Claims:We Claim:

1. A process for preparation of compound of Formula II, comprising:

Formula I Formula II
wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl,
a) dissolving a compound of Formula I in a suitable organic solvent,
b) adding an acid to the step a) solution,
c) adding first part of suitable oxidizing agent at a temperature of about 0°C to about 60°C,
d) heating the solution to about 65°C to reflux,
e) cooling the solution to about 0°C to about 60°C,
f) adding second part of suitable oxidizing agent at a temperature of about 0°C to about 60°C,
g) repeating the steps d) to f) until complete addition of the remaining parts of suitable oxidizing agent, and
h) isolating the compound of Formula II.

2. The process as claimed in claim 1, wherein the R1” is methyl or ethyl, wherein the R2, R5-R7 are each hydrogen, wherein the R3 is bromo and wherein the R4 is chloro.

3. The process as claimed in claim 1, wherein in the suitable organic solvent is selected from the group consisting of tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methylene chloride, ethylene chloride, chloroform, N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, l,3-dimethyl-2-imidazolidinone, acetonitrile and mixture thereof.

4. The process as claimed in claim 1, wherein in the acid is selected from the group consisting of sulfuric acid, phosphoric acid, oleum, hydro bromic acid, hydrochloric acid, acetic acid, propanoic acid, p-toluenesulfonic acid or benzoic acid and mixture thereof.

5. The process as claimed in claim 1, wherein in the suitable oxidizing agent is selected from the group consisting of bromine, hydrogen peroxide (H2O2), Potassium persulfate (K2S2O8), sodium persulfate (Na2S2O8), ammonium persulfate ((NH4)2S2O8), potassium monopersulfate (KHSO5), sodium monopersulfate (NaHSO5), potassium permanganate (KMnO4) and mixture thereof.

6. The process as claimed in claim 1, wherein in the oxidizing agent is about 0.3 to about 5 equivalents to starting compound of formula I.

7. The process as claimed in claim 1, wherein in the addition of oxidizing agent is carried out in about 3 to about 10 parts of the total quantity.

8. The process as claimed in claim 1, wherein in the each part of oxidizing agent is about 0.1 to about 0.5 equivalents to the starting compound of Formula I.

9. The process as claimed in claim 1, wherein the oxidizing agent is about 1.5 equivalents to the starting compound of Formula I; wherein the addition of oxidizing agent is about 3 to about 6 parts of the total quantity; wherein the each part contains about 0.25 to about 0.5 equivalents to the starting compound of Formula I and where in addition of oxidizing agent is at a temperature of about 45°C to about 60°C.

10. A process for preparation of compound of Formula II having N-oxide impurity less than 0.5% by HPLC, comprising:

Formula II
wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl.
a) dissolving a compound of Formula II having about 0.5% or more N-oxide impurity by HPLC in a suitable solvent,
b) adding an anti-solvent to the step a) solution, and
c) Isolating the compound of Formula II having N-oxide impurity less than 0.5% by HPLC.

11. The process as claimed in claim 10, wherein in the suitable solvent is selected from the group consisting of dimethylacetamide, dimethylformamide, N-methylpyrrolidone, ethyl acetate, methyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, propionitrile, methylene chloride, ethylene chloride, chloroform, toluene, xylene and mixture thereof.

12. The process as claimed in claim 10, wherein in the anti-solvent is selected from the group consisting of tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, hexane, heptane, pentane, cyclohexane, cycloheptane, cyclopentane and mixture thereof; water and mixture thereof.
, Description:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10, rule 13)

“METHOD FOR PREPARATION OF PYRAZOLE-CARBOXYLATE INTERMEDIATES”

Laurus Labs Limited, an Indian company of DS-1, IKP Knowledge Park, Genome Valley, Turkapally, Shameerpet Mandal, Medchal-Malkajgiri district, Hyderabad-500 078, Telangana, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of pyrazole-carboxylate intermediates useful for preparation of certain anthranilamide compounds, for example chlorantraniliprole and cyantraniliprole.

BACKGROUND OF THE INVENTION

Pyrazole-carboxylate intermediates are valuable intermediate in the preparation of certain anthranilamide compounds, a new class of selective insecticides featuring a novel mode of action to control a range of pests belonging to the order Lepidoptera and some other Coleoptera, Diptera and Isoptera species.

