FUNGICIDAL SC FORMULATIONS 1. FIELD OF THE INVENTION [0001] Aspects of the disclosure relate to compositions, especially stable aqueous suspension concentrates (SC) of (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3- acetoxy-4-methoxypicolinoyl)-L-alaninate (Compound I), also disclosed herein are stable compositions including crystalline forms of (S)-1,1-bis(4- fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoyl)-L-alaninate (Compound I), each for use in agriculture. 2. BACKGROUND [0002] Liquid pre-mix concentrates containing a pesticide or otherwise pesticidally active ingredient are useful in a wide variety of agricultural applications. For example, two or more pesticidal active ingredients may be combined in order to control a wider spectrum of pests, or to utilize multiple modes of action, compared to the individual active ingredients alone. [0003] Water insoluble pesticide active ingredients may be formulated in water as aqueous suspension concentrates (SC) or by dissolving the water insoluble pesticide in an organic solvent and forming an emulsifiable concentrate (EC). The preparation of these liquid, pre-mix concentrates can be challenging owing to chemical and/or physical instability issues. [0004] Suspension concentrate compositions, SC’s, are widely used in crop protection. It was an object of the present disclosure to provide a suspension concentrate which overcome certain limitations of, e.g. stability, amongst others, of formulations of Compound I. 3. SUMMARY [0005] In some aspects of the disclosure herein provides fungicidal compositions comprising (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoyl)- L-alaninate (Florylpicoxamid, i.e. Compound I) and acid that are stable, that possess a significantly increased biological activity or significantly better toxicity profile. Further, said compositions are tested to have compatible emulsifiers, dispersants and adjuvants. [0006] In some aspects of the disclosure herein provides fungicidal compositions that include a second fungicidal compound.
[0007] In some aspects of the disclosure herein provides fungicidal compositions that include adjuvant(s) that improves the fungicidal performance of the composition. [0008] In some aspects of the disclosure herein provides fungicidal compositions comprising a fungicidal compound of the Compound I:
, fatty acid ethoxylate; surfactant, and acid. [0009] In some aspects, the composition includes organic acid. [0010] In some aspects, Compound I is a polymorph. [0011] In some aspects, the present disclosure provides a process to make stable aqueous compositions of Compound I. 4. DETAILED DESCRIPTION Active [0012] Some aspects of the disclosure described herein include fungicidal compositions in the form of an suspension concentrate (SC) that contains a fungicidally effective amount of Compound I, Florylpicoxamid. The chemical structure of (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4-methoxypicolinoyl)- L-alaninate (Compound I) is:
. [0013] A description of the structure, synthesis, and use of Compound I is found in International Patent Application Number: PCT/US2015/066760, which is hereby incorporated by reference in its entirety along with all the references cited therein.
Moreover, Compound I is a known fungicide and provides control of a variety of fungal pathogens in economically important crops including, but not limited to, the causal agent of barley scald, Rhynchosporium secalis (RHYNSE). [0014] In some aspects Compound I is a polymorph A. In some aspects Compound I is a polymorph B. In still other aspects Compound I is a mixture of both polymorph A and B. Compound I is unusually difficult to make in a crystalline form. The amorphous material isolated from working up an organic layer containing Compound I, either by column chromatography or by isolation of a salt, results in the formation of an agglomerated solid. [0015] In fact, it was found that one tried and true method to increase the crystalline formation of an organic compound was not successful for Compound I. Specifically, increasing the oil concentration of a crude suspension containing Compound I (and seed) did not induce crystallization. The procedure followed was: an acid wash procedure was used on the crude reaction mixture containing Compound I, which created more oil during the crystallization. The temperature was then increased during a solvent exchange which increased the oil concentration as well. After the solvent exchange, the temperature was held at 30 °C for 2 hours, then cooled to 8 °C over 12 hours. The following morning, the reaction mixture had completely oiled. The resulting sample showed that the concentration was 7.02 wt% of Compound I. The mixture was readily redissolved, seeded with 1% seed Compound I (relative to Compound I in the mixture) at 25 °C. The general temperature profile (holding at 25 °C for two hours, cooling to 8 °C over 12 hours) produced Compound I agglomerates stuck inside of the reactor. After initiating the filtration of the solids, the cake was washed and attempted to be collected. Unfortunately, more agglomerates were observed throughout the filtered reaction slurry. [0016] A stable form screen of Compound I was carried out. Many screening experiments produced either an oil or gel of Compound I. Two polymorphs were identified, designated as forms A and B. It was determined that the forms are monotropic. The melting point of each of the two crystalline forms is about 90 °C, while the amorphous form exhibited a glass transition (Tg) event near 55 °C. The crystalline materials are flowable. [0017] The described fungicidal compositions herein exhibit good storage stability and readily forms a stable, non-homogenous suspension upon dilution in water or any other aqueous solution and is and/or will perform as a spray formulation. The described fungicidal composition exhibits protectant and curative
