Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• a PROCESS FOR PREPARATION OF ANTHRANILAMIDE COMPOUND AND INTERMEDIATE THEREOF FIELD OF THE INVENTION The present invention relates to a process for preparation of an anthranilamide compound or its salt thereof. More particularly, the present invention relates to a process for preparation of cyantraniliprole and intermediate thereof.
• Anthranilamides are a new class of compounds with extremely potent insecticidal activity. These nitrogen-containing aromatic compounds selectively act on targeted ryanodine receptors which form calcium ion channels, responsible for muscle function in insects.
• cyantraniliprole chemically known as 3-bromo-1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6- (methylcarbamoyl) phenyl]-1H-pyrazole-5-carboxamide, and structurally represented as formula (I): Cyantraniliprole was first disclosed in PCT publication number WO2004067528. The process for preparation of cyantraniliprole is also known in prior art. Additionally, another U.S. patent 8410278 discloses that cyantraniliprole exists in two polymorphic forms namely, Polymorph A and Polymorph B.
• the present invention also provides highly pure intermediates having formula (II) which directly impacts the purity of final product, i.e., cyantraniliprole, and the process for preparation of the same.
• OBJECTIVES OF THE INVENTION It is a primary objective of the present invention to provide a process for preparation of cyantraniliprole having formula (I), which is free of impurities. It is another objective of the present invention to provide a process for preparation of cyantraniliprole (I) ), which is free of impurities. It is another objective of the present invention to provide a highly pure intermediate compound having formula (II), which is useful for preparation of cyantraniliprole.
• a process for preparation of cyantraniliprole (I), which is free of impurities comprising the steps: a) reacting a compound of formula (III) with a compound of formula (IV) in presence of a solvent to obtain a compound of formula (II); Formula (III) Formula (IV) Formula (II) b) reacting the compound of formula (II) with methyl amine to obtain crude cyantraniliprole; and c) treating the crude cyantraniliprole with at least one solvent having a dielectric constant of less than 6 and isolating obtained cyantraniliprole having formula (I), which is free of impurities.
• cyantraniliprole (I) comprising purity more than 95% and comprising less than 1% water.
• a crystalline intermediate of formula (II) characterized by a X-ray powder diffraction pattern.
• Figure 1 illustrates powder X-ray diffraction (PXRD) pattern of cyantraniliprole (I), which is free of impurities prepared according to the present invention.
• Figure 2 illustrates powder X-ray diffraction (PXRD) pattern of crystalline compound of formula (II) prepared according to present invention.
• Figure 3 illustrates differential scanning calorimetric (DSC) thermogram of crystalline compound of formula (II) prepared according to present invention.
• Figure 4 illustrates Fourier transform infrared (FTIR) spectroscopy of crystalline compound of formula (II) prepared according to present invention.
• FTIR Fourier transform infrared
• room temperature unless stated otherwise, essentially means temperature in range from about 20°C to about 35°C.
• purity means purity as determined by high pressure liquid chromatography (HPLC).
• Cyantraniliprole (I) free of impurities means cyantraniliprole free of impurities including chemical impurities, volatile impurities and water.
• Croantraniliprole (I) substantially free of water used herein means cyantraniliprole comprising less than 1% of water.
• Crude cyantraniliprole means cyantraniliprole obtained by methods known to any person ordinarily skilled in art. The term is inclusive of amorphous form of cyantraniliprole, any crystalline form of cyantraniliprole or mixtures thereof.
• Dielectric constant of a solvent is a measure of its polarity. A higher dielectric constant means, higher the polarity and greater is the ability of the solvent to stabilize the charge.
• moisture content and “water content” are used interchangeably throughout the specification.
• the present invention provides a process for preparation of cyantraniliprole (I) free of impurities, the process comprising: treating crude cyantraniliprole with at least one solvent having a dielectric constant less than 6.
• impurities comprise water.
• impurities includes chemical impurities and water.
• the crude cyantraniliprole is prepared according to process known in prior art.
• the crude cyantraniliprole comprises more than 1% water.
• the crude cyantraniliprole comprises from about 1% to about 8% water.
• the crude cyantraniliprole comprises from about 1% to about 5% water. In an embodiment, the crude cyantraniliprole is present in an amorphous form. In an embodiment, the crude cyantraniliprole is present in any crystalline form of cyantraniliprole or a mixture thereof.
• Series of experiments were performed to identify suitable solvents for isolating cyantraniliprole (I) free of impurities comprising tetrahydrofuran, 2- methyltetrahydrofuran, cyclohexane, o-xylene, m-xylene, p-xylene, mixture of xylenes, mesitylene, chlorobenzene, hexane, or combinations thereof.
