CRYSTALLINE FORMS OF /V-(5,7-DIMETHOXY-[l,2,4]TRIAZOLO[l,5-A]PYRIMIDIN-2- YL)-2-METHOXY-4-(TRIFLUOROMETHYL)PYRIDINE-3-SULFONAMIDE

RELATED APPLICATIONS

This application claims the benefit of priority of U.S. Provisional Patent Application No. 62/820,303 filed on 19 March 2019, the contents of which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

Crystalline forms of N-(5,7-dimethoxy-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-met hoxy-4- (trifluoromethyl)pyridine-3-sulfonamide (pyroxsulam), to processes for their preparation, mixtures and compositions comprising the novel crystalline forms and their use as pesticidal agents.

BACKGROUND OF THE INVENTION

Herbicides are compounds, of natural or synthetic origin, which are applied to agricultural land and crops to control unwanted vegetation that inhibits crop growth. To help combat this problem there is always the need in developing varieties of chemicals and chemical formulations effective in the control of such unwanted growth.

WO 2002/036595 discloses certain N-(5,7-dimethoxy[l,2,4]triazolo[l,5-a]pyrimidin-2-yl) arylsulfonamide compounds which have herbicidal activity, in particular, pyroxsulam.

Pyroxsulam has both foliar and soil activity and is translocated to growing points where it inhibits the acetolactate synthase enzyme (ALS) which is essential for branched-chain amino acid synthesis. It gives post-emergence control of a broad spectrum of annual grass and broadleaf weeds, is applied at a low rate of active ingredient per hectare, is selective to wheat, has a wide window of application, rapid soil degradation, can be tank mixed with most broadleaf herbicides and has a favorable environmental and toxicological profile.

Polymorphism, the occurrence of different crystalline forms, is a property of certain compounds that causes the atoms and/or molecules to arrange in different ways in the crystal. A single substance may give rise to a variety of polymorphs having distinct crystal structures and physical properties such as shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. When the compound is biologically active, such as an herbicide, different salts and crystalline forms (including polymorphs, solvates and hydrates) may have properties which make it more desirable and more advantageous in a particular use relative to another solid form of the same compound.

Discovering new crystalline forms of biologically active agents may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. Thus, new crystalline forms of biologically active agents such as herbicides, in particular, pyroxsulam, can also provide an opportunity to improve the performance characteristics of agrochemical formulations.

In the case of N-(5,7-dimethoxy-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-met hoxy-4- (trifluoromethyl)pyridine-3-sulfonamide (pyroxsulam), no crystalline forms (including polymorphs, solvates and hydrates) are known.

SUMMARY OF THE INVENTION

The present subject matter relates to novel crystalline forms including polymorph, solvates and/or hydrates of N-(5,7-dimethoxy-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-met hoxy-4- (trifluoromethyl)pyridine-3-sulfonamide (pyroxsulam). Each one of the disclosed crystalline Forms A-G of pyroxsulam exhibit a unique X-ray powder diffraction pattern of characteristic peaks.

The subject invention further provides several methods for preparing these novel crystalline forms.

The subject invention also provides mixtures comprising combinations of the crystalline forms as well as herbicidal compositions comprising the crystalline forms or the combination thereof with one or more herbicidal carriers or diluents.

Moreover, the invention relates to a method for controlling weeds comprising applying an herbicidally effective amount of the crystalline forms to the weeds and/or their habitat.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

Figure 1 Shows an X-ray powder diffraction spectrum of pyroxsulam Form A.

Figure 2 Shows an X-ray powder diffraction spectrum of pyroxsulam Form B.

Figure 3 Shows an X-ray powder diffraction spectrum of pyroxsulam Form C.

Figure 4 Shows an X-ray powder diffraction spectrum of pyroxsulam Form D.

Figure 5 Shows an X-ray powder diffraction spectrum of pyroxsulam Form E.

Figure 6 Shows an X-ray powder diffraction spectrum of pyroxsulam Form F.

Figure 7 Shows an X-ray powder diffraction spectrum of pyroxsulam Form G. Figure 8 Shows DSC pattern of pyroxsulam Form A.

Figure 9 Shows DSC pattern of pyroxsulam Form B.

Figure 10 Shows DSC pattern of pyroxsulam Form C.

Figure 11 Shows DSC pattern of pyroxsulam Form D.

Figure 12 Shows DSC pattern of pyroxsulam Form E.

Figure 13 Shows DSC pattern of pyroxsulam Form F.

Figure 14 Shows DSC pattern of pyroxsulam Form G.

DETAILED DESCRIPTION

The present invention encompasses novel crystalline forms of N-(5,7-dimethoxy- [l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-methoxy-4-(trifluoro methyl)pyridine-3-sulfonamide (pyroxsulam), including polymorphs, solvates and/or hydrates, which has the following structure:

In addition, the present invention further encompasses processes for preparation of pyroxsulam novel crystalline forms. In particular, seven novel solid crystalline forms of pyroxsulam, their mixtures, compositions, method of their preparation and use have now been discovered.

