WO2021175029A1

WO2021175029A1 - A novel form of metrafenone, a process for its preparation and use of the same

Info

Publication number: WO2021175029A1
Application number: PCT/CN2021/072802
Authority: WO
Inventors: James Timothy Bristow
Original assignee: Jiangsu Rotam Chemistry Co., Ltd
Priority date: 2020-03-06
Filing date: 2021-01-20
Publication date: 2021-09-10
Also published as: GB202003282D0; CN115244027A; EP4114817A1; GB2592668A; EP4114817A4

Abstract

A crystalline modification I of (3-bromo-6-methoxy-2-methylphenyl) (2, 3, 4-trimethoxy-6-methylphenyl) methanone (metrafenone) is provided. A method of preparing the crystalline modification I, a composition comprising the crystalline modification I and its use in controlling fungal infestations are also provided.

Description

A NOVEL FORM OF METRAFENONE, A PROCESS FOR ITS PREPARATION AND USE OF THE SAME

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the priority of GB 2003282.7, filed on October 6, 2020, titled with “A NOVEL FORM OF METRAFENONE, A PROCESS FOR ITS PREPARATION AND USE OF THE SAME” , and the disclosure of which is hereby incorporated by reference.

FIELD

The present invention relates to a novel form of (3-bromo-6-methoxy-2-methylphenyl) (2, 3, 4-trimethoxy-6-methylphenyl) methanone (metrafenone) , in particular to a novel crystalline form of metrafenone. The present invention further relates to a method for the preparation of the novel form of metrafenone. Still further, the present invention relates to the use of the novel form of metrafenone in agrochemical preparations and in the control of fungicidal infestations.

BACKGROUND

3-bromo-6-methoxy-2-methylphenyl- (2, 3, 4-trimethoxy-6-methylphenyl) methanone, having the common name metrafenone, belongs to the chemical class of benzophenones and exhibits a broad spectrum of fungicidal activity. Metrafenone has a molecular formula of C ₁₉H ₂₁BrO ₅ and has the following structure:

metrafenone is an innovative fungicide and finds particular use in the control of control of oomycetes of powdery mildew produced by Uncinula necator in all commercial varieties of grape vines. Metrafenone is used in the control and prevention of downy mildew and late blight diseases with excellent selectivity and can be applied for the inhibition of all stages of fungal development.

The biochemical mode of action of metrafenone is unknown. However, it has been proposed that the mode of action of metrafenone is through the disruption of actins, which are structural proteins regulating the cell division and function. Based on morphological observations, it appears that metrafenone inhibits the growth of the mycelium on the leaf surface, leaf penetration, and the formation of haustoria and sporulation. The mode of action of metrafenone is discussed by K.S. Opalski, et al., ‘Metrafenone: studies on the mode of action of a novel cereal powdery mildew fungicide’ , Pest Management Science, Volume 62, Issue 5, May 2006, Pages 393 to 401.

Metrafenone may be used to control and prevent infestations by varieties of powdery mildew (Podosphaera xanthii) or powdery mildew (Erysiphe necator) on a range of crops, including grapes, potatoes, tomatoes and other Solanaceae, cucurbits, leafy and fruiting vegetables, bulb vegetables, brassicas, hops and ornamentals.

EP 0897904 is concerned with certain benzophenone compounds and discloses compounds having the general formula (I) below.

The compounds of general formula (I) include metrafenone.

EP 0897904 discloses a process for producing the benzophenones of general formula (I) , including 2-methoxybenzophenones derivatives. Metrafenone is included in the derivatives that may be formed by the process disclosed in EP 0897904.

The commercially available metrafenone is usually manufactured by the process described in EP 0897904 and is present in an amorphous form having a melting point in the range of from 89 to 91℃.

References herein to a ‘residue’ are references to traces of a chemical compound that remain in or on the soil after a particular time. Excess fungicides or harmful derivatives thereof remaining in the soil may be a threat to the environment. This is particularly the case for fungicidal compounds having a long half-life. In particular, fungicide residues can lower the microbiological and biochemical activity of the soil and lead to yield declines. Fungicide residues may also contaminate the groundwater. In light of this, it is important to manage fungicide residues properly, in order to maintain the optimal function of soil ecosystems and to preserve our environment.

