EP4720043A1 - Solid form of a quinoline carboxamide compound - Google Patents

Abstract

The present invention relates to a crystalline polymorph of the compound of formula (I) which has a powder X-ray diffraction pattern comprising at least three 2θ angle values selected from the group consisting of consisting of 7.1 ±0.2, 7.8 ± 0.2°, 8.9 ± 0.2°, 11.4 ± 0.2°, 13.5 ± 0.2°, 14.2 ± 0.2°, 14.7 ± 0.2°, 16.2 ± 0.2°, 17.7 ± 0.2°, 18.4 ± 0.2°, 20.0 ± 0.2°, 20.8 ± 0.2°, 21.2 ± 0.2°, 21.5 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°, 23.6 ± 0.2°, 24.0 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°, 26.2 ± 0.2°, 27.3 ± 0.2°, 27.7 10 ± 0.2°, 28.6 ± 0.2°, 29.6 ± 0.2°, 30.3 ± 0.2°.

Description

SOLID FORM OF A QUINOLINE CARBOXAMIDE COMPOUND

This invention relates to a solid form of a quinoline carboxamide derivative, a process to prepare said solid form, to a composition comprising said solid form, and to a method of its use as fungicide.

WO 2017/153380 discloses that certain quinoline carboxamide derivatives have a microbicidal activity, such as a fungicidal activity. In particular, a compound of formula I: N-(1-benzyl-1 ,3-dimethyl- butyl)-8-fluoro-quinoline-3-carboxamide:

Mixtures of this compound with other fungicides are disclosed in WO 2019/052930, as well as processes for the preparation of quinoline carboxamide derivatives have been disclosed.

There are two enantiomers of the compound of formula I: compounds l-R and l-S, shown below:

(l-R) (l-S)

A new solid form of this compound and its preparation have now been discovered. Accordingly, the present invention relates to a novel crystalline form of a quinoline carboxamide derivative, said derivative being a crystalline polymorph of the compound of formula (l-R). The novel crystalline form is designated Form A. Different enantiomers have the same physical properties so they will have the same polymorphs. Compound (l-S) has the same solid form Form A as compound (l-R).

It has also been found that when compounds (l-R) and (l-S) are present together, they combine and form a conglomerate racemic solid form, which is designated as Form RAC. The crystalline Form RAC causes crystal growth in aqueous suspensions. When formulating a compound, such as compound (l-R), it is desirable to limit crystal growth.

The crystalline polymorph Form A according to the present invention presents an optimized handling and processing, especially on manufacturing scale. More particularly, the crystalline polymorph Form A can provide a higher purity, an easier washing of the solids, or guarantee a significant improvement in reducing filtration times. More particularly, the crystalline Form A of compound of formula (l-R) may be characterized by a powder X-ray diffraction pattern expressed in terms of 20 angles and/or d spacings.

The crystalline Form A of compound of formula (l-R) can have a powder X-ray diffraction pattern comprising at least three 20 angle values, preferably at least six 20 angle values, preferably at least eight 20 angle values, and more preferably at least ten 20 angle values, selected from the group consisting of 7.1 ±0.2, 7.8 ± 0.2°, 8.9 ± 0.2°, 11.4 ± 0.2°, 13.5 ± 0.2°, 14.2 ± 0.2°, 14.7 ± 0.2°, 16.2 ± 0.2°, 17.7 ± 0.2°, 18.4 ± 0.2°, 20.0 ± 0.2°, 20.8 ± 0.2°, 21 .2 ± 0.2°, 21 .5 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°,

23.6 ± 0.2°, 24.0 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°, 26.2 ± 0.2°, 27.3 ± 0.2°, 27.7 ± 0.2°, 28.6 ± 0.2°, 29.6 ± 0.2°, 30.3 ± 0.2°.

In a preferred embodiment, the crystalline Form A of compound of formula (l-R) can have a powder X-ray diffraction pattern comprising at least three 20 angle values, preferably at least six 20 angle values, preferably at least eight 20 angle values, and more preferably at least ten 20 angle values, selected from the group consisting of 7.1 ±0.2, 7.8 ± 0.2°, 11 .4 ± 0.2°, 13.5 ± 0.2°, 14.2 ± 0.2°, 14.7 ± 0.2°, 16.2 ± 0.2°, 17.7 ± 0.2°, 18.4 ± 0.2°, 25.0 ± 0.2°, 26.2 ± 0.2°.

More particularly, the crystalline Form A of compound of formula (l-R) can have a powder X-ray diffraction pattern comprising at least the following 20 angle values: 7.8 ± 0.2°, 11 .4 ± 0.2°, 16.2 ± 0.2°,

17.7 ± 0.2°; preferably at least the following 20 angle values: of 7.1 ±0.2, 7.8 ± 0.2°, 11.4 ± 0.2°, 13.5 ± 0.2°, 14.2 ± 0.2°, 14.7 ± 0.2°, 16.2 ± 0.2°, 17.7 ± 0.2°, 18.4 ± 0.2°, 25.0 ± 0.2°, 26.2 ± 0.2°; and more preferably at least the following 20 angle values: 7.1 ±0.2, 7.8 ± 0.2°, 8.9 ± 0.2°, 11 .4 ± 0.2°, 13.5 ± 0.2°, 14.2 ± 0.2°, 14.7 ± 0.2°, 16.2 ± 0.2°, 17.7 ± 0.2°, 18.4 ± 0.2°, 20.0 ± 0.2°, 20.8 ± 0.2°, 21 .2 ± 0.2°, 21 .5 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°, 23.6 ± 0.2°, 24.0 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°, 26.2 ± 0.2°, 27.3 ± 0.2°,

27.7 ± 0.2°, 28.6 ± 0.2°, 29.6 ± 0.2°, 30.3 ± 0.2°.