• the solvent having dielectric constant 6 or less than 6 is a non-polar solvent or mixture thereof.
• the solvent used is selected from the group comprising cyclohexane, o-xylene, m-xylene, p-xylene, xylene, mixture of xylenes, mesitylene, chlorobenzene, hexane, or mixtures thereof.
• the solvent is a mixture of cyclohexane and xylene.
• the ratio of cyclohexane to xylene is in a range from about 1:99 to about 99:1.
• the ratio of cyclohexane to xylene is in a range from about 60:40 to about 90:10 In an embodiment, the ratio of cyclohexane to xylene is in a range of about 75 to 85 : 15 to 25. In an embodiment, the ratio of cyclohexane to xylene is about 85:15. In another embodiment, the ratio of cyclohexane to xylene is about 80:20. In another embodiment, the ratio of cyclohexane to xylene is about 75:25. In another embodiment, the solvent/s is a mixture of hexane and xylene.
• the ratio of hexane to xylene is in a range from about 1:99 to about 99:1.
• the solvent is a mixture of cyclohexane and chlorobenzene.
• the ratio of cyclohexane to chlorobenzene is in a range from about 1:99 to about 99:1.
• the solvent is a mixture of cyclohexane and mesitylene.
• the ratio of cyclohexane to mesitylene is in a range from about 1:99 to about 99:1.
• the ratio of cyclohexane to mesitylene is in a range from about 60:40 to about 90:10.
• the ratio of cyclohexane to mesitylene is about 80:20.
• the present invention provides a process for preparation of cyantraniliprole (I) free of impurities, the process comprising treating crude cyantraniliprole with at least one solvent having a dielectric constant less than 6 and a second solvent.
• the second solvent is any suitable solvent selected from organic solvent or water.
• the treatment of crude cyantraniliprole comprises heating a mixture of crude cyantraniliprole and at least one solvent having a dielectric constant less than 6 at a temperature above 30°C.
• the treatment comprises heating a mixture of crude cyantraniliprole and at least one solvent having a dielectric constant less than 6 at a temperature above 40°C. In an embodiment, the treatment comprises heating a mixture of crude cyantraniliprole and at least one solvent having a dielectric constant less than 6 at a temperature in a range from about 40°C to about 180°C. In another embodiment, the treatment further comprises reducing the moisture content of the mixture to less than about 5%, preferably less than about 2%. The moisture content is reduced by conventionally known methods such as distillation. In another embodiment, the moisture content is reduced by azeotropic distillation. The process of the present invention further comprises cooling the mixture and isolation of cyantraniliprole (I) free of impurities.
• Cyantraniliprole (I) free of impurities obtained according to present invention has more than 95% purity.
• cyantraniliprole (I) free of impurities obtained according to present invention is characterized by bulk density and particle size distribution.
• a process for preparation of cyantraniliprole (I) substantially free of impurity comprising: treatment of crude cyantraniliprole with at least one solvent having a dielectric constant less than 6; wherein said impurity is water.
• cyantraniliprole (I) substantially free of impurity wherein said impurity is water and wherein the content of water is less than 1%.
• a process for preparation of cyantraniliprole of formula (I) free of impurities comprising: a) reacting a compound of formula (III) with a compound of formula (IV) in an organic solvent to obtain a compound of formula (II); Formula (III) Formula (IV) Formula (II) b) reacting the compound of formula (II) with methyl amine to obtain crude cyantraniliprole; and c) treating the crude cyantraniliprole with at least one solvent having a dielectric constant less than 6 at a temperature in a range from about 40°C to about 180°C and isolating cyantraniliprole of formula (I) free of impurities.
• the compound of formula (III) and the compound of formula (IV) are prepared by processes known in prior art.
• the compound of formula (III) is prepared from 3-Bromo-1-(3- chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid having following formula (A) Formula (A)
• the compound of formula (III) is prepared by reacting 3-Bromo- 1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid having formula (A) with a chlorinating agent.
• the chlorinating agent used is selected from the group comprising thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, or combinations thereof.
• the reaction of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole- 5-carboxylic acid having formula (A) with a chlorinating agent is carried out in presence of a solvent.
• the solvent used is selected from, but not limited to, a halogenated solvent, a hydrocarbon solvent, an ether or a nitrile.
• the solvent used is selected from a halogenated solvent such as dichloromethane, dichloroethane, chloroform and the likes; a hydrocarbon solvent such as toluene, xylene and the like; ether such as tetrahydrofuran and the like; or a nitrile like acetonitrile.
