GB2581208A

GB2581208A - A novel form of metconazole, a process for its preperation and use of the same

Info

Publication number: GB2581208A
Application number: GB1901847.2A
Authority: GB
Inventors: Timothy Bristow James
Original assignee: Rotam Agrochem International Co Ltd
Current assignee: Rotam Agrochem International Co Ltd
Priority date: 2019-02-11
Filing date: 2019-02-11
Publication date: 2020-08-12
Anticipated expiration: 2039-02-11
Also published as: WO2020164287A1; EP3924346A1; GB2581208B; GB201901847D0; EP3924346A4

Abstract

A crystalline modification I of 5-(4-chlorobenzy1)-2,2-dimethy1-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol (metconazole) characterized by exhibiting at least 3 of the following reflexes, in any combination, as 2θ ± 0.2 degree in an X-ray powder diffractogram (X-RPD) recorded using Cu—Ka radiation at 25°C: 10.3 ± 0.2, 15.6 ± 0.2, 20.6 ± 0.2, 22.2 ± 0.2, 23.3 ± 0.2. The crystalline modification I may be further characterized by exhibiting functional group vibrational peaks at wavenumbers (cm-1 ± 0.2%) of one or more of 3337, 2963, 2871, 1508, 1492, 1425, 1406, 1385, 1271, 1137 and 1013; or by exhibiting a differential scanning calorimetry (DSC) profile having an endothermic melting peak maximum at 113.3 °C. The crystalline modification may be characterized by spectra substantially as shown in Figures 1-3. A method of preparing the crystalline modification is also provided, particularly wherein the crystalline modification is provided by recrystallizing metconazole from xylene, methyl t-butyl ether or a mixture thereof, such method may include the use of seed crystals of the crystalline modification. Compositions comprising the crystalline modification and its use in controlling fungal infestations are also provided.

Description

A NOVEL FORM OF METCONAZOLE, A PROCESS FOR ITS

PREPARATION AND USE OF THE SAME

The present invention relates to a novel form of 5-(4-chlorobenzy1)-2,2-dimethyl-1 -(1 H-1,2,4-triazol-1-ylmethyl)cyclopentanol (metconazole), in particular to a novel crystalline form of metconazole. The present invention further relates to a method for the preparation of the novel form of metconazole and, still further to the use of the novel form of metconazole in agrochemical preparations and in the control of fungicidal infestations.

5-(4-chlorobenzy1)-2,2-dimethy1-1 -(1 H-1,2,4-triazol-1 -ylmethyl) cyclopentanol (metconazole) belongs to the chemical class of azoles exhibiting a broad spectrum of fungicidal activity. Metconazole has a molecular formula of C17H22C1N130 and has the following structure: Metconazole is a chiral molecule existing as a mixture of two pairs of diastereomers, cis-and trans-isomers. Metconazole is a systemic fungicide with a mode of action preventing spore formation and inhibiting mycelia! growth. Metconazole is taken up into plant leaves and exhibits penetrant, local and acropetal systemicity. Metconazole exhibits both curative and protectant HC. H3C 1 OH \

N Ci

properties and has demonstrated long term activity in the control of plant disease organisms.

EP 0 329 397 discloses a process for producing azolylmethylcyclopentanol derivatives. Metconazole is included in the derivatives that may be formed by the process.

The commercially available metconazole, which is usually manufactured by the process described in EP 0 329 397, is present in an amorphous state. However, it has been found that metconazole in an amorphous state is not suitable for being formulated into fungicidal compositions. In particular, metconazole in an amorphous state has a high tendency to aggregate, in turn blocking filters and the nozzles of the spray apparatus used in the formulation process. Therefore, there is a need to reduce the tendency for metconazole to aggregate, and thereby improve the processes for its formulation.

It has been found that metconazole, when present in a crystalline form, herein referred to as "crystalline modification I", exhibits little to no tendency to aggregate, in turn significantly improving the processes for formulating fungicidal compositions.

In a first aspect, the invention provides a crystalline form of 5-(4-chlorobenzy1)-2,2-dimethy1-1-(1H-1,2,4-triazol-1-ylmethyl) cyclopentanol (metconazole) exhibiting at least 3 of the following reflexes, in any combination, as 20 ± 0.2 degree in an X-ray powder diffractogram (X-RPD) recorded using Cu-Ka radiation at 25 °C: = 10.3 ± 0.2 (1) 28 = 14.3 ± 0.2 (2) 28 = 14.9 ± 0.2 (3) 28 = 15.8 ± 0.2 (4) 28 = 20.6 ± 0.2 (5) 28 = 22.2 ± 0.2 (6) = 23.3 ± 0.2 (7) = 23.6 ± 0.2 (8) 28 = 27.0 ± 0.2 (9) = 28.1 ± 0.2 (10).