For instance, the crystalline Form A of compound of formula (l-R) has a powder X-ray diffraction pattern comprising all 20 angle values selected from the group consisting of 7.1 ±0.2, 7.8 ± 0.2°, 8.9 ± 0.2°, 11 .4 ± 0.2°, 13.5 ± 0.2°, 14.2 ± 0.2°, 14.7 ± 0.2°, 16.2 ± 0.2°, 17.7 ± 0.2°, 18.4 ± 0.2°, 20.0 ± 0.2°,

20.8 ± 0.2°, 21 .2 ± 0.2°, 21 .5 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°, 23.6 ± 0.2°, 24.0 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°, 26.2 ± 0.2°, 27.3 ± 0.2°, 27.7 ± 0.2°, 28.6 ± 0.2°, 29.6 ± 0.2°, 30.3 ± 0.2°. These peak values, along with the corresponding d spacing values are shown in Table 1 below.

Table 1

W= Weak, M= Medium, S= Strong

These 20 angle values are derived from a powder X-ray diffraction pattern of the polymorph of formula 1 1 designated Form A obtained using the method of Example 1 . The values are generated using an average wavelength of 1 .54056A with a 20 step size of 0.02°.

The crystalline polymorph (Form A) of the invention may be characterized by the unit cell parameters of its single crystal as shown in Table 2. The polymorph Form A was obtained using the methods described in Example 1 .

Table 2

In Table 2, a, b, c are the lengths of the edges of the unit cell; a, p, y are the angles of the unit cell; and Z is the number of molecules per cell.

In a particular embodiment of the present invention, the crystalline polymorph can have the following lattice parameters: a=12.9 ± 0.1 A, b=12.9 A ± 0.1 A, c=21.0 A ± 0.1 A, a = 90°, p = 90°, y = 120°, and volume = 3030 ± 20 A³.

In another embodiment, the crystalline polymorph according to the invention can have a melting point ranging from 143 to 148 °C (peak position), and preferably ranging from 146 to 148 °C (peak position). This melting point is obtained using Differential Scanning Calorimetry (DSC) with a heating rate of 10 °C/minute. Variability of the melting point may depend on the enantiomeric purity.

The crystalline polymorph designated Form A may also be characterized by a IR spectra expressed in terms of IR shift (cm'¹). Thus, in another embodiment of the invention, the crystalline polymorph has a IR spectra comprising at least three, at least six, at least nine, at least twelve, at least fifteen, or all IR shift values selected from the group consisting of:

3246 ±2 cm- ¹, 3077 ±2 cm ¹, 3030 ±2 cm ¹, 2983 ±2 cm ¹, 2960 ±2 cm ¹, 2946 ±2 cm ¹, 2925 ±2 cm ¹, 2866 ±2 cm ¹, 1629 ±2 cm ¹, 1608 ±2 cm ¹, 1560 ±2 cm ¹, 1495 ±2 cm ¹, 1466 ±2 cm ¹, 1451

±2 cm ¹, 1415 ±2 cm ¹, 1374 ±2 cm ¹, 1343 ±2 cm ¹, 1318 ±2 cm ¹, 1300 ±2 cm ¹, 1280 ±2 cm ¹, 1248

±2 cm ¹, 1220 ±2 cm ¹, 1199 ±2 cm ¹, 1163 ±2 cm ¹, 1142 ±2 cm ¹, 1101 ±2 cm ¹, 1076 ±2 cm ¹, 1044

±2 cm- ¹ , 986 ±2 cm’ ¹ , 959 ±2 cnr ¹ , 944 ±2 cnr ¹ , 927 ±2 cnr ¹ , 875 ±2 cnr ¹ , 825 ±2 cm- ¹ , 781 ±2 cnr ¹ ,

749 ±2 cm ¹, 740 ±2 cm ¹, 701 ±2, 648 ±2 cm ¹, 633 ±2 cm ¹, 623 ±2 cm ¹, 606 ±2 cm ¹, 581 ±2 cm ¹, 564 ±2 cm^{- 1} and 543 ±2 cm^{- 1}.

The crystalline polymorph Form A of compound (l-S) has the same physical properties as the crystalline polymorph Form A of compound (l-R), such as the same powder X-ray diffraction pattern, the same unit cell parameters of its single crystal, and the same melting point.

However, as will be shown in the examples, the solid Form RAC has a different melting point than the melting point of Form A of compound (l-R) and of compound (l-S).

In the context of the present invention, a polymorph is a particular crystal form of a chemical compound that can exist in more than one crystal form in the solid state. A crystal form of a compound contains the constituent molecules arranged in orderly repeating patterns extending in all three spatial dimensions (in contrast, an amorphous solid form has no long-range order in the position of molecules). Different polymorphs of a compound have different arrangements of atoms and or molecules in their crystal structure. When the compound is a biologically active compound, such as a fungicide, the difference in crystal structures can lead to different polymorphs having different chemical, physical and biological properties. Properties which may be affected include crystal shape, density, hardness, colour, chemical stability, melting point, hygroscopicity, suspensibility, dissolution rate and biological availability. As such, a specific polymorph may have properties which make it more advantageous in a particular use relative to another polymorph of the same compound: in particular, the physical, chemical and biological properties listed above can have a significant effect on the development of production methods, especially at manufacturing scale, and on formulations; on the ease with which a compound can be combined in a formulation with other active ingredients and formulation components; and/or on the quality and efficacy of plant treatment agents, such as fungicides. It is noted that predicting whether the solid state of a compound may be present as more than one polymorph is not possible and nor is it possible to predict the properties of any of these crystal forms.

