GB2546498A

GB2546498A - Novel crystalline form of picoxystrobin, method of preparing and use of the same

Info

Publication number: GB2546498A
Application number: GB1600977.1A
Authority: GB
Inventors: Timothy Bristow James
Original assignee: Rotam Agrochem International Co Ltd
Current assignee: Rotam Agrochem International Co Ltd
Priority date: 2016-01-19
Filing date: 2016-01-19
Publication date: 2017-07-26
Anticipated expiration: 2036-01-19
Also published as: CN108368047A; CN108368047B; GB2546498B; TWI721083B; MX394228B; WO2017125010A1; MX2018007273A; GB201600977D0; BR112017023886A2; AR107167A1; TW201731818A

Abstract

A crystalline modification of the compound of Formula (I) commonly known as picoxystrobin: Wherein the crystalline form conforms to various X-ray diffraction, Infra-red and scanning calorimetry data as defined within. The crystalline form of picoxystrobin may be prepared by crystallization from solution in a suitable solvent or mixtures thereof, preferred solvent systems include chloroform-hexane, THF-hexane, dichloromethane-hexane and THF water. The preparation method may also include the use of seed crystals. Fungicidal compositions comprising the crystalline form, a method for controlling fungal infestations at a locus and a use of the crystalline form are also provided.

Description

NOVEL CRYSTALLINE FORM OF PICOXYSTROBIN, METHOD OF PREPARING

AND USE OF THE SAME

The present invention relates to a novel crystalline form of picoxystrobin. The present invention further relates to a method for preparing the novel crystalline form. Still further, the present invention relates to the use of the novel crystalline form.

Picoxystrobin, having the chemical name methyl (E)-3-methoxy-2-[2-(6-trifluoromethyl-2-pyridyloxymethyl)phenyl]acrylate, has the following structural formula (I):

(I)

Picoxystrobin belongs to the strobilurin group of chemicals, which are used as fungicide, in particular to control a range of fungal diseases including brown rust, tan spot, powdery mildew and net blotch in cereals, pulses and oilseeds. Picoxystrobin is a preventive and curative fungicide with systemic and translaminar movement, acting by the inhibition of mitochondrial respiration by blocking electron transfer at the Qo centre of cytochrome Bc1.

The commercially available picoxystrobin product is usually manufactured by processes as described in EP 0 278 595, US 6,015,905, CN 102115458A, CN 103030598A and CN 103626691A.

For example, US 6,015,905 discloses a method for preparing picoxystrobin starting from methyl-2-(o-tolyl)acetate, according to the reaction scheme as shown in Scheme 1 below.

Scheme 1

Picoxystrobin prepared by these aforementioned processes is amorphous and is difficult to formulate. In particular, the product has a high tendency to aggregate, in particular after prolonged storage.

Therefore, there is a need in the art for novel forms of picoxystrobin exhibiting improved properties, for example an improved storage stability. A novel crystalline modification of picoxystrobin has now been found, which is readily formulated into an agrochemical composition and which exhibits a high degree of stability when formulated. In particular, the crystalline modification, hereafter referred to as ‘crystalline modification Γ, exhibits a very low tendency to aggregate when formulated.

Accordingly, in a first aspect, the present invention provides a crystalline modification I of picoxystrobin, the crystalline modification exhibiting at least 4 of the following reflexes as 20 values in an X-ray powder diffractogram recorded using Cu— Ka radiation at 25 °C: 20 = 8.4613 ±0.2 (1) 20 = 12.0227 ± 0.2 (2) 20 = 12.7030 ± 0.2 (3)

2Θ= 13.8834 ±0.2 (4) 2Θ = 14.5237 ± 0.2 (5) 2Θ = 16.2243 ± 0.2 (6) 2Θ = 16.3844 ± 0.2 (7) 2Θ= 17.1247 ±0.2 (8) 2Θ= 17.6249 ±0.2 (9) 2Θ= 18.7653 ±0.2 (10) 2Θ = 20.3659 ± 0.2 (11) 20 = 21.2663 ±0.2 (12) 20 = 22.0466 ± 0.2 (13) 20 = 22.1466 ±0.2 (14) 20 = 22.9469 ± 0.2 (15) 20 = 23.7272 ± 0.2 (16) 20 = 24.1474 ±0.2 (17) 20 = 25.3278 ± 0.2 (18) 20 = 25.6479 ± 0.2 (19) 20 = 26.1681 ±0.2 (20) 20 = 26.7884 ± 0.2 (21) 20 = 28.3890 ± 0.2 (22) 20 = 31.0300 ±0.2 (23) 20 = 35.4117 ±0.2 (24)

As noted above, the crystalline modification I of picoxystrobin displays at least 4 of the reflexes listed above in its X-ray powder diffractogram. More preferably, the crystalline modification I exhibits at least 5, at least 7 of the aforementioned reflexes.