It has been found that commercially available metrafenone, when employed to control fungal infestations, for example as summarized above, results in a residue in soil after application in the field. Metrafenone in this commercially available form has a significant half-life in soil after application of greater than 120 days. In particular, the persistance of metrafenone in soil is discussed in ‘Conclusion regarding the peer review of the pesticide risk assessment of the active substance metrafenone finalised: 13 January 2006’ , EFSA Scientific Report (2006) 58, pages 1 to 72. It is indicated that metrafenone is highly persistent in soil under aerobic conditions (DT ₅₀ lab 20℃ of 182 to 365 days) . The results of a further study are reported, in which degradation proceeded at a slower rate with 82% AR remaining as parent after 120 days (extrapolated DT ₅₀ of 693 days) . As a result, metrafenone remains active in the soil for a significant period of time after application to the plants or locus being treated.

There is therefore a need for a way to reduce the length of time metrafenone residues remain active in the soil after application to the plants and their locus.

SUMMARY

A novel crystalline form of metrafenone has now been found, herein referred to as “crystalline modification I” . Most advantageously, it has been found that the amount of metrafenone residue present in the soil after application of metrafenone in this new crystalline modification I is significantly reduced. In the context, the term “crystalline modification” has the same meaning with the term “crystalline form” .

A further problem existing in the art is the increasing resistance of fungal species to fungicides. It is has further been found that the resistance of fungal species to metrafenone in this new crystalline modification I is significantly reduced.

In a first aspect, the invention provides a crystalline modification I of (3-bromo-6-methoxy-2-methylphenyl) (2, 3, 4-trimethoxy-6-methylphenyl) methanone (metrafenone) exhibiting at least 3, more preferably 4, 5, 6, 7, 8, 9, 10, 11 or more, of the following reflexes, in any combination, as 2θ ± 0.2 degrees in an X-ray powder diffractogram (X-RPD) recorded using Cu-Kα radiation at 25℃:

2θ = 8.6 ± 0.2 (1)

2θ = 10.0 ± 0.2 (2)

2θ = 10.6 ± 0.2 (3)

2θ = 11.5 ± 0.2 (4)

2θ = 12.2 ± 0.2 (5)

2θ = 15.6 ± 0.2 (6)

2θ = 17.3 ± 0.2 (7)

2θ = 20.5 ± 0.2 (8)

2θ = 21.7 ± 0.2 (9)

2θ = 22.6 ± 0.2 (10)

2θ = 25.0 ± 0.2 (11)

2θ = 25.6 ± 0.2 (12)

2θ = 25.7 ± 0.2 (13)

2θ = 27.3 ± 0.2 (14)

2θ = 28.4 ± 0.2 (15)

2θ = 28.9 ± 0.2 (16)

2θ = 32.1 ± 0.2 (17) .

In one preferred embodiment, the crystalline modification I of metrafenone according to the first aspect of the invention, exhibits at least 3, more preferably 4, 5, 6, 7, 8, 9, 10, 11 or more, still more preferably all, of the reflexes, in any combination from the following:

2θ = 8.6 ± 0.2 (1)

2θ = 10.0 ± 0.2 (2)

2θ = 10.6 ± 0.2 (3)

2θ = 11.5 ± 0.2 (4)

2θ = 12.2 ± 0.2 (5)

2θ = 15.6 ± 0.2 (6)

2θ = 17.3 ± 0.2 (7)

2θ = 20.5 ± 0.2 (8)

2θ = 21.7 ± 0.2 (9)

2θ = 22.6 ± 0.2 (10)

2θ = 25.0 ± 0.2 (11)

2θ = 27.3 ± 0.2 (14)

2θ = 32.1 ± 0.2 (17) .

In one preferred embodiment, the crystalline modification I of metrafenone according to the first aspect of the invention, exhibits the following reflexes:

2θ = 8.6 ± 0.2 (1)

2θ = 11.5 ± 0.2 (4)

2θ = 25.0 ± 0.2 (11) .

2θ = 8.6 ± 0.2 (1)

2θ = 11.5 ± 0.2 (4)

2θ = 22.6 ± 0.2 (10)

2θ = 25.0 ± 0.2 (11) .

2θ = 8.6 ± 0.2 (1)

2θ = 11.5 ± 0.2 (4)

2θ = 17.3 ± 0.2 (7)

2θ = 20.5 ± 0.2 (8)

2θ = 22.6 ± 0.2 (10)

2θ = 25.0 ± 0.2 (11) .

2θ = 8.6 ± 0.2 (1)

2θ = 10.0 ± 0.2 (2)

2θ = 11.5 ± 0.2 (4)

2θ = 17.3 ± 0.2 (7)

2θ = 20.5 ± 0.2 (8)

2θ = 22.6 ± 0.2 (10)

2θ = 25.0 ± 0.2 (11) .