Preparation of known anthranilamide compounds developed by DuPont such as Chlorantraniliprole and Cyantraniliprole involves Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1h-pyrazole-5-carboxylate as Pyrazole-carboxylate intermediate. Chlorantraniliproleand Cyantraniliprole, chemically known as 3-Bromo-N-[4-chloro-2-methyl-6-(methyl carbamoyl) phenyl]-1-(3-chloro-2-pyridine-2-yl)-1H-pyrazole-5-carboxamide and 3-bromo-1-(3-chloro-2-pyridyl)-4-cyano-2-methyl-(methyl carbamoyl) pyrazole-5-carboxaniliderespectively and are having the following chemical structures:

Chlorantraniliprole Cyantraniliprole

Various known literatures disclosed preparation of Pyrazole-carboxylate intermediate such as Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1h-pyrazole-5-carboxylate, which are as follows:

PCT application Number: 2003/015518 (“the ‘518 publication”) discloses a process for preparation of pyrazole-carboxylate intermediate, specifically Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1h-pyrazole-5-carboxylateby addition of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate, potassium persulfate, sulfuric acid in acetonitrile followed by heating to reflux for the reaction completion. The process disclosed in the ‘518 publication is as follows:

Zhengming Li et al. in Journal of Agricultural and Food Chemistry 2020, 68, 40, 11282–11289 discloses a process for preparation of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1h-pyrazole-5-carboxylate through an oxidation of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylatein acetonitrile in the presence of potassium persulfate using sulfuric acid as a catalyst at 75°C. The process disclosed by Zhengming Li et al. is as follows:

Further other known literatures for ex: WO2003/015519, WO2021/096903, WO2003/016283, CN102093335B and CN102627629A discloses a process for preparation of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1h-pyrazole-5-carboxylate by addition of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylatein either single or multiple parts, potassium persulfate, sulfuric acid in acetonitrile followed by heating to reflux for the reaction completion.

Anthranilamide compounds such as chlorantraniliprole and cyantraniliprole are the important insecticides available in the market. Pyrazole-carboxylate intermediate is the key cost contributor in the preparation of these anthranilamide compounds. The key step in the preparation of pyrazole-carboxylate intermediate is the use of oxidizing agent for example potassium persulfate in the oxidation reaction. At higher temperatures potassium persulfate is possibly undergo thermal decomposition and releases oxygen gas as well as noxious fog or fumes of sulfur dioxide and this leading to incomplete conversion of starting materials and getting low product yield.

Hence, it is always desired to improve the product yield, quality of its intermediates involved in the preparation of these anthranilamide compounds and there by reducing the manufacturing cost.

Hence, it’s important to develop a simple and cost effective improved process for preparation of pure anthranilamide compound ssuch as chlorantraniliprole and cyantraniliprole or its intermediates with high yield, which is readily amenable to large scale production and free from its impurities.

The main object of the present invention is to provide a simple, cost effective, high yield process for the preparation of pyrazole-carboxylate intermediate. Further, the present invention relates to conversion of the pyrazole-carboxylate intermediate to certain anthranilamide compounds, such as for examplechlorantraniliprole or cyantraniliprole.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for preparation of pyrazole-carboxylate intermediate. Further, the present invention provides an improved process for preparation of certain anthranilamide compounds for example, chlorantraniliprole or cyantraniliprole through preparing the pyrazole-carboxylate intermediate of the present invention.

In accordance with one embodiment, the present invention provides an improved process for preparation of compound of Formula II, comprising:reacting a compound of Formula I with a suitable oxidizing agent, an acid in a suitable organic solvent to obtain a compound of Formula II; wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl and wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity.

Formula I Formula II

In accordance with another embodiment, the present invention provides an improved process for preparation of compound of Formula II, comprising:reacting a compound of Formula I with a suitable oxidizing agent, an acid in a suitable organic solvent to obtain a compound of Formula II; wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity and wherein the each part contains about 0.1 to about 0.5 equivalents of oxidizing agent to the starting compound of Formula I.

In accordance with another embodiment, the present invention provides an improved process for preparation of compound of Formula II, comprising:reacting a compound of Formula I with a suitable oxidizing agent, an acid in a suitable organic solvent to obtain a compound of Formula II; wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity at a temperature of about 0°C to about 60°C and wherein the each part contains about 0.1 to about 0.5 equivalents of oxidizing agent to the starting compound of Formula I.

In accordance with another embodiment, the present invention provides an improved process for preparation of compound of Formula II, comprising:

Formula I Formula II
wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl
a) dissolving a compound of Formula I in a suitable organic solvent,
b) adding an acid to the step a) solution,
c) adding first part of suitable oxidizing agent at a temperature of about 0°C to about 60°C,
d) heating the solution to about 65°C to reflux,
e) cooling the solution to about 0°C to about 60°C,
f) adding second part of suitable oxidizing agent at a temperature of about 0°C to about 60°C,
g) repeating the steps d) to f) until complete addition of the remaining parts of suitable oxidizing agent, and
h) isolating the compound of Formula II; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity.

In accordance with another embodiment, the present invention provides an improved process for preparation of compound of Formula II, comprising:
a) dissolving a compound of Formula I in a suitable organic solvent,
b) adding an acid to the step a) solution,
c) adding first part of suitable oxidizing agent at a temperature of about 0°C to about 60°C,
d) heating the solution to about 65°C to reflux,
e) cooling the solution to about 0°C to about 60°C,
f) adding second part of suitable oxidizing agent at a temperature of about 0°C to about 60°C,
g) repeating the steps d) to f) until complete addition of the remaining parts of suitable oxidizing agent, and
h) isolating the compound of Formula II; wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity; and wherein the each part contains about 0.1 to about 0.5 equivalents of oxidizing agent to the starting compound of Formula I.