In one preferred embodiment, the crystalline modification according to the first aspect of the invention, exhibits at least 3, more preferably 4 or all of the reflexes, in any combination from the following: 28 = 10.3 ± 0.2 (1) 28 = 15.8 ± 0.2 (4) = 20.6 ± 0.2 (5) 28 = 22.2 ± 0.2 (6) 28 = 23.3 ± 0.2 (7).

In one preferred embodiment, the crystalline modification according to the first aspect of the invention exhibits an X-ray powder diffraction pattern substantially as shown in Figure 1.

In a second aspect, the present invention provides a crystalline form of 5-(4-chlorobenzy1)-2,2-dimethy1-1-(1H-1,2,4-triazol-1-ylmethyl) cyclopentanol (metconazole) exhibiting an infrared (I R) spectrum with characteristic functional group vibration peaks at wavenumbers (cm-1, ± 0.2%) of one or more of 3337, 2963, 2871, 1508, 1492, 1425, 1406, 1385, 1271, 1137 and 1013 cm-1 as shown in Figure 2.

In one preferred embodiment, the crystalline modification according to the second aspect of the invention exhibits an IR spectrum substantially as shown in Figure 2.

In one preferred embodiment, the crystalline form of metconazole of the second aspect of the present invention further comprises the features hereinbefore described as characterizing the crystalline form of metconazole of the first aspect of the present invention.

In a third aspect, the present invention provides a crystalline form of 5-(4-chlorobenzy1)-2,2-dimethy1-1-(1H-1,2,4-triazol-1-ylmethyl) cyclopentanol (metconazole) exhibiting a melting point of from about 112 to about 114°C.

In one preferred embodiment, the crystalline form of metconazole of the third aspect of the present invention further comprises the features hereinbefore described as characterizing the crystalline form of metconazole of one or both of the first and second aspects of the present invention.

In a fourth aspect, the present invention provides a crystalline form of 5-(4-chlorobenzy1)-2,2-dimethy1-1-(1H-1,2,4-triazol-1-ylm ethyl)cyclopentanol (metconazole) exhibiting a differential scanning calorimetry (DSC) profile having an endothermic melting peak maximum of about 113.3°C.

In one preferred embodiment, the crystalline modification according to the fourth aspect of the invention exhibits a DSC thermogram substantially as shown in Figure 3.

In one preferred embodiment, the crystalline form of metconazole of the fourth aspect of the present invention further comprises the features hereinbefore described as characterizing the crystalline form of metconazole of one or more of the first, second and third aspects of the present invention.

It has been found that the crystalline modification I of metconazole exhibits a significant increase in its anti-aggregation properties, which significantly reduces the aggregation problem encountered in current commercially available formulations. In addition, it has been found that the crystalline modification I of metconazole is easier to comminute or grind, compared with amorphous metconazole prepared in accordance with known and commonly applied procedures, such as the method disclosed in EP 0329397. This allows metconazole to used in the preparation of commercial formulations such as suspension concentrates (SC), oil-based suspension concentrates (OD), water-dispersible granules (WG) and water-soluble granules (SG). As a result, the crystalline modification I of metconazole may be formulated into a wide range of commercial compositions, details of which are disclosed hereinafter.

In a further aspect, the present invention provides a method for preparing the crystalline modification I of metconazole, the method comprising the steps of: i) dissolving metconazole in a solvent system comprising one or more solvents; H) precipitating the dissolved metconazole from solution in the solvent system to yield the crystalline modification I of metconazole; and iii) isolating the precipitated crystalline modification I. The metconazole starting material used in step i) of the method may be any suitable metconazole material. In one embodiment, the metconazole employed in step i) of the method is amorphous metconazole. Methods for preparing amorphous metconazole are known in the art. Amorphous metconazole is manufactured and available on a commercial scale. A particularly suitable method for preparing amorphous metconazole is described in EP 0 329 397.

As noted above, in step i) of the method, metconazole is dissolved in a solvent system. The solvent system may comprise a single solvent or a mixture of two or more solvents. Any suitable solvent that yields the crystalline modification I of metconazole may be employed in the solvent system. In one preferred embodiment, the solvent system comprises one or more solvents selected from ethers, aliphatic and aromatic hydrocarbons.

Preferred ethers for use in the solvent system include, for example, methyl t-butyl ether, ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol, diphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, dichlorodiethyl ether, polyethers of ethylene oxide and/or propylene oxide. Petroleum ether is also a particularly suitable solvent.

Preferred aliphatic hydrocarbons include, for example, aliphatic hydrocarbons having from 1 to 20 carbon atoms, preferably from 2 to 15 carbon atoms, more preferably from 4 to 12 carbon atoms, such as pentane, hexane, heptane, octane, and nonane. The aliphatic hydrocarbons may be straight chain or branched, with straight chain aliphatic hydrocarbons being preferred, such as n-hexane, n-heptane and n-octane.