In particular, use of a specific polymorph may allow use of new formulations compared with existing polymorphic/amorphous forms of a compound. This might be advantageous for a number of reasons. For example, a suspension concentrate (SC) formulation may be preferred over an emulsion concentrate (EC) because the lack of solvent in the suspension concentrate may mean that the SC formulation is likely to be less phytotoxic than an equivalent EC formulation. However, if the existing form of a compound is not stable in such an SC formulation, polymorphic conversion might occur leading to unwanted crystal growth. Such crystal growth is detrimental because it may lead to, for example, thickening of the formulation, and even potentially to solidification of the formulation. A direct consequence may be blockage in application equipment, e.g. in spray nozzles in agricultural application machinery. Using a stable polymorphic form would overcome these issues. Assaying the solid phase for the presence of crystals may be carried out by conventional methods known in the art. For example, it is convenient and routine to use powder X-ray diffraction techniques. Other techniques which may be used include differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), IR spectroscopy, near infra-red spectroscopy, mid infra-red spectroscopy, nuclear magnetic resonance (NMR), gas chromatography or high-performance liquid chromatography (HPLC). Single crystal X-ray diffraction is especially useful in identifying crystal structures.

Another object of the present invention relates to a method of preparing the crystalline polymorph (Form A), comprising the following steps:

(i) mixing the compound l-R, with an organic solvent, such as ethyl acetate, , to obtain a solution of compound l-R,

(ii) crystallizing the compound from the solution obtained in step (i) either by evaporating said organic solvent, or by cooling the solution, to obtain solids.

In step (i), the solution may be saturated, meaning that no more solute (compound of formula I) can be dissolved in the solvent. Preferably, step (i) is performed at a temperature of less than 30 °C, and more preferably of up to 25 °C.

Step (i), may be followed with a filtration step. A filtration step can help to remove all remaining solid particles, such as for example undissolved solids, crystals, and/or dust. This optional step can limit or prevent nucleation points during the preparation method.

Step (ii) can be advantageously performed under constant stirring, and more preferably under constant mild stirring. Preferably, step (ii) is performed by evaporation of the said solvent.

The step (ii) can be followed by a filtering step of the suspension, in order to isolate the crystals generated in the step (ii) from their solvent(s) and use them as solid seeds.

The polymorphs of the invention may be applied in unchanged form but are more preferably incorporated into an agrochemical composition by conventional means. Accordingly, a further object according to the invention relates to an agrochemical composition comprising the crystalline polymorph as defined in the present invention, and at least one an agriculturally acceptable carrier or diluent. The agrochemical composition comprising the crystalline polymorph of the present invention can be used for the control of plant pathogenic fungi on a number of plant species.

In addition, compositions of the invention may comprise more than one polymorph of the invention. In particular, the compound of formula l-R is more biologically active than the compounds of formula l-S. As such, whilst the compositions of the invention may contain a mixture of the compounds l-R and l-S in the polymorphic forms disclosed herein or otherwise in any amounts, they may also be enriched for the compound of formula l-R or a polymorph of the compound of formula l-R. In particular, they may be enriched for the polymorph designated Form A. “Enriched” means that the molar proportion of the compound or polymorph of formula l-R compared to the total amount of the compounds of formula l-R and l-S is greater than 50%, e.g, at least 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or at least 99%. Preferably, the molar proportion of the compound or polymorph of formula l-R compared to the total amount of the compounds of formula l-R and l-S is greater than 90%, more preferably greater than 95%, such as, greater than 98%. If compound of formula (l-R) and compound of formula (l-S) are both present in a composition, it is expected that they may crystallize and form a conglomerate racemic solid Form RAC. The remainder of the most abundant enantiomer will crystalize or remain as a pure enantiomer Form A. As an example, if a composition contains compound l-R and compound l-S in a ratio l-R I l-S of 90 : 10, the composition will contain 80mol% of Form A and 20mol% of Form RAC after crystallization. As compound of formula (l-S) and compound of formula (l-R) have the same molecular weight, the ratio l-R / l-S may be viewed as a molar ratio as well as a weight ratio. Other examples are given in Table A below:

Table A

Another object of the present invention relates to a method of preventing or controlling fungal infection on plants or plant propagation material comprising treating the plant or plant propagation material with said agrochemical composition, and preferably with a fungicidally effective amount of said agrochemical composition.

The term “plants” refers to all physical parts of a plant, including seeds, seedlings, saplings, roots, tubers, stems, stalks, foliage, and fruits.

The term "plant propagation material" is understood to denote all the generative parts of the plant, such as seeds, which can be used for the multiplication of the latter including vegetative plant material such as cuttings. There may be mentioned, as plant propagation material, seeds (in the strict sense), roots, fruits, tubers, bulbs, rhizomes, or parts of plants. Germinated plants and young plants which are to be transplanted after germination or after emergence from the soil, may also be mentioned. These young plants may be protected before transplantation by a total or partial treatment by immersion. The plant propagation material can be treated with the composition of the invention before the material is sown or planted. Alternatively, the plant propagation material may be treated with the composition of the invention during sowing or planting. Additionally, the composition of the invention may be applied to the previously treated propagation material before orduring its planting. The composition ofthe invention may be applied during the sowing of the seed. The composition may also be used to plant propagation material derived from plants grown in a green house and/or during transplantation.