In one preferred embodiment, the crystalline modification I of metrafenone 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 modification I of (3-bromo-6-methoxy-2-methylphenyl) (2, 3, 4-trimethoxy-6-methylphenyl) methanone (metrafenone) exhibiting an infrared (IR) spectrum with characteristic functional group vibration peaks at wavenumbers (cm ^-1, ± 0.2%) of one or more, more preferably 2, 3, 4, 5, 6, 7 or more, still more preferably all, of 3386, 3259, 3133, 1660, 1635, 1574, 1527, 1503, 1461, 1436, 1383, 1343, 1300, 1265, 1202, 1077, 1061, 1041, 1028, 928, 762, 639 and 562 cm ^-1.

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

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

In a third aspect, the present invention provides a crystalline modification I of metrafenone exhibiting a differential scanning calorimetry (DSC) profile having an endothermic melting peak with onset at 97.7℃ and peak maximum at 99.5℃, further optionally with a melting enthalpy of 68.38 J/g.

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

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

It has been found that the crystalline modification I of metrafenone exhibits a significant improvement on residue control in soil, in particular resulting in a significant reduction in the metrafenone residue in the soil after application, which significantly increase the environmental safety.

In a further aspect, the present invention provides a method for preparing the crystalline modification I of metrafenone, the method comprising the steps of:

i) dissolving metrafenone in a solvent system comprising one or more solvents;

ii) precipitating the dissolved metrafenone from solution in the solvent system to yield the crystalline modification I of metrafenone; and

iii) isolating the precipitated crystalline modification I of metrafenone.

The metrafenone starting material used in step i) of the method may be any suitable metrafenone material. In one embodiment, the metrafenone employed in step i) of the method is a crystalline modification of metrafenone other than the crystalline modification I of metrafenone, for example the known crystalline form of metrafenone, such as commercially available metrafenone. Methods for preparing a suitable metrafenone starting material are known in the art. Commercial metrafenone is manufactured and available on a commercial scale. A particularly suitable method for preparing metrafenone for use in step i) of the aforementioned method is described in EP 0897904.

As noted above, in step i) of the method, metrafenone 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 metrafenone upon crystallization from the solution may be employed in the solvent system. In one preferred embodiment, the solvent system comprises one or more solvents selected from ethers, aromatic hydrocarbons, and a mixture thereof.

In one embodiment, the solvent system comprises an ether having the general formula R–O–R ¹, wherein R and R ¹ independently represent an alkyl group, preferably a lower alkyl group having from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms, still more preferably from 1 to 4 carbon atoms. The alkyl groups may be straight chain or branched chain.

In one embodiment, the ether in the solvent system is a glycol ether.

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, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, and dichlorodiethyl ether.

Another examples of the ether are polyethers, including polyethers of ethylene oxide and/or propylene oxide.

Preferred aromatic hydrocarbon solvents include benzene and alkyl-substituted benzene, preferably C ₁ to C ₄ alkyl-substituted benzene derivatives, provided that in the case of C ₁ alkyl substituents, two or more alkyl substituents are present, more preferably C ₁ to C ₃ alkyl-substituted benzene derivatives, such as ethyl benzene, xylene, mesitylene and cymene.

Petroleum fractions within a boiling range of from 70℃ to 190℃ and ligroin are also suitable as solvents.

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

In step i) of the method of the present invention, the crystalline modification I of metrafenone is prepared by dissolving metrafenone in a solvent system to form a metrafenone solution. The dissolution of metrafenone 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 metrafenone is prepared at the reflux temperature of the solvent system. The concentration of the metrafenone solution depends on such factors as the solubility of metrafenone in the solvent system employed.

The metrafenone solution prepared in step i) of the method is then used to produce the crystalline modification I of metrafenone. This is achieved by crystallization. Any suitable technique or combination of techniques may be employed to crystallize the crystalline modification I of metrafenone 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℃ to about 20℃ to crystallize the desired crystalline form from the solvent.

Alternatively, or in addition, the crystalline modification I of metrafenone may 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 metrafenone from the solution may also be effected or aided by adding seed crystals to the solution, preferably seed crystals of metrafenone, more preferably seed crystals of the desired crystalline form, that is the crystalline modification I of metrafenone. The addition of seed crystals acts to promote or accelerate the crystallization.