Preferred aromatic hydrocarbon solvents include benzene and alkyl-substituted benzene, preferably Ci to C4 alkyl-substituted benzene, provided that in the case of Ci alkyl substituents, two or more alkyl substituents are present, more preferably Ci to C3 alkyl-substituted benzene, such as ethyl benzene, xylene, mesitylene and cymene. Petroleum fractions within a boiling range of from 70°C to 190°C and ligroin are also suitable as solvents.

In the method of the present invention, the solvent system does not include cyclohexane, methylcyclohexane, toluene, tetrahydrofuran and dioxane.

In a preferred embodiment, the solvent system comprises one or more solvents selected from aromatic hydrocarbons, ether and mixtures thereof. Particularly preferred solvents are xylene, methyl t-butyl ether and mixtures thereof.

In the method of the present invention, the crystalline modification I of metconazole is prepared by dissolving metconazole in a solvent system to form as solution. The dissolution of metconazole may be performed at ambient temperature Alternatively, the solvent system may be heated, preferably to a temperature at or below the reflux temperature of the solvent system. In one embodiment, the solution of metconazole is prepared at the reflux temperature of the solvent system. The concentration of the solution depends on such factors as the solubility of metconazole in the solvent system employed.

The metconazole solution prepared in step i) of the method is then used to produce the crystalline modification I of metconazole. This is achieved by crystallization. Any suitable technique may be employed to crystallize metconazole from solution in the solvent system.

For example, the solution may be cooled, for example to room temperature or to a temperature of from about 0°C to about 20°C to crystallize the desired crystalline form from the solvent.

The crystalline modification I of metconazole may also be crystallized out of solution by concentrating the solution by removing the solvent system. The solvent system may be removed by techniques known in the art, for example by evaporation with or without applying a vacuum, optionally with cooling to below the reflux temperature of the solvent system.

Production of the crystalline modification I of metconazole from the solution can also be effected or aided by adding seed crystals to the solution, preferably seed crystals of metconazole, more preferably seed crystals of the desired crystalline form. The addition of seed crystals acts to promote or accelerate the crystallization.

The amount of seed crystals added to the metconazole solution may be any suitable amount required to promote or accelerate crystallization and is typically in the range of 0.001% to 10% by weight based on the weight of metconazole used to prepare the solution, preferably from 0.001% to 2.5% by weight, more preferably from 0.005 to 0.5% by weight based on the weight of metconazole used for the preparation of the solution in step (i). Preferably, the seed crystals, if employed, are added to the concentrated solution at the temperature below the boiling point of the solvent system.

Crystallization of the crystalline modification I of metconazole from the solution formed in step i) may be carried out batchwise, semi-continuously or continuously.

The precipitated crystalline modification I of metconazole obtained from step ii) of the method may be isolated and revered by solid component separation techniques known in the art, such as filtration, centrifugation and/or decantation.

Thereafter, the isolated solid is preferably washed with a solvent one or more times. Preferably, the solvent employed in the washing stage consists of or at least comprises one or more components of the solvent system employed for preparation of metconazole solution in step i) of the method, as described above. The washing step is preferably carried out using the solvent at a temperature from 0°C to room temperature, depending on the solubility of the crystalline metconazole in the solvent system being employed, in order to minimize or avoid the loss of crystalline material.

In one embodiment of the method of the invention, the crystalline modification I of metconazole is dissolved and recrystallized. The washings and/or the solvent system used for crystallization in any of the method steps may be concentrated to obtain solid metconazole, which may then be recycled for use in step i) of the method.

In a further aspect, the present invention provides a crystalline modification I of metconazole obtainable by the method hereinbefore described.

In the present invention, it is preferred that the crystalline metconazole material has a content of the crystalline modification I of metconazole of at least 98% by weight.

In a further aspect, the present invention provides a fungicidal composition comprising the crystalline modification I of metconazole as hereinbefore described and at least one auxiliary.

The composition may comprise the crystalline modification I of metconazole in any suitable amount to provide the desired fungicidal effects. Preferably, the amount of the crystalline modification I of metconazole in the composition is less than 90% by weight of the composition, more preferably less than 75% by weight of the composition, still more preferably less than 60% by weight of the composition, more preferably still in many embodiments less than 50% by weight of the composition. Preferably, the amount of the crystalline modification I of metconazole in the composition is greater than 0.1% by weight of the composition, more preferably greater than 1% by weight of the composition, still more preferably greater than 5% by weight of the composition, more preferably still in many embodiments greater than 10% by weight of the composition, for example greater than 15% by weight. In many embodiments, the crystalline modification I of metconazole is present in the composition in an amount of about 40% by weight.

The use of metconazole as fungicide is well known in the art and metconazole is used on a commercial scale. The crystalline modification I of metconazole is active in preventing, treating and controlling fungal infestations in plants and plant parts. Techniques of formulating and applying metconazole are known in the art. The crystalline modification I of metconazole can be formulated and applied in analogous manners to those known and employed in the art for metconazole.

