TW201741289A - A novel form of SULFENTRAZONE, a process for its preparation and use the same - Google Patents

Abstract

A new crystalline form of sulfentrazone of formula (I), the crystal preparation process, the analyses of the crystal through various analytical methods and using the crystal to prepare stable agrochemical formulation. The invention also describes the use of various solvents towards the crystalline form preparation conditions. The novel crystal form is particularly suitable for use in herbicidal compositions and in the control of unwanted plant growth.

Description

Novel form of mefenacetamide (SULFENTRAZONE), preparation method and use thereof

The present disclosure describes N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-sideoxy-1H-1,2,4 - Crystalline form of triazol-1-yl]phenyl]methanesulfonamide (sulfentrazone), a process for its preparation and its use in agrochemical formulations.

N-[2,4-Dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole A member of the -1-yl]phenyl]methanesulfonamide (mesulamide) is an aryl triazolinone chemical. Mesalamine is a pre-emergence and post-emergence herbicide and is very effective against sedge in turfgrass. It controls weeds by a generally known mode of action known as protoporphyrinogen oxidase (PPO) inhibition. The active ingredient, mesotrione, is mainly absorbed by the roots, and the mesalil in the soil-treated plants can be identified by root-stalk soil placement studies. Therefore, soil-treated plants become necrotic and die after exposure to sunlight, while leaf-contacted plant tissues cause dryness and necrosis. Metotriamide controls annual and perennial sedges, cold-season grasses, and broadleaf weeds in established warm-season, perennial grasses. In addition, it is used to remove high foxtail and sedge from warm-season turfgrass and bluegrass.

Metotriamide has the molecular formula of C ₁₁ H ₁₀ Cl ₂ F ₂ N ₄ O ₃ S. Its chemical structure

Commercially available mesalamide, which is typically produced by the process described in U.S. Patent No. 4,818,275, which is incorporated herein by reference in its entirety, in The status exists. It has been found that mesalil in an amorphous state is not suitable for use as a composition or formulation because it is extremely susceptible to direct photolysis in aqueous solutions. Direct aqueous photolysis of the mesalamine aqueous solution exposed to simulated sunlight has a half-life of about 1-12 hours. Therefore, there is a need to develop a novel form of mesotrione that exhibits improved photolysis stability in aqueous solution.

In order to address some or all of the problems in the amorphous form of mesotrione, new and stable crystalline forms of mesalil have been prepared.

In a first aspect, the invention provides N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-sideoxy-1H a novel crystalline form of -1,2,4-triazol-1-yl]phenyl]methanesulfonamide (messulfamide), referred to as "crystalline variant I", which utilizes Cu-Kα radiation at 25 At least 3 of the following reflections are present in any combination of X-ray powder diffraction patterns (X-RPD) recorded at ° C, denoted as 2θ ± 0.2 degrees: 2θ = 6.3 ± 0.2 (1)

2θ=6.8±0.2 (2)

2θ=12.1±0.2 (3)

2θ=17.0±0.2 (4)

2θ=17.6±0.2 (5)

2θ=18.5±0.2 (6)

2θ=19.1±0.2 (7)

2θ=19.9±0.2 (8)

2θ=21.6±0.2 (9)

2θ=22.6±0.2 (10)

2θ=24.3±0.2 (11)

2θ=24.6±0.2 (12)

2θ=28.5±0.2 (13)

2θ=29.0±0.2 (14)

2θ=32.2±0.2 (15)

2θ=34.4±0.2 (16)

In a specific example, the crystalline variant according to the first aspect of the invention exhibits at least 3, 4, 5, 6, 7, 8, or all of the following reflections (in any combination) :2θ=6.3±0.2 (1)

2θ=6.8±0.2 (2)

2θ=12.1±0.2 (3)

2θ=17.0±0.2 (4)

2θ=18.5±0.2 (6)

2θ=19.1±0.2 (7)

2θ=21.6±0.2 (9)

2θ=24.6±0.2 (12)

2θ=29.0±0.2 (14)

In a second aspect, optionally in accordance with the first aspect of the invention, the invention provides a crystalline variant I of mesalil which is present at about 3236, 1741, 1613, 1483, 1394, 1318, 1145, 1096 and 1056 cm. one or more of ^-1 wavenumber (cm ^-1, ± 0.2%) at a functional group having characteristic infrared vibrational peak (IR) spectroscopy.

In a third aspect, the invention according to the first or second aspect of the invention provides a crystalline variant I of mesalil which exhibits a melting point of from 126 ° C to 130 ° C, optionally from 127 ° C to 129 °C, further depending on the situation is 128 °C.

In a fourth aspect, according to any one of the first to third aspects of the present invention, the present invention provides a crystalline variant I of mesalil which exhibits an endothermic melting peak starting at 125 ° C and having a peak maximum at A differential scanning calorimetry (DSC) profile at 128 ° C further has a melting enthalpy of 73 J/g, as appropriate.

In a fifth aspect, according to any one of the first to fourth aspects of the invention, the invention provides a crystalline variant I of mesalil, characterized by an X-ray substantially as shown in Figure 2. The powder diffraction pattern, and/or characterized by an IR spectrum substantially as shown in Figure 1, and/or characterized by a DSC thermogram substantially as shown in Figure 3.

In a sixth aspect, according to any one of the first to fifth aspects of the invention, the invention provides a crystalline variant I of mesalil, which can be substantially as described in Example 2 or 3 The method is obtained.