control of the important fungal diseases. Some of these diseases include Septoria tritici (wheat leaf blotch) and Puccinia triticina (wheat brown rust) when utilized in spray applications. [0018] In some aspects the fungicidal compositions described herein may comprise, with respect to the composition, from about 1 gram active ingredient per liter (g ai/L) to about 1.3 kg ai/L, from about 5 g ai/L to about 10 kg ai/L, from about 10 g ai/L to about 10 kg ai/L, from about 20 g ai/L to about 10 kg ai/L, from about 25 g ai/L to about 10 kg ai/L, from about 30 g ai/L to about 10 kg ai/L, from about 40 g ai/L to about 10 kg ai/L, from about 25 g ai/L to about 10 kg ai/L, from about 50 g ai/L to about 10 kg ai/L, from about 60 g ai/L to about 10 kg ai/L, from about 70 g ai/L to about 10 kg ai/L, from about 80 g ai/L to about 10 kg ai/L, from about 90 g ai/L to about 10 kg ai/L, from about 100 g ai/L to about 10 kg ai/L, from about 200 g ai/L to about 10 kg ai/L, from about 500 g ai/L to about 10 kg ai/L, from about 750 g ai/L to about 10 kg ai/L, from about 2 kg ai/L to about 10 kg ai/L, from about 5kg ai/L to about 10 kg ai/L, from about 7 kg ai/L to about 10 kg ai/L, from about 8 kg ai/L to about 10 kg ai/L, of the compound of Compound I. Surfactants [0019] The fungicidal composition described herein may include more than one surfactant which may include one or more than one each of an ionic and a non- ionic surfactant. Such surfactants may be used as an emusifier, dispersant, solubilizer, wetter, penetrant, protective colloid, or for other purposes. Examples of surfactants are listed in McCutcheon's, Vol.1: Emulsifiers & Detergents, McCutcheon's Directories, Glen Rock, USA, 2008 (International Ed. or North American Ed.). Since the described fungicidal composition is a suspension concentrate (SC), surfactants are used as wetters and dispersant that protect and disperse AI microparticle in aqueous phase, as well as being used as surfactants to emulsifer oil adjuvants when appliable. [0020] Suitable dispersants for use in the SCs with the fungicidal composition described herein may include anionic polymers, such as poly(meth)acrylate, polystyrene, polyacrylamides, polyolefins, alkylaryl polymers, liginins with carboxylates, sulfonates dangling groups, and mixtures thereof. [0021] In some aspects the fungicidal composition described herein may comprise, with respect to the composition, from about 1 gram per liter (g/L) to about 100 g/L, from about 5 g/L to about 100 g/L, from about 10 g/L to about 100 g/L, from about 20 g/L to about 100 g/L, from about 30 g/L to about 100 g/L,
from about 30 g/L to about 90 g/L, from about 30 g/L to about 80 g/L, from about 40 g/L to about 70 g/L, from about 50 g/L to about 70 g/L, or from about 55 g/L to about 65 g/L of at least one of the anionic polymer dispersants. [0022] Suitable dispersants for use in the SCs with the fungicidal composition described herein may include nonionic polymers, such as poly(meth)acrylate, polystyrene, polyacrylamides, with poly(ethylene oxide) i.e., poly(ethylene gylcol) dangling groups, and mixtures thereof. Examples of PEO-containing nonionic dispersants are Polystyrene-PEO copolymers and Tristyrylphenol ethoxylate. [0023] In some aspects the fungicidal composition described herein may comprise, with respect to the composition, from about 1 gram per liter (g/L) to about 100 g/L, from about 5 g/L to about 100 g/L, from about 10 g/L to about 100 g/L, from about 20 g/L to about 100 g/L, from about 30 g/L to about 100 g/L, from about 30 g/L to about 90 g/L, from about 30 g/L to about 80 g/L, from about 40 g/L to about 70 g/L, from about 50 g/L to about 70 g/L, or from about 55 g/L to about 65 g/L of at least one of the nonionic polymer dispersants. [0024] Suitable ionic surfactants for use in the SCs described herein may include anionic surfactants such as alkali, alkaline earth or ammonium salts of sulfonates, sulfates, phosphates, carboxylates, and mixtures thereof. Examples of sulfonates are alkylarylsulfonates, diphenylsulfonates, alpha-olefin sulfonates, lignin sulfonates, sulfonates of fatty acids and oils, sulfonates of ethoxylated alkylphenols, sulfonates of alkoxylated arylphenols, sulfonates of condensed naphthalenes, sulfonates of dodecyl- and tridecylbenzenes, sulfonates of naphthalenes and alkylnaphthalenes, sulfosuccinates or sulfosuccinamates. Examples of sulfates are sulfates of fatty acids and oils, of ethoxylated alkylphenols, of alcohols, of ethoxylated alcohols, or of fatty acid esters. Examples of phosphates are phosphate esters. Examples of carboxylates are alkyl carboxylates, and carboxylated alcohol or alkylphenol ethoxylates. Preferred anionic surfactants are sulfates and sulfonates. [0025] In some aspects the ionic surfactant for use with the fungicidal composition described herein may include an anionic surfactant such as an alkali, alkaline earth or ammonium salt of an alkylarylsulfonic acid such as sulfonate salts of dodecyl- and/or tridecylbenzenes, sulfonate salts of naphthalenes and/or alkylnaphthalenes, and salts of sulfosuccinates and/or sulfosuccinamates. In some aspects the ionic surfactant is an alkaline earth salt of an alkylaryl sulfonate. In some aspects the ionic surfactant is an alkaline earth salt of an arylsulfosuccinates.
