Polymorphs of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidin-2-one

Abstract

To provide a fungicide for controlling fungal attack on plants.SOLUTION: A crystalline form of a compound having the following structure is provided. The crystalline form of the compound of formula (I) includes (a) Form II having a powder X-ray diffraction pattern comprising characteristic peaks at 2-theta angles of 9.20, 11.88, 22.33, and 22.59; (b) a hydrate having a powder X-ray diffraction pattern comprising characteristic peaks at 2-theta angles of 5.34, 7.48, 10.68, and 16.05; and (c) a solvate containing 1,4-dioxane, tetrahydrofuran, or ethyl acetate.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application is the benefit of U.S. Provisional Patent Application No. 62 / 533,509, filed July 17, 2017. The benefit of which is claimed, the contents of which are specifically incorporated herein by reference.

[0002] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are incorporated herein by reference. Reference is hereby made to this application for a more complete description of the state of the art to which this invention pertains. It is incorporated as. [Background technology]

[0003] Fungicides are natural or synthetic compounds that act to protect plants from damage caused by fungi. are compounds of synthetic origin. Current agricultural practices rely heavily on the use of fungicides. In fact, some crops cannot be grown usefully without the use of fungicides. By doing so, farmers can increase the yield and quality of their crops, resulting in In many cases, the increase in the value of agricultural products is due to the use of fungicides. It is worth at least three times the cost of 5-fluoro-4-imino-3-methyl- 1-Tosyl-3,4-dihydropyrimidin-2(1H)-one is an important plant stimulator of economically important agricultural crops. It is a fungicide that provides control of a variety of pathogens in wheat, including wheat leaf blight. disease, Septoria tritici, (SEPTTR), and These include pathogens of diseases caused by fungi of the classes Ascomycota and Basidiomycota. , but not limited to these. Summary of the Invention [Means for solving the problem]

[0004] The present invention relates to a compound having the following structure: [ka] The present invention provides a crystalline form of a compound having the formula:

[0005] The present invention also provides a structure [ka] Also provided is a fungicidal composition comprising a solution of a compound having the formula:

[0006] The present invention further provides a method for controlling fungal attack on roots and / or seeds and / or plants. The method is as follows: i) Structure [ka] obtaining a solution of a compound having ii) Applying the solution to the roots, seeds or foliage of the plants at the places where infestation is to be prevented and / or to the plants. spraying, thereby controlling fungal attack on the roots and / or seeds and / or plants. Equipped with.

[0007] The present invention still further provides a method for controlling fungal attack on a plant, the method comprising: i) the following structure: [ka] obtaining a crystalline form of a compound having the formula: ii) spraying the crystalline form on the site where the fungus is present, on the site to be prevented from infestation, and / or on the plants; and thereby controlling fungal attack on the plant. Equipped with. [Brief explanation of the drawings]

[0008] [Figure 1] 1 is an X-ray powder diffraction spectrum of Form I. [Figure 2] TG-FTIR of Form I. [Figure 3] 1 is a differential scanning calorimetry (DSC) thermogram of Form 1. [Figure 4] 1 is an X-ray powder diffraction spectrum of Form II. [Figure 5] TG-FTIR of Form II. [Figure 6] 1 is a differential scanning calorimetry (DSC) thermogram of Form II. [Figure 7] 1 is an X-ray powder diffraction spectrum of the hydrate. [Figure 8] TG-FTIR of the hydrate. [Figure 9] 1 is a differential scanning calorimetry (DSC) thermogram (closed pan) of the hydrate. [Figure 10] 1 is a differential scanning calorimetry (DSC) thermogram (open pan) of the hydrate. [Figure 11] 1 is an X-ray powder diffraction spectrum of solvated S5. [Figure 12] TG-FTIR thermogram of solvated S5. [Figure 13] 1 is an X-ray powder diffraction spectrum of solvated S8. [Figure 14] TG-FTIR thermogram of solvated S8. [Figure 15] 1 is an X-ray powder diffraction spectrum of solvated S1. [Figure 16] TG-FTIR thermogram of solvated S1. DETAILED DESCRIPTION OF THE INVENTION

[0009] The present invention relates to a compound having the following structure: [ka] 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyridine This relates to the crystalline form of mydin-2(1H)-one.

[0010] In one embodiment, 5-fluoro-4-imino-3-methyl-1-tosyl-3,4- Anhydrous crystalline form of dihydropyrimidin-2(1H)-one.

[0011] In one embodiment, 5-fluoro-4-imino-3-methyl-1-tosyl-3,4- Polymorphs of dihydropyrimidin-2(1H)-one.

[0012] In one embodiment, 5-fluoro-4-imino-3-methyl-1-tosyl-3,4- Hydrate of dihydropyrimidin-2(1H)-one.

[0013] In one embodiment, 5-fluoro-4-imino-3-methyl-1-tosyl-3,4- Solvates of dihydropyrimidin-2(1H)-one.

[0014] In one embodiment, the solvate contains 1,4-dioxane.

[0015] In one embodiment, the solvate contains tetrahydrofuran.

[0016] In one embodiment, the solvate contains ethyl acetate.

[0017] In one embodiment, 5-fluoro-4-imino-3-methyl-1-tosyl-3,4- Pseudopolymorphs of dihydropyrimidin-2(1H)-one.

[0018] These polymorphs, solvates and hydrates can be analyzed by their X-ray diffraction patterns, differential scanning calorimetry, Distinct spectral characteristics shown by DSC thermograms and FTIR thermograms It exhibits sexuality.

[0019] In one embodiment, the present invention provides a crystalline polymorphic form designated "Form I" Form I: 9.08, 10.98, 14.05, 17.51, 18.75, 21. 63, 23.33, 24.70, 24.83, 25.37, 26.51 and 29.23 It exhibits the X-ray powder diffraction pattern shown in Figure 1, with characteristic peaks at 2-theta angle values. In an embodiment, the powder X-ray diffraction pattern of Form I is 14.05, 17.51, 1 It includes characteristic peaks at 2-theta angle values ​​of 8.75, 21.63, and 26.51. In the powder X-ray diffraction pattern of Form I, It contains characteristic peaks at 2-theta angle values ​​of 5 and 21.63.

[0020] Form I also exhibits the TG-FTIR thermogram shown in Figure 2, which shows that It is characterized by decomposition that begins at temperatures above

[0021] Form I also exhibits the differential scanning calorimetry (DSC) thermogram shown in Figure 3, which A prominent endothermic peak with a peak temperature of about 160°C, a prominent endothermic peak with an onset temperature of about 159°C A prominent endothermic peak and a prominent endothermic peak with a fusion enthalpy of approximately 110 J / g It can be characterized as follows.

[0022] In one embodiment, the present invention provides a crystalline polymorphic form designated "Form II." Form II is 7.98, 9.20, 9.96, 11.88, 15.99, 18. Characteristic peaks at 2-theta angle values ​​of 49, 21.23, 22.33, 22.59, and 26.73 4, having the X-ray powder diffraction pattern shown in FIG. The powder X-ray diffraction pattern of II is 9.20, 9.96, 11.88, 22.33 and 22 In one embodiment, the powder of Form II contains a characteristic peak at a 2-theta angle value of 0.59. The X-ray diffraction pattern shows 2-theta positions at 9.20, 11.88, 22.33 and 22.59. Including characteristic peaks at angle values.

[0023] Form II also exhibits the TG-FTIR thermogram shown in Figure 5, which shows that at 210°C It is characterized by decomposition that begins at temperatures above

[0024] Form II also exhibits the differential scanning calorimetry (DSC) thermogram shown in Figure 6. has a pronounced endothermic peak with a peak temperature of about 157°C, an onset temperature of about 156°C A prominent endothermic peak and a prominent endothermic peak with a melting enthalpy of approximately 112 J / g More characterized.

[0025] In one embodiment, the present invention provides a crystalline hydrated form, referred to as a "hydrate." Japanese products: 5.34, 7.48, 10.68, 16.05, 21.79, 22.99, 23 with characteristic peaks at 2-theta angle values ​​of .19, 24.95, 26.95, and 27.63; The X-ray powder diffraction pattern of the hydrate is shown in FIG. The fold patterns are 5.34, 7.48, 10.68, 16.05 and 21.79 2-seat In one embodiment, the powder X-ray diffraction pattern of the hydrate comprises characteristic peaks at It contains characteristic peaks at 2-theta angle values ​​of 5.34, 7.48, 10.68 and 16.05.

[0026] The hydrate also exhibits the TG-FTIR thermogram shown in Figure 8, which shows that the It is characterized by decomposition that begins at a certain temperature.

[0027] The hydrate also exhibits the differential scanning calorimetry (DSC) thermogram shown in Figure 9, which shows approximately A prominent endothermic peak with a peak temperature of 139.5°C, a prominent endothermic peak with an onset temperature of about 139°C A prominent endothermic peak and a prominent endothermic peak with a melting enthalpy of about 115 J / g The DSC is measured in a sealed pan.

[0028] The hydrate also exhibits the differential scanning calorimetry (DSC) thermogram shown in Figure 10, which shows: A prominent endothermic peak with a peak temperature of about 160°C, a prominent endothermic peak with an onset temperature of about 159°C It is characterized by a prominent endothermic peak and a melting enthalpy of about 98 J / g. The DSC is measured in an open pan.

[0029] In one embodiment, the present invention provides a crystalline solvate designated "Form S5." FormS5 is available in 5.42, 7.50, 10.06, 10.82, 12.80, and 1 2-theta: 6.91, 21.55, 23.13, 24.83, 26.81, 27.77 The compound exhibits an X-ray powder diffraction pattern shown in FIG. 11, with characteristic peaks at angle values. In the powder X-ray diffraction pattern of Form S5, It includes characteristic peaks at 2-theta angle values ​​of 10.82 and 16.91. , the powder X-ray diffraction pattern of Form S5 shows 5.42, 7.50, 10.82 and 16. It contains a characteristic peak at a 2-theta angle value of 91.

[0030] Form S5 also exhibits the TG-FTIR thermogram shown in Figure 12, which shows It is characterized by decomposition that begins at temperatures above 100°C.

[0031] In one embodiment, the present invention provides a crystalline solvate designated "FormS8." FormS8 is 4.7, 5.00, 5.38, 6.26, 9.66, 15.93 , with characteristic peaks at 2-theta angle values ​​of 21.05, 23.97, and 24.69, Fig. 13 In one embodiment, the powder X-ray diffraction pattern of Form S8 is The diffraction pattern is at 2-theta angles of 4.7, 5.00, 5.38, 6.26 and 23.97. In one embodiment, the powder X-ray diffraction pattern of S8 includes a characteristic peak at a value of 4.7 , containing characteristic peaks at 2-theta angle values ​​of 5.00, 9.66 and 23.97.

[0032] Form S8 also exhibits the TG-FTIR thermogram shown in Figure 14, which shows It is characterized by decomposition that begins at temperatures above 100°C.

[0033] In one embodiment, the present invention provides a crystalline solvate designated "Form S1." FormS1 is available in 5.34, 7.48, 10.10, 10.68, 12.90, and 1 Characteristic peaks at 2-theta angle values ​​of 6.07, 21.83, 23.09, 24.91, and 26.93 The X-ray powder diffraction pattern shown in FIG. 15 has a peak. The powder X-ray diffraction pattern of ormS1 showed 2-seq at 5.34, 7.48, and 10.68. In one embodiment, the powder X-ray diffraction pattern of Form S1 includes characteristic peaks at various angles. The ion exhibits characteristic peaks at 2-theta angle values ​​of 5.34, 7.48, 10.68, and 21.83. In one embodiment, the powder X-ray diffraction pattern of Form S1 is 5.34, 7. It contains characteristic peaks at 2-theta angle values ​​of 48, 10.68, 16.07 and 21.83.

