TW202328056A - A crystalline form of methoxyfenozide, a process for its preparation and use of the same - Google Patents

Abstract

A crystalline modification I of N’-tert-butyl-N’-(3,5-dimethylbenzoyl)-3-methoxy-2-methylbenzohydrazide (Methoxyfenozide) is provided. There is also provided a process for preparing this crystalline form. The use of this novel crystalline form to combat insecticidal infestation in crops is also provided.

Description

Crystalline forms of methphenol, processes for their preparation and uses thereof

The present invention relates to a crystallization of N'-tertiary butyl-N'-(3,5-dimethylbenzoyl)-3-methoxy-2-methylbenzoylhydrazine (mefenol) form, a process for the preparation of the crystalline form and its use in agrochemical formulations.

N'-tertiary butyl-N'-(3,5-dimethylbenzoyl)-3-methoxy-2-methylbenzoylhydrazine (mefenol) exhibits insecticidal activity carbohydrazine. Mefenox acts as a molt accelerating compound (MAC) and is effective against a wide range of pests belonging to species belonging to the order Lepidoptera . Upon ingestion of methphenox, the larval stage of the pest undergoes an incomplete and premature molt which is ultimately lethal. Mefenox is used to protect a wide range of crops including vegetables, cotton, fruit, corn, etc.

Mephenox has _a molecular _{formula of C22H28N2O3} . Its chemical structure can be represented by the following formula (I): (I)

Commercially available mefenox can be produced by a series of methods, such as those disclosed in US 5,530,028, CN 1435411 A, CA 2103110 C, CN 102040540 A, CN 102584573 A and CN 104803879 A.

It is to be noted that the dispersibility of mefenol was not satisfactory in the commercially available formulations containing the formulated product. Therefore, there is a need to improve the dispersibility of methphenol. It would also be advantageous if the storage stability of methphenox could also be improved.

Surprisingly, novel crystalline modifications of methphenox have been found which exhibit significantly improved dispersibility and storage stability. This novel crystalline modification of mefenox can be prepared using a number of different solvents and/or solvent mixtures, in particular allowing to obtain this crystalline modification in high yields.

In a first aspect, the present invention provides a kind of N'-tertiary butyl-N'-(3,5-dimethylbenzoyl)-3-methoxy-2-methylbenzoylhydrazine ( A crystalline modification I of methphenol) which exhibits the following reflections in any combination as 2θ ± 0.20 degrees in an X-ray powder diffraction pattern (X-RPD) recorded using Cu-Kα radiation at 25°C At least three of: 2θ = 9.47 ± 0.20 (1) 2θ = 9.81 ± 0.20 (2) 2θ = 12.63 ± 0.20 (3) 2θ = 14.26 ± 0.20 (4) 2θ = 16.49 ± 0.20 (5) 2θ = 16.70 ± 0.20 (6) 2θ = 18.01 ± 0.20 (7) 2θ = 18.49 ± 0.20 (8) 2θ = 19.65 ± 0.20 (9) 2θ = 20.47 ± 0.20 (10) 2θ = 21.44 ± 0.20 (11) 2θ = 22.43 ± 0.20 (12) 2θ = 23.55 ± 0.20 (13) 2θ = 23.93 ± 0.20 (14) 2θ = 25.41 ± 0.20 (15) 2θ = 26.63 ± 0.20 (16).

In a preferred embodiment, the crystalline modification I of methphenol exhibits at least four of the aforementioned reflections, more preferably at least five of the aforementioned reflections, still more preferably at least 6, and also More preferably at least seven, especially at least eight, more especially at least nine, still more especially at least ten, especially at least eleven, more especially at least twelve.

Preferred embodiments of the crystalline modification I of methphenox exhibit two or more, more preferably three or more, still more preferably four or more of the following reflections , still more preferably at least five, especially at least six, more especially at least seven, still more especially at least eight, still more especially at least nine: 2θ = 9.47 ± 0.20 (1) 2θ = 9.81 ± 0.20 (2) 2θ = 12.63 ± 0.20 (3) 2θ = 16.70 ± 0.20 (5) 2θ = 18.01 ± 0.20 (6) 2θ = 18.49 ± 0.20 (7) 2θ = 20.47 ± 0.20 (9) 2θ = 21.44 ± 0.20 (10) 2θ = 22.43 ± 0.20 (11) 2θ = 23.55 ± 0.20 (12).

A more preferred embodiment of the crystalline modification I of methphenox exhibits two or more, more preferably three or more, still more preferably four or more of the following reflections species, more preferably at least five: 2θ = 9.47 ± 0.20 (1) 2θ = 9.81 ± 0.20 (2) 2θ = 12.63 ± 0.20 (3) 2θ = 16.70 ± 0.20 (5) 2θ = 18.01 ± 0.20 (6) 2θ = 18.49 ± 0.20 (7) 2θ = 23.55 ± 0.20 (12).

A preferred crystalline modification I of mefenox exhibits an X-ray powder diffraction pattern (X-RPD) recorded using Cu-Kα radiation at 25° C. substantially as shown in FIG. 2 .

