Crystal form of indaziflam, and preparation method and application thereof

Abstract

The invention relates to a crystalline form of indaziflam, a preparation method thereof, an agrochemical composition containing the crystalline form of indaziflam and a method for preparing the agrochemical composition.

Description

Technical Field

[0001] The present invention belongs to the field of agricultural chemistry and relates to a novel crystal form of N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-1-yl]-6-(1-fluoroethyl)-1,3,5-triazine-2,4-diamine (indazine fluazifop). Background Art

[0002] Triazine compounds are a class of compounds suitable for use as herbicides. Triazine compounds such as atrazine, ametryn, indazine fluazifop or triazine fluazifop belong to compounds used as herbicides.

[0003] The prior art discloses different methods for preparing indoxazolidinone in EP 1592674 A1, EP 2231679 A1 or EP 3347342 A1. However, these methods do not disclose the crystalline form of indoxazolidinone.

[0004] Therefore, there is a need to provide a novel crystalline form of indoxazine fluazifop with improved properties. It would be advantageous if the crystalline form of indoxazine fluazifop could provide improved flowability. Flowability is a characteristic of significant importance in achieving good manufacturing efficiency and product quality in the solids processing industry to avoid undercapacity and production interruptions. Summary of the invention

[0005] A first aspect of the present invention is a crystalline form of indoxazolidinone having a compression index less than or equal to 17.

[0006] A second aspect of the present invention is a method for preparing a crystalline form of indoxazolidinone having a compression index less than or equal to 17, wherein indoxazolidinone is recrystallized in a solvent selected from the group consisting of: alcohols, alcohols mixed with water, amides, lactams, esters of carboxylic acids, optionally halogenated aliphatic or aromatic solvents.

[0007] A third aspect of the present invention is an agricultural chemical composition comprising a crystalline form of indoxazolidinone having a compression index of 17 or less.

[0008] The fourth aspect of the present invention is a method for preparing an agrochemical composition comprising indoxazolidinone, wherein the method includes the steps of crushing a powder or slurry of a crystalline form of indoxazolidinone having a compression index less than or equal to 17, and mixing the crushed powder or slurry with one or more agriculturally acceptable inert additives or adjuvants of the agrochemical composition. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1is the X-ray powder diffraction pattern (XRD) of the crystalline form of indoxazolidinone of the present invention from the sample obtained from Example 1 and recorded at 25°C using Cu-Ka radiation.

[0010] Figure 2 is an infrared (IR) spectrum of the crystalline form of indoxazolidinone of the present invention from a sample obtained from Example 2. DETAILED DESCRIPTION

[0011] definition

[0012] Embodiments of the present invention are discussed in detail below. When describing the embodiments, specific terms are used for clarity. However, the present invention is not intended to limit the specific terms so selected. Although specific exemplary embodiments have been discussed, it should be understood that this is only for illustrative purposes. Those skilled in the relevant art will recognize that other components and configurations can be used without departing from the spirit and scope of the present invention. Although multiple embodiments and features are described herein, it should be understood that, unless mutually exclusive or contrary to the specific description, the aspects of the various features and embodiments of the present invention, even if described separately, can also be combined. All references cited herein are incorporated by reference as if each reference was incorporated separately.

[0013] As used herein, the transitional term "comprising" or "that comprises," which is synonymous with "including" or "containing," is inclusive or open-ended, and does not exclude additional, unrecited elements or method steps. However, each time "comprising" is recited herein, as an alternative embodiment, the term is also intended to encompass the phrases "consisting essentially of" and "consisting of," wherein "consisting of" excludes any elements or steps not specified, and "consisting essentially of" permits the inclusion of additional, unrecited elements or steps that do not materially affect the essential or basic and novel characteristics of the composition or method under consideration.

[0014] For the purpose of full disclosure, "compression index" in this invention means the compression index according to the United States Pharmacopeia method as revised on January 20, 2023 <1174> Compressibility index for powder flow measurements.

[0015] Before describing the present subject matter in detail, it may be helpful to provide definitions of certain terms used herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter belongs.

[0016] As used herein, the term "water-immiscible solvent" refers to a solvent that is immiscible or nearly immiscible with water, and in particular, the term "water-immiscible solvent" is used in the present invention to encompass any solvent having a water solubility of less than 1 g / l measured at 25° C. The term "water-miscible solvent" has the opposite meaning to "water-immiscible solvent".

[0017] As used herein, the term "aprotic solvent" refers to a solvent that lacks acidic protons.

[0018] As used herein, the term "polar aprotic solvent" refers to a polar solvent lacking acidic protons. Polar solvent is a synonym for a water-miscible solvent. In particular, the term "polar aprotic solvent" is used in the present invention to encompass any water-miscible solvent lacking acidic protons and having a dielectric constant of 12 or more measured at 25°C.

[0019] Unless otherwise specifically stated, the terms "a / an" as used herein include the singular and the plural. Therefore, the terms "a / an" or "at least one" can be used interchangeably in this application.

[0020] For the purpose of better understanding the content of this teaching and in no way limiting the scope of these teaching contents, unless otherwise specified, all numerical values ​​of expression amount, percentage or ratio and other numerical values ​​used in the specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise specified, the numerical parameters listed in the following specification and the appended claims are approximate values, which can change according to the desired characteristics sought to be obtained. At least, each numerical parameter should at least be interpreted according to the number of reported significant figures and by applying ordinary rounding techniques. In this regard, the term "about" used herein specifically includes ± 10% of the indicated value within the range. In addition, the endpoints of all ranges of the same component or characteristic herein include endpoints, are independently combinable, and include all intermediate points and ranges. Similarly, the scope and amount of each element of the technology described herein can be used together with the scope or amount of any other element.

[0021] Crystalline form of indoxazine fluazifop

[0022] The present invention relates to a crystalline form of indoxazolidinone, which has a compression index lower than or equal to 17.

[0023] This crystalline form of indoxazolidinone provides higher flowability than indoxazolidinone obtained by prior art processes. Flowability is a characteristic of significant importance in achieving good manufacturing efficiency and product quality in the solids processing industry to avoid capacity shortfalls and production interruptions.

[0024] The crystalline form of indoxazolidinone may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees.

[0025] The crystalline form of indoxazolidinone may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and may also have additional peaks at diffraction angles 2θ±0.2 degrees of 13.0, 16.1, 21.5, 24.6 degrees.

[0026] The crystalline form of indoxazolidinone can show a wave number (±2cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 Infrared (IR) spectrum with characteristic functional peaks at .

[0027] The crystalline form of indoxazolidinone can show a wave number (±2cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 The infrared (IR) spectrum has a characteristic functional peak at wave number (±2cm -1 ) are 637, 709, 874, 895, 996, 1124, 1306, 1372, 1393, 1638, 2948, 3222, 3319, 3432cm -1 Additional functional peaks at .

[0028] The crystalline form of indoxazolidinone may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25° C. using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and may exhibit a peak at wavenumbers (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1The crystalline form of indoxazolidinone may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation with peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and may also have additional peaks at diffraction angles 2θ±0.2 degrees of 13.0, 16.1, 21.5, 24.6 degrees, and may exhibit peaks at wave numbers (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 The infrared (IR) spectrum has a characteristic functional peak at wave number (±2cm -1 ) are 637, 709, 874, 895, 996, 1124, 1306, 1372, 1393, 1638, 2948, 3222, 3319, 3432cm -1 Additional functional peaks at .

[0029] The crystalline form of indoxazolidinone may exhibit a melting point of 181.4°C to 183.4°C.

[0030] The crystalline form of indoxazolidinone may exhibit a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C.

[0031] The crystalline form of indoxazolidinone may exhibit a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C, and it may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees.

[0032] The crystalline form of indoxazolidinone may exhibit a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C, and may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and the diffraction pattern may also have additional peaks at diffraction angles 2θ±0.2 degrees of 13.0, 16.1, 21.5, 24.6 degrees.

[0033] The crystalline form of indoxazolidinone may exhibit a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C, it may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and it may exhibit a peak at wave numbers (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 Infrared (IR) spectrum with characteristic functional peaks at .