The amount of seed crystals added to the metrafenone 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 metrafenone 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 metrafenone 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 metrafenone from the solution formed in step i) may be carried out batchwise, semi-continuously or continuously.

The precipitated crystalline modification I of metrafenone 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 the metrafenone 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℃ to room temperature, depending on the solubility of the crystalline metrafenone 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 metrafenone 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 metrafenone, 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 metrafenone obtainable by the method hereinbefore described.

In the present invention, it is preferred that the crystalline metrafenone material has a content of the crystalline modification I of metrafenone of at least 97.5% by weight.

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

The composition may comprise the crystalline modification I of metrafenone in any suitable amount to provide the desired fungicidal effects. Preferably, the amount of the crystalline modification I of metrafenone in the composition is less than 75% by weight of the composition, more preferably less than 50% by weight of the composition, still more preferably less than 40% by weight of the composition, more preferably still in many embodiments less than 25% by weight of the composition. Preferably, the amount of the crystalline modification I of metrafenone 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 25% by weight. In many embodiments, the crystalline modification I of metrafenone is present in the composition in an amount of about 50% by weight.

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

The crystalline modification I of metrafenone 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) .

Formulations containing the crystalline modification I of metrafenone may be prepared using techniques known in the art, for example, by extending the crystalline modification I of metrafenone with water, solvents and carriers, using, if appropriate, emulsifiers and/or dispersants, and/or other auxiliaries.

The compositions are prepared by combining the crystalline modification I of metrafenone with one or more agriculturally acceptable auxiliaries. The auxiliaries employed in the composition and their amounts will depend upon the type of formulation and/or the manner in which the formulation is to be applied by the end user. Suitable auxiliaries are customary formulation adjuvants or components, such as dispersants, wetting agents, emulsifiers, extenders, carriers, solvents, surfactants, stabilizers, anti-foam agents, anti-freezing agents, preservatives, antioxidants, colourants, thickeners, biocides, solid adherents and inert fillers. Such auxiliaries are known in the art and are commercially available. Their use in the formulation of the compositions of the present invention will be apparent to the person skilled in the art.

Surfactants can be an emulsifier, dispersant or wetting agent of ionic or nonionic type.

Examples which may be used include, but are not limited to, salts of polyacrylic acids, salts of lignosulphonic acid, salts of phenylsulphonic or naphthalenesulphonic acids, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols, especially alkylphenols, sulphosuccinic ester salts, taurine derivatives, especially alkyltaurates, or phosphoric esters of polyethoxylated phenols or alcohols.

Liquid diluents include, but are not limited to, water, N, N-dimethylamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, propylene carbonate, dibasic esters, paraffins, alkylbenzenes, alkyl naphthalenes, glycerine, triacetine, oils of olive, castor, linseed, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, acetates such as hexyl acetate, heptyl acetate and octyl acetate, and alcohols such methanol, cyclohexanol, decanol, benzyl and tetrahydrofurfuryl alcohol, and mixtures thereof.

The composition may further comprise one or more polymeric stabilizers. Suitable polymeric stabilizers that may be used in the present invention include, but are not limited to, polypropylene, polyisobutylene, polyisoprene, copolymers of monoolefins and diolefins, polyacrylates, polystyrene, polyvinyl acetate, polyurethanes or polyamides. Suitable stabilizers are known in the art and are commercially available.

The composition may further comprise one or more anti-foam agents. Suitable anti-foam agents include those substances which can normally be used for this purpose in agrochemical compositions and will be readily apparent to the person skilled in the art. Suitable anti-foam agents are known in the art and are commercially available. Particularly preferred anti-foam agents are mixtures of polydimethylsiloxanes and perfluroalkylphosphonic acids, such as the silicone anti-foam agents (for example commercially available from GE or Compton) . Other examples of anti-foam agents are fatty acids, tallow, and sodium salts.

The composition may further comprise one or more preservatives. Suitable preservatives include those substances which can normally be used for this purpose in agrochemical compositions of this type and again are well known in the art. Suitable examples that may be mentioned include

(commercially available from Bayer AG) and

(commercially available from Bayer AG) .

The composition may further comprise one or more antioxidants. Suitable antioxidants are substances which can normally be used for this purpose in agrochemical compositions, as is known in the art. Preference is given, for example, to butylated hydroxytoluene.

The composition may further comprise one or more solid adherents. Such adherents are known in the art and available commercially. Suitable solid adherents include organic adhesives, including tackifiers, such as celluloses of substituted celluloses, natural and synthetic polymers in the form of powders, granules, or lattices, and inorganic adhesives such as gypsum, silica, or cement.