Definitions

Prior to setting forth the present subject matter in detail, it may be helpful to provide definitions of certain terms to be used herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this subject matter pertains. The following definitions are provided for clarity.

The term“a” or“an” as used herein includes the singular and the plural, unless specifically stated otherwise. Therefore, the terms“a,”“an,” or“at least one” can be used interchangeably in this application.

As used herein, the term“about” when used in connection with a numerical value includes +10% from the indicated value. In addition, all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges. It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention.

The term“herbicide” is used herein to mean an active ingredient that controls or adversely modifies the growth of plants. The terms“plants” and“vegetation” are meant to include germinant seeds, emerging seedlings and established vegetation. The term“herbicidally effective amount” refers to an amount of active ingredient which causes an adversely modifying effect and includes deviations from natural development, killing, regulation, desiccation, retardation, and the like. The term“weed” as used herein refers to an unwanted plant that is growing in a place or in a manner that is detrimental to a plant of interest. The term "weed control" as used herein means killing, damaging, or inhibiting the growth of the weed; it refers to significant damage, caused by the herbicide, to the bulk of the weeds wherein said weeds are either dead or dying, thereby not competing with crops for subsistence.

The term“crystalline form”, as used herein includes polymorphs, solvates or hydrates. The term’’solvate”, as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate. " The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.

The term“mixture” or“combination” as used herein refers, but is not limited to, a combination in any physical form, e.g., blend, solution or the like.

As used herein, the term“substantially free” when used refers to the solid state forms of the present disclosure containing about 20% (w/w) or less of polymorphs, or a specified polymorph of N-(5,7-dimethoxy-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-met hoxy-4-

(trifluoromethyl)pyridine-3-sulfonamide (pyroxsulam). According to some embodiments, the solid state form of the present disclosure contains about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, about 0.2% (w/w) or less of polymorphs, or of a specified polymorph of pyroxsulam. In other embodiments, solid state forms of pyroxsulam of the present disclosure contain from about 1% (w/w) to about 20% (w/w), or from about 5% (w/w) to 10% (w/w) of any solid state forms or a specified polymorph of pyroxsulam.

A solid state form, such as a crystal form or amorphous form, may be referred to herein as being characterized by graphical data "as depicted in" or "as substantially depicted in" a Figure. Such data include, for example, powder X-ray diffractograms, IR, melting point, thermal behaviors (measured by several techniques such as differential scanning calorimetry -“DSC”), and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called "fingerprint") which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of pyroxsulam referred to herein as being characterized by graphical data "as depicted in" or "as substantially depicted in" a Figure will thus be understood to include any crystal forms of pyroxsulam characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.

Depending on which other solid state forms comparison is made, the crystalline forms of pyroxsulam of the present invention have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability- such as chemical stability, thermal and/or mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility, and bulk density.

In some embodiments, the crystalline forms of pyroxsulam of the present invention are substantially free of any other form of pyroxsulam, or a specific polymorphic form of pyroxsulam, respectively.

The present invention provides a novel crystalline polymorphic form of N-(5,7-dimethoxy- [l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-methoxy-4-(trifluoro methyl)pyridine-3-sulfonamide (pyroxsulam), designated“Form A”. This novel and surprising polymorph may be characterized by, for example, DSC, X-ray powder diffraction spectrometry and/or IR spectrometry.

Form A exhibits an X-ray powder diffraction pattern as shown in FIG. 1, having characteristic peaks expressed in degrees 2Q (± 0.20°Q) at about 11.4, about 19.5 and about 23.8 and in the absence of at least one peak expressed in degrees 2Q (± O.2O°0) at about 12.4, or about 16.3, or about 18.0. In one embodiment, the powder X-ray diffraction pattern of Form A comprises characteristic peaks expressed in degrees 2Q (± 0.20°Q) at about 11.4, about 19.5 and about 23.8 and in the absence of peaks expressed in degrees 2Q (± 0.20°Q) at about 12.4 and about 16.3. In one embodiment, the powder X-ray diffraction pattern of Form A comprises characteristic peaks expressed in degrees 2Q (± 0.20°Q) at about 11.4, about 19.5 and about 23.8 and in the absence of peaks expressed in degrees 2Q (± 0.20°Q) at about 12.4 and about 18.0. In one embodiment, the powder X-ray diffraction pattern of Form A comprises characteristic peaks expressed in degrees 2Q (± 0.20°Q) at about 11.4, about 19.5 and about 23.8 and in the absence of peaks expressed in degrees 2Q (± 0.20°Q) at about 16.3 and about 18.0. In one embodiment, the powder X-ray diffraction pattern of Form A comprises characteristic peaks expressed in degrees 2Q (± 0.20°Q) at about 11.4, about 19.5 and about 23.8 and in the absence of peaks expressed in degrees 2Q (+ 0.20°Q) at 12.4, about 16.3 and about 18.0.

In some embodiments, Form A exhibits DSC pattern as shown in FIG. 8.