More preferably the plant propagation material is plant seeds. The seed treatment can occur to an unsown seed, and the term "unsown seed" is meant to include seed at any period between the harvest of the seed and the sowing of the seed in the ground for the purpose of germination and growth of the plant. Treatment to an unsown seed is not meant to include those practices in which the composition is applied to the soil but would include any application practice that would target the seed during the sowing/planting process. The treated plant propagation material of the present invention can be treated in the same manner as conventional plant propagation material. The treated propagation material can be stored, handled, sown and tilled in the same manner as any other pesticide treated material. The agrochemical composition of the invention can be used to control, for example, Ascomycetes (e.g. Venturia, Podosphaera, Erysiphe, Monilinia, Mycosphaerella, Uncinula, Corynespora, Phyllachora); Fungi imperfecti (also known as Deuteromycetes; e.g. Botrytis, Helminthosporium, Fusarium, Cercospora, Altemaria and Pyricularia).

The agrochemical composition of the present invention is suitable for controlling such disease on a number of plants and their propagation material including, but not limited to the following target crops: cereals (wheat, barley, rye, oats, maize (including field corn, pop corn and sweet corn), rice, sorghum and related crops); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, sunflowers); cucumber plants (marrows, cucumbers, melons); fibre plants (cotton, flax, hemp, jute); vegetables (spinach, lettuce, asparagus, cabbages, eggplants, onions, pepper, tomatoes, potatoes,); plantation crops (bananas, fruit trees,), ornamentals (flowers, shrubs,); as well as other plants such as vines, bushberries (such as blueberries), caneberries, cranberries, and turf grasses including, but not limited to, cool-season turf grasses (for example, bluegrasses (Poa L.), such as Kentucky bluegrass (Poa pratensis L.), rough bluegrass (Poa trivialis L.), Canada bluegrass (Poa compressa L.) and annual bluegrass (Poa annua L.); bentgrasses (Agrostis L.), such as creeping bentgrass (Agrostis palustris Huds.), colonial bentgrass (Agrostis tenius Sibth.), velvet bentgrass (Agrostis canina L.) and redtop (Agrostis alba L.); fescues (Festuca L.), such as tall fescue (Festuca arundinacea Schreb.), meadow fescue (Festuca elatiorL.) and fine fescues such as creeping red fescue (Festuca rubra L.), chewings fescue (Festuca rubra var. commutata Gaud.), sheep fescue (Festuca ovina L.) and hard fescue (Festuca longifolia); and ryegrasses (Lolium L.), such as perennial ryegrass (Lolium perenne L.) and annual (Italian) ryegrass (Lolium multiflorum Lam.)) and warm-season turf grasses, for example, Bermuda grasses (Cynodon L. C. Rich), including hybrid and common Bermudagrass; Zoysiagrasses (Zoysia Willd .), St. Augustine grass (Stenotaphrum secundatum (Walt.) Kuntze); and centipedegrass (Eremochloa ophiuroides (Munro.) Hack.).

In addition ‘crops’ are to be understood as also including those crops which have been rendered tolerant to herbicides like bromoxynil or classes of herbicides such as ALS-, EPSPS-, GS-, HPPD- and PPO-inhibitors. An example of a crop that has been rendered tolerant to imidazolinones, e.g. imazamox, by conventional methods of breeding is Clearfield® summer canola. Examples of crops that have been rendered tolerant to herbicides by genetic engineering methods include e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady®, Herculex I® and LibertyLink®.

Crops are also to be understood as being those which naturally are or have been rendered resistant to harmful insects. This includes plants transformed by the use of recombinant DNA techniques, for example, to be capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria. Examples of toxins which can be expressed include 8-endotoxins, vegetative insecticidal proteins (Vip), insecticidal proteins of bacteria colonising nematodes, and toxins produced by scorpions, arachnids, wasps and fungi.

An example of a crop that has been modified to express the Bacillus thuringiensis toxin is the Bt maize KnockOut® (Syngenta Seeds). An example of a crop comprising more than one gene that codes for insecticidal resistance and thus expresses more than one toxin is VipCot® (Syngenta Seeds). Crops or seed material thereof can also be resistant to multiple types of pests (so-called stacked transgenic events when created by genetic modification). For example, a plant can have the ability to express an insecticidal protein while at the same time being herbicide tolerant, for example Herculex I® (Dow AgroSciences, Pioneer Hi-Bred International).

In particular, the composition according to the invention is particularly effective against leafspot species; early blights and molds; especially against Fusarium in cereals; Sclerotinia in vegetables and oil seed rape; grey mold in vine; Botrytis cinerea, Monilinia spp. and Venturia spp. in fruits; and Phyllachora maydis in corn.

Therefore, the invention also relates to the use of Form A of compound (l-R), or of a composition containing it, to prevent or control a fungal infection on plants, in particular to prevent or control fungal infection caused by Fusarium spp. in cereals, such as wheat, barley, oat, or rye; to prevent or control fungal infection caused by Sclerotinia in vegetables, or in oil seed rape; to prevent or control grey mold in vine; to prevent or control fungal infection caused by Botrytis cinerea, Monilinia spp. or Venturia spp., in fruits; and to prevent or control fungal infection caused by Phyllachora maydis in corn.

The composition according to the invention is furthermore particularly effective against seedborne and soilborne diseases, such as Botrytis cinerea, Cercospora spp., Colletotrichum spp., Fusarium graminearum, Fusarium moniliforme, Fusarium oxysporum, Fusarium proliferatum, Fusarium solani, Fusarium subglutinans, Pyricularia oryzae, Sclerotinia spp., in particular against pathogens of cereals, such as wheat, barley, rye or oats; maize; rice; turf; and oil seed rape.