[0034] Form S1 also exhibits the TG-FTIR thermogram shown in Figure 16, which shows that It is characterized by decomposition that begins at temperatures above 100°C.

[0035] In some embodiments, the structure: [ka] A mixture of crystalline forms of a compound having the formula: .

[0036] In some embodiments, the structure: [ka] The mixture of crystalline forms of the compound having the formula (I) is a mixture of one or more anhydrous crystalline forms of the present invention. be.

[0037] In some embodiments, the structure: [ka] The mixture of crystalline forms of the compound having the formula: is a mixture of crystalline form I and crystalline form II.

[0038] In some embodiments, the mixture is at least 25% crystalline Form I.

[0039] In some embodiments, the mixture is at least 50% crystalline Form I.

[0040] In some embodiments, the mixture is at least 75% crystalline Form I.

[0041] In some embodiments, the structure: [ka] The mixture of crystalline forms of the compound having the formula: is a mixture of crystalline Form I and a crystalline hydrated form.

[0042] In some embodiments, the mixture is at least 25% crystalline Form I.

[0043] In some embodiments, the mixture is at least 50% crystalline Form I.

[0044] In some embodiments, the mixture is at least 75% crystalline Form I.

[0045] In some embodiments, the structure: [ka] The mixture of crystalline forms of the compound having the formula: is a mixture of crystalline Form II and a crystalline hydrated form.

[0046] In some embodiments, the mixture is at least 25% crystalline Form II.

[0047] In some embodiments, the mixture is at least 50% crystalline Form II.

[0048] In some embodiments, the mixture is at least 75% crystalline Form II.

[0049] In some embodiments, the fungicidal mixture comprises one or more crystalline forms of the present invention. nothing.

[0050] In some embodiments, the fungicidal mixture comprises a crystalline polymorph, solvate or Includes hydrates.

[0051] In some embodiments, a bactericidal amount of a polymorph, solvate, or hydrate of the present invention is A fungicidal mixture comprising:

[0052] In some embodiments, the fungicidal mixture comprises a crystalline polymorph, solvate or hydrate and one or more fungicidal carriers.

[0053] In some embodiments, the crystalline polymorphs, solvates or hydrates of the present invention comprise at least Each is mixed with a minimum amount of one additional fungicide.

[0054] In some embodiments, the crystalline polymorphs, solvates or hydrates of the present invention comprise at least Both are mixed with one excipient.

[0055] In some embodiments, the fungicidal mixture of the present invention comprises at least one additional fungicidal agent. Contains antifungal agents.

[0056] In some embodiments, the mixture or fungicidal mixture of the present invention is a tank mix. is.

[0057] In some embodiments, the components of the mixtures or fungicidal mixtures of the present invention are dispersed separately. It will be distributed.

[0058] In some embodiments, the components of the mixture or fungicidal mixture of the present invention are dispersed simultaneously. It will be distributed.

[0059] In some embodiments, the components of the mixtures or fungicidal mixtures of the present invention are present in a single composition. They are scattered together as objects.

[0060] In some embodiments, the components of the mixtures or fungicidal mixtures of the present invention are in separate compositions. It is sprayed as a compound.

[0061] In some embodiments, the tank mix contains one or more crystalline forms of the present invention. and at least one or more other pesticidal compounds.

[0062] In some embodiments, the tank mix further comprises at least one excipient. include.

[0063] In some embodiments, the mixture or fungicidal mixture of the present invention is a solid mixture. do.

[0064] In some embodiments, the mixture or fungicidal mixture of the present invention is a liquid mixture. do.

[0065] In some embodiments, the fungicidal mixture of the present invention comprises at least one additional fungicidal agent. Further includes a fungicide.

[0066] In some embodiments, the composition comprises a crystalline polymorph, solvate, or hydrate of the present invention. Includes.

[0067] In some embodiments, the fungicidal composition comprises a crystalline polymorph, solvate or Includes hydrates.

[0068] In some embodiments, the composition comprises a mixture of the present invention.

[0069] In some embodiments, the fungicidal composition comprises a mixture of the present invention.

[0070] In some embodiments, a bactericidal amount of a polymorph, solvate, hydrate or A fungicidal composition is provided that includes the mixture.

[0071] In some embodiments, the fungicidal composition comprises a crystalline polymorph, solvate or hydrate and one or more fungicidal carriers.

[0072] In some embodiments, the composition or fungicidal composition comprises at least one excipient Further includes:

[0073] In some embodiments, the composition or fungicidal composition is prepared in a tank mix. The composition further comprises at least one excipient.

[0074] In some embodiments, the composition or fungicidal composition of the present invention is a solid composition. do.

[0075] In some embodiments, the compositions or fungicidal compositions of the present invention are liquid compositions. do.

[0076] In some embodiments, the fungicidal compositions of the present invention comprise at least one additional fungicidal agent. Further includes a fungicide.

[0077] In some embodiments, the at least one additional fungicide is a fungicidal steroid. It is an inhibitor of benzodiazepine biosynthesis.

[0078] In some embodiments, the sterol biosynthesis inhibitor is prothioconazole, ethoxybenzone, benzophenone-3, benzodiazepine ...phenone-3, benzophenone-3, benzophenone-3, benzophenone-3, benzophenone-3, benzophenone-3, Poxiconazole, cyproconazole, myclobutanil, prochloraz, metconazole , difenoconazole, tebuconazole, tetraconazole, fenbuconazole, pro Piconazole, fluquinconazole, flusilazole, flutriafol, and fenflurazole is selected from the group consisting of lopimorph.

[0079] In some embodiments, the sterol biosynthesis inhibitor is epoxiconazole, cinnamoyl Proconazole, myclobutanil, metconazole, propiconazole, prothioconazo from the group consisting of fluquinconazole, flutriafol, and difenoconazole be selected.

[0080] In some embodiments, the at least one additional fungicide is succinaldehyde. It is an arginase inhibitor.

[0081] In some embodiments, the succinate dehydrogenase inhibitor is fluxapyroxine. Sado, Benzovindiflupyr, Penthiopyrad, Isopyrazam, Bixafen, Boscali The compound is selected from the group consisting of fluopyram, penflufen, and fluopyram.

[0082] In some embodiments, the succinate dehydrogenase inhibitor is fluxapyroxine. Sado, benzovindiflupyr, penthiopyrad, isopyrazam, boscalid, and fluo pyrams.

[0083] In some embodiments, the at least one additional fungicide is a strobilurin. It is a fungicide.

[0084] In some embodiments, the strobilurin fungicide is pyraclostrobin, fluorouracil, Ruoxastrobin, azoxystrobin, trifloxystrobin, picoxystrobin and kresoxim-methyl.

[0085] In some embodiments, the at least one additional fungicide is a fungicidal multisodium It is a thrombus inhibitor.

[0086] In some embodiments, the fungicidal multi-site inhibitor is chlorothalonil, mannitol, Selected from the group consisting of cozeb, folpet, and captan.

[0087] In some embodiments, the fungicidal multi-site inhibitor is folpet or cayenne It's Putan.

[0088] In some embodiments, the crystalline polymorphs, solvates, or hydrates of the present invention may be used alone. or the crystalline polymorph, solvate or hydrate of the present invention with at least one additional fungicide. In combination with the agent, it provides control of fungal pathogens, and the fungal pathogen is wheat leaf blight (L Leaf Blotch of Wheat) Mycoferella graminicola (Mycos phaerella graminicola), anamorph: Septoria tritici (Septoria tritici), Wheat Brown Rust Rust (Puccinia triticina), crest Stripe Rust (Puccinia stripiformis) striiformis f.sp.tritici), apple scab (Venturia Venturia inaequalis, corn smut (Blister Smut) (Ustilago maydis) )), powdery mildew of grapevines (Uncinula necato r)), barley scald (Rhynchosporium secharis secalis), rice blast (Magnaporthe grisea), soybean rust (Phakopsora p achyrhizi), wheat blight (Leptosphaeria nodorum (Lept osphaeria nodorum), powdery mildew of wheat (Blumelia graminis) Differentiated tritici (Blumeria graminis f.sp. tritici) , powdery mildew of barley (Blumeria graminis hordei) raminis f.sp.hordei), powdery mildew of Cucurbitaceae plants (Erysiphesis Erysiphe cichoracearum), anthracnose of cucurbits Disease (Glomerella lagenarium), Kae Leaf spot disease of spinach (Cercospora beticola) , Tomato summer blight (Alternaria solani) and and barley net blotch (Pyrenophora teres) It's one of them.

[0089] In some embodiments, the fungus is wheat leaf blotch. f Wheat) Mycosphaerella graminicola (Mycosphaerella gr aminicola, anamorph: Septoria tritici (Septoria tr itici), Wheat Brown Rust (Puccinia triticina (Puccinia triticina), Stripe rust (Stripe R ust) (Puccinia striiformis) f.sp.tritici), apple scab (Venturiainaequalis (Vent uria inaequalis), Blister smut of corn t) (Ustilago maydis), grapevine udon Powdery mildew (Uncinula necator), barley scald ( Rhynchosporium secalis, rice Rice blast (Magnaporthe grisea), soybean Rust (Phakopsora pachyrhizi), Wheat gall blight (Leptosphaeria nodorum) dorum), powdery mildew of wheat (Blumeria graminis var. specialis tritici (Blum eria graminis f.sp.tritici), powdery mildew of barley ( Blumeria graminis f.sp hordei), powdery mildew of Cucurbitaceae plants (Erysiphe sicoracearum (Erysi phe cichoracearum), anthracnose of cucurbits (Glomerella lagenariu Glomerella lagenarium), leaf spot of turnip (Cercos Cercospora beticola, tomato late blight (Arte Alternaria solani) and barley net blotch (Pyreno It is one of the Pyrenophora teres.

[0090] In some embodiments, a method for controlling fungal attack on a plant, the method comprising: The law is i) the following structure: [ka] obtaining a crystalline form of a compound having and ii) spraying the crystalline form on the site where the fungus is present, on the site to be prevented from infestation, and / or on the plants; and thereby controlling fungal attack on the plant. Equipped with.

[0091] In some embodiments, the method for controlling fungal attack on a plant comprises: and applying the crystalline form, mixture or composition of the present invention to the location and / or plant to be prevented from infestation. to thereby control fungal attack.

[0092] In some embodiments, a method for controlling fungal attack on a plant, the method comprising: The method involves applying a synergistic fungicide to the site where the fungus is present, to the site to be prevented from infestation, and / or to the plant. the method comprising spraying a fungal mixture comprising: i) a fungicidally effective amount of a crystalline form of the present invention; and ii) at least one additional fungicide, thereby providing a Control fungal attack of.

[0093] In some embodiments, the fungal attack on the roots and / or seeds and / or plants is prevented. The method comprises applying an infestation to the roots, seeds or stems of a plant at the location where the infestation is to be prevented. and / or spraying the plant with a crystalline form, mixture, or composition of the present invention, This prevents fungal attack on the roots and / or seeds and / or plants.

[0094] In some embodiments, in the method, the mixing is a tank mix.

