Purified solid form of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidin-2-one

Abstract

The present invention provides a pure solid comprising flumetyl sulforim, wherein the solid comprises 4% or less by weight of compound(s) different than flumetyl sulforim (impurities) and having the crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

Description

[0001] PURIFIED SOLID FORM OF 5-FLUORO-4-IMINO-3-METHYL-l-TOSYL-3,4- DIHYDROPYRIMIDIN-2-ONE

[0002] Throughout this application various publications are referenced. The disclosures of these documents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[0003] BACKGROUND

[0004] Fungicides are compounds, of natural or synthetic origin, which act to protect plants against damage caused by fungi. Current methods of agriculture rely heavily on the use of fungicides. In fact, some crops cannot be grown usefully without the use of fungicides. Using fungicides allows a grower to increase the yield and the quality of the crop, and consequently, increase the value of the crop. In most situations, the increase in value of the crop is worth at least three times the cost of the use of the fungicide.

[0005] 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidin-2(1H)-one (flumetylsulforim) having the structure of a Formula I:

[0006]

[0007] Formula I

[0008] is a fungicide which provides control of a variety of pathogens in economically important crops including, but not limited to, the causal agent of leaf blotch in wheat, Septoria tritici, (SEPTTR) and diseases caused by fungi of the classes Ascomycetes and Basidiomycetes.

[0009] Solid forms of flumetylsulforim are disclosed in different PCT International Application Publications. WO / 2015 / 103142 and WO / 2015 / 103144 disclose synthesis of flumetylsulforim. In addition, polymorphs of flumetylsulforim are described in PCT International Application Publication No. WO / 2019 / 038583 (published February 28, 2019), and WO2022234487 (Published November 10, 2022) the entire content of which is hereby incorporated by reference into this application.SUMMARY

[0010] The present invention provides a pure solid comprising flumetylsulforim having crystalline polymorphic form exhibiting an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

[0011] The present invention provides a pure solid comprising flumetylsulforim, wherein the solid comprises 4% or less by weight of compound(s) different than flumetylsulforim (impurities) and has crystalline polymorphic form exhibiting an XRPD pattern having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

[0012] The present invention further provides a solid mixture comprising flumetylsulforim, wherein 96% or more by weight of the mixture is the compound of Formula I, and wherein the mixture has crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

[0013] The present invention further provides a combination of (1) a solid comprising flumetylsulforim, wherein the solid comprises 4% or less by weight of compound(s) different than flumetylsulforim (impurities), and wherein the solid has a crystalline polymorphic form exhibiting an XRPD pattern having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ and (2) one or more carriers.

[0014] The present invention further provides a composition comprising (1) pure solid comprising flumetylsulforim having crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ and (2) at least one agriculture acceptable additive.

[0015] The present invention further provides a method for the control of fungal attack on a plant, the method comprising:

[0016] (1) obtaining a pure solid of flumetylsulforim, (2) formulating the pure solid, (3) diluting the formulated pure solid in water and (4) applying the to a locus of the fungus, to a locus in which the infestation is to be prevented, and / or to the plant, so as to thereby control fungal attack on the plant.

[0017] The present invention further provides a process for obtaining a pure solid comprising flumetylsulforim having crystalline polymorphic form which exhibits an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, with 4% or less by weight ofcompounds different than flumetylsulforim (impurities), the process comprises obtaining a slurry of the solid in a solution of acetonitrile in water at RT-40C.

[0018] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1: XRPD spectrum of pure solid obtained according to Example 4.DETAILED DESCRIPTION OF THE INVENTION

[0019] Definitions

[0020] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by persons of ordinary skill in the art to which this subject matter pertains.

[0021] 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.

[0022] 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. For example, “0.1-80%” includes 0.1%, 0.2%, 0.3%, etc. up to 80%.

[0023] As used herein the term "plant" or “crop” includes reference to whole plants, plant organs (e.g. leaves, stems, twigs, roots, trunks, limbs, shoots, fruits etc.), plant cells, or plant seeds. This term also encompasses plant crops such as fruits. In yet another embodiment, the term “plant” may include the propagation material thereof, which may include all the generative parts of the plant such as seeds and vegetative plant material such as cuttings and tubers, which can be used for the multiplication of the plant. This includes seeds, tubers, spores, corms, bulbs, rhizomes, sprouts basal shoots, stolons, and buds and other parts of plants, including seedlings and young plants, which are to be transplanted after germination or after emergence from soil.

[0024] As used herein, the term "locus" includes not only areas in which the infestation is to be controlled, but also areas in which the infestation is to be prevented and also to areas under cultivation.

[0025] As used herein, the term “combination” refers, but is not limited, to a combination in any physical form, e.g., blend, solution, alloy, or the like.

[0026] As used herein, the term "effective amount" refers to an amount of the compound that, when applied, is sufficient to achieve a good level of control.

[0027] As used herein, the phrase "agrochemically acceptable" means which is known and accepted in the art for use in agricultural / pesticidal use.As used herein, the term “adjuvant” is broadly defined as any substance that itself is not a fungicide, but which enhances or is intended to enhance the effectiveness of the fungicide with which it is used. Adjuvants may be understood to include, but are not limited to, spreading agents, penetrants, compatibility agents, and drift retardants.

[0028] As used herein, the term "additive" is defined as any substance that itself is not a fungicide but is added to the composition such as sticking agents, surfactants, synergists, buffers, acidifiers, defoaming agents and thickeners.

[0029] As used herein, the term “tank mix” means that at least one pesticide and / or additive and / or adjuvant are mixed in the spray tank prior to the application or at the time of spray application.

[0030] As used herein, the phrase "agriculturally acceptable carrier" means carriers which are known and accepted in the art for the formation of compositions for agricultural or horticultural use.

[0031] As used herein, the term “w / w” means percentage by weight based on the total weight of the solid or mixture.

[0032]

[0033] solid

[0034] The present invention provides a pure solid comprising flumetyl sulforim having crystalline polymorphic form exhibiting an XRPD pattern having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °20 ± 0.2 °20.