In another aspect, the present invention provides processes for preparing polymorph Form A.

In some embodiments, the present invention provides a process for preparation of Form A comprising a) combining 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine with 3- (Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine in the presence of 3,5-Lutidine and DMSO; wherein the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3- (Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine and DMSO is from about 1: 1.1:0.001 to about 1:1.3:0.02 ; b) addition of an organic solvent to the solution obtained in a); and c) filtering the precipitated solid from the solution of step b).

In certain embodiments, the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2- indenylamine, 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine and DMSO is from about 1:1.1:0.01 to about 1: 1.3:0.02. In more specific embodiments, the molar ratio between 4,6- Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine and DMSO is about 1: 1.2:0.017.

In some embodiments, the present invention provides a process for preparation of Form A, wherein the solution in step a) is stirred at a temperature lower than 40 °C for at least 5 hours before proceeding to step b). In certain embodiments, the solution in step a) is stirred at about 25° C.

In some embodiments, the present invention provides a process for preparation of Form A, further comprising cooling the solution obtained in step b) to a temperature under 15 °C; in certain embodiments, to a temperature of about 10 °C.

In some embodiments, the present invention provides a process for preparation of Form A, wherein the organic solvent is selected from the group comprising, for example acetonitrile, butyronitrile, isobutyronitrile, propionitrile or a combination thereof; in certain embodiments, the organic solvent is acetonitrile. In some embodiments, the present invention provides a process for preparation of Form A, wherein the molar ratio of 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine and the organic solvent is between about 1: 10 to about 1:40; in certain embodiments, the molar ratio is between about 1:15 to about 1:20 and in more specific embodiments, the molar ratio is about 1: 18.8.

The present invention provides a crystalline polymorphic form designated“Form B”. This novel and surprising polymorph may be characterized by, for example, DSC, X-ray powder diffraction spectrometry and/or IR spectrometry.

Form B exhibits an X-ray powder diffraction pattern as shown in FIG. 2, having characteristic peaks expressed in degrees 2Q (± 0.20°Q) at about 13.4, about 13.9, about 15.7, about 23.5 and about 24.8 and in the absence of at least one peak expressed in degrees 2Q (± 0.20°Q) at about 8.6 or about 9.8. In one embodiment, the powder X-ray diffraction pattern of Form B comprises characteristic peaks expressed in degrees 20 (± O.2O°0) at about 13.4, about 13.9, about 15.7, about 23.5 and about 24.8 and in the absence of peaks expressed in degrees 2Q (± O.2O°0) at about 8.6 and about 9.8.

In some embodiments, Form B exhibits DSC pattern as shown in FIG. 9.

In another aspect, the present invention provides processes for preparing polymorph Form B.

The present invention provides a process for preparation of Form B comprising: a) dissolving of pyroxsulam in an organic solvent; b) cooling the solution of pyroxsulam; and c) separating the crystals.

In some embodiments, the present invention provides a process for preparation of Form B, wherein the solution in step b) is cooled to a temperature lower than 40 °C; in certain embodiments, the solution in step b) is cooled to about 25 °C.

In some embodiments, the present invention provides a process for preparation of Form B, wherein the organic solvent is selected from a group comprising: acetonitrile, butyronitrile, isobutyronitrile, propionitrile or a combination thereof; in certain embodiments, the organic solvent is acetonitrile.

In some embodiments, the present invention provides a process for preparation of Form B, wherein the solution of step a) also contains water. In some embodiments, the present invention provides a process for preparation of Form B, wherein the volume ratio of the organic solvent and the water in step a) is between about 5: 1 to about 20: 1; in certain embodiments, the volume ratio of the organic solvent and the water in step a) is between about 7:1 to about 9: 1 and in more specific embodiments, the volume ratio of the organic solvent and the water in step a) is about 8: 1. In some embodiments, the present invention provides a process for preparation of Form B, wherein the water is added to the organic solvent dropwise. In some embodiments, the present invention provides a process for preparation of Form B, wherein the molar ratio of pyroxsulam and the organic solvent is between about 1 :30 to about 1 :90; in certain embodiments, the molar ratio of pyroxsulam and the organic solvent is between about 1:50 to about 1:80; preferably the molar ratio of pyroxsulam and the organic solvent is between about 1:60 to about 1:70 and in more specific embodiments, the molar ratio of pyroxsulam and the organic solvent is about 1:67.

In some embodiments, the present invention provides a process for preparation of Form B, wherein the molar ratio of pyroxsulam and the water is between about 1:10 to about 1:35; in certain embodiments, molar ratio of pyroxsulam and the water is between about 1 :20 to about 1 :30 and in more specific embodiments, the molar ratio of pyroxsulam and the water is about 1:24.

The present invention provides a crystalline polymorphic form designated“Form C”. This novel and surprising polymorph may be characterized by, for example, DSC, X-ray powder diffraction spectrometry and/or IR spectrometry.

Form C exhibits an X-ray powder diffraction pattern as shown in FIG. 3, having characteristic peaks expressed in degrees 2Q (+ 0.20°Q) at about 9.4, 15.3, 24.5, 24.9 and 25.4.