The crystalline modification I of metconazole may be formulated into any suitable composition. Such formulations and their preparation are known in the art. Preferably, the composition is in the form of a suspension concentrate (SC), an oil dispersion (OD), water-soluble granules (SG), a dispersible concentrate (DC), an emulsifiable concentrate (EC), an emulsion seed dressing, a suspension seed dressing, granules (GR), microgranules (MG), a suspoemulsion (SE) or water-dispersible granules (WG). In one preferred embodiment, the composition is in the form of a suspension concentrate (SC).

The crystalline modification I of metconazole formulations may be prepared using techniques known in the art, for example, by extending the crystalline modification I of metconazole with water, solvents and carriers, using, if appropriate, emulsifiers and/or dispersants, and/or other auxiliaries. These formulations may be prepared in a known manner by mixing the crystalline modification I of metconazole with at least one customary additive, for example, wetting agents, dispersants, thickening agent, anti-freezing agents, biocide and any necessary adjuvants and other formulation ingredients.

Wetting agents include, but are not limited to, alkyl sulfosuccinates, laureates, alkyl sulfates, phosphate esters, acetylenic diols, ethoxyfluornated alcohols, ethoxylated silicones, alkyl phenol ethoxylates, benzene sulfonates, alkyl-substituted benzene sulfonates, alkyl a-olefin sulfonates, naphthalene sulfonates, alkyl-substituted naphthalene sulfonates, condensates of naphthalene sulfonates and alkyl-substituted naphthalene sulfonates with formaldehyde, and alcohol ethoxylates. Alkyl naphthalene sulphonates, sodium salts are particularly useful for the composition of the invention.

Dispersants may be a non-ionic dispersing agent or an anionic dispersing agent. Suitable non-ionic dispersing agents for use in the stabilizing component of the concentrate of the present invention are known in the art and are commercially available. The non-ionic dispersing agent is preferably an ethoxylated non-ionic dispersing agent, in particular polytheyleneoxide-polypropyleneoxide block-copolymers. Such compounds are available commercially, for example Pluronic®, available from BASF A.G.

Alternatively, the non-ionic dispersing agent may be a polyoxyethylene fatty acid or polyoxyethylene alcohol. Again, such compounds are known in the art and can be prepared by the alkoxylation of fatty acids, alcohols or alkylphenols having from 9 to 24 carbon atoms, more preferably from 12 to 22 carbon atoms, in particular from 14 to 20 carbon atoms. The alkoxylation is preferably carried out using ethylene oxide. The aliphatic moieties of the fatty acids and alcohols may be straight chained or branched chain. Particularly preferred compounds of this class are alkylethoxylates, alkylarylethoxylates and alkyloxyethoxylates, for example Arkopal®, available from Clariant GmbH, and Genopal®, available from Clariant GmbH.

Suitable anionic dispersing agents for use in the stabilizing component of the concentrate of the present invention are known in the art and are commercially available. The anionic dispersing agent is preferably a sulfonate, sulphate or phosphate of ammonia, an alkali metal or alkaline earth metal, in particular an alkylnaphthalene sulfonic acid formaldehyde condensate, tristyrylphenols or distyrylphenols. Such compounds are available commercially, for example Morwet® D425, available from Akzo-Nobel, and Soprophor0, available from Rhodia Chemical Company.

Thickening agents include, but are not limited to, guar gum, pectin, casein, carrageenan, xanthan gum, alginates, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose. Synthetic thickeners include derivatives of the former categories, and also polyvinyl alcohols, polyacrylam ides, polyvinylpyrrolidones, various polyethers, their copolymers as well as polyacrylic acids and their salts. Alkylpolyvinylpyrrolidones are particularly useful for the composition of the invention Suitable anti-freezing agents are urea, glycerine, liquid polyols, for example ethylene glycol, propylene glycol or glycerol. The amount of anti-freezing agents 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.

Biocides may also be added to the composition according to the invention. Suitable Biocides are those based on isothiazolones, for example Proxel® from ICI or Acticide® RS from Thor Chem ie or Kathone MK from Rohm & Haas. The amount of biocides is typically from 0.05% to 0.5% by weight, based on the total weight of composition.

Other formulation ingredients can also be used in the present invention, such as dyes, anti-foaming agents, drying agents, and the like. The crystalline modification I of metconazole may be formulated together with inhibitors which reduce degradation of the active compound after their application in the environment of the plant, on the surface of plant parts or in plant tissues. These ingredients are known to one skilled in the art and are commercially available.

The present invention further provides a method for preventing, treating and/or controlling fungal infestation of a plant, comprising applying to the plant, plant parts, or the surroundings of the plant, a fungicidally effective amount of crystalline modification I of metconazole as hereinbefore described, or a composition as hereinbefore described.