The composition may further comprise one or more inert fillers. Such inert fillers are known in the art and available commercially. Suitable fillers include, for example, natural ground minerals, such as kaolins, aluminas, talc, chalk, quartz, attapulgite, montmorillonite, and diatomaceous earth, or synthetic ground minerals, such as highly dispersed silicic acid, aluminum oxide, silicates, and calcium phosphates and calcium hydrogen phosphates. Suitable inert fillers for granules include, for example, crushed and fractionated natural minerals, such as calcite, marble, pumice, sepiolite, and dolomite, or synthetic granules of inorganic and organic ground materials, as well as granules of organic material, such as sawdust, coconut husks, corn cobs, and tobacco stalks. Examples of inert fillers also include sodium tripolyphosphate and sucrose.

Solid diluents can be water-soluble or water-insoluble. Water-soluble solid diluents include, but are not limited to, salts such as alkali metal phosphates (for example sodium dihydrogen phosphate) , alkaline earth phosphates, sulfates of sodium, potassium, magnesium and zinc, sodium and potassium chloride, sodium acetate, sodium carbonate and sodium benzoate, and sugars and sugar derivatives such as sorbitol, lactose, sucrose and mannitol. Examples of water-insoluble solid diluents include, but are not limited to clays, synthetic and diatomaceous silicas, calcium and magnesium silicates, titanium dioxide, aluminum, calcium and zinc oxide, and mixtures thereof.

Wetting agents include, but are not limited to, alkyl sulfosuccinates, laureates, alkyl sulfates, phosphate esters, acetylenic diols, ethoxyfluornated alcohols, ethoxylated silicones, alkyl phenol ethyoxylates, 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, and mixtures thereof. Alkyl naphthalene sulphonates, sodium salts are particularly useful for the composition of the invention.

Dispersants for use in the formulations 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

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

available from Clariant GmbH, and

available from Clariant GmbH.

Suitable anionic dispersing agents for use in the formulations 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

D425, available from Akzo-Nobel, and

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, and mixtures thereof. Synthetic thickening agents include derivatives of the former categories, and also polyvinyl alcohols, polyacrylamides, polyvinylpyrrolidones, various polyethers, their copolymers, as well as polyacrylic acids and their salts, and mixtures thereof. Alkylpolyvinylpyrrolidones are particularly useful for the composition of the invention.

Anti-freezing agents are known in the art and are commercially available. Suitable anti-freezing agents include 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 include those based on isothiazolones, for example

from LONZA Inc. or

RS from Thor Chemie or

MK from Rohm & Haas. The amount of biocides is typically from 0.01% to 0.04% by weight, based on the total weight of composition.

Other formulation components can also be used in the present invention such as dyes, drying agents, and the like. These components and their uses are known to one skilled in the art.

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 metrafenone 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 metrafenone 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 metrafenone 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 metrafenone or employed in the form of one or more separate compositions.

Preferred mixing partners of the crystalline modification I of metrafenone can be epoxiconazole, fenpropimorph, 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 their mixtures.

Particular preferred mixing partners are epoxiconazole and the combination of epoxiconazole and fenpropimorph.

All plants and plant parts may be treated with the crystalline modification I of metrafenone 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℃.

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 seeds.

Metrafenone, which is an active ingredient of the fungicidal composition of the invention, is known to be effective against a range of fungi, such as powdery mildew.

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 grapes, potatoes, tomatoes, barley, oats, peaches, pumpkins, roses, rye, wheat and other Solanaceae, cucurbits, leafy and fruiting vegetables, bulb vegetables, brassicas, hops and ornamentals.

As discussed hereinbefore, the crystalline modification I of metrafenone prepared using a solvent system comprising an aromatic hydrocarbon and/or an ether exhibits a significantly reduced half-life, in particular under aerobic conditions normally prevailing in soil in the field, leading to a significant reduction in metrafenone residues remaining in the soil after application.

Therefore, in a further aspect, the present invention provides the use of a solvent system comprising a solvent selected from aromatic hydrocarbons, ethers and mixtures thereof to produce a crystalline form of metrafenone having a significantly reduced half-life.

In particular, under aerobic conditions in soil at ambient conditions, the half-life of metrafenone can be reduced from 120 days to between 7 to 14 days, more preferably from 10 to 11 days. In this respect, the half-life of the metrafenone prepared by crystallization from the aforementioned solvent system may be reduced by 90 to 95%.