[0095] In some embodiments, the method comprises the tank mix comprising at least It further comprises one excipient.

[0096] The present invention also provides a method for controlling fungal attack on roots and / or seeds and / or plants. , the method is i) Structure [ka] obtaining a solution of a compound having and ii) spraying the solution on the roots, seeds or foliage of the plants where infestation is to be prevented and / or on the plants; applying the fungus to the roots and / or seeds and / or plants, thereby controlling fungal attack on the roots and / or seeds and / or plants. Equipped with.

[0097] The present invention also provides a method for controlling fungal attack on roots and / or seeds and / or plants. , how to do it i) obtaining a solution of a crystalline form or mixture of the present invention; and ii) spraying the solution on the roots, seeds or foliage of the plants where infestation is to be prevented and / or on the plants; applying the fungus to the plant, thereby controlling fungal attack on the plant. Equipped with.

[0098] In some embodiments, in the method, the mixing is a tank mix.

[0099] In some embodiments, the method comprises tank mixing at least one It further comprises a seed excipient.

[0100] The present invention also provides a structure [ka] Also provided is a fungicidal composition comprising a compound having the formula:

[0101] The present invention also provides a fungicidal composition comprising a crystalline form of the invention or a mixture of the invention.

[0102] The present invention also provides a method for controlling fungal attack on a plant, the method comprising: i) Structure [ka] obtaining a composition of compounds having and ii) spraying the composition at the site where the fungus is present, at the site to be prevented from infestation, and / or on the plant; thereby controlling fungal attack on the plant. Equipped with.

[0103] The present invention also provides a method for controlling fungal attack on a plant, the method comprising: i) obtaining a composition of the crystalline form or mixture of the present invention; and ii) spraying the composition at the site where the fungus is present, at the site to be prevented from infestation, and / or on the plant; thereby controlling fungal attack on the plant. Equipped with.

[0104] The present invention also provides a method for controlling fungal attack on plants and / or roots and / or seeds. , the method is i) obtaining a composition of the crystalline form or mixture of the present invention; and ii) Plant roots, seeds, and root systems to control various fungi without damaging the commercial value of the plants. spraying the composition on the shoots or foliage Equipped with.

[0105] The present invention also provides a method for controlling fungal attack on roots and / or seeds and / or plants. , how to do it i) Structure [ka] obtaining a composition of compounds having the formula: and ii) applying the composition to the roots, seeds or foliage of the plant at the location where infestation is to be prevented and / or to the plant. spraying to thereby control fungal attack on the plants. Equipped with.

[0106] In another aspect, the present invention provides polymorphs Form I and Form II, hydrates, and Processes for preparing solvates S5, S8 and S1 are provided.

[0107] In some embodiments, the process includes the step of forming a crystalline polymorph, solvate, or hydrate. is formed by cooling crystallization, evaporation crystallization or suspension crystallization.

[0108] In some embodiments, the process for preparing a crystalline polymorphic form of Form I comprises: a) In an organic solvent, [ka] providing a compound having the formula: b) filtering the precipitated solid from the solution of step a). Equipped with.

[0109] In some embodiments, in the process, the organic solvent is toluene, isopropyl Alcohol, tetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, methyl tetrahydrofuran and / or diethyl carbonate.

[0110] In some embodiments, in the process, the organic solvent is toluene, isopropyl The solvent is alcohol, tetrahydrofuran, or methyl tert-butyl ether.

[0111] In some embodiments, the process further comprises water mixed with the organic solvent.

[0112] In some embodiments, in the process, the organic solvent is isopropanol. be.

[0113] In some embodiments, the process comprises: , 0.1 or 0.3 water activity.

[0114] In some embodiments, the process comprises: a) providing a compound in toluene or tert-butyl ether; and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by suspension crystallization.

[0115] In some embodiments, the process comprises: a) providing a compound in toluene, and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by cooling crystallization.

[0116] In some embodiments, the process comprises: a) providing a compound in methyltetrahydrofuran and diethyl carbonate , and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by cooling crystallization.

[0117] In some embodiments, the process comprises: a) providing a compound in tetrahydrofuran, and b) filtering the precipitated solid from the solution of step a). wherein the crystalline polymorph is formed by evaporative crystallization.

[0118] In some embodiments, the process comprises: a) providing a compound in cyclopentyl methyl ether; and b) filtering the precipitated solid from the solution of step a). wherein the crystalline polymorph is formed by evaporative crystallization.

[0119] In some embodiments, in the process, the solution is prepared at room temperature.

[0120] In some embodiments, the process involves heating the solution at a temperature ranging from about 50°C to about 60°C. It is prepared at ambient temperature.

[0121] In some embodiments, the process involves heating the solution at a temperature in the range of about 0°C to about 10°C. The mixture is cooled to a temperature of 100°C.

[0122] In some embodiments, in the process, the solution of step a) is Stir at room temperature for 1 to 15 days before proceeding to step b).

[0123] In some embodiments, in the process, the solution of step a) is The mixture is stirred at room temperature for approximately 11 days before proceeding to b).

[0124] In some embodiments, in the process, the solution of step a) is Stir at room temperature for approximately 2 days before proceeding to b).

[0125] In some embodiments, in the process, the solution of step a) is Stir for 0.5 to 24 hours at room temperature before proceeding to step b).

[0126] In some embodiments, in the process, the solution of step a) is Stir for 2 hours at room temperature before proceeding to b).

[0127] In some embodiments, the process for preparing the crystalline polymorphic form of Form II comprises: a) The following structure [ka] providing a solution of a compound having the formula: b) filtering the precipitated solid from the solution of step a). Equipped with.

[0128] In some embodiments, in the process, the organic solvent is methyl ethyl ketone Or tetrahydrofuran.

[0129] In some embodiments, the process further comprises water mixed with the organic solvent.

[0130] In some embodiments, in the process, the organic solvent is tetrahydrofuran is.

[0131] In some embodiments, the process includes a mixture of tetrahydrofuran and water. has a water activity of 0.1 or 0.3.

[0132] In some embodiments, the process comprises: a) providing a compound in methyl ethyl ketone, and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by suspension crystallization.

[0133] In some embodiments, in the process, the solution is prepared at room temperature.

[0134] In some embodiments, in the process, the solution of step a) is Stir at room temperature for 1 to 15 days before proceeding to step b).

[0135] In some embodiments, in the process, the solution of step a) is The mixture is stirred at room temperature for approximately 11 days before proceeding to b).

[0136] In some embodiments, in the process, the solution of step a) is Stir at room temperature for approximately 2 days before proceeding to b).

[0137] In some embodiments, in the process, the solution of step a) is Stir for 0.5 to 24 hours at room temperature before proceeding to step b).

[0138] In some embodiments, in the process, the solution of step a) is Stir for 2 hours at room temperature before proceeding to b).

[0139] In some embodiments, the process for preparing the crystalline hydrated form comprises: a) In an organic solvent, [ka] providing a compound having the formula: b) filtering the precipitated solid from the solution of step a). Equipped with.

[0140] In some embodiments, in the process, the organic solvent is acetonitrile, methyl ethanol, ethyl acetate, ethanol, acetone, tetrahydrofuran, dichloromethane, methyltetrahydrofuran, and / or 1-propanol.

[0141] In some embodiments, in the process, the organic solvent is acetonitrile, methyl ethanol, ethyl acetate, ethanol, acetone, tetrahydrofuran or dichloromethane is.

[0142] In some embodiments, the process further comprises water mixed with the organic solvent.

[0143] In some embodiments, the process comprises the step of: is mixed with

[0144] In some embodiments, in the process, the mixture of organic solvent and water is It is a 4:1 mixture of nitrile:water.

[0145] In some embodiments, the process comprises: a) providing a compound in acetonitrile for at least 3 hours; and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by cooling crystallization.

[0146] In some embodiments, the process comprises: a) providing a compound in methanol; and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by cooling crystallization.

[0147] In some embodiments, the process comprises: a) providing the compound in ethanol for at least 3 days; and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by cooling crystallization.

[0148] In some embodiments, the process comprises: a) providing the compound in ethyl acetate for at least 3 weeks; and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by cooling crystallization.

[0149] In some embodiments, the process comprises: a) providing a compound in methyltetrahydrofuran and methanol; and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by cooling crystallization.

[0150] In some embodiments, the process comprises: a) providing a compound in methyltetrahydrofuran and 1-propanol; Beauty b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by cooling crystallization.

[0151] In some embodiments, the process comprises: a) providing a compound in water mixed with methyltetrahydrofuran; and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by cooling crystallization.

[0152] In some embodiments, the process comprises: a) providing a compound in acetone, and b) filtering the precipitated solid from the solution of step a). wherein the crystalline polymorph is formed by evaporative crystallization.

[0153] In some embodiments, in the process, the solution of step a) is The mixture is stirred at about 25°C for 1 to 15 days before proceeding to step b).

[0154] In some embodiments, in the process, the solution of step a) is It is stirred at about 25° C. for 11 days before proceeding to b).

[0155] In some embodiments, in the process, the solution of step a) is It is stirred at about 25° C. for 2 days before proceeding to b).

[0156] In some embodiments, in the process, the solution of step a) is Before proceeding to b), the mixture is stirred at about 25°C for 0.5 to 24 hours.

[0157] In some embodiments, in the process, the solution of step a) is Stir for 2 hours at approximately 25°C before proceeding to b).

[0158] In some embodiments, the process comprises: a) providing a compound in dichloromethane, and b) filtering the precipitated solid from the solution of step a). wherein the crystalline polymorph is formed by evaporative crystallization.

[0159] In some embodiments, in the process, the solution is prepared at about 60°C.

[0160] In some embodiments, in the process, the solution is prepared at about 47°C.

[0161] In some embodiments, in the process, the solution is prepared at about 52°C.

[0162] In some embodiments, the solution is cooled to about 5°C.

[0163] In some embodiments, in the process, the solution of step a) is Stir at approximately 25°C for 16-20 hours before proceeding to b).

[0164] In some embodiments, a mixture of the crystalline polymorphic form of Form I and a crystalline hydrated form is used. The process for preparing the compound is a) In an organic solvent, [ka] providing a compound having the formula: b) filtering the precipitated solid from the solution of step a). Equipped with.

[0165] In some embodiments, in the process, the organic solvent is methyl tetrahydrofuran. Furan and / or isopropanol.

[0166] In some embodiments, the process comprises: a) providing a compound in methyltetrahydrofuran and isopropanol; Beauty b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by evaporative crystallization.

[0167] In some embodiments, in the process, the solution is prepared at about 50°C.

[0168] In some embodiments, the process for preparing the crystalline solvate Form S5 comprises: a) The following structure [ka] providing a solution of a compound having the formula: b) filtering the precipitated solid from the solution of step a). Equipped with.

[0169] In some embodiments, in the process, the solution is prepared at room temperature.

[0170] In some embodiments, in the process, the solution of step a) is Stir at room temperature for 1 to 15 days before proceeding to step b).

[0171] In some embodiments, in the process, the solution of step a) is The mixture is stirred at room temperature for approximately 11 days before proceeding to b).

[0172] In some embodiments, in the process, the solution of step a) is It is stirred at about 25° C. for 2 days before proceeding to b).

[0173] In some embodiments, in the process, the solution of step a) is Before proceeding to b), the mixture is stirred at about 25°C for 0.5 to 24 hours.

[0174] In some embodiments, in the process, the solution of step a) is Stir for 2 hours at about 25°C before proceeding to b).

