrogen or fluoro;

R 3 is chloro, bromo or cyano;

X is halogen.

10 . The process according to claim 2 , wherein,

R 1 is methyl or halogen;

R 2 is hydrogen or halogen;

R 3 is halogen or cyano;

R 10 is OR 9 or NR 4a R 4b ;

R 9 hydrogen, methyl, ethyl n-propyl, iso-propyl, iso-butyl, tert-butyl,

R 4a is methyl, ethyl, n-propyl, iso-propyl, cyclopropyl methylcyclopropyl, ethylcyclopropyl, iso-butyl or tert-butyl;

R 4b is hydrogen or methyl,

R 5 is selected from the group consisting of bromo, chloro, and -A-C 3 -C 5 heterocyclyl;

wherein -A- is selected from the group consisting of direct bond, CHR 6 , —O— and —S—; and said heterocyclyl may optionally be substituted with one or more group selected from hydrogen, halogen, cyano, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;

R 6 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl.

11 . The process according to claim 2 , wherein, R 1 is methyl, chloro or bromo;

R 2 is hydrogen or fluoro;

R 3 is chloro, bromo or cyano;

R 5 is selected from the group consisting of bromo, chloro, and

R 6 is selected from the group consisting of hydrogen, bromo, chloro, and fluoro.

12 . The process according to claim 1 , wherein said suitable acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, an acidic ion-exchange resin and a mixture thereof.

13 . The process according to claim 1 , wherein said suitable base is selected from ammonia, alkali or alkaline earth metal hydroxide or carbonate or bicarbonate, methylamine, dimethyl amine, diethyl amine, triethylamine, diisopropylamine, diisopropyl ethyl amine, pyridine, alkylated and dialkylated pyridines, dimethylamino pyridine, piperidine and mixtures thereof.

14 . The process according to claim 1 , wherein said suitable halogenating reagent is selected from HX, SOCl 2 , SO 2 Cl 2 , COCl 2 , X 2 , C(═O)(OCl 3 ) 2 , t-BuOCl, NaOCl, NaOBr, chloramine-T, N-halosuccinamides, methanesulfonyl chloride, POX 3 , PX 3 , PX 5 and metal halides; wherein X is Cl, Br, I or F.

15 . The process according to claim 11 , wherein said suitable halogenating reagent is selected from HX, SOCl 2 , X 2 , NaOCl, NaOBr and N-halosuccinamides.

16 . The process as claimed in claim 1 , wherein said reaction steps are carried out using suitable solvent selected from hexane, heptane, cyclohexane, methylcyclohexane, toluene, xylene, decalin, chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane, trichloroethane, diethylether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxy ethane, 1,2-diethoxyethane, anisole, acetonitrile, propionitrile, n- or iso-butyronitrile, benzonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, dimethyl sulfoxide, sulfones, sulfolane, methanol, ethanol, isopropanol, water and mixtures thereof.

17 . A compound of formula (Z) or a salt thereof,

wherein,

R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl and C 3 -C 6 cycloalkyl;

R 3 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 haloalkyl and C 3 -C 6 cycloalkyl;

R is selected from the group consisting of hydrogen and COR 11 ;

wherein, R 11 is selected from the group consisting of C 1 -C 4 alkoxy, O-benzyl and O-phenyl;

X represent chloro or bromo;

with the proviso that the compounds 1-(2-amino-5-chlorophenyl)-2,2,2-trichloroethan-1-one and 1-(2-amino-5-fluorophenyl)-2,2,2-trichloroethan-1-one, are excluded from the compounds of formula (Z).