• a halogenated solvent such as dichloromethane, dichloroethane, chloroform and the likes
• a hydrocarbon solvent such as toluene, xylene and the like
• ether such as tetrahydrofuran and the like
• a nitrile like acetonitrile is carried out in presence of a catalyst.
• the catalyst used is dimethylformamide.
• the compound of formula (III) obtained by reaction of 3-Bromo- 1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid having formula (A) with a chlorinating agent is not isolated.
• the compound of formula (III) is prepared from 3-bromo-1-(3- chloro-2-pyridinyl)-4,5-dihydro-1H-Pyrazole-5-carboxylic acid having formula (B).
• the compound of formula (III) is prepared by subjecting compound of formula (B) to pyrazoline aromatization using a halogenating agent.
• the halogenating agent is selected from thionyl chloride, phosgene, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, or combinations thereof.
• the halogenating agent is thionyl chloride.
• pyrazoline aromatization reaction is carried out in presence of a halogenated hydrocarbon solvent.
• the halogenated hydrocarbon solvent is selected from dichloromethane, dichloroethane, trichloromethane, chloroform, carbon tetrachloride and halogenated aromatic hydrocarbons.
• the pyrazoline aromatization is carried out optionally in the presence of a catalyst.
• the catalyst is an organic base.
• the catalyst is triethylamine or dimethylformamide.
• the reaction is carried out at a temperature from about 30° to about 70°C, preferably at a temperature from about 30° to about 65°C.
• the reaction mixture comprising the compound of formula (III) obtained by pyrazoline aromatization of 3-bromo-1-(3-chloro-2-pyridinyl)- 4,5-dihydro-1H-Pyrazole-5-carboxylic acid having formula (B); is reacted with the compound of formula (IV) in step a) of the process.
• the reaction mixture comprising the compound of formula (III) obtained by reaction of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5- carboxylic acid having formula (A) with a chlorinating agent; is reacted with the compound of formula (IV) in step a) of the process.
• the step a) is carried out in an organic solvent selected from, but not limited to, halogenated solvent, hydrocarbon solvent, ether or acetonitrile.
• the step a) is carried out in halogenated solvent such as dichloromethane, dichloroethane, chloroform and the likes.
• the step a) is carried out in hydrocarbon solvent such as toluene, xylene, heptane, hexane, cyclohexane and the likes. In an embodiment, the step a) is carried out in acetonitrile. In an embodiment, the step a) is carried out at a temperature in the range from about 30°C to about 120°C. In an embodiment, the compound of formula (II) obtained in step a) is not isolated. In another embodiment, the compound of formula (II) obtained in step a) is isolated.
• step a) further comprises step of isolating compound of formula (II) and treating with the compound of formula (II) obtained in step a) is isolated and treated with a solvent.
• the solvent used for treatment of the compound of formula (II) is selected from water, organic solvent or mixture thereof.
• the organic solvent used is selected from alcohol, halogenated solvents, nitriles or mixtures thereof.
• step a) comprises isolating the obtained compound of formula (II) and treating with a solvent selected from alcohol, halogenated solvents, nitriles or mixtures thereof.
• the organic solvent is selected from alcohols, halogenated solvents, nitriles, or mixtures thereof.
• step a) comprises isolating the obtained compound of formula (II) and treating with a solvent selected from water, organic solvent, or mixtures thereof.
• the compound of formula (II) obtained according to present invention has purity of more than 95%, preferably more than 98%. The purity of compound of formula (II) directly impacts purity of final cyantraniliprole obtained. Hence, it is important to obtain purified compound of formula (II).
• the methylamine used in step b) is either gaseous methylamine or an aqueous solution of methylamine.
• reaction is carried out by purging methylamine gas.
• methyl amine gas is purged at a temperature range from about 0°C to about 35°C.
• methyl amine gas is purged from about 1 to about 12 hours.
• the step b) of the process is carried out in an organic solvent.
• the organic solvent such as halogenated solvent, hydrocarbon solvent, ethers or nitriles is used.
• the step b) is carried out in an organic solvent selected from halogenated hydrocarbon solvent like dichloromethane, dichloroethane; an ether like tetrahydrofuran; or nitriles like acetonitrile. In an embodiment, the step b) is carried out in acetonitrile. In an embodiment, the step c) of the process ensures removal of residual water, water of hydration and other volatile impurities from crude cyantraniliprole to obtain cyantraniliprole (I) substantially free of water.