[0175] In some embodiments, the process for preparing the crystalline solvate Form S8 comprises: a) The following structure [ka] providing a tetrahydrofuran solution of a compound having the formula: b) filtering the precipitated solid from the solution of step a); and c) concentrating the mother liquor from the filtration of step b) by evaporation Equipped with.

[0176] In some embodiments, in the process, the solution is prepared at about 30°C.

[0177] In some embodiments, in the process, the solution of step a) is Stir at room temperature for 1 to 15 days before proceeding to step b).

[0178] In some embodiments, in the process, the solution of step a) is The mixture is stirred at room temperature for approximately 11 days before proceeding to b).

[0179] In some embodiments, in the process, the solution of step a) is It is stirred at about 25° C. for 2 days before proceeding to b).

[0180] In some embodiments, in the process, the solution of step a) is Before proceeding to b), the mixture is stirred at about 25°C for 0.5 to 24 hours.

[0181] In some embodiments, in the process, the solution of step a) is Stir for 2 hours at about 25°C before proceeding to b).

[0182] In some embodiments, in the process, the solution of step a) is Stir at room temperature for 16-36 hours before proceeding to step b).

[0183] In some embodiments, in the process, the solution of step a) is The mixture is stirred at room temperature for approximately 24 hours before proceeding to step b).

[0184] In some embodiments, the process for preparing the crystalline solvate Form S1 comprises: a) The following structure [ka] providing an ethyl acetate solution of a compound having the formula: b) filtering the precipitated solid from the solution of step a). Equipped with.

[0185] In some embodiments, in the process, the solution is prepared at about 60°C.

[0186] In some embodiments, in the process, the solution of step a) is Stir at room temperature for 1 to 15 days before proceeding to step b).

[0187] In some embodiments, in the process, the solution of step a) is The mixture is stirred at room temperature for approximately 11 days before proceeding to b).

[0188] In some embodiments, in the process, the solution of step a) is It is stirred at about 25° C. for 2 days before proceeding to b).

[0189] In some embodiments, in the process, the solution of step a) is Before proceeding to b), the mixture is stirred at about 25°C for 0.5 to 24 hours.

[0190] In some embodiments, in the process, the solution of step a) is Stir for 2 hours at about 25°C before proceeding to b).

[0191] In some embodiments, in the process, the solution of step a) is Stir at approximately 25°C for 16-20 hours before proceeding to b).

[0192] In some embodiments, the process comprises: a) providing a compound in ethyl acetate, and b) filtering the precipitated solid from the solution of step a). and the crystalline polymorph is formed by cooling crystallization.

[0193] In one embodiment, the process for producing a fungicidal composition comprises obtaining a crystalline form of the invention. and combining the crystals with an excipient to thereby produce a fungicidal composition. The method includes the step of:

[0194] In one embodiment, the process for producing a fungicidal composition comprises obtaining a crystalline form of the invention. and combining the crystals with an adjuvant to thereby produce a fungicidal composition. Equipped with steps.

[0195] In one embodiment, the process for producing the fungicidal composition is and combining the mixture with an excipient to thereby produce a fungicidal composition. The method includes the step of:

[0196] In one embodiment, the process for producing the fungicidal composition is and combining the mixture with an adjuvant to thereby produce a fungicidal composition. Equipped with steps.

[0197] In some embodiments of the above process, the fungicide is in a crystalline form or a mixture, and and further combining with an excipient or auxiliary agent.

[0198] The present invention also provides a structure [ka] Also provided is a fungicidal composition comprising a solution of a compound having the formula:

[0199] The present invention also relates to a fungicidal composition comprising a solution of the crystalline form of the invention or a solution of the mixture of the invention. Also provided.

[0200] In some embodiments, the fungicidal composition further comprises at least one excipient. nothing.

[0201] In some embodiments, the fungicidal composition is added at least 10 times for the preparation of a tank mix. The composition further comprises at least one excipient.

[0202] The present invention also provides a method for controlling fungal attack on a plant, the method comprising: i) Structure [ka] obtaining a solution of a compound having ii) spraying the solution at the location where the fungus is present, at the location to be prevented from infestation, and / or on the plant, thereby controlling fungal attack on the plant. Equipped with.

[0203] The present invention also provides a method for controlling fungal attack on a plant, the method comprising: i) obtaining a solution of a crystalline form or mixture of the present invention; and ii) spraying the solution at the location where the fungus is present, at the location to be prevented from infestation, and / or on the plant, thereby controlling fungal attack on the plant. Equipped with.

[0204] In some embodiments, in the method, the mixing is a tank mix.

[0205] In some embodiments, the method comprises tank mixing at least one It further comprises a seed excipient.

[0206] In some embodiments, the disclosed crystalline forms and / or at least one crystalline form of the disclosed crystalline forms are Compositions containing the crystalline forms of the present invention and / or mixtures with at least one other pesticidal compound. (including mixtures with at least one other pesticidal compound) does not damage the commercial value of the plant. It is applied to the roots, seeds or foliage of plants to control a variety of fungi without affecting the plant's growth.

[0207] In some embodiments, the disclosed crystalline forms and / or at least one crystalline form of the disclosed crystalline forms are Mixtures with at least one other pesticidal compound may be used to control various pests without damaging the commercial value of the plant. It is applied to the roots, seeds or foliage of plants to control various fungi.

[0208] In some embodiments, the crystalline form of the compound (polymorph Form I or II, Hydrates or solvates (Forms S1, S5 or S8) are provided, and the crystalline forms are At least about 50% by weight or more of polymorphs, hydrates, solvates or the like, based on the total amount of In some embodiments, the crystalline form is present as a material comprising a mixture of the compounds The material contains at least about 60% by weight of polymorphs, hydrates, or solvates based on the total amount. In some embodiments, the crystalline form is present in at least one of the total amounts of the compound. Both exist as polymorphs, hydrates or solvates of material, with approximately 70% by weight of the material. In embodiments, the crystalline form is at least about 80% by weight of polymorphic form, based on the total amount of compound. In some embodiments, the crystalline form The compound is at least about 90% by weight of a polymorph, hydrate, or solvate based on the total amount of the compound. In some embodiments, the crystalline form is present as a material containing as a material containing at least about 95% by weight of a polymorph, hydrate, or solvate thereof In some embodiments, the crystalline form has a crystallinity of at least about 98% based on the total amount of the compound. The material may exist as a polymorph, hydrate, or solvate, with a weight percent of the material being present. For example, the crystalline form may be at least about 99% by weight of a polymorph, hydrate, or the like, based on the total amount of compound. or exists as a solvated material.

[0209] In some embodiments, crystalline polymorph Form I or II is provided, and the polymorph The body is substantially free of the amorphous compound and substantially free of hydrates and solvates of the amorphous compound. It exists as a material.

[0210] Formulations or compositions comprising or consisting essentially of the disclosed crystalline forms are useful as pesticides. They are prepared according to conventional procedures in the art, e.g., Foy, C. L. and Pritchard, hard, D. W. (1996) Pesticide formulation and See Adjuvant Technology. CRC Press.

[0211] The disclosed crystalline form concentrates can be dispersed in water or another liquid for application; Alternatively, the formulation may be in powder or granular form, after which the formulation may be further processed. The formulations are prepared according to procedures conventional in the agrochemical field, but the formulations The disclosed concentrated formulations of the crystalline forms are novel and important because they exist in a crystalline form. The formulation may be dispersed in water or another liquid for application, or may be in the form of a powder or granules. and can be diluted before application.

[0212] The disclosed crystalline forms, and / or the disclosed crystalline forms and at least one other pesticidal compound. The concentration of the mixture in the formulation is usually about 0.5% by weight to about 90% by weight based on the total weight of the formulation. % by weight, and more preferably about 25% to about 75% by weight.

[0213] The most commonly applied formulations are aqueous suspensions or emulsions. Either suspensions or emulsions are usually solids known as wettable powders. or liquid, usually known as an emulsifiable concentrate, aqueous suspension, or suspension concentrate. The present disclosure provides a method for preparing a synergistic composition for delivery and use as a fungicide. All vehicles that can be formulated are contemplated.

[0214] As will be readily apparent, the activity of these synergistic compositions as antifungal agents is Any material to which the disclosed compositions can be added as long as it does not unduly interfere with the desired utility. It may be used in.

[0215] The wettable powder that can be compressed to form a wettable powder granule comprises a synergistic composition, a carrier and The concentration of the disclosed composition in a wettable powder is , based on the total weight of the formulation, usually about 10% to about 90% by weight, more preferably about 25% Approximately 75% by weight of wettable powder In preparing the ons, the synergistic composition can incorporate any finely divided solid.

[0216] The disclosed compositions comprise at least 1% by weight of one or more of the compositions in combination with another pesticidal compound. Such additional pesticidal compositions may optionally be included with the product. The compound is compatible with the synergistic composition of the present disclosure in the medium selected for application. and which do not antagonize the activity of the compounds of the present invention, The compound may be a podicide, a fungicide, or a combination thereof. In embodiments, the other pesticidal compounds are used in the control of the same or different pests. Pesticidal compounds and synergistic compositions are generally used in a 1:1 ratio. They can be mixed together in a weight ratio of 00 to 100:1.

[0217] Solids exist in either amorphous or crystalline form. In the case of crystalline form: The molecules are positioned at three-dimensional lattice positions.

[0218] When a compound recrystallizes from a solution or slurry, the compound crystallizes in a different spatial lattice arrangement. It may also crystallize, resulting in a phenomenon known as "isomorphism" and different individual forms known as "polymorphs." Different polymorphic forms of a given substance vary in solubility and dissociation properties, true density, crystalline form, etc. The properties of the composites are comparable to one or more physical properties such as shape, compaction behavior, flowability and / or solid stability. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent incorporated within the crystal structure. If the incorporated solvent is water, it is a crystalline solid adduct containing either Solvates are also commonly known as hydrates. Solvates or hydrates are also known as "pseudopolysaccharides." It is also commonly known as "kata".

[0219] The new polymorphic, hydrated or solvated forms may have improved physical properties such as stability or solubility. The polymorphs disclosed herein can provide a variety of benefits, including the ability to produce purer and more potent There is fruit.

[0220] As used herein, the term "mixture" or "combination" refers to, for example, a blend. It refers to any physical combination such as, but not limited to, a liquid, a solution, an alloy, etc.

[0221] As used herein, the term "composition" refers to a compound of the invention in crystalline form and at least Both include one or more mixtures with another component that contains one additional fungicide.

[0222] As used herein, the term "tank mix" refers to the mixing or composition of the present invention. One or more ingredients and / or one or more added excipients are sprayed Or it means that it is mixed in a spray tank before spray application.

[0223] As used herein, the term "excipient" refers to a pesticide such as a surfactant, solvent, or adjuvant. refers to any chemical substance that has no effect whatsoever. One or more excipients may be It can be added to either the mixture or the composition.

[0224] As used herein, the terms "a" or "an" refer to both the singular and the plural, unless otherwise specified. Thus, the terms "a," "an," or "at least one" are used in this application. can be used interchangeably.

[0225] Throughout this application, descriptions of various embodiments use the term "comprising." However, those skilled in the art will recognize that in some specific instances, an embodiment may be It will be appreciated that this can be alternatively explained using "consisting of" or "consisting of."

[0226] As used herein, the term "about" specifically includes a range of ±10% from the stated value. The endpoints of all ranges reciting the same component or property in the specification are inclusive and may be independently It is combinable and includes all intermediate points and ranges.