Crystalline modification I of methphenox can alternatively be characterized by its infrared (IR) spectrum. Accordingly, there is also provided a crystalline modification I of mefenox exhibiting a crystalline modification at about 3305 cm ⁻¹ , 3006 cm ⁻¹ , 2966 cm ⁻¹ , 1683 cm ⁻¹ , 1639 cm ⁻¹ , 1587 cm ⁻¹ , With characteristic functional group vibration peaks at one or more wavenumbers (cm ^-1 , ±0.2%) of 1494 cm ^-1 , 1274 cm ^-1 , 1244 cm ^-1 , 1027 cm ^-1 and 861 cm ^-1 Infrared (IR) spectrum, preferably the IR spectrum as shown in FIG. 1 .

Crystalline modification I of methphenox can alternatively be characterized by its melting point. Therefore, there is also provided a crystalline modification I of methphenol which exhibits a differential scanning calorimetry (DSC) melting peak with an endothermic melting peak at 196.2° C. )curve.

In a preferred embodiment, the present invention provides a crystalline modification I of methphenox, which is diffracted by X-ray powder as previously described, preferably substantially as shown in FIG. 2 ( XRD) pattern, and/or it is characterized by an IR spectrum as previously described, preferably substantially as shown in Figure 1, and/or it is characterized by a melting point of 196.2°C.

It has been found that the crystalline modification I of mefenox according to the present invention exhibits a high degree of stability when formulated compared to known forms of mefenox (as prepared according to the disclosure of CN 104803879 A). By virtue of its good stability profile, the crystalline modification I of mefenox provides the formulation with a desired long shelf-life.

In a further aspect, the present invention provides a process for the preparation of crystalline modification I of mefenox comprising the steps of: i) dissolving mefenox in a solvent system comprising one or more solvents; ii) Precipitating the dissolved compound in step i) as crystalline modification I of mefenox; and iii) Isolation of precipitated crystalline modification I.

In step i) of the method, a solution is formed by dissolving mefenox in the solvent system. The methphenox used for formation in step i) is amorphous methphenox or a crystalline form of methphenox. In a preferred embodiment, the mefenol used to form the solution in step i) is amorphous, eg commercially available or prepared using prior art methods as discussed above.

The process for the preparation of crystalline modification I of mefenox employs a solvent system. A solvent system contains one solvent or a mixture of two or more solvents. Any suitable solvent which dissolves mefenox and produces crystalline modification I may be used. Preferably, the solvent system comprises one or more solvents selected from the group consisting of ketones, such as alkanones and cycloalkanones; and sulfur-containing organic compounds, such as argon.

Preferred alkanones are those having from 2 to 6 carbon atoms, more preferably from 2 to 4 carbon atoms. Preferred cycloalkanones are those having from 3 to 8 carbon atoms, more preferably from 4 to 6 carbon atoms, with cyclohexanone being an especially preferred cycloalkanone.

Preferred pyridines are dialkylpyridines having the general formula R-SO-R', wherein each of R and R' has from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms , Still more preferred is an alkyl group of from 1 to 3 carbon atoms. Preferably, R and R' are the same. A particularly preferred arsonite is dimethyl arsonite.

In a preferred embodiment, the solvent system consists of cyclohexanone, dimethylsulfoxide or a mixture thereof.

Mefenox may be dissolved in the solvent system in any suitable manner. In one embodiment, mefenox is dissolved in the solvent system in step i) by heating the solvent system from ambient temperature to a temperature equal to or lower than the reflux temperature of the solvent system. Preferably, the solution of mefenol is prepared by dissolving mefenol at the reflux temperature of the solvent system. The concentration of the solution formed in step i) will depend on the solubility of mefenox in the solvent system.

The solution of mefenox prepared in step i) is used in step ii) to form a precipitate of crystalline modification I. The precipitate of crystalline modification I of methphenox may be formed in any suitable manner. For example, the solution prepared in step i) can be cooled to cause precipitation of methphenol from the solution. Preferably, the solution is cooled to a temperature of from about 0°C to 20°C to crystallize the desired crystalline form from the solvent. It is also possible to concentrate the solution by removing the solvent, for example crystallizing crystalline modification I of mefenox from solution with or without application of vacuum and cooling below the reflux temperature of the solvent system. Alternatively, or in addition, crystalline modification I may be precipitated out of solution by adding a solvent or other component that reduces the solubility of mefenox in the solvent system.

The formation of crystalline modification I of mefenol from solution can also be achieved or enhanced by adding seeds of mefenol to the solution. Preferably, the seed crystal is a crystal of crystalline modification I of mefenox. Crystallization can be facilitated or accelerated using seeds.

Seed crystals, if used, can be employed in any suitable amount. The amount of seed crystals added to the solution is typically in the range of 0.001% to 10% by weight, preferably 0.005% to 0.5% by weight, based on the weight of mefenox used to prepare the concentrated solution in step (i) In the range. Preferably, the seeds are added to the solution at a temperature below the boiling point of the solvent system.