• the solvent use in step c) is selected from the group comprising o-xylene, m-xylene, p-xylene, mixture of xylenes, cyclohexane, mesitylene, chlorobenzene, hexane or mixture thereof.
• the solvent used in step c) is a mixture of xylene/s and cyclohexane.
• the solvent used in step c) is a mixture of xylene/s and hexane.
• the solvent used in step c) is a mixture of cyclohexane and chlorobenzene.
• the solvent used in step c) is a mixture of cyclohexane and mesitylene.
• the step c) treatment comprises heating a mixture of crude cyantraniliprole and at least one solvent having a dielectric constant less than 6 at a temperature above 30°C.
• the step c) treatment comprises heating a mixture of crude cyantraniliprole and at least one solvent having a dielectric constant less than 6 at a temperature in the range from about 40°C to about 180°C.
• the step c) treatment further comprises reducing the moisture content of the reaction mixture to less than 5%, preferably less than 2%. The moisture content is reduced by conventionally known methods such as distillation.
• the moisture content is reduced by azeotropic distillation.
• the process of the present invention further comprises cooling the mixture and isolation of cyantraniliprole free of impurities.
• the process of present invention provides in step c) cyantraniliprole (I) free of impurities, wherein the impurities comprise water.
• the process of present invention provides in step c) cyantraniliprole (I), which is substantially free of water.
• the process of present invention provides in step c) cyantraniliprole (I) having less than 1% water.
• a process for preparation of cyantraniliprole (I) substantially free of impurity comprising: a) reacting a compound of formula (III) with a compound of formula (IV) in an organic solvent to obtain a compound of formula (II); Formula (III) Formula (IV) Formula (II) b) reacting the compound of formula (II) with methyl amine to obtain crude cyantraniliprole; and c) treating the crude cyantraniliprole with at least one solvent having a dielectric constant less than 6 and isolating cyantraniliprole (I) substantially free of impurity; wherein said impurity is water.
• cyantraniliprole (I) is substantially free of impurity; wherein said impurity is water and wherein content of water is less than 1%.
• cyantraniliprole (I) comprising more than 95% purity and less than 1% water. It is observed that the cyantraniliprole (I) obtained by process according to present invention remains stable without significant change in water content, thereby making it suitable for further use.
• cyantraniliprole (I) obtained according to present invention characterized by a X-ray powder diffraction pattern exhibiting at least one peak selected from 6.62, 10.32, 10.89, 11.67, 13.67, 14.59, 15.21, 15.47, 16.45, 18.33, 18.65, 19.15, 19.74, 20.71, 21.89, 22.34, 22.96, 23.92, 24.30, 25.03, 25.83, 26.72, 29.74, 31.372 ⁇ ⁇ 0.2° 2 ⁇ .
• cyantraniliprole obtained according to present invention is having an X-ray powder diffraction pattern as shown in Figure 1.
• cyantraniliprole (I) obtained according to the present invention comprising bulk density from about 0.4 mg/ml to about 0.8 mg/ml.
• a novel crystalline compound of formula (II) characterized by data selected from the group comprising: i) a X-ray powder diffraction pattern exhibiting at least one peak selected from 11.91, 15.00, 15.82, 16.79, 18.23, 18.51, 19.53, 20.57, 21.81, 23.49, 23.88, 24.06, 24.48, 25.25, 25.89, 27.25, 28.09, 29.42, 30.28, 31.212 ⁇ ⁇ 0.2° 2 ⁇ ; ii) a differential scanning calorimetric (DSC) thermogram having an endotherm at about 203°C to about 208°C.
• DSC differential scanning calorimetric
• the present invention provides the crystalline compound of formula (II) having an X-ray powder diffraction pattern exhibiting at least one peak selected from group comprising 11.91, 15.00, 15.82, 16.79, 18.23, 18.51, 19.53, 20.57, 21.81, 23.49, 23.88, 24.06, 24.48, 25.25, 25.89, 27.25, 28.09, 29.42, 30.28, 31.212 ⁇ ⁇ 0.2° 2 ⁇ .
• the present invention provides the crystalline compound of Formula (II) having X-ray powder diffraction pattern as shown in Figure 2.
• the present invention provides the crystalline compound of Formula (II) having differential scanning calorimetric (DSC) thermogram having endotherm from about 203°C to about 208°C. In an embodiment, the present invention provides the crystalline compound of Formula (II) having differential scanning calorimetric (DSC) thermogram as shown in Figure 3.