The composition according to the invention is furthermore particularly effective against post harvest diseases such as Botrytis cinerea, Colletotrichum musae, Monilinia fructicola, Monilinia fructigena, Monilinia laxa, in particular against pathogens of fruits, such as pomefruits, for example apples and pears, stone fruits, for example peaches and plums, and berries, for example strawberries,

The composition according to the invention is particularly useful for controlling the following diseases on the following crops: Botrytis cinerea in strawberries, tomatoes, sunflower, pulse crops, vegetables and grapes, such as Botrytis cinerea on grape; Colletotrichum species in fruit and vegetables, such as Colletotrichum acutatum in strawberries ; Fusarium species in cereals Mycosphaerella fijiensis in banana; Pyricularia oryzae in rice; Sclerotinia species in lawns, lettuce, vegetables and oil seed rape, such as Sclerotinia sclerotiorum on oilseed rape Venturia species in fruits, such as Venturia inequalis on apple; and Monilinia species on fruits.

The rate at which the agrochemical composition of the invention is applied will depend upon the particular type of fungus to be controlled, the degree of control required and the timing and method of application and can be readily determined by the person skilled in the art. In general, the composition of the invention can be applied at an application rate of between 0.005 kilograms/hectare (kg/ha) and about 5.0 kg/ha, based on the total amount of active fungicide in the composition. An application rate of between about 0.1 kg/ha and about 1.5 kg/ha is preferred, with an application rate of between about 0.3 kg/ha and 0.8 kg/ha being especially preferred.

In preferred embodiments, the agrochemical composition comprises a molar ratio of compound l-R I compound l-S of at least 80 : 20, preferably at least 90 : 10. It may be applied at a rate of about 100 g to 200 g of active ingredient (i.e. compound l-R plus compound l-S) per hectare, to target the pathogens listed in Table B below:

Table B

In practice, the agrochemical composition comprising the polymorphs of the invention is applied as a formulation containing the various adjuvants and carriers known to or used in the industry. They may thus be formulated as granules, as wettable powders, as emulsifiable concentrates, as suspension concentrates (including oil dispersions), as powders or dusts, as flowables, as solutions, as suspensions or emulsions, suspo-emulsions or as controlled release forms such as microcapsules. Suitably, the agrochemical composition of the invention may be formulated as a suspension concentrate, a suspo- emulsion, an emulsion concentrate or a wet granulation. These formulations are described in more detail below and may contain as little as about 0.5% to as much as about 95% or more by weight of the active ingredient in the form of the polymorph. The optimum amount will depend on formulation, application equipment and nature of the plant pathogenic fungi to be controlled. Wettable powders are in the form of finely divided particles which disperse readily in water or other liquid carriers. The particles contain the active ingredient retained in a solid matrix. Typical solid matrices include fuller’s earth, kaolin clays, silicas and other readily wet organic or inorganic solids. Wettable powders normally contain by weight about 5% to about 95% of the active ingredient plus a small amount of wetting, dispersing or emulsifying agent.

Emulsifiable concentrates are homogeneous liquid compositions dispersible in water or other liquid and may consist entirely of the active compound with a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone and other non-volatile organic solvents. In use, these concentrates are dispersed in water or other liquid and normally applied as a spray to the area to be treated. The amount of active ingredient by weight may range from about 0.5% to about 95% of the concentrate.

Suspension concentrates are formulations in which finely divided solid particles of the active compound are stably suspended. The solid particles may be suspended in an aqueous solution or in an oil (as an oil dispersion). Such formulations include anti-settling agents and dispersing agents and may further include a wetting agent to enhance activity as well an anti-foam and a crystal growth inhibitor. In use, these concentrates are diluted in water and normally applied as a spray to the area to be treated. The amount of active ingredient by weight may range from about 0.5% to about 95% of the concentrate.

Granular formulations include both extrudates and relatively coarse particles and may be applied without dilution to the area in which control of plant pathogenic fungi is required or dispersed in a spray tank before application, for example. Typical carriers for granular formulations include sand, fuller’s earth, attapulgite clay, bentonite clays, montmorillonite clay, vermiculite, perlite, calcium carbonate, brick, pumice, pyrophyllite, kaolin, dolomite, plaster, wood flour, ground corn cobs, ground peanut hulls, sugars, sodium chloride, sodium sulphate, sodium silicate, sodium borate, magnesia, mica, iron oxide, zinc oxide, titanium oxide, antimony oxide, cryolite, gypsum, diatomaceous earth, calcium sulphate and other organic or inorganic materials which absorb or which can be coated with the active compound. Granular formulations for use without dilution normally contain by weight about 5% to about 25% active ingredients which may include surface-active agents such as heavy aromatic naphthas, kerosene and other petroleum fractions, or vegetable oils; and/or stickers such as dextrins, glue or synthetic resins. When the granules are to be dispersed in a spray tank before application, the active ingredient content by weight may be increased up to 80%.

Dusts are free-flowing admixtures of the active ingredient with finely divided solids such as talc, clays, flours and other organic and inorganic solids which act as dispersants and carriers.

Microcapsules are typically droplets or granules of the active ingredient enclosed in an inert porous shell which allows escape of the enclosed material to the surroundings at controlled rates. Encapsulated droplets are typically from about 1 to about 50 microns in diameter. The enclosed liquid typically constitutes about 50 to 95% of the weight of the capsule and may include solvent in addition to the active compound. Encapsulated granules are generally porous granules with porous membranes sealing the granule pore openings, retaining the active species in liquid form inside the granule pores. Granules typically range from 1 millimetre to 1 centimetre (and preferably from 1 to 2 millimetres) in diameter. Granules are formed by extrusion, agglomeration or prilling, or are naturally occurring. Examples of such materials are vermiculite, sintered clay, kaolin, attapulgite clay, sawdust and granular carbon. Shell or membrane materials include natural and synthetic rubbers, cellulosic materials, styrenebutadiene copolymers, polyacrylonitriles, polyacrylates, polyesters, polyamides, polyureas, polyurethanes and starch xanthates.