In some embodiments, Form C exhibits DSC pattern as shown in FIG. 10.

In another aspect, the present invention provides processes for preparing polymorph Form C.

In some embodiments, the present invention provides a process for preparation of Form C comprising: a) combining 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine with 3-

(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine in the presence of 3,5-Lutidine and DMSO; wherein the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3- (Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine and DMSO is from about 1:1:0.001 to about 1:1.05:0.02; and b) filtering the precipitated solid from the solution of step a). In certain embodiments, the present invention provides a process for preparation of Form C wherein the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3-(Chlorosulfonyl)-2- methoxy-4-(trifluoromethyl) pyridine and DMSO is from about 1:1:0.01 to about 1: 1.05:0.02 and in more specific embodiments, the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2- indenylamine, 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine and DMSO is about 1:1.03:0.017.

In some embodiments, the present invention provides a process for preparation of Form C wherein the solution in step a) is stirred at a temperature lower than 40 °C for at least 5 hours before proceeding to step b); in certain embodiments the solution in step a) is stirred at about 25 °C. In some embodiments, the present invention provides a process for preparation of Form C further comprising cooling the solution obtained in step b) to a temperature under 15 °C; in certain embodiments, to a temperature of about 10 °C.

The present invention provides a crystalline form designated“Form D”. This novel and surprising crystalline may be characterized by, for example, DSC, X-ray powder diffraction spectrometry and/or IR spectrometry.

Form D exhibits an X-ray powder diffraction pattern as shown in FIG. 4, having characteristic peaks expressed in degrees 2Q (+ 0.20°Q) at about 8.5, 10.4, 11.4, 14.7, 20.0 and 21.3.

In some embodiments, Form D exhibits DSC pattern as shown in FIG. 11.

In another aspect, the present invention provides processes for preparing crystalline Form D.

In some embodiments, the present invention provides a process for preparation of Form D comprising: a) combining 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine with 3-

(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine in the presence of pyridine and DMSO; wherein the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3-

(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine and DMSO is from about 1:1:0.001 to about 1:2:0.02; and b) filtering the precipitated solid from the solution of step a). In certain embodiments, the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3- (Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine and DMSO is from about 1:1:0.01 to about 1:2:0.02 and in more specific embodiments, the molar ratio is about 1: 1.7:0.017.

In some embodiments, the present invention provides a process for preparation of Form D wherein the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3-

(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine, pyridine and DMSO is from about 1:1:3:3:0.001 to about 1:2:4:0.02. In certain embodiments, the molar ratio between 4,6- Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine, pyridine and DMSO is from about 1: 1:3:3:0.01 to about 1:2:4:0.02 and in more specific embodiments, the molar ratio is about 1: 1.7:3.36:0.017.

In some embodiments, the present invention provides a process for preparation of Form D wherein the solution in step a) is stirred at a temperature lower than 40 °C for at least 5 hours before proceeding to step b); in certain embodiments the solution in step a) is stirred at about 25 °C. In some embodiments, the present invention provides a process for preparation of Form D further comprising cooling the solution obtained in step b) to a temperature under 15 °C; in certain embodiments, to a temperature of about 10 °C.

The present invention provides a crystalline polymorphic form designated“Form E”. This novel and surprising polymorph may be characterized by, for example, DSC, X-ray powder diffraction spectrometry and/or IR spectrometry.

Form E exhibits an X-ray powder diffraction pattern as shown in FIG. 5, having characteristic peaks expressed in degrees 2Q (+ 0.20°Q) at about 11.7, 12.3, 16.4, 18.1, 18.9 and 23.2.

In some embodiments, Form E exhibits DSC pattern as shown in FIG. 12.

In another aspect, the present invention provides processes for preparing polymorph Form E.

In some embodiments, the present invention provides a process for preparation of Form E comprising: a) dissolving of pyroxsulam in an organic solvent; b) cooling the solution; c) adding water; and d) separating the crystals.

In some embodiments, the present invention provides a process for preparation of Form E wherein the solution in step b) is cooled to a temperature lower than 40 °C; in certain embodiments the solution in step b) is cooled to about 25 °C.

In some embodiments, the present invention provides a process for preparation of Form E wherein the organic solvent is selected from the group comprising: acetonitrile, butyronitrile, isobutyronitrile, propionitrile or a combination thereof; in certain embodiments, the organic solvent is acetonitrile.

In some embodiments, the present invention provides a process for preparation of Form E wherein the volume ratio of the organic solvent and the water is between about 5: 1 to about 30: 1 ; in certain embodiments, the volume ratio of the organic solvent and the water is between about 7:1 to about 9:1 and in more specific embodiments, the volume ratio of the organic solvent and the water is about 8:1.

In some embodiments, the present invention provides a process for preparation of Form E wherein the molar ratio of pyroxsulam and the organic solvent is between about 1 :30 to about 1 :90, preferably between about 1:50 to about 1:80. In certain embodiments, the molar ratio of pyroxsulam and the organic solvent is between about 1:60 to about 1:70, preferably between about 1:60 to about 1:67.