In a seventh aspect, according to any one of the first to sixth aspects of the invention, the invention provides a crystalline variant I of mesalil, which is obtainable by the method of the eighth aspect of the invention.

It has been found that the crystalline variant I of mesalil has a significant improvement in its photolysis stability. In addition, it has been found that the crystalline variant I of mesalil is easier to filter, comminute or grind than the amorphous mesochloramide prepared according to the disclosure of U.S. Patent No. 4,818,275. It was also found that the formulation prepared using the crystal modification I was stable after long-term storage. In addition, the crystal modification I has a lower tendency to degrade (photolysis) after exposure to light, as compared to the amorphous state described in U.S. Patent No. 4,818,275. This allows the preparation of commercial formulations such as aqueous suspensions (SC) and water-dispersible granules (WG). For these reasons, the crystal modification I is more suitable for the preparation of commercial formulations. Due to its high photolysis stability, the crystalline variant I of mesalil gives the formulation a desired long term shelf life. Thus, any formulation can be prepared from crystalline variant I of mesalamine, which formulations are disclosed below.

In an eighth aspect, the present invention provides a process for the preparation of crystalline variant I of mesalil comprising the steps of: i) dissolving mesalil in a solvent or a mixture of solvents; ii) dissolving The compound precipitated as crystalline variant I of mesalil; and iii) the crystallized variant I of the precipitate was isolated.

In a specific embodiment of the eighth aspect of the present invention, the mesalil-based amorphous mesotrione in the step i).

Methods for preparing amorphous mesoxalam are known in the art. Amorphous mesotrione is produced on a commercial scale and is available. A particularly suitable method for the preparation of amorphous mesochloramide is described in U.S. Patent No. 4,818,275.

In a specific embodiment of the eighth aspect of the invention, the solvent is selected from the group consisting of halogenated hydrocarbons (eg, chlorobenzene, bromobenzene, dichlorobenzene, trifluoromethylbenzene, and trichlorobenzene), Ether (eg, diethyl ether, ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, glycol dimethyl ether, diphenyl ether, dipropyl ether, diisopropyl ether) , di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, methyl tetrahydrofuran, two , dichlorodiethyl ether, methyl-tetrahydrofuran, polyether of ethylene oxide and/or propylene oxide, nitrated hydrocarbons (eg, nitromethane, nitroethane, nitropropane, nitrobenzene, chlorinated nitrate) a benzene, ethylbenzene), aliphatic, alicyclic or aromatic hydrocarbon (eg, pentane, n-hexane, n-heptane, n-octane, decane), cymene, having a temperature from 70 ° C to 190 ° C Boiling range of petroleum fractions, cyclohexane, methylcyclohexane, petroleum ether, petroleum, octane, benzene and xylene), esters (eg, malonate, n-butyl acetate (n-butyl acetate)) , methyl acetate, ethyl acetate, isobutyl acetate, dimethyl carbonate, diethyl carbonate, dibutyl carbonate and ethyl carbonate), and aliphatic alcohols (eg, methanol, ethanol, n-propanol, Isopropanol, n-butanol and tertiary pentanol), mesitylene, diethyl ketone, methyl ethyl ketone, acetonitrile and mixtures thereof.

In a specific embodiment of the eighth aspect of the present invention, the solvent is selected from the group consisting of xylene, benzene, chlorobenzene, dichlorobenzene, ethylbenzene, trifluoromethylbenzene, mesitylene, and nitrate a mixture of benzene, ether, diethyl ketone, methyl ethyl ketone, methanol, ethanol, isopropanol, acetonitrile or the following: THF-hexane, ethyl acetate-hexane, dichloromethane-hexane, two Methyl chloride-methanol, THF-water and methanol-water. Solvent mixtures of more than 2, 3 or 4 components are also contemplated by the specific examples of the invention.

In a specific embodiment of the eighth aspect of the invention, the solvent is selected from the group consisting of diethyl ketone, xylene or mixtures thereof.

According to an embodiment of the eighth aspect of the invention, the crystalline variant I of mesalil is prepared by heating from ambient temperature to the reflux temperature of the solvent or the solvent mixture in a solvent or solvent mixture or The amorphous mesalil is dissolved in a concentrated solution below the reflux temperature. The concentrated solution can be prepared at the reflux temperature of the solvent, as the case may be. The concentration of the solution depends on the solubility of mesochlor in the corresponding solvent or solvent mixture.

In a specific embodiment of the eighth aspect of the invention, the concentrated homogeneous solution thus prepared as in step (i) is subsequently cooled to room temperature or a temperature of from about 0 ° C to 20 ° C to crystallize from the solvent to the desired Crystal form. By removing or removing the solvent or the solvent mixture to or after applying or not applying a vacuum and cooling to a temperature below the reflux temperature of the solvent or the solvent mixture The homogenized solution is concentrated in a fixed volume, and crystal modification I of mesalil can also be crystallized.

In a specific embodiment of the eighth aspect of the present invention, a seed crystal can also be produced by adding a seed crystal of a desired crystal form (which can promote or accelerate crystallization) to the solution prepared in the step (i) during crystallization. Crystalline variant I of sulforaphane.

The amount of seed added to the concentrated solution is typically in the range of 0.001% to 10% by weight, optionally 0.001% to 2.5%, and further optionally 0.005% to 0.5%, based on the preparation. The weight of mesochloramide in the concentrated solution in step (i). Optionally, the seed crystals are added to the concentrated solution at a temperature below the boiling point of the corresponding solvent or solvent mixture.