Other useful formulations for agrochemical applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene and other organic solvents. Pressurised sprayers, wherein the active ingredient is dispersed in finely-divided form as a result of vaporisation of a low boiling dispersant solvent carrier, may also be used.

Many of the formulations described above include wetting, dispersing or emulsifying agents. Examples are alkyl and alkylaryl sulphonates and sulphates and their salts, polyhydric alcohols; polyethoxylated alcohols, esters and fatty amines. These agents, when used, normally comprise from 0.1 % to 40% by weight of the formulation.

Suitable agricultural adjuvants and carriers that are useful in formulating the composition of the invention in the formulation types described above are well known to those skilled in the art. Suitable examples of the different classes are found in the non-limiting list below.

Liquid carriers that can be employed include water and any solvents in which the polymorph has no or limited solubility e.g. toluene, xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone, cyclohexanone, acetic anhydride, acetonitrile, acetophenone, amyl acetate, 2-butanone, chlorobenzene, cyclohexane, cyclohexanol, alkyl acetates, diacetonalcohol, 1 ,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethyl formamide, dimethyl sulfoxide, 1 ,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkyl pyrrolidinone, ethyl acetate, 2-ethyl hexanol, ethylene carbonate, 1 ,1 ,1- trichloroethane, 2-heptanone, alpha pinene, d-limonene, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone, glycerol, glycerol diacetate, glycerol monoacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropyl benzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octyl amine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol (PEG400), propionic acid, propylene glycol, propylene glycol monomethyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylene sulphonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, methanol, ethanol, isopropanol, and higher molecular weight alcohols such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, ethylene glycol, propylene glycol, glycerine, N- methyl-2-pyrrolidinone, and the like. Water is generally the carrier of choice for the dilution of concentrates.

Suitable solid carriers include talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, chalk, diatomaceous earth, lime, calcium carbonate, bentonite clay, fuller’s earth, cotton seed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour, lignin and the like.

A broad range of surface-active agents are advantageously employed in both said liquid and solid compositions, especially those designed to be diluted with carrier before application. The surface- active agents can be anionic, cationic, non-ionic or polymeric in character and can be employed as emulsifying agents, wetting agents, suspending agents or for other purposes. Typical surface-active agents include salts of alkyl sulphates, such as diethanolammonium lauryl sulphate; alkylarylsulphonate salts, such as calcium dodecylbenzenesulphonate; alkylphenol-alkylene oxide addition products, such as nonylphenol-C.sub. 18 ethoxylate; alcohol-alkylene oxide addition products, such as tridecyl alcohol- C.sub. 16 ethoxylate; soaps, such as sodium stearate; alkylnaphthalenesulphonate salts, such as sodium dibutylnaphthalenesulphonate; dialkyl esters of sulphosuccinate salts, such as sodium di(2- ethylhexyl) sulphosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryl trimethylammonium chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono and dialkyl phosphate esters.

Other adjuvants commonly utilized in agricultural compositions include crystallisation inhibitors, viscosity modifiers, suspending agents, spray droplet modifiers, pigments, antioxidants, foaming agents, light-blocking agents, compatibilizing agents, antifoam agents, sequestering agents, neutralising agents and buffers, corrosion inhibitors, dyes, odorants, spreading agents, penetration aids, micronutrients, emollients, lubricants, sticking agents, and the like.

Each of the above formulations can be prepared as a package containing the fungicides together with other ingredients of the formulation (diluents, emulsifiers, surfactants, etc.). The formulations can also be prepared by a tank mix method, in which the ingredients are obtained separately and combined at the grower site.

These formulations can be applied to the areas where control is desired by conventional methods. Dust and liquid compositions, for example, can be applied by the use of power-dusters, broom and hand sprayers and spray dusters. The formulations can also be applied from airplanes as a dust or a spray or by rope wick applications. Both solid and liquid formulations may also be applied to the soil in the locus of the plant to be treated allowing the active ingredient to penetrate the plant through the roots. The formulations of the invention may also be used for dressing applications on plant propagation material to provide protection against fungus infections on the plant propagation material as well as against phytopathogenic fungi occurring in the soil. Suitably, the active ingredient may be applied to plant propagation material to be protected by impregnating the plant propagation material, in particular, seeds, either with a liquid formulation of the fungicide or coating it with a solid formulation. In special cases, other types of application are also possible, for example, the specific treatment of plant cuttings or twigs serving propagation.

Suitably, the agrochemical compositions and formulations of the present invention are applied prior to disease development. Rates and frequency of use of the formulations are those conventionally used in the art and will depend on the risk of infestation by the fungal pathogen.

The compositions and formulations of the present invention can also be used in combination with other active ingredients, e.g. other fungicides, and/or insecticides, and/or acaricides, and/or nematocides, and/or molluscicides, and/or biologicals, and/or plant growth regulators. Such mixtures, and the use of such mixtures to control weeds and/or undesired plant growth form yet further aspects of the invention. In a preferred embodiment, the agrochemical composition can comprise at least one further fungicide, and optionally can further comprise at least one insecticide and/or at least one nematicide.