The present invention provides a crystalline form designated“Form F”. This novel and surprising crystalline may be characterized by, for example, DSC, X-ray powder diffraction spectrometry and/or IR spectrometry. Form F exhibits an X-ray powder diffraction pattern as shown in FIG. 6, having characteristic peaks expressed in degrees 2Q (+ 0.20°Q) at about 9.8, 10.4, 11.5, 13.2, 13.9, 14.4, 19.5 and 25.1. In some embodiments, Form F exhibits DSC pattern as shown in FIG. 13.

In another aspect, the present invention provides processes for preparing crystalline Form F.

In some embodiments, the present invention provides a process for preparation of Form F comprising: a) combining 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine with 3-

(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine in the presence of pyridine and DMSO; wherein the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3-

(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine and DMSO is from about 1: 1.1:0.001 to about 1: 1.3:0.02; and b) filtering the precipitated solid from the solution of step a). In certain embodiments, the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3- (Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine and DMSO is from about 1: 1.1:0.01 to about 1: 1.3:0.02; and in more specific embodiments, the molar ratio between 4,6-Dimethoxy- l,3,3a,7-tetraaza-2-indenylamine, 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine and DMSO is about 1: 1.2:0.017.

In some embodiments, the present invention provides a process for preparation of Form F wherein the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3-

(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine, pyridine and DMSO is from about 1:1.1:3:0.001 to about 1:1.3:4:0.02; preferably about 1: 1.1:3:0.01 to about 1:1.3:4:0.02 and more preferably about 1:1.2:3.36:0.017.

In some embodiments, the present invention provides a process for preparation of Form F wherein the solution in step a) is stirred at a temperature lower than 40 °C for at least 5 hours before proceeding to step b); in certain embodiments the solution in step a) is stirred at about 25 °C.

In some embodiments, the present invention provides a process for preparation of Form F further comprising cooling the solution obtained in step b) to a temperature under 15 °C and in certain embodiments, to a temperature of about 10 °C.

The present invention provides a crystalline polymorphic form designated“Form G”. This novel and surprising polymorph may be characterized by, for example, DSC, X-ray powder diffraction spectrometry and/or IR spectrometry.

Form G exhibits an X-ray powder diffraction pattern as shown in FIG. 7, having characteristic peaks expressed in degrees 2Q (+ 0.20°Q) at about 9.9, 10.4, 11.3, 12.5, 18.0 and 25.4. In some embodiments, Form G exhibits DSC pattern as shown in FIG. 14.

In another aspect, the present invention provides processes for preparing polymorph Form G.

In some embodiments, the present invention provides a process for preparation of Form G comprising a) combining 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine with 3- (Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine in the presence of 3,5-Lutidine and DMSO; wherein the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3- (Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine and DMSO is from about 1: 1.1:0.001 to about 1: 1.3:0.02; and b) filtering the precipitated solid from the solution of step a). In certain embodiments, the molar ratio between 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine, 3- (Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine and DMSO is from about 1: 1.1:0.01 to about 1:1.3:0.02. In more specific embodiments, the molar ratio between 4,6-Dimethoxy-l,3,3a,7- tetraaza-2-indenylamine, 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl) pyridine and DMSO is about 1: 1.2:0.017.

In some embodiments, the present invention provides a process for preparation of Form G wherein the solution in step a) is stirred at a temperature lower than 40 °C for at least 5 hours before proceeding to step b); in certain embodiments the solution in step a) is stirred at about 25 °C.

In some embodiments, the present disclosure provides a process for preparation of Form G further comprising cooling the solution obtained in step b) to a temperature under 15 °C and in certain embodiments, to a temperature of about 10 °C.

In some embodiments, the present invention further relates to a mixture of at least two of the crystalline Forms A-G of N-(5,7-dimethoxy-[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-met hoxy- 4-(trifluoromethyl)pyridine-3 -sulfonamide (pyroxsulam). In some embodiments, the mixtures of the present invention comprises from about 0.01% to about 90% by weight of each of the crystalline Forms A-G. The mixture can be prepared by mixing pyroxsulam Forms A-G at the appropriate and desired range.

In some embodiments, the crystalline Forms A-G of the present invention and/or their mixtures are for use in weed control. In certain embodiments, crystalline Forms A-G of the present invention and/or their mixtures provide control of broadleaf and grassy weeds.

In some embodiments, the crystalline Forms A-G of the present invention and/or their mixtures are applied as preemergence and postemergence herbicides. In more specific embodiments, crystalline Forms A-G of the present invention and/or their mixtures are applied as postemergence herbicides. In some embodiments, the present invention relates to a composition comprising the crystalline Forms A-G. In some embodiments, the present invention relates to an herbicidal composition comprising the crystalline Forms A-G. In some embodiments, an herbicidal composition is provided including an herbicidal effective amount of the crystalline Forms A-G of the present invention. In some embodiments, an herbicidal composition comprises crystalline Forms A-G, of the present invention and one or more herbicidal carriers and/or diluents.