In a specific example of the eighth aspect of the present invention, the precipitated mesalil crystal obtained from the step (ii) is separated from the solution by a usual solid component separation technique such as filtration, centrifugation or decantation. Variant I. The separated solid is then washed one or more times with a solvent. Optionally, as described above, the solvent used in the washing stage consists of one or more components of the solvent or solvent mixture used to prepare the concentrated solution in step (i). Depending on the solubility of the crystals, washing is usually carried out between room temperature and 0 ° C using the corresponding solvent or solvent mixture to minimize or avoid loss of crystalline material in the respective wash solvent. In a specific example of the eighth aspect of the invention, the crystalline variant I of mesalil is dissolved and recrystallized. The washing liquid and/or the crystallization solvent in any of the methods can be concentrated to obtain a recyclable solid mesotrione.

In a ninth aspect, the present invention provides a crystalline material comprising crystalline variant I of mesalil obtained according to the eighth aspect of the invention, the crystalline material having a content of at least 98% by weight of mesalil Crystalline variant I.

In a tenth aspect, the present invention provides a composition comprising the crystalline variant I of mesalil according to any one of the first to seventh and ninth aspects of the present invention, and at least one Auxiliary.

In an eleventh aspect, the present invention provides the crystalline variant I of mesalil according to any one of the first to seventh and ninth aspects of the present invention, or according to the tenth aspect of the present invention The composition is used for weed control purposes.

In a specific embodiment of the tenth aspect of the present invention, the amount of the crystalline variant I of mesalil is less than 90% by weight of the composition, and optionally less than 75% by weight of the composition, further Optionally, less than 60% by weight of the composition, still further about 50% by weight of the composition, as appropriate.

The use of amorphous mesochloramide as a herbicide is known in the art and is used on a commercial scale. It has been found that the crystalline variant I of mesalil is also active in controlling unwanted plants such as weeds. Thus, techniques known in the art for the formulation and administration of mesoxalam for amorphous mesoxalam, such as those disclosed in the prior art documents described above, can also be applied to the present invention in a similar manner. Mesalamine which is a crystalline variant I.

Accordingly, the present invention provides a composition comprising mesalamine in the form of crystalline variant I as defined above.

Further, the present invention provides a method of preparing a composition for controlling an undesired plant such as a weed using the crystal modification I of mesalil.

The invention also provides a method for controlling unwanted plant growth, the method comprising applying a herbicidally effective amount to any of the first to seventh and ninth aspects of the invention according to the plant, plant part or plant environment A crystalline variant I of mesalil, or a composition according to the tenth aspect of the invention. Thus, this provides a method for controlling unwanted plants in plants, plant parts, and/or their surroundings, comprising applying a herbicidally effective amount of methane to the leaves or fruits of the plants, the plant parts, or the surrounding environment of the plants. Crystalline variant I of grass amine.

In a specific example of the tenth aspect of the present invention, the composition is in the form of an aqueous suspension (SC), a water-dispersible oil suspension (OD), a water-soluble granule (SG), and a moisture. A bulk emulsion (DC), an emulsion (EC), an emulsified seed dressing, a suspension seed dressing, a granule (GR), a microgranule (MG), a concentrated emulsion (SE) or a water-dispersible granule (WG). Crystalline variant I of mesalil can be included in such conventional formulations in a manner known per se, using suitable auxiliaries, carriers and solvents, etc., in a manner known per se.

In a specific embodiment of the tenth aspect of the invention, the composition is in the form of an aqueous suspension (SC).

In a specific example of the tenth aspect of the invention, the composition is in the form of a water-dispersible granule (WG).

In a particular embodiment of the tenth aspect of the invention, the crystalline variant I of mesalil can be present in a concentration sufficient to achieve the dosage required when applied to the plant or its location, desirably in the weight of the total mixture A concentration of from about 1% to about 75% is present. The formulation is prepared, for example, by incorporating water, a solvent and a carrier in the crystalline variant I of mesalamine, if appropriate with emulsifiers and/or dispersants and/or other auxiliaries.

By the crystalline variant I of mesalil and at least one herbicidally acceptable auxiliary, such as a surfactant, a liquid diluent, a solid diluent, a wetting agent, a dispersing agent, a thickening agent, an antifoaming agent The formulations are prepared by mixing antifreeze, preservatives, antioxidants, solid binders, inert fillers, and other formulation ingredients.

The surfactant may be an ionic or nonionic emulsifier, dispersant or wetting agent. Examples which may be used include, but are not limited to, salts of polyacrylic acid, salts of ligninsulfonic acid, salts of benzenesulfonic acid or naphthalenesulfonic acid, polycondensates of fatty alcohols or ethylene oxides having fatty acids or having fatty amines, and substitutions Phenols (especially alkylphenols), sulfosuccinates, taurine derivatives (especially alkyl taurine), or polyethoxylated phenols or phosphates of alcohols.

Liquid diluents include, but are not limited to, water, N,N-dimethyl decylamine, dimethyl hydrazine, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, propylene carbonate, dibasic esters, paraffin , Alkylbenzene, alkylnaphthalene, 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), and alcohols (such as methanol, Cyclohexanol, decyl alcohol, benzyl and tetrahydrofurfuryl alcohol), and mixtures thereof.