[0026] In some aspects the fungicidal composition described herein may comprise, with respect to the composition, from about 1 gram per liter (g/L) to about 100 g/L, from about 5 g/L to about 100 g/L, from about 10 g/L to about 100 g/L, from about 20 g/L to about 100 g/L, from about 30 g/L to about 100 g/L, from about 30 g/L to about 90 g/L, from about 30 g/L to about 80 g/L, from about 40 g/L to about 70 g/L, from about 50 g/L to about 70 g/L, or from about 55 g/L to about 65 g/L of at least one of an ionic surfactant. [0027] In some aspects, the fungicidal composition described herein may include a nonionic surfactant. Suitable nonionic surfactants for use with the fungicidal compositions described herein may include alkoxylates, N-substituted fatty acid amides, amine oxides, esters, sugar-based surfactants, polymeric surfactants, castor oil ethoxylate, and mixtures thereof. Examples of alkoxylates are compounds such as alcohols, alkylphenols, amines, amides, arylphenols, fatty acids or fatty acid esters which have been alkoxylated with from 1 to 50 molar equivalents of an alkoxylating agent such as ethylene oxide (EO) and/or propylene oxide (PO). [0028] In some aspects the fungicidal composition described herein may include a nonionic surfactant that is an alkoxylate such as, for example, an alcohol initiated EO/PO block copolymer such as a butanol initiated EO/PO block copolymer, which may also be known as a polyalkylene glycol monobutyl ether, a poly(ethylene glycol-co-propylene glycol) monobutyl ether, or a propylene oxide ethylene oxide polymer monobutyl ether. In some aspects the butanol initiated EO/PO block copolymer may have a degree of ethoxylation of from about 20 to about 30 and a degree of propoxylation of from about 20 to about 30. [0029] In some aspects the fungicidal composition described herein may include a nonionic surfactant that is a castor oil ethoxylate. In some aspects the castor oil ethoxylate may have a degree of ethoxylation of from about 10 to about 40. [0030] In some aspects the nonionic surfactant for use with the fungicidal composition described herein that is ahigh purity castor oil ethoxlyate may provide improved active ingredient stability to the composition. [0031] In some aspects the fungicidal composition described herein may include a nonionic surfactant that is a sorbitan ethoxylate such as a sorbitan triloeate ethoxylate, a sorbitan monooleate ethoxylate. In some aspects the sorbitan ethoxylate may have a degree of ethoxylation from about 1 to about 50.
[0032] In some aspects the fungicidal composition described herein may include surfactants selected from the group consisting of at least one ionic surfactant that is an anionic surfactant and at least two non-ionic surfactants. [0033] In some aspects the fungicidal composition described herein may comprise, with respect to the composition, from about 1 gram per liter (g/L) to about 300 g/L, from about 10 g/L to about 190 g/L, from about 10 g/L to about 180 g/L, from about 20 g/L to about 160 g/L, from about 30 g/L to about 150 g/L, from about 40 g/L to about 140 g/L, from about 50 g/L to about 130 g/L, from about 60 g/L to about 120 g/L, from about 70 g/L to about 110 g/L, from about 80 g/L to about 100 g/L, or from about 85 g/L to about 95 g/L of at least one of a non-ionic surfactant. [0034] In certain aspects, the described fungicidal composition may include a second fungicidal compound. Suitable second fungicidal compounds may include, for example, azoxystrobin, bifujunzhi, coumethoxystrobin, coumoxystrobin, dimoxystrobin, enestroburin, enoxastrobin, fenaminstrobin, fenoxystrobin, flufenoxystrobin, fluoxastrobin, jiaxiangjunzhi, kresoxim-methyl, mandestrobin, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin, pyrametostrobin, pyraoxystrobin, triclopyricarb, trifloxystrobin, methyl 2-[2-(2,5- dimethylphenyloxymethyl)phenyl]-3-methoxyacrylate, pyribencarb, triclopyricarb/chlorodincarb, famoxadon, fenamidon, cyazofamid, amisulbrom, benodanil, bixafen, boscalid, carboxin, fenfuram, fluopyram, flutolanil, fluxapyroxad, furametpyr, isopyrazam, mepronil, oxycarboxin, penflufen, penthiopyrad, sedaxane, tecloftalam, thifluzamide, N-(4'-trifluoromethylthio- biphenyl-2-yl)-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide, N-(2-(1 ,3,3- trimethylbutyl)phenyl)-1,3-dimethyl-5-fluoro-1 H-pyrazole-4-carboxamide, N-[9- (dichloromethylene)-l,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl]-3- (difluoromethyl)-1- methyl-1 H-pyrazole-4-carboxamide, diflumetorim, binapacryl, dinobuton, dinocap, meptyl-dinocap, fluazinam, ferimzone, ametoctradin, silthiofam, azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, diniconazole-M, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imibenconazole, ipconazole, metconazole, myclobutanil, oxpoconazole, paclobutrazole, penconazole, propiconazole, prothioconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triticonazole, uniconazole, imazalil, pefurazoate, prochloraz, triflumizole, pyrimidines, fenarimol, nuarimol, pyrifenox, triforine, aldimorph, dodemorph, dodemorph acetate, fenpropimorph, tridemorph, fenpropidin,