More preferably, the X-ray powder diffractogram of the crystalline modification I of picoxystrobin displays at least 4, more preferably at least 5, still more preferably at least 7, more preferably still all of the following reflexes: 20 = 8.4613 ±0.2 (1) 20 = 12.7030 ± 0.2 (3) 20= 13.8834 ±0.2 (4) 20 = 16.3844 ± 0.2 (7) 20= 17.6249 ±0.2 (9) 20 = 21.2663 ±0.2 (12) 20 = 22.9469 ± 0.2 (15) 20 = 25.3278 ± 0.2 (18)

In one preferred embodiment, the crystalline modification I of picoxystrobin exhibits all of the aforementioned reflexes (1) to (24).

In a particularly preferred embodiment, the crystalline modification I of picoxystrobin displays a powder X-ray diffraction pattern substantially the same as shown in Figure 1.

In addition, the crystalline modification I of picoxystrobin can be alternatively characterized, preferably further characterized, by IR spectroscopy. The IR spectroscopy is conducted with the number of scans being 32 and a resolution of 4 cm'1. The IR spectrum of the crystalline modification I of picoxystrobin is shown in Figure 2, with characteristic bands at about 1704.95, 1629.04, 1577.46, 1352.22, 1258.08, 1201.97, 1124.12, 983.51 and 810.19 cm'1.

The crystalline modification I of picoxystrobin according to the invention may be alternatively characterized, preferably further characterized, by differential scanning calorimetry (DSC), the results of which are shown in Figure 3. An endothermic peak at about 79.115 °C with an onset temperature of about 73.872 °C are shown in Figure 3.

As used herein, the term “about 79.115 °C” means a range of 75 °C to 80 °C. As used herein, the term “about 73.872 °C” means a range of 72 °C to 75 °C. A particularly preferred crystalline modification I of picoxystrobin is one exhibiting the X-ray powder diffractogram as described above, together with one or both of the IR spectrum and the DSC spectrum described above. A study of single crystals of the crystalline modification I of picoxystrobin shows that the basic crystal structure is monoclinic and has the space group P2i/c. The characteristic data of the crystal structure of the crystalline modification I of picoxystrobin is shown in the Table 1 below:

Table 1: Crystallographic data of the crystalline modification I of picoxystrobin

wherein: a, b, c = length of the edges of the unit cell α, β, γ = angles of the unit cell

Z = Number of molecules in the unit cell

The crystal structure of the crystalline modification I of picoxystrobin is shown in Figure 4.

The crystalline modification I of picoxystrobin of the present invention may be easily prepared by crystallizing the crystalline modification from solution of picoxystrobin in a solvent system. The solution may be prepared using any form of picoxystrobin, in particular amorphous picoxystrobin.

Accordingly, in a further aspect, the present invention provides a method of forming the crystalline modification I of picoxystrobin, the method comprising: i) providing a solution of picoxystrobin in a solvent system comprising one or more solvents; ii) crystallizing the dissolved compound into the crystalline modification I of picoxystrobin of formula I; and iii) separating the crystallized solid from the solvent system to yield the crystalline modification I of picoxystrobin.

As noted above, the solution of picoxystrobin may be formed by dissolving a suitable form of picoxystrobin in the solvent system. Amorphous picoxystrobin is one preferred starting material for forming the solution.

In general, any suitable solvent may be employed in the solvent system. Preferred solvents for use in the solvent system for preparing the crystalline modification I of picoxystrobin are alcohols, in particular secondary and tertiary alcohols, optionally in admixture with water; aliphatic or alicyclic alkanes, in particular C5 to C10 alkanes, more preferably C5 to C7 alkanes, the alkanes preferably substituted with one or more halogen moieties; substituted aromatic solvents, especially substituted benzenes, in particular nitro- and halo-substituted aromatic compounds; aromatic ethers; ketones, in particular lower alkyl ketones; nitriles, in particular lower alkyl nitriles; and mixtures thereof. ‘Lower alkyl’ is a reference to an alkyl moiety having from 1 to 4 carbon atoms. A preferred halo-substituent is a chlorine moiety.

It is preferred to avoid the use of primary alcohols, in particular lower alcohols, especially methanol, and unsubstituted aromatic solvents, such as toluene.