In a still further aspect, the present invention provides the use of the crystalline modification I of metconazole as hereinbefore described, or a composition as hereinbefore described, for preventing, treating and/or controlling fungal infestations in plants and/or plant parts.

The crystalline modification I of metconazole can be employed with other active compounds, such as insecticides, attractants, sterilizing agents, bactericides, acaricides, nematicides, fungicides, growth-regulating substances, herbicides, safeners, fertilizers and semiochemicals, or with agents for improving plant properties. Such other compounds and agents may be included in the same composition as the crystalline modification I of metconazole or employed in the form of one or more separate compositions.

Preferred mixing partners of the crystalline modification I of metconazole include pyraclostrobin, picoxystrobin, prothioconazole, cyproconazole, azoxystrobin, tebuconazole, difenoconazole, boscalid, dimethomorph, chlorothalonil, bromuconazole, diniconazole, epoxiconazole, fenbuconazole, fuquinconazole, fusilazole, hexaconazole, prochloraz, propiconazole, tetraconazole, trifumizol, futriafol, myclobutanil, kresomix-methyl, dimoxystrobin, benomyl, carbendazim, debacarb, fuberidazole, thiabendazole, thiophanate-methyl, benalaxyl, ofurace, metalaxyl, furalaxyl, oxadixyl and mixtures thereof.

Particularly preferred mixing partners are pyraclostrobin, picoxystrobin, azoxystrobin, difenoconazole, prothioconazole, boscalid, dimethomorph, chlorothalonil and mixtures thereof.

All plants and plant parts may be treated with the crystalline modification I of metconazole in accordance with the present invention. In the present context, plants are to be understood as meaning all plants and plant populations such as desired and undesired wild plants or crop plants, including naturally occurring crop plants. Crop plants may be plants which can be obtained by conventional breeding and optimization methods, by biotechnological and genetic engineering methods, or by combinations of these methods, including the transgenic plants and the plant cultivars which can or cannot be protected by plant breeders' rights. Plant parts are to be understood as meaning all parts and organs of plants above and below the ground, such as shoots, leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes. Harvested materials, and vegetative and generative propagation materials, for example, cuttings, tubers, meristem tissue, rhizomes, offsets, seeds, single and multiple plant cells and any other plant tissues, are also considered as being plant parts.

Throughout the description and claims of this specification, the words "comprise" and variations of the words, for example "comprising" and "comprises", mean "including but not limited to", and do not exclude other moieties, additives, components, integers or steps. Moreover the singular encompasses the plural unless the context otherwise requires: in particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

Preferred features of each aspect of the invention may be as described in connection with any of the other aspects. Other features of the invention will become apparent from the following examples Generally speaking the invention extends to any novel one, or any novel combination, of the features disclosed in this specification, including any accompanying claims and drawings. Thus features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. Moreover unless stated otherwise, any feature disclosed herein may be replaced by an alternative feature serving the same or a similar purpose.

Where upper and lower limits are quoted for a property then a range of values defined by a combination of any of the upper limits with any of the lower limits may also be implied.

In this specification, references to properties are, unless stated otherwise, to properties measured under ambient conditions, that is at atmospheric pressure and at a temperature of about 20°C.

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

"Surrounding" as used herein, refers to the place on which the plants are growing, the place on which the plant propagation materials of the plants are sown or the place on which the plant propagation materials of the plants will be sown.

Treatment according to the invention of the plants and plant parts with the compositions or formulations of the invention may be carried out directly or by allowing the compositions or formulations to act on their surroundings, habitat or storage space by the customary treatment methods. Examples of these customary treatment methods include dipping, spraying, vaporizing, fogging, broadcasting, painting on in the case of propagation material, and applying one or more coats particularly in the case of seed.

Metconazole, which is an active ingredient of the fungicidal composition of the invention; is known to be effective against a range of fungi; such as brown rust, yellow rust, Septoria leaf spot and Fusarium.

The benefits of the present invention are seen most when the fungicidal composition is applied to prevent, treat and control fungal infestation in growing crops of useful plants: such as cereals, rape, soybean, rice, vine, fruit and vegetable.

"Precipitation" as used herein, refers to the sedimentation of a solid material (a precipitate), including the sedimentation of a crystalline material, from a liquid solution in which the solid material is present in amounts greater than its solubility in the amount of liquid solution.

Various features and aspects of the embodiments of the invention disclosed herein can be more clearly understood by reference to the accompanying drawings, which are intended to exemplify and illustrate, but not to limit, the scope of the invention, and wherein: FIG. 1 is an X-ray powder diffractogram (X-RPD) of a crystalline modification I of metconazole; FIG. 2 is an infrared (IR) spectrum of a crystalline modification I of metconazole; and FIG. 3 is a differential scanning calorimetry (DSC) thermogram of a crystalline modification I of metconazole.