In accordance with the preferred embodiment, the present invention provides an improved process for preparation of compound of Formula II, wherein the R1” is methyl or ethyl, wherein the R2, R5-R7 are each hydrogen, wherein the R3 is bromo and wherein the R4 is chloro.

In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula II having N-oxide impurity less than 0.5% by HPLC, comprising:
a) dissolving a compound of Formula II having about 0.5% or more N-oxide impurity by HPLC in a suitable solvent,
b) adding an anti-solvent to the step a) solution, and
c) Isolating the compound of Formula II having N-oxide impurity less than 0.5% by HPLC; wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl.

In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula II having N-oxide impurity less than 0.5% by HPLC, comprising:
a) dissolving a compound of Formula II having about 0.5% or more N-oxide impurity by HPLC in a suitable solvent,
b) adding an anti-solvent to the step a) solution, and
c) isolating the compound of Formula II having N-oxide impurity less than 0.5% by HPLC;
wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl; wherein the suitable solvent is selected from the group consisting of amides, esters, ketones, nitriles, halogenated hydrocarbons, aromatic hydrocarbons and mixtures thereof; the anti-solvent is selected from the group consisting of ethers, aliphatic and alicyclic hydrocarbon, water and mixture thereof.

In accordance with another embodiment, the present invention provides an improved process for preparation of chlorantraniliprole, comprising:

Chlorantraniliprole

a) preparing a compound of Formula II according to the processes described as above embodiments, and
b) converting the compound of Formula II in to chlorantraniliprole; wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl.

In accordance with another embodiment, the present invention provides an improved process for preparation of cyantraniliprole, comprising:

Cyantraniliprole
a) preparing a compound of Formula II according to processes described as above embodiments, and
b) converting the compound of Formula II in to cyantraniliprole; wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl.

In accordance with another embodiment, the present invention provides a composition comprising chlorantraniliprole or cyantraniliprole, prepared by the process of compound of Formula II of the present invention and/or at least one excipient.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses an improved process for the preparation of pyrazole-carboxylate intermediate with high product yield and quality, wherein the improvements involve part wise and predefined quantity of addition of oxidizing agent at lower temperature to avoid decomposition of oxidizing agent and thereby attaining complete conversion of starting material.

The present invention further relates to a process for purification of pyrazole-carboxylate intermediate which is substantially free of N-oxide impurity.

The pyrazole-carboxylate intermediate is the key cost contributor in the preparation of certain anthranilamide compounds, for example chlorantraniliprole and cyantraniliprole. Oxidation process according to the process disclosed in the art involves either adding entire potassium persulfate at higher temperature (at 75°C) in one part in to the reaction mass or in two parts. Generally at higher temperature (70-75°C) potassium persulfate is having tendency to thermal decomposition and thereby releases excess oxygen also emit noxious fog or fumes of Sulfur dioxide (SO2), Peroxydisulfate (S2O8) and Potassium oxide (K2O) and thereby chances of ignition due to excess oxygen levels.

Further, due to the large availability of potassium persulfate in the reaction the entire persulfate available in the reaction is participated instantaneously and liberates kinetic energy, which leads to sudden increase in the heat of reaction thereby sudden temperature shoot up in the reaction. Due to the rapid increase of the reaction temperature unreacted potassium persulfate possibly to decompose thereby availability of potassium persulfate in the reaction is less to oxidize the starting material and therefore incomplete reaction conversion which results lower yield and low purity.

Hence, it is an object of the present invention to provide process to oxidize compound of Formula I completely by avoiding decomposition of potassium persulfate. Further, it is also important to minimize the N-oxide impurity in compound of Formula II.

The present invention provides an improved process for oxidation of Formula I, which involves part wise addition of oxidizing agent (about 3 to about 10 parts) and predefined quantity (about 0.1 to 0.5 equivalents of oxidizing agent to the starting compound of Formula I) of oxidizing agent for each part at lower temperature to avoid decomposition of oxidizing agent and thereby attaining complete conversion of starting material. Further, the present invention also provides effective purification process of Formula II to minimize the N-oxide impurity.

In accordance with one embodiment, the present invention provides an improved process for preparation of compound of Formula II, comprising: reacting a compound of Formula I with a suitable oxidizing agent, an acid in a suitable organic solvent to obtain a compound of Formula II; wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl; and wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity.

Formula I Formula II

Unless otherwise specified the term “C1-4 alkyl” used herein is selected from but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl and the like. Optionally the C1-4 alkyl may be further substituted with a suitable substituent, which may be selected from the group comprising halogen, aryl and the like.

Unless otherwise specified the term “halogen” used herein is selected from bromo, chloro and Iodo.