The solid diluent can be water soluble or water insoluble. Water-soluble solid diluents include, but are not limited to, salts such as alkali metal phosphates (eg, sodium dihydrogen phosphate), alkaline earth metal phosphates, sodium, potassium, magnesium, and zinc sulfates, sodium chloride and potassium chloride, acetic acid. Sodium, sodium carbonate and sodium benzoate, as well as sugars and sugar derivatives such as sorbitol, lactose, sucrose and mannitol. Examples of water insoluble solid diluents include, but are not limited to, clay, synthetic and diatomaceous earth, calcium silicate and magnesium ruthenate, 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, phosphates, acetylenic diols, ethoxylated fluorinated alcohols, ethoxylated fluorenone, alkyl groups a phenol ethoxylate, a besylate, an alkyl-substituted besylate, an alkyl alpha-olefin sulfonate, a naphthalenesulfonate, an alkyl-substituted naphthalenesulfonate, a naphthalenesulfonate, and a condensate of an alkyl substituted naphthalene sulfonate with formaldehyde, and an alcohol ethoxylate, and mixtures thereof. The sodium alkylnaphthalenesulfonate salt is especially useful in the compositions of the present invention.

Dispersing agents 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 acid And naphthalene sulfonate-formaldehyde condensate. Lignosulfonates such as sodium lignosulfonate are particularly useful in the compositions of the present invention. Naphthalenesulfonate-formaldehyde condensates such as naphthalenesulfonic acid, polymers and sodium salts of formaldehyde are particularly useful in the compositions of the present invention.

Thickeners include, but are not limited to, guar gum, pectin, casein, carrageenan, xanthan gum, alginate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and carboxymethyl Base fiber Vitamins and their mixtures. Synthetic thickeners include derivatives of the foregoing classes, as well as polyvinyl alcohol, polyacrylamide, polyvinylpyrrolidone, various polyethers, copolymers thereof, together with polyacrylic acid and salts thereof, and mixtures thereof. Alkyl polyvinylpyrrolidone is particularly useful in the compositions of the present invention.

Defoamers include all materials that can normally be used for this purpose in agrochemical compositions. Suitable antifoams are known in the art and are commercially available. A particularly preferred antifoaming agent is a mixture of polydimethyl siloxane and perfluoroalkyl phosphate, such as an fluorenone defoamer available from GE or Compton.

Preservatives include all materials that can normally be used for this purpose in this type of agrochemical composition, and are also well known in the art. Suitable examples that may be mentioned include PREVENTOL® (from Bayer AG) and PROXEL® (from Bayer).

Antioxidants include all materials that can normally be used for this purpose in agrochemical compositions, as is known in the art. Preferred is butylated hydroxytoluene.

Solid adhesives include organic binders including tackifiers such as cellulose or substituted cellulose, natural and synthetic polymers in powder, granule, or lattice form, and inorganic binders such as Gypsum, vermiculite or cement.

Inert fillers include, but are not limited to, natural ground minerals such as kaolin, alumina, talc, chalk, quartz, attapulgite, montmorillonite, and diatomaceous earth; or synthetic ground minerals such as highly dispersed tannins, alumina , citrate, and calcium phosphate and calcium hydrogen phosphate. Suitable inert fillers for the particles include, for example, comminuted and classified natural minerals (such as calcite, marble, pumice, sepiolite, and dolomite), or synthetic particles of inorganic and organic abrasive materials, as well as particles of organic materials (eg, Sawdust, coconut shells, corn cobs, and tobacco stems).

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

In a particular embodiment of the tenth aspect of the invention, the crystalline variant I of mesalil can be present in the formulation and in other forms prepared from the formulations, and as other active compounds (eg, Attractants, disinfectants, fungicides, acaricides, nematicides, fungicides, growth regulators, herbicides, safeners, fertilizers, chemical pheromones and other insecticides) or used to improve plant performance A mixture of reagents is present.

According to any aspect or embodiment of the invention, all plants, plant parts and their surroundings can be treated with the crystalline variant I of mesalil. As used herein, a plant is to be understood to mean all plants and plant populations, such as wild plants or crop plants (including naturally occurring crop plants) that are needed and not needed. A crop plant can be a plant that can be obtained by conventional breeding and optimization methods, by biotechnological and genetic engineering methods, or by a combination of such methods, including genetically modified plants and which may or may not be protected by the rights of the plant breeder. Plant cultivars. Plant parts are understood to mean all parts and organs of plants above and below ground, such as branches, leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes. Also included are harvested materials, as well as nutritional and reproductive reproductive materials such as cuttings, tubers, meristems, rhizomes, stalks, seeds, single and multiple plant cells, and any other plant tissue.

Treatment of plants, plant parts, and/or their surroundings with such compositions or formulations of the invention may be carried out directly or by conventional processing methods to permit such compositions or formulations The object acts on its surroundings, habitat or storage space. Examples of such conventional processing methods include dipping, spraying, vaporizing, atomizing, spreading, smearing (in the case of propagation materials) and applying one or more coatings (especially in the case of seeds).

The benefits of the present invention are most pronounced when the herbicidal composition is used to kill weeds in the growing crops of the following useful plants: legumes (eg, soybeans), oilseed plants (eg, sunflower), maize (corn) (including field corn, pop corn and sweet corn), cotton, grain, barley, wheat, rice, oats, potatoes, beets, plantation crops (such as bananas, fruit trees, rubber trees, saplings), vines, citrus , olives, landscaping amenity, vegetables (such as spinach, lettuce, asparagus, cabbage, carrots, onions, tomatoes, potatoes, peppers, garlic and leeks), shrubs (such as blueberries), raspberries, cranberries, Linen, sorghum, okra, mint, rhubarb, peanut green mint, turfgrass, vines and sugar cane. In the present invention, the treatment of soybean, sunflower, peanut and sugar cane is particularly beneficial.