When the crystalline polymorph of the invention is combined with at least one additional fungicide, the following fungicidal mixing partners are preferred:

- a strobilurin fungicide selected from the group consisting of azoxystrobin, dimoxystrobin, fluoxastrobin, kresoxim-methyl, metominostrobin, orysastrobin, picoxystrobin, pyraclostrobin, trifloxystrobin;

- an azole fungicide selected from the group consisting of azaconazole, bromuconazole, cyproconazole, difenoconazole, diniconazole, diniconazole-M, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imazalil, imibenconazole, ipconazole, metconazole, myclobutanil, oxpoconazole, pefurazoate, penconazole, prochloraz, propiconazole, prothioconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triflumizole, triticonazole, diclobutrazol, etaconazole, furconazole, furconazole-cis and quinconazole;

- a morpholine fungicide selected from the group consisting of aldimorph, dodemorph, fenpropimorph, tridemorph, fenpropidin, spiroxamine and piperalin;

- an anilino-pyrimidine fungicide selected from the group consisting of cyprodinil, mepanipyrim and pyrimethanil; and/or

- a fungicide selected from the group consisting of benalaxyl, benalaxyl-M, benomyl, bitertanol, boscalid, captan, carboxin, carpropamid, chlorothalonil, copper, cyazofamid, cymoxanil, diethofencarb, dithianon, famoxadone, fenamidone, fenhexamide, fenoxycarb, fenpiclonil, fluazinam, fludioxonil, flutolanil, folpet, guazatine, hymexazole, iprodione, lufenuron, mancozeb, metalaxyl, mefenoxam, metrafenone, nuarimol, paclobutrazol, pencycuron, penthiopyrad, procymidone, proquinazid, pyroquilon, quinoxyfen, silthiofam, sulfur, thiabendazole, thiram, triazoxide, tricyclazole, isopyrazam, sedaxane, fluxapyroxad, benzovindiflupyr and 3-(difluoromethyl)-N-methoxy-1-methyl-N-[1-methyl-2- (2,4,6-trichlorophenyl)ethyl]pyrazole-4-carboxamide.

Whilst compositions comprising the polymorph of the invention and another fungicide are explicitly disclosed above, the skilled person will appreciate that the invention extends to three-way, and further multiple combinations comprising the above two-way mixtures.

For the avoidance of doubt, even if not explicitly stated above, the mixing partners of may also be in the form of any suitable agrochemically acceptable ester or salt, as mentioned e.g. in The Pesticide Manual, Nineteenth Edition, British Crop Protection Council 2021.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will now be described by way of the following non-limiting examples and figures, wherein:

FIG. 1 shows the powder X-ray diffraction pattern of the crystalline polymorph (Form A) according to the present invention. Legend: x-axis: 20 angle (°); y-axis: count

FIG. 2 shows the X-ray diffraction pattern calculated from the unit cell parameters according to Table 2, of the crystalline polymorph (Form A) according to the present invention. Legend: x-axis: 20 angle (°); y-axis: count. FIG. 3 shows a DSC trace of the crystalline polymorph (Form A) according to the present invention. Legend: x-axis: temperature (°C); y-axis: normalised heat flow (W/g).

FIG. 4 shows a IR spectroscopy trace of the crystalline polymorph (Form A) according to the present invention. Legend x-axis: wavenumbers (cm'¹); y-axis: transmittance (%).

FIG. 5 shows a DSC trace of the racemic mixture (Form RAC). Legend: x-axis: temperature (°C); y-axis: normalised heat flow (W/g).

FIG. 6 shows the particle size distribution of suspension concentrates prepared as explained in Example 3, before and after storage (logarithmic scale).

EXAMPLES

Example 1 - Form A of compound of formula l-R

1 . Preparation of the polymorph

The compound of formula (l-R) (0.08g) was dissolved in ethyl acetate (1 mL) at room temperature (about 20°C). The solution was left to evaporate for at least 16 hours. Any crystals formed were harvested and analysed by powder X-ray diffraction (pXRD), differential scanning calorimetry (DSC) and I R spectroscopy.

2. Analysis of the polymorph

After preparation by the method detailed above, the samples were subject to analysis by powder X-ray diffraction, and/or single crystal X-ray diffraction, and/or differential scanning calorimetry, and/or near infra-red spectroscopy, and/or mid infra-red spectroscopy.

Powder X-ray diffraction analysis of solid material was carried out using a Malvern Panalytical Empyrean powder diffractometer at room temperature (20 °C) and at relative humidities above 40%. Samples were mounted in a standard PMMA sample holders and the samples flattened. The sample holder was rotated, and X-rays were collected from 3.5 to 40° 20 with a step size of 0.02° and incident x-rays with wavelength of 1.5406 A. The powder X-ray diffraction pattern of the crystalline polymorph (Form A) according to the invention is shown in FIG. 1 .

Single crystal intensity data was collected on an Rigaku Supernova diffractometer using Cu Ka radiation (a=1 .54056 A) with a graphite monochromator. The crystal was mounted in NVH oil at -173 °C for data collection. The data was solved using the CRYSTALS software package, and the results are gathered in Table 2 (unit cell parameters). The X-ray diffraction pattern calculated from the unit cell parameters of the crystalline polymorph (Form A) is shown in FIG. 2.

DSC was carried out using a TA DSC2500, using standard 40 pL aluminium sample holders with pierced lids (to allow the escape of any gas formed during the heating of the sample), heating from 25 to 200 °C at a rate of 10 °C / minute. The DSC trace of the crystalline polymorph (Form A) according to the invention is shown in FIG. 3. The peak temperature is about 146°C with an onset at about 144°C.