The precipitated crystalline modification I of mefenox obtained from step ii) is isolated from the solvent system to yield a crystalline product. Any suitable technique for isolating the crystalline product from the solvent system may be used and suitable techniques are known in the art. Suitable techniques include filtration, centrifugation or decantation or combinations thereof.

Thereafter, the isolated crystalline solid is preferably washed one or more times with a solvent. Preferably, the solvent used in the washing stage consists of one or more components of the solvent system used to prepare the solution in step i), as described above. Washing can be carried out using a solvent or a mixture of solvents at a temperature equal to or lower than ambient temperature (such as between room temperature and 0 ° C), depending on the solubility of the crystalline material in the solvent, so that the crystalline material can be dissolved in the corresponding washing solvent. The loss in is minimized.

The washings and/or the crystallization solvent can be concentrated to obtain mefenol as a solid which can be recycled.

As noted above, the crystalline modification I of mefenox according to the present invention exhibits significantly improved dispersibility and stability compared to known forms of mefenox. As described above, crystalline modification I can be prepared by crystallization from solution in a suitable solvent system.

Thus, in a further aspect, the present invention provides the use of a solvent system for improving the dispersibility and/or stability of mefenox. Suitable solvent systems are those comprising solvents which yield crystalline modification I when crystallizing mefenox from solution in the solvent system, and are as previously described.

The present invention further provides a crystalline material comprising crystalline modification I of mefenol obtainable by the process of the invention, having a content of crystalline modification I of mefenol of at least 98% by weight.

As previously described, mefenox is known to be active as an insecticide and finds use in the prevention and control of insect infestation. It has been found that the crystalline modification I of mefenox is also active in the control of insect pests. As a result, the techniques known in the art for formulating and administering mefenox can also be applied in a similar manner to mefenox for crystalline modification I of the invention.

Accordingly, in a further aspect, the present invention provides an insecticide composition comprising crystalline modification I of mefenox as defined above. In many embodiments, the insecticide composition comprising crystalline modification I of mefenox further comprises at least one adjuvant.

Further, the present invention provides a use of a crystalline modification I of mefenox or a composition as described herein for controlling insects.

As noted above, the present invention provides an insecticide composition comprising crystalline modification I of mefenox and at least one adjuvant. Mefenox may be present in the composition in any suitable amount to provide the desired insecticidal activity. In one embodiment, the amount of crystalline modification I of mefenox in the composition is less than 75% by weight of the composition, preferably less than 60% by weight of the composition. In a preferred embodiment, the amount of crystalline modification I of mefenox is less than 50% by weight of the composition, more preferably less than 40%, even more preferably less than 30% by weight. %, such as about 24% by weight of the composition.

The insecticide composition may be provided in any suitable formulation. Such formulation types are known in the art. In one embodiment, the composition is in the following forms: aqueous suspension (SC), solution (SL), oil-based suspension (OD), water-soluble granule (SG), dispersible emulsion (DC), emulsifiable concentrate ( EC), emulsified seed dressing, suspension seed dressing, granules (GR), microgranules (MG), suspoemulsion (SE) or water dispersible granules (WG). These various formulations can be prepared using suitable auxiliaries, carriers and solvents as known in the art.

In a preferred embodiment, the composition is in the form of a suspension (SC).

The crystalline modification I of mefenox is present in the concentration sufficient to achieve the desired dosage when applied to the plant or its loci, preferably at a concentration of from about 1% to about 75% by weight of the total mixture. in the preparation. The formulations are prepared, for example, by expanding the crystalline modification I of mefenox with water, solvents and carriers, where appropriate, using emulsifiers and/or dispersants and/or other auxiliaries.

These aforementioned formulations are prepared by combining the crystalline modification I of mefenox with at least one auxiliary agent as known in the art (for example, surfactants, liquid diluents, solid diluents, wetting agents, dispersing agents, thickener, antifreeze, biocide and any necessary adjuvants and other formulation ingredients).

Surfactants can be ionic or nonionic emulsifiers, dispersants or wetting agents. Examples that may be used include, but are not limited to, salts of polyacrylic acid, ligninsulfonic acid, benzenesulfonic acid or naphthalenesulfonic acid, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (especially alkylphenols), sulfosuccinate salts, taurine derivatives (especially alkyl taurates) or phosphate esters of polyethoxylated phenols or alcohols.

Liquid diluents include, but are not limited to, water, N,N-dimethylamide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, propylene carbonate, dibasic esters, paraffin, alkylbenzene, alkanes Naphthalene, glycerin, triacetin, olive oil, castor oil, linseed oil, sesame oil, corn oil, peanut oil, cottonseed oil, soybean oil, rapeseed oil and coconut oil, ketones (such as cyclohexanone, 2-heptanone , isophorone, and 4-hydroxy-4-methyl-2-pentanone), acetates (such as hexyl acetate, heptyl acetate, and octyl acetate), water, and alcohols (such as methanol, cyclohexanol, decyl alcohol, benzyl and tetrahydrofurfuryl alcohol), and mixtures thereof.