Particularly preferred solvent systems for preparing the crystalline modification I of picoxystrobin include iso-propyl alcohol, tertiary butyl alcohol, chloroform, dichloroethane, hexane, nitrobenzene, chlorobenzene, dichlorobenzene, trifluoro-methyl benzene, methyl ethyl ketone, acetonitrile or a mixture of one or more thereof. Preferred mixtures of solvents include chloroform-hexane, THF-hexane, dichloromethane-hexane and THF-water.

In the present invention, the crystalline modification I of picoxystrobin may be prepared by dissolving amorphous picoxystrobin in a solvent system comprising one or a mixture of solvents. The amorphous starting material is dissolved in the solvent system to form a concentrated solution. The dissolution may be carried out with heating the solvent system to a temperature of from room temperature or ambient temperature to the reflux temperature of the solution. Preferably, the solution is prepared at the reflux temperature of the solution. The concentration of picoxystrobin in the final solution depends on the solubility of picoxystrobin in the solvent system being employed.

The resultant homogeneous solution may then be cooled to the required temperature, for example to a temperature at or above room or ambient temperature, to crystallize the desired crystalline form from the solution. Alternatively, or in addition, the crystalline modification I may also be crystallized by concentrating the homogeneous solution, either with or without the action of a vacuum, at or below the reflux temperature of the solution.

In one preferred embodiment, crystallization of the crystalline modification I is aided by adding seed crystals of the desired crystalline form during crystallization, which can promote or accelerate the process of crystallization. The amount of seed crystals added is typically in the range of 0.001% to 10% by weight, more preferably 0.002% to 5%, more preferably still from 0.003% to 2.5%, still more preferably from 0.005% to 0.5% by weight, based on the weight of picoxystrobin present in the solution. The seed crystals are preferably added to the solution at a temperature below the boiling point of the solution.

The crystalline modification I of picoxystrobin is recovered by separating the crystallized material from the solvent system. Suitable techniques for this separation are known in the art and include filtration, centrifugation and decantation.

Thereafter, the separated solid is preferably washed with a suitable solvent, which may be the same solvent system used for the preparation of concentrated solution in step (i) or a different solvent. Washing is usually carried out under cooling, for example between room temperature and 0 °C, to reduce the loss of the crystallized product. The washing temperature depends upon the solubility of the crystals in the solvent system being employed.

The crystalline modification I of picoxystrobin of the present invention is particularly suitable for formulating into a fungicidal composition.

Accordingly, in a further aspect, the present invention provides a fungicidal composition comprising the crystalline modification I of picoxystrobin hereinbefore described.

The fungicidal compositions may comprise the crystalline modification I of picoxystrobin in any suitable amount to provide the required activity. Preference is given to compositions comprising less than 80% by weight of the crystalline modification I of picoxystrobin, more preferably less than 50% by weight. Compositions comprising about 25% by weight of the crystalline modification I of picoxystrobin are preferred for many applications.

The crystalline modification I of picoxystrobin may be formulated in a known manner to provide a range of customary formulations. Examples of such formulations include suspension concentrates (SC), oil-based suspension concentrates (OD), soluble granules (SG), dispersible concentrates (DC), emulsifiable concentrates (emulsion concentrates) (EC), emulsion seed dressings, suspension seed dressings, granules (GR), microgranules (MG), suspo-emulsions (SE), and water-dispersible granules (WG).

The crystalline modification I of picoxystrobin is particularly suitable for formulation as a suspension concentrate (SC). In addition to the active compound, suspension concentrates typically comprise surfactants, and also, if appropriate, one or more thickeners, antifreeze agents, biocides and any necessary adjuvants.

The crystalline modification I of picoxystrobin may be present in the suspension concentrate (SC) composition at a concentration sufficient to achieve the required dosage in the field, for example from about 0.1% to about 50% by weight of the total mixture. In general, the suspension concentrate (SC) formulations are prepared by extending the crystalline modification I of picoxystrobin with a solvent, in particular water, one or more dispersants or surfactants, and one or more other auxiliaries.

Suitable dispersants are known in the art and are commercially available. Suitable dispersants include, but are not limited to, sodium, calcium and ammonium salts of ligninsulfonates (optionally polyethoxylated); sodium and ammonium salts of maleic anhydride copolymers; sodium salts of condensed phenolsulfonic acid; and naphthalene sulfonate-formaldehyde condensates. Ligninsulfonates, such as sodium ligninsulfonates, are particularly useful for use in the compositions of the invention. Naphthalene sulfonate-formaldehyde condensates, such as naphthalenesulfonic acid polymers with formaldehyde, and their salts, such as sodium salts, are also particularly useful for the compositions of the present invention.