• the present invention provides the crystalline compound of Formula (II) exhibiting Fourier transform infrared (FTIR) spectrum with peaks at wavenumbers 3749, 3649, 3245, 3124, 3028, 3002, 2953, 2323, 2225, 1698, 1471, 1441, 1378, 1338, 1296, 1282, 1237, 1141, 993, 901, 878, 822, 813, 794, 783, 755, 744, 659, 600 (cm -1 ⁇ 0.2%).
• the crystalline compound of formula (II) having Fourier transform infrared (FTIR) spectroscopy as shown in Figure 4.
• the compound of formula (II) having purity above 98% is obtained.
• the present invention provides a process for the preparation of cyantraniliprole; wherein the process proceeds via a crystalline form of the compound of formula (II).
• the crystalline compound of formula (II) according to present invention is used for preparation of cyantraniliprole (I).
• Advantages of the present invention 1.
• the present invention provides a highly pure cyantraniliprole. 2.
• the present invention provides a process for preparation of cyantraniliprole, which is free of impurities.
• the present invention provides a crystalline form of compound of formula (II) having high purity.
• the present invention also provides process for preparation of crystalline form of compound of formula (II). 5.
• the processes provided in present invention are industrially viable, simple and economical.
• DSC Differential scanning calorimetry thermogram was measured by a Differential scanning calorimeter (DSC-3, Mettler Toledo) having temperature range of 40°C to 250°C with 5.00 K/min, N220.0 ml/min; 3.
• Example 2 Process for preparation of Methyl 2- bromo-1-(3-chloro-2- pyridinyl)-1H-pyrazol-5-yl]carbonyl]amino]-5-cyano-3-methylbenzoate- compound of formula (II)
• the mixture of 150g methyl 2-amino-5-cyano-3-methylbenzoate i.e., compound of formula (IV) and 450g (572ml) of acetonitrile was heated to 65°C to 75°C and to this mixture was added slowly 1065g compound of formula (III) obtained in Example 1. The mixture was maintained at 70°C to 75°C for about 5 to 6 hours.
• Example 3 Process for preparation of crude cyantraniliprole of formula (I) The mixture of 150g compound of formula (II) and 450g (572ml) acetonitrile was cooled to 5°C to 10°C and 59g of methylamine gas was purged into the mixture for 3 to 5 hours.
• Example 4 Process for preparation of cyantraniliprole (I) substantially free of water impurity[using mixture of cyclohexane and xylene/s (80:20)] To the crude cyantraniliprole obtained in Example 3 was added mixture of cyclohexane and xylene [360g (465ml) cyclohexane and 90g (104ml) mixture of xylenes] and the mixture was heated to 75°C to 85°C. The moisture content of the mixture was then reduced to below 0.1% by azeotropic distillation at same temperature.
• Example 5 Process for preparation of cyantraniliprole (I) substantially free of water impurity [using mixture of cyclohexane and xylene/s (85:15)] To the 98g crude cyantraniliprole obtained in similar way as in Example 3, was added mixture of cyclohexane and xylene [250g (323ml) cyclohexane and 44g (51ml) mixture of xylenes] and the mixture was heated to 85°C to 90°C.
• the moisture content of the mixture was then reduced to below 0.1% by azeotropic distillation at same temperature.
• the mixture was then cooled to room temperature, filtered, and dried to obtain 86g cyantraniliprole (I) having purity of 97.41% (moisture content: 0.43%).
• Example 6 Process for preparation of cyantraniliprole (I) substantially free of water impurity [using mixture of cyclohexane and xylene/s (75:25)] To the 140g wet cake of crude cyantraniliprole (obtained in similar way as in Example 3), was added mixture of cyclohexane and xylenes [315g (407ml) cyclohexane and 105g (121ml) mixture of xylenes] and the mixture was heated to 85°C to 90°C. The moisture content of the mixture was then reduced to below 0.1% by azeotropic distillation at same temperature.
• Example 7 Process for preparation of cyantraniliprole (I) substantially free of water impurity [using mixture of cyclohexane and mesitylene (80:20)] To the 92g wet cake of crude cyantraniliprole (92g, obtained in similar way as in Example 3), was added mixture of cyclohexane and mesitylene [220.8g (285ml) cyclohexane and 55.2g (64ml) mesitylene] and the mixture was heated to 85°C to 90°C.
• Example 8 Chemical and physically stability of cyantraniliprole obtained in Examples 3-7 The chemically and physically stability of cyantraniliprole obtained in Examples 3, 4, 5, 6 & 7 was determined by storing the 10g sample at ambient conditions for 1 month. The samples were tested by Karl-fisher titrator and HPLC for purity and moisture content. The results are given in Table 1.

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