DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10, rule 13)

“PROCESS FOR PREPARATION OF CHLORANTRANILIPROLE OR A SALT THEREOF”

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 process for preparation of chlorantraniliprole or a salt thereof. Further, the present invention relates to an improved process for preparation of intermediate of chlorantraniliprole.

BACKGROUND OF THE INVENTION

Chlorantraniliprole is a class of anthranilic-diamide insecticide derivative compounds and is 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, it has the following structure:

Chlorantraniliprole (Formula I)

Chlorantraniliprole is being developed world-wide by DuPont belonging to 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 chlorantraniliprole was disclosed in different patent publications; for example, PCT application Number: 2003/015519 (“the ‘519 publication”) disclosed process to prepare chlorantraniliprole by the following scheme:

PCT application Number: 2004/111030 (“the ‘030 publication”) discloses an alternative process for preparation of chlorantraniliprole. The ‘030 publication disclosed process is as follows:

PCT application Number: 2006/062978 (“the ‘978 publication”) discloses an alternative process for preparation of chlorantraniliprole, as follows:

PCT application Number: 2019/207595 (“the ‘595 publication”) discloses an alternative process for preparation of chlorantraniliprole, as follows:

All the above reported process involves expensive raw materials and involves formation of impurities with low yields and purity.

Chlorantraniliprole is one of the important insecticide available in the market. Hence, it’s important to develop simple and cost effective processes for preparation of pure chlorantraniliprole with readily available inexpensive raw materials, which is readily amenable to large scale production and free from its impurities.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides process for preparation of chlorantraniliprole or a salt thereof of Formula I. The present invention also relates to an improved process for preparation of chlorantraniliprole or a salt thereof without isolating the intermediates.

In accordance with one embodiment, the present invention provides a process for preparation of chlorantraniliprole of Formula I, comprising:

Formula I
a) reacting a compound of Formula III; wherein “R” is selected from straight or branched chain C1-6 alkyl group, with a compound of Formula IV in presence of a suitable activating agent, a suitable base and a suitable solvent to obtain a compound of Formula II, wherein “R” is selected from straight or branched chain C1-6 alkyl group; and

Formula III Formula IV Formula II
b) reacting the compound of Formula II with a source of monomethylamine to obtain chlorantraniliprole.

In accordance with another embodiment, the present invention provides a process for preparation of chlorantraniliprole of Formula I, comprising:
a) reacting a compound of Formula III; wherein “R” is selected from straight or branched chain C1-6 alkyl group, with a compound of Formula IV in presence of a suitable activating agent, a suitable base and a suitable solvent to obtain a compound of Formula II, wherein “R” is selected from straight or branched chain C1-6 alkyl group; and
b) reacting the compound of Formula II with a source of monomethylamine to obtain chlorantraniliprole; wherein the compound of Formula II is not isolated as a solid.

In accordance with another embodiment, the present invention provides a process for preparation of chlorantraniliprole of Formula I, comprising:
a) reacting a compound of Formula III; wherein “R” is selected from straight or branched chain C1-6 alkyl group, with a compound of Formula IV in presence of a suitable activating agent, a suitable base and a suitable solvent to obtain a solution containing compound of Formula II, wherein “R” is selected from straight or branched chain C1-6 alkyl group; and
b) adding a source of monomethylamine to the step a)to obtain chlorantraniliprole.

In accordance with another embodiment, the present invention provides a process for preparation of chlorantraniliprole of Formula I, comprising:
a) reacting a compound of Formula III; wherein “R” is selected from straight or branched chain C1-6 alkyl group, with a compound of Formula IV in presence of a suitable activating agent, a suitable base and a suitable solvent at a temperature of about 25°C to reflux temperature,
b) cooling the step a) solution to below 25°C,
c) adding a source of monomethylamine to the step b) solution,
d) heating the step c) to about 25°C to reflux temperature,
e) concentrating the step d) reaction mass to obtain a solid compound,
f) adding a suitable organic solvent to the step e) and heating to reflux temperature,
g) cooling the solution to below 35°C, and
h) filtering the chlorantraniliprole.

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

Formula IV
a) mixing a suitable oxidizing agent, a suitable acid and a suitable organic solvent,
b) heating the reaction mass to about 40°C to reflux temperature,
c) adding a compound of Formula V to the above step b) reaction mass,

Formula V
d) isolating the compound of Formula VI; wherein “R” is selected from straight or branched chain C1-6 alkyl group, and

Formula VI
e) hydrolyzing the compound of formula VI, wherein “R” is selected from straight or branched chain C1-6 alkyl group to obtain a compound of Formula IV.