The present invention provides in a still further aspect, the use of a solvent system comprising a solvent selected from aromatic hydrocarbons, ethers and mixtures thereof to produce a crystalline form of metrafenone exhibiting reduced residues in soil.

Suitable and preferred solvents are discussed hereinbefore.

BRIEF DESCRIPTION OF DRAWINGS

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:

Figure 1 is an X-ray powder diffractogram (X-RPD) of a crystalline modification I of metrafenone;

Figure 2 is an infrared (IR) spectrum of a crystalline modification I of metrafenone;

Figure 3 is a differential scanning calorimetry (DSC) thermogram of a crystalline modification I of metrafenone; and

Figure 4 is an X-ray powder diffraction spectrum (X-RPD) of an amorphous metrafenone.

DETAILED DESCRIPTION

The present invention will now be described by way of 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 % unless otherwise indicated.

References herein to ‘room temperature’ are to a temperature in the range of from 20 to 25℃.

All X-ray powder diffractograms were determined using a powder diffractometer in reflection geometry at 25℃, 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 metrafenone can be identified by its characteristic functional group vibration peaks at wavenumbers (cm ^-1, ± 0.2%) of one or more of 3386, 3259, 3133, 1660, 1635, 1574, 1527, 1503, 1461, 1436, 1383, 1343, 1300, 1265, 1202, 1077, 1061, 1041, 1028, 928, 762, 639 and 562 cm ^-1 as shown in Figure 2.

All IR spectra were obtained using the following acquisition parameters:

FT-IR spectrometer	Nicolet ^TM iS 5
Diamond ATR unit	Thermo Scientific ^TM 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:

EXAMPLES

Example 1: Preparation of crystalline metrafenone in accordance with the disclosure of EP 0897904 (Example 6C)

A mixture of 5-Bromo-6-methyl-2-methoxybenzoic acid (24 g, 10 mmol) , 3, 4, 5-trimethoxytoluene (1.82 g; 10 mmol) , P ₂O ₅ (10.0 g) and dichloromethane (150 mL) was stirred at room temperature for 16 hours. Subsequently, the dichloromethane was distilled off and the residue was diluted with ethyl acetate. The organic phase was washed with water and concentrated. The residue was purified by column chromatography (petrol ether: ethyl acetate, 8: 2 v/v) and recrystallized from diisopropylether. The solid material was collected by vacuum filtration, washed with cold petrol ethers: diisopropylether (1: 1 v/v) and dried, yielding white solid (2.2 g, 54%) , having a melting point 89 to 91℃.

The reaction sequence may be illustrated as follows:

As shown in Figure 4, the X-ray powder diffraction pattern of the resulting metrafenone product has no significant signals, which indicates the metrafenone product prepared in accordance with the disclosure of EP 0897904 is amorphous.

Example 2: Preparation of the crystalline modification I of metrafenone from xylene

Example 1 was repeated a few times and the solid metrafenone obtained was combined. 4 g of the metrafenone from 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℃ to get a homogeneous solution. The insoluble particles, if any, were removed by filtration 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 mL of cooled xylene. The filtered crystals were dried under vacuum at 40℃ 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 metrafenone having the characteristics shown in Figure 1, Figure 2 and Figure 3 respectively.

The IR spectrum of the crystalline metrafenone exhibited the functional group characteristic vibration peaks at wavenumbers of one or more of 3386, 3259, 3133, 1660, 1635, 1574, 1527, 1503, 1461, 1436, 1383, 1343, 1300, 1265, 1202, 1077, 1061, 1041, 1028, 928, 762, 639 and 562 cm ^-1 as shown in Figure 2.

The DSC thermogram of the crystalline metrafenone exhibited an endothermic melting peak maximum at 99.5℃ as shown in Figure 3.

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

Table 1

Example 3: Preparation of the crystalline modification I of metrafenone from methyl t-butyl ether

4 g of the metrafenone 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℃ to get a homogeneous solution. The insoluble particles, if any, were removed by filtration 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℃ in order to remove the methyl t-butyl ether traces from the crystalline product.

The crystalline product thus obtained had a purity of 98% and the yield was found to be about 88%. The crystalline modification I of metrafenone was obtained, as determined using X-RPD, IR spectrometry and DSC analysis.

Example 4: Preparation of suspension concentrate (SC)

Samples were prepared by mixing all the components listed in Table 2 uniformly and grinding with a Dyno-Mill (manufactured by Willy A. Bachofen AG) to obtain a suspension concentrate.