[0035] In some embodiments, the XRPD pattern of the solid compound of flumetyl sulforim comprises at least 5 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °29 ± 0.2 °29, wherein the at least 5 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0036] In some embodiments, the XRPD pattern of the solid compound of flumetyl sulforim comprises at least 6, 7, 8, 9, or 10 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °29 ± 0.2 °29, wherein the at least 6, 7, 8, 9, or 10 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0037] The present invention provides a pure solid comprising flumetylsulforim, wherein the solid comprises 4% or less by weight of compound(s) different than flumetylsulforim (impurities) and has crystalline polymorphic form exhibiting an XRPD pattern having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.In some embodiments, the XRPD pattern of the solid compound of flumetylsulforim comprises at least 5 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 5 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5

[0038] In some embodiments, the XRPD pattern of the solid compound of flumetylsulforim comprises at least 6 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 6 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0039] In some embodiments, the XRPD pattern of the solid compound of flumetylsulforim comprises at least 7 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 7 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0040] In some embodiments, the XRPD pattern of the solid compound of flumetylsulforim comprises at least 8 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 8 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0041] In some embodiments, the XRPD pattern of the solid compound of flumetylsulforim comprises at least 9 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 9 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0042] In some embodiments, the XRPD pattern of the solid compound of flumetylsulforim comprises characteristic peaks at 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ.

[0043] In some embodiments, the XRPD pattern of the solid compound of flumetyl sulforim comprises at least 5, 6, 7, 8, 9, or 10 characteristic peaks selected from the XRPD pattern of FIG. 1, wherein the at least 5, 6, 7, 8, 9, or 10 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0044] In some embodiments, the XRPD pattern of the solid compound of flumetyl sulforim comprises at least 5, 6, 7, 8, 9, or 10 characteristic peaks selected from Table 1, wherein the at least 5, 6, 7, 8, 9, or 10 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0045] In some embodiments, the XRPD pattern of FIG. 1 comprises the peaks listed in Table 1.Table 1:

[0046] XRD peak positions

[0047] (°2θ)

[0048] 5.3

[0049] 6.1

[0050] 7.5

[0051] 8.8

[0052] 10.1

[0053] 10.7

[0054] 12.1

[0055] 12.7

[0056] 12.8

[0057] 13.6

[0058] 14.5

[0059] 14.9

[0060] 16.0

[0061] 17.5

[0062] 18.0

[0063] 18.6

[0064] 20.0

[0065] 20.8

[0066] 21.7

[0067] 22.0

[0068] 22.9

[0069] 23.8

[0070] 24.9

[0071] 25.4

[0072] 25.9

[0073] 26.9

[0074] 27.6

[0075] 29.2

[0076] 29.5

[0077] 30.4

[0078]

[0079] 30.8

[0080] In some embodiments, the solid compound comprising flumetyl sulforim with 4% or less by weight of impurities displays an XRPD pattern substantially as depicted in FIG. 1.

[0081] In some embodiments, the solid material comprising flumetyl sulforim with 4% or less by weight of impurities displays an XRPD pattern as depicted in FIG. 1.In some embodiments, the solid compound comprising flumetylsulforim with 4% or less by weight of impurities displays an XRPD pattern substantially as depicted in FIG. 1, and preferably wherein the XRPD pattern comprises peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

[0082] In some embodiments, the solid compound comprising flumetylsulforim with 4% or less by weight of impurities displays an XRPD pattern substantially as depicted in FIG. 1, and preferably wherein the powder X-ray diffraction pattern comprises peaks at 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ.

[0083] In some embodiments, the solid comprises 4% or less by weight of impurities. In some embodiments, the solid comprises less than 3% by weight of impurities. In some embodiments, the solid comprises less than 2% by weight of impurities. In some embodiments, the solid comprises less than 1% by weight of impurities. In some embodiments, the solid comprises less than 0.5% by weight of impurities. In some embodiments, the solid comprises less than 0.4% by weight of impurities. In some embodiments, the solid comprises less than 0.3% by weight of impurities. In some embodiments, the solid comprises less than 0.2% by weight of impurities. In some embodiments, the solid comprises less than 0.1% by weight of impurities. In some embodiments, the solid comprises less than 0.05% by weight of impurities. In some embodiments, the solid comprises less than 0.01% by weight of impurities.

[0084] The purity of the solid refers to the amount of impurities in the solid which may be used to prepare a composition or combination. For example, when it is described that the pure solid comprises 4% or less by weight impurities, this means that the solid contains 96% or more by weight of the compound of Formula I.

[0085] In some embodiments, “pure solid” refers to chemical purity.

[0086] Pure solids can provide various advantages, including improved stability, shelf life and storage, better tolerance to heat, humidity, and mechanical stress, better formulation control in terms of uniform particle behavior (flow, milling, dispersion), better compatibility with surfactants, binders, and carriers, reduced risk of caking or sedimentation, improved solubility, apparent solubility, dissolution rate, manufacturability and increased bioavailability.

[0087] In some embodiments, pure is when 4% or less by weight of the solid are impurities. In some embodiments, pure is when less than 3% by weight of the solid are impurities. In some embodiments, pure is when less than 2% by weight of the solid are impurities. In some embodiments, pure is when less than 1% by weight of the solid are impurities. In some embodiments, pure is when less than 0.5%by weight of the solid are impurities. In some embodiments, pure is when less than 0.4% by weight of the solid are impurities. In some embodiments, pure is when less than 0.3% by weight of the solid are impurities. In some embodiments, pure is when less than 0.2% by weight of the solid are impurities. In some embodiments, pure is when less than 0.1% by weight of the solid are impurities. In some embodiments, pure is when less than 0.05% by weight of the solid are impurities. In some embodiments, pure is when less than 0.01% by weight of the solid are impurities.

[0088] In some embodiments, the pure solid as described herein has polymorphic purity of at least 80%, more preferably 85%, more preferably 90%, more preferably 95%, most preferably 99%.