[0034] The crystalline form of indoxazolidinone may exhibit a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C, which may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, the diffraction pattern may also have additional peaks at diffraction angles 2θ±0.2 degrees of 13.0, 16.1, 21.5, 24.6 degrees, the crystalline form may exhibit a peak at wave number (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 The infrared (IR) spectrum has a characteristic functional peak at wave number (±2cm -1 ) are 637, 709, 874, 895, 996, 1124, 1306, 1372, 1393, 1638, 2948, 3222, 3319, 3432cm -1 Additional functional peaks at .

[0035] The crystalline form of indoxazolidinone may exhibit a plate-like morphology.

[0036] Method for preparing crystalline form of indoxazine fluazifop

[0037] The present invention also relates to a process for preparing a crystalline form of indoxazolidinone having a compression index less than or equal to 17, wherein indoxazolidinone is recrystallized in a solvent selected from the group consisting of alcohols, alcohols mixed with water, amides, lactams, esters of carboxylic acids, optionally halogenated aliphatic or aromatic solvents.

[0038] As mentioned above, it has been found that the crystalline form of indifoxamidosulf having a compression index lower than or equal to 17 exhibits higher flowability than indifoxamidosulf obtained by the methods of the prior art.

[0039] Indoxazolidinone having a compression index of less than or equal to 17 can be prepared by any of the methods for preparing indoxazolidinone disclosed in the priority document of application No. EP 22182294.3 or EP 22217081.3.

[0040] Indoxazolidinone having a compressibility index less than or equal to 17 can be prepared according to a process comprising the following steps:

[0041] a1) a first step of preparing (1R,2S)-1-(biguanidino)-2,6-dimethylindane or an acid addition salt thereof by reacting 1-cyanoguanidine with (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine in a mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. and a solvent immiscible with water;

[0042] Or alternatively,

[0043] a2) a first step of preparing (1R,2S)-1-(biguanidino)-2,6-dimethylindane or an acid addition salt thereof by reacting 1-cyanoguanidine with (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine in a mixture comprising a trimethylsilyl-containing compound and an optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl-substituted γ-, δ-, ε-lactone;

[0044] b) a second step of adding a base and (R)-methyl 2-fluoropropionate to the (1R,2S)-1-(biguanidino)-2,6-dimethylindane or an addition salt thereof obtained in the first step a1) or a2), and

[0045] c) recrystallizing the indoxazolidinone obtained in step b) in a solvent selected from the group consisting of alcohols, alcohols mixed with water, amides, lactams, esters of carboxylic acids, optionally halogenated aliphatic or aromatic solvents.

[0046] Steps a1), a2) and b) of the process of the present invention are carried out under a protective gas atmosphere.

[0047] The amount of (R)-2-fluoropropionic acid methyl ester in step b) of the process of the present invention may be in the range of 1 to 5 moles, 1 to 3 moles, 1 to 2 moles based on the mole of (1R,2S)-1-(biguanidino)-2,6-dimethylindan.

[0048] The base in step b) of the process of the present invention may be selected from the group consisting of hydroxides, hydrides, alkoxides, carbonates, bicarbonates, phosphates, hydrogen phosphates or dihydrogen phosphates of alkali metals, alkaline earth metals or ammonium, or tertiary amines or aromatic amines or mixtures thereof. The base in step b) of the process of the present invention may be selected from the group consisting of hydroxides, alkoxides, carbonates, bicarbonates or mixtures thereof of alkali metals or alkaline earth metals. The base in step b) of the process of the present invention may be selected from the group consisting of hydroxides, methoxides, ethoxides, propoxides, butoxides, carbonates or mixtures thereof of alkali metals.

[0049] The amount of the base in step b) of the process of the present invention may be in the range of 1 to 5 moles, 1 to 4 moles, 1 to 3 moles based on the mole of (1R,2S)-1-(biguanidino)-2,6-dimethylindan.

[0050] The amount of the base in step b) of the process of the present invention may be in the range of 1 to 5 moles by mole of (1R,2S)-1-(biguanidino)-2,6-dimethylindane, and the base may be selected from the group consisting of hydroxides, hydrides, alkoxides, carbonates, bicarbonates, phosphates, hydrogenphosphates or dihydrogenphosphates of alkali metals, alkaline earth metals or ammonium, or tertiary or aromatic amines or mixtures thereof. The amount of the base in step b) of the process of the present invention may be in the range of 1 to 4 moles by mole of (1R,2S)-1-(biguanidino)-2,6-dimethylindane, and the base may be selected from the group consisting of hydroxides, alkoxides, carbonates, bicarbonates of alkali metals or alkaline earth metals, or mixtures thereof. The amount of the base in step b) of the process of the present invention may be in the range of 1 to 3 moles of (1R,2S)-1-(biguanidino)-2,6-dimethylindane by mole, and the base may be selected from the group consisting of: hydroxides, methoxides, ethoxides, propoxides, butoxides, carbonates or mixtures thereof of alkali metals.

[0051] The solvent for the reaction in step b) can be any organic solvent. The solvent for the reaction in step b) can be selected from the group consisting of: optionally halogen-substituted aromatic hydrocarbons, optionally halogen-substituted aliphatic hydrocarbons, nitrogen heterocyclic compounds, optionally alkyl-substituted cyclic ethers, aliphatic ethers, ethers of aromatic hydrocarbons, nitriles, ketones, esters, amides, alcohols or diols. The solvent for the reaction in step b) can be selected from the group consisting of: toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chloromethane, dichloromethane, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, pentane, hexane, heptane, cyclohexane, decalin, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, pyrrolidone ... The solvent for the reaction in step b) can be selected from the group consisting of toluene, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, dibutyl ether, tert-butyl methyl ether, anisole, acetonitrile, benzonitrile, acetone, butanone, ethyl acetate, n-butyl acetate, hexyl acetate, dimethylformamide or dimethylacetamide, ethanol, methanol, butanol, tert-butanol, propanol, isopropanol, isopentanol, phenol, ethylene glycol, propylene glycol, diethylene glycol or dimethoxyethane. The solvent for the reaction in step b) can be selected from the group consisting of toluene, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, acetonitrile, dimethylformamide, dimethylacetamide, ethanol, methanol or butanol. The solvent for the reaction in step b) can be ethanol or methanol.

[0052] The temperature of step b) of the process of the present invention may be from room temperature to the reflux temperature of the solvent in step b).

[0053] The acid addition salt of (1R,2S)-1-(biguanidino)-2,6-dimethylindane in step a1) or a2) can be, for example, a salt of an acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, carbonic acid, monofunctional or difunctional carboxylic acids and hydroxycarboxylic acids, such as acetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid or lactic acid, and also a sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid or 1,5-naphthalenedisulfonic acid.

[0054] The process for preparing indazine fluazifop can be carried out in a one-pot synthesis without isolating (1R,2S)-1-(biguanidino)-2,6-dimethylindane or its acid addition salt, or it can be carried out in 2 separate steps, wherein (1R,2S)-1-(biguanidino)-2,6-dimethylindane or its acid addition salt is isolated after step a1) or a2).

[0055] In one embodiment, (1R,2S)-1-(biguanidinyl)-2,6-dimethylindane or its acid addition salt can be isolated after step a1) or a2) by any conventional method known to those skilled in the art or by crystallization of (1R,2S)-1-(biguanidinyl)-2,6-dimethylindane or its acid addition salt, including but not limited to filtering, washing the reaction product with a solvent or solvent mixture to dissolve impurities of (1R,2S)-1-(biguanidinyl)-2,6-dimethylindane or its acid addition salt.

[0056] In another embodiment, (1R, 2S)-1-(biguanidino)-2,6-dimethylindane or its acid addition salt is not isolated, but the preparation of indazine fluazifop is carried out in a one-pot synthesis, and the solvent from step a1) or a2) is removed before the reaction of step b) of the process of the present invention. The solvent can be removed by any conventional method known to those skilled in the art, including but not limited to distillation, or distillation under vacuum.