In accordance with another embodiment, the present invention provides a process for preparation of chlorantraniliprole of Formula I, comprising:
a) mixing a suitable oxidizing agent, a suitable acid and a suitable organic solvent
b) heating the reaction mass to about 40°C to reflux temperature,
c) adding a compound of Formula V, wherein “R” is selected from straight or branched chain C1-6 alkyl group, to the above step b) reaction mass
d) isolating the compound of Formula VI; wherein “R” is selected from straight or branched chain C1-6 alkyl group,
e) hydrolyzing the compound of formula VI, wherein “R” is selected from straight or branched chain C1-6 alkyl group to obtain a compound of Formula IV;
f) reacting the compound of Formula IV with a compound of Formula III; wherein “R” is selected from straight or branched chain C1-6 alkyl group, in presence of a suitable activating agent, a suitable base and a suitable solvent at a temperature of about 25°C to reflux temperature,
g) cooling the step f) solution to below 25°C,
h) adding a source of monomethylamine to the step g) solution,
i) heating the step h) to about 25°C to reflux temperature,
j) concentrating the step i) reaction mass to obtain a solid compound,
k) adding a suitable organic solvent to the step j) and heating to reflux temperature,
l) cooling the solution to below 35°C, and
m) filtering the chlorantraniliprole.

In accordance with another embodiment, the present invention provides a process for preparation of chlorantraniliprole of Formula I, comprising: reacting a compound of Formula II; wherein “R” is selected from straight or branched chain C1-6 alkyl group, with a source of monomethylamine in a suitable solvent to obtain chlorantraniliprole.

In accordance with another embodiment, the present invention provides a process for preparation of chlorantraniliprole of Formula I, comprising:
a) reacting a compound of Formula III; wherein “R” is methyl, with a compound of Formula IV in presence of a suitable activating agent, a suitable base and a suitable solvent to obtain a compound of Formula II, wherein “R” is methyl; and
b) reacting the compound of Formula II, wherein “R” is methyl with a source of monomethylamine to obtain chlorantraniliprole; wherein the compound of Formula II is not isolated as a solid.

In accordance with another embodiment, the present invention provides crystalline chlorantraniliprole characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In accordance with another embodiment, the present invention provides crystalline chlorantraniliprole characterized by X-Ray diffraction (XRD) pattern having at least one peak selected from at about 8.6, 10.0, 10.5, 10.6, 11.4, 11.7, 12.2, 14.0, 14.2, 14.4, 14.6, 14.9, 15.6, 16.1, 16.6, 17.3, 17.5, 17.8, 18.3, 18.5, 20.0, 20.3, 20.5, 20.7, 21.1, 21.2, 21.4, 21.5, 21.7, 22.7, 22.9, 23.4, 24.3, 24.7, 24.9, 25.3, 25.6, 26.1, 27.2, 27.5, 28.4, 29.0, 29.2, 29.4, 29.8, 30.0 and 30.3±0.2° 2?.

In accordance with another embodiment, the present invention provides a crystalline compound of Formula IIa characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 2.

In accordance with another embodiment, the present invention provides a crystalline compound of Formula IIa characterized by X-Ray diffraction (XRD) pattern having at least one peak selected from at about 6.8, 8.2, 9.3, 10.1, 11.1, 12.4, 12.8, 13.5, 14.3, 14.8, 15.6, 15.7, 15.9, 16.5, 18.1, 18.7, 19.0, 19.5, 19.9, 20.4, 20.9, 21.7, 22.0, 22.5, 22.7, 23.2, 23.5, 24.0, 24.3, 24.8, 25.3, 25.9, 26.4, 27.2, 27.7, 27.9, 28.3, 28.9, 29.1, 29.2, 29.8 and 30.5 ±0.2° 2?.

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

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

Figure 1 is the characteristic powder X-ray diffraction (PXRD) pattern of chlorantraniliprole prepared according to Example-1.

Figure 2 is the characteristic powder X-ray diffraction (PXRD) pattern of Formula IIa prepared according to Example-4.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses process for preparation of chlorantraniliprole of Formula I. The present invention also relates to an improved process for preparation of chlorantraniliprole or a salt thereof without isolating compound of Formula II.

In accordance with one embodiment, the present invention provides a process for preparation of chlorantraniliprole of Formula I, comprising:

Formula I
a) reacting a compound of Formula III; wherein “R” is selected from straight or branched chain C1-6 alkyl group, with a compound of Formula IV in presence of a suitable activating agent, a suitable base and a suitable solvent to obtain a compound of Formula II, wherein “R” is selected from straight or branched chain C1-6 alkyl group; and

Formula III Formula IV Formula II
b) reacting the compound of Formula II with a source of monomethylamine to obtain chlorantraniliprole.