Suitable carriers or diluents should not be phytotoxic to valuable crops, particularly at the concentrations employed in applying the compositions for selective weed control in the presence of crops and should not react chemically with the crystalline Forms A-G of the present invention or other composition ingredients. These compositions can be applied directly to weeds or their locus or can be concentrated or diluted with additional carriers before application. The term "locus" refers to the area where weeds grow or are likely to grow and is intended to include, but is not limited to, soil, seeds, and seedlings, as well as established vegetation. The weeds may be in an area of land that also includes plants or crops. In this instance, the herbicidal composition may, depending on the crop, be applied to both the crops and weeds. Preferably, when applied to a crop growing area, the rate of application should be sufficient to control the growth of weeds without causing substantial permanent damage to the crop.

The term "herbicidal carrier" is intended to include any material that facilitates application of a composition of the invention to the intended subject, which may for example be a weed and/or a locus thereof, or that facilitates storage, transport or handling. A suitable carrier may be a solid, liquid, or semi-solid depending on the desired formulation and are well known in the art. The term "herbicidal carrier" also covers all adjuvants that are ordinarily used in herbicidal formulation technology and are well known to those skilled in the art; for example, antifoam agents, sequestering agents, neutralizing agents, buffers, dyes, odorants, spreading agents, sticking agents, dispersing agents, thickening agents, freezing point depressants, antioxidants, antimicrobial agents, and the like.

The compositions can be solids, such as, for example, dusts, granules, water dispersible granules or wettable powders, or liquids such as, for example, emulsifiable concentrates, solutions, emulsions or suspensions, or as controlled release forms, such as, for example, microcapsules, or others.

It may be desirable to incorporate one or more surface- active agents into the compositions of the present invention. The surface-active agents can be anionic, cationic or nonionic in character and can be employed as emulsifying agents, wetting agents, suspending agents, or for other purposes. The concentration of the active ingredients in the herbicidal compositions of the present invention is generally from 0.001% to 98% by weight. The optimum concentration for a given compound will depend upon the type of composition, mode of application, application equipment, and nature of the weeds to be controlled, etc.

The present compositions can be applied to weeds or their locus using conventional ground or aerial dusters, sprayers, and granule applicators, by addition to irrigation water, and by other conventional means known to those skilled in the art.

The crystalline Forms A-G can be employed at higher, non-selective rates of application to control essentially all the vegetation in an area. In some cases, they can also be employed at lower, selective rates of application for the control of undesirable vegetation in grass crops or in broadleaf crops. In such instances, the selectivity can often be improved using safeners.

Application rates of 0.001 to 1 kg/ha are generally employed in postemergence operations; for preemergence applications, rates of 0.01 to 2 kg/ha are generally employed. The higher rates designated generally give non-selective control of a broad variety of undesirable vegetation. The lower rates typically give selective control and, by judicious election of compounds, timing, and rates of application, can be employed in the locus of crops.

In some embodiments, the herbicidal composition of the present invention further contains other compatible components, for example, other herbicides, herbicide safeners, plant growth regulators, fungicides, insecticides, and the like and can be formulated with liquid fertilizers or solid, particulate fertilizer carriers such as ammonium nitrate, urea and the like.

In some embodiments, the herbicidal composition of the present invention comprises one or more other herbicides to obtain control of a wider variety of undesirable vegetation. When used in conjunction with other herbicides, the crystalline Forms A-G can be formulated with the other herbicide or herbicides, tank mixed with the other herbicide or herbicides, or applied sequentially with the other herbicide or herbicides. Some of the herbicides that can be employed beneficially in combination with the crystalline Forms A-G of the present invention include but are not limited to substituted triazolopyrimidinesulfonamide compounds, such as diclosulam, florasulam, cloransulam-methyl, and flumetsulam. Other herbicides such as acifluorfen, bentazon, chlorimuron, clomazone, lactofen, carfentrazone-methyl, fumiclorac, fluometuron, fomesafen, imazaquin, imazethapyr, linuron, metribuzin, fluazifop, haloxyfop, glyphosate, glufosinate, 2,4- D, acetochlor, metolachlor, sethoxydim, nicosulfuron, clopyralid, fluroxypyr, metsulfuron-methyl, amidosulfuron, tribenuron, and others can also be employed. It is generally preferred to use the compounds in conjunction with other herbicides that have a similar crop selectivity. It is further usually preferred to apply the herbicides at the same time, either as a combination formulation or as a tank mix.

In one embodiment, the crystalline Forms A-G of the present invention can generally be employed in combination with a wide variety of known herbicide safeners, such as cloquintocet, mefenpyr, furilazole, dichlormid, benoxacor, flurazole, fluxofenim, daimuron, dimepiperate, thiobencarb, and fenclorim, to enhance their selectivity. Herbicide safeners that act by modifying the metabolism of herbicides in plants by enhancing the activity of cytochrome P-450 oxidases are usually especially effective. This is often a preferred embodiment of the invention. The crystalline Forms A-G can additionally be employed to control undesirable vegetation in many crops that have been made tolerant to or resistant to herbicides by genetic manipulation or by mutation and selection. For example, crops that have been made tolerant or resistant to herbicides in general or to herbicides that inhibit the enzyme acetolactate synthase in sensitive plants can be treated.