[0227] In yet another embodiment, the product of any disclosed process may be any of the methods known in the art. The compound can be isolated from the reaction mixture by conventional techniques such as concentration. , extraction, precipitation, cooling, filtration, crystallization, and centrifugation, followed by drying. These can include, but are not limited to:

[0228] In yet another embodiment, the product of any disclosed process is optionally a compound that is known in the art. Such purification can be carried out by any conventional technique known in the art. , slurrying, washing with a suitable solvent, filtering through a particle-packed column, and dissolution and reprecipitation by adding a second solvent in which the compound is insoluble, or These include, but are not limited to, combinations of:

[0229] While the subject matter of the present invention has been shown and described in connection with its preferred embodiments, The vendor reserves the right to make numerous substitutions, modifications, and variations thereon without departing from the spirit and scope thereof. It will be understood that the present invention can be applied to the above-mentioned cases. It is intended to embrace all such alternatives, modifications and variations that fall within the scope of the present invention.

[0230] All publications, patents, and patent applications mentioned herein are to be construed as separate entities each representing a separate patent, patent application, or other technology. All patents and patent applications are specifically and individually indicated to be incorporated by reference herein. to the same extent as set forth herein, which is incorporated by reference in its entirety.

[0231] The following examples illustrate the practice of the subject matter of the present invention in some of its embodiments. The present invention should not be construed as limiting the scope of the disclosed subject matter. Other embodiments are within the scope of the present specification and embodiments. This specification, including the examples, will become apparent to those skilled in the art upon consideration of the examples. are to be considered illustrative only, without limiting the scope and spirit of the present subject matter. can be done. [Example]

[0232] XRPD: Stoe Stadi P with Mythen 1K detector; Cu-Kα1 Radiation; 40kV and 40mA tube power; curved Ge monochromator; 0.02° 2θ Step width, 12 seconds step time, 1.5 to 50.5° 2θ range; detector mode: step Scanning; 1° 2θ detector step. Place the sample (20–40 mg) between two acetate foils ( Place the sample between two pieces of paper (dry sample) or between two Kapton foils (wet sample) and The sample was fixed to a transmission sample holder, which was rotated during the measurement.

[0233] XRPD:Bruker D8 Advance;Cu-Kα radiation;Standard measurement conditions: Bragg-Brentano reflection configuration; 40kV and 40mA tube power; Lynx Eye detector; 0.02° 2θ step width, 37 sec step time, 2.5 to 50.5° 2 θ measurement (measurement time: approximately 10 minutes); cavity processing to rotate the sample holder during measurement The sample was spread on a silicon single crystal substrate without any adhesive, flattened, and then a 0.5 mm deep sample was added. The lens holder was attached.

[0234] All sample preparation and measurements were performed in ambient air, and wet samples were prepared using The analysis was carried out immediately.

[0235] FT-Raman spectroscopy: Bruker Multi with OPUS 6.5 software i-RAM; Nd:YAG 1064-nm excitation, Ge detector, 3500–50 cm Range; Typical measurement conditions: 300mW nominal laser power, 64 scans, 2cm-1 resolution The sample is pressed into the cavity of the aluminum sample holder. TG-FTIR:Bruker FT-IR Spectrometer Vector Netzsch Thermo-Microbalance TG 20 with 22 9; Aluminum crucible (with microholes); N2 atmosphere; 10°C / min heating rate, 25-3 00℃.

[0236] DSC: TA Instruments DSC Q2000; sealed gold crucible N2 atmosphere; 10°C / min heating rate, 20-190°C. The melting point is taken as the peak onset.

[0237] Solvents: Fluka, Merck or ABCR analytical grade solvents were used for all examples. All of the methods used were to prepare mixtures of water and organic solvents with precise water activities under dry conditions. In the examples, the organic solvent was pre-dried over molecular sieves (4 Å) for a few days.

[0238] The composition of a solvent mixture with water and an organic solvent for a specific water activity at a given temperature is D .Behrens,R.Eckermann,Chemistry Data Seri J. Gmehling in es, Dechema, Frankfurt, 1977, U.Onken,Vapor-Liquid-Equilibrium Data Co The compositions of solvent mixtures are interpreted as volume ratios unless otherwise stated. do.

[0239] Example 1. Form I All of the following examples resulted in Form I.

[0240] Form I was prepared by suspension crystallization.

[0241] 1) Approximately 100 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di Hydropyrimidin-2(1H)-one was dissolved in 1.0 ml of pre-dried 4 Å molecular sieves. The suspension was stirred at room temperature for 11 days and then filtered through a 0.2-μm PTFE centrifuge. The samples were filtered through a microfiber filter and analyzed without drying, or dried under N2 vapor at room temperature for 1 hour. It was dried in air. 2) Approximately 100 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di Hydropyrimidin-2(1H)-one was dissolved in 1.0 ml of pre-dried 4 Å molecular sieves. The suspension was stirred at room temperature for 11 days. The mixture was stirred, filtered through a 0.2-μm PTFE centrifugal filter, and analyzed without drying. 3) Approximately 100 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di Hydropyrimidin-2(1H)-one was dissolved in 1.0 ml of pre-dried 4 Å molecular sieves. The suspension was stirred at room temperature for 11 days and then passed through a 0.2-μm PTFE centrifuge filter. The solution was filtered through a filter and analyzed without drying. 4) Approximately 1800g of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4- Dihydropyrimidin-2(1H)-one was suspended in 16000g of toluene and the suspension The solution was stirred for 2 hours at 30° C. The solid was filtered in a centrifugal filter and added to 1 liter of torr. Washed with benzene and dried at 65°C. 5) Approximately 100 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di Hydropyrimidin-2(1H)-one was dissolved in 2.0 ml of 2-PrOH / water = 99.7 / 0. 3 (v / v) at room temperature (aw=0.1) or 2.0 ml of 2-PrOH / water The suspension was suspended in HCl / HCl 97.5 / 2.5 (v / v) at room temperature (aw=0.1) and the mixture was After stirring for 3 days, the suspension turned into a more dilute suspension by appearance over the weekend. It was then seeded with unstable solvated forms, Form I and Form II, to further After stirring for 2 days, the solid was filtered through a 0.2-μm PTFE centrifugal filter and dried. Either the solids were analyzed fresh or they were allowed to dry under ambient conditions for 5 days.

[0242] Form I was also prepared by cooling crystallization.

[0243] 1) Approximately 100 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di The hydropyrimidin-2(1H)-one was dissolved in 4.0 ml of toluene (previously filtered with 4 Å molecular sieves). The solution was then filtered through a 0.45-μm PTFE filter. The clear solution was cooled steadily to 25°C within 4 hours and then filtered hot. Stir magnetically for 1 minute, then store the milky solution at 5 °C for 1 day and then at -25 °C for 3 days without stirring. The solid was filtered through a 0.22-μm PTFE centrifugal filter without any drying. The samples were analyzed wet without drying or dried under dry N2 steam for 1 hour at room temperature. 2) Approximately 7g of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydriodide The lopyrimidin-2(1H)-one was dissolved in 95g of toluene and the solution was washed with water. After mixing at 50°C for 1 hour, the mixture was cooled to 10°C and the solid was filtered through a centrifugal filter. , dried in a vacuum oven and analyzed. 3) Approximately 6g of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydriodide 14g of MeTHF and 19g of diethylcarbamate were added to the pyrimidin-2(1H)-one. The solution was heated to 55°C, cooled to 0°C, and then centrifuged. The solid was filtered through a filtration tube and analyzed without drying.

[0244] Form I was also prepared by evaporative crystallization.

[0245] 1) Approximately 150 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di The hydropyrimidin-2(1H)-one was dissolved in 2.0 ml of THF at 30° C., and the solution Filter the solution through a 0.45-μm PTFE filter and purify the clear solution with gentle N2 vapor. The mixture was evaporated at room temperature, and when about three-quarters of the solvent had evaporated, the mixture turned into a suspension. The vial was open to the ambient air through the needle, so the suspension The solid was filtered through a 0.22-μm PTFE centrifugal filter and dried. They were analyzed either fresh or allowed to dry under ambient conditions for 2 days. 2) Approximately 6.7g of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di Hydropyrimidin-2(1H)-one was dissolved in 30g of cyclopentyl methyl ether (CP ME), the solution was mixed and after partial evaporation at 60°C (185 mbar) The mixture was cooled, the solid was filtered through a centrifugal filter and analyzed without drying. 3) Approximately 6g of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydriodide The thoropyrimidin-2(1H)-one was dissolved in 54 g of CPME and the solution was heated at 50° C. in water. The solution was washed with CPME, evaporated to dryness, and the solid was analyzed.

[0246] Form I was also prepared by dehydration of the hydrate.

[0247] 1) Measurement by open pan DSC, water of crystallization in the temperature range of 20 to 100°C After that, a sharp endothermic event due to melting occurred at 159 °C in the thermogram (Figure 1). 0). The melting point coincides with that of Form I. Therefore, the dehydration of the hemihydrate is The result is anhydrous Form I.

[0248] Example 2. Form II The following example resulted in Form II.

[0249] Form II was prepared by suspension crystallization. Approximately 120 mg of 5-fluoro-4-imino- 3-Methyl-1-tosyl-3,4-dihydropyrimidin-2(1H)-one was added over a 4 Å The mixture was suspended in 0.8 ml of methyl ethyl ketone (MEK) that had been previously dried through a sieve. The suspension was stirred at room temperature for 11 days and filtered through a 0.2-μm PTFE centrifugal filter. The solid was allowed to dry under ambient conditions for 1 day.

[0250] Example 3. Hydrate All of the following examples resulted in hydrates.

[0251] The hydrate was prepared by suspension crystallization.

[0252] 1) Approximately 100 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di Hydropyrimidin-2(1H)-one was dissolved in 2.0 ml of THF / water = 78.7 / 21.3 ( v / v) at room temperature (aw=0.9), the solution turned clear, and an additional 8 5 mg of solid was added and the suspension was stirred at room temperature for 3 days, over the weekend the suspension was visibly The unstable solvated forms, Form I and Form II, were converted to more dilute suspensions. After seeding it with ml and stirring for another 2 days, the mixture was filtered through a 0.2-µm PTFE centrifuge. The solids were analyzed without drying or after 5 days under ambient conditions. It was dried for a while. 2) Approximately 90 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydrochloride Dropyrimidin-2(1H)-one was dissolved in 0.5 ml of THF / water = 96.4 / 3.6 (v / v) v) at room temperature (aw=0.7). It was almost dissolved, but within a few minutes It thickens slightly and after stirring for a day, it is dissolved in hydrate, Form I and Form II. After seeding and stirring for another 2 days, the mixture was filtered through a 0.2-μm PTFE centrifugal filter. The solid was analyzed without drying. 3) Approximately 100 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di Hydropyrimidin-2(1H)-one in 2.0 ml of 2-PrOH / water = 94.7 / 5. 3 (v / v) at room temperature (aw=0.5). It became a clear solution, and additional 100 mg of the solid was also dissolved in the solution, and another 130 mg of the solid was added. It became thicker but was still stirrable. It was stirred at room temperature for 3 days and then over the weekend. The suspension turned into a much more dilute suspension judging from its appearance. After seeding it with Form I and Form II and stirring for another 2 days, 0.2-µm After filtration through a PTFE centrifugal filter, the solid was allowed to dry under ambient conditions for 5 days.