Unless otherwise specified the term “straight or branched chain C1-6 alkyl” used herein is selected from but not limited to methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, iso-pentyl, hexyl, iso-hexyl, iso-amyl and the like. Optionally the straight or branched chain C1-6 alkyl may be further substituted with a suitable substituent, which may be selected from the group comprising halogen, aryl and the like; preferably methyl, ethyl or iso-butyl; more preferably methyl or ethyl.

The term "one-pot reaction" as used in this application means a process uses a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one solvent/reactor. This is much desired by chemists because avoiding a lengthy separation process and purification of the intermediate chemical compounds can save time and resources, improves the efficiency of a chemical reaction, and offers better chemical yield.

The starting materials, a compound of Formula III and Formula IV are known in the art and can be produced by methods known and recognized by the organic chemist of ordinary skill in the art, for example US9301529 and US7232836. Alternatively Formula IV can also be prepared by the procedure as described by the following embodiments of the invention.

The step a) of forgoing process involves reaction of a compound of Formula III with a compound of Formula IV in presence of a suitable activating agent, a suitable base and a suitable solvent to obtain a compound of Formula II in a solution.

In a preferred embodiment the exemplary compound of Formula III and Formula II can be represented as follows:

Formula IIIa
Formula IIa

The suitable activating agent used in aforementioned step a) is selected from the group consisting of but not limited to acid-chloride reagents such asthionyl chloride, pivaloyl chloride and the like, sulfonyl-chloride reagents such asmethane sulfonyl chloride, ethane sulfonyl chloride, benzene sulfonyl chloride, p-toluenesulfonyl chloride, p-nitro sulfonyl chloride and the like, coupling agents such ascarbonyldiimidazole (CDI), diisopropylcarbodiimide (DCI), N-(3-dimethylaminopropyl)-N’-ethyl carbodiimide (EDC), dicyclohexyl carbodiimide (DCC), propanephosphonic acid cyclic anhydride (PPA), benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), bromo- tripyrrolidino- phosphonium hexafluorophosphate (PyBrOP), benzotriazol-1-yloxy-tris (dimethylamino)-phosphonium hexafluorophosphate (BOP), Propylphosphonic anhydride (T3P), 2-(7-aza-1H-benzotriazol-1-yl)- N,N,N’,N’-tetramethylaminium hexafluorophosphate) (HATU), (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU), N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluoro phosphate (HBTU), 2-(1H-Benzotriazol-1-yl)-N,N,N’,N’-tetramethylaminium tetrafluoroborate (TBTU) and the like and mixture thereof; preferably pivaloyl chloride, methane sulfonyl chloride or carbonyldiimidazole; more preferably methane sulfonyl chloride.

The suitable base used in aforementioned step a) is selected from the group consisting of but not limited to inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; organic bases selected from the group comprising of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine, 2-picoline, 3-picoline and the like and mixtures thereof; preferably sodium hydroxide, sodium methoxide, triethylamine, diisopropyl ethylamine or 3-picoline; more preferably 3-picoline.

The suitable solvent used in aforementioned step a) is selected from the group consisting of but not limited to amides, sulfoxides, ketones, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons and the like and mixtures thereof. The amides include, but are not limited to dimethylacetamide, dimethylformamide, N-methylpyrrolidone and the like and mixtures thereof; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like and mixtures thereof; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture thereof; preferably acetonitrile, tetrahydrofuran or methylene chloride; more preferably acetonitrile or methylene chloride.

The reaction of a Formula III with a compound of Formula IV is carried out at a temperature of about 25°C to reflux temperature; preferably at about 25°C to about 35°C for a period of time from about 30 min to until completion of the reaction.

After completion of the step a) reaction, the resultant compound of Formula II may be isolated as a solid or may be insitu converted to chlorantraniliprole without isolating the compound of Formula II as a solid by directly adding a source of monomethylamine to the step a) solution.

In a preferred embodiment, after completion of the step a) reaction, optionally the obtained compound of Formula II can be isolated from step a) reaction massby conventional techniques such as precipitation by cooling the reaction mass, isolated by solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably if isolation involves compound of Formula II can be isolated by precipitation by adding a suitable solvent such as water, and proceed for step b) reaction.

In another preferred embodiment, after completion of the step a) reaction the step b) reaction is carried out in a one pot reaction without isolating the compound of formula II as solid. The reaction includes an optional step of washing the organic layer obtained from the step a) with water and separating the product containing organic layer and to this source of monomethylamine may be added.

The source of monomethylamine used in aforementioned step b) is selected from the group consisting aqueous methyl amine, methyl amine in a solvent, methyl amine gas and the like; preferably aqueous methyl amine or methyl amine gas.