[0089] Fungicidal solid mixture

[0090] The present invention further provides a solid mixture comprising flumetylsulforim, wherein 96% or more by weight of the mixture is the compound of Formula I, and wherein the mixture has crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

[0091] In some embodiments, the XRPD pattern of the solid mixture of flumetylsulforim comprises at least 5 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 5 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0092] In some embodiments, the XRPD pattern of the solid mixture of flumetylsulforim comprises at least 6 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 6 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0093] In some embodiments, the XRPD pattern of the solid mixture of flumetylsulforim comprises at least 7 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 7 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0094] In some embodiments, the XRPD pattern of the solid mixture of flumetylsulforim comprises at least 8 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 8 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.In some embodiments, the XRPD pattern of the solid mixture of flumetylsulforim comprises at least 9 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 9 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0095] In some embodiments, the XRPD pattern of the solid mixture of flumetylsulforim comprises characteristic peaks at 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ.

[0096] In some embodiments, the XRPD pattern of the solid mixture of flumetyl sulforim comprises at least 5, 6, 7, 8, 9, or 10 characteristic peaks selected from the XRPD pattern of FIG. 1, wherein the at least 5, 6, 7, 8, 9, or 10 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0097] In some embodiments, the mixture comprising flumetyl sulforim, wherein 96% or more by weight of the mixture is the compound of Formula I, displays an XRPD pattern substantially as depicted in FIG. 1.

[0098] In some embodiments, the mixture comprising flumetyl sulforim, wherein 96% or more by weight of the mixture is the compound of Formula I, that displays an XRPD pattern as depicted in FIG. 1.

[0099] In some embodiments, the solid compound comprising flumetylsulforim, wherein 96% or more by weight of the mixture is the compound of Formula I, displays an XRPD pattern comprising at least 5, 6, 7, 8, 9, or 10 characteristic peaks selected from the XRPD pattern of FIG. 1, wherein the at least 5, 6, 7, 8, 9, or 10 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5, and preferably wherein the XRPD pattern comprises peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

[0100] In some embodiments, the solid compound comprising flumetylsulforim, wherein 96% or more by weight of the mixture is the compound of Formula I, displays an XRPD pattern substantially as depicted in FIG. 1, and preferably wherein the XRPD pattern comprises peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

[0101] In some embodiments, the solid compound comprising flumetylsulforim, wherein 96% or more by weight of the mixture is the compound of Formula I, displays an XRPD pattern substantially as depicted in FIG. 1, and preferably wherein the powder X-ray diffraction pattern comprises peaks at 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ.

[0102] In some embodiments, 96% or more by weight of the mixture is the compound of Formula I. In some embodiments, 97% or more by weight of the mixture is the compound of Formula I. In someembodiments, 98% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99. 5% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99.9% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99.99% by weight of the mixture is the compound of Formula I.

[0103] The purity of the compound of Formula I refers to the amount of the compound of Formula I in the solid which may be used to prepare a composition or combination. For example, when it is described that the purity of the compound of Formula I is 96% or more by weight, this means that the solid contains 96% or more by weight of the compound of Formula I and 4% or less by weight of impurities.

[0104] In some embodiments, “pure solid” refers to chemical purity.

[0105] In some embodiments, pure is when 96% or more by weight of the solid is the compound of Formula I. In some embodiments, 97% or more by weight of the solid is the compound of Formula I. In some embodiments, 98% or more by weight of the solid is the compound of Formula I. In some embodiments, 99% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99. 5% or more by weight of the solid is the compound of Formula I. In some embodiments, 99.9% or more by weight of the solid of is the compound of Formula I. In some embodiments, 99.99% by weight of the solid of is the compound of Formula I.

[0106] The present invention provides a solid mixture comprising flumetylsulforim, wherein 96%, more preferably 97%, more preferably 98%, most preferably 99% or more by weight of the mixture is the compound of Formula I and wherein the compound of Formula I has crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

[0107] In one embodiment, the XRPD pattern of the solid mixture comprises characteristic peaks at 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ.

[0108] In another embodiment, the solid mixture comprising flumetylsulforim, wherein 96%, more preferably 97%, more preferably 98%, most preferably 99% or more by weight of the mixture is the compound of Formula I, displays an XRPD pattern substantially as depicted in FIG. 1.

[0109] In some embodiments, the mixture comprising flumetylsulforim is mixed with at least one excipient.In some embodiments, the mixture comprising flumetyl sulforim, wherein 96%, more preferably 97%, more preferably 98%, most preferably 99% or more by weight of the mixture is the compound of Formula I having the crystalline polymorphic form exhibiting an XRPD pattern substantially as depicted in FIG. 1, with characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, is mixed with at least one excipient.

[0110] In some embodiments, the mixture comprising flumetyl sulforim, wherein 96% or more by weight of the mixture is the compound of Formula I having the crystalline polymorphic form exhibiting an XRPD pattern substantially as depicted in FIG. 1, with characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, is formulated as liquid or solid formulation which optionally comprises additional fungicide and / or other excipient such as adjuvant and the formulation is mixed with other formulation.

[0111] Fungicidal combination

[0112] The present invention provides a combination of (1) a solid comprising flumetyl sulforim, wherein the solid comprises 4% or less by weight of compound(s) different than flumetylsulforim (impurities), and wherein the solid has a crystalline polymorphic form exhibiting an XRPD pattern having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ and (2) one or more carriers.

[0113] In some embodiments, the XRPD pattern of the solid compound of flumetylsulforim comprises at least 5 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 5 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0114] In some embodiments, the XRPD pattern of the solid compound of flumetylsulforim comprises at least 6 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 6 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0115] In some embodiments, the XRPD pattern of the solid compound of flumetylsulforim comprises at least 7 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 7 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0116] In some embodiments, the XRPD pattern of the solid compound of flumetylsulforim comprises at least 8 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0,18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 8 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0117] In some embodiments, the XRPD pattern of the solid compound of flumetyl sulforim comprises at least 9 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ, wherein the at least 9 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0118] In some embodiments, the XRPD pattern of solid comprises characteristic peaks at 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ.

[0119] In some embodiments, the XRPD pattern of the solid compound of flumetyl sulforim comprises at least 5, 6, 7, 8, 9, or 10 characteristic peaks selected from the XRPD pattern of FIG. 1, wherein the at least 5, 6, 7, 8, 9, or 10 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0120] In some embodiments, the combination comprises (1) a solid mixture comprising flumetyl sulforim, wherein 96% or more by weight of the mixture is the compound of Formula I, and wherein the mixture has crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, and (2) one or more carriers.