[0253] Hydrates were also prepared by cooling crystallization.

[0254] 1) Approximately 100 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di The hydropyrimidin-2(1H)-one was dissolved in 2.0 ml of MeOH (previously filtered with 4 Å molecular sieves). The solution was then filtered through a 0.45-μm PTFE filter. The clear solution was cooled steadily to 25°C within 4 hours and then filtered hot. The mixture was magnetically stirred for a short time, and the solid was filtered through a 0.22-µm PTFE centrifugal filter and dried. The samples were analyzed without drying or dried under ambient conditions for 3 days and then analyzed. 2) Approximately 100 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di The hydropyrimidin-2(1H)-one was dissolved in 4.0 ml of EtOH (previously filtered with 4 Å molecular sieves). The solution was then filtered through a 0.45-μm PTFE filter. The clear solution was cooled steadily to 25°C within 4 hours and then filtered hot. Stir magnetically for 10 min, and filter the solid through a 0.22-µm PTFE centrifugal filter. A stable solvate was formed and it was allowed to dry under ambient conditions for 3 days. 3) Approximately 120 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di The hydropyrimidin-2(1H)-one was dissolved in 1.0 ml of MeCN (previously filtered with 4 Å molecular sieves). The solution was then filtered through a 0.45-μm PTFE filter. The clear solution was cooled steadily to 25°C within 4 hours and then filtered hot. The mixture was magnetically stirred for 1 hour to form an unstable solvate, which was then allowed to dry under ambient conditions for 3 days. 4) Approximately 120 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di The hydropyrimidin-2(1H)-one was pre-dissolved in 1.0 ml of EtOAc (pre-dissolved in 4 Å molecular sieves). The solution was filtered through a 0.45-μm PTFE filter. The clear solution was cooled steadily to 25°C within 4 hours and then filtered hot. The solid was dried under ambient conditions for 3 days with magnetic stirring for 1 hour. After approximately 4 weeks, the solid was evaporated under dry N2. The sample was dried in air at 40°C for 20 hours. 5) Approximately 7.6g of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di Hydropyrimidin-2(1H)-one was dissolved in 170g MeTHF and 65g water in 6 Dissolve at 0°C for 30 minutes, gradually cool the solution, and filter the solid through a centrifugal filter. The samples were analyzed without drying. 6) Approximately 4g of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydriodide The pyrimidin-2(1H)-one was dissolved in 20g of MeTHF and 32g of MeOH. The solution was heated to 47°C, gradually cooled to 5°C, and the solid was filtered through a centrifugal filter. was filtered, dried in a vacuum oven at 55°C and analyzed. 7) Approximately 2g of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydriodide lopyrimidin-2(1H)-one in 10 gr MeTHF and 15 gr n-PrOH The solution was heated to 52°C, cooled to 5°C, and the solid was filtered through a centrifugal filter. It was filtered, dried in a vacuum oven at 55°C and analyzed.

[0255] Hydrates were also prepared by evaporative crystallization.

[0256] 1) Approximately 150 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di The hydropyrimidin-2(1H)-one was dissolved in 2.0 ml of DCM at 30° C., and the solution Filter the solution through a 0.45-μm PTFE filter and purify the clear solution with gentle N2 vapor. The solvent was evaporated at room temperature by distillation, and when about 0.2 ml of solvent remained, the evaporation was stopped. After another day, the sample was removed from the vial. 2) Approximately 150 mg of 5-fluoro-4-imino-3-methyl-1-tosyl-3,4-di Hydropyrimidin-2(1H)-one was dissolved in 2.0 ml of acetone at 30°C. The solution was filtered through a 0.45-µm PTFE filter and placed in a needle with a septum at room temperature. The clear solution was evaporated via filtration. The next day, evaporation was accelerated by gentle N2 steam. When about half of the solvent had evaporated, the crystals that appeared on the wall of the vial were suspended in the solution and obtained. The suspension was stirred for an additional day at room temperature, and the solid was filtered through a 0.22-μm PTFE centrifugal filter. The solution was filtered to form an unstable solvate, which was allowed to dry under ambient conditions for 2 days.

[0257] Crystallization from a warm solution (40°C) of a solid in acetonitrile with water in a 2:1 ratio / The crude hydrated product was purified by precipitation. 1100g of crude compound was added to 3500g of acetone. The mixture was heated to 60°C and 1000g of acetonitrile was added. However, the mixture was not clear. The mixture was cooled to 40°C and 7530g of water was added. The mixture was cooled to 15°C, filtered and dried in a vacuum oven at 55°C and 10 mbar. It was dried.

[0258] Example 4. Form I and hydrate The following examples resulted in a mixture of Form I and a hydrate.

[0259] A mixture of Form I and the hydrate was prepared by crystallization. Approximately 6.7g of 5-fluorouracil was used. -4-Imino-3-methyl-1-tosyl-3,4-dihydropyrimidin-2(1H)-o Dissolve the amine in 75g of MeTHF, wash the solution with water, and add 25g of MeTHF. The solution was evaporated, 75g of 2-PrOH was added, the solution was heated to 50°C, and the solution was cooled. The solids were filtered through a centrifugal filter and analyzed.

[0260] Example 5. Solvated S5 All of the following examples resulted in solvated S5.

[0261] Solvated S5 was prepared by suspension crystallization. Approximately 120 mg of 5-fluoro-4-imino-3 -Methyl-1-tosyl-3,4-dihydropyrimidin-2(1H)-one was The suspension was suspended in 0.8 ml of 1,4-dioxane that had been pre-dried with water, and the suspension was allowed to stand at room temperature for 1 Stir for 1 day, filter through a 0.2-µm PTFE centrifugal filter, and separate without drying. The samples were either precipitated or allowed to dry under ambient conditions for 1 day.

[0262] Solvated S5 was prepared by evaporative crystallization. The mother liquor of the product of the above suspension crystallization was evaporated to dryness at room temperature. The solid was dried with dry N2 steam at room temperature for 1 day or at 40°C in dry N2 steam. It was dried for 20 hours and analyzed.

[0263] Example 6. Solvated S8 The following example resulted in solvated S8.

[0264] Solvated S8 was prepared by evaporative crystallization. Approximately 150 mg of 5-fluoro-4-imino-3 2.0 ml of 1-methyl-1-tosyl-3,4-dihydropyrimidin-2(1H)-one Dissolve in THF at 30 °C and filter the solution through a 0.45-µm PTFE filter. The clear solution was then evaporated with a gentle stream of N2 at room temperature until approximately three-quarters of the solvent had evaporated. At some point, it turned into a suspension. The suspension was stirred for another day. The suspension became thicker as it was open to the ambient air through the 0.22-μm The samples were filtered through a PTFE centrifugal filter and analyzed without drying or under ambient conditions. The mother liquor of the above-mentioned suspension crystallization product was evaporated to dryness at room temperature or dried at 40°C. Drying in dry N2 steam for 20 h provided solvated S8.

[0265] Example 7. Solvated S1 All of the following examples resulted in solvated S1.

[0266] Solvate S1 was prepared by suspension crystallization. Approximately 100 mg of 5-fluoro-4-imino-3 -Methyl-1-tosyl-3,4-dihydropyrimidin-2(1H)-one was The mixture was suspended in 1.0 ml of ethyl acetate pre-dried with ethanol, and the suspension was stirred at room temperature for 11 days. The mixture was stirred, filtered through a 0.2-μm PTFE centrifugal filter, and analyzed without drying.

[0267] Solvate S1 was also prepared by cooling crystallization. Approximately 120 mg of 5-fluoro-4-imino-3 1.0 ml of 1-methyl-1-tosyl-3,4-dihydropyrimidin-2(1H)-one Dissolved in EtOAc (pre-dried over 4 Å molecular sieves) at 60° C. and the solution was diluted to 0.4 Hot-filter through a 5-μm PTFE filter and allow the clear solution to stand at a constant rate for at least 4 hours. The mixture was cooled to 25°C within 1 hour and magnetically stirred for a further 16 hours. The solid was then analyzed without any drying. or dried under ambient conditions for 3 days or in dry N2 vapor at 40°C for 20 hours. It was dried for a while.

[0268] Example 8. Critical Water Activity In 2-PrOH / water mixtures and THF / water mixtures, hydrated and anhydrous F We attempted to determine the critical water activity of ormI and II. First, the starting materials were mixed with a solvent. After 2-3 days of slurrying, the hemihydrate and anhydrous Form I and For The suspension was seeded with mlI. After stirring for another 2 days at room temperature, the suspension was filtered through a centrifugal filter. The solid was separated from the liquid. The experimental conditions and results are shown in Table 1.

[0269] [Table 1]

[0270] The results showed that at a water activity of 0.3 or less, anhydrous Fo was the most effective of the three suspended forms. It can be seen that rmI is thermodynamically the most stable. The hemihydrate form appears to be more stable at a water activity of 0.7. In this case, Form II was found to be more stable in suspension. is the water activity of the hydrated form at a specific temperature and below (below) It is thermodynamically proven that both the water and water forms are more stable than the anhydrous form. is considered to be contrary to the law and therefore untrue.

[0271] To explore the nature of the surprising results regarding critical water activity, three further experiments were carried out. Freshly prepared solvent mixtures were used to measure the solubility of sucrose at water activities of 0.5 and 0.7. The suspension was then repeated to obtain a suspension equilibrium at a water activity of 0.7 in a 2-PrOH / water mixture. The formation of a thick suspension was again noted in the 2-PrOH / water mixture. The thick suspension obtained in 1 became a well-stirred slurry after stirring for 1 day. It was seeded in a single layer and stirred for an additional 2 days before isolating the solid. The results obtained are shown in Table 2.

[0272] [Table 2]

[0273] The hemihydrate was found to be significantly more stable than the two anhydrous forms in all suspensions. However, in the 2-PrOH / water mixture, the conversion was not complete and Fo A small fraction of rmII was detected, which may be due to its poor solubility in the solvent mixture. The hemihydrate reproduces the slightly different patterns obtained from various experiments. The diffraction patterns vary slightly from sample to sample, and their actual shape varies depending on the sample. It does not appear to have a direct correlation with average water activity. At room temperature and above a water activity of 0.5, the substance exists in two water forms (Form I and Form II). II) It is more stable than

[0274] Example 9. Relative Stability of Forms I and II Based on the DSC results, Form II has a lower melting point and a higher melting end point than Form I. (156°C and 112 J / g vs. 159°C and 110 J / g). The two forms are tautomerically related. Form II is thermodynamically stable at low temperatures. Form I is a stable form at high temperatures. However, the enthalpy of fusion The differences are rather small and not necessarily conclusive (1 using both samples). (Only one measurement was performed). Therefore, the two forms are monovariately related, and For It is possible that mI is a more stable form at all temperatures below its melting point.

[0275] The relative thermodynamic stabilities of the polymorphs were determined by slurry experiments at room temperature and 5°C. It was demonstrated that rmI is more stable at water activities of 0.1 and 0.3. These results already provide evidence that Form I is thermodynamically more stable than Form II at room temperature. The stability was further investigated at 5°C, and further experiments were performed in MEK at room temperature. MEK was the only solvent that formed Form II when the starting materials were slurried. MEK was chosen as the suspension medium because it is a suitable suspending medium. The solubility is quite high in MEK. Conversion to the more stable form is expected to occur fairly quickly at both temperatures. The experiments in TBME were actually carried out only as a control. Shown in Table 3.