In accordance with another preferred embodiment, the present invention provides an improved process for preparation of compound of Formula II, comprising: reacting a compound of Formula I with a suitable oxidizing agent, an acid in a suitable organic solvent to obtain a compound of Formula II; wherein the “R1” is selected from hydrogen or C1-4 alkyl;preferably methyl or ethyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl, preferably R2 and R5-R7 are hydrogen, R3 is bromo and R4 is chloro; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity and wherein the each part contains about 0.1 to about 0.5 equivalents of oxidizing agent to the starting compound of Formula I.

In accordance with another preferred embodiment, the present invention provides an improved process for preparation of compound of Formula II, comprising: reacting a compound of Formula I with a suitable oxidizing agent, an acid in a suitable organic solvent to obtain a compound of Formula II; oxidizing agent, an acid in a suitable organic solvent to obtain a compound of Formula II; wherein the “R1” is selected from hydrogen or C1-4 alkyl, preferably methyl or ethyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl, preferably R2 and R5-R7 are hydrogen, R3 is bromo and R4 is chloro; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity and wherein the each part contains about 0.1 to about 0.5 equivalents of oxidizing agent to the starting compound of Formula I, at a temperature of about 0°C to about 60°C.

In accordance with another preferred embodiment, the present invention provides an improved process for preparation of compound of Formula II, comprising:
a) dissolving a compound of Formula I in a suitable organic solvent,
b) adding an acid to the step a) solution,
c) adding first part of suitable oxidizing agent at a temperature of about 0°C to about 60°C,
d) heating the solution to about 65°C to reflux,
e) cooling the solution to about 0°C to about 60°C,
f) adding second part of suitable oxidizing agent at a temperature of about 0°C to about 60°C,
g) repeating the steps d) to f) until complete the addition of the remaining parts of suitable oxidizing agent, and
h) isolating the compound of Formula II; wherein the “R1” is selected from hydrogen or C1-4 alkyl, preferably methyl or ethyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl, preferably R2 and R5-R7 are hydrogen, R3 is bromo and R4 is chloro.

In accordance with another preferred embodiment, the compound of Formula I and Formula II specifically represents as following compound of Formula Ia or Formula IIa:

Formula Ia Formula IIa

The compound of Formula Ia, which is used herein as a starting material is known in the art and can be prepared by any known methods. For example, may be prepared as per the process disclosed in WO2003/015519.

The suitable oxidizing agent used in aforementioned process is selected from the group consisting of but not limited to bromine, hydrogen peroxide (H2O2), Potassium persulfate (K2S2O8), sodium persulfate (Na2S2O8), ammonium persulfate ((NH4)2S2O8), potassium monopersulfate (KHSO5), sodium monopersulfate (NaHSO5), potassium permanganate (KMnO4) and the like and mixture thereof; preferably Potassium persulfate or sodium persulfate; more preferably Potassium persulfate.

In a preferred embodiment, the present invention provides an improved process for preparation of compound of Formula II; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity; preferably about 3 to about 8 parts of the total quantity; more preferably about 3 to about 6 parts of the total quantity.

The acid used in the aforementioned process is selected from the group consisting of but not limited to an inorganic acid, which is selected from the group consisting of but not limited to sulfuric acid, phosphoric acid, oleum, hydro bromic acid, hydrochloric acid and the like and mixture thereof; organic acids, which is selected from the group consisting of but not limited to acetic acid, propanoic acid, p-toluenesulfonic acid or benzoic acid and the like and mixture thereof; preferably sulfuric acid or hydrochloric acid; more preferably sulfuric acid.

In another preferred embodiment, the present invention provides an improved process for preparation of compound of Formula II; wherein the acid is added in to reaction mass in about 30 min to 4 hrs; preferably about 1 hr to 3 hrs.

The suitable organic solvent used in aforementioned process is selected from the group consisting of but not limited to ethers, include but are not limited to tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like and mixture thereof; esters, include but are not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like and mixture thereof; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixtures thereof;aprotic organic solvent, include but are not limited to N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide, l,3-dimethyl-2-imidazolidinone, acetonitrile and the like and mixture thereof; preferablytetrahydrofuran, methylene chloride or acetonitrile; more preferably acetonitrile.

In another preferred embodiment, the present invention provides an improved process for preparation of compound of Formula II; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity at a temperature of about 0°C to about 60°C; preferably at about 25°C to about 60°C; more preferably about 45°C to about 60°C.

In another embodiment, the present invention provides an improved process for preparation of compound of Formula II; wherein the total quantity of oxidizing agent is about 0.3 to about 5 equivalents to starting compound of formula I; preferably about 0.5 to about 3 equivalents, more preferably about 1.0 to about 2 equivalents to starting compound of formula I.

In another preferred embodiment, the present invention provides an improved process for preparation of compound of Formula II; wherein the oxidizing agent is added in about 3 to about 10 parts of the total quantity and each part contains about 0.1 to 0.5 equivalents to starting compound of formula I at a temperature of about 0°C to about 60°C.