[0121] In some embodiments, 96% or more by weight of the mixture is the compound of Formula I. In some embodiments, 97% or more by weight of the mixture is the compound of Formula I. In some embodiments, 98% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99. 5% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99.9% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99.99% by weight of the mixture is the compound of Formula I.

[0122] In some embodiments, the solid comprising flumetyl sulforim displays an XRPD pattern substantially as depicted in FIG. 1.

[0123] In some embodiments, the solid comprising flumetyl sulforim displays an XRPD pattern as depicted in FIG. 1.

[0124] In some embodiments, the fungicidal combination comprises (1) a mixture comprising high purity flumetyl sulforim, wherein 96%, more preferably 97%, more preferably 98%, most preferably 99% or more by weight of the mixture is the compound of Formula I having the crystalline polymorphicform exhibiting an XRPD pattern as depicted in FIG. 1, with characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, and (2) one or more carriers.

[0125] In some embodiments, the combination is composition.

[0126] In some embodiments, the composition is a storable composition.

[0127] In some embodiments, the composition is a diluted composition.

[0128] In some embodiments, the combination is a tank mix.

[0129] The present invention provides a composition comprising (1) pure solid comprising flumetyl sulforim having crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, and (2) at least on agriculture acceptable additive.

[0130] In some embodiments, the term “pure” means 96%, more preferably 97%, more preferably 98%, most preferably 99% or more by weight of the solid is the compound of Formula I.

[0131] In some embodiments, 96% or more by weight of the solid is the compound of Formula I. In some embodiments, 97% or more by weight of the solid is the compound of Formula I. In some embodiments, 98% or more by weight of the solid is the compound of Formula I. In some embodiments, 99% or more by weight of the solid is the compound of Formula I. In some embodiments, 99. 5% or more by weight of the solid is the compound of Formula I. In some embodiments, 99.9% or more by weight of the solid is the compound of Formula I. In some embodiments, 99.99% by weight of the solid is the compound of Formula I.

[0132] In some embodiments, the term “pure” means 4% or less, more preferably less than 3%, more preferably less than 2% by weight, most preferably less than 1% by weight of compound(s) different than flumetyl sulforim (impurities).

[0133] In some embodiments, the solid comprises 4% or less by weight of impurities. In some embodiments, the solid comprises less than 3% by weight of impurities. In some embodiments, the solid comprises less than 2% by weight of impurities. In some embodiments, the solid comprises less than 1% by weight of impurities. In some embodiments, the solid comprises less than 0.5% by weight of impurities. In some embodiments, the solid comprises less than 0.4% by weight of impurities. In some embodiments, the solid comprises less than 0.3% by weight of impurities. In some embodiments, the solid comprises less than 0.2% by weight of impurities. In some embodiments, the solid comprises less than 0.1% by weight of impurities. In some embodiments, the solid comprisesless than 0.05% by weight of impurities. In some embodiments, the solid comprises less than 0.01% by weight of impurities.

[0134] In some embodiments, the XRPD pattern of the solid comprises characteristic peaks at 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °2θ ± 0.2 °2θ.

[0135] In some embodiments, the XRPD pattern of the solid compound of flumetyl sulforim comprises at least 5, 6, 7, 8, 9, or 10 characteristic peaks selected from the XRPD pattern of FIG. 1 wherein the at least 5, 6, 7, 8, 9, or 10 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

[0136] In some embodiments, the pure solid is a mixture comprising flumetyl sulforim.

[0137] In some embodiments, 96% or more by weight of the mixture is the compound of Formula I. In some embodiments, 97% or more by weight of the mixture is the compound of Formula I. In some embodiments, 98% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99. 5% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99.9% or more by weight of the mixture is the compound of Formula I. In some embodiments, 99.99% by weight of the mixture is the compound of Formula I.

[0138] In some embodiments, the mixture comprises 4% or less by weight of impurities. In some embodiments, the mixture comprises less than 3% by weight of impurities. In some embodiments, the solid comprises less than 2% by weight of impurities. In some embodiments, the mixture comprises less than 1% by weight of impurities. In some embodiments, the mixture comprises less than 0.5% by weight of impurities. In some embodiments, the mixture comprises less than 0.4% by weight of impurities. In some embodiments, the mixture comprises less than 0.3% by weight of impurities. In some embodiments, the mixture comprises less than 0.2% by weight of impurities. In some embodiments, the mixture comprises less than 0.1% by weight of impurities. In some embodiments, the mixture comprises less than 0.05% by weight of impurities. In some embodiments, the mixture comprises less than 0.01% by weight of impurities.

[0139] In some embodiments, the composition comprises (1) a mixture comprising flumetyl sulforim, wherein 96%, more preferably 97%, more preferably 98%, more preferably 99% or more by weight of the mixture is the compound of Formula I having a crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, and (2) at least on agriculture acceptable additive.In some embodiments, the composition comprises solid flumetyl sulforim, having a crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, and (2) at least on agriculture acceptable additive.

[0140] In some embodiments, the agriculture acceptable additive is a dispersant.

[0141] In some embodiments, the fungicidal combination is mixed with at least one additional fungicide.

[0142] In some embodiments, the fungicidal combination comprises at least one additional fungicide.

[0143] In some embodiments, the additional fungicide and the flumetyl sulforim of the present invention, are mixed together in tank and / or are applied separately.

[0144] In some embodiments, the additional fungicide(s) and the flumetyl sulforim of the present invention are applied separately.

[0145] In some embodiments, the additional fungicide(s) and the flumetyl sulforim of the present invention are applied simultaneously.

[0146] In some embodiments, the additional fungicide(s) and the flumetyl sulforim of the present invention are formulated together in a single composition.

[0147] In some embodiments, the additional fungicide(s) and the flumetyl sulforim of the present invention are applied in separate compositions.

[0148] In some embodiments, the mixture of the present invention and the additional fungicide(s) are applied as tank mix.

[0149] In some embodiments, the composition or fungicidal composition of the present invention is a solid composition.

[0150] In some embodiments, the composition or fungicidal composition of the present invention is a liquid composition.