[0057] The temperature of the reaction in step a1) of the process of the present invention may be in the range of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The temperature of the reaction in step a1) of the process of the present invention may be the reflux temperature of the solvent mixture. The mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 and a water-immiscible solvent in step a1) may have a boiling point of at least 105°C. The temperature of the reaction in step a1) of the process of the present invention may be the reflux temperature of a mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 and a water-immiscible solvent when measured at 25°C, the boiling point of the mixture being 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. This reaction of step a1) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0058] In the solvent mixture used for the reaction in step a1) of the process of the present invention, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the solvent immiscible with water may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. The ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the solvent immiscible with water may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture in step a1) may have a boiling point of at least 105°C. The ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture in step a1) may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, this solvent mixture in step a1) may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in step a1) of the process of the present invention may be the reflux temperature of the solvent mixture. This reaction of step a1) may be carried out at atmospheric pressure or at a pressure higher than atmospheric pressure.

[0059] The polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. can be added dropwise, or can be added all at once to the mixture of 1-cyanoguanidine with (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine and the water-immiscible solvent in step a1), or can be added dropwise together with 1-cyanoguanidine to the mixture of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine and the water-immiscible solvent in step a1) of the process of the present invention.

[0060] The polar aprotic solvent in step a1) having a dielectric constant higher than 12.0 when measured at 25°C may have a dielectric constant higher than 15.0, higher than 20.0, higher than 25.0.

[0061] In step a1) of the process of the present invention, the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. may be selected from the group consisting of: N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea. The polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25° C. in step a1) may be selected from the group consisting of: N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone. The polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25° C. in step a1) may be selected from the group consisting of: N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide. The polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25° C. in step a1) may be N-methylpyrrolidone.

[0062] In step a1) of the process of the present invention, the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea, and the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. In step a1) of the process of the present invention, the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C may be selected from the group consisting of: N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of at least 105°C. In step a1) of the process of the present invention, the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C may be N-methylpyrrolidone, the weight ratio between the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, this solvent mixture may have a boiling point of 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in step a1) of the process of the present invention may be the reflux temperature of the solvent mixture. This reaction of step a1) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0063] In step a1) of the method of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether. The water-immiscible solvent in step a1) may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil. The water-immiscible solvent in step a1) may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil. The water-immiscible solvent in step a1) may be chlorobenzene.

[0064] In step a1) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether, and the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethylurea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea. In step a1) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil, and the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone. In step a1) of the process of the present invention, the solvent immiscible with water may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil, and the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide. In step a1) of the process of the present invention, the solvent immiscible with water may be chlorobenzene, and the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C may be N-methylpyrrolidone.

[0065] In step a1) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether, and the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. In step a1) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of at least 105°C. In step a1) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, 125°C to 139°C. The water-immiscible solvent may be chlorobenzene, the weight ratio between the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, this solvent mixture may have a boiling point of 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in step a1) of the process of the present invention may be the reflux temperature of the solvent mixture. This reaction of step a1) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0066] In step a1) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, decalin, n-butyl acetate, hexyl acetate, white mineral oil, tetrachloroethylene or dibutyl ether, and the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. may be selected from the group consisting of N,N-dimethylformamide, dimethyl ethyl ether. amide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, nitromethane, nitrobenzene, γ-butyrolactone, cyclopentane, nitromethane, tetramethyl urea, propylene carbonate, hexamethylphosphoramide, butanone, methyl isobutyl ketone, acetone, pyridine or N,N-dimethylpropylene urea, and the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25°C and the water-immiscible solvent can be in the range of 1:1 to 1:5, or 1:1.5 to 1:3. In step a1) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, toluene, benzene, ethylbenzene, xylene, isopropylbenzene, n-butyl acetate, hexyl acetate, white mineral oil, the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, benzonitrile, butanone, methyl isobutyl ketone or acetone, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 15.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of at least 105°C. In step a1) of the process of the present invention, the water-immiscible solvent may be selected from the group consisting of o-chlorobenzene, dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, anisole, hexyl acetate or white mineral oil, the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C may be selected from the group consisting of N,N-dimethylformamide, N-methylpyrrolidone or dimethyl sulfoxide, the ratio by weight between the polar aprotic solvent having a dielectric constant higher than 20.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, and this solvent mixture may have a boiling point of 105°C to 150°C, 110°C to 148°C, 120°C to 139°C, or 125°C to 139°C.The water-immiscible solvent may be chlorobenzene, the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C may be N-methylpyrrolidone, the weight ratio between the polar aprotic solvent having a dielectric constant higher than 25.0 when measured at 25°C and the water-immiscible solvent may be in the range of 1:1 to 1:5, or 1:1.5 to 1:3, this solvent mixture may have a boiling point of 120°C to 139°C, 125°C to 139°C, and the temperature of the reaction in step a1) of the process of the present invention may be the reflux temperature of the solvent mixture. This reaction in step a1) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0067] The reaction temperature in step a2) of the present invention may be in the range of 60 to 100° C., 65 to 100° C., 70 to 100° C. The reaction in step a2) may be carried out at atmospheric pressure or above atmospheric pressure.

[0068] In step a2) of the process of the present invention, the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be added dropwise, or they may be added all at once to the mixture of 1-cyanoguanidine and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine. In step a2) of the process of the present invention, the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be added together or separately.

[0069] In step a2) of the process of the present invention, the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15. In step a2) of the process of the present invention, the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15, and the temperature of the reaction may be in the range of 60°C to 100°C. The reaction of step a2) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0070] In step a2) of the process of the present invention, the amount of the trimethylsilyl-containing compound may be at least 1 mole, at least 1.02 moles, at least 1.05 moles of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine by mole. In step a2) of the process of the present invention, the amount of the trimethylsilyl-containing compound may be at least 1 mole, at least 1.02 moles, at least 1.05 moles of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine by mole; and the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15. In step a2) of the process of the present invention, the amount of the trimethylsilyl-containing compound can be at least 1 mole, at least 1.02 moles, or at least 1.05 moles of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine on a molar basis; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the reaction temperature can be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C. In step a2) of the process of the present invention, the amount of the trimethylsilyl-containing compound may be at least 1.05 moles of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine by mole; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the molar ratio between the trimethylsilyl-containing compound and 1-cyanoguanidine may be in the range of 0.6:1 to 1:0.6; and the temperature of the reaction may be in the range of 60°C to 100°C. The reaction of step a2) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0071] In step a2) of the process of the present invention, the amount of optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be at least 1 mole, at least 1.5 moles, at least 2 moles on a molar basis of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine. In step a2) of the process of the present invention, the amount of optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be at least 1 mole, at least 1.5 moles, or at least 2 moles of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine on a molar basis; and the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15. In step a2) of the process of the present invention, the amount of optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be at least 1 mole, at least 1.5 moles, or at least 2 moles of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine on a molar basis; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C. In step a2) of the method of the present invention, the amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone can be at least 1 mol, at least 1.5 mol, at least 2 mol of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine by mole; The molar ratio between the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine can be in the range of 1:1 to 5:1, 1.5:1 to 3:1; and the reaction temperature can be in the range of 60°C to 100°C, 65°C to 100°C, 70°C to 100°C.In step a2) of the process of the present invention, the amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole, at least 1.5 moles, at least 2 moles of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine by mole; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or in the range of 1:20 to 1:30. The molar ratio of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone to 1-cyanoguanidine can be in the range of 1:1 to 5:1, 1.5:1 to 3:1; the molar ratio of the trimethylsilyl-containing compound to 1-cyanoguanidine can be in the range of 0.6:1 to 1:0.6, 0.8:1 to 1:0.8; and the reaction temperature can be in the range of 60°C to 100°C, 65°C to 100°C, 70°C to 100°C. In step a2) of the process of the present invention, the amount of the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be at least 1 mole of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine by mole; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; in the optional The molar ratio between the alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine can be in the range of 1:1 to 5:1; the molar ratio between the trimethylsilyl-containing compound and 1-cyanoguanidine can be in the range of 0.6:1 to 1:0.6; the amount of the trimethylsilyl-containing compound can be at least 1.05 moles of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine by mole; and the temperature of the reaction can be in the range of 60°C to 100°C. The reaction of step a2) can be carried out at atmospheric pressure or above atmospheric pressure.

[0072] In step a2) of the process of the present invention, the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl halides, trimethylsilyl haloalkyl sulfonates, trimethylsilyl halosulfonates, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilanes, trimethylsilylalkynes, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamides, or secondary or tertiary (trimethylsilyl)amines. In step a2) of the process of the present invention, the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilylacetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine. In step a2) of the method of the present invention, the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine. In step a2) of the method of the present invention, the trimethylsilyl-containing compound may be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate.