The present invention will now be described by the following examples, and in which the following measurement techniques have been employed, and which the examples are provided for illustrative purposes only, and not intended to limit the scope of the disclosure.

All percentages are given in weight °A unless otherwise indicated.

All X-ray powder diffractograms were determined using powder diffractometer in reflection geometry at 25°C, using the following acquisition parameters: X'Pert Pro MPD from PANalytical B.V.

Theta compensating slit and graphite monochromator Copper (K-alpha) radiation, 40 kV, 40 mA Step size: 0.03 degree 2-theta Count time: 1.0 second Maximum peak intensity: 1705 counts per second Scan range 3-60 degrees 2-theta The IR spectrum was measured with the resolution of 4 cm-1 and with the number of scans being 16 for the crystallized samples. The crystalline modification I of metconazole can be identified by its characteristic functional group vibration peaks at wavenumbers (cm-1, ± 0.2%) of one or more of 3337, 2963, 2871, 1508, 1492, 1425, 1406, 1385, 1271, 1137 and 1013 cm-1 as shown in Figure 2.

All IR spectra were obtained using the following acquisition parameters: FT-IR NicoletTM iS 5 spectrometer Diamond ATR unit Thermo ScientificTM iD5 ATR Wavelength range 550-4000 cm-1 Resolution 4 cm-1 Number of scans 16 All DSC thermograms were obtained using the following acquisition parameters: Differential Scanning DSC 214 Polyma from NETZSCH-Calorimeter Geratebau GmbH Range 50°C/5.0(K/min)/250°C Sample car./TC DSC 214 Corona sensor /E Segments 1/1 Crucible Pan Al, closed Atmosphere N2, 50.0 ml/min / N2, 70.0 ml/min Corr/m. range 000/5000 pV

Examples

Example 1: Preparation of amorphous metconazole in accordance with the disclosure of EP 0329397 (Example 1) Into a 300 mL four-necked flask equipped with a cooler having a calcium chloride cylinder, an agitator, a thermometer and a nitrogen-introducing pipe, 3.5 g of 60% oily sodium hydride was charged and washed with dried hexane. The hexane was removed. 30 mL of N-methyl-2-pyrrolidone was added to the flask and the resulting mixture was stirred. 6.49 g of trimethylsulfoxonium bromide was added to the reaction mixture in a small quantity at a time and formed dimethyloxosulfonium methylide.

After bubbling was over, 3.45 g of 1,2,4-triazole was added in a small quantity at a time. After stirring the whole mixture for 30 minutes, 30 mL of tert-amyl alcohol and 5.9 g of 5-(4-chlorobenzyI)-2,2-dimethylcyclopentanone were added and the resulting mixture was stirred at 100°C for 4 hours.

After cooling to room temperature the reaction solution was poured into iced water, extracted with chloroform and yielded an organic layer. The layer was washed with water and dried over anhydrous sodium sulfate and chloroform was then distilled off to obtain 9.3 g of an oily material.

The oily material was purified with column chromatography using silica gel. 4.37 g of the target compound, 5-(4-chlorobenzyI)-2,2-dimethyl-1-(1H1,2,4-triazol-1-ylmethyl) cyclopentanol (metconazole) was obtained.

The reaction sequence may be illustrated as follows: Cl C14H.17C10 236.74 1,2,4-triazole, clt-OH NaH, NMP, 90 °C Cl cH2 cH2 N, (CH3)3SBr C N °C, 8 h Ci7H22CiN30 319.83 The X-ray powder diffraction pattern of the resulting metconazole product has no significant signals, which indicates the metconazole product prepared in accordance with the disclosure of Example 1 of EP 0329397 is amorphous.

Example 2: Preparation of the crystalline modification I of metconazole from xylene 4 g of the metconazole sample prepared in Example 1 was placed in a 3-neck round bottom flask along with 25 mL of xylene and the resulting slurry was heated to 65°C to get a homogeneous solution. The insoluble particles, if any, were filtered and the solution was slowly cooled to ambient temperature. Fine crystals were formed during the cooling and the mixture was stirred at ambient temperature for 2 hours.

Thereafter, the slurry was filtered and washed with 3 m L of xylene. The filtered crystals were dried under vacuum at 40°C in order to remove the xylene traces from the crystalline product. The crystalline product thus obtained had a purity of 98% and the yield was found to be about 90%.

The crystals were analyzed by X-RPD, IR spectrometry and DSC and found to be a crystalline modification I of metconazole having the characteristics shown in Figure 1, Figure 2 and Figure 3, respectively.

The IR spectrum of the crystalline metconazole exhibited the functional group characteristic vibration peaks at wavenumbers of one or more of 3337, 2963, 2871, 1508, 1492, 1425, 1406, 1385, 1271, 1137 and 1013 cm-1 as shown in Figure 2.