Advantageously, source of monomethylamine may be added to the reaction mass by cooling the reaction mass temperature to below 25°C; preferably at 0-5°C and then the reaction of a Formula II with a source of monomethylamine is carried out at a temperature of about 25°C to reflux temperature; preferably at about 30°C to about 40°C.

Optionally the step b) is carried out in presence of a suitable base. The suitable base optionally used in aforementioned step b) is selected from the group consisting of but not limited to inorganic bases selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; organic bases selected from the group comprising of triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine, 2-picoline, 3-picoline and the like and mixtures thereof.

In another embodiment, if the forgoing process involves isolation of compound of Formula II after step a), then the step b) reaction may be optionally carried out in presence of a suitable solvent, wherein the solvent is selected from the group consisting of but not limited to alcohols, amides, sulfoxides, ketones, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons, water and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, butanol, pentanol, isopropanol, isopentanol and the like and mixtures thereof; amides include, but are not limited to dimethylacetamide, dimethylformamide, N-methylpyrrolidone and the like and mixtures thereof; sulfoxides include, but are not limited to dimethyl sulfoxide, diethyl sulfoxide and the like and mixtures thereof; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; preferably acetonitrile, tetrahydrofuran or methylene chloride; more preferably acetonitrile or methylene chloride.

After completion of the step b) reaction, the resultant chlorantraniliprole can be isolated by conventional techniques such as precipitation by cooling the reaction mass, isolated by solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably isolated by precipitation by adding a suitable solvent such as water and then filtering the product or complete concentrating of the solvent by subjecting the solution to heating followed by isolating the product from another solvent such as methanol or acetone.

Then the chlorantraniliprole obtained by the process described as above may optionally be stirred with a suitable organic solvent at a temperature of about 25°C to about reflux temperature. The organic solvent used herein is selected from the group consisting of but not limited to alcohols, ketones, ethers, alicyclic hydrocarbons, water and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, butanol, pentanol, isopropanol, isopentanol and the like and mixtures thereof; ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like;alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like and mixture thereof; preferably methanol, acetone, methyl tetrahydrofuran or cyclohexane; more preferably methanol or acetone.

Then the resultant chlorantraniliprole can be isolated by conventional techniques such as precipitation by cooling the reaction mass, isolated by solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably precipitation by cooling the reaction mass to below 30°C. The resultant product may optionally be further dried at a temperature of about 35°C to about 85°C for sufficient period of time. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like; preferably drying is carried out under vacuum at a temperature of about 45°C to about 75°C for sufficient period of time.

The present invention provides chlorantraniliprole of Formula I prepared by the processes described as above having a purity of at least about 98%, as measured by HPLC, preferably at least about 99% as measured by HPLC.

In another embodiment, the present invention provides crystalline chlorantraniliprole characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 1.

In another embodiment, the present invention provides crystalline chlorantraniliprole characterized by X-Ray diffraction (XRD) pattern having at least one peak selected from at about 8.6, 10.0, 10.5, 10.6, 11.4, 11.7, 12.2, 14.0, 14.2, 14.4, 14.6, 14.9, 15.6, 16.1, 16.6, 17.3, 17.5, 17.8, 18.3, 18.5, 20.0, 20.3, 20.5, 20.7, 21.1, 21.2, 21.4, 21.5, 21.7, 22.7, 22.9, 23.4, 24.3, 24.7, 24.9, 25.3, 25.6, 26.1, 27.2, 27.5, 28.4, 29.0, 29.2, 29.4, 29.8, 30.0 and 30.3 ±0.2° 2?.

In another embodiment, the present invention provides a crystalline compound of Formula IIa characterized by a powder X-ray diffraction (PXRD) pattern substantially in accordance with Figure 2.

In another embodiment, the present invention provides a crystalline compound of Formula IIa characterized by X-Ray diffraction (XRD) pattern having at least one peak selected from at about 6.8, 8.2, 9.3, 10.1, 11.1, 12.4, 12.8, 13.5, 14.3, 14.8, 15.6, 15.7, 15.9, 16.5, 18.1, 18.7, 19.0, 19.5, 19.9, 20.4, 20.9, 21.7, 22.0, 22.5, 22.7, 23.2, 23.5, 24.0, 24.3, 24.8, 25.3, 25.9, 26.4, 27.2, 27.7, 27.9, 28.3, 28.9, 29.1, 29.2, 29.8 and 30.5 ±0.2° 2?.

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

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

Formula IV

a) mixing a suitable oxidizing agent, a suitable acid and a suitable organic solvent,
b) heating the reaction mass to about 40°C to reflux temperature,
c) adding a compound of Formula V to the above step b) reaction mass,

Formula V

d) isolating the compound of Formula VI; wherein “R” is selected from straight or branched chain C1-6 alkyl group, and

Formula VI

e) hydrolyzing the compound of formula VI, wherein “R” is selected from straight or branched chain C1-6 alkyl group to obtain a compound of Formula IV.