[0151] The composition may be employed or prepared in any conventional form, for example, as wettable powders (WP), emulsion concentrates (EC), microemulsion concentrates (MEC), water-soluble powders (SP), water-soluble concentrates (SL), suspoemulsion (SE), oil dispersions (OD), concentrated emulsions (BW) such as oil-in-water and water-in-oil emulsions, sprayable solutions or emulsions, capsule suspensions (CS), suspension concentrates (SC), suspension concentrates, dusts(DP), oil-miscible solutions (OL), a mixed formulation of CS and SC (ZC), a mixed heterogeneous formulation of CS and SE (ZE), a mixed heterogeneous formulation CS and EW (ZW), seed-dressing products, granules (GR) in the form of microgranules, spray granules, coated granules and absorption granules, granules for soil application or broadcasting, water-soluble granules (SG), water- dispersible granules (WDG), ULV formulations, microcapsules or waxes. These individual formulation types are known in the art.

[0152] In some embodiments, the at least one additional fungicide is a fungicidal sterol biosynthesis inhibitor.

[0153] In some embodiments, the sterol biosynthesis inhibitor is selected from the group consisting of prothioconazole, epoxiconazole, cyproconazole, myclobutanil, prochloraz, metconazole, difenoconazole, tebuconazole, tetraconazole, fenbuconazole, propiconazole, fluquinconazole, flusilazole, flutriafol, and fenpropimorph.

[0154] In some embodiments, the sterol biosynthesis inhibitor is selected from the group consisting of epoxiconazole, cyproconazole, myclobutanil, metconazole, propiconazole, prothioconazole, fluquinconazole, flutriafol, and difenoconazole.

[0155] In some embodiments, the at least one additional fungicide is a succinate dehydrogenase inhibitor.

[0156] In some embodiments, the succinate dehydrogenase inhibitor is selected from the group consisting of fluxapyroxad, benzovindiflupyr, penthiopyrad, isopyrazam, bixafen, boscalid, penflufen, and fluopyram.

[0157] In some embodiments, the succinate dehydrogenase inhibitor is selected from the group consisting of fluxapyroxad, benzovindiflupyr, penthiopyrad, isopyrazam, boscalid, and fluopyram.

[0158] In some embodiments, the at least one additional fungicide is a strobilurin fungicide.

[0159] In some embodiments, the strobilurin fungicide is selected from the group consisting of pyraclostrobin, fluoxastrobin, azoxystrobin, trifloxystrobin, picoxystrobin, and kresoxim-methyl.

[0160] In some embodiments, the at least one additional fungicide is a fungicidal multisite inhibitor.

[0161] In some embodiments, the fungicidal multisite inhibitor is selected from a group consisting of chlorothalonil, mancozeb, folpet, and captan.

[0162] In some embodiments, the fungicidal multisite inhibitor is folpet or captan.In some embodiments, the solid mixture or solid material of the present invention alone, or in combination with at least one additional fungicide provides control of a fungal pathogen and the fungal pathogen is one of Leaf Blotch of Wheat {Mycosphaerella graminicola; anamorph: Septoria tritici), Wheat Brown Rust {Puccinia triticina), Stripe Rust {Puccinia striiformis f. sp. tritici), Scab of Apple {Venturia inaequalis), Blister Smut of Maize {Ustilago may dis), Powdery Mildew of Grapevine {Uncinula necator), Barley scald {Rhynchosporium secalis), Blast of Rice {Magnaporthe grisea), Rust of Soybean {Phakopsora pachyrhizi), Glume Blotch of Wheat {Leptosphaeria nodorum), Powdery Mildew of Wheat {Blumeria graminis f. sp. tritici), Powdery' Mildew of Barley {Blumeria graminis f. sp. hordei), Powdery Mildew of Cucurbits {Erysiphe cichoracearum), Anthracnose of Cucurbits {Glomerella lagenarium), Leaf Spot of Beet (Cercospora beticola), Early Blight of Tomato {Altemaria solani), and Net Blotch of Barley {Pyrenophora teres).

[0163] In some embodiments, the fungus is one of Leaf Blotch of Wheat{Mycosphaerella graminicola; anamorph: Septoria tritici), Wheat Brown Rust {Puccinia triticina), Stripe Rust {Puccinia striiformis f. sp. tritici), Scab of Apple {Venturia inaequalis), Blister Smut of Maize {Ustilago maydis), Powdery Mildew of Grapevine {Uncinula necator), Barley scald {Rhynchosporium secalis), Blast of Rice {Magnaporthe grisea), Rust of Soybean {Phakopsora pachyrhizi), Glume Blotch of Wheat{Leptosphaeria nodorum), Powdery' Mildew of Wheat {Blumeria graminis f. sp. tritici), Powdery Mildew of Barley {Blumeria graminis f. sp. hordei), Powdery Mildew of Cucurbits {Erysiphe cichoracearum), Anthracnose of Cucurbits {Glomerella lagenarium), Leaf Spot of Beet{Cercospora beticola), Early Blight of Tomato {Altemaria solani ), and Net Blotch of Barley {Pyrenophora teres).

[0164] Method for controlling a fungal attack

[0165] The present invention further provides a method for the control of fungal attack on a plant, the method comprising:

[0166] (1) obtaining a pure solid of flumetyl sulforim, (2) formulating the pure solid, (3) diluting the formulated pure solid in water and) applying the to a locus of the fungus, to a locus in which the infestation is to be prevented, and / or to the plant, so as to thereby control fungal attack on the plant.

[0167] In some embodiments, the composition and / or method of the present invention may further comprise other solid form of flumetyl sulforim as disclosed in WO2019 / 038583 and WO2022 / 234487, the content of which is hereby incorporated by reference.Process

[0168] The present invention provides a process for obtaining the pure solid comprising flumetyl sulforim as described herein.

[0169] In some embodiments, the pure solid is a mixture, as described herein.

[0170] In some embodiments, the process for obtaining a pure solid comprising flumetyl sulforim having crystalline polymorphic form which exhibits an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, with 4% or less by weight of compounds different than flumetyl sulforim (impurities), comprises obtaining a slurry of the solid in solution of acetonitrile in water.

[0171] In some embodiments, the slurry is stirred at a temperature of about 40° C.