The words "comprise" and variations of the phrase (eg, "comprising and comprises") mean "including but not limited to" throughout the description and claims of the specification. Other parts, additives, components, integers or steps. In addition, the singular encompasses the singular and the singular, and the singular and singular.

Preferred features of each aspect of the invention may be as described in connection with any other aspect. Other features of the present invention will become apparent from the following examples. In general, the invention extends to any novel feature or novel combination of features disclosed in the specification, including any accompanying claims and drawings. Thus, features, integers, properties, compounds, chemical moieties or groups described in the specific aspects of the invention, specific examples or examples of the invention are to be understood as being applicable to any of the other described herein, unless incompatible with each other. Aspect A body instance or instance. In addition, any features disclosed herein may be replaced by alternative features for the same or similar purpose, unless stated otherwise.

When the upper and lower limits are referred to for the nature, a series of values defined by any combination of the upper and the lower limits may also be implied.

In this specification, unless otherwise stated, performance refers to properties measured under ambient conditions, i.e., at atmospheric pressure and at a temperature of about 20 °C.

As used herein, the term "about or around" when used in connection with a numerical quantity or range, means slightly more or less than the numerical quantity or range, and, for example, deviates from the numerical quantity or the range. ±10% of the endpoint.

As used herein, "ambient environment" refers to the place where the plants are grown, where the plant propagation material of the plant is to be sown, or where the plant propagation material of the plant will be sown.

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

The term "herbicidally effective amount" as used herein refers to an amount of such a compound or a composition of such a compound capable of producing a plant growth controlling effect. Control effects include all deviations from the natural development of the target plant, such as killing, retardation of one or more aspects of plant development and growth, leaf burns, albinism, dwarf disease, and the like.

All percentages are given in weight % unless otherwise stated.

The various features and aspects of the specific embodiments of the invention disclosed herein may be more clearly understood by reference to the accompanying drawings. Figure 1 is an infrared (IR) spectrum of the crystalline variant I of mesalil; Figure 2 is an X-ray powder diffraction pattern (X-RPD) of the crystalline variant I of mesalamine; A differential scanning calorimetry (DSC) thermogram of the crystal modification I of the amine; and FIG. 4 is a diffraction pattern of the X-ray powder of the amorphous mesalamine.

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

All X-ray diffraction patterns were determined using the following acquisition parameters in a reflection geometry at 25 ° C using a powder diffractometer:

For the crystallized sample, the IR spectrum was measured with a resolution of 4 cm-1 and a number of scans of 16. By its characteristics at one or more wave numbers (cm-1, ±0.2%) in about 3236, 1741, 1613, 1483, 1394, 1318, 1145, 1096, and 1056 cm ^-1 as shown in FIG. The functional group vibration peak is used to identify the crystalline variant I of the mesalil.

All IR spectra were obtained using the following acquisition parameters:

All DSC thermograms were obtained using the following acquisition parameters:

Instance

Example 1: Preparation of amorphous mesotrione (Example 13, Example 14, and Example 15) according to the disclosure of U.S. Patent No. 4,818,275:

1. 1-(5-Amino-2,4-dichlorophenyl)-3-methyl-4-difluoromethyl-Δ ² -1,2,4-triazoline-5 as an intermediate - Preparation of ether (Example 13)

Step A - Synthesis of pyruvic acid as an intermediate, 2,4-dichlorophenylhydrazine

To a stirred solution of 16.2 g (0.07 mol) of commercially available 2,4-dichlorophenylhydrazine hydrochloride in 100 ml of ethanol, 9.2 g (0.11 mol) of pyruvic acid in 100 ml of water was added in one portion. The reaction mixture was stirred for 10 minutes and the obtained solid was collected by filtration to yield 13.5 g of pyruvic acid, 2, 4-dichlorophenylhydrazine, m.p. 193 ° C - 194 ° C. This reaction was repeated several times.

Step B - Synthesis of 1-(2,4-dichlorophenyl)-3-methyl-Δ ² -1,2,4-triazolin-5-one as an intermediate

To a stirred suspension of 13.6 g (0.054 mol) of pyruvic acid, 2,4-dichlorophenylhydrazine in 100 ml of toluene was added 5.5 g (0.054 mol) of triethylamine. The reaction mixture became homogeneous and 14.9 g (0.054 mol) of triphenylphosphonium azide was added. After the addition was completed, the reaction mixture was heated to reflux, which was stirred for 2 hr. The reaction mixture was cooled to ambient temperature and extracted with 300 mL of 1N aqueous sodium hydroxide. The extract was neutralized with concentrated hydrochloric acid and a solid precipitate was collected by filtration. The solid was washed with water and dried. The yield of 1-(2,4-dichlorophenyl)-3-methyl-Δ ² -1,2,4-triazolin-5-one was 13.0 g; mp 174 ° C - 175 ° C. This reaction was repeated several times.