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 (e.g., monobasic sodium phosphate), alkaline earth metal phosphates, sulfates of sodium, potassium, magnesium, and zinc, sodium and potassium chloride, acetic acid Sodium, 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 silica and diatomaceous earth, calcium and magnesium silicates, titanium dioxide, aluminum oxide, calcium oxide, and zinc oxide, and mixtures thereof.

Wetting agents include, but are not limited to: alkyl sulfosuccinates, laurates, alkyl sulfates, phosphate esters, acetylene glycols, ethoxylated fluorinated alcohols, ethoxylated silicones, alkylphenol ethyl alcohols Oxylate, benzene sulfonate, alkyl substituted benzene sulfonate, alkyl α-olefin sulfonate, naphthalene sulfonate, alkyl substituted naphthalene sulfonate, naphthalene sulfonate and alkyl substituted Condensates of naphthalenesulfonates and formaldehyde, and alcohol ethoxylates. Polyalkylene glycol ethers are particularly useful in the compositions of the present invention.

Dispersants include, but are not limited to, sodium, calcium and ammonium salts of lignosulfonic acid (optionally polyethoxylated); sodium and ammonium salts of maleic anhydride copolymers; sodium salts of condensed phenolsulfonic acids; And naphthalenesulfonate-formaldehyde condensate. In particular compositions comprising up to 10% by weight of dispersant. Lignosulfonates such as sodium lignosulfonate are particularly useful in the compositions of the present invention. Sodium alkylnaphthalene sulfonate-formaldehyde condensates are particularly useful in the compositions of the present invention.

Thickeners include, but are not limited to, guar gum, pectin, casein, carrageenan, xanthan gum, alginates, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and carboxymethyl cellulose. Synthetic thickeners include derivatives of the preceding classes, and also polyvinyl alcohols, polyacrylamides, polyvinylpyrrolidone, various polyethers, their copolymers, and polyacrylic acid and its salts. Xanthan gum is particularly useful in the compositions of the present invention.

Suitable antifreeze agents include liquid polyols such as ethylene glycol, propylene glycol or glycerin. The amount of antifreeze is generally from about 1% to about 20% by weight, especially from about 5% to about 10% by weight, based on the total weight of the composition.

Biocides can also be added to the compositions according to the invention. Suitable biocides include isothiazolone based biocides such as Proxel® from ICI or Acticide® RS from Thor Chemie UK or Kathon® MK from Rohm & Haas. The amount of biocide is typically from 0.05% to 0.5% by weight based on the total weight of the composition.

Antifoams include all substances which can normally be used for this purpose in agrochemical compositions. Suitable antifoaming agents are known in the art and are commercially available. A particularly preferred antifoam agent is a mixture of polydimethylsiloxane and perfluoroalkyl phosphate, such as the silicone antifoam agents available from GE or Compton.

Antioxidants include all substances which can normally be used for this purpose in agrochemical compositions, as known in the art. Preferred is butylated hydroxytoluene (BHT).

Other formulation ingredients may also be used in the present invention, such as dyes, desiccants, and the like. Such ingredients are known to those skilled in the art.

The present invention furthermore provides a process for the preparation of compositions for controlling pests using crystalline modification I of mefenox. Techniques for forming compositions such as the aforementioned formulations will be known to those skilled in the art.

The present invention also provides a method for controlling or preventing insect infestation of plants, comprising applying an insecticidally effective amount of mefenox as previously described to the plants, plant parts, or the surrounding environment of the plants. Crystal modification I, or a composition as described above.

The method provides control of insects in the plants, plant parts, and/or their surroundings, and includes applying an effective amount of mefenox to the leaves or fruits of the plants, plant parts, or their surroundings. Crystalline modification I.

Whole plants and plant parts can be treated according to the invention. In this context, plants are understood to mean 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 obtainable by conventional breeding and optimization methods, by biotechnological and genetic engineering methods or by a combination of these methods, including transgenic plants and plant cultivars which may or may not be protected by plant breeders' rights Variety. Plant parts are understood to mean all aboveground and belowground parts and organs of plants, such as buds, leaves, needles, stems, stalks, flowers, fruiting bodies, fruits, seeds, roots, tubers and rhizomes. Also included are harvested material, and vegetative and reproductive propagation material, such as cuttings, tubers, meristems, rhizomes, runners, seeds, single and multiple plant cells and any other plant tissue.

The crystalline modification I of mefenox according to the invention can be combined with one or more other active compounds, such as insecticides, attractants, bactericides, bactericides, acaricides, nematocides, fungicides, growth Conditioning substances, herbicides, safeners and fertilizers are used in combination.

Treating the plants and plant parts with the compositions or formulations of the present invention by applying the compositions or formulations to the plants or plant parts or by allowing the compositions or formulations to act on their surroundings , habitat or storage space directly. Conventional methods of manipulation are known in the art. Examples of such conventional treatment methods include dipping, spraying, vaporizing, misting, broadcasting, spreading (in the case of propagation material) and applying one or more coatings (especially in the case of seeds).