[0073] In step a2) of the process of the present invention, the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl halides, trimethylsilyl haloalkyl sulfonates, trimethylsilyl halosulfonates, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilanes, trimethylsilylalkynes, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamides, or secondary or tertiary (trimethylsilyl)amines; and the reaction temperature may be in the range of 60°C to 100°C, 65°C to 100°C, or 70°C to 100°C. In step a2) of the method of the present invention, the trimethylsilyl-containing compound can be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilyl acetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl) )acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C, 70°C to 100°C.In step a2) of the method of the present invention, the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; The molar ratio between the compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the amount of the trimethylsilyl-containing compound can be at least 1 mole, at least 1.02 moles, at least 1.05 moles of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine on a molar basis; and the reaction temperature can be in the range of 60°C to 100°C, 65°C to 100°C. In step a2) of the method of the present invention, the trimethylsilyl-containing compound may be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1.5 to 1:15; the amount of the trimethylsilyl-containing compound may be at least 1.05 moles of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine by mole; the molar ratio between the trimethylsilyl-containing compound and 1-cyanoguanidine may be in the range of 0.6:1 to 1:0.6; and the temperature of the reaction may be in the range of 60°C to 100°C. The reaction of step a2) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0074] In step a2) of the process of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18)alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkyl caprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone. In step a2) of the process of the invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, 1-tert-butylpyrrolidone, 1-pentylpyrrolidone, N-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone, 1-dodecyl-2-pyrrolidone, 1-tetradecyl-2-pyrrolidone. , 5-methyl-1-tetradecyl-2-pyrrolidone, 1-octadecyl-2-pyrrolidone, 3-methyl-1-octadecyl-2-pyrrolidone, N-methyl-2-piperidone, 1-ethyl-2-piperidone, 1-propyl-2-piperidone, 1-butyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, γ-valerolactone, γ-caprolactone, γ-octalactone, γ-nonalactone, γ-decanolactone, γ-undecalactone, δ-valerolactone, δ-octalactone, δ-decanolactone, δ-undecalactone, ε-caprolactone, ε-decanolactone or ε-dodecalactone. In step a2) of the process of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, δ-valerolactone or ε-caprolactone. In step a2) of the process of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be N-methylpyrrolidone.

[0075] In step a2) of the process of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18)alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkyl caprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone; and the trimethylsilyl-containing compound can be selected from the group consisting of: trimethylsilyl halide, trimethylsilyl haloalkyl sulfonate, trimethylsilyl halosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen-substituted alkyltrimethylsilane, trimethylsilylalkyne, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen-substituted (trimethylsilyl)alkylamide, or secondary or tertiary (trimethylsilyl)amine.In step a2) of the process of the invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, 1-tert-butylpyrrolidone, 1-pentylpyrrolidone, N-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone, 1-dodecyl-2-pyrrolidone, Pyrrolidone, 1-tetradecyl-2-pyrrolidone, 5-methyl-1-tetradecyl-2-pyrrolidone, 1-octadecyl-2-pyrrolidone, 3-methyl-1-octadecyl-2-pyrrolidone, N-methyl-2-piperidone, 1-ethyl-2-piperidone, 1-propyl-2-piperidone, 1-butyl-2-piperidone, N-methyl caprolactam, N-ethyl caprolactam, γ-butyrolactone, γ-valerolactone, γ-caprolactone, γ-octanolactone, γ-nonalactone, γ-decanolactone, γ-undecalactone, δ-valerolactone, δ -octanolactone, δ-decanoic acid, δ-undecalactone, ε-caprolactone, ε-decanoic acid or ε-dodecalactone; the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilyl Alkyl acetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; and the reaction temperature can be in the range of 60°C to 100°C, 65°C to 100°C, 70°C to 100°C.In step a2) of the process of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, δ-valerolactone or ε-caprolactone; the trimethylsilyl-containing compound may be selected from the group consisting of: trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonic acid Ester, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone can be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; and the temperature of the reaction can be in the range of 60°C to 100°C, 65°C to 100°C. In step a2) of the process of the present invention, the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be N-methylpyrrolidone; the trimethylsilyl-containing compound may be trimethylsilyl chloride or trimethylsilyl trifluoromethanesulfonate; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20, or 1:1.5 to 1:15; the molar ratio between the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone and 1-cyanoguanidine may be in the range of 1:1 to 5:1; and the temperature of the reaction may be in the range of 60°C to 100°C. The reaction of step a2) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0076] In one embodiment, step a2) for preparing (1R, 2S)-1-(biguanidino)-2,6-dimethylindane or an acid addition salt thereof may optionally contain an aprotic solvent. In step a2) of the method of the present invention, the aprotic solvent may be selected from the group consisting of: an aromatic hydrocarbon optionally substituted with halogen, an aliphatic hydrocarbon optionally substituted with halogen, a nitrogen heterocyclic compound, an optionally alkyl-substituted cyclic ether, an aliphatic ether, an ether of an aromatic hydrocarbon, a nitrile, a ketone, an ester or a tertiary amide. In step a2) of the process of the present invention, the aprotic solvent may be selected from the group consisting of toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, methyl chloride, dichloromethane, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, pentane, hexane, heptane, cyclohexane, decalin, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, pyridine, pyridazine, pyrimidine, pyrazine, triazine, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, dibutyl ether, tert-butyl methyl ether, anisole, acetonitrile, benzonitrile, acetone, butanone, ethyl acetate, n-butyl acetate, hexyl acetate, dimethylformamide or dimethylacetamide. In step a2) of the process of the present invention, the aprotic solvent may be selected from the group consisting of toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, hexane, cyclohexane, quinoline, pyridine, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, acetonitrile, benzonitrile, acetone, ethyl acetate, dimethylformamide or dimethylacetamide. In step a2) of the process of the present invention, the aprotic solvent may be selected from the group consisting of toluene, chlorobenzene, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole or acetonitrile.

[0077] In step a2) of the process of the present invention, the aprotic solvent may be selected from the group consisting of: optionally halogen-substituted aromatic hydrocarbons, optionally halogen-substituted aliphatic hydrocarbons, nitrogen heterocyclic compounds, optionally alkyl-substituted cyclic ethers, aliphatic ethers, ethers of aromatic hydrocarbons, nitriles, ketones, esters or tertiary amides; and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of: optionally alkyl-substituted N-(C1-C 18)alkylpyrrolidone, optionally alkyl-substituted N-(C1-C4)alkyl 2-piperidone, optionally alkyl-substituted N-(C1-C4)alkyl caprolactam, optionally alkyl-substituted γ-butyrolactone, optionally alkyl-substituted δ-valerolactone, optionally alkyl-substituted ε-caprolactone.In step a2) of the process of the present invention, the aprotic solvent may be selected from the group consisting of toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chloromethane, dichloromethane, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, pentane, hexane, heptane, cyclohexane, decalin, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, pyridine, pyridazine, pyrimidine, pyrazine, triazine, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, dibutyl ether, tert-butyl methyl ether, anisole, acetonitrile, benzonitrile, acetone, butanone, ethyl acetate, The optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2-pyrrolidone, N-butyl-2-pyrrolidone, 1-tert-butylpyrrolidone, 1-pentylpyrrolidone, N-hexyl-2-pyrrolidone, 1-octyl-2-pyrrolidone, N-decyl-2-pyrrolidone, 1-dodecyl-2-pyrrolidone, 1-tetradecyl-2-pyrrolidone, 5-methyl-1-tetradecyl-2-pyrrolidone, 1- ... Octaalkyl-2-pyrrolidone, 3-methyl-1-octadecyl-2-pyrrolidone, N-methyl-2-piperidone, 1-ethyl-2-piperidone, 1-propyl-2-piperidone, 1-butyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, γ-valerolactone, γ-caprolactone, γ-octalactone, γ-nonalactone, γ-decanolactone, γ-undecalactone, δ-valerolactone, δ-octalactone, δ-decanolactone, δ-undecalactone, ε-caprolactone, ε-decanolactone or ε-dodecalactone; and the trimethylsilyl-containing compound may be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, ... bromide, trimethylsilyl bromide, trimethylsilyl bromide, trimethylsilyl bromide, trimethylsilyl bromide, trimethylsilyl bromide, trimethylsilyl bromide, trimethylsilyl bromide, trimethylsilyl bromide, trimethylsilyl Silyl trifluoromethanesulfonate, trimethylsilyl chlorosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, tetramethylsilane, (trimethylsilyl)methyl chloride, 1-(trimethylsilyl)propyne, trimethylsilylacetylene, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine.In step a2) of the process of the present invention, the aprotic solvent may be selected from the group consisting of toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, hexane, cyclohexane, quinoline, pyridine, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole, acetonitrile, benzonitrile, acetone, ethyl acetate, dimethylformamide or dimethylacetamide; the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be selected from the group consisting of N-methylpyrrolidone, N-ethyl-2-pyrrolidone, N-propyl-2 -pyrrolidone, N-butyl-2-pyrrolidone, N-methyl-2-piperidone, N-methylcaprolactam, N-ethylcaprolactam, γ-butyrolactone, δ-valerolactone or ε-caprolactone; the trimethylsilyl-containing compound can be selected from the group consisting of trimethylsilyl chloride, trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl trifluoromethanesulfonate, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)trifluoroacetamide, N-methyl-N-(trimethylsilyl)trifluoroacetamide, N-(trimethylsilyl)diethylamine, bis(trimethylsilyl)amine or tris(trimethylsilyl)amine; and the reaction temperature can be in the range of 60°C to 100°C, 65°C to 100°C. In step a2) of the process of the present invention, the aprotic solvent may be selected from the group consisting of toluene, chlorobenzene, 1,4-dioxane, tetrahydropyran, methyltetrahydropyran, tetrahydrofuran, methyltetrahydrofuran, anisole or acetonitrile; the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be N-methylpyrrolidone; the trimethylsilyl-containing compound may be trimethylsilyl chloride or trimethyl trifluoromethanesulfonate; the molar ratio between the trimethylsilyl-containing compound and the optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl-substituted γ-, δ-, ε-lactone may be in the range of 1:1 to 1:20; and the temperature of the reaction may be in the range of 60°C to 100°C. The reaction of step a2) may be carried out at atmospheric pressure or a pressure higher than atmospheric pressure.