In another more preferred embodiment, the present invention provides an improved process for preparation of compound of Formula II; wherein the oxidizing agent is added in about 3 to about 6 parts of the total quantity and each part contains about 0.25 to 0.5 equivalents to starting compound of formula I at a temperature of about 45°C to about 60°C.

In another preferred embodiment, after addition of each part of oxidizing agent the reaction temperature may be increased to about 65°C to about reflux; preferably to about 70°C to about 75°C, and then if necessary maintain the reaction for about 15 minutes to about 90 minutes at the same temperature and then allowed for cooling the reaction to 0°C to 60°C for addition of subsequent parts of oxidizing agent as process mentioned above embodiments.

As per the known art, the oxidizing agent is added either in one part or two equal parts at higher temperatures such as 70-75°C and this temperature leads to decomposition of the unconsumed oxidizing agent due to highly exothermic nature of the reaction which results incomplete conversion of starting material thereby getting lower yields and starting material contamination. Wherein the present invention surprisingly found an alternative procedure to overcome the difficulties associated with the prior art process by adopting multiple part wise addition and predefined quantity of oxidizing agent for each part and at addition of oxidizing agent at lower temperature to avoid the possibility of heat of reaction so that oxidizing agent decomposition is greatly eliminated thereby complete conversion of the starting material and getting higher yields and high pure product.

After completion of the reaction, optionally water may be added to the reaction mass and then the resultant compound of Formula II may be isolated from reaction mass by conventional techniques such as solvent extraction, solvent precipitation, and crystallization, concentrated by subjecting the solution to heating, decantation or filtration.

The present invention provides compound of Formula IIa prepared by the process described as above having a purity of at least about 95%, as measured by HPLC, preferably at least about 97% as measured by HPLC; and content of N-oxide impurity is about 5%, as measured by HPLC, more preferably is about 3% as measured by HPLC.

In another embodiment, oxidation reaction involved in the conversion of formula I to formula II there always possibility to formation of N-oxide as impurity and is possibility of formation is higher when the oxidation reaction at higher temperatures. The N-oxide impurity once formed is very difficult to separate from the product due to less polarity difference with the product. Further, the N-oxide impurity formed is reacted in subsequent stages and carries forward to final stages and is very difficult to separate from the final product.

Hence, it is an object of the present invention to provide a process for the purification of compound of Formula II with substantially free of N-oxide impurity. The present inventors have surprisingly found that the N-oxide impurity can be separated from the product by dissolving the compound of Formula II having N-oxide impurity in a suitable solvent and precipitating the compound of Formula II by adding an anti-solvent to obtain the compound of Formula II substantially free of N-oxide impurity.

In accordance with another embodiment, the present invention provides a process for preparation of compound of Formula II having N-oxide impurity less than 0.5% by HPLC, comprising:
a) dissolving a compound of Formula II having about 0.5% or more N-oxide impurity by HPLC in a suitable solvent,
b) adding an anti-solvent to the step a) solution, and
c) Isolating the compound of Formula II having N-oxide impurity less than 0.5% by HPLC; wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl.

The step a) process may be involves dissolving a compound of Formula II having N-oxide impurity more than 0.5% by HPLC in a suitable solvent at a temperature of about ambient temperature to reflux temperature.

The suitable solvent used to dissolve compound of Formula II, wherein the “R1” is selected from hydrogen or C1-4 alkyl, preferably methyl or ethyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl, preferably R2 and R5-R7 are hydrogen, R3 is bromo and R4 is chloro; having about 0.5% or more N-oxide impurity by HPLC is selected from the group consisting of but not limited to amides include, but are not limited to dimethylacetamide, dimethylformamide, N-methylpyrrolidone and the like and mixtures thereof; esters include, but are not limited to ethyl acetate, methyl acetate and the like and mixtures thereof; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like and mixture thereof; nitriles include, but are not limited to acetonitrile, propionitrile and the like and mixture thereof; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like and mixture thereof; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture thereof; preferably ethyl acetate, acetone or acetonitrile; more preferably acetonitrile.

The anti-solvent used in aforementioned step b) process is selected from the group consisting of but not limited to ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like and mixture thereof; aliphatic and alicyclichydrocarbons include, but are not limited to hexane, heptane, pentane, cyclohexane, cycloheptane, cyclopentane and the like and mixture thereof; water and mixture thereof; preferably hexane, cyclohexane or water; more preferably water.

Then the pure compound of Formula II having N-oxide impurity less than 0.5% by HPLC may be isolated from reaction mass by conventional techniques such as solvent extraction, solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration.

In accordance with another embodiment, the compound of Formula II obtained by the purification processes described as above, having purity of at least about 98% as measured by HPLC, preferably at least about 99% as measured by HPLC and substantially free of N-oxide impurity; wherein the word "substantially free" refers to compound of Formula II having less than 1 % of N-oxide impurity as measured by HPLC, preferably less 0.5 % of N-oxide impurity as measured by HPLC.