Table 2

Compositions S2 and S3 contain the crystalline modification I of metrafenone and are embodiments of the present invention. Composition S1 is a comparative example.

Example 5: Residue Test in Soil

A 140g soil sample was collected from the field and divided into 14 different pots (6cm diameter plastic pots) . The metrafenone product obtained in Examples 1 to 3 and the compositions S1, S2 and S3 prepared in Example 4 were each added to the soil in two pots, to provide two replications, in an amount such that the final concentration of metrafenone in the soil in the pots was 50ppm.

In addition, metrafenone prepared by recrystallization from a solvent system of 15% wt ethyl acetate in heptane was also added to the soil in one pot, to provide a further comparison.

Untreated soil was used as a control.

All the pots were maintained in a greenhouse at an ambient temperature of about 20℃. The soil in the pots had a humidity of about 60%.

The amount of metrafenone remaining in the soil in each pot was determined at regular intervals after treatment, as follows:

1 g of soil sample was collected from each pot and added to a 10mL centrifuge tube. Deionized water (1mL) and acetonitrile (2mL) were added and mixture subjected to mixing for 3 minutes. Thereafter, sodium chloride (1 g) was added and the resulting mixture subjected to mixing for a further 5 minutes. Finally, the tube was centrifuged at 4000rpm for 5 minutes.

The supernatant was collected and filtered through a 0.2 m membrane for analysis using chromatography, as follows.

All the samples were analyzed using UPLC-MS/MS, under the following conditions:

Mobile phase was acetonitrile and deionized water with 0.2% Formic acid;

Flow: 0.3mL/min;

Inject Volume: 5 L;

Column: Waters Acquity UPLC HSS T3 having internal diameter of 2.1mm, 100mm length, and 1.8 m particle size;

Column temperature was 35℃.

The retention time of metrafenone in the column is 2.87 minutes.

Gradient of mobile phase:

TIME (minute)	Acetonitrile	H ₂O (0.2% HCOOH)
0	10	90
1.5	90	10
3	90	10
3.1	10	90
4	10	90
50.01	STOP

The results are set out in Table 3 below.Table 3

As can be seen from the data in Table 3, metrafenone prepared according to the known method of the prior art (Example 1) and present in the suspension concentrate containing the same (S1) remained in the soil in significant amounts after 7 days, with significant amounts still remaining after 130 days. A similar result was obtained using crystalline metrafenone prepared using ethyl acetate/heptane as the solvent.

In contrast, the crystalline modification I of metrafenone (Examples 2 and 3) and the compositions containing the same (S2 and S3) resulted in a significant reduction in the metrafenone residue present in the soil after just 7 days. The data show that the persistence of the crystalline modification I of metrafenone is significantly reduced, compared with the metrafenone product of the prior art.

It is to be noted that the metrafenone product of the prior art exhibited a half-life in the soil of about 120 days. In contrast, the crystalline modification I of metrafenone according to the present invention exhibited a significantly reduced half-life in the soil, in particular between 7 and 14 days, more particularly from 10 to 11 days.

Claims

A crystalline modification I of (3-bromo-6-methoxy-2-methylphenyl) (2, 3, 4-trimethoxy-6-methylphenyl) methanone (metrafenone) 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-Kα radiation at 25℃:

2θ = 8.6 ± 0.2     (1)

2θ = 10.0 ± 0.2    (2)

2θ = 10.6 ± 0.2    (3)

2θ = 11.5 ± 0.2    (4)

2θ = 12.2 ± 0.2    (5)

2θ = 15.6 ± 0.2    (6)

2θ = 17.3 ± 0.2    (7)

2θ = 20.5 ± 0.2    (8)

2θ = 21.7 ± 0.2    (9)

2θ = 22.6 ± 0.2    (10)

2θ = 25.0 ± 0.2    (11)

2θ = 25.6 ± 0.2    (12)

2θ = 25.7 ± 0.2    (13)

2θ = 27.3 ± 0.2    (14)

2θ = 28.4 ± 0.2    (15)

2θ = 28.9 ± 0.2    (16)

2θ = 32.1 ± 0.2    (17) .
The crystalline modification I of metrafenone according to claim 1, exhibiting at least 3, more preferably 4, 5, 6, 7, 8, 9, 10, 11 or more, still more preferably all, of the reflexes, in any combination from the following:

2θ = 8.6 ± 0.2     (1)