The DSC thermogram of the crystalline metconazole exhibited an endothermic melting peak maximum at 113.3°C as shown in Figure 3.

The X-ray powder diffractogram of the metconazole crystals exhibited the reflexes in Figure 1 and the values are summarized in Table 1 below.

Table 1

Crystalline Modification I 2 6 (°) d (A) 10.3 ± 0.2 10.01 ± a05 14.3 ± 0.2 7.21 ± 0.05 14.9 ± 0.2 6.90 ± 0.05 15.8 ± 0.2 6.51 ± 0.05 20.6 ± 0.2 5.01 ± 0.05 22.2 ± 0.2 4.64 ± 0.05 23.3 ± 0.2 4.44 ± 0.05 23.6 ± 0.2 4.38 ± 0.05 27.0 ± 0.2 3.82 ± 0.05 28.1 ± 0.2 3.68 ± 0.05 Example 3: Preparation of the crystalline modification I of metconazole from methyl t-butyl ether 4 g of the metconazole sample prepared in Example 1 was placed in a 3-neck round bottom flask along with 30 mL of methyl t-butyl ether and the resulting slurry was heated to 40°C to get a homogeneous solution. The insoluble particles, if any, were filtered and the solution was slowly cooled to ambient temperature. Fine crystals were formed during the cooling and the mixture was stirred at ambient temperature for 2 hours.

Thereafter, the slurry was filtered, washed with 3 mL of methyl t-butyl ether. The filtered crystals were dried under vacuum at 40°C in order to remove the methyl t-butyl ether traces from the crystalline product.

The crystalline product thus obtained had a purity of 99% and the yield was found to be about 88%. Metconazole crystalline modification I was obtained.

Example 4: Preparation of suspension concentrate (SC) of amorphous metconazole All the components listed in Table 2 below were mixed uniformly and the resulting mixture was ground with a Dyno-Mill (manufactured by Willy A. Bachofen AG) to obtain a suspension concentrate.

Table 2

Ingredients Weight % Function Amorphous metconazole 40 Active compound (prepared in Example 1) Alkylnaphthalene sulfonic acid 8.00 Dispersant formaldehyde condensate (Morwet® D425) Ethyleneoxide/propyleneoxide block 10.00 Dispersant copolymer (Pluronic® PE10500) Alkylpolyvinylpyrrolidone 10.00 Thickening agent Butylated hydroxytoluene (BHT) 5.00 Antioxidant Propylene glycol 3.00 Anti-freezing agent 1,2-Benzisothiazol-3(2H)-one (Proxe10) 1.00 Biocide Water Balance to Filler Example 5: Preparation of suspension concentrate (SC) of crystalline modification I of metconazole All the components listed in Table 3 below were mixed uniformly and the resulting mixture was ground with a Dyno-Mill (manufactured by Willy A. Bachofen AG) to obtain a suspension concentrate.

Table 3

Ingredients Weight % Function Metconazole, crystalline modification I, 98% (prepared in Example 2 -Xylene) 40 Active compound Alkylnaphthalene sulfonic acid 8.00 Dispersant formaldehyde condensate (Morwet® D425) Ethyleneoxide/propyleneoxide block 10.00 Dispersant copolymer (Pluronic® PE10500) Alkylpolyvinylpyrrolidone 10.00 Thickening agent Butylated hydroxytoluene (BHT) 5.00 Antioxidant Propylene glycol 3.00 Anti-freezing agent 1,2-Benzisothiazol-3(2H)-one (Proxe0) 1.00 Biocide Water Balance to Filler Example 6: Preparation of suspension concentrate (SC) of crystalline modification I of metconazole All the components listed in Table 4 below were mixed uniformly and the resulting mixture was ground with a Dyno-Mill (manufactured by Willy A. Bachofen AG) to obtain a suspension concentrate.

Table 4

Ingredients Weight % Function Metconazole, crystalline modification I, 40 Active compound 98% (prepared in Example 3 -methyl t-butyl ether) Alkylnaphthalene sulfonic acid 8.00 Dispersant formaldehyde condensate (Morwet0 D425) Ethyleneoxide/propyleneoxide block 10.00 Dispersant copolymer (Pluronic0 PE10500) Alkylpolyvinylpyrrolidone 10.00 Thickening agent Butylated hydroxytoluene (BHT) 5.00 Antioxidant Propylene glycol 3.00 Anti-freezing agent 1,2-Benzisothiazol-3(2H)-one (Proxel®) 1.00 Biocide Water Balance to Filler Example 7: Wet Sieve Test The compositions of Examples 4 to 6 and other comparative examples were diluted with water with a dilution factor of 50 and their residue was compared by passing through a wet sieve of 325 mesh (44 pm openings). The residue deposit on the sieve was observed. The results are set out in Table 5 below.

The further comparative examples employed crystalline forms of metconazole prepared by crystallization from solution in each of methylcyclohexane, cyclohexane, tetrahydrofuran and dioxane.