Suitable thickeners for inclusion in the compositions are known in the art and are commercially available. Suitable thickening agent include, but are not limited to, guar gum, pectin, casein, carrageenan, xanthan gum, alginates, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose. Synthetic thickeners may be used and include derivatives of the aforementioned agents, as well as polyvinyl alcohols, polyacrylamides, polyvinylpyrrolidones, various polyethers, their copolymers as well as polyacrylic acids and their salts. Alkylpolyvinylpyrrolidone is a particularly useful thickener for the compositions of the present invention.

Suitable antifreeze agents for inclusion in the compositions are known in the art and are commercially available. Suitable antifreeze agents include liquid polyols, for example ethylene glycol, propylene glycol or glycerol. The amount of antifreeze agent present is generally from about 1% to about 20% by weight, in particular from about 5% to about 10% by weight, based on the total weight of the composition.

One or more biocides or preservatives may also be included in the composition according to the invention. Suitable biocides are known in the art and include those based on isothiazolones, for example Proxel® from Lonza, Acticide® RS from Thor Chemie, or Kathon® MK from Rohm & Haas. The amount of preservative present in the composition is typically from 0.05% to 0.5% by weight, based on the total weight of the composition.

The crystalline modification I of picoxystrobin may be the only active ingredient in the pesticidal formulation or may be present in combination with one or more other active compounds, including one or more insecticides, attractants, sterilizing agents, bactericides, acaricides, nematicides, fungicides, growth-regulating substances, herbicides, safeners, fertilizers and semiochemicals.

Preferred active compounds for use in combination with the crystalline modification I of picoxystrobin are metalaxyl, dodemorph, fenpropimorph, fenpropidin, guazatine, spiroxamine, tridemorph, pyrimethanil, cyprodinyl, bitertanol, bromoconazole, cyproconazole, difenoconazole, dinitroconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, hexaconazole, imazalil, metconazole, myclobutanil, penconazole, propiconazole, prochloraz, prothioconazole, tebuconazole, triadimefon, triadimenol, triflumizole, triticonazole, iprodione, vinclozolin, maneb, mancozeb, metiram, thiram, boscalid, carbendazim, carboxin, oxycarboxin, cyazofamid, dithianon, famoxadone, fenamidone, fenarimol, flutolanil, quinoxyfen, thiophanate-methyl, thiophanate-ethyl, triforine, dinocap, nitrophthal-isopropyl, phenylpyrroles, such as fenpiclonil or fludioxonil, acibenzolar-S-methyl, benthiavalicarb, carpropamid, chlorothalonil, cyflufenamid, cymoxanil, fenhexamid, fentinacetate, fenoxanil, fluazinam, fosetyl, fosetyl-aluminum, iprovalicarb, metrafenone, zoxamide, captan, folpet, dimethomorph, azoxystrobin, dimoxystrobin, fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, pyraclostrobin, prothioconazole or trifloxystrobin.

Particularly preferred active components for use in combination with the crystalline modification I of picoxystrobin are cyproconazole, metconazole, penconazole, tebuconazole, difenoconazole, prothioconazole, boscalid and pyraclostrobin.