[0078] The indoxazolidinone obtained according to step b) of the preparation process is recrystallized in step c) in a solvent which may be selected from the group consisting of alcohols, alcohols mixed with water, amides, lactams, esters of carboxylic acids, optionally halogenated aliphatic or aromatic solvents. The indazine fluazifop obtained according to step b) of the preparation method is recrystallized in a solvent in step c), which solvent can be selected from the group consisting of ethanol, methanol, butanol, tert-butanol, propanol, isopropanol, isoamyl alcohol, phenol (any of the above alone or mixed with water), dimethylformamide, dimethylacetamide, N-methylcaprolactam, N-ethylcaprolactam, ethyl acetate, n-butyl acetate, hexyl acetate, toluene, benzene, ethylbenzene, xylene, cumene, isopropylbenzene, mesitylene, biphenyl, chlorobenzene, bromobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, methyl chloride, dichloromethane, chloroform, tetrachloromethane, dichloroethane, trichloroethane, trichloroethylene, tetrachloroethylene, pentane, hexane, heptane, or cyclohexane.

[0079] The recrystallization in step c) of the preparation process can be achieved by dissolving the indoxazolidinone obtained according to step b) in a selected solvent at any suitable temperature, which can be, for example, room temperature to the reflux temperature of the selected solvent, and then precipitating the indoxazolidinone from the solution by any suitable technique, which can be, for example, by cooling to any suitable temperature and / or by removing an appropriate portion of the selected solvent to cause precipitation of indoxazolidinone with a compression index less than or equal to 17. Finally, the precipitated indoxazolidinone with a compression index less than or equal to 17 is separated or recovered from the selected solvent by any suitable technique, which can be, for example, by filtration, centrifugation and / or decantation. The person skilled in the art is familiar with the different techniques and steps for recrystallization of the product.

[0080] Compositions comprising a crystalline form of indoxazine fluazifop

[0081] The present invention also relates to an agrochemical composition comprising a crystalline form of indoxazolidinone having a compression index of less than or equal to 17.

[0082] The crystalline form of indoxazolidinone in the agrochemical composition may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25° C. using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees.

[0083] The crystalline form of indoxazolidinone in the agricultural chemical composition may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and may also have additional peaks at diffraction angles 2θ±0.2 degrees of 13.0, 16.1, 21.5, 24.6 degrees.

[0084] The crystalline form of indoxazolidinone in the agricultural chemical composition may exhibit a crystal structure having a wavelength (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 Infrared (IR) spectrum with characteristic functional peaks at .

[0085] The crystalline form of indoxazolidinone in the agricultural chemical composition may exhibit a crystal structure having a wavelength (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 The infrared (IR) spectrum has a characteristic functional peak at wave number (±2cm -1 ) are 637, 709, 874, 895, 996, 1124, 1306, 1372, 1393, 1638, 2948, 3222, 3319, 3432cm -1 Additional functional peaks at .

[0086] The crystalline form of indoxazolidinone in the agricultural chemical composition may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25° C. using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and may exhibit a peak at wavenumbers (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 The crystalline form of indoxazolidinone in the agricultural chemical composition may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation with peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and may also have additional peaks at diffraction angles 2θ±0.2 degrees of 13.0, 16.1, 21.5, 24.6 degrees, and may exhibit peaks at wave numbers (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm-1 The infrared (IR) spectrum has a characteristic functional peak at wave number (±2cm -1 ) are 637, 709, 874, 895, 996, 1124, 1306, 1372, 1393, 1638, 2948, 3222, 3319, 3432cm -1 Additional functional peaks at .

[0087] The crystalline form of indoxazolidinone in the agrochemical composition may exhibit a melting point of 181.4°C to 183.4°C.

[0088] The crystalline form of indoxazolidinone in the agricultural chemical composition may exhibit a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C.

[0089] The crystalline form of indoxazolidinone in the agricultural chemical composition may exhibit a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C, and it may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees.

[0090] The crystalline form of indoxazolidinone in the agricultural chemical composition may exhibit a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C, and may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and the diffraction pattern may also have additional peaks at diffraction angles 2θ±0.2 degrees of 13.0, 16.1, 21.5, 24.6 degrees.

[0091] The crystalline form of indoxazolidinone in the agricultural chemical composition may exhibit a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C, it may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and it may exhibit a peak at wavenumbers (±2 cm -1) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 Infrared (IR) spectrum with characteristic functional peaks at .

[0092] The crystalline form of indoxazolidinone in the agricultural chemical composition may exhibit a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C, which may show an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, the diffraction pattern may also have additional peaks at diffraction angles 2θ±0.2 degrees of 13.0, 16.1, 21.5, 24.6 degrees, the crystalline form may exhibit a peak at wave number (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 The infrared (IR) spectrum has a characteristic functional peak at wave number (±2cm -1 ) are 637, 709, 874, 895, 996, 1124, 1306, 1372, 1393, 1638, 2948, 3222, 3319, 3432cm -1 Additional functional peaks at .

[0093] The agrochemical composition comprising a crystalline form of indoxazolidinone having a compression index of less than or equal to 17 may be in the form of a suspension concentrate (SC), granules (GR) in the form of microgranules, sprayable granules, coated granules and absorption granules, water-dispersible granules (WG), water-soluble granules (SG), dispersible concentrates (DC), oil dispersions (OD), wettable powders (WP), water-soluble powders (SP), water-soluble concentrates (SL), emulsion concentrates (EC), or suspoemulsions (SE). The agrochemical composition comprising a crystalline form of indoxazolidinone having a compression index of less than or equal to 17 may be in the form of a suspension concentrate (SC), granules (GR) in the form of microgranules, sprayable granules, coated granules and absorption granules, water-dispersible granules (WG), water-soluble granules (SG), dispersible concentrates (DC) or oil dispersions (OD). The agrochemical composition comprising the crystalline form of indoxazolidinone having a compression index lower than or equal to 17 may be in the form of a suspension concentrate (SC) or water dispersible granules (WG).

