DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10, rule 13)

“AN IMPROVED 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 processes for preparation of chlorantraniliprole or a salt thereof of Formula I.

In accordance with one embodiment, the present invention provides an improved process for preparation of chlorantraniliprole of Formula I,

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

Formula II Formula III

In accordance with another embodiment, the present invention provides an improved process for preparation of chlorantraniliprole of Formula I, comprising: reacting a compound of Formula II with a compound of Formula III; wherein “R” is ethyl, in presence of a suitable base and a suitable solvent to obtain chlorantraniliprole.

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

Formula III

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 IV to the above step b) reaction mass, and

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

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 IV, wherein “R” is selected from straight or branched chain C1-6 alkyl group, to the above step b) reaction mass

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

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

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.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses process for preparation of chlorantraniliprole of Formula I.

In one embodiment, the present invention provides an improved process for preparation of chlorantraniliprole of Formula I,

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

Formula II Formula III

The starting materials, a compound of Formula II and Formula III 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 US7232836. Alternatively Formula III can also be prepared by the procedure as described by the following embodiments of the invention.

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.

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

Formula IIIa

The base used for reaction of compound of Formula II with a compound of Formula IIIis selected from silyl bases such as Lithium bis(trimethylsilyl)amide, Sodium bis(trimethylsilyl)amide, Potassium bis(trimethylsilyl)amide and the like; hydroxides such as Potassium hydroxide, Sodium hydroxide, Cesium hydroxide and the like; alkyl hydroxides such as sodium methoxide, sodium ethoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide and the like and mixture thereof; preferably Lithium bis(trimethylsilyl)amide, Sodium bis(trimethylsilyl)amide or sodium methoxide; more preferably Lithium bis(trimethylsilyl)amide.

The suitable solvent used herein for reaction of compound of Formula II with a compound of Formula III is selected from the group consisting of but not limited to amides, sulfoxides, ketones, nitriles, ethers, halogenated hydrocarbons, aromatic hydrocarbons 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 dimethylformamide, acetonitrile or tetrahydrofuran; more preferably tetrahydrofuran.

The reaction of a Formula II with a compound of Formula III is carried out at a temperature of about -60°C to 25°C; preferably at about -40°C to about -50°C for a period of time from about 30 min to until completion of the reaction.

After completion of the reaction, the resultant product is isolated by known methods such as extraction of the product from the solution, cooling the solution to precipitation, concentration of the reaction solution, solvent crystallization and the like. Preferably the product can be isolated by extraction of the product from the solution by first adding water and water immiscible organic solvent to the reaction solution so that aqueous and organic layers are formed and the product containing organic layer can be separated easily and then concentrated by known procedures. The suitable water immiscible organic solvent includes but is not limited to toluene, ethyl acetate, methylene chloride and the like; preferably with ethyl acetate.

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 85°C for sufficient period of time.

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

Formula III
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 IV to the above step b) reaction mass, and

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

The starting materials, a compound of Formula a IV 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°Cfor 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 IV to the step b) reaction mass at about 75°C to about 85°C. Advantageously, compound of Formula IV 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, un dissolved salts may be separated by filtration and the compound was Formula III 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.

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 a composition comprising chlorantraniliprole, prepared by the processes of the present invention and/or at least one excipient.

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

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’=Ethyl; 100 gm) and tetrahydrofuran (500 mL) were added in to a round bottom flask at about 25°C to about 30°C. To the reaction mass was added compound of Formula II (60.1 gm) at about 25°C to about 30°C. Then reaction mass was cool to about -40°C to about -50°C and was added 1M LiHMDS in tetrahydrofuran (906 mL) at same temperature and stir for 1 hr at same temperature. After completion of the reaction, to the reaction mass was charged water (1 lit) and ethyl acetate (1 lit) at about -40°C to about -50°C. Reaction mass temperature was heated to 25-30°C and separated the organic and aqueous layers. Organic layer was concentrated under vacuum at 40-45°C to obtain a solid. Then the obtained solid was mixed with acetonitrile (500 mL) at 25-30°C. To the reaction mass was added water (250 mL) at 25-30°C and stir for 1 hr at same temperature. Precipitated solid was filtered and washed with water (100 mL), acetonitrile (50 mL) and dried the wet material under vacuum at 50-60°C to obtain title compound. Wt: 75 gm.

EXAMPLE-2:

Preparation of compound of Formula III

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 IV)

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 III; 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, IV (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.

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,

Formula I
comprising: reacting a compound of Formula II

Formula II
with a compound of Formula III; wherein “R” is selected from straight or branched chain C1-6 alkyl group,

Formula III
in presence of a suitable base and a suitable solvent to obtain chlorantraniliprole.

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

3. The process as claimed in claim 1, wherein the suitable base is selected from the group consisting of Lithium bis(trimethylsilyl)amide, Sodium bis(trimethylsilyl)amide, Potassium bis(trimethylsilyl)amide, Potassium hydroxide, Sodium hydroxide, Cesium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide and mixture thereof.

4. The process as claimed in claim 1, wherein the suitable solvent is selected from the group consisting of 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 mixture thereof.

5. The process as claimed in claim 1, wherein the reaction is carried out at a temperature of about -40°C to about -50°C.

6. The process as claimed in claim 1, wherein the C1-6 alkyl group is ethyl, the suitable base is Lithium bis(trimethylsilyl)amide and the suitable solvent is tetrahydrofuran.

7. An improved process for preparation of a compound of Formula III, comprising:

Formula III
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 IV to the above step b) reaction mass, and

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

8. The process as claimed in claim 7, 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.

9. The process as claimed in claim 7, 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.

10. The process as claimed in claim 7, 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.