The compositions of the present invention comprising the crystalline modification I of picoxystrobin are active in controlling all undesirable fungal pathogens which can be controlled using known formulations of picoxystrobin. Fungal pathogens causing fungal diseases that may be controlled include, for example: o Alternaria sp. on vegetables, oilseed rape, sugarbeet, soybean, cereals, cotton, fruit and rice (for example A. solani or A. alternata on potatoes and other plants), o Aphanomyces sp. on sugarbeet and vegetables, o Ascochyta sp. on cotton and rice, o Bipolaris and Drechslera spp. on corn, cereals, rice and lawns (for example D. teres on barley, D. tritci-repentis on wheat), o Blumeria graminis (powdery mildew) on cereals, o Botrytis cinerea (gray mold) on strawberries, vegetables, flowers and grapevines, o Botryodiplodia sp. on cotton, o Bremia lactucae on lettuce, o Cercospora sp. on corn, soybean, rice and sugarbeet (for example C. beticula on sugarbeet), o Cochliobolus sp. on corn, cereals, rice (for example Cochliobolus sativus on cereals, Cochliobolus miyabeanus on rice), o Corynespora sp. on soybean, cotton and other plants, o Colletotrichum sp. on soybean, cotton and other plants (for example C. acutatum on various plants), o Curvularia sp. on cereals and rice, o Diplodia sp. on cereals and rice, o Exserohilum sp. on corn, o Erysiphe cichoracearum and Sphaerotheca fuliginea on cucumber plants, o Fusarium and Verticillium spp. (for example V. dahliae) on various plants (for example F. graminearum on wheat), o Gaeumanomyces graminis on cereals, o Gibberella sp. on cereals and rice (for example Gibberella fujikuroi on rice), o Grainstaining complex on rice, o Helminthosporium sp. (for example H. graminicola) on corn and rice, o Macrophomina sp. on soybean and cotton, o Michrodochium sp. on plants, for example M. nivale on cereals, o Mycosphaerella sp. on cereals, bananas and peanuts (for example M. graminicola on wheat, M. fijiesis on bananas), o Phaeoisaripsis sp. on soybean, o Phakopsara sp. on plants, for example P. pachyrhizi and Phakopsara meibomiae on soybean, o Phoma sp. on soybeans, o Phomopsis sp. on soybeans, sunflowers and grapevines (for example P. viticola on grapevines, P. helianthii on sunflowers), o Phytophthora infestans on potatoes and tomatoes, o Plasmopara viticola on grapevines, o Penecilium sp. on soybeans and cotton, o Podosphaera leucotricha on apples, o Pseudocercosporella herpotrichoides on cereals, o Pseudoperonospora sp. on hops and cucumber plants (for example P. cubenis on cucumber), o Puccinia sp. on cereals, corn and asparagus (for example P. triticina and P. striformis on wheat, P. asparagi on asparagus), o Pyrenophora sp. on cereals, o Pyricularia oryzae, Corticium sasakii, Sarocladium oryzae, S. attenuatum, Entyloma oryzae on rice, o Pyricularia grisea on lawns and cereals, o Pythium spp. on lawns, rice, corn, cotton, oilseed rape, sunflowers, sugarbeet, vegetables and other plants, o Rhizoctonia sp. (for example R. solani) on cotton, rice, potatoes, lawns, corn, oilseed rape, potatoes, sugarbeet, vegetables and other plants, o Rynchosporium sp. (for example R. secalis) on rice and cereals, o Sderotinia sp. (for example S. sclerotiorum) on oilseed rape, sunflowers and other plants, o Septoria tritici and Stagonospora nodorum on wheat, o Erysiphe (syn. Uncinula necator) on grapevines, o Setospaeria sp. on corn and lawns, o Sphacelotheca reilinia on corn, o Thievaliopsis sp. on soybean and cotton, o Tilletia sp. on cereals, o Ustilago sp. on cereals, corn and sugarbeet, and o Venturis sp. (scab) on apples and pears (for example V. inaequalis on apple).

In a yet further aspect, the present invention provides a method for controlling fungal infestations at a locus, the method comprising applying to the locus the crystalline modification I of picoxystrobin hereinbefore described.

In a still further aspect, the present invention provides the use of the crystalline modification I of picoxystrobin hereinbefore described in the control of a fungal infestation.

As used herein, the term “about,” when used in connection with a numerical amount or range, means somewhat more or somewhat less than the stated numerical amount or range, to a deviation of ± 10% of the stated numerical amount or endpoint of the range.

As used herein the term “room temperature” refers to a temperature range of from about 20 °C to 26°C.

Embodiments of the present invention will now be described, for illustration purposes only, by way of the following Examples and having reference to the accompanying figures, in which:

Figure 1 is an X-ray powder diffraction spectrum of the crystalline modification I of picoxystrobin of the present invention;

Figure 2 is an IR spectrum of the crystalline modification I of picoxystrobin of the present invention;

Figure 3 is a Differential Scanning Calorimetry (DSC) spectrum of the crystalline modification I of picoxystrobin of the present invention;

Figure 4 shows the crystal structure of the crystalline modification I of picoxystrobin of the present invention; and

Figure 5 is an X-ray powder diffraction spectrum of amorphous picoxystrobin as obtained in Example 1 below.

In the following examples, percentages are weight percentages, unless otherwise indicated.

