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

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

wherein,

R 1 is selected from the group consisting of halogen, C 1 -C 4 alkyl and C 3 -C 4 -cycloalkyl;

R 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 alkyl and C 3 -C 4 -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 4a R 4b wherein R 4a and R 4b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 cycloalkyl-C 1 -C 4 alkyl;

comprising a) through d)

a) reacting a compound of formula (II) with a compound of formula (III) to afford a compound of formula (IV), optionally in the presence of a base and a solvent;

wherein,

R 9 is selected from the group consisting of CI, Br and C 1 -C 4 alkoxy;

R 10 is selected from the group consisting of cyano, CH 2 X, CH 2 —(C═O)—OR a , COOR a , C(O)R c and CR d ═NR e ;

R a is selected from the group consisting of hydrogen and C 1 -C 4 -alkyl,

R c is selected from the group consisting of N(R a ) 2 and two R a together with the atoms to which they are attached or together with further atoms selected from the group consisting of C, N, O, S and optionally including 1 to 3 ring members selected from the group consisting of C(═O), C(═S), S(O) m and SiR′ 2 may form a five to six membered non-aromatic ring;

—R d is selected from the groups consisting of hydrogen, C 1 -C 4 -alkyl, (C═O)—R a , COOR a , CON(R a ) 2 and phenyl;

R e is selected from the groups consisting of hydroxy and C 1 -C 4 alkoxy;

X represents halogen;

b) reacting the compound of formula (IV) with an acid to obtain isatin of formula (V), optionally in the presence of a solvent;

c) oxidizing the isatin of formula (V) to obtain isatoic anhydride of formula (VI) in presence of a oxidizing agent and a catalyst, optionally in the presence of a solvent;

or

hydrolyzing the isatin of formula (V) to obtain an anthranilic acid of formula (Vlla) in presence of a hydrolysisng agent, optionally in the presence of a solvent;

and

d) reacting the compound of formula (VI) with a compound of formula (VIII), to obtain a compound of formula (VII), optionally in the presence of an acid and a solvent; as shown in the following scheme:

2 . A process for preparing the compound of formula (I), wherein said process further comprises the step of:

reacting the compound of formula (VII), obtained according to the process of claim 1 , with a compound of formula (IX) to obtain a compound of formula (I);

wherein 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— and —S—; and said heterocyclyl may optionally be substituted with one or more group selected from the group consisting of 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;

W is selected from the group consisting of OH, Cl, O—C 1 -C 4 alkyl, O—C(O)C 1 -C 4 alkyl and imidazolyl;

optionally in the presence of a base, a coupling agent,

or

i. reacting the compound of formula (VIIa), obtained in step c) with a compound of formula (IX), to obtain a compound of formula (IA),

and

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

3 . A process for the synthesis of a compound of formula (V),

wherein,

R 1 is selected from the group consisting of halogen, C 1 -C 4 alkyl and C 3 -C 4 -cycloalkyl;

R 2 is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 alkyl and C 3 -C 4 -cycloalkyl;

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

comprising the steps of:

a) reacting a compound of formula (II) with a compound of formula (III) to afford a compound of formula (IV), optionally in the presence of a base and a solvent;

wherein,

R 9 is selected from the group consisting of Cl, Br and C 1 -C 4 alkoxy;

R 10 is selected from the group consisting of cyano, CH 2 X, CH 2 —(C═O)—OR a , —COOR a , C(O)R c and CR d =NR e ;

R a is selected from the group comprising consisting of hydrogen and C 1 -C 4 -alkyl,

R c is selected from the group consisting of N(R a ) 2 and two R a together with the atoms to which they are attached or together with further atoms selected from the group consisting of C, N, O, S and optionally including 1 to 3 ring members selected from the group consisting of C(═O), C(═S), S(O) m and SiR′2 may form a five to six membered non-aromatic ring;

R d is selected from the groups consisting of hydrogen and —C 1 -C 4 -alkyl, (C═O)—R a , COOR a , CON(R a ) 2 and phenyl;

R e is selected from the groups comprising consisting of hydroxy and C 1 -C 4 alkoxy;

X represents halogen; and

b) reacting the compound of formula (IV) with an acid to obtain isatin of formula (V), optionally in the presence of a solvent;