piperalin, spiroxamine, fenhexamid, benalaxyl, benalaxyl-M, kiralaxyl, metalaxyl, metalaxyl-M (mefenoxam), ofurace, oxadixyl, hymexazole, octhilinone, oxolinic acid, bupirimate, benomyl, carbendazim, fuberidazole, thiabendazole, thiophanate- methyl, 5-chloro-7-(4-methyl- piperidin-1-yl)-6-(2,4,6-trifluorophenyl)-[1 ,2,4]triazolo[1 ,5-a]pyrimidine, diethofencarb, ethaboxam, pencycuron, fluopicolid, zoxamid, metrafenon, pyriofenon, cyprodinil, mepanipyrim, pyrimethanil, fluoroimide, iprodione, procymidone, vinclozolin, fenpiclonil, fludioxonil, quinoxyfen, edifenphos, iprobenfos, pyrazophos, isoprothiolane, dicloran, quintozene, tecnazene, tolclofos-methyl, biphenyl, chloroneb, etridiazole, dimethomorph, flumorph, mandipropamid, pyrimorph, benthiavalicarb, iprovalicarb, valifenalate and 4-fluorophenyl N-(1 -(1 -(4- cyanophenyl)ethanesulfonyl)but-2-yl)carbamate, propamocarb, propamocarb hydrochloride, ferbam, mancozeb, maneb, metiram, propineb, thiram, zineb, ziram, anilazine, chlorothalonil, captafol, captan, folpet, dichlofluanid, dichlorophen, flusulfamide, hexachlorobenzene, pentachlorophenol, phthalid, tolylfluanid, N-(4- chloro-2-nitrophenyl)-N-ethyl-4-methylbenzenesulfonamide, guanidine, dithianon, validamycin, polyoxin B, pyroquilon, tricyclazole, carpropamid, dicyclomet, fenoxanil, benzovindiflupyr, isoflucypram, fluindapyr, mefentrifluconazole, metyltetraprole; folpet; sulphur (sulfur) and any mixtures thereof. [0035] In some aspects, the described fungicidal composition that includes a second fungicidal compound may show synergistic fungicidal activity. [0036] In some aspects the fungicidal composition described herein may comprise, with respect to the composition, from about 1 gram active ingredient per liter (g ai/L) to about 200400g ai/L, from about 5 g ai/L to about 200 g ai/L, from about 10 g ai/L to about 150 g ai/L, from about 20 g ai/L to about 150 g ai/L, from about 20 g ai/L to about 125 g ai/L, from about 20 g ai/L to about 10 g ai/L, from about 20 g ai/L to about 90 g ai/L, from about 30 g ai/L to about 90 g ai/L, from about 40 g ai/L to about 90 g ai/L, from about 40 g ai/L to about 80 g ai/L, from about 45 g ai/L to about 75 g ai/L, or from about 45 g ai/L to about 70 g ai/L of the second fungicidal compound. The fungicidal composition described herein may also comprise from about from about 30 g ai/L to about 150 g ai/L, from about 40 g ai/L to about 150 g ai/L, from about 50 g ai/L to about 150 g ai/L, from about 60 g ai/L to about 150 g ai/L, from about 70 g ai/L to about 150 g ai/L, from about 80 g ai/L to about 150 g ai/L, from about 90 g ai/L to about 150 g ai/L, from about 10 kg ai/L to about 150 g ai/L, from about 110 g ai/L to about 150 g ai/L, from about 120 g ai/L to about 150 g ai/L, from about 125 g ai/L to
about 140 g ai/L, or from about 125 g ai/L to about 135 g ai/L of the second fungicidal compound. Adjuvants [0037] Adjuvants are compounds which have negligible or even no pesticidal activity themselves, and which improve the biological performance of a pesticidal composition on one or more target pests. Examples of such adjuvants may include surfactants such as alcohol ethoxylates, alcohol alkoxylate, alkyl naphthalene sulphonates, alkyl phosphonates, alkylbenzene sulphonates, benzyldimethylcocalkyl ammonium salts, sorbitan ester ethoxylates, and modified organosilicones; also, mineral or vegetable oils, and other auxilaries. Further examples of adjuvants are listed by Knowles in, “Adjuvants and Additives,” Agrow Reports DS256, T&F Informa UK, 2006, Chapter 5. [0038] In some aspects, the fungicidal composition described herein may include an adjuvant to improve fungicidal performance. [0039] In some aspects, the fungicidal composition described herein may include an adjuvant to improve fungicidal performance selected from the class of modified organosilicone surfactants such as, for example, the polyether modified organopolysiloxanes such as Break-thru® S233, which is available from Evonik Industries (Parsippany, NJ). [0040] In some aspects, the fungicidal composition described herein may include an adjuvant to improve fungicidal performance selected from the class of alkyl phosphonate adjuvants such as, for example, bis (2-ethylhexyl) 2- ethylhexylphosphonate (also known as BEEP), which is available from Rhodia (Cranberry, NJ). [0041] In some aspects, non-ionic surfactants such as, for example, an alcohol alkoxylate may serve as an adjuvant that improves the fungicidal performance of the fungicidal composition described herein. [0042] In some aspects, the fungicidal composition described herein may include, with respect to the composition, from about 1 g/L to about 400 g/L of one or more adjuvants used to improve fungicidal performance. In some aspects, the fungicidal composition may include from about 1 g/L to about 150 g/L, from about 5 g/L to about 150 g/L, from about 10 g/L to about 150 g/L, from about 20 g/L to about 150 g/L, from about 25 g/L to about 140 g/L, from about 30 g/L to about 130 g/L, from about 35 g/L to about 125 g/L, from about 40 g/L to about 120 g/L, from about 40 g/L to about 110 g/L, from about 40 g/L to about 100 g/L, from about 40 g/L to about 90 g/L, from about 40 g/L to about 80 g/L, from about 40