In accordance with another embodiment, the present invention provides an improved process for the preparation of anthranilamide compounds such as chlorantraniliprole and/or cyantraniliprole, comprising preparing the compound of Formula II as process described above, and converting the compound of Formula II in to chlorantraniliprole or cyantraniliprole by any process known in the art for example WO2006/062978,WO2004/067528 or by the process described in the present specification.

In accordance with another embodiment, the present invention provides a composition comprising anthranilamide compounds such as chlorantraniliprole and/or cyantraniliprole, prepared by the process of the compound of Formula II by the present invention and/or at least one excipient.

In accordance with another embodiment, the present invention relates to a process for preparation of compound of Formula II, which is depicted in below scheme:

wherein the “R1” is selected from hydrogen or C1-4 alkyl;and each of R2-R7 is independently selected from hydrogen, halogen andC1-4 alkyl.

In accordance with another preferred embodiment, the present invention relates to a process for preparation of compound of Formula IIa, which is depicted in below scheme:

The present invention provides chlorantraniliprole or cyantraniliprole and its intermediates, obtained by the above process, as analyzed using high performance liquid chromatography (“HPLC”) with the conditions are tabulated below:

Column Zorbax RX-C8
Mobile phase Mobile phase-A: Buffer and Acetonitrile
Mobile phase-B: Acetonitrile and water
Flow rate 1.0 mL/min
Elution Gradient
Detection 260 nm
Injection volume 20 µL
Run time 75 min
Mode Time (min) Mobile phase-A
(% v/v) Mobile phase-B
(% v/v)
0 80 20
40 55 45
60 20 80
70 80 20

EXAMPLES

The following non-limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

EXAMPLE-1:

Preparation of compound of Formula IIa (Oxidizing agent addition in 3 lots)

Compound of Formula Ia (12.0 g), acetonitrile (36 mL) and 98% sulphuric acid (7.1 g) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 45-55°C and was added first part of potassium persulfate (4.78 g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added second part of potassium persulfate (4.78 g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added third part of potassium persulfate (4.78 g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. After completion of the reaction, temperature was cool to 55-65°C and was added water (48 mL) at same temperature. Then the product containing organic layer and aqueous layers were separated at 55-65°C. Back extract the aqueous layer with acetonitrile (12 mL). To the combined organic layer was added water (36 mL) at 55-65°C.Cool to 25-35°C and stir for 3 hrs. Filtered the solids and washed the wet cake with water (12 mL) and dry the wet material to obtain title compound. Wt.: 8.5g; Purity by HPLC: 98.5%; N-oxide by HPLC: 0.5%; Compound of Formula Ia by HPLC:Not detected; Yield: 71%.

Reaction monitoring by HPLC:
Sample after potassium persulfate addition HPLC (% area)
Formula IIa Formula Ia 0.17
RRT 0.52 RRT 0.57 RRT
(N-Oxide) 0.72 RRT 0.97 RRT 1.23 RRT
1st part 30.42 67.95 0.85 0.25 0.25 0.5 0.19 0.49
2nd part 69.2 25.0 1.76 0.5 0.88 1.19 0.59 0.68
3rd part 93.47 0.05 0.72 0.13 2.44 1.11 1.05 1.03
Isolated 98.5 ND 0.19 0.13 0.5 0.12 0.5 0.06
*ND: Not detected by HPLC

EXAMPLE-2:

Preparation of compound of Formula IIa (Oxidizing agent addition in 4 lots)

Compound of Formula Ia (12 g), acetonitrile (36 mL) and 98% sulphuric acid (7.1 g) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 45-55°C and was added first part of potassium persulfate (3.59 g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added second part of potassium persulfate (3.59 g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added third part of potassium persulfate (3.59 g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added fourth part of potassium persulfate (3.59 g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. After completion of the reaction, temperature was cool to 55-65°C and was added water (48 mL) at same temperature. Then the product containing organic layer and aqueous layers were separated at 55-65°C. Back extract the aqueous layer with acetonitrile (12 mL). To the combined organic layer was added water (36 mL) at 55-65°C.Cool to 25-35°C and stir for 3 hrs. Filtered the solids and washed the wet cake with water (12 mL) and dry the wet material to obtain title compound. Wt.: 8.6 g; Purity by HPLC:98.6%; N-oxide by HPLC: 0.49%; Compound of Formula Ia by HPLC:Not detected; Yield: 72%.