Infra-red (IR) analysis was carried out using a Thermo Scientific™ Nicolet iS5 FT-IR Spectrometer with an iD7 ATR attachment. The analysis was performed using a scan range of 500- 4000 cm'¹’ with 16 repeat scans. A background scan was measured with no sample present, before adding 1-10mg of sample to cell. The IR spectroscopy trace of the crystalline polymorph (Form A) is shown in FIG. 4.

Example 2 - Form RAC of racemate

1 . Preparation of Form RAC

RAC form was prepared by dissolving equal masses of the compound of formula l-R and l-S in ethyl acetate, the solvent was then allowed to evaporate for at least 16 hours. The resulting solid was analysed by DSC.

2. Analysis of Form RAC

DSC was carried out using a TA DSC2500, using standard 40 pL aluminium sample holders with pierced lids (to allow the escape of any gas formed during the heating of the sample), heating from 25 to 200 °C at a rate of 1 °C / minute. The DSC trace of the racemic mixture (Form RAC) according to the invention is shown in FIG. 5. The peak temperature is about 113°C with an onset at about 111 °C.

3. Results of the analysis

The crystalline polymorph Form RAC can have a melting point ranging from 110 to 115 °C (peak position), such as from 111 to 113 °C (peak position). This melting point is obtained using Differential Scanning Calorimetry (DSC) with a heating rate of 1 °C/minute.

Example 3 - Formulation stability

Various suspension concentrate formulations (SC) were prepared and stored under controlled conditions. The formulations contained 10%w/w of active ingredient with various enantiomer ratios, as shown in Table 3 below:

Table 3

Storage conditions A: 4 weeks at 40°C

Storage conditions B: 4 weeks cycling at 10°C for 12 hours then 40°C for 12 hours, followed by an additional 100 weeks at ambient conditions(about 20°C)

Storage conditions C: 12 weeks cycling at 10°C for 12 hours then 40°C for 12 hours, followed by an additional 49 weeks at ambient conditions (about 20°C)

A typical suspension concentrate formulation is given in Table 4 below:

Table 4

The particle size distribution was measured at the beginning of storage and after storage under the storage conditions A, B or C. The measurement was performed via static laser diffraction using a Malvern Mastersizer 3000 with a Hydro MV automatic liquid sample dispersion unit. A sample of SC was diluted into water within the dispersion unit until an appropriate obscuration was achieved, at which point the median volume distribution (d(50)) was calculated for each sample via MIE theory calculation. The d(50) results are shown in Table 5 below.

Table 5 Legend for Figure 6, size distribution, logarithmic scale:

Figure 6A: initial = solid line; after storage A = dotted lined; after storage B = dashed line for SC1 Figures 6B, 6C and 6D: initial = solid line; after storage C = dashed line for SC2, SC3 and SC4 respectively.

This shows that the formulation SC1 , which contains only Form RAC, undergoes crystal growth during storage throughout the sample, whereas in SC2, SC3 and SC4, which contain a smaller fraction of Form RAC, only a smaller fraction of the particles grows during storage.

Claims

1. A crystalline polymorph of the compound of formula l-R

(l-R) which has a powder X-ray diffraction pattern comprising at least three 20 angle values selected from the group consisting of 7.1 ±0.2, 7.8 ± 0.2°, 8.9 ± 0.2°, 11 .4 ± 0.2°, 13.5 ± 0.2°, 14.2 ± 0.2°, 14.7 ± 0.2°, 16.2 ± 0.2°, 17.7 ± 0.2°, 18.4 ± 0.2°, 20.0 ± 0.2°, 20.8 ± 0.2°, 21 .2 ± 0.2°, 21 .5 ± 0.2°, 22.3 ± 0.2°, 22.9 ± 0.2°, 23.6 ± 0.2°, 24.0 ± 0.2°, 24.3 ± 0.2°, 25.0 ± 0.2°, 26.2 ± 0.2°, 27.3 ± 0.2°, 27.7 ± 0.2°, 28.6 ± 0.2°, 29.6 ± 0.2°, 30.3 ± 0.2°.

2. The crystalline polymorph according to claim 1 , characterized in that the powder X-ray diffraction pattern comprises at least six 20 angle values selected from the group consisting of 7.1 ±0.2, 7.8 ± 0.2°, 11 .4 ± 0.2°, 13.5 ± 0.2°, 14.2 ± 0.2°, 14.7 ± 0.2°, 16.2 ± 0.2°, 17.7 ± 0.2°, 18.4 ± 0.2°, 25.0 ± 0.2°, 26.2 ± 0.2°.

3. The crystalline polymorph according to claim 1 or claim 2, characterized in that the powder X- ray diffraction pattern comprises at least the following 20 angle values: 7.8 ± 0.2°, 11.4 ± 0.2°, 16.2 ± 0.2°, 17.7 ± 0.2°.

4. The crystalline polymorph according to any one of the preceding claims, characterized in that it has the following lattice parameters:

5. The crystalline polymorph according to any one of the preceding claims, characterized in that it has a melting point ranging from 143 °C to 148 °C (peak position), and preferably ranging from 146 °C to 148 °C (peak position).

6. An agrochemical composition comprising the crystalline polymorph as claimed in any one of the preceding claims, and at least one agriculturally acceptable carrier or diluent.

7. The composition according to claim 6, characterized in that it comprises at least one further fungicide.

8. The composition according to claim 6 or claim 7, characterized in that the further fungicide is a strobilurin or an azole.

9. The composition according to any one of claims 6 to 8, characterized in that it further comprises at least one insecticide and/or at least one nematicide.

10. A method of preventing or controlling fungal infection on plants or plant propagation material comprising treating the plant or plant propagation material with the agrochemical composition as claimed in any one of claims 6 to 9.