The crystalline modification I of mefenox can be used to control a wide range of insects and protect a wide range of crop plants. When the crystalline modification I of mefenox or a composition thereof is applied to growing crops of plants where applicable, it kills piercing-sucking pests such as armyworms, borers, budworms, cabbage worms ( cabbageworm), caterpillars, corn borers, cutworms, earworms, fruit worms, hornworms, leafhoppers, leaf miners, leaf rollers, inchworms, melon worms, moths, pickleworms ) and web-spinning caterpillars, such as almonds, apples, avocados, blueberries, citrus, coffee, heart pears, vines, kiwi, longan, lychees, macadamia trees, pear trees, pepper and tomato.

As used herein, the term "about" when used in conjunction with a numerical amount or range means slightly greater or slightly less than the stated numerical amount or range by ±10% of the stated numerical amount or the endpoint of the range.

The "surrounding environment" as used herein refers to the place where the plant grows, the place where the plant propagation material of the plant is sown or the place where the plant propagation material of the plant will be sown.

As used herein, "precipitation" refers to the precipitation of a solid substance (precipitate), including precipitation of crystalline material, from a liquid solution in which the solid substance is present in an amount greater than its solubility in the amount of the liquid solution.

Throughout the specification and claims of this specification, the word "comprise" and variations of that word (such as "comprising" and "comprises") means "including but not limited to", And does not exclude other parts, additives, components, integers or steps. Furthermore, the singular includes the plural unless the context requires otherwise: in particular, where an indefinite article is used, this specification should be read to contemplate the plural as well as the singular unless the context requires otherwise.

Preferred features of each aspect of the invention may be as described in combination with any other aspect. Other features of the invention will become apparent from the following examples. In general, the invention extends to any novel one or any novel combination of 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. Allow. Furthermore, 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 cited for a characteristic, a range of values defined by the combination of either upper limit and any lower limit may also be implied.

In this specification, unless otherwise stated, properties refer to properties measured under ambient conditions, ie at atmospheric pressure and at temperatures from about 20°C to 26°C.

As used herein, the term "crystal" refers to a solid state form in which molecules are arranged to form a crystal lattice comprising resolvable unit cells. In general, crystalline materials can be identified, for example, by producing diffraction peaks when subjected to X-ray radiation and/or exhibiting an endothermic melting peak curve with a characteristic peak under Differential Scanning Calorimetry (DSC).

All percentages herein are given in % by weight unless otherwise indicated.

Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that such prior art forms part of the common general knowledge.

The invention will now be described by means of the following examples, which are provided for illustrative purposes only.

The following measurement techniques have been used:

All X-ray diffraction patterns were determined using a powder diffractometer in reflection geometry at 25°C using the following acquisition parameters: X'Pert Pro MPD from PANalytical BV Theta compensation slit and graphite monochromator Copper (K-α) radiation, 40 kV, 40 mA Step size: 0.03 degrees 2-theta Counting time: 1.0 seconds Maximum peak intensity: 1705 times per second Scanning range: 3 degrees -60 degrees 2-theta

For crystallized samples, IR spectra were measured with a resolution of 4 cm ⁻¹ and with 16 scans. The crystalline modification I of methphenol can be obtained by its at 3305 cm ^-1 , 3006 cm ^-1 , 2966 cm ^-1 , 1683 cm ^-1 , 1639 cm ^-1 , 1587 cm ^-1 , 1494 cm ^-1 , 1274 cm ^-1 , 1244 cm ^-1 , 1027 cm ^-1 and 861 cm ^-1 at one or more wavenumbers (cm ^-1 , ±0.2%) to identify the characteristic functional group vibration peaks, as shown in Figure 1 out.

All IR spectra were acquired using the following acquisition parameters: FT-IR spectrometer Nicolet™ iS 5 Diamond ATR Unit Thermo Scientific™ iD5 ATR wavelength range 550‑4000 cm ^-1 resolution 4 cm ^-1 scan times 16 Example Example 1 : Preparation of amorphous methphenol according to the disclosure of CN 104803879 A

Tertiary butylhydrazine hydrochloride and dichloroethane were added to the reactor vessel at room temperature. The reactor vessel was cooled to about -5°C to -6°C with brine. Liquid base is added to the reactor vessel. The reactor vessel was then allowed to stand until the contents separated. Remove the aqueous layer. Keep the organic layer at -5°C to -6°C. 3-Methoxy-2-methylbenzoyl chloride was added dropwise while maintaining the temperature of the reactor not greater than 0°C. After 7 to 9 hours, samples were separated and analyzed. Add water. The contents of the reactor vessel were stirred. The reactor vessel was then allowed to stand until the contents again separated. Remove the aqueous layer. The organic layer was heated to 75°C to 85°C under atmospheric pressure to remove dichloroethane, and then cooled to room temperature and finally dissolved in toluene.

The contents of the reactor vessel were kept at a temperature below 0°C while 3,5-dimethylbenzoyl chloride and liquid base were added dropwise to adjust the pH to slightly acidic. After 7 to 9 hours, samples were separated and analyzed. The reactor vessel was then allowed to stand until the contents separated. Remove the aqueous layer. The organic layer was maintained at a temperature of 100°C to 120°C under atmospheric pressure to remove toluene. It was then cooled to room temperature and finally dissolved in toluene and water for recrystallization. The product was dried at 60°C to 70°C.