[0172] In some embodiments, the slurry is stirred at about 40° C-50° C.

[0173] In some embodiments, the slurry is stirred at RT.

[0174] In some embodiments, the slurry is stirred for at least 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h up to 48 hr.

[0175] In some embodiments, the slurry is obtained by introducing to acetonitrile and water Flumetyl sulforim that was prepared in a process comprising the alkylation of 4- Amino-5 -fluoro- 1-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone as described in WO 2015 / 103142 and WO 2015 / 103144, the content of which is incorporated herein by reference.

[0176] In some embodiments, when the slurry is obtained by introducing to acetonitrile and water Flumetyl sulforim that was prepared in a process comprising the alkylation of 4- Amino-5 -fluoro- 1-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone, the slurry is stirred for 2.5h to about 12h.

[0177] In some embodiments, when the slurry is obtained by introducing to acetonitrile and water Flumetyl sulforim that was prepared in a process comprising the alkylation of 4- Amino-5 -fluoro- 1-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone, the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is higher than 2.1:1. In some embodiments, the weight ratio is higher than 2.4:1, 2.6:1, 3:1, 3.1:1, 4:1, 5:1, 5.4:1 or 6:1. In some embodiments, the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is between 2.2:1 to 10:1. In some embodiments, the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is between 2.3:1 to 10:1. In some embodiments, the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is between 2.4:1 to 10:1. In some embodiments, the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is between 2.4:1 to 9:1. In some embodiments, the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is between 2.4:1 to 8:1. In some embodiments, the weight ratio is between 2.4:1 to 7:1. In some embodiments, the weight ratio is between 2.4:1 to 6:1. In some embodiments, the weight ratio is between 2.4:1 to 7:1. In some embodiments, the weight ratio is between 2.4:1 to 5.4:1.

[0178] In some embodiments, when the slurry is obtained by introducing to acetonitrile and water Flumetyl sulforim that was prepared in a process comprising the alkylation of 4- Amino-5 -fluoro- 1-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone, and the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is higher than 2.1:1, the slurry is stirred for at least about 2.5h. In some embodiments, the slurry is stirred at between RT to about 40°C.

[0179] In some embodiments, when the slurry is obtained by introducing to acetonitrile and water pure flumetyl sulforim that was prepared in a process comprising the alkylation of 4- Amino-5 -fluoro- 1-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone, and the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is less than 2.1:1, the slurry is stirred at about 40° C for at least 8h, 9h, or lOh, for example 8-24 h or 10-24h or 12-24.

[0180] In some embodiments, when the slurry is obtained by introducing to acetonitrile and water flumetyl sulforim that was prepared in a process comprising the alkylation of 4- Amino-5 -fluoro- 1-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone, and the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is higher than 2.1:1, for example between 2.2:1-10:1, such as 2.4:1, 2.6:1, 3: 1, 3.1:1, 4: 1, 5:1, 5.4:1 or 6:1, the slurry is stirred for about 2.5h at RT.

[0181] In some embodiments, when the slurry is obtained by introducing to acetonitrile and water Flumetyl sulforim that was prepared in a process comprising the alkylation of 4- Amino-5 -fluoro- 1-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone, and the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is higher than 2.1:1, for example between 2.2:1-10:1, such as 2.4:1, 2.6:1, 3: 1, 3.1:1, 4: 1, 5:1, 5.4:1 or 6:1, the slurry is stirred for about 2.5h at 40°C.In some embodiments, when the slurry is obtained by introducing to acetonitrile and water pure flumetyl sulforim that was prepared in a process comprising the alkylation of 4- Amino-5 -fluoro- 1-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone, and the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is less than 2.1:1, the slutty is stirred overnight at about 40°C. In some embodiments, when the slurry is stirred for 12 h at about 40°C.

[0182] In some embodiments, when the slurry is obtained by introducing to acetonitrile and water pure flumetyl sulforim that was prepared in a process comprising the alkylation of 4- Amino-5 -fluoro- 1-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone, and the weight ratio between the acetonitrile and the 4-Amino-5-fluoro-l-[(4-methylphenyl)sulfonyl]-2(lH)-Pyrimidinone is less than 2.1:1, the slutty is stirred overnight at about 50°C. In some embodiments, when the slurry is stirred for 12 h at about 50°C.

[0183] In some embodiments, the slurry is obtained by introducing Flumetyl sulforim Form I or Form III in acetonitrile and water. In some embodiments, Flumetyl sulforim Form I or Form III are prepared as described for example in WO 2019 / 038583 and WO 2022 / 234487, respectively, the content of which is incorporated herein by reference.

[0184] In some embodiments, when the slurry is obtained by introducing Flumetylsulforim Form I or Form III in acetonitrile and water, the slurry is stirred at 40° C. In some embodiments the slurry is stirred for 12h to 48h. In some embodiments the slurry is stirred overnight. In some embodiments the slurry is stirred for 48h.

[0185] In some embodiments, when the slurry is obtained by introducing Flumetylsulforim Form I or Form III in acetonitrile and water, the weight ratio between the acetonitrile and the Flumetylsulforim is between 2.1:1 to 10:1. In some embodiments, when the slurry is obtained by introducing Flumetylsulforim Form I or Form III in acetonitrile and water, the weight ratio between the acetonitrile and the Flumetylsulforim is between 2.2:1 to 10:1. In some embodiments, when the slurry is obtained by introducing Flumetylsulforim Form I or Form III in acetonitrile and water, the weight ratio between the acetonitrile and the Flumetylsulforim is between 2.2:1 to 9:1. In some embodiments, when the slurry is obtained by introducing Flumetylsulforim Form I or Form III in acetonitrile and water, the weight ratio between the acetonitrile and the Flumetylsulforim is between 2.2:1 to 8:1. In some embodiments, when the slurry is obtained by introducing Flumetylsulforim Form I or Form III in acetonitrile and water, the weight ratio between the acetonitrile and the Flumetylsulforim is between 2.2:1 to 7:1. In some embodiments, when the slurry is obtained byintroducing Flumetyl sulforim Form I or Form III in acetonitrile and water, the weight ratio between the acetonitrile and the Flumetyl sulforim is between 2.2:1 to 6:1. In some embodiments, when the slurry is obtained by introducing Flumetylsulforim Form I or Form III in acetonitrile and water, the weight ratio between the acetonitrile and the Flumetylsulforim is between 2.2:1 to 5:1. In some embodiments, when the slurry is obtained by introducing Flumetylsulforim Form I or Form III in acetonitrile and water, the weight ratio between the acetonitrile and the Flumetylsulforim is between 2.2:1 to 4:1. In some embodiments, when the slurry is obtained by introducing Flumetylsulforim Form I or Form III in acetonitrile and water, the weight ratio between the acetonitrile and the Flumetylsulforim is between 2.4:1 to 3.1:1.