g/L to about 70 g/L, from about 50 g/L to about 70 g/L, from about 40 g/L to about 130 g/L, from about 50 g/L to about 120 g/L, from about 60 g/L to about 120 g/L, from about 70 g/L to about 120 g/L, from about 80 g/L to about 120 g/L, from about 90 g/L to about 120 g/L, or from about 100 g/L to about 120 g/L, of one or more adjuvants used to improve fungicidal performance. Storage Stability [0043] As used herein, stable compositions are compositions that are stable physically and/or chemically for defined periods of time to the environments in which they are produced, transported and/or stored. Aspects of stable compositions include, but are not limited to: physical stability at temperatures that range from about 0 °C to about 54 °C, homogeneity, pourability, liquids that form little or no precipitated solids or crystals or exhibit little or no phase separation, compositions that readily emulsify when poured into a spray tank of water and retain their biological efficacy when applied, for example, by spray application to target pests. [0044] In some aspects, the described composition forms a stable suspension concentrate that does not exhibit appreciable phase separation under the storage conditions. In some aspects, the described composition exhibits very little change in viscosity under the storage conditions. In some aspects, the described composition exhibits very little chemical decomposition of the active ingredient or active ingredients under the storage conditions. [0045] In some aspects, the described fungicidal composition is stable at temperatures of greater than or equal to about 25 °C for a period of at least 2, 4, 6 or 8 weeks. In some aspects, the described composition is stable at temperatures of greater than or equal to about 40 °C for a period of at least 2, 4, 6 or 8 weeks. In some aspects, the described composition is stable at temperatures of greater than or equal to about 54 °C for a period of at least about 2 weeks. [0046] In some aspects, the described fungicidal composition does not exhibit or does not significantly exhibit separation, precipitation or crystallization of any of the components at low temperatures. In some aspects, the described fungicidal composition remains as a stable suspension concentrate after storage for at least about 2 weeks at temperatures below about 20 °C, below about 10 °C, or equal to or less than about 5 °C, or equal to or less than about 0 °C, or equal to or less than about -5 °C, or equal to or less than about -10 °C. In certain aspects, the compositions are stable at these temperatures for at least about 2, 4, 6, or 8 weeks.
[0047] In some aspects, the described fungicidal composition remains as a stable suspension concentrate after subjecting it to freeze/thaw (F/T) conditions for at least about 2 or 4 weeks where the temperature is cycled from about -10 °C to about 40 °C every 24 hours. [0048] In some aspects, the chemical stability of the active ingredient or active ingredients in the described fungicidal composition may be improved by selecting proper dispersants in the composition. [0049] In some aspects, the chemical stability of the active ingredient or active ingredients in the described fungicidal composition may be improved by including a nonionic surfactant in the composition. [0050] In some aspects, the chemical stability of the active ingredient or active ingredients in the described fungicidal composition may be improved by an addition of acid or organic acid in the composition. [0051] In some aspects, the chemical stability of the first active ingredient in the described fungicidal composition may be reduced by adding a second fungicidal compound to the composition. Methods of Preparation and Use [0052] Also described herein is a process or method for the preparation of the described fungicidal composition which includes mixing together the one or more fungicide active ingredients, the inert ingredients into water. [0053] In some aspects, the fungicidal composition (suspension concentrate) described herein may be prepared by the steps of: [0054] (1) preparing a dispersion of the fungicidal compound(s) in the water containing emuslfiers, dispersant; [0055] (2) homogenizing the dispersion in step (1) to break down large solids into sub-milimeter particle; [0056] (3) mill the disperson in step 2 into fine suspension with desired particle sizes; and [0057] (4) prepare the described fungicidal composition by topping off the slurry suspension prepared in step (3) by adding the rest coformulants, including, but not limited to, rheology modifiers, antifreezing agents, antifoam agents, biocide agents, adjuvant oil emulsions. [0058] The described fungicidal composition may also be prepared by adding or eliminating steps to the preparation described herein as may be readily determined by one of ordinary skill in the art.