[0094] The amount of the crystalline form of indoxazolidinone having a compression index lower than or equal to 17 in the agrochemical composition may be between 5% and 90% by weight of the total composition. The amount of the crystalline form of indoxazolidinone having a compression index lower than or equal to 17 in the agrochemical composition may be between 10% and 80% by weight of the total composition. The amount of the crystalline form of indoxazolidinone having a compression index lower than or equal to 17 in the agrochemical composition may be between 15% and 60% by weight of the total composition.

[0095] The amount of the crystalline form of indoxazolidinone having a compression index less than or equal to 17 in the agrochemical composition can be between 5% and 90% by weight of the total weight of the composition, and the crystalline form of indoxazolidinone can exhibit an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees. The amount of the crystalline form of indoxazolidinone having a compression index lower than or equal to 17 in the agrochemical composition may be between 10% and 80% by weight of the total weight of the composition, and the crystalline form of indoxazolidinone may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25° C. using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, and may exhibit a peak at wavenumbers (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 The amount of the crystalline form of indoxazolidinone having a compression index lower than or equal to 17 in the agrochemical composition may be between 15% and 60% by weight of the total weight of the composition, and the crystalline form of indoxazolidinone may exhibit an X-ray powder diffraction pattern (XRD) recorded at 25° C. using Cu-Kα radiation with peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees, which may exhibit peaks at wave numbers (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 The invention can also be used to describe an infrared (IR) spectrum of the compound of claim 1 , and it can exhibit a characteristic functional peak at , and it can show a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4° C.±0.2° C. and reaching a maximum peak at 182.8° C.±0.2° C.

[0096] The agrochemical composition comprising a crystalline form of indoxazolidinone having a compression index less than or equal to 17 may be in the form of a suspension concentrate (SC), granules (GR) in the form of microgranules, spray granules, coated granules and absorbent granules, water-dispersible granules (WG), water-soluble granules (SG), dispersible concentrate (DC), oil dispersion (OD), wettable powder (WP), water-soluble powder (SP), water-soluble concentrate (SL), emulsion concentrate (EC), or suspoemulsion (SE), and the amount of the crystalline form of indoxazolidinone may be between 5% and 90% by weight of the total composition. The agrochemical composition comprising a crystalline form of indoxazolidinone having a compression index lower than or equal to 17 may be in the form of a suspension concentrate (SC), granules (GR) in the form of microgranules, spray granules, coated granules and absorption granules, water-dispersible granules (WG), water-soluble granules (SG), dispersible concentrates (DC) or oil dispersions (OD), and the amount of the crystalline form of indoxazolidinone may be between 10% and 80% by weight of the total composition. The agrochemical composition comprising a crystalline form of indoxazolidinone having a compression index lower than or equal to 17 may be in the form of a suspension concentrate (SC) or water-dispersible granules (WG), and the amount of the crystalline form of indoxazolidinone may be between 15% and 60% by weight of the total composition.

[0097] The agrochemical composition comprising the crystalline form of indoxazolidinone having a compression index of less than or equal to 17 may further comprise one or more agriculturally acceptable inert additives or adjuvants. The agrochemical composition comprising the crystalline form of indoxazolidinone having a compression index of less than or equal to 17 may further comprise one or more agriculturally acceptable inert additives or adjuvants selected from the group consisting of chelating agents, thickeners, defoamers, pH buffers, antifreeze agents, dispersants, surfactants, emulsifiers, wetting agents or wetting agents, suspending agents, stabilizers, plant penetrants (or translocators), safeners, spreaders, compatibilizers, drift retardants, antioxidants, preservatives, drift retardants, conversion agents, soil penetrants, UV absorbers, adhesives, stickers, fertilizers, inert fillers, pigments, colorants, solvents or mixtures thereof.

[0098] The agrochemical composition comprising a crystalline form of indazine fluazifop having a compression index of less than or equal to 17 may further comprise one or more herbicide active ingredients. The agrochemical composition comprising a crystalline form of indazine fluazifop having a compression index of less than or equal to 17 may further comprise one or more herbicide active ingredients selected from the group consisting of aclonifen, acrolein, azafenidin, acifluorfen, azimsulfuron, asulam, acetochlor, atrazine, anilofos, amicarbazine, amidosul furon), amitrole, aminocyclopyrachlor, aminopyralid, amiprofos-methyl, ametryn, alachlor, alloxydim, ioxynil, isouron, isoxachlortole, isoxaflutole, isoxaben, isoproturon ), ipfencarbazone, imazaquin, imazapic, imazapyr, imazamethabenz-methyl, imazamox, imazethapyr, imazosulfuron, indanofan, eglinazine-ethyl, esprocarb, ethametsulfuron-methyl on-methyl), ethalfluralin, ethidimuron, ethoxysulfuron, ethoxyfen-ethyl, ethofumesate, etobenzanid, endothal-disodium, oxadiazon, oxadiargyl, oxaziclomefone, oxasulfuron,Oxyfluorfen, oryzalin, orthosulfamuron, orbencarb, oleic acid, cafenstrole, carfentrazone-ethyl, karbutilate, carbetamide, quizalofop-ethyl, quizalofop-P-ethyl, quizalofop-P-tefuryl, Quinoclamine, quinclorac, quinmerac, cumyluron, clacyfos, glyphosate, glufosinate, clethodim, clodinafop-propargyl, clopyralid, clomazone, chlomethoxyfen, clomeprop, clomethoxyfen-methyl ransulam-methyl), chloramben, chloridazon, chlorimuron-ethyl, chlorsulfuron, chlorthal-dimethyl, chlorthiamid, chlorphthalim, chlorflurenol-methyl, chlorpropham, chlorbromuron, chloroxuron, Chlorotoluron, ketospiradox, saflufenacil, sarmentine, cyanazine, cyanamide, diuron, diethatyl-ethyl, dicamba, cycloate, cycloxydim, diclosulam, cyclosulfamuron, cyclopyranil,Cyclopyrimorate, dichlobenil, diclofop-P-methyl, diclofop-methyl, dichlorprop, dichlorprop-P, diquat, dithiopyr, siduron, diinitramine, cinidon-ethyl, cinosulfuron, dinoseb, dinoterb, cyhalofop-butyl, diphenamid, difenzoquat, diflufenican, dimethoate diflufenzopyr, simazine, dimethachlor, dimethametryn, dimethenamid, dimethenamid-P, simetryn, dimepiperate, dimefuron, cinmethylin, sulcotrione, sulfentrazone, sulfosate, sulfosulfuron, sulfometuron-methyl, sethoxydim, terbacil, daimuron, thaxtomin A A), dalapon, thiazopyr, tiafenacil, thiencarbazone, tiocarbazil, thiobencarb, thidiazimin, thifensulfuron-methyl, desmedipham, desmetryne, tetflupyrolimet, thenylchlor, tebutam, tebuthiuron, tepraloxydim, tefuryltrione, tembotrione,terbuthylazine, terbutryn, terbumeton, topramezone, tralkoxydim, triaziflam, triasulfuron, triafamone, triallate, trietazine, triclopyr, triclopyr-butotyl, trifludimoxazin, triaziflam, triasulfuron, triafamone, triallate, trietazine, triclopyr, triclopyr-butotyl, trifludimoxazin, triaziflam, triaziflam, triasulfuron, triafamone, triallate, trietazine, triclopyr, triclopyr-butotyl, trifludimoxazin, triaziflam, triaziflam, triasulfuron, triafamone, triaziflam, triaziflam tritosulfuron, triflusulfuron-methyl, trifluralin, trifloxysulfuron, tribenuron-methyl, tolpyralate, naptalam, naproanilide, naproxamide, naproxamide-M, nicosulfuron, neburon, norfluraz on), vernolate, paraquat, halauxifen-benzyl, halauxifen-methyl, haloxyfop, haloxyfop-P, haloxyfop-etotyl, halosafen, halosulfuron-methyl, bixlozone, picloram, picolinafen, haloxyfop bicyclopyrone, bispyribac-sodium, pinoxaden, bifenox, piperophos, pyraclonil, pyrasulfotole, pyrazoxyfen, pyrazosulfuron-ethyl, pyrazolynate, bialafos, pyraflufen-ethyl, pyridafol,Pyrithiobac-sodium, pyridate, pyriftalid, pyributicarb, pyribenzoxim, pyrimisulfan, pyriminobac-methyl, pyroxasulfone, pyroxsulam, phenisopham, fenuron, fenoxasulfone, fenoxaprop, Fenoxaprop-P, fenquinotrione, fenthiaprop-ethyl, fentrazamide, phenmedipham, butachlor, butafenacil, butamifos, butylate, butenachlor, butralin, butroxydim, flazasulfuron, flamprop ), flamprop-M, primisulfuron-methyl, fluazifop-butyl, fluazifop-P-butyl, fluazolate, fluometuron, fluoroglycofen-ethyl, flucarbazone-sodium, fluchloralin, flucetosulfuron, fluthiacet-meth yl), flupyrsulfuron-methyl-sodium, flufenacet, flufenpyr-ethyl, flupropanate, flupoxame, flumioxazin, flumiclorac-pentyl, flumetsulam, fluridone, flurtamone, fluroxypyr, flurochloridone,pretilachlor, procarbazone-sodium, prodiamine, prosulfuron, prosulfocarb, propaquizafop, propachlor, propazine, propanil, propyzamide, propisochlor, propyrisulfuron, propham, profluazamide ol), propoxycarbazone-sodium, profoxydim, bromacil, brompyrazon, prometryn, prometon, bromoxynil, bromofenoxim, bromobutide, florasulam, florpyrauxifen, hexazinone, pethoxamid, benazide olin), penoxsulam, heptamaloxyloglucan, beflubutamid, beflubutamid-M, pebulate, nonanoic acid, bencarbazone, pendimethalin, benzfendizone, bensulide, bensulfuron-methyl, benzobicyclon, benzofechloridone nap), bentazone, pentanochlor, pentoxazone, benfluralin, benfuresate, fosamine, fomesafen, foramsulfuron, mecoprop, mesosulfuron-methyl, mesotrione, metazachlor, metazosulfuron,methabenzthiazuron, metamitron, metamifop, DSMA (disodium methyl arsenate), metiozolin, methyldymuron, metoxuron, metosulam, metsulfuron-methyl, metobromuron, metobenzuron, metolachlor, S-metolachlor, metribuzin, mefenacet, mono Monosulfuron, monolinuron, molinate, iodosulfuron, iodosulfuron-methyl-sodium, iofensulfuron, lactofen, lancotrione, linuron, rimsulfuron, lenacil, 2,2,2-trichloroacetic acid, 2,3,6-trichlorobenzoic acid, 2,4,5-trichlorophenoxyacetic acid, 2,4-D (2,4-dichlorophenoxyacetic acid), or agriculturally acceptable salts of these herbicide active ingredients.