Table 5

Sample Residues observed Example 4, amorphous metconazole, 98% (prepared in ++++

Example 1)

Example 5, metconazole, crystalline modification I, 98% - (prepared in Example 2) Example 6, metconazole, crystalline modification I, 98% (prepared in Example 3) SC formulation prepared by crystallization of metconazole +++ from solution in methylcyclohexane SC formulation prepared by crystallization of metconazole ++++ from solution in cyclohexane SC formulation prepared by crystallization of metconazole +++ from solution in tetrahydrofuran SC formulation prepared by crystallization of metconazole ++ from solution in dioxane

In Table 5 above:

"+++++" means significant aggregation was observed. "2 means no aggregation was observed.

As can be seen from the results set out in Table 5, the crystalline modification I of metconazole according to the present invention and prepared according to the method of the present invention exhibited no aggregation. In contrast, amorphous metconazole and crystalline metconazole prepared by other methods exhibited a significant aggregation of the metconazole particles.

Claims

CLAIMS1. A crystalline modification I of 5-(4-chlorobenzy1)-2,2-dimethy1-1- 0H-1,2,4-triazol-1-ylmethypcyclopentanol (metconazole) exhibiting at least 3 of the following reflexes, in any combination, as 20 ± 0.2 degree in an X-ray powder diffractogram (X-RPD) recorded using Cu-Ka radiation at 25°C: 28 = 10.3 ± 0.2 (1) 28 = 15.8 ± 0.2 (4) 28 = 20.6 ± 0.2 (5) 28 = 22.2 ± 0.2 (6) 28 = 23.3 ± 0.2 (7).
2. A crystalline modification I of metconazole exhibiting an IR spectrum with characteristic functional group vibration peaks at wavenumbers (cm-1, ± 0.2%) of one or more of 3337, 2963, 2871, 1508, 1492, 1425, 1406, 1385, 1271, 1137 and 1013 cm-1.
3. A crystalline modification I of metconazole exhibiting a melting point of about 112-114°C.
4. A crystalline modification I of metconazole exhibiting a differential scanning calorimetry (DSC) profile having an endothermic melting peak maximum at 113.3 °C.
5. A crystalline modification I of metconazole according to any preceding claim, characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1, and/or characterized by an IR spectrum substantially as shown in Figure 2, and/or characterized by a DSC thermogram substantially as shown in Figure 3.
6. A method for the preparation of a crystalline modification I of metconazole according to any of the preceding claims, the method comprising: i) dissolving metconazole in a solvent system comprising one or more solvents, H) precipitating the dissolved metconazole from solution in the solvent system to yield the crystalline modification I of metconazole; and iii) isolating the precipitated crystalline modification I.
7. The method according to claim 6, where the metconazole in step is amorphous metconazole.
8. The method according to either of claims 6 or 7, wherein the solvent system comprises a solvent selected from aromatic hydrocarbons, ethers and mixtures thereof.
9. The method according to claim 8, where the solvent system comprises xylene, methyl t-butyl ether or a mixture thereof.
10. The method according to any of claims 6 to 9, wherein step ii) comprises concentrating the solution by removal of solvent and/or cooling the solvent system.
11. The method according to any of claims 6 to 10, wherein in step ii) seed crystals are added to the solution formed in step i).
12. The method according to claim 11, wherein the seed crystals comprise the crystalline modification I of metconazole.
13. A crystalline material comprising a crystalline modification I of metconazole obtainable by the method according to any of claims 6 to 12.
14. A composition comprising the crystalline modification I of metconazole according to any of claims 1 to 5 or claim 13 and at least one auxiliary.
15. The composition according to claim 14, wherein the auxiliary is selected from surfactants, diluents, wetting agents, dispersants, thickening agents, anti-foaming agents, anti-freezing agents, preservatives, antioxidants, solid adherents, inert fillers and mixtures thereof.
16. The composition according to either of claims 14 or 15, wherein the composition is in the form of a suspension concentrate (SC), an oil dispersion (OD), water-soluble granules (SG), a dispersible concentrate (DC), an emulsifiable concentrate (EC), an emulsion seed dressing, a suspension seed dressing, granules (GR), microgranules (MG), a suspoemulsion (SE) or water-dispersible granules (WG).
17. The composition according to claim 16, wherein the composition is in the form of a suspension concentrate (SC).
18. A method for preventing, treating and/or controlling fungal infestation of a plant, comprising applying to the plant, plant parts, or the surroundings of the plant, a fungicidally effective amount of crystalline modification I of metconazole according to any of claims 1 to 7, or claim 13, or a composition according to any of claims 14 to 17.
19. Use of a crystalline modification I of metconazole according to any of the claims 1 to 7, or claim 13 for preventing, treating and/or controlling fungal infestation in a plant or plant parts