[0059] The disclosure furthermore relates to a suspension obtainable (preferably obtained) by mixing water with the suspension concentrate described herein. The mixing ratio of water to concentrate may be in the range of from 1000 to 1 up to 1 to 1, preferably 200 to 1 up to 3 to 1. [0060] Also provided herein is a method of controlling plant derived fungal pathogens or diseases comprising contacting the vegetation or an area adjacent thereto to prevent the growth of the fungal pathogens or diseases a fungicidally effective amount of a fungicidal compositions disclosed herein comprising: a fungicidal compound of the Compound I. [0061] Plant fungal pathogens that may be controlled by the described fungicidal compositions include Septoria tritici, Puccinia triticina, Mycosphaerella graminicola, Puccinia triticina, Puccinia striiformis, Venturia inaequalis, Ustilago maydis, Uncinula necator, Rhynchosporium secalis, Leptosphaeria nodorum, Magnaporthe grisea, Monilinia fructicola, Pseudoperonospora cubensis, Pseudocercosporella herpotrichoides, Phakopsora pachyrhizi, Phaeosphaeria nodorum, Blumeria graminis tritici, Blumeria graminis hordei, Erysiphe cichoracearum, Ezysiphe graaminis, Glomerella lagenarium, Cercospora beticola, Alternaria solani, Rhizoctonia solani, Plasmopara viticola, Phytophthora infestans, Pyricularia oryzae, and Pyrenophora teres. [0062] Plant fungal diseases that may be controlled by the described fungicidal compositions include anthracnose, blasts, botrytis, brown rust, blister smut, brown rot, downy mildew, fusarium, powdery mildew, rusts, glume blotch, leaf blotch, net blotch, sheath blight, stripe rust, scab, eye spot, leaf spot, early blight, and late blight. [0063] In some aspects, the described fungicidal composition, after spray application to plant surfaces, exhibits rainfast properties by offering good fungicidal efficacy after exposure to rain or other moisture causing events. [0064] This described method includes use of the described fungicidal composition for protecting a plant against attack by a phytopathogenic organism or the treatment of a plant already infested by a phytopathogenic organism, comprising the step of applying the described fungicidal composition, to soil, a plant, a part of a plant, foliage, flowers, fruit, and/or seeds, or any surface adjacent to a plant in a disease inhibiting and phytologically acceptable amount. The term “disease inhibiting and phytologically acceptable amount” refers to an amount of a compound that kills or inhibits the plant disease for which control is desired, in an amount not significantly toxic to the plant being treated. The exact concentration
of active compound required varies with the fungal disease to be controlled, the type of compositions employed, the method of application, the particular plant species, climate conditions, and the like, as is well known in the art. [0065] The fungicidal compositions described herein may optionally be diluted in an aqueous spray mixture for agricultural application such as for the control of phytopathogenic fungi in crop fields. Such compositions are typically diluted with an inert carrier, such as water, before application. The diluted compositions, which are usually applied, for example, to crops, the locus of crops or the locus of where phytopathogenic fungi may eventually emerge, in some aspects contain about 0.0001 to about 1 weight percent of the active ingredient or from 0.001 to about 1 weight percent of the active ingredient. The present compositions can be applied, for example, to crop plants or their locus by the use of conventional ground or aerial sprayers, and by other conventional means known to those skilled in the art. Other Ingredients [0066] The compositions disclosed herein may contain inert composition ingredients such as, but not limited to, dispersants, surfactants and wetting agents. These optional inert ingredients may include surfactants conventionally used in the art of composition that are described, inter alia, in “McCutcheon’s Detergents and Emulsifiers Annual,” MC Publishing Corp., Ridgewood, New Jersey, 1998 and in the “Encyclopedia of Surfactants,” Vol. I-III, Chemical Publishing Co., New York, 1980-81. These surface-active agents can be anionic, cationic or nonionic in character and can be employed as emulsifying agents, wetting agents, suspending agents, or for other purposes. [0067] In addition to the specific methods and compositions set forth above, the methods and compositions described herein also may include compositions containing one or more additional compatible ingredients. These additional ingredients may include, for example, one or more pesticides or other ingredients, which may be dissolved or dispersed in the composition and may be selected from acaricides, algicides, antifeedants, avicides, bactericides, bird repellents, chemosterilants, defoliants, desiccants, disinfectants, fungicides, herbicide safeners, herbicides, insect attractants, insecticides, insect repellents, mammal repellents, mating disrupters, molluscicides, nematicides, plant activators, plant growth regulators, rodenticides, semiochemicals, synergists, and virucides. Also, any other additional ingredients providing functional utility such as, for example, antifoam agents, antimicrobial agents, buffers, corrosion inhibitors, dispersing