[0099] Method for preparing an agrochemical composition comprising a crystalline form of indoxazolidinone

[0100] The present invention also relates to a method for preparing an agrochemical composition comprising indoxazolidinone, wherein the method comprises the steps of pulverizing a powder or slurry comprising a crystalline form of indoxazolidinone having a compression index less than or equal to 17, and mixing the pulverized powder or slurry with one or more agriculturally acceptable inert additives or adjuvants of the agrochemical composition.

[0101] The step of mixing the comminuted powder or slurry comprising the crystalline form of indoxazolidinone having a compression index less than or equal to 17 with one or more agriculturally acceptable inert additives or adjuvants may further comprise one or more herbicide active ingredients.

[0102] The agrochemical composition comprising indoxazolidinone in the method for preparing the agrochemical composition comprising indoxazolidinone may be in the form of a suspension concentrate (SC), granules (GR) in the form of microgranules, spray granules, coated granules and absorption granules, water-dispersible granules (WG), water-soluble granules (SG), dispersible concentrate (DC), oil dispersion (OD), wettable powder (WP), water-soluble powder (SP), water-soluble concentrate (SL), emulsion concentrate (EC), or suspoemulsion (SE).

[0103] The one or more agriculturally acceptable inert additives or adjuvants in the method for preparing an agrochemical composition comprising indoxazolidinone may be selected from the group consisting of a chelating agent, a thickener, a defoamer, a pH buffer, an antifreeze agent, a dispersant, a surfactant, an emulsifier, a wetting agent or a moistening agent, a suspending agent, a stabilizer, a plant penetrant (or translocator), a safener, a spreading agent, a compatibilizer, a drift retardant, an antioxidant, a preservative, a drift retardant, a conversion agent, a soil penetrant, a UV absorber, an adhesive, a sticking agent, a fertilizer, an inert filler, a pigment, a colorant, a solvent or a mixture thereof.

[0104] The following examples are included for illustrative purposes only and are not to be construed as limitations of the invention claimed herein.

[0105] Examples

[0106] Materials and Methods

[0107] X-ray powder diffraction pattern (XRD) was performed on a Panalytical Empyrean powder diffractometer II (Cu K α radiation, ). Conventional continuous scanning was performed over a 2θ range of 3.5÷40°, with a step size equal to about 0.0131°, a time / step size of about 40 seconds, and a scan speed of about 0.0847° / s. The powder sample was lightly ground and loaded into a standard quartz plate XRD sample holder of 0.5 mm depth and leveled with a piece of glass.

[0108] Infrared (IR) measurement A Thermo Fisher Scientific NICOLETiS5 FT-IR spectrometer and ATR accessory were used. For each measurement, the -1 16 scans were performed with a resolution of 1.5 %. Spectral region 525-4000cm -1A small amount of powder is placed on the diamond crystal and the pressure tower is lowered until it is pressed firmly against the powder. While the sample is in place, measurements are collected on the OMNIC software.

[0109] DSC measurements The DSC3 Mettler Toledo instrument was used. The sample preparation and measurement were performed according to the instructions in the Mettler Toledo DSC3 manual.

[0110] Example 1: Synthesis of N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine using monochlorobenzene and N-methylpyrrolidone

[0111] This example follows the process for the preparation of indoxazolidinone according to steps a1), b) and c).

[0112] (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine HCl salt (16.33 Kg, 82.60 mol, 1 equivalent) was dissolved in 81.65 liters of monochlorobenzene and the mixture was heated to 130°C under a protective gas atmosphere. Next, 1-cyanoguanidine (13.88 Kg, 165.2 mol, 2 equivalents) previously dissolved in 49 liters of N-methylpyrrolidone was added dropwise. The reaction mixture was then stirred at 130°C for 8 hours. After completion, the mixture was cooled to 50°C, and then monochlorobenzene was distilled off under vacuum. Afterwards, under protective gas atmosphere, the reaction mixture was cooled to room temperature, and then 32.66 liters of MeOH were added to the flask, followed by the addition of NaOMe 30% solution (37.8 Kg, 206.5 mol, 2.5 equivalents) and (R)-2-fluoropropionic acid methyl ester (17.51 ​​kg, 165.2 mol, 2 equivalents) in MeOH. The mixture was stirred for an additional 4 h. When the reaction was completed, water was added dropwise and stirred for an additional 0.5 h. Afterwards, the mixture was filtered, and the filter cake was washed with water. Finally, the material was dried in a baking oven at 70 ° C under vacuum and crystals were collected. The chemical yield obtained was 84%.

[0113] Example 2: Synthesis of N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine using monochlorobenzene, N-methylpyrrolidone and trimethylsilyl chloride

[0114] This example follows the process for the preparation of indoxazolidinone according to steps a2), b) and c).

[0115] Under nitrogen atmosphere, 2.8 liters of monochlorobenzene were loaded into a reactor equipped with a nitrogen inlet and a Teflon-coated magnetic stirring bar. Trimethylsilyl chloride (TMSCl) (1.05 equivalents, 2.60mol, 329ml) was added, and the reaction mixture was heated to 90°C. At this temperature, a pre-prepared solution of 1-cyanoguanidine (1.1 equivalents, 2.73mol, 229.5g) and (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 equivalent, 2.48mol, 400g) in N-methylpyrrolidone (570ml) was added dropwise over 1.5 hours, forming a viscous off-white mixture during this period. Once the component addition is complete, the reactants are mixed for 14 hours. Once termination of step 1 was seen via HPLC, the reactants were cooled to room temperature and (R)-methyl 2-fluoropropionate (1.7 eq., 4.22 mol, 447.6 g) was added in one go, followed by dropwise addition of NaOMe / MeOH solution (2.1 eq., 5.21 mol, 30% w / w, 940 g). Once termination was seen, the mixture was transferred to a round bottom flask and concentrated under reduced pressure. The resulting solid wax was then recrystallized according to the following procedure: MeOH (5 ml / g (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine) was added to the product and heated until complete dissolution was seen. The mixture was stirred at room temperature and water (2.8 ml / g (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine) was added dropwise over 0.5 h, followed by additional stirring for 2 hours. During this period, formation of an off-white precipitate occurred. The resulting suspension was filtered and the off-white crystals obtained were washed twice with 100 ml of hot water. Finally, the material was dried in an oven at 70° C. under vacuum. The chemical yield obtained was 88%.