In some embodiments, the compositions of the present invention are for use in weed control. In certain embodiments, the compositions provide control of broadleaf and grassy weeds. In some embodiments, the compositions are applied as preemergence and postemergence herbicides. In more specific embodiments, the compositions are applied as postemergence herbicides.

The method of the invention involves applying the composition to the locus of the weeds where control is desired. Thus, the method according to the invention involves applying an herbicidally effective amount of the crystalline Forms A-G of pyroxsulam as described herein to an area of land comprising weeds and/or in which pre-emergent control is desired.

The application of the herbicide may be for example to weeds and/or locus thereof (such as soil) to control the germination or growth of the weed species.

The amount of the herbicide used can vary within a substantial range. The optimum amount employed can be determined for the use in each case by series of tests. The rate of application of the compositions of the invention will depend on several factors including, the nature of the desired effect, the identity of the weeds whose growth is to be controlled, the formulations selected for use, whether the compound is to be applied for pre-emergent or post-emergent control, and other factors. It is well within an ordinary skill in the art to determine the necessary amount of the active ingredient.

When applied to a crop-growing area, preferably the rate of application should be sufficient to control the growth of weeds without causing substantial permanent damage to the crop. EXPERIMENT AF DETAILS XRD:

The XRD measurement was performed on powder X-Ray diffractometer Empyrean, Panalytical. Cu radiation, 40kv, 30mA. The powder sample was introduced in a cavity sample holder, with zero-background.

DSC:

The DSC experiments were performed using a method of heating the samples from 30-250 °C at a rate of 5°C/min on Mettler Toledo, DSC 1, STAR System, Swiss.

Example 1. Form A

10 gr of 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine (0.051 mol, 1 eq) were charged on 250 ml round bottom flask. 16.9 gr of 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine (0.062 mol, 1.2 eq) was added followed by 36 ml of dry Acetonitrile. Then 18.4 gr of 3,5-Lutidine (0.172 mol, 3.36 eq) was added followed by 0.068 gr (0.001 mol, 0.017 eq) of DMSO. The reaction mixture was stirred for 16 hours at 25°C under N2. Upon completion, 50 ml of Acetonitrile were added followed by 52.5 ml of HC1 4N solution and the reaction mixture was stirred for additional 2 hours. An iced-water cooling bath was added and the reaction was cooled to 10°C and stirred for 1 hour. The precipitated solid was then filtered and the filter cake was washed with 27 ml of 2:1 (v/v) water: Acetonitrile solution, then washed twice with 13.6 ml of Ethanol (95%). The product was then dried in a vacuum oven (30 mbar) at 50°C for 16 hours to obtain N - (5,7-dimethoxy [1,2,4] triazolo [1,5-a] pyrimidin-2-yl)-2-methoxy-4- (trifluoromethyl) pyridine-3 - sulfonamide- as Form A.

Example 2. Form B:

Procedure 1:

10 gr of N-(5,7-dimethoxy[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-meth oxy-4-(trifluoromethyl) pyridine-3 -sulfonamide were mixed with 80 ml of Acetonitrile, then heated to reflux (82 °C) and stirred for 3 hours. Clear solution was obtained. The heating block was then removed and the reaction mixture was left to cool to 25°C and stirred for additional lh. The precipitated solid was filtrated and dried at 50°C under vacuum (30 mbar) for 16 hours to obtain N-(5,7- dimethoxy[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-methoxy-4- (trifluoromethyl) pyridine-3 - sulfonamide - as Form B . Procedure 2:

160 gr of N-(5,7-dimethoxy[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-meth oxy-4-(trifluoromethyl) pyridine-3 -sulfonamide were mixed with 1280 ml of Acetonitrile and heated to reflux (82 °C) and stirred for 4 hours. Clear solution was obtained. Then 160 ml of water were added dropwise for 15 minutes. The heating block was then removed and the reaction mixture was left to cool to 25 °C and stirred for additional lh. The precipitated solid was filtrated and dried at 50°C under vacuum (30 mbar) for 16 hours to obtain N-(5,7-dimethoxy[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2- methoxy-4-(trifluoromethyl)pyridine-3 sulfonamide - as Form B.

