Method for producing tetrazole-substituted anthranilic acid diamide derivatives

Abstract

This invention provides a method for preparing crystalline tetrazole-substituted anthranilic acid diamide derivatives with high purity and high yield. [Solution] A method for preparing a compound of formula (I) in crystalline form, characterized by dissolving the compound of formula (I) in at least one amide solvent, crystallizing it in the presence of at least one poor solvent and / or by lowering the temperature to obtain a solvate, then filtering and drying it. TIFF2026053590000022.tif36164

Description

[Technical Field]

[0001] This invention provides high purity and high yield of a solvate crystal, which is in crystalline form of formula (I)

[0002] [ka] This invention relates to a method for producing tetrazole-substituted anthranilic acid diamide derivatives. Furthermore, compared to the tetrazole-substituted anthranilic acid diamide derivative according to the above formula (I) in crystalline form In comparison, this also relates to novel solvent-solvate crystals characterized by improved filtration properties. ru. [Background technology]

[0003] WO2011 / 157664A1 is a tetrazole-substituted anthranilic acid diamide derivative. In particular, it describes a method for producing derivatives according to the above formula (I). WO2011 / 1 57664A1 is also a tetrazole-substituted anthranilic acid diamide induction according to the above formula (I). This document describes a method for preparing the crystalline form of a conductor, which is used to determine its physicochemical properties. Therefore, it is easy to handle and enables the manufacture of stable formulations.

[0004] The drawback of the method described in WO2011 / 157664A1 is its filtration characteristics. The above formula (I) describes a tetrazole-substituted anthranilic acid diamide derivative. These are the physical properties of the crystal form. The method described in WO2011 / 157664A1. According to this, the compound according to formula (I) above requires a long filtration time during isolation by filtration. As a result, the filter cake has a high residual moisture content and settles in the form of fine needles. The high residual moisture content in the luthier cake further contributes to the long drying time of the moist material. For the given problem, tetrazole-substituted anthranilic acid diamide according to formula (I) above. The method described in WO2011 / 157664A1 for preparing derivatives is large It is not suitable for industrial manufacturing. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2011 / 157664 [Overview of the project]

[0006] Therefore, the object of the present invention is to obtain the above formula (I) in crystalline form with high purity and high yield. This provides a novel method for preparing tetrazole-substituted anthranilic acid diamide derivatives. This is advantageous even in large-scale industrial production that takes economic factors into consideration.

[0007] The purpose of this is equation (I).

[0008] [ka] The compound is dissolved in at least one amide solvent, and in the presence of at least one poor solvent... , and / or by lowering the temperature, crystallization is performed to obtain a solvate, which is then filtered, The present invention relates to a method for preparing a compound of formula (I) in crystalline form, characterized by drying. This was achieved by [method / method].

[0009] The present invention further relates to the crystalline form as described in WO2011 / 157664A1 Compared to the tetrazole-substituted anthranilic acid diamide derivative of formula (I) above, this is an improvement. Also for the solvent-solvate crystals of formula (I) formed by the method according to the invention, which are characterized by overcharacteristics relates to. Thus, the formation of solvent-solvate crystals of the compound of formula (I) is important for the economic feasibility of the method according to the invention and its feasibility on an industrial production scale .

[0010] WO2011 / 157664A1 does not describe solvent-solvate crystals, their possibility of formation, nor their advantageous properties. Even though it is known that an amide solvent is a good solvent for the compound of formula (I), it was surprisingly possible to obtain solvent-solvate crystals from an amide solvent during the process of the method according to the invention.

[0011] Also, particularly surprisingly, during the process of the method according to the invention, the compound of formula (I) can be obtained in its thermodynamically stable crystal form by drying the solvent-solvate crystals .

[0012] The crystal form of the compound of formula (I) obtained by the method according to the invention is preferably a thermodynamically stable crystal form .

[0013] Similarly preferably, the method of the invention provides a crystal form of the compound of formula (I) having characteristic powder X-ray diffractograms, Raman spectra and IR spectra (Tables 1 and 2, Figures 1, 2, 3). The compound of formula (I) in this crystal form has a powder X-ray diffractogram using Cu Kα radiation at a temperature of 25 °C having at least the following reflections (2θ) : 5.8°, 6.4°, 11.6°, 17.5°, 19.8°, 20.8°, 23.5° and 24.2° (±0.2° in each case) and is characterized by. Preferably At 25°C, the powder X-ray diffractogram of crystalline form using CuKα radiation is at least Further reflections (2θ) are as follows: 10.2°, 12.8°, 16.7°, 19.0°, 2 It has angles of 5.3°, 27.5°, and 29.4° (each ±0.2°). Further preference of the present invention In a modified form, crystalline powder X-rays using CuKα radiation at a temperature of 25°C The diffractogram essentially corresponds to the diffractogram shown in Figure 1.

[0014] Particularly preferred is that the Raman spectrum of the crystalline form has at least the following bands [cm] -1 ]: 2927, 1663, 1386, 1334, 1022, 638 (each ±20cm) -1 ) has. In a more particularly preferred embodiment of the present invention, the crystalline form of Ramanspe The Kutor essentially corresponds to the spectrum shown in Figure 2.

[0015] Particularly preferable is that the IR spectrum of the crystalline form has at least the following bands [cm] -1 ] :3286, 1662, 1219, 1181, 1154, 1055 (each ±20cm) -1 ) has. In a more particularly preferred embodiment of the present invention, the IR spectrum of the crystalline form The Toll essentially corresponds to the spectrum shown in Figure 3.

[0016] All powder X-ray diffraction data for the crystalline morphology were obtained at 25°C using the following acquisition parameters. reta: Diffraction meter type: PANalytic X'Pert PRO Anode material: Copper Radiation: CuKα1 Wavelength: 1.54060Å Scan mode: Transparency Scan type: 2θ: Omega Range: 2θ (peak maximum) ±0.2° The Raman spectra of the crystalline form were obtained at 25°C and 1064 nm laser wavelengths and 2 cm. -1 With this resolution, an FT-Raman spectrometer from Bruker (e.g., RFS100 or Recorded using a MultiRam type.

[0017] The IR spectrum of the crystal morphology was obtained at 25°C at 4 cm. -1 A universal die with high resolution Bruker IR spectrometer with a Diamond ATR unit (e.g., Tensor 3) Recorded using a Type 7 camera. [Brief explanation of the drawing]

[0018] [Figure 1] Figure 1 shows the powder X-ray diffractogram of the crystalline form. [Figure 2] Figure 2 shows the Raman spectrum of the crystalline form. [Figure 3] Figure 3 shows the IR spectrum of the crystal morphology. [Figure 4] Figure 4 shows the powder X-ray diffractogram of the DMAc solvate. [Figure 5] Figure 5 shows the powder X-ray diffractogram of the NMP solvate. [Figure 6] Figure 6