[0116] Comparative Example 3: Synthesis of N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine using 1-methoxy-2-propanol.

[0117] This comparative example reproduces the prior art process for the preparation of indazine fluazifop as disclosed in EP 2231679 B1 as indicated in paragraph

[0120] for compound V-10 according to Example A8) in a similar manner to prepare N-[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-yl]-6-[(1R)-1-fluoroethyl]-1,3,5-triazine-2,4-diamine.

[0118] 800 ml of 1-methoxy-2-propanol was added to the reactor, 496 g of aluminum isopropoxide (2 eq., 2.48 mol) was added. Then 153.3 g of cyanoguanidine (1.5 eq., 1.82 mol) was added. The resulting mixture was then heated to 100 ° C for 1 hour. 200 g of (1R, 2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine (1 eq., 1.24 mmol) was added over 30 minutes and mixed for an additional 8 hours at 100 ° C. Once termination of the reaction was seen, 1-methoxy-2-propanol was distilled off. The reactants were then cooled to 70 ° C and 800 ml of MeOH was added. Then 88.3 g of NaOMe (30%) (0.4 eq., 0.496 mol) and 219.3 g of (R)-2-fluoropropionic acid methyl ester (1.7 eq., 2.1 mol) were added. The reactants were mixed for an additional 8 hours at 70°C until termination was seen via HPLC. MeOH was distilled off and 1 liter of toluene was added. 1 liter of HCl (16%) was added to the toluene solution and each phase was separated. The aqueous phase was extracted twice with 400ml toluene, and the combined toluene layer was washed with 400ml water. The toluene phase was then decompressed, and the resulting slurry was dissolved in 1 liter of MeOH and 400ml of water was added. The resulting solution was then cooled to 5°C and NaOH (45%) was added until pH=10 was reached. The resulting slurry was then filtered and the crystals were washed with hot water and dried under vacuum. The chemical yield obtained was 77%.

[0119] Example 4: Compression Index of Crystalline Samples from Example 1, Example 2 and Comparative Example 3

[0120] Bulk density and tap density measurements are obtained by placing the sample on waxed paper. The sample is then poured into a tared graduated cylinder until the 250 ml mark is reached. The amount of sample is weighed. A rubber stopper is fitted into the graduated cylinder. The graduated cylinder is placed in a drop box and manually tapped (dropped) 50 times with a time difference of about 1 second between taps. As revised from the USP method on January 20, 2023 <1174> The compressibility index is calculated from the bulk density and tap density as explained in Powder Flow.

[0121]

[0122] The indoxazolidinone crystalline samples obtained from Examples 1 and 2 showed a compression index less than or equal to 17 and thus showed good flowability, as specified in the United States Pharmacopoeia method as revised on January 20, 2023. <1174> However, the compression index of the indoxazolidinone crystalline sample obtained by the prior art method in Comparative Example 3 showed a poor value, and the flowability of the crystalline sample was not good.

Claims

1. A crystalline form of indoxazolidinone having a compression index less than or equal to 17.

2. The crystalline form of indoxazolidinone according to claim 1, which exhibits an X-ray powder diffraction pattern (XRD) recorded at 25°C using Cu-Kα radiation having peaks at diffraction angles 2θ±0.2 degrees of 14.3, 16.9, 18.9, 20.1, 22.5 and 25.2 degrees.

3. The crystalline form of indoxazolidinone according to any one of the preceding claims, which exhibits a crystalline form having a wavelength of (±2 cm -1 ) are 569, 822, 1055, 1422, 1449, 1474, 1527, 1575cm -1 Infrared (IR) spectrum with characteristic functional peaks at .

4. The crystalline form of indoxazolidinone according to any one of the preceding claims, which exhibits a melting point of 181.4°C to 183.4°C.

5. The crystalline form of indoxazolidinone according to any one of the preceding claims, which exhibits a differential scanning calorimetry (DSC) curve having an endothermic melting peak starting at 182.4°C±0.2°C and reaching a maximum peak at 182.8°C±0.2°C.

6. A process for preparing a crystalline form of indoxazolidinone having a compression index less than or equal to 17, wherein indoxazolidinone is recrystallized in a solvent selected from the group consisting of alcohols, alcohols mixed with water, amides, lactams, esters of carboxylic acids, optionally halogenated aliphatic or aromatic solvents.

7. The method according to claim 6, comprising: a1) a first step of preparing (1R,2S)-1-(biguanidino)-2,6-dimethylindane or an acid addition salt thereof by reacting 1-cyanoguanidine with (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-amine in a mixture of a polar aprotic solvent having a dielectric constant higher than 12.0 when measured at 25° C. and a solvent immiscible with water; Or alternatively, a2) a first step of preparing (1R,2S)-1-(biguanidino)-2,6-dimethylindane or an acid addition salt thereof by reacting 1-cyanoguanidine with (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine in a mixture comprising a trimethylsilyl-containing compound and an optionally alkyl-substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl-substituted γ-, δ-, ε-lactone; b) a second step of adding a base and (R)-methyl 2-fluoropropionate to the (1R,2S)-1-(biguanidino)-2,6-dimethylindane or an addition salt thereof obtained in the first step a1) or a2), and c) recrystallizing the indoxazolidinone obtained in step b) in a solvent selected from the group consisting of alcohols, alcohols mixed with water, amides, lactams, esters of carboxylic acids, optionally halogenated aliphatic or aromatic solvents.

8. An agrochemical composition comprising a crystalline form of indoxazolidinone having a compression index of less than or equal to 17.

9. The agricultural chemical composition according to claim 8, wherein The composition is in the form of a suspension concentrate (SC), granules (GR) in the form of microgranules, spray granules, coated granules and absorbent granules, water-dispersible granules (WG), water-soluble granules (SG), dispersible concentrate (DC), oil dispersion (OD), wettable powder (WP), water-soluble powder (SP), water-soluble concentrate (SL), emulsion concentrate (EC), or suspoemulsion (SE).

10. The agricultural chemical composition according to any one of claims 8 to 9, wherein The amount of the crystalline form of indoxazolidinone in the composition is between 5% and 90% by weight of the total weight of the composition.

11. The agricultural chemical composition according to any one of claims 8 to 10, wherein The agrochemical composition further comprises one or more agriculturally acceptable inert additives or adjuvants.

12. The agricultural chemical composition according to claim 11, wherein The one or more agriculturally acceptable inert additives or adjuvants are selected from the group consisting of: chelating agents, thickeners, defoamers, pH buffers, antifreeze agents, dispersants, surfactants, emulsifiers, wetting agents or wetting agents, suspending agents, stabilizers, plant penetrants (or translocators), safeners, spreading agents, compatibilizers, drift retardants, antioxidants, preservatives, drift retardants, conversion agents, soil penetrants, UV absorbers, adhesives, stickers, fertilizers, inert fillers, pigments, colorants, solvents or mixtures thereof.

13. The agricultural chemical composition according to any one of claims 8 to 12, wherein The agrochemical composition further comprises one or more herbicide active ingredients.

14. A method for preparing an agrochemical composition comprising indoxazolidinone, wherein the method comprises the steps of pulverizing a powder or slurry comprising a crystalline form of indoxazolidinone having a compression index less than or equal to 17, and mixing the pulverized powder or slurry with one or more agriculturally acceptable inert additives or adjuvants of the agrochemical composition.

15. The method for preparing an agricultural chemical composition comprising indoxazolidinone according to claim 14, wherein: The crystalline form of indoxazolidinone and the one or more agriculturally acceptable inert additives or adjuvants are mixed with one or more herbicide active ingredients.

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