Examples

Example 1 - Preparation of Amorphous Picoxystrobin

For the purposes of comparison, the method disclosed in US 6,015,905 was used to prepare picoxystrobin. The details of the procedure followed are as follows:

Gaseous hydrogen chloride (HCI) was bubbled through a solution of 3-isochromanone (2.0 g, 13.5 mmol) in methanol (30 ml_) for 0.5 hours at room temperature. The solution was further stirred for an additional 2 hours. Methanol was removed under reduced pressure and the resultant residue was dissolved in dichloromethane. Any insoluble material present was removed by filtration, after which the solution was dried by percolating over calcium carbonate, to remove water. Finally, the solvent was removed to give methyl 2-chloromethylphenylacetate (2.62 g, 98%) as an oil which was used in the following step without further purification. A mixture of 2-hydroxy-6-trifluoromethylpyridine (2.0 g, 12.3 mmol), sodium hydroxide (0.52 g, 12.9 mmol) and 15-crown-5 (1 drop) in dry toluene (25 ml_) was stirred under reflux for 2 hours. Toluene was removed under reduced pressure and the white salt residue was dissolved in dry dimethylformamide (DMF) (15 ml_). Methyl 2-chloromethylphenylacetate (2.44 g, 12.3 mmol) in dry DMF (15 ml_) was added dropwise along with sodium iodide (10 mg). The mixture was stirred at 75 °C for 2 hours, then poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and the remaining ether removed in vacuo leaving an oil, which was purified by column chromatography (silica eluted with 10% ethyl acetate in hexane) to give methyl 2-(6-tri-fluoromethylpyrid-2-yloxymethyl)phenylacetate (3.3 g, 83%).

Sodium methoxide (0.725 g, 13 mmol) and methyl formate (0.8 mL, 13 mmol) were added portionwise to a stirred solution of the methyl 2-(6-trifluoromethylpyrid-2-yloxymethyl)phenylacetate (2.0 g, 6.0 mmol) in dry toluene (15 mL) under a nitrogen atmosphere at room temperature. After 6 hours at room temperature, the mixture was poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and then the ether removed to give (E)-methyl 2-(2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (95% purity) as a yellow gum which was used in the next stage without further purification.

Dimethyl sulphate (0.65 mL, 6.9 mmol) was added dropwise to a mixture of the (E)-methyl 2-[2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-hydroxyacrylate (2.12 g, 6 mmol) and anhydrous potassium carbonate (1.2 g, 8.7 mmol) in dry DMF (10 mL). After stirring at room temperature for 6 hours, the mixture was poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and then concentrated to give a crude product. The crude product was purified by column chromatography (silica eluted with 20% ethyl acetate in hexane) to give amorphous (E)-methyl 2-[2-(6-trifluoromethylpyrid-2-yloxymethyl)phenyl]-3-methoxyacrylate (98% purity).

The product was analysed using an X-ray powder diffractometer. Figure 5 shows the X-ray powder diffraction pattern of the product as having no significant signals. The results indicate the product is amorphous.

Example 2 - Preparation of crystalline modification I of picoxvstrobin (Crystallization from iso-propyl alcohoh 5 g of the amorphous picoxystrobin sample prepared in Example 1 was charged to a flask containing 35 mL of iso-propyl alcohol. The mixtures was stirred to yield a homogeneous suspension. The resulting suspension was slowly heated in a water bath at 50 °C under stirring for 20 to 25 minutes to obtain a clear solution. The reaction mixture was allowed to cool at room temperature. Crystals were formed during the following 45 to 50 hours. The resultant crystals were filtered and dried under vacuum at room temperature to remove remaining traces of iso-propyl alcohol from the crystals. The crystals had a purity of 98% and were produced in a molar yield of 80% w/w.

The crystals were characterized by IR, powder X-ray and single crystal X-ray diffraction analyses and found out to be the crystalline modification I of picoxystrobin as shown in Figures 1 and 2.

The melting point of the product was measured by DSC. The onset temperature was at 73.872 °C and a maximum peak temperature was at 79.115 °C.

Figure 2 shows the characteristic peaks of the crystalline modification I of picoxystrobin on an IR spectrum to be at 1704.95, 1629.04, 1577.46, 1352.22, 1258.08, 1201.97, 1124.12, 983.51 and 810.19 cm1.

The powder X-ray diffractogram of crystals of the crystalline modification I of picoxystrobin showed the reflexes as shown in Figure 2 and the values are summarized in Table 2 below.

Table 2. Powder X-ray diffractogram reflexes of the crystalline modification I of picoxystrobin

The characteristic data of the crystal structure of the crystalline modification I of picoxystrobin are shown in the Table 3 below.

Table 3: Crystallographic data of the crystalline modification I of picoxystrobin

wherein: a, b, c = Length of the edges of the unit cell α, β, γ = Angles of the unit cell Z = Number of molecules in the unit cell

Example 3 - Preparation of crystalline modification I of picoxvstrobin (Crystallization from hexane and chloroform^ 5 g of the amorphous picoxystrobin sample prepared in Example 1 was charged to a flask containing 40 ml_ of hexane and chloroform (1:1). The mixture was stirred until the picoxystrobin dissolved to give a clear solution. The solution was left aside and undisturbed at room temperature for a few days to allow slow and steady crystallization to occur. The crystals formed were recovered by filtration.