4 . The process according to claim 3 , wherein, said step-a is carried out by one or more steps selected from i-a to v-a

i-a reacting a compound of formula (II) with a compound of formula (XII) or a compound of formula (XIII) to obtain a compound of formula (IVa)

or

ii-a reacting a compound of formula (II) with malonate ester of formula (IIIa) CH 2 (COOC 1 -C 2 alkyl) 2 to a obtain compound of formula (IVc);

and optionally isolating the compound of formula (IVc) or further reacting the compound of formula (IVc) with an inorganic nitrite reagent and an acid or an organic nitrite reagents to obtain a compound of formula (IVd),

or

iii-a reacting a compound of formula (IVf) with amine of formula N (R a ) 2 to obtain a compound of formula (IVg)

or

iv-a reacting a compound of formula (IVf) with ammonia to obtain a compound of formula (IVh)

and reacting compound of formula (IVh) with reagent-2 to obtain a compound of formula (IVi)

or

v-a reacting a compound of formula (II) with a compound of formula (X) or a compound of formula (XI) to obtain a compound of formula (IVj)

wherein R 3 is hydrogen.

5 . The process according to claim 3 , wherein, said step-b is carried out by one or more steps selected from i-b to v-b

i-b reacting the compound of formula (IVa) with hydroxyl amine derivative using a base to obtain a compound of formula (IVb)

and further reacting compound of formula (IVb) with an acid to obtain isatin of formula (V)

or

ii-b reacting compound of formula (IVd) with a base to obtain a compound of formula (IVe)

and optionally isolating compound of formula (IVe) or reacting compound of formula (IVe) with an acid to obtain isatin of formula (V)

or

iii-b reacting compound of formula (IVi) with a Lewis acid to obtain isatin formula (V)

or

iv-b reacting the compound of formula (IVg) with a reagent-2 to obtain isatin of formula (V)

or

v-b reacting compound of formula (IVj) with an acid to obtain isatin of formula (V)

6 . The process according to claim 3 , wherein said process further comprises the step of:

hydrolyzing isatin of formula (V) to obtain an anthranilic acid of formula (VIIa) in the presence of a hydrolyzing agent, optionally in the presence of a solvent;

7 . The process according to claim 1 , wherein, said process for the synthesis of a compound of (VII),

from compound of formula (IVa),

comprising the steps of:

A-1. reacting the compound of formula (II) with compound of formula (XII) or compound of formula (XIII) to obtain a compound of formula (IVa)

B-1. converting the compound of formula (IVa) to a compound of formula (IVb) by reacting it with a hydroxyl amine derivative in the presence of a base and a solvent:

C-1. converting the compound of formula (IVb) to isatin of formula (V) by reacting it with sulphuric acid in the presence of a solvent

D-1. oxidising isatin of formula (V) using an oxidizing agent in the presence of a catalyst to obtain a compound of formula (VI);

and

E-1. reacting the compound of formula (VI) with a compound of formula (VIII), to obtain a compound of formula (VII), optionally in the presence of an acid and a solvent;

8 . The process according to claim 1 , wherein, said process for the synthesis of a compound of (VII),

from the compound of formula (II),

comprising the steps of:

A-2. reacting the compound of formula (II) with a malonate ester of formula CH 2 (COOC 1 -C 2 alkyl) 2

IIIa to obtain a compound of formula (IVc) that can be optionally isolated and subsequently converted to the compound of formula (IVd) by reacting it with an inorganic nitrite in the presence of an acid, or with an organic nitrite in the presence of a solvent;

B-2. reacting the compound of formula (IVd) with a base, optionally in the presence of a solvent to obtain intermediate of formula (IVe) that can be optionally isolated and further treated with sulphuric acid, optionally in the presence of a solvent to obtain a compound of formula (V);

C-2. oxidising isatin of formula (V) using a oxidizing agent in the presence of a catalyst to obtain compound of formula (VI);

and

D-2. reacting the compound of formula (VI) with a compound of formula (VIII), to obtain a compound of formula (VII), optionally in the presence of an acid and a solvent;

9 . The process according to claim 1 , wherein, said process for the preparation of a compound of formula (VII),

from the compound of formula (IVf),

comprising the steps of:

A-3. reacting the compound of formula (IVf) with amine of formula NH(R a ) 2 , optionally in the presence of a solvent; to obtain a compound of formula (IVg);

B-3. the compound of formula (IVg) is converted to the compound of formula (V) by reacting with a reagent-2 at a suitable temperature;

C-3. oxidising isatin of formula (V) using an oxidizing agent and in the presence of a catalyst to obtain compound of formula (VI);

and

D-3. reacting the compound of formula (VI) with a compound of formula (VIII), to obtain a compound of formula (VII), optionally in the presence of an acid and a solvent;

10 . 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 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, tert-butyl;

R 4b is hydrogen or methyl;

X is halogen.