[0186] In some embodiments, when the slurry is obtained by introducing Flumetylsulforim Form I or Form III in acetonitrile and water, the weight ratio between the water and the Flumetylsulforim is between 6:1 to 7:1.

[0187] In some embodiments, the slurry is stirred overnight at about RT - 40° C. In some embodiments, the slurry is stirred for 8h-48h at about 40° C-50° C.

[0188] In some embodiments, the slurry is stirred for a time sufficient to achieve a pure solid of flumetylsulforim having crystalline polymorphic form exhibiting an XRPD pattern having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 16.0, °29 ± 0.2 °29 with polymorphic purity of at least 80%. For instance at least 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h up to 48 hr at about 40 - 500C. In some embodiments, the slurry is stirred at about 400C.

[0189] In some embodiments, the process is a purification process for obtaining a pure solid comprising flumetylsulforim having crystalline polymorphic form which exhibits an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, the purification process comprising a slurry of flumetylsulforim in a solution of acetonitrile in water, where the ratio between the solution to flumetylsulforim is at least 9:1. In some embodiments, the ratio between the solution to flumetylsulforim is between 9: 1 to 20: 1.

[0190] The term “pure” means 96%, more preferably 97%, more preferably 98%, most preferably 99% or more by weight of flumetylsulforim.

[0191] In some embodiments, the weight ratio between the solution of acetonitrile in water to flumetylsulforim is between 9: 1 to 20: 1. In some embodiments, the weight ratio between the solution of acetonitrile in water to flumetylsulforim is at least 10:1. In some embodiments, the weight ratio between the solution of acetonitrile in water to flumetylsulforim is at least 9: 1 In some embodiments,the weight ratio between the solution of acetonitrile in water to flumetyl sulforim is about 20:1. In some embodiments, the weight ratio between the solution of acetonitrile in water to flumetyl sulforim is about 10: 1. In some embodiments, the weight ratio between the solution of acetonitrile in water to flumetyl sulforim is about 9:1.

[0192] Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention. In addition, when lists are provided, the list is to be considered as a disclosure of any one member of the list.

[0193] While the present subject matter has been shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that many alternatives, modifications and variations may be made thereto without departing from the spirit and scope thereof. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0194] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference.

[0195] The following examples illustrate the practice of the present subject matter in some of its embodiments but should not be construed as limiting the scope of the present subject matter. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. It is intended that the specification, including the examples, is considered exemplary only, without limiting the scope and spirit of the present subject matter.

[0196] EXPERIMENTAL DETAILS

[0197] Compound I may be prepared using any process, including but not limited to those that are described in PCT International Application Nos. PCT / US2014 / 072566, PCT / US2014 / 072569, PCT / IB2020 / 058893 and PCT / IB2021 / 051957.

[0198] The crystalline form which exhibits an XRPD pattern, having characteristic peaks at 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °20± 0.2 °20 can be prepared as describedin WO / 2015 / 103142 or WO / 2015 / 103144.The XRPD patterns were recorded at room temperature using copper Ka radiation on a PANalytical X'Pert Pro powder diffractometer model PW3050 / 60 in Bragg-Brentano geometry (9 / 29) equipped with a point detector. The samples were prepared by mounting few milligrams of the sample on spinner PW3064 a Zero Background Holder, spinning 8 / sec. and scanned from 4 to 49 29, using the following acquisition parameters: generator tension 49 kV, generator current 39 mA, step size 9.94, country time (s) 2,99 sec, scan mode continous, number of steps 1925 and total time 34 min.

[0199] Purity of compounds was determined by normalization in HPLC. HPLC analysis was carried out on Dionex UHPLC Ultimate 3000 with DAD detector with column Kinetex® 2.6 pm XB-C18 (4.6x50mm), IlOA, column no. 00B-4496-E0. Conditions: 0.1% (v / v) formic acid in water / 0.1% (v / v) formic acid in acetonitrile =95 / 5 to 5 / 95, flow rate = 1 mL / min, 235 nm).

[0200] Polymorphic purity method:

[0201] Quantitation of crystal forms can be done by X-Ray powder diffraction by calculating the intensity ratio of any suitable peak of any crystal form of flumetyl sulforim and any suitable peak of flumetyl sulforim having crystalline polymorphic form exhibiting an XRPD pattern having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0, °29 ± 0.2 °29, as known by the skilled-in-the-art. Due to possible preferred orientation effects, peak intensities may slightly vary between measurements. For instance, form III may be quantitated.

[0202] Quantitation is done using a calibration curve. Mixtures used for calibration may be for instance, 3%, 5%, 7%, 10%, 15%, 20% (or any relevant mixture) form III. The intensity ratios of the most suitable peak of form III and flumetyl sulforim having crystalline polymorphic form exhibiting an XRPD pattern having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0, °29 ± 0.2 °29 are calculated.

[0203] A suitable peak of form III is found at about 9.1 or 11.8 ± 0.2° 29, for instance.

[0204] Example 1:

[0205] To a mixture of 4-amino-5-fluoro-l-tosyipyrimidin-2(lJ7)-one (21.95 g, 77.49 mmol, 1.00 eq) and Li2CO3(3.44 g, 46.49 mmol, 0.6 eq) in DMF (77.0 mL) was added Mel (14.5 mL, 32.99 g, 232.46 mmol, 3.00 eq) and stirred 5 h at 40°C. The reaction mixture was cooled to room temperature, diluted with MeCN (38 mL) and treated with 2.5% aqueous Na2S2O3(77 mL). The resulting mixture wasstirred at room temperature for 10 min and the solids were collected by filtration. The filter cake was washed with 10% MeCN in H2O (500 mL) and air dried for 2 h on filter.