Step C- Synthesis of 1-(2,4-dichlorophenyl)-3-methyl-4-difluoromethyl-Δ ² -1,2,4-triazolin-5-one as intermediate

16.0 g (0.065 mol) of 1-(2,4-dichlorophenyl)-3-methyl-Δ ² -1,2,4-triazolin-5-one, 7.3 g (0.13 mol) A stirred solution of potassium hydroxide, and 10.5 g (0.03 mol) of tetrabutylammonium bromide in 150 ml of tetrahydrofuran was cooled in an ice bath, and chlorodifluoromethane was bubbled into the reaction mixture. The ice bath was removed and chlorodifluoromethane was continuously bubbled into the reaction mixture until coagulation was observed on the dry ice condenser connected to the reaction vessel. After the addition was complete, the reaction mixture was stirred at ambient temperature for 16 hours. An additional 6.7 g (0.12 mol) of powdered potassium hydroxide was added to the reaction mixture and again saturated with chlorodifluoromethane. The reaction mixture was stirred for two hours and then diluted with water. The mixture was extracted with diethyl ether and the combined extracts were washed with water. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. This residue was dissolved in dichloromethane and passed through a pad of silica gel. The eluate was concentrated under reduced pressure to give a solid residue. The solid was precipitated from dichloromethane-heptane. The yield of 1-(2,4-dichlorophenyl)-3-methyl-4-difluoromethyl-Δ ² -1,2,4-triazolin-5-one is 4.1 g; mp 108 ° C- 110 ° C. This reaction was repeated several times.

Step D - 1-(2,4-Dichloro-5-nitrophenyl)-3-methyl-4-difluoromethyl-Δ ² -1,2,4-triazoline as an intermediate Synthesis of 5-ketone

To 4.0 g (0.013 mol) of 1-(2,4-dichlorophenyl)-3-methyl-4-difluoromethyl-Δ ² -1,2,4-triazolin-5-one 1.2 ml (0.015 mol) of 70% nitric acid was slowly added to the stirred solution in 20 ml of concentrated sulfuric acid while maintaining the temperature of the reaction mixture at 25 °C. After the addition was completed, the reaction mixture was stirred at 25 ° C for 30 minutes and then poured into ice water. The resulting solid was collected by filtration. The solid was dissolved in dichloromethane and passed through a pad of silicone. The eluate was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 - petroleum ether: dichloromethane. The appropriate fractions were combined and concentrated under reduced pressure. The yield of 1-(2,4-dichloro-5-nitrophenyl)-3-methyl-4-difluoromethyl-Δ ² -1,2,4-triazolin-5-one is 3.0 g; mp 95 ° C - 97 ° C. This reaction was repeated several times.

Step E - 1-(5-Amino-2,4-dichlorophenyl)-3-methyl-4-difluoromethyl-Δ ² -1,2,4-triazoline as an intermediate Synthesis of 5-ketone

To maintain a temperature of the reaction mixture below 35 ° C to 2.5 g (0.007 mol) of 1-(2,4-dichloro-5-nitrophenyl)-3-methyl-4-difluoromethyl- Δ ² -1,2,4-Triazolin-5-one In a stirred solution of 6 ml of acetic acid and 60 ml of water, 2.5 g (0.045 mol) of powdery iron was added in portions. After the addition was completed, the reaction mixture was stirred at 25 ° C to 30 ° C for two hours. The reaction mixture was diluted with diethyl ether with stirring and then filtered over Celite. The stirred filtrate was made alkaline with 10% aqueous sodium bicarbonate solution and solid potassium carbonate. The organic layer was separated, washed with three portions of water and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give residue. The residue was purified by column chromatography on silica gel using dichloromethane:EtOAc. The appropriate fractions were combined and concentrated under reduced pressure. The yield of 1-(5-amino-2,4-dichlorophenyl)-3-methyl-4-difluoromethyl-Δ ² -1,2,4-triazolin-5-one is 2.0 g; mp 133 ° C - 135 ° C. This reaction was repeated several times.

2. 1-[2,4-Dichloro-5-[bis(N-methylsulfonyl)amino]phenyl]-3-methyl-4-difluoromethyl Preparation of -Δ2-1,2,4-triazolin-5-one (Example 14)

Stir 1.2 g (0.004 mol) of 1-(5-amino-2,4-dichlorophenyl)-3-methyl-4-difluoromethyl-1,2,4-triazoline-5- A solution of the ketone, and 0.95 g (0.009 mol) of triethylamine in 15 mL of dichloromethane was cooled in an ice/acetone bath. 0.97 g (0.009 mol) of methotrexate chloride was added dropwise at a rate to keep the temperature of the reaction mixture below 0 °C. It takes five minutes to fully add. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature, which was stirred for 16 h. After this time, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel using 50: 1-dichloromethane: acetone as eluent. The appropriate fractions were combined and concentrated under reduced pressure to give a solid. The solid was precipitated from acetone/heptane. 1-[2,4-Dichloro-5-[bis(N-methylsulfonyl)amino]phenyl]-3-methyl-4-difluoromethyl-1,2,4-triazole The yield of porphyrin-5-one was 1.3 g; mp 213 ° C - 214 ° C.

3. Preparation of mesotrione (Example 15)

Stirring 0.8 g (0.002 mol) of 1-[2,4-dichloro-5-[bis(N-methylsulfonyl)amino]phenyl]-3-methyl-4-difluoromethyl- A solution of 1,2,4-triazolin-5-one in 10 ml of ethanol and 0.14 g (0.003 mol) of sodium hydroxide in 0.3 ml of water. After the addition was completed, the reaction mixture was stirred for 15 minutes and then poured into 100 ml of water. The mixture was neutralized with concentrated hydrochloric acid and a solid precipitate was collected by filtration. N-[2,4-Dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole The yield of -1-yl]phenyl]methanesulfonamide (messulfamide) was 0.5 g; mp 75 ° C - 78 ° C.