agents, dyes, fragrants, freezing point depressants, neutralizing agents, odorants, penetration aids, sequestering agents, spray drift control agents, spreading agents, stabilizers, sticking agents, viscosity-modifying additives, water soluble solvents and the like, may be included in these compositions. [0068] When the described compositions are used in combination with the additional active ingredients such as, for example, insecticide active ingredients, the compositions described herein can be formulated with the other active ingredient or active ingredients as premix concentrates, tank-mixed in water with the other active ingredient or active ingredients for spray application or applied sequentially with the other active ingredient or active ingredients in separate spray applications. [0069] The compositions and methods described herein may be used in controlling fungal diseases in crops possessing single, multiple or stacked genomic traits conferring tolerance to one or more herbicide chemistries and/or inhibitors with single or multiple modes of action. 5. EXAMPLES The following Examples are presented to illustrate various aspects of the compositions described herein and should not be construed as limitations to the claims. 5.1. Polymorph of Compound I GENERAL EXAMPLE: Generic Overview of the crystallization process to make polymorph crystalline forms of Compound I. [0070] The reaction mixture (post-work up) typically contains about 2000 ppm of water. Compound I degrades with water present. After the work-up, the organic layer is distilled and then undergoes a solvent exchange. In the present examples reduced to practice, the solvent is dichloromethane (DCM) and the exchange solvent is with isopropyl alcohol (IPA). The typical large-scale, industrial-sized crystallization process - which has been reduced to practice - demonstrates about 75g–100kg (93-99%) of Compound I from 60-80 kg crude starting material as an observed as yield out of the crystallization process. [0071] In another generic but more specific example, the process used distillation to first remove the solvent: 80-85% of the feed volume (DCM, water) is distilled overhead under 1 atm. The mixture starts boiling at about 40 °C, reaching about 54 °C at the end. This drives off any residual water, typically reducing the water content from around 2000 ppm to <300 ppm water, and of the DCM.
[0072] After the DCM distillation, jacket temperature is brought down to 30 °C and room temperature isopropyl alcohol (IPA) (water spec <1000ppm) is loaded. The vacuum is then set to 180 mm Hg and the jacket temperature to 55°C. Under 180 mm Hg, the mixture starts boiling at around 38 °C and distillation ends at a final bottom temperature of about 51.3 °C when the bottoms specifications are met (<0.5 wt% residual DCM, 25-27 wt% Compound I). [0073] Following the solvent exchange, the distillation bottoms are cooled to 30 °C and transferred to the crystallizer. If the transfer occurs at a lower temperature, Compound I may come out as oil or amorphous solid. A 5-20% seed loading (seed crystal size D50 <20um, pretty small, seed loading is pretty high compared to a normal process, which is typically less than 1%) could be used for this process. After seed is loaded, the temperature is held at 30 °C for 2-6 hours and then temperature can be brought down to 8 °C over 4-7 hours. [0074] The crystallization is usually filtered when mother liquor concentration drops below 2.5wt% . The crystals are filtered and then washed with heptanes. The wet cake is then plowed and scraped into drier where it is dried under a heated vacuum (45 mm Hg and 50 °C max temperature). [0075] Two possible polymorphs are possibly formed from Compound I. Both polymorphic forms are crystalline while amorphous Compound I is not crystalline. EXAMPLE 1: Method of Crystal Formation 1 Synthesis of crystalline (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy-4- methoxypicolinoyl)-L-alaninate (Compound I). Distillation [0076] Post work-up, the organic layer (723.18 g) containing Compound I was analyzed by Karl Fischer to determine the water content (1620ppm). A LC sample of the organic layer was taken after the base wash (Compound I wt% = 10.89%). The remaining organic layer was then transferred into the distillation vessel. Jacket is set to be 55 °C for the DCM-H2O distillation. Content temperature rose from 10 °C and started boiling at 40 °C. The distillation was stopped at 43 °C (contents temperature) after which point the water content was analyzed by Karl Fisher (257ppm). The organic layer was cooled to 0 °C and held overnight (16 hours) in the reactor. [0077] The distillation was continued next morning (jacket temperature 65 °C) until the content temperature reached 54 °C. Isopropanol (355.05 g, 423 ppm water, 35.1 equiv.) was then added to the bottom. The pressure was set to 180 mmHg (jacket temperature 60°C). The mixture starts boiling at around 38 °C and
distillation ends at a final bottom temperature of about 51.3 °C until the dichloromethane bottom specifications are met (<0.5 wt% residual DCM). The solution was cooled back to 30 °C and was analyzed by HPLC assay – 26.4 wt%. Crystallization [0078] The post distillation mixture (293.05g) was then transferred to the crystallizer. Seed slurry (15.04 g solid Compound I polymorph A, purity 97%, active: 14.58g, d50 -10 μm; 45.12 g IPA) was added to the reactor (at 30 °C) and agitated at 500 rpm. The temperature profile used was a gradual step-down over 24 hours from 30 °C to 8 °C. [0079] The slurry was filtered when the concentration of Compound I fell below 2.5 wt%. The mother liquor was used to rinse the reactor of solids. The mother liquor was analyzed by HPLC to determine the Compound I content (244.3 g, 2.22 wt% Compound I, active lost 5.42 g). The wet cake was held on the filter for 30 minutes before a heptane wash (102.42 g) was used to rinse the reactor and wash the wet cake. The wet cake (88.42 g) was held on the filter for 30 min and then dried in a vacuum oven at 50 °C overnight to give a colorless solid. Based on XRD the solid formed is polymorph A.