The starting materials, a compound of Formula a V was known in the art and can be produced by methods known and recognized by the organic chemist of ordinary skill in the art, for example US7232836.

The suitable oxidizing agent in aforementioned step a) is selected from the group consisting of but not limited to hydrogen peroxide, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate, sodium monopersulfate, potassium permanganate and the like and mixture thereof; preferably potassium persulfate.

The suitable acid used in aforementioned step a) is selected from the group consisting of but not limited to acetic acid, propanoic acid, p-toluenesulphonic acid, benzoic acid, sulphuric acid, phosphoric acid, oleum, hydrobromic acid, hydrochloric acid and the like and mixture thereof; preferably sulphuric acid.

The suitable organic solvent used in aforementioned step a) is selected from the group consisting of but not limited to ketones, nitriles, ethers, esters, halogenated hydrocarbons, aromatic hydrocarbons and the like and mixtures thereof. The ketones include, but are not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but are not limited to tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; ethers include, but are not limited to ethyl acetate, isopropyl acetate, butyl acetate and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like and mixture thereof; preferably acetonitrile, tetrahydrofuran or methylene chloride; more preferably acetonitrile.

The step b) of forgoing process involves heating the step a) reaction mass to about 40°C to reflux temperature; preferably at about 75°C to about 85°C for a period of time from about 30 min to until completion of the reaction.

The step c) of forgoing process involves addition of a compound of Formula V to the step b) reaction mass at about 75°C to about 85°C. Advantageously, compound of Formula V is dissolved in a suitable organic solvent and added drop wise in to the step b) reaction mass for a period of about 30 min to 5 hrs at about 75°C to about 85°C. The suitable organic solvent is same as used in the step a).

After completion of the step c) reaction, undissolved salts may be separated by filtration and the compound was Formula VI can be isolated by conventional techniques such as precipitation by cooling the reaction mass, isolated by solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably isolated by precipitation by adding a suitable solvent such as water. The resultant product may optionally be further dried at a temperature of about 35°C to about 65°C. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven and the like; preferably drying is carried out under vacuum at a temperature of about 45°C for sufficient period of time.

Then the above obtained compound was Formula VI is hydrolyzed in presence of a suitable acid or base selected from hydrochloric acid, sulphuric acid, sodium hydroxide, potassium hydroxide and the like, by methods known and recognized by the organic chemist of ordinary skill in the art, for example US7232836.

In another embodiment, the present invention relates to a one-pot process for preparation of chlorantraniliprole of Formula I, which is depicted in below scheme:

In another embodiment, the present invention relates to a process for preparation of chlorantraniliprole of Formula I, which is depicted in below scheme:

The present invention provides chlorantraniliprole, 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 20µL
Run time 70 min
Mode Time in min Mobile phase A
(% v/v) Mobile phase B (% v/v)
0 80 20
50 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 chlorantraniliprole

Compound of Formula III (R=Me; 66 gm) and Formula IV (100 gm), 3-picoline (77 gm) and acetonitrile (500 mL) were added in to a round bottom flask at about 25°C to about 30°C and stir for 10 min at same temperature. Reaction mass was cool to 0-5°C and was added methanesulfonyl chloride (45.5 gm) and stir for 1 hr at same temperature. Then the reaction mass was allowed to 25-30°C and stir for 2 hrs at same temperature. After completion of the reaction, reaction mixture was washed with water (600 mL). Then the organic layer was cool to 0-5°C and was passed methyl amine gas (86 gm) and stir fir 1 hr at same temperature. Then the reaction mass was allowed to 25-30°C and stir for 4 hrs at same temperature. After completion of the reaction, reaction mass was concentrated under vacuum at below 50°C and co-distilled with methanol (50 mL) to obtain a solid. To the solid was added methanol (50 mL) and heated to reflux for 1 hr. Reaction mass was cool to 25-30°C and stir for 4 hr at same temperature. Then the solid was filtered and washed with methanol (50 mL) and dry the wet material initially at 25-30°C for 30-60 min, then dry at 60-65°C for 6 hr to obtain title compound. Wt: 160 gm. Purity by HPLC: 99.5%; PXRD: Fig 1; TGA: No weight loss; DSC: Endothermic peaks at 204°C and 237.2°C.