Preparation of crystalline variant I of mesalil

Example 2 - Crystallization of self-xylene

A sample of amorphous mesalamine (10 g) prepared as in Example 1 was placed in a three-necked round bottom flask together with xylene (60 ml). The resulting slurry was heated to 90 ° C to give a homogeneous solution. The homogeneous solution was stirred at 90 °C for 2 h and the insoluble particles (if any) were filtered and the solution was slowly cooled to 20 °C - 25 °C. After cooling, fine crystals were formed, and the resulting heterogeneous mixture was stirred at 20 ° C for 2 hours. Then, the slurry was filtered and washed with xylene (3 ml) at 20 °C. The filtered crystals were dried under vacuum at 60 °C. The resulting crystalline product had a purity of about 98% and the yield of the recovered crystalline product was found to be about 85%.

The crystals obtained by IR spectroscopy, X-RPD and DSC analysis were found to be crystalline variants I of mesalamine as shown in Figures 1, 2 and 3, respectively.

The IR spectrum of mefenacetamide exhibits functional group characteristics at one or more wave numbers in about 3235.67, 1740.65, 1613.45, 1482.73, 1393.54, 1318.30, 1145.46, 1095.85, and 1056.05 cm ^-1 as shown in FIG. Vibration peak.

The DSC thermogram of mesotrile exhibits an endothermic melting peak starting at 125.2 ° C and a maximum peak of 128.3 ° C, and further has a melting enthalpy of 73.42 J/g as shown in FIG. 3 .

The X-ray powder diffraction pattern of the crystals exhibited the reflections in Figure 2 and the values are summarized in Table 1.

Table 1. X-ray powder diffraction pattern reflection of crystalline variant I of mesalil

Example 3 - Crystallization from diethyl ketone

A sample of mesalamine (5 g) prepared as in Example 1 was placed in a three-necked round bottom flask together with diethyl ketone (35 ml). The resulting slurry was heated to 80 ° C to give a homogeneous solution. The resulting hot solution was stirred at 80 ° C for 2 h and the insoluble particles (if any) were filtered and the solution was slowly cooled to 20 °C. After cooling, fine crystals are formed and the resulting heterogeneous mixture is obtained Stir at 20 ° C for 2 hours. Then, the slurry was filtered, washed with diethyl ketone (3 ml) at 20 ° C, and dried at 50 ° C under vacuum. The resulting crystalline product had a purity of about 98% and was found to have a recovery yield of about 85%.

These crystals were characterized as mesalil crystal modification I using IR spectroscopy, X-ray powder diffraction and DSC as described in Example 2.

Example 4 - Preparation of an aqueous suspension of amorphous mesalil (SC)

All the components listed in the following Table 2 were uniformly mixed, and the resulting mixture was ground with Dyno-Mill (manufactured by Willy A. Bachofen AG) to obtain an aqueous suspension.

Example 5 - Preparation of an aqueous suspension (SC) of crystalline variant I of mesalil

All the components listed in Table 3 below were uniformly mixed, and the resulting mixture was ground with Dyno-Mill (manufactured by Willy A. Bachofen AG). Obtain an aqueous suspension.

Example 6 - Preparation of a water-dispersible granule (WG) of amorphous mesalil

All of the components listed in Table 4 below were mixed, blended and ground in a high speed rotary mill. Sufficient water is added to obtain an extrudable paste. The paste is extruded through a die or screen to form an extrudate. The wet extrudate was dried in a vacuum oven at 70 ° C and then screened through a 0.71 mm - 2 mm screen to obtain product granules.

Example 7 - Preparation of water-dispersible granules (WG) of crystalline variant I of mesalil

All of the components listed in Table 5 below were mixed, blended and ground in a high speed rotary mill. Sufficient water is added to obtain an extrudable paste. The paste is extruded through a die or screen to form an extrudate. The wet extrudate was dried in a vacuum oven at 70 ° C and then screened through a 0.71 mm - 2 mm screen to obtain product granules.

Example 8 - Photolysis Stability Test

The test was carried out by dispersing a sample of mesalamine prepared in Examples 4 to 7 in water to give a concentration of 25% by weight of mesalamine. 20 mL of the obtained methanesulfuric acid suspension of each sample was added to a quartz tube. The tube was continuously illuminated with UV light from a UV lamp at room temperature. An aliquot of each suspension was taken from the tube for analysis at 20 minute intervals. The concentration of mesalamine in each aliquot was determined by high pressure liquid chromatography (HPLC) with reverse phase chromatography and UV detection. This test was repeated 5 times to ensure accuracy.

The results are summarized in Table 6 below.

It was surprisingly found that the crystalline variant I of the crystalline mesochloramide obtained in Examples 5 and 7 exhibited very high photolysis stability compared to the amorphous mesochloramide products of Examples 4 and 6. That is, after 60 minutes under these severe test conditions, Examples 5 and 7 (containing the crystallite I of the mefenacetamide) showed little decomposition. In contrast, the concentration of mesochloramide (containing the amorphous mesalil) in Examples 4 and 6 has been halved.