[0276] [Table 3]

[0277] The results showed that Form I was significantly more efficient than Form II only in TBME at 5°C. The ultimate finding of these competitive slurry experiments was Form I and Form II are monotropically related, with Form I being thermodynamically more stable. Form I is more stable at temperatures above 5°C, or they are tautomerically related. It is either in a high temperature form or

[0278] Consideration The crystalline form of the present application provides a stable form that is more easily formulated for agricultural use. The crystalline solvated forms of the present invention offer advantages in organic reaction procedures. Different solvates are particularly The solvated forms obtained offer compatibility in organic solvents that can be used in the separation step. It is easily filtered and washed.

[0279] The crystalline hydrated forms of the present invention also offer the advantage that the separation step in the reaction can be carried out in the aqueous phase. The hydrated form is easily precipitated, filtered, and washed in the presence of water.

[0280] Crystalline Form I of the present application offers advantages in granulation procedures. It is suitable for suspensions, liquids and It can be easily ground and used to prepare solid formulations.

[0281] 5-Fluoro-4-imino-3-methylpropional is obtained by suspension crystallization, cooling crystallization and / or evaporation crystallization. 1-Tosyl-3,4-dihydropyrimidin-2(1H)-one is dissolved in EtOAc (F Form S1), 1,4-dioxane (Form S5), and THF (Form S8) It can be seen that it forms a solvate with

[0282] 5-Fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidine The 2(1H)-one reacts with toluene, 2-PrOH, and TBME in a thermodynamically stable reaction at room temperature. It was also found that the compound did not form a solvate. In these suspensions, the compound was found to be the anhydrous polymorph F ormI was formed.

[0283] 5-Fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidine It was found that 2(1H)-one does not form a kinetically stable solvate with MEK at room temperature. In these suspensions, the compound formed the anhydrous polymorph Form II.

[0284] 5-Fluoro-4-imino-3-methyl-1-tosyl-3,4-dihydropyrimidine 2(1H)-one forms a hydrate with water.

[0285] Form I is more pure than the hydrated form. Form I is a polymorph above 5°C. II, and at room temperature at a water activity of 0.3 or less, it is more thermodynamically stable than the hydrated form. is also thermodynamically stable and is non-hygroscopic, so it is resistant to dehydration in the solid state (solid Even at high relative humidity, the kinetic stability is high (hydrates are thermodynamically more stable at this temperature). Shows qualitative.

Claims

1. The following structure 【Chemistry 1】 The crystalline form of the compound having

2. a. the crystalline form is an anhydrous crystalline form, and the anhydrous crystalline form is a polymorph; b. the crystalline form is a hydrate, or c. The crystalline form is a solvate The crystalline form of claim 1.

3. The solvate contains 1,4-dioxane, tetrahydrofuran, or ethyl acetate. The crystalline form of claim 2.

4. the crystalline anhydrous polymorph has a powder X-ray diffraction pattern substantially in accordance with the pattern of Figure 1; Preferably, the powder X-ray diffraction pattern is 14.05, 17.51, 18.75, 21.

3. The crystalline form of claim 2, comprising peaks at 2-theta angle values ​​of 63 and 26.

51.

5. a. Differential scanning calorimetry (DSC) curve showing an endothermic peak with a peak temperature of about 160°C line, b. Differential scanning calorimetry (DSC) curve showing an endothermic peak with an onset temperature of approximately 159°C 、 c. Differential scanning calorimetry (DSC) showing an endothermic peak with a melting enthalpy of about 110 J / g. DSC curve, and / or d. TG-FTIR thermogram showing decomposition begins at temperatures above 210°C 5. The crystalline form of claim 4, characterized by:

6. the crystalline anhydrous polymorph has a powder X-ray diffraction pattern substantially in accordance with the pattern of Figure 4; Preferably, the powder X-ray diffraction pattern is 9.20, 11.88, 22.33 and 22.

3. The crystalline form of claim 2, comprising a peak at a 2-theta angle value of 59.

7. a. Differential scanning calorimetry (DSC) curve showing an endothermic peak with a peak temperature of about 157°C line, b. Differential scanning calorimetry (DSC) curve showing an endothermic peak with an onset temperature of approximately 156°C 、 c. Differential scanning calorimetry (DSC) showing an endothermic peak with an enthalpy of fusion of approximately 112 J / g. DSC curve, and / or d. TG-FTIR thermogram showing decomposition begins at temperatures above 210°C 7. The crystalline form of claim 6, characterized by:

8. Preferably, the crystalline hydrated form has a powder X-ray diffraction pattern substantially in accordance with the pattern of FIG. Preferably, the powder X-ray diffraction pattern is 5.34, 7.48, 10.68 and 16.05 3. The crystalline form of claim 2, comprising a peak at a 2-theta angle value of

9. a. Differential scanning calorimetry (DSC) showing an endothermic peak with a peak temperature of about 139.5°C ) Differential scanning calorimetry (DSC) curves, wherein the DSC is measured in a closed pan. 、 b. Differential scanning calorimetry (DSC) curve showing an endothermic peak with an onset temperature of approximately 139°C wherein the DSC is a differential scanning calorimetry (DSC) curve measured in a closed pan; c. Differential scanning calorimetry (DSC) showing an endothermic peak with an enthalpy of fusion of approximately 115 J / g. A differential scanning calorimetry (DSC) curve, wherein the DSC is measured in a closed pan. )curve, d. Differential scanning calorimetry (DSC) curve showing an endothermic peak with a peak temperature of about 160°C. A differential scanning calorimetry (DSC) curve measured in an open pan. 、 e. Differential scanning calorimetry (DSC) curve showing an endothermic peak with an onset temperature of approximately 159°C wherein the DSC is a differential scanning calorimetry (DSC) curve measured in an open pan; f. Differential scanning calorimetry (DSC) showing an endothermic peak with a melting enthalpy of about 98 J / g. The DSC is a differential scanning calorimetry (DSC) curve measured in an open pan. C) curves, and / or g. TG-FTIR thermogram showing decomposition begins at temperatures above 190°C 9. The crystalline form of claim 8, characterized by:

10. a. The crystalline solvate has a powder X-ray diffraction pattern substantially in accordance with the pattern in FIG. Preferably, the powder X-ray diffraction pattern is 5.42, 7.50, 10.82 and 16 Contains a peak at a 2-theta angle value of .91, b. The crystalline solvate has a powder X-ray diffraction pattern substantially in accordance with the pattern of FIG. Preferably, the powder X-ray diffraction pattern is 4.7, 5.00, 9.66 and 23.9 contains a peak at a 2-theta angle value of 7, or c. The crystalline solvate has a powder X-ray diffraction pattern substantially in accordance with the pattern of FIG. Preferably, the powder X-ray diffraction pattern is 5.34, 7.48, 10.68, 16. Contains peaks at 2-theta angle values ​​of 21.07 and 21.83 4. The crystalline form of claim 2 or 3.

11. a. TG-FTIR thermograms showing that decomposition begins at temperatures above 180°C; teeth b. TG-FTIR thermogram showing that decomposition begins at temperatures above 200°C 11. The crystalline form of claim 10, characterized by:

12. The following structure 【Chemistry 2】 A mixture of crystalline forms of a compound having a. A mixture of one or more crystalline forms according to any one of claims 1 to 11. b. A mixture of one or more crystalline forms according to any one of claims 4 to 7. c. A mixture of crystalline form I and crystalline form II, or d. A mixture of crystalline Form I and a crystalline hydrate form A mixture of

13. a. the mixture is at least 25% of crystalline Form I b. the mixture is at least 50% crystalline Form I, or c. the mixture is at least 75% of crystalline Form I The mixture of claim 12.

14. The mixture is a tank mix, and preferably the tank mix contains the compound and at least one other pesticidal compound.

14. The mixture according to claim 2 or 13.

15. The crystalline form of any one of claims 1 to 13 or any one of claims 12 to 14 A composition comprising the mixture described in claim 1.

16. 1. A fungicidal composition comprising: a. The crystalline form according to any one of claims 1 to 13 or any one of claims 12 to 14 a mixture according to claim 1 or 2, or b. The crystalline form according to any one of claims 1 to 13 or any one of claims 12 to 14 1. A mixture according to claim 1 and one or more fungicidal carriers.

1. A fungicidal composition comprising:

17. and optionally, said composition further comprises at least one additional fungicide. and at least one additional fungicide, preferably a. the at least one additional fungicide is a fungicidal sterol biosynthesis inhibitor; b. the at least one additional fungicide is a succinate dehydrogenase inhibitor 、 c. the at least one additional fungicide is a strobilurin fungicide, and / or or d. The at least one additional fungicide is a fungicidal multi-site inhibitor.

17. The composition of claim 16.

18. a. The sterol biosynthesis inhibitor is prothioconazole, epoxiconazole, cyproconazole, Roconazole, myclobutanil, prochloraz, metconazole, difenoconazole, Tebuconazole, tetraconazole, fenbuconazole, propiconazole, fluquin From the group consisting of conazole, flusilazole, flutriafol, and fenpropimorph Preferably, the sterol biosynthesis inhibitor is selected from the group consisting of epoxiconazole, cipro, Conazole, myclobutanil, metconazole, propiconazole, prothioconazole , fluquinconazole, flutriafol, and difenoconazole And, b. The succinate dehydrogenase inhibitor is selected from the group consisting of fluxapyroxad, benzovindifluthrin, and the like. Pill, penthiopyrad, isopyrazam, bixafen, boscalid, penflufen, and and fluopyram, and preferably, the succinate dehydrogenase inhibitor The drugs include fluxapyroxad, benzovindiflupyr, penthiopyrad, isopyrazam, selected from the group consisting of boscalid and fluopyram; c. The strobilurin fungicide is pyraclostrobin, fluoxastrobin, azotobacter, Zoxystrobin, trifloxystrobin, picoxystrobin, and kresoxim methyl; and / or d. The fungicidal multi-site inhibitor is chlorothalonil, mancozeb, folpet, and captan, preferably the fungicidal multi-site inhibitor is selected from the group consisting of fulvastatin, fulvastatin, captan ... Volpet or Captan 18. The composition of claim 17.

19. a. the composition is a solid composition, or b. The composition is a liquid composition. A composition comprising the crystalline form of any one of claims 15 to 18.

20. 1. A fungicidal composition comprising: a. structure 【Transformation 3】 or a solution of a compound having b. A solution of the crystalline form according to any one of claims 1 to 11 or any one of claims 12 to 14 A solution of the mixture according to any one of claims 1 to 4.

1. A fungicidal composition comprising:

21. 21. The composition according to any one of claims 12 to 20, further comprising at least one excipient. The composition described in

22. The composition further comprises at least one excipient for the preparation of a tank mix.

22. The composition according to any one of claims 12 to 21.

23. 1. A method for controlling fungal attack on a plant, said method comprising: a.i) the following structure: 【Chemistry 4】 obtaining a crystalline form of a compound having the formula: ii) on the site where the fungus is present, on the site to be prevented from infestation, and / or on the plant. spraying the crystalline form to thereby control fungal attack on said plants; or b. The crystalline form according to any one of claims 1 to 11, any one of claims 12 to 14 or the composition according to any one of claims 15 to 22, and / or spraying the plant at the location where the infestation is to be prevented, thereby preventing Steps for controlling fungal attack on plants A method for providing the above.