Wet cake: 88.42 g
Dry cake: 88.38 g LOD: 0.05 wt% solvent The dry cake was analyzed by HPLC (97.2wt%). active isolated: 85.91 g, Seed active loaded: 14.58 g EXAMPLE 2: Method of Crystal Formation 2 [0080] Synthesis of crystalline (S)-1,1-bis(4-fluorophenyl)propan-2-yl (3-acetoxy- 4-methoxypicolinoyl)-L-alaninate (Compound I). [0081] Distillation [0082] Post work-up, the organic layer (727.4 g) was analyzed by Karl Fischer to determine the water content (1852ppm). A LC sample of the organic layer was taken after the base wash (Compound I wt% = 10.95%). The remaining organic layer was then transferred into the distillation vessel. [0083] Jacket is set to be 55 °C for the DCM-H2O distillation. Content temperature rose from 10 °C and started boiling at 40 °C. The distillation was stopped at 43 °C (contents temperature) after which point the water content was analyzed by Karl Fisher (298ppm). The organic layer was cooled to 0 °C and held overnight (16 hours) in the reactor. [0084] The distillation was continued next morning (jacket temperature 65 °C) until the content temperature reached 54 °C. Isopropanol (355.73 g, 355 ppm water) was then added to the bottom. The pressure was set to 180 mmHg (jacket temperature 60 °C). The mixture starts boiling at around 38 °C and distillation ends at a final bottom temperature of about 51.3 °C until the dichloromethane bottoms specifications are met (<0.5 wt% residual DCM). The solution was cooled back to 30 °C and was analyzed by HPLC assay – 26.6 wt%. Crystallization [0085] The post distillation mixture (298.1g) was then transferred to the crystallizer. Seed slurry (15.9 g solid Compound I polymorph B, purity 97%, active: 15.42g, d50 -20 μm; 48.2g IPA) was added to the reactor (at 30 °C) and agitated at 500 rpm. The temperature profile used was a gradual step-down over 24 hours from 30 °C to 8 °C. [0086] The slurry was filtered when the concentration of Compound I fell below 2.5 wt%. The mother liquor was used to rinse the reactor of solids. The mother liquor was analyzed by HPLC to determine the Compound I content (215 g, 1.8 wt% Compound I, active lost 3.87 g). The wet cake was held on the filter for 30 minutes before a heptane wash (101.6 g) was used to rinse the reactor and wash the wet cake. The wet cake (88.1 g) was held on the filter for 30 min and then dried in a
vacuum oven at 50 °C overnight to give a colorless solid. Based on XRD the solid formed is polymorph B.
Wet cake: 88.1 g Dry cake: 87.2 g LOD: 0.05 wt% solvent The dry cake was analyzed by HPLC (97.5 wt%). active isolated: 85.02 g, Seed active loaded: 15.42 g [0087] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein. [0088] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the
term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. [0089] Preferred aspects of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred aspects may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context. 5.2. Chemical Stability Example 1. Suspension concentrate of Florylpicoxamid and a second active ingredient Fluoxastrobin with loading of 90 g/L Florylpicoxamid and 252 g/L fluoxastrobin. Fine selection of dispersants and wetters results in formulation with stable physical properties and chemical retention of Florylpicoxamid ~ 98.2% after 2 week 54 oC storage. Formulation1:
Example 2. Suspension concentrate of Florylpicoxamid and a second active ingredient Fluoxastrobin with loading of 60 g/L Florylpicoxamid and 168 g/L fluoxastrobin. In addition, 120 g/L adjuvant mineral oil is added in the formulation to improves the fungicidal performance of the composition. Fine selection of dispersants and wetters results in formulation with stable physical properties and chemical retention of Florylpicoxamid ~ 98.6% after 2 week 54 oC storage. Formulation2:
Formulation3:
Formulation4:
Formulation5:
Formulation6:
Formulation7:
Formulation8:
The present disclosure is not limited in scope by the aspects disclosed herein which are intended as illustrations of a few aspects of the disclosure and any aspects which are functionally equivalent are within the scope of this disclosure. Various modifications of the processes, methods, and compositions in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. Further, while only certain representative combinations of the process and method steps and composition components disclosed herein are specifically discussed in the aspects above, other combinations of the composition components and process and method steps will become apparent to those skilled in the art and also are intended to fall within the scope of the appended claims. Thus, a combination of components or steps may be explicitly mentioned herein; however, other combinations of components and steps are included, even though not explicitly stated. The term
comprising and variations thereof as used herein is used synonymously with the term including and variations thereof and are open, non-limiting terms.