Example 3. Form C:

10 gr of 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine (0.051 mol, 1 eq) were charged on 250 ml round bottom flask. 14.5 gr of 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine (0.053 mol, 1.03 eq) was added followed by 36 ml of dry Acetonitrile. Then 18.4 grof 3,5-Lutidine (0.172 mol, 3.36 eq) was added followed by 0.068 gr (0.001 mol, 0.017 eq) of DMSO. The reaction mixture was stirred for 16 hours at 25°C under N2. Upon completion, 52.5 ml of HC1 4N solution was added and the reaction mixture was stirred for additional 2 hours. An iced-water cooling bath was added and the reaction was cooled to 10°C and stirred for 1 hour. The precipitated solid was then filtered and the filter cake was washed with 27 ml of 2: 1 (v/v) water: Acetonitrile solution, then washed twice with 13.6 ml of Ethanol (95%). The product was then dried in a vacuum oven (30 mbar) at 50°C for 16 hours to obtain N-(5,7-dimethoxy[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)- 2-methoxy-4- (trifluoromethyl) pyridine-3 - sulfonamide- as Form C.

Example 4. Form D:

20 gr of 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine (0.103 mol, 1 eq) were charged on 500 ml round bottom flask. 47.9 gr of 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine (0.174 mol, 1.7 eq) was added followed by 72 ml of dry Acetonitrile. Then 27.2 gr of Pyridine (0.345 mol, 3.36 eq) was added followed by 0.136 gr (0.002 mol, 0.017 eq) of DMSO. The reaction mixture was stirred for 16 hours at 25 °C under N2. Upon completion, 105 ml of HC1 4N solution was added and the reaction mixture was stirred for additional 2 hours. An iced-water cooling bath was added and the reaction was cooled to 10°C and stirred for 1 hour. The precipitated solid was then filtered and the filter cake was washed with 54 ml of 2: 1 (v/v) water: Acetonitrile solution, then washed twice with 27 ml of Ethanol (95%). The product was then dried in a vacuum oven (30 mbar) at 50°C for 16 hours to obtain - as Form D. Example 5. Form E:

10 gr of N-(5,7-dimethoxy [1,2,4] triazolo [l,5-a]pyrimidin-2-yl) - 2- methoxy - 4 - (trifluoromethyl) pyridine-3-sulfonamide were mixed with 80 ml of Acetonitrile and heated to reflux (82 °C) and stirred for 3 hours. Clear solution was obtained. The heating block was then removed and the reaction mixture was left to cool to 25°C and stirred for additional lh. Then 10 ml of distilled water were added. The reaction mi ture was stirred for additional lh. The precipitated solid was filtrated and dried at 50°C under vacuum (30 mbar) for 16 hours to obtain N-(5,7-dimethoxy[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)-2-meth oxy-4-(trifluoromethyl)pyridine- 3-sulfonamide - as Form E.

Example 6. Form F:

10 gr of 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine (0.051 mol, 1 eq) were charged on 250 ml round bottom flask. 16.9 gr of 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine (0.062 mol, 1.2 eq) was added followed by 36 ml of dry Acetonitrile. Then 13.6 gr of Pyridine (0.172 mol, 3.36 eq) was added followed by 0.068 gr (0.001 mol, 0.017 eq) of DMSO. The reaction mixture was stirred for 16 hours at 25°C under N2. Upon completion, 52.5 ml of HC1 4N solution was added and the reaction mixture was stirred for additional 2 hours. An iced-water cooling bath was added and the reaction was cooled to 10°C and stirred for 1 hour. The precipitated solid was then filtered and the filter cake was washed with 27ml of 2:1 (v/v) water: Acetonitrile solution, then washed twice with 13.6 ml of Ethanol (95%). The product was then dried in a vacuum oven (30 mbar) at 50°C for 16 hours to obtain N-(5,7-dimethoxy[l,2,4]triazolo[l,5-a]pyrimidin-2-yl)- 2-methoxy-4-(trifluoromethyl)pyridine-3-sulfonamide- as Form F.

Example 7. Form G:

100 gr of 4,6-Dimethoxy-l,3,3a,7-tetraaza-2-indenylamine (0.51 mol, 1 eq) were charged on 2000 ml round bottom flask. 169.2 gr of 3-(Chlorosulfonyl)-2-methoxy-4-(trifluoromethyl)pyridine (0.615 mol, 1.2 eq) was added followed by 360 ml of dry Acetonitrile. Then 184.6 gr of 3,5- Futidine (1.72 mol, 3.36 eq) was added followed by 0.68 gr (0.01 mol, 0.017 eq) of DMSO. The reaction mixture was stirred for 16 hours at 25°C under N2. Upon completion, 525 ml of HC1 4N solution was added and the reaction mixture was stirred for additional 2 hours. An iced- water cooling bath was added and the reaction was cooled to 10°C and stirred for 1 hour. The precipitated solid was then filtered and the filter cake was washed with 270 ml of 2:1 (v/v) water: Acetonitrile solution, then washed twice with 136 ml of Ethanol (95%). The product was then dried in a vacuum oven (30 mbar) at 50°C for 16 hours to obtain N - (5,7-dimethoxy [1,2,4] triazolo [l,5-a]pyrimidin- 2-yl)-2-methoxy-4- (trifluoromethyl) pyridine-3 - sulfonamide- as Form G.

In addition, any priority document(s) of this application is/are hereby incorporated herein by reference in its/their entirety.