11 . 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.

12 . 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 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.

13 . 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 er and fluoro.

14 . The process according to claim 2 , wherein compound of formula (I) is selected from the group consisting of chlorantraniliprole, cyantraniliprole, cyclaniliprole, tetraniliprole, tetra-chlorantraniliprole, bromantraniliprole and fluchlordiniliprole.

15 . The process as claimed in claim 3 , wherein the said process comprises the steps of:

reacting compound of formula (IVa-1) with a Lewis acid to obtain compound of formula (Va)

halogenating compound of formula (Va) to obtain compound of formula (Vb)

further, oxidizing compound of formula (Vb) using an oxidizing agent and a catalyst to obtain compound of formula (Vc) or converting compound of formula (Vc) to a compound of formula (Vd) using an oxidizing agent and a catalyst, further, reacting compound of formula (Vc) or compound of formula (Vd) with an acid or a base to obtain compound of formula (VIIa)

16 . The process according to claim 1 , wherein said acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, an acidic ion-exchange resin and mixtures thereof.

17 . 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, triethyl amine, diisopropylamine, diisopropyl ethyl amine, pyridine, alkylated and dialkylated pyridines, dimethylamino pyridine, piperidine and mixtures thereof.

18 . The process according to claim 15 , wherein said suitable halogenating reagent is selected from HX, CuX 2 , MgX 2 , CsX, ZnX 2 , SOCl 2 , SO 2 Cl 2 , COCl 2 , X 2 , C(═O)(OCl 3 ) 2 , t-BuOCl, NaOCl, chloramine-T, N-halosuccinamides, POX 3 , PX 3 , PX 5 and metal halides; wherein X is Cl, Br, I and F.

19 . The process as claimed in claim 1 , wherein said reaction steps are carried out using suitable solvent selected from 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, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, dimethyl sulfoxide, sulfones, sulfolane, methanol, ethanol, n- or i-propanol, n-, i-, sec- or tert-butanol, water and mixtures thereof.

20 . The process as claimed in claim 2 , wherein said suitable coupling reagent is selected from I-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC), I-cyclohexyl-3-(2-morpholmoethyl) carbodiimide, 1,3-di-tert-butylcarbodiimide, I-(dimethylaminopropyl)-3-ethylcarbodiimide methiodide, I-tert-butyl-3-(1liphenylmethyl)-carbodiimide, 1,3-diisopropylcarbodiimide, bis-(diphenylmethyl)-carbodiimide, I-tert-butyl-3-ethylcarbodiimide, 1-methyl-2-chloropyridinium iodide, 2-ethoxy-I-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), BOP-chloride and isobutyl chloroformate.

21 . The process as claimed in claim 15 , wherein said Lewis acid is selected from AlX 3 , BX 3 , FeX 3 , ZnX 2 , GaX 3 , InX 3 , TiX 4 , BiX 3 , SbX 3 , SnX 2 , SnX 4 , SiX 4 , and hypovalent Lewis acids, wherein X is halogen.

22 . The process as claimed in claim 1 , wherein said oxidizing agent is selected from hydrogen peroxide, oxone, hydrogen peroxide, t-butyl-hydroperoxide, tungstic peroxide, m-chloroperbenzoic acid, benzoyl peroxide, hypohalous acid, ceric ammonium nitrate, oxone, Sodium (meta) periodateperiodic acid, peracetic acid, performic acid hydrogen peroxide urea-adduct, sodium perborate, pyridinium chlorochromate, Ruthenium (II) oxide, Manganese (II) oxide, Copper (II) acetate/O 2 and dimethyl sulfoxide.

23 . The process as claimed in claim 1 , wherein said catalyst is selected from selenic acid, selenous acid, selenium dioxide.