Reaction monitoring by HPLC:
Sample after potassium persulfate addition HPLC (% area)
Formula IIa Formula Ia 0.17
RRT 0.52 RRT 0.57 RRT
(N-Oxide) 0.72 RRT 0.97 RRT 1.23 RRT
1st part 25.5 72.84 0.01 0.12 0.87 0.41 0.06 0.18
2nd part 55.27 41.9 0.01 0.31 1.25 0.89 0.26 0.11
3rd part 77.27 15.08 2.95 0.47 2.09 1.44 0.63 0.07
4th part 94.69 0.02 0.04 0.07 2.74 1.17 0.74 0.53
Isolated 98.6 ND 0.22 0.02 0.49 0.1 0.48 0.09
*ND: Not detected by HPLC

EXAMPLE-3:

Preparation of compound of Formula IIa (Oxidizing agent addition in 5 lots)

Compound of Formula Ia (120 g) and acetonitrile (360 mL) were added in to a round bottom flask and stir for 15-30 min at 25-35°C. To the reaction mass was added slowly 98% sulphuric acid (70.9 gm) at 25-35°C. Reaction mass was heated to 45-55°C and was added first part of potassium persulfate (23.9 g; 0.24 mole) at same temperature. Reaction mass was further heated to 72-78°C and allowed to stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added second part of potassium persulfate (23.9 g; 0.24 mole) at same temperature. Reaction mass was further heated to 72-78°C and allowed to stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added third part of potassium persulfate (23.9 g; 0.24 mole) at same temperature. Reaction mass was further heated to 72-78°C and allowed to stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added fourth part of potassium persulfate (23.9 g; 0.24 mole) at same temperature. Reaction mass was further heated to 72-78°C and allowed to stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added fifth part of potassium persulfate (47.8 g; 0.49 mole) at same temperature. Reaction mass was further heated to 72-78°C and allowed to stir for 1 hr at same temperature. After completion of the reaction, temperature was cool to 40-50°C and was added water (480 mL) at same temperature. Reaction mass was heated to 60-70°C and stirs for 10-20 min at same temperature. Then the product containing organic layer and aqueous layers were separated at 60-70°C. Back extract the aqueous layer with acetonitrile (120 ml).To the combined organic layer added water (360 mL) in 30 min at <60°C. Reaction mass was allowed to cool to 25-35°C and stir for 3 hrs at same temperature. Filtered the solids and washed the wet cake with water (120 mL) and dry the wet material to obtain title compound. Wt.: 85 gm; Purity by HPLC: 98%; N-oxide by HPLC: 0.44%; Compound of Formula Ia by HPLC:Not detected; Yield: 71%.

Reaction monitoring by HPLC:
Sample after potassium persulfate addition HPLC (%area)
Formula IIa Formula Ia 0.17
RRT 0.52 RRT 0.57 RRT
(N-Oxide) 0.72 RRT 0.97 RRT 1.23 RRT
4th part 74.5 15.0 2.92 0.25 3.54 2.33 0.34 1.12
5th part 94.27 0.02 0.9 0.09 3.04 0.9 0.3 0.3
Isolated 98.58 ND 0.22 ND 0.44 0.28 0.2 0.28
*ND: Not detected by HPLC

EXAMPLE-4:

Purification of compound of Formula IIa

To the crude compound of Formula IIa(10 g) added acetonitrile (40 mL) and heated to 55-65°C and stir for 10 min at same temperature. To the solution was added water (30 mL) at <65°C. Reaction mass was allowed to cool to 25-35°C and stir for 3 hrs at same temperature. Filtered the solids and washed the wet cake with water (10 mL) and dry the wet material to obtain title compound. Wt.: 8.5 g; Purity by HPLC: 98.9%; N-oxide by HPLC: 0.4%; Compound of Formula Ia by HPLC:Not detected; Yield: 85%.
Purity by HPLC:
Sample HPLC (% area)
Formula IIa Formula Ia 0.17
RRT 0.52 RRT 0.57 RRT
(N-Oxide) 0.72 RRT 0.97 RRT 1.23 RRT
Crude 84.4 ND 1.6 0.18 8.13 1.59 2.07 2.01
Pure 98.9 ND 0.19 0.02 0.4 0.03 0.4 0.06
*ND: Not detected by HPLC

EXAMPLE-5:

Preparation of compound of Formula IIa (Oxidizing agent addition in 6 lots)

Compound of Formula Ia (60 g), acetonitrile (180 mL) and 98% sulphuric acid (35.45 g) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 45-55°C and was added first part of potassium persulfate (11.95g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added second part of potassium persulfate (11.95g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added third part of potassium persulfate (11.95 g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added fourth part of potassium persulfate (11.95g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added fifth part of potassium persulfate (11.95 g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. Reaction mass was allowed to cool to 45-55°C and was added sixth part of potassium persulfate (11.95 g) at same temperature. Reaction mass was heated to 72-78°C and stir for 1 hr at same temperature. After completion of the reaction, temperature was cool to 55-65°C and was added water (240 mL) at same temperature. Then the product containing organic layer and aqueous layers were separated at 55-65°C. Back extract the aqueous layer with acetonitrile (60 ml).To the combined organic layer added water (180 mL) at <65°C .Cool to 25-35°C and stir for 3 hrs at same temperature. Filtered the solids and washed the wet cake with water (60 mL) and dry the wet material to obtain title compound. Wt.: 43 g; Purity by HPLC: 98.7%; N-oxide by HPLC: 0.39%; Compound of Formula Ia by HPLC: Not detected; Yield: 72%.