EXAMPLE-2:

Preparation of chlorantraniliprole

Compound of Formula III (R=Me; 66 gm) and Formula IV (100 gm), 3-picoline (77 gm) and methylene chloride (500 mL) were added in to a round bottom flask at about 25°C to about 30°C and stir for 10 min at same temperature. Reaction mass was cool to 0-5°C and was added methanesulfonyl chloride (45.5 gm) and stir for 1 hr at same temperature. Then the reaction mass was allowed to 25-30°C and stir for 2 hrs at same temperature. After completion of the reaction, reaction mixture was cool to 0-5°C and was passed methyl amine gas (82 gm) and stir fir 1 hr at same temperature. Then the reaction mass was allowed to 25-30°C and stir for 4 hrs at same temperature. After completion of the reaction, reaction mass was concentrated under vacuum at below 50°C and co-distilled with acetone (50 mL) to obtain a solid. To the solid was added acetone (300 mL) and heated to reflux for 1 hr. Reaction mass was cool to 25-30°C and stir for 4 hr at same temperature. Then the solid was filtered and washed with acetone (50 mL) and dry the wet material initially at 25-30°C for 30-60 min, then dry at 60-65°C for 6 hr to obtain title compound. Wt: 159 gm.

EXAMPLE-3:

Preparation of chlorantraniliprole

Compound of Formula III (R=Me; 66 gm) and Formula IV (100 gm), 3-picoline (77 gm) and acetonitrile (500 mL) were added in to a round bottom flask at about 25°C to about 30°C and stir for 10 min at same temperature. Reaction mass was cool to 0-5°C and was added methanesulfonyl chloride (45.5 gm) and stir for 1 hr at same temperature. Then the reaction mass was allowed to 25-30°C and stir for 2 hrs at same temperature. After completion of the reaction, reaction mass was cool to 0-5°C and was passed methyl amine gas (86 gm) and stir fir 1 hr at same temperature. Then the reaction mass was allowed to 25-30°C and stir for 4 hrs at same temperature. After completion of the reaction, reaction mass was concentrated under vacuum at below 50°C and co-distilled with methanol (50 mL) to obtain a solid. To the solid was added methanol (50 mL) and heated to reflux for 1 hr. Reaction mass was cool to 25-30°C and stir for 4 hr at same temperature. Then the solid was filtered and washed with methanol (50 mL) and dry the wet material initially at 25-30°C for 30-60 min, then dry at 60-65°C for 6 hr to obtain title compound. Wt: 163 gm. Purity by HPLC: 99.6%
EXAMPLE-4:

Preparation of compound of Formula II (R= methyl)

Compound of Formula III (R=Me; 66 gm) and Formula IV (100 gm), 3-picoline (92.3 gm) and acetonitrile (500 mL) were added in to a round bottom flask at about 25°C to about 30°C and stir for 10 min at same temperature. Reaction mass was cool to 0-5°C and was added methanesulfonyl chloride (53.1 gm) at same temperature. Then the reaction mass was allowed to 25-30°C and stir for 1 hrs at same temperature. After completion of the reaction, to the reaction mass was charged water (250 mL) at 25-30°C and stir for 1 hrs at same temperature. Precipitated solid was filtered and washed with water (100 mL) and dried the wet material under vacuum at 50-60°C to obtain title compound. Wt: 160 gm; PXRD: Fig 3; TGA: 0.08%; DSC: Endothermic peaks at 155.5°C and 176°C.

EXAMPLE-5:

Preparation of chlorantraniliprole

Compound of Formula II (R=Me; 100 gm) and acetonitrile (300 mL) were added in to a round bottom flask at about 25°C to about 30°C. Reaction mass was cool to 0-5°C and was passed methyl amine gas at same temperature for 1 to 1.5 hrs. Then the reaction mass was allowed to 25-30°C and stir for 12 hrs at same temperature. After completion of the reaction, to the reaction mass was charged water (150 mL) at 25-30°C. Precipitated solid was filtered and washed with water (50 mL), acetonitrile (50 mL) and dried the wet material under vacuum at 50-60°C to obtain title compound. Wt: 90 gm. Purity by HPLC: 99.4%.

EXAMPLE-6:

Preparation of chlorantraniliprole

Compound of Formula II (R=Me; 100 gm) and acetonitrile (300 mL) were added in to a round bottom flask at about 25°C to about 30°C. To the reaction mass was added aqueous methylamine (10 gm) at about 25°C to about 30°C and stir for 24 hrs at same temperature. After completion of the reaction, to the reaction mass was charged water (150 mL) at 25-30°C. Precipitated solid was filtered and washed with water (50 mL), acetonitrile (50 mL) and dried the wet material under vacuum at 50-60°C to obtain title compound. Wt: 93 gm.