[0206] All the dried filter cake obtained was dissolved in MeCN (150 mL) at 40°C and the solution was treated with H2O (300 mL). Then, the solution was cooled to room temperature and stirred for 2.5 h. Solid was filtered and filter cake washed with 10% MeCN in H2O (500 mL) and dried on rotavapor at 50°C for 3 h. Flumetyl sulforim was obtained in purity 96.5%.

[0207]

[0208] 2:

[0209] 2 g of flumetyl sulforim, prepared according to example 1 (purity 96.5%), in 30% MeCN in H2O (20 mL) was stirred at 40°C overnight. Precipitate was filtered, washed with 30% MeCN in H2O (20 mL), and dried on rotavapor at 50°C for 2 h. Flumetyl sulforim was obtained in purity 98.7%.

[0210]

[0211] 3:

[0212] 2 g of flumetyl sulforim prepared according to example 1 (purity 96.5%), in 20% MeCN in H2O (20 mL) was stirred at 40°C overnight. Precipitate was filtered, washed with 20% MeCN in H2O (20 mL), and dried on rotavapor at 50°C for 2 h. 5 Flumetyl sulforim was obtained in purity 97.9%.

[0213]

[0214] 4:

[0215] 2 g of flumetyl sulforim, prepared according to example 1 (purity 96.5%), in 10% MeCN in H2O (20 mL) was stirred at 40°C overnight. Precipitate was filtered, washed with 10% MeCN in H2O (20 mL), and dried on rotavapor at 50°C for 2 h. Flumetyl sulforim was obtained in purity 97.4%.

[0216]

[0217] 5:

[0218] 2 g flumetyl sulforim (Form I with purity 99.8%, prepared as described in WO2019038583) in solution 33% MeCN in H2O (20 mL) was stirred at 40°C overnight. Precipitate was filtered, washed with 33% MeCN in H2O (20 mL), and dried on rotavapor at 50°C for 2h. flumetyl sulforim was obtained in purity 99.2%.

[0219]

[0220] 6:

[0221] 500 mg flumetyl sulforim (Form III with purity 99.3%, prepared as described in WO2022234487) was suspended in 30% ACN / water (5 ml) and the resulting suspension was stirred at 50°C over 48 h, then cooled to RT. It was filtered through a sintered glass funnel, washed with 30% ACN / water (5 ml), and dried in vacuo at 50 °C for 2 h. Flumetyl sulforim was obtained in purity 99.8%.Example 7:

[0222] 500 mg flumetyl sulforim (Form III with purity 99.3%, prepared as described in WO2022234487) was suspended in 40% ACN / water (5 ml) and the resulting suspension was stirred at 40°C over 48 h, then cooled to RT. It was filtered through a sintered glass funnel, washed with 40% ACN / water (5 ml), and dried in vacuo at 50 °C for 2 h. Flumetyl sulforim was obtained in purity 99.2%.

[0223] Example 8:

[0224] To a mixture of 5-fhioro-4-imino-3-methyl-l-tosyl-3,4-dihydropyrimidin-2(lJ7)-one (21.95 g, 77.49 mmol, 1 eq.) and Li2CO3(3.44 g, 46.49 mmol, 0.6 eq.) in DMF (77 ml) Mel (14.5 ml, 32.99 g, 232.46 mmol, 3 eq.) was added. The resulting mixture was stirred for 5 h at 40 °C. It was cooled to RT, diluted with ACN (38 ml), and Na2S2O3(2.5% aq., 77 ml) was added. The resulting mixture was stirred for 10 min, filtered, and the resulting solid was washed with 10% ACN / water (500 ml) and air-dried for 2 h. The obtained solid was dissolved in ACN (150 ml) at 40 °C and water (30 ml) was added. The resulting suspension was stirred for 2.5 h at 40 °C, cooled to RT, and filtered. The resulting solid was washed with 10% ACN / water (500 ml) and dried at 50 °C for 3 h. Flumetyl sulforim was obtained in purity 99.1%.

[0225] All solids of example 1-8, display an XRPD pattern substantially in accordance with the pattern of FIG. 1

Claims

CLAIMS1. A pure solid comprising flumetyl sulforim wherein the solid comprises 4% or less by weight of impurities and has a crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

2. The pure solid of claim 1, wherein the XRPD pattern comprises at least 6, 7, 8, 9, or 10 characteristic peaks selected from a group comprising of 5.3, 7.5, 8.8, 10.7, 13.6, 14.5, 16.0, 18.0, 18.6, 22.9 °29 ± 0.2 °29, wherein the at least 6, 7, 8, 9, or 10 characteristic peaks include the peaks 8.8 and / or 13.6 and / or 14.5.

3. The pure solid of claim 1, having an XRPD pattern substantially as depicted in FIG. 1.

4. A pure solid mixture comprising flumetyl sulforim, wherein 96% or more by weight of the mixture is flumetyl sulforim having a crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ.

5. A combination of (1) a solid comprising flumetyl sulforim, wherein the solid comprises 4% or less by weight impurities and having a crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, and (2) one or more carriers.

6. A composition comprising (1) a solid comprising flumetyl sulforim having a crystalline polymorphic form exhibiting an XRPD pattern, having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °20 ± 0.2 °29 and (2) at least on agriculture acceptable additive.

7. A process for obtaining a pure solid comprising flumetyl sulforim having a crystalline polymorphic form exhibiting an X-ray powder diffraction pattern having characteristic peaks at 5.3, 8.8, 10.7, 14.5, 18.0 °2θ ± 0.2 °2θ, with 4% or less by weight of impurities, the process comprising obtaining slurry of the solid in solution of acetonitrile in water.

8. A method for the control of fungal attack on a plant, the method comprising: (1) obtaining the pure solid of any one of claims 1-4, (2) formulating the pure solid, (3) diluting the formulated pure solid in water and (4) applying the to a locus of the fungus, to a locus in which the infestation is to be prevented, and / or to the plant, so as to thereby control fungal attack on the plant.

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