The recovered crystals were characterized by IR, powder X-ray and single crystal X-ray diffraction analyses, as described in Example 2. The results were the same as those obtained in Example 2, which indicated that the solid product was the crystalline modification I of picoxystrobin.

Formulation Examples

Example 4 - Preparation of Amorphous Picoxvstrobin suspension concentrate (SC) A suspension concentrate (SC) formulation was prepared from the components indicated in Table 4 below.

All the components were combined and mixed uniformly. The resulting mixture was ground with a Dyno-Mill (manufactured by Willy A. Bachofen AG) to obtain a suspension concentrate.

Table 4

Example 5 - Preparation of the crystalline modification I of picoxvstrobin suspension concentrate (SC^ A suspension concentrate (SC) formulation was prepared from the components listed in Table 5 below.

Table 5

Example 6: Comparison of storage stability

Samples of the compositions prepared in Examples 6 and 7 were stored at a temperature of 54 °C for 1 month, 3 months and 6 months. The procedures followed were according to CIPAC MT 46.3.

The concentration of picoxystrobin was measured at the end of each storage period by HPLC. The aggregation was measured by observation. The original concentration of picoxystrobin in each formulation was 25 %.

The results are listed in Table 6 below.

Table 6 * Notes:

The extent of aggregation is indicated, with “+” indicating a low amount of observed aggregation, “+++++”a high amount of observed aggregation, and indicating no aggregation observed.

The results set out in Table 6 show that the amorphous picoxystrobin product obtained following the prior art procedures exhibited a very poor storage stability, with the amount of picoxystrobin in the formulation decreasing significantly over the period of the test and significant aggregation of the picoxystrobin active ingredient being observed. In contrast, the crystalline modification I of picoxystrobin of the present invention exhibited little to no degradation of the picoxystrobin active ingredient and no observable aggregation.

Claims

1. A crystalline modification I of picoxystrobin, the crystalline modification exhibiting at least 4 of the following reflexes as 20 values in an X-ray powder diffractogram recorded using Cu—Ka radiation at 25 °C: 2Θ = 8.4613 ±0.2 (1) 2Θ= 12.0227 ±0.2 (2) 2Θ= 12.7030 ±0.2 (3) 2Θ= 13.8834 ±0.2 (4) 2Θ= 14.5237 ±0.2 (5) 2Θ= 16.2243 ±0.2 (6) 2Θ= 16.3844 ±0.2 (7) 2Θ= 17.1247 ±0.2 (8) 2Θ= 17.6249 ±0.2 (9) 2Θ= 18.7653 ±0.2 (10) 2Θ = 20.3659 ± 0.2 (11) 20 = 21.2663 ±0.2 (12) 20 = 22.0466 ± 0.2 (13) 20 = 22.1466 ±0.2 (14) 20 = 22.9469 ± 0.2 (15) 20 = 23.7272 ± 0.2 (16) 20 = 24.1474 ±0.2 (17) 20 = 25.3278 ± 0.2 (18) 20 = 25.6479 ± 0.2 (19) 20 = 26.1681 ±0.2 (20) 20 = 26.7884 ± 0.2 (21) 20 = 28.3890 ± 0.2 (22) 2Θ = 31.0300 ±0.2 (23) 2Θ = 35.4117 ±0.2 (24)

2. The crystalline modification according to claim 1, wherein at least 5 of the reflexes (1) to (24) are exhibited.

3. The crystalline modification according to claim 2, wherein at least 7 of the reflexes (1) to (24) are exhibited.

4. The crystalline modification according to any preceding claim, wherein the crystalline modification exhibiting at least 4 of the following reflexes as 2Θ values in an X-ray powder diffractogram recorded using Cu—Ka radiation at 25 °C: 20 = 8.4613 ±0.2 (1) 20= 12.7030 ±0.2 (3) 20= 13.8834 ±0.2 (4) 20 = 16.3844 ± 0.2 (7) 20= 17.6249 ±0.2 (9) 20 = 21.2663 ±0.2 (12) 20 = 22.9469 ± 0.2 (15) 20 = 25.3278 ± 0.2 (18)

5. The crystalline modification according to claim 4, wherein at least 5 of the reflexes (1), (3), (4), (7), (9), (12), (15) and (18) are exhibited.

6. The crystalline modification according to claim 5, wherein at least 7 of the reflexes (1), (3), (4), (7), (9), (12), (15) and (18) are exhibited.