The reaction scheme for the preparation of methphenol is as follows:

The product was subjected to analysis by means of X-ray diffraction. The obtained X-ray diffraction pattern is shown in FIG. 4 . As can be seen in Fig. 4, the X-ray powder diffraction pattern of the obtained mefenol product has no significant signal, which indicates that the mefenol product prepared according to the disclosure of CN 104803879 A is amorphous. Example 2 : Preparation of crystalline modification I of mefenox with cyclohexanone

The mefenol (10 g) prepared in Example 1 was placed together with cyclohexanone (60 mL) in a 3-neck round bottom flask, and the resulting slurry was heated to 80° C. to form a homogeneous solution. The homogeneous solution was stirred at 80°C for 2 hours and insoluble particles, if any, were removed by filtration. Thereafter, the solution was slowly cooled to room temperature.

Upon cooling, fine crystals formed and the resulting heterogeneous mixture was stirred at 20° C. for 2 hours. The resulting slurry was then filtered and washed with cooled cyclohexanone (6 mL). The filtered crystals were dried at 50 °C under vacuum in order to remove traces of solvent from the crystallized product. The obtained crystalline product had a purity of 98% and a product yield of 85%.

The product was characterized as crystalline modification I of mefenox by means of IR spectroscopy and XRD, exhibiting the spectra shown in Figures 1 and 2, respectively.

^{The IR} spectrum ^{of the} mefenox ^product as given in Figure 1 shows ^{the -1} , 1274 cm ^-1 , 1244 cm ^-1 , 1027 cm ^-1 and 861 cm ^-1 characteristic vibrations of functional groups.

The X-ray powder diffraction pattern of the methphenol product exhibits the reflections shown in Figure 2 and the equivalents are summarized in Table 1. [Table 1] crystal modification crystal modification crystal modification 2θ (°) d (Å) 2θ (°) d (Å) 2θ (°) d (Å) 4.70±0.2 18.80±0.05 21.44±0.2 4.15±0.05 30.78±0.2 2.91±0.05 9.47±0.2 9.34±0.05 22.43±0.2 3.96±0.05 31.04±0.2 2.88±0.05 9.81±0.2 9.02 ± 0.05 23.55±0.2 3.78±0.05 32.20±0.2 2.78±0.05 11.66±0.2 7.59±0.05 23.93±0.2 3.72±0.05 33.57±0.2 2.67±0.05 12.08±0.2 7.33±0.05 24.78±0.2 3.59±0.05 34.37±0.2 2.61±0.05 12.63±0.2 7.01±0.05 25.24±0.2 3.53±0.05 35.07±0.2 2.56±0.05 14.26±0.2 6.21±0.05 25.41±0.2 3.51±0.05 36.42±0.2 2.47±0.05 16.49±0.2 5.38±0.05 25.92±0.2 3.44±0.05 39.35±0.2 2.29±0.05 16.70±0.2 5.31±0.05 26.30±0.2 3.39±0.05 40.58±0.2 2.22±0.05 18.01±0.2 4.93±0.05 26.63 ± 0.2 3.35±0.05 41.50 ± 0.2 2.17±0.05

A DSC thermogram of the methphenol product was obtained and exhibited an endothermic melting peak starting at 188.1°C and a peak at 196.2°C, and a melting enthalpy of 58.47 J/g. The DSC thermogram is shown in FIG. 3 . Example 3 : Preparation of crystalline modification I of mefenox with dimethylsulfoxide

A sample of mefenol (5 g) prepared in Example 1 was placed in a 3-neck round bottom flask together with dimethylsulfoxide (35 mL), and the resulting slurry was heated to 80° C. to obtain a homogeneous solution. The resulting hot solution was stirred at 80°C for 2 hours and filtered to remove insoluble particles, if any, and the solution was slowly cooled to ambient temperature. The desired crystalline product precipitated out as fine crystals during cooling, and the mixture was stirred at 20° C. for 2 hours. The resulting slurry was then filtered, washed with cooled dimethylsulfoxide (6 mL) and dried under vacuum at 50 °C in order to remove traces of solvent from the crystals. The obtained product had a purity of 98% and a product yield of 85%.