2θ = 10.0 ± 0.2    (2)

2θ = 10.6 ± 0.2    (3)

2θ = 11.5 ± 0.2    (4)

2θ = 12.2 ± 0.2    (5)

2θ = 15.6 ± 0.2    (6)

2θ = 17.3 ± 0.2    (7)

2θ = 20.5 ± 0.2    (8)

2θ = 21.7 ± 0.2    (9)

2θ = 22.6 ± 0.2    (10)

2θ = 25.0 ± 0.2    (11)

2θ = 27.3 ± 0.2    (14)

2θ = 32.1 ± 0.2    (17) .
The crystalline modification I of metrafenone according to claim 1 or 2, characterized by an X-ray powder diffraction pattern substantially as shown in Figure 1.
A crystalline modification I of metrafenone exhibiting an IR spectrum with characteristic functional group vibration peaks at wavenumbers (cm ^-1, ± 0.2%) of one or more of 3386, 3259, 3133, 1660, 1635, 1574, 1527, 1503, 1461, 1436, 1383, 1343, 1300, 1265, 1202, 1077, 1061, 1041, 1028, 928, 762, 639 and 562 cm ^-1.
The crystalline modification I of metrafenone according to claim 4, characterized by an IR spectrum substantially as shown in Figure 2.
A crystalline modification I of metrafenone exhibiting a differential scanning calorimetry (DSC) profile having an endothermic melting peak with onset at 97.7 ℃ and peak maximum at 99.5 ℃.
The crystalline modification I of metrafenone according to claim 6, characterized by a DSC thermogram substantially as shown in Figure 3.
The crystalline modification I of metrafenone according to any one of claims 1 to 3, further exhibiting an IR spectrum according to either of claims 4 or 5 and/or a differential scanning calorimetry (DSC) profile according to either of claims 6 or 7.
A method for the preparation of a crystalline modification I of metrafenone according to any one of claims 1 to 8, the method comprising:

i) dissolving metrafenone in a solvent system comprising one or more solvents;

ii) precipitating the dissolved metrafenone from solution in the solvent system to yield the crystalline modification I of metrafenone; and

iii) isolating the precipitated crystalline modification I.
The method according to claim 9, wherein the metrafenone in step i) is a crystalline modification of metrafenone other than the crystalline modification I of metrafenone.
The method according to claim 9 or 10, wherein the solvent system comprises a solvent selected from aromatic hydrocarbons, ethers and mixtures thereof.
The method according to any one of claims 9 to 11, wherein the solvent system comprises an ether of the general formula R – O – R ¹, wherein R and R ¹ each independently represent a lower alkyl group.
The method according to claim11 or 12, wherein the solvent system comprises xylene and/or methyl t-butyl ether.
The method according to any one of claims 9 to 13, wherein step ii) comprises concentrating the solution by removal of solvent and/or cooling the solvent system.
The method according to any one of claims 9 to 14, wherein in step ii) seed crystals are added to the solution formed in step i) .
The method according to claim 15, wherein the seed crystals comprise the crystalline modification I of metrafenone.
A crystalline material comprising the crystalline modification I of metrafenone produced by the method according to any one of claims 9 to 16.
A composition comprising the crystalline modification I of metrafenone according to any one of claims 1 to 8 or the crystalline material according to claim 17 and at least one auxiliary.
The composition according to claim 18, wherein the auxiliary is selected from surfactants, dispersants, wetting agents, emulsifiers, extenders, carriers, solvents, surfactants, stabilizers, anti-foam agents, anti-freezing agents, preservatives, antioxidants, colourants, thickeners, biocides, solid adherents, inert fillers, and mixtures thereof.
The composition according to claim 18 or 19, 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) .
The composition according to claim 20, wherein the composition is in the form of a suspension concentrate (SC) .
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 the crystalline modification I of metrafenone according to any one of claims 1 to 8 or the crystalline material according to claim 17, or the composition according to any one of claims 18 to 21.
Use of the crystalline modification I of metrafenone according to any one of claims 1 to 8 or the crystalline material according to claim 17 for preventing, treating and/or controlling fungal infestation in a plant or plant parts.
Use of a solvent system comprising a solvent selected from aromatic hydrocarbons, ethers and mixtures thereof to produce a crystalline form of metrafenone having a significantly reduced half-life.
Use of a solvent system comprising a solvent selected from aromatic hydrocarbons, ethers and mixtures thereof to produce a crystalline form of metrafenone exhibiting reduced residues in soil.