24. 1. A method for controlling fungal attack on plants, said method comprising: and spraying the synergistic fungicidal mixture on the plant and / or in the area to be prevented from being infested by the fungus. wherein the mixture comprises: i) a bactericidal amount of the crystalline form of any one of claims 1 to 11, claims 12 to 14 or a composition according to any one of claims 15 to 22, and ii) at least one additional fungicide thereby controlling fungal attack on said plant.

25. A method for controlling fungal attack on roots and / or seeds and / or plants, said method comprising: 、 a. i) Structure 【Transformation 5】 obtaining a solution of a compound having ii) on the roots, seeds or foliage of the plant at the location where infestation is to be prevented, and / or spraying the solution on the plants, thereby infusing the roots and / or seeds and / or plants combating fungal attack, or b. i) a solution of the crystalline form according to any one of claims 1 to 11, or claims 12 to 1 4. Obtaining a solution of the mixture according to any one of claims 1 to 3; ii) on the roots, seeds or foliage of the plant at the location where the infestation is to be prevented and / or spraying the solution on the plants, thereby infecting the roots and / or seeds and / or plants with the fungus Steps to mitigate the attack A method for providing the above.

26. 26. The method of any one of claims 23 to 25, wherein the mixture is a tank mix.

27. 1. A method for controlling fungal attack on a plant, said method comprising: i) Structure 【Transformation 6】 obtaining a composition of a compound having ii) applying the fungus to the location where it is present, to the location where its infestation is to be prevented, and / or to the plant. spraying the composition to thereby control fungal attack on the plant. A method for providing the above.

28. A method for controlling fungal attack on roots and / or seeds and / or plants, said method comprising: 、 i) Structure 【Transformation 7】 obtaining a composition of a compound having ii) on the roots, seeds or foliage of the plant at the location where infestation is to be prevented, and / or The plant is sprayed with the composition, thereby infusing the roots and / or seeds and / or roots of the plant. Steps to prevent fungal attack A method for providing the above.

29. (a) a method for controlling fungal attack on a plant, said method comprising: i) obtaining a composition according to any one of claims 15 to 22, and ii) on the site where the fungus is present, on the site to be prevented from infestation, and / or on the plant. spraying the composition to thereby control fungal attack on the plant. Method, or (b) a method for controlling fungal attack on plants and / or roots and / or seeds, comprising the steps of: The method is i) obtaining a composition according to any one of claims 15 to 22, and ii) plant growth regulators to control various fungi without damaging the commercial value of the plant; spraying the composition on the roots, seeds or foliage of the plant; A method for providing the above.

30. 6. A process for preparing the crystalline anhydrous polymorphic form of claim 4 or 5, comprising: i) in an organic solvent, 【Transformation 8】 providing a compound having the formula: ii) filtering the precipitated solid from the solution of step i). A process comprising:

31. The organic solvent is toluene, isopropanol, tetrahydrofuran, methyl tert -butyl ether, cyclopentyl methyl ether, methyl tetrahydrofuran and / or is diethyl carbonate, and preferably the organic solvent is toluene, isopropanol 31. The method according to claim 30, wherein the solvent is methyl tert-butyl ether, tetrahydrofuran, or methyl tert-butyl ether. process.

32. It further comprises water mixed with said organic solvent, and preferably said organic solvent is isopropanol. Preferably, the mixture of isopropanol and water has a water activity of 0.1 or 0.

3.

32. The process of claim 31, wherein

33. a. (i) providing the compound in toluene or tert-butyl ether and (ii) filtering the precipitated solid from the solution of step i), forming the crystalline polymorph by suspension crystallization b. (i) providing said compound in toluene; and (ii) reacting step i). filtering the solid precipitated from the solution, wherein the crystalline polymorph is obtained by cooling crystallization. Steps formed by c. (i) providing the compound in methyltetrahydrofuran and diethyl carbonate and (ii) filtering the precipitated solid from the solution of step i). wherein the crystalline polymorph is formed by cooling crystallization. d. (i) providing said compound in tetrahydrofuran; and (ii) Step i) filtering the solid precipitated from the solution, wherein the crystalline polymorph is , by evaporation crystallization, or e. (i) providing said compound in cyclopentyl methyl ether, and ii) filtering the precipitated solid from the solution of step i), Polymorphs are formed by evaporative crystallization The process of any one of claims 30 to 32, comprising:

34. the solution is prepared at room temperature or at a temperature in the range of about 50°C to about 60°C; and / or a. The solution of step i) is stirred at room temperature for 1-15 days before proceeding to step ii). or b. The solution of step i) is stirred at room temperature for about 11 days before proceeding to step ii). can The process of any one of claims 30 to 33.

35. 8. A process for preparing the crystalline anhydrous polymorphic form of claim 6 or 7, comprising: i) a molecule of the following structure: 【Chemistry 9】 providing a solution of a compound having the formula: ii) filtering the precipitated solid from the solution of step i). A process comprising:

36. 36. The method of claim 35, wherein the organic solvent is methyl ethyl ketone or tetrahydrofuran. process.

37. It further comprises water mixed with said organic solvent, and preferably said organic solvent is tetrahydrofuran. and preferably the mixture of tetrahydrofuran and water is 0.1 or 0.3% water. The process of claim 36, having a partial activity.

38. i) providing the compound in methyl ethyl ketone; and ii) filtering the precipitated solid from the solution of step i).

36. The process of claim 35, wherein the crystalline polymorph is formed by suspension crystallization.

39. the solution is prepared at room temperature, and / or a. The solution of step i) is stirred at room temperature for 1-15 days before proceeding to step ii). or b. The solution of step i) is stirred at room temperature for about 11 days before proceeding to step ii). can The process of any one of claims 35 to 38.

40. 10. A process for preparing the crystalline hydrated form of claim 8 or 9, comprising: i) a molecule of the following structure: 【Chemistry 10】 providing a solution of a compound having the formula: ii) filtering the precipitated solid from the solution of step i). A process comprising:

41. The organic solvent is acetonitrile, methanol, ethyl acetate, ethanol, acetone, tetrahydrofuran, dichloromethane, methyltetrahydrofuran, and / or 1-pro and the organic solvent is preferably acetonitrile, methanol, or ethyl acetate. ethanol, acetone, tetrahydrofuran, or dichloromethane. The process of.

42. It further comprises water mixed with said organic solvent, preferably said mixture of organic solvent and water comprising:

42. The process of claim 41, wherein the mixture is 4:1 acetonitrile:water.

43. a. (i) providing said compound in acetonitrile for at least 3 hours; and ii) filtering the precipitated solid from the solution of step i), forming the polymorph by cooling crystallization; b. (i) providing said compound in methanol, and (ii) step i) filtering the precipitated solid from the solution of forming a c. (i) providing the compound in ethanol for at least 3 days; and i) filtering the solid precipitated from the solution of step i), forming the form by cooling crystallization; d. (i) providing said compound in ethyl acetate for at least 3 weeks; and i) filtering the solid precipitated from the solution of step i), forming the form by cooling crystallization; e. (i) providing said compound in methyltetrahydrofuran and methanol. and (ii) filtering the precipitated solid from said solution of step i). wherein the crystalline polymorph is formed by cooling crystallization; f. (i) providing the compound in methyltetrahydrofuran and 1-propanol and (ii) filtering the precipitated solid from the solution of step i). wherein the crystalline polymorph is formed by cooling crystallization; g. (i) providing said compound in water mixed with methyltetrahydrofuran and (ii) filtering the precipitated solid from the solution of step i), forming the crystalline polymorph by cooling crystallization; h. (i) providing said compound in acetone, and (ii) filtering the solid precipitated from the solution, wherein the crystalline polymorph is obtained by evaporative crystallization; or i. (i) providing the compound in dichloromethane, and (ii) i) filtering the precipitated solid from the solution, Steps formed by crystallization The process of any one of claims 40 to 42, comprising:

44. The solution is prepared at about 47°C, about 52°C, or about 60°C, and / or step i) is stirred at about 25° C. for 16 to 20 hours before proceeding to step ii).

44. The process of any one of claims 40 to 43.

45. 12. A process for preparing the crystalline solvated form of claim 10 or 11, comprising: a.i) the following structure: 【Chemistry 11】 providing a solution of a compound having the formula: ii) filtering the precipitated solid from the solution of step i); b.i) the structure: 【Chemistry 12】 providing a tetrahydrofuran solution of a compound having the formula: ii) filtering the precipitated solid from the solution of step i); and iii) concentrating the mother liquor from the filtration of step ii) by evaporation; or c. i) the following structure: 【Chemistry 13】 providing an ethyl acetate solution of a compound having the formula: ii) filtering the precipitated solid from the solution of step i). A process comprising:

46. the solution is prepared at room temperature and / or a. The solution of step i) is stirred at room temperature for 1-15 days before proceeding to step ii). or b. The solution of step i) is stirred at room temperature for about 11 days before proceeding to step ii). can 46. ​​The process of claim 45.

47. the solution is prepared at about 30°C; and / or a. The solution of step i) is stirred at room temperature for 16-36 hours before proceeding to step ii). Stirred, or b. The solution of step i) is stirred at room temperature for about 24 hours before proceeding to step ii). can 46. ​​The process of claim 45.

48. a. the solution is prepared at about 60°C, and / or b. The solution of step i) is heated at about 25°C for 16-20 minutes before proceeding to step ii). Stirred for a period of time 46. ​​The process of claim 45.

49. a) providing the compound in ethyl acetate, and b) filtering the precipitated solid from the solution of step i); 46. ​​The process of claim 45, wherein the crystalline polymorph is formed by cooling crystallization.

50. A crystalline anhydrous polymorphic form according to claim 4 or 5 and a crystalline hydrated form according to claim 8 or 9. A process for preparing a mixture consisting of: a) the following structure: 【Chemistry 14】 providing a solution of a compound having the formula: b) filtering the precipitated solid from the solution of step a), preferably The organic solvent is methyltetrahydrofuran and / or isopropanol. P A process comprising:

51. a) providing said compound in methyltetrahydrofuran and isopropanol; pu, and b) filtering the precipitated solid from the solution of step a).

51. The process of claim 50, wherein the crystalline polymorph is formed by evaporative crystallization.

52. 52. The process of claim 50 or 51, wherein the solution is prepared at about 50°C.

53. A process for preparing the crystalline form of any one of claims 1 to 11, comprising: a. The crystalline form has the following structure in a suitable solvent: 【Chemistry 15】 It is prepared by cooling and crystallizing a compound having the formula: b. The crystalline form has the following structure in a suitable solvent: 【Chemistry 16】 or c. The crystalline form has the following structure in a suitable solvent: 【Chemistry 17】 It is prepared by suspension crystallization of a compound having the formula process.

54. 1. A process for producing a fungicidal composition, said process comprising: a. The crystalline form according to any one of claims 1 to 11 or any one of claims 12 to 14 1. To obtain the mixture according to claim 1 and to prepare the fungicidal composition therewith, with an excipient; or b. The crystalline form according to any one of claims 1 to 11 or any one of claims 12 to 14 1. To obtain the mixture according to claim 1 and to prepare the fungicidal composition therewith, combining with an auxiliary agent. A process comprising:

55. The solution of step i) is stirred at room temperature for 0.5 to 24 hours before proceeding to step ii). Preferably, the solution of step i) is allowed to stand at room temperature for about 2 hours before proceeding to step ii).

46. ​​Any one of claims 30 to 33, 35 to 38, 40, 43, or 45, wherein the mixture is stirred for a period of time. The process described in

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