7. The crystalline modification according to claim 5, wherein all of the reflexes (1), (3), (4), (7), (9), (12), (15) and (18) are exhibited.

8. The crystalline modification according to claim 7, wherein all of the reflexes (1) to (24) are exhibited.

9. The crystalline modification according to any preceding claim, wherein the X-ray diffraction pattern is substantially the same as the pattern shown in Figure 1.

10. A crystalline modification I of picoxystrobin, the crystalline modification exhibiting an IR spectrum with characteristic bands at about 1704.95, 1629.04, 1577.46, 1352.22, 1258.08, 1201.97, 1124.12, 983.51 and 810.19 cm-1, the IR spectroscopy being conducted with the number of scans being 32 and a resolution of 4 cm-1.

11. The crystalline modification according to claim 10, wherein the IR spectrum of the crystalline modification is substantially the same as shown in Figure 2.

12. A crystalline modification I of picoxystrobin, the crystalline modification exhibiting a differential scanning calorimetry (DSC) spectrum having an endothermic peak at about 79.115 °C with an onset temperature of about 73.872 °C.

13. The crystalline modification according to claim 12, wherein the differential scanning calorimetry (DSC) spectrum is substantially the same as shown in Figure 3.

14. A method of forming the crystalline modification I of picoxystrobin, the method comprising: i) providing a solution of picoxystrobin in a solvent system comprising one or more solvents; ii) crystallizing the dissolved compound into the crystalline modification I of picoxystrobin of formula I; and iii) separating the crystallized solid from the solvent system to yield the crystalline modification I of picoxystrobin.

15. The method according to claim 14, wherein the solvent system comprises an alcohol, an aliphatic or alicyclic alkane, a substituted aromatic solvent, an aromatic ether; a ketone; or a mixture thereof.

16. The method according to claim 15, wherein the alcohol is a secondary or tertiary alcohol.

17. The method according to either of claims 15 or 16, wherein the alcohol is present in admixture with water.

18. The method according to claim 15, wherein the aliphatic or alicyclic alkane is substituted with one or more halogen moieties.

19. The method according to claim 15, wherein the alkane is selected from Cs to C10 alkanes.

20. The method according to claim 19, wherein the alkane is selected from Cs to C7 alkanes.

21. The method according to claim 15, wherein the aromatic solvent is a benzene compound.

22. The method according to claim 21, wherein the benzene compound is substituted with one or more halogen or nitro moieties.

23. The method according to any of claims 14 to 22, wherein the solvent system comprises iso-propyl alcohol, tertiary butyl alcohol, chloroform, dichloroethane, hexane, nitrobenzene, chlorobenzene, dichlorobenzene, trifluoro-methyl benzene, methyl ethyl ketone, acetonitrile, or a mixture of one or more thereof.

24. The method according to any of claims 14 to 23, wherein the solvent system comprises a mixture of solvents selected from chloroform-hexane, THF-hexane, dichloromethane-hexane and THF-water.

25. The method according to any of claims 14 to 24, wherein the picoxystrobin is dissolved in the solvent system at a temperature of from room temperature to the reflux temperature of the solution.

26. The method according to claim 25, wherein the temperature is the reflux temperature of the solution.

27. The method according to any of claims 14 to 26, wherein step (ii) is conducted with seed crystals of the crystalline modification I present in the solution.

28. The method according to claim 27, wherein the seed crystals are present in an amount of from 0.005 to 0.5% by weight of the solution.

29. A fungicidal composition comprising the crystalline modification I of picoxystrobin according to any of claims 1 to 13.

30. The fungicidal composition according to claim 29, wherein the composition is a formulation selected from suspension concentrates (SC), oil-based suspension concentrates (OD), soluble granules (SG), dispersible concentrates (DC), emulsifiable concentrates (emulsion concentrates) (EC), emulsion seed dressings, suspension seed dressings, granules (GR), microgranules (MG), suspo-emulsions (SE), and water-dispersible granules (WG).

31. The fungicidal composition according to either of claims 29 or 30, wherein the composition is a suspension concentrate (SC).

32. A method of controlling fungal infestations at a locus, the method comprising applying to the locus the crystalline modification I of picoxystrobin according to any of claims 1 to 13 or a composition according to any of claims 29 to 31.

33. The use of the crystalline modification I of picoxystrobin according to any of claims 1 to 13 in the control of a fungal infestation.

34. A crystalline modification of picoxystrobin substantially as hereinbefore described, having reference to any of Figures 1 to 4.

35. A method of preparing the crystalline modification I of picoxystrobin substantially as hereinbefore described.

36. A method for controlling a fungal infestation substantially as hereinbefore described.