The product was characterized by IR spectroscopy, DSC and XRD, and the resulting spectra observed were substantially identical to those given in Figures 1, 2 and 3, respectively. Formulation Example Example 4 : Preparation of Aqueous Suspension ( SC ) of Amorphous Mefenox

All the components listed in Table 2 below were uniformly mixed, and the resulting mixture was ground with a Dyno-Mill (manufactured by Willy A. Bachofen AG) to obtain an aqueous suspension. [Table 2] components Amount ( %wt ) effect Mefenol (prepared in Example 1) 20 active ingredient Sodium alkylnaphthalene sulfonate-formaldehyde condensate (MORWET D-425® POWDER) 3 Dispersant Polyalkylene Glycol Ether (ATLASTM G-5000) 2 D Butylated Hydroxytoluene (BHT) 1 Antioxidants Modified polydimethylsiloxane formulation (SAG 1529) 0.5 Defoamer Propylene Glycol 8 antifreeze xanthan gum 0.2 thickener 1,2-Benzisothiazol-3(2H)-one (Proxel®) 0.2 Biocide water Balance to 100 filler Example 5 : Preparation of Aqueous Suspension ( SC ) of Crystalline Modification I of Mefenox

All the components listed in Table 3 below were uniformly mixed, and the resulting mixture was ground with a Dyno-Mill (manufactured by Willy A. Bachofen AG) to obtain a suspension concentrate. [table 3] components Amount ( %wt ) effect Mefenox, crystalline modification I (prepared in Example 2) 20 active ingredient Sodium alkylnaphthalene sulfonate-formaldehyde condensate (MORWET D-425® POWDER) 3 Dispersant Polyalkylene Glycol Ether (ATLASTM G-5000) 2 D Butylated Hydroxytoluene (BHT) 1 Antioxidants Modified polydimethylsiloxane formulation (SAG 1529) 0.5 Defoamer Propylene Glycol 8 antifreeze Xanthan Gum (AG-RHO POL 23/W) 0.2 thickener 1,2-Benzisothiazol-3(2H)-one (Proxel®) 0.2 Biocide water Balance to 100 filler Example 6 : Comparison of Storage Stability

Samples of the formulations prepared in Examples 4 and 5 were stored at 54°C in a heated oven with the same atmosphere for 1 month, 3 months and 6 months. The procedure followed is based on CIPAC MT 46.3. The concentration of mefenox was measured by high pressure liquid chromatography (HPLC) at the end of each storage period. Aggregation of particles in aqueous suspensions was measured by observation.

The original concentration of mefenol in each formulation was 20%.

List the results in Table 4. [Table 4] storage period Features/Samples Example 4 Example 5 1 month Concentration of methphenol (%) 20 20 gather + - 3 months Concentration of methphenol (%) 18 20 gather ++ - 6 months Concentration of methphenol (%) 14 20 gather ++++ + Remarks: "+" means a small amount of aggregation; "++++" means a lot of aggregation; "-" means no aggregation was observed.

As can be seen from the results listed in Table 4, the concentration of crystalline modification I of mefefenox in the aqueous suspension formulation remained constant at 20% wt, indicating that there was no degradation or loss of components, which in turn indicated that mefenox The crystalline modification I of Novo is stable. In contrast, amorphous methphenox exhibited poor stability in the formulation, where its concentration decreased significantly after 3 months and especially after 6 months. It should also be noted that the crystalline modification I of mefenox remained well dispersed in the aqueous suspension formulation. In contrast, amorphous methphenox exhibited significant aggregation in aqueous suspension during the test period, especially after 3 and 6 months.

none

This article refers to the accompanying drawings, in which: [ FIG. 1 ] Infrared (IR) spectrum of one embodiment of crystalline modification I of methphenox; [ FIG. 2 ] X-ray diffraction (XRD) spectrum of one embodiment of crystalline modification I of methphenox; [ FIG. 3 ] Differential Scanning Calorimetry (DSC) spectrum of one embodiment of crystalline modification I of methphenox; and [Figure 4] is the X-ray diffraction (XRD) spectrum of amorphous methphenox.

none

Claims (25)