Claims (23)

N-[2,4-Dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-sideoxy-1H-1,2,4-tri Crystalline variant I of oxazol-1-yl]phenyl]methanesulfonamide (sulfentrazone), which is X-ray powder diffraction recorded at 25 ° C using Cu-Kα radiation In the figure (X-RPD), at least 3 of the following reflections are presented in any combination, which is recorded as 2θ±0.2 degrees: 2θ=6.3±0.2 (1) 2θ=6.8±0.2 (2) 2θ=12.1±0.2 (3) 2θ=17.0±0.2 (4) 2θ=17.6±0.2 (5) 2θ=18.5±0.2 (6) 2θ=19.1±0.2 (7) 2θ=19.9±0.2 (8) 2θ=21.6±0.2 (9) 2θ= 22.6±0.2 (10) 2θ=24.3±0.2 (11) 2θ=24.6±0.2 (12) 2θ=28.5±0.2 (13) 2θ=29.0±0.2 (14) 2θ=32.2±0.2 (15) 2θ=34.4± 0.2 (16). Crystalline variant I of mesalil as described in claim 1 which exhibits at least 3 of the following reflections in any combination in an X-ray powder diffraction pattern recorded with Cu-Kα radiation at 25 ° C. One: 2θ=6.3±0.2 (1) 2θ=6.8±0.2 (2) 2θ=12.1±0.2 (3) 2θ=17.0±0.2 (4) 2θ=18.5±0.2 (6) 2θ=19.1±0.2 (7) 2θ= 21.6 ± 0.2 (9) 2θ = 24.6 ± 0.2 (12) 2θ = 29.0 ± 0.2 (14). Depending on the case, the crystalline variant I of mesalil described in claim 1 or 2, which is present in about 3236, 1741, 1613, 1483, 1394, 1318, 1145, 1096 and 1056 cm ^-1 An IR spectrum having a characteristic functional group vibrational peak at one or more wave numbers (cm ^-1 , ± 0.2%). The crystalline variant I of mesalil, as described in any one of claims 1 to 3, which exhibits a melting point of 126 ° C to 130 ° C, optionally 127 ° C to 129 ° C, further optionally It is 128 °C. Crystalline variant I of mesalil, as described in any one of claims 1 to 4, which exhibits an endothermic melting calorimetry starting at 125 ° C and having a peak maximum at 128 ° C. The method (DSC) profile, further optionally having a melting enthalpy of 73 J/g. A crystalline variant I of mesalil, as described in any one of claims 1 to 5, characterized by an X-ray powder diffraction pattern substantially as shown in Figure 2, and/or It is characterized by an IR spectrum substantially as shown in Figure 1, and/or characterized by a DSC thermogram substantially as shown in Figure 3. A crystalline variant of mesulfamem as described in any one of claims 1 to 6 of the patent application. I, which can be obtained by a method substantially as described in Example 2 or 3. The crystalline variant I of mesalil according to any one of claims 1 to 7 which can be obtained by the method according to any one of claims 9 to 14 . A method of preparing crystalline variant I of mesalil according to any one of claims 1 to 5, which comprises: i) dissolving mesalil in a solvent or a mixture of solvents; Ii) precipitating the dissolved compound as crystalline variant I of mesalil; and iii) isolating the precipitated crystalline variant I. The method of claim 9, wherein the mesalamide in the step i) is amorphous mesalil. The method of claim 9 or 10, wherein the solvent is selected from the group consisting of xylene, benzene, chlorobenzene, dichlorobenzene, ethylbenzene, trifluoromethylbenzene, and mesitylene. , nitrobenzene, ether, diethyl ketone, methyl ethyl ketone, methanol, ethanol, isopropanol, acetonitrile or a mixture of the following: THF-hexane, ethyl acetate-hexane, dichloromethane-hexane , dichloromethane-methanol, THF-water and methanol-water, and mixtures thereof. The method of any one of claims 9 to 11, wherein the solvent comprises diethyl ketone, xylene or a mixture thereof. The method of any one of clauses 9 to 12, wherein the step ii) comprises concentrating the solution and/or cooling and/or adding a solubility-reducing solvent and/or adding the mesalil crystal Seed crystal of body I. The method of claim 13, wherein step ii) is cooled to about 0 ° C to 20 ° C. A crystalline material comprising crystalline variant I of mesalil obtained according to the process of any one of the claims and comprising at least 98% by weight of crystallite I of mesalil the amount. A composition comprising crystalline variant I of mesalil and at least one adjuvant as described in claims 1 to 8 and 15. The composition of claim 16, wherein the auxiliary agent is selected from the group consisting of surfactants, diluents, wetting agents, dispersing agents, thickeners, antifoaming agents, antifreeze agents , preservatives, antioxidants, solid binders, inert fillers, and mixtures thereof. The composition of claim 17, wherein the other formulation ingredients are dyes and desiccants. The composition according to any one of claims 16 to 18, which is in the form of an aqueous suspension (SC), a water-dispersible oil suspension (OD), a water-soluble granule (SG). , water-dispersible emulsion (DC), emulsion (EC), emulsified seed dressing, suspension seed dressing, granule (GR), microgranule (MG), concentrated emulsion (SE) or water-dispersible granule (WG ). The composition of claim 19, which is in the form of an aqueous suspension (SC) or a water-dispersible granule (WG). A method for controlling the growth of unwanted plants, comprising applying a herbicidally effective amount to the plant, plant part, or the surrounding environment of the plant, as described in any one of claims 1 to 8 and 15. The crystallized variant I of mesalamine, or the composition of any one of claims 16 to 20. A crystal modification I of mesalamine according to any one of claims 1 to 8 and 15 or a composition according to any one of claims 16 to 20 The use of weed control. Crystallization variant I of mesalil as described in any one of claims 1 to 8 which is substantially as described above with reference to any of the examples, the drawings or the specification.