EXAMPLE-7:

Preparation of compound of Formula IV

i) Preparation of (3-chloropyridin-2-yl) hydrazine

2,3-Dichloropyridine (100 gm), ethanol (l50 mL) and hydrazine hydrate (162 mL) were added in to a round bottom flask at about 25°C to about 30°C. Reaction mass was heated to reflux for 15 hrs. After completion of the reaction, reaction mass was cool to 25-30°C and was added water (100 mL). The precipitated solid compound was filtered and washed with water (300 mL) and dried the wet material under vacuum at 65-75°C to obtain title compound. Wt: 101 gm.

ii) Preparation of 2-(3-Chloro pyridin-2-yl)-5-oxo-pyrazolidine-3-carboxylic acid ethyl ester

Sodium ethoxide (21% w/w) in ethanol (300 mL) and ethanol (250 mL) were added in to a round bottom flask at about 25°C to about 30°C. Reaction mass was heated to about 55-60°C for 5-10 min. To the reaction mass was added of (3-chloropyridin-2-yl) hydrazine (100 gm) and diethyl maleate (132.6 gm) at 55-60°C. After completion of the reaction, reaction mass was cool to 25-30°C and was added acetic acid (90 mL) at same temperature. Then the reaction mass was completely concentrated under vacuum at below 50°C to obtain a residue. To the residue was added water (500 mL) and the product was extracted with methylene chloride (500 mL). Organic layer was concentrate completely under vacuum at below 40°C. Then the obtained product was crystallized from ethanol and dried the wet material under vacuum at 50-55°C to obtain title compound. Wt: 120 gm.

iii) Preparation of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (Formula V)

2-(3-Chloro pyridin-2-yl)-5-oxo-pyrazolidine-3-carboxylic acid ethyl ester (100 gm), acetonitrile (200 mL) and Phosphoryl bromide (84.9 gm) were added in to a round bottom flask at about 25°C to about 30°C. Reaction mass was heated to reflux for 4 hrs. After completion of the reaction, reaction mass was cool to 25-30°C and was added water (500 mL) and extracted with methylene chloride (500 mL). Then the organic layer was washed with 5%Sodium metabisulphite solution (500 mL) and followed by 5% sodium bicarbonate solution (500 mL). Organic layer was concentrate completely under vacuum below 40°C to obtain title compound. Wt: 120 gm.

iv) Preparation of Ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (Formula VI; ethyl)

Sulphuric acid (58.98 gm), potassium persulfate (119.5 gm) and acetonitrile (200 mL) were added in to a round bottom flask at about 25°C to about 30°C. Reaction mass was heated to reflux and was added solution of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate of Formula V (100 gm dissolved in 100 mL acetonitrile) and stir for 3 hrs at same temperature. After completion of the reaction, reaction mass was cool to 60-65°C and undissolved salts were filtered. Ten the filterate was added in to water (500 mL) at 25-30°C and stir for 2 hrs at same temperature. The precipitated solid compound was filtered and washed with water (100 mL) and dried the wet material under vacuum at 50-55°C to obtain title compound. Wt: 94.6 gm.

v) Preparation of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (Formula IV)

Ethyl 3-bromo-1-(3-Chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate of Formula VI (100 gm), methanol (300 mL), water (200 mL) and sodium hydroxide (13.31 gm) were added in to a round bottom flask at about 25°C to about 30°C and stir for 2 hrs at same temperature. After completion of the reaction, concentratedthe solvent under vacuum at below 50°C and was added water (500 mL). Aqueous layer was cool to 5°C and pH was adjusted to 1.5 ±0.5 with hydrochloric acid at 5°C.The precipitated solid compound was filtered and washed with water (100 mL) and dried the wet material under vacuum at 50-55°C to obtain title compound. Wt: 80 gm.

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.
,CLAIMS:We Claim:

1. A process for preparation of chlorantraniliprole of Formula I, comprising:

Formula I
a) reacting a compound of Formula III; wherein “R” is selected from straight or branched chain C1-6 alkyl group, with a compound of Formula IV in presence of a suitable activating agent, a suitable base and a suitable solvent to obtain a compound of Formula II, wherein “R” is selected from straight or branched chain C1-6 alkyl group; and

Formula III Formula IV Formula II
b) reacting the compound of Formula II with a source of monomethylamine to obtain chlorantraniliprole.

2. The process as claimed in claim 1, wherein in the C1-6 alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, isopentyl, hexyl, isohexyl and isoamyl.

3. The process as claimed in claim 1, wherein in the suitable activating agent in step a) is selected from the group consisting thionyl chloride, pivaloyl chloride, methane sulfonyl chloride, ethane sulfonyl chloride, benzene sulfonyl chloride, p-toluenesulfonyl chloride, p-nitro sulfonyl chloride, carbonyldiimidazole, diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N’-ethyl carbodiimide, dicyclohexylcarbodiimide, propanephosphonic acid cyclic anhydride, benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate, bromo- tripyrrolidino- phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris (dimethylamino)-phosphonium hexafluorophosphate, Propylphosphonic anhydride, 2-(7-Aza-1H-benzotriazol-1-yl)- N,N,N’,N’-tetra methylaminium hexafluorophosphate), (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate, N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluoro phosphate, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluoro phosphate, 2-(1H-benzotriazol-1-yl)-N,N,N’,N’-tetramethylaminiumtetrafluoroborate and mixture thereof.