A crystalline modification I of N′-tertiary butyl-N′-(3,5-dimethylbenzoyl)-3-methoxy-2-methylbenzoylhydrazine (Mefenol) , which exhibit at least three of the following reflections in any combination as 2θ ± 0.20 degrees in an X-ray powder diffraction pattern (X-RPD) recorded using Cu-Kα radiation at 25°C: 2θ = 9.47 ± 0.20 (1) 2θ = 9.81 ± 0.20 (2) 2θ = 12.63 ± 0.20 (3) 2θ = 14.26 ± 0.20 (4) 2θ = 16.49 ± 0.20 (5) 2θ = 16.70 ± 0.20 (6) 2θ = 18.01 ± 0.20 (7) 2θ = 18.49 ± 0.20 (8) 2θ = 19.65 ± 0.20 (9) 2θ = 20.47 ± 0.20 (10) 2θ = 21.44 ± 0.20 (11) 2θ = 22.43 ± 0.20 (12) 2θ = 23.55 ± 0.20 (13) 2θ = 23.93 ± 0.20 (14) 2θ = 25.41 ± 0.20 (15) 2θ = 26.63 ± 0.20 (16). Crystalline modification 1 of mefenox as claimed in claim 1, which exhibits at least two of the following reflexes in any combination: 2θ = 9.47 ± 0.20 (1) 2θ = 9.81 ± 0.20 (2) 2θ = 12.63 ± 0.20 (3) 2θ = 16.70 ± 0.20 (5) 2θ = 18.01 ± 0.20 (6) 2θ = 18.49 ± 0.20 (7) 2θ = 20.47 ± 0.20 (9) 2θ = 21.44 ± 0.20 (10) 2θ = 22.43 ± 0.20 (11) 2θ = 23.55 ± 0.20 (12). Crystalline modification 1 of mefenox as claimed in claim 2, which exhibits at least two of the following reflexes in any combination: 2θ = 9.47 ± 0.20 (1) 2θ = 9.81 ± 0.20 (2) 2θ = 12.63 ± 0.20 (3) 2θ = 16.70 ± 0.20 (5) 2θ = 18.01 ± 0.20 (6) 2θ = 18.49 ± 0.20 (7) 2θ = 23.55 ± 0.20 (12). ^Crystalline modification I of mefenox as ^claimed in any ^one of the preceding claims ^, which exhibits ^an Characteristic functionalities at one or more wavenumbers (cm ^-1 , ±0.2%) of cm ^-1 , 1494 cm ^-1 , 1274 cm ^-1 , 1244 cm ^-1 , 1027 cm ^-1 and 861 cm ^-1 IR spectrum of the fundamental vibrational peak. Crystalline modification I of mefenox as claimed in any one of the preceding claims, which exhibits a melting point of 196.2°C. Crystalline modification I of mefenox according to any one of the preceding claims, characterized by an X-ray powder diffraction pattern substantially as shown in Figure 2, and/or by an X-ray powder diffraction pattern substantially as shown in Figure 1 Characterized by the IR spectrum shown, and/or exhibited a melting point of 196.2°C. A method for preparing the crystalline modification I of mefenox as described in any one of the preceding claims, comprising the following steps i) dissolving mefenol in a solvent system comprising one or more solvents; ii) Precipitating the dissolved compound as crystalline modification I of mefenox; and iii) Isolation of the precipitated crystalline modification I. The method as claimed in item 7, wherein the methphenol used in step i) is amorphous methphenol or a crystalline form of methphenol. The method according to any one of claims 7 or 8, wherein the solvent system comprises a solvent selected from ketones and sulfur-containing organic compounds. The method according to claim 9, wherein the solvent system comprises a solvent selected from alkanone, cycloalkanone, or argon. The method according to claim 10, wherein the solvent system comprises cyclohexanone or dimethylsulfoxide or a mixture thereof. The method according to any one of claims 7 to 11, wherein step ii) comprises concentrating the solution and/or cooling and/or adding a solubility reducing solvent and/or adding seed crystals. The method of claim 12, wherein step ii) comprises cooling the solution to a temperature from about 0°C to 20°C. A crystalline modification I of mefenol obtained by the method as described in any one of claims 7 to 13 and having a content of crystalline modification I of mefenol of at least 98% by weight. An insecticide composition comprising the crystalline modification I of mefenox as described in any one of claims 1 to 6 and 14 and at least one adjuvant. The composition as described in Claim 15, wherein the composition is prepared as a water suspension (SC), an oil-based suspension (OD), a solution (SL), a water-soluble granule (SG), or a dispersible emulsion (DC), emulsifiable concentrate (EC), emulsified seed dressing, suspension seed dressing, granule (GR), microgranule (MG), suspoemulsion (SE) or water dispersible granule (WG). The composition according to claim 16, wherein the composition is formulated as a suspension (SC). The composition according to any one of claims 15 to 17, wherein the composition comprises crystalline modification I of mefenol in an amount of less than 75% by weight. The composition of claim 18, wherein the composition comprises crystalline modification I of mefenol in an amount of about 20% by weight. A use of the crystalline modification I of mefenox as described in any one of claims 1 to 6 and 14, or the composition as described in any one of claims 15 to 19 for controlling pests. The use of the crystal modification I of mefenox as described in claim 20, wherein the pest is selected from armyworms, borers, budworms, cabbage caterpillars, caterpillars, corn borers, cutworms, earworms, Fruit insects, hawkmoth larvae, leafhoppers, leaf miners, leaf rollers, inchworms, melon worms, moths, pickle bugs, and netting caterpillars. Use of the crystalline modification I of mefenox as described in any one of claims 20 or 21 for the control of almonds, apples, avocados, blueberries, citrus, coffee, avocado, grapevine, kiwi, Pests on longan, lychee, macadamia, pear, pepper and tomato trees. A method of controlling insects at a locus, the method comprising applying to the locus the crystalline modification I of mefenox as described in any one of claims 1 to 6 and 14, or the crystalline modification I of any one of claims 15 to 19 The composition mentioned in the item. The method as described in claim 23, wherein the insects are selected from armyworms, borers, budworms, cabbage caterpillars, caterpillars, corn borers, cutworms, earworms, fruit insects, hawkmoth larvae, leafhoppers, Leaf miners, leaf rollers, inchworms, melon bugs, moths, pickle bugs, and netting caterpillars. The method as described in any one of claim 23 or 24, wherein, the site is planted at a place selected from almonds, apples, avocados, blueberries, citrus, coffee, heart pears, grapevines, kiwi, longan, litchi, Australian Crops of nut trees, pear trees, peppers and tomatoes.