Reaction monitoring by HPLC:
Sample after potassium persulfate addition HPLC (% area)
Formula IIa Formula Ia 0.17
RRT 0.52 RRT 0.57 RRT
(N-Oxide) 0.72 RRT 0.97 RRT 1.23 RRT
1st part 12.00 85.72 1.21 0.01 0.57 0.27 0.03 0.19
2nd part 24.74 70.47 2.29 0.01 1.57 0.51 0.11 0.3
3rd part 49.89 44.7 2.69 0.32 0.85 0.93 0.26 0.36
5th part 89.77 2.87 0.99 0.54 2.22 2.02 0.67 0.92
6th part 94.00 0.04 0.39 0.02 2.94 0.9 0.72 0.99
Isolated 98.7 ND ND ND 0.39 ND 0.77 0.14
*ND: Not detected by HPLC

EXAMPLE-6:

Preparation of compound of Formula IIa (compound of Formula I addition at 80°C)

Potassium persulfate (14.34g), 98% sulphuric acid (7.1 g) and acetonitrile (36 mL) were added in to a round bottom flask at 25-35°C. Reaction mass was heated to 80±2°C and stir for 2 hrs at same temperature (observed exothermic and reaction mass was self heated to reflux). To the reaction mass was added a solution of compound of Formula Ia (12 g in 12 ml of acetonitrile) at 80±2°C overs a period of 30 min and stir for 4hrs at 80±2°C.

Reaction monitoring by HPLC:
Sample HPLC (% area)
Formula IIa Formula Ia 0.17
RRT 0.52 RRT 0.57 RRT
(N-Oxide) 0.72 RRT 0.97 RRT 1.23 RRT
After
4 hrs 8.49 90.02 0.86 0.04 0.48 0.01 0.07 0.01

Based on the above results, the starting material compound of Formula Ia was around 90% and the product formation is around 8.4% after 4 hours of reaction maintenance at 80°C. Reaction was not completed due to decomposition of potassium persulfate at higher temperatures.

EXAMPLE-7:

Preparation of compound of Formula IIa (as per comparative Example-2 of WO2021/096903)

Compound of Formula Ia(12 g), acetonitrile (36 mL), potassium persulfate (14.34g) and 98% sulphuric acid (7.1 g) were added in to a round bottom flask and heated to 65°C (observed exothermic and reaction mass was self heated to reflux), stir for 30 min at same temperature. Reaction mass further hated to reflux and stir for 4 hrs at same temperature.

Reaction monitoring by HPLC:
Sample HPLC (% area)
Formula IIa Formula Ia 0.17
RRT 0.52 RRT 0.57 RRT
(N-Oxide) 0.72 RRT 0.97 RRT 1.23 RRT
After 4 hrs 74.88 10.05 0.01 0.1 10.98 1.11 0.92 1.95
*ND: Not detected by HPLC

Based on the above results, the starting material compound of Formula Ia was around 10% and the product formation is around 74 % after 4 hours of reaction maintenance at reflux. Reaction was not completed due to decomposition of potassium persulfate at higher temperatures.

EXAMPLE-8:

Preparation of compound of Formula IIa (as per Journal of Agricultural and Food Chemistry 2020, 68, 40, 11282–11289)

Compound of Formula Ia (12 g), acetonitrile (84 mL), first part of potassium persulfate (5.01g) and 98% sulphuric acid (7.1 g) were added in to a round bottom flask and heated to 75°C, stir for 2 hrs at same temperature. To the reaction mass was added second part of potassium persulfate (5.1g) and the reaction mass was refluxed for 2 hrs. Inorganic salts were separated by filtration and diluted with ethyl acetate (60mL) and water (60.mL). Then the product containing organic layer was separated and concentrated under vacuum to obtain title compound. Wt.:7.5g; Purity by HPLC: 67.27%; N-oxide by HPLC: 2.36%; Compound of Formula Ia by HPLC:16.67%.

Reaction monitoring by HPLC:
Sample HPLC (% area)
Formula IIa Formula
Ia 0.17
RRT 0.52 RRT 0.57 RRT
(N-Oxide) 0.72 RRT 0.97 RRT 1.23 RRT
After 1st part addition 26.46 70.0 0.3 0.26 1.48 0.55 0.2 0.75
After 2nd part addition 66.44 27.02 0.54 0.2 3.08 1.08 0.64 1.0
Isolated 67.27 26.66 0.18 0.21 2.36 1.3 0.63 1.39

Note: Based on the above results, around ~26% of Formula-Ia was observed; due to decomposition of potassium persulfate at higher temperatures.

It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.