4. The process as claimed in claim 1, wherein in the suitable base in step a) is selected from the group consisting lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropyl ethylamine, N-methyl morpholine, piperidine, pyridine, 2-picoline, 3-picoline and mixtures thereof.

5. The process as claimed in claim 1, wherein in the suitable solvent in step a) is selected from the group consisting dimethylacetamide, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, diethyl sulfoxide, acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, propionitrile, tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, methylene chloride, ethylene chloride, chloroform, toluene, xylene and mixtures thereof.

6. The process as claimed in claim 1, wherein in the step b) is carried out by one-pot reaction without isolating the compound of Formula II as a solid.

7. The process as claimed in claim 1, wherein in the source of monomethylamine is selected from the group consisting of aqueous methyl amine, methyl amine in solvent and methyl amine gas.

8. The process as claimed in claim 1, wherein the process further comprises:
a) cooling the step a) solution to below 25°C,
b) adding a source of monomethylamine to the step b) solution,
c) heating the step c) to about 25°C to reflux temperature,
d) concentrating the step d) reaction mass to obtain a solid compound,
e) adding a suitable organic solvent to the step e) and heating to reflux temperature,
f) cooling the solution to below 35°C, and
g) filtering the chlorantraniliprole.

9. The process as claimed in claim 8, wherein in the suitable organic solvent in step e) is selected from the group consisting of methanol, ethanol, butanol, pentanol, isopropanol, isopentanol, acetone, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and mixture thereof.

10. The process as claimed in claim 1, wherein the compound Formula IV is prepared by the process, comprising:
a) mixing a suitable oxidizing agent, a suitable acid and a suitable organic solvent,
b) heating the reaction mass to about 40°C to reflux temperature,
c) adding a compound of Formula V, wherein “R” is selected from straight or branched chain C1-6 alkyl group, to the above step b) reaction mass,

Formula V

d) isolating the compound of Formula VI; wherein “R” is selected from straight or branched chain C1-6 alkyl group,

Formula VI

e) hydrolyzing the compound of formula VI, wherein “R” is selected from straight or branched chain C1-6 alkyl group to obtain a compound of Formula IV.

11. The process as claimed in claim 10, wherein in the C1-6 alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, isopentyl, hexyl, isohexyl and isoamyl; wherein the suitable oxidizing agent is selected from the group consisting of hydrogen peroxide, potassium persulfate, sodium persulfate, ammonium persulfate, potassium monopersulfate, sodium monopersulfate, potassium permanganate and mixture thereof; wherein the suitable acid is selected from the group consisting of acetic acid, propanoic acid, p-toluenesulphonic acid, benzoic acid, sulphuric acid, phosphoric acid, oleum, hydrobromic acid, hydrochloric acid and mixture thereof; and wherein the suitable organic solvent is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, propionitrile, tetrahydrofuran, methyl tetrahydrofuran, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, butyl acetate, methylene chloride, ethylene chloride, chloroform, toluene, xylene and mixture thereof.

12. Crystalline chlorantraniliprole having an X-Ray diffraction (XRD) at least one peak selected from at about 8.6, 10.0, 10.5, 10.6, 11.4, 11.7, 12.2, 14.0, 14.2, 14.4, 14.6, 14.9, 15.6, 16.1, 16.6, 17.3, 17.5, 17.8, 18.3, 18.5, 20.0, 20.3, 20.5, 20.7, 21.1, 21.2, 21.4, 21.5, 21.7, 22.7, 22.9, 23.4, 24.3, 24.7, 24.9, 25.3, 25.6, 26.1, 27.2, 27.5, 28.4, 29.0, 29.2, 29.4, 29.8, 30.0 and 30.3 ±0.2° 2?.

13. Crystalline compound of Formula IIa

Formula IIa

having an X-Ray diffraction (XRD) at least one peak selected from at about 6.8, 8.2, 9.3, 10.1, 11.1, 12.4, 12.8, 13.5, 14.3, 14.8, 15.6, 15.7, 15.9, 16.5, 18.1, 18.7, 19.0, 19.5, 19.9, 20.4, 20.9, 21.7, 22.0, 22.5, 22.7, 23.2, 23.5, 24.0, 24.3, 24.8, 25.3, 25.9, 26.4, 27.2, 27.7, 27.9, 28.3, 28.9, 29.1, 29.2, 29.8 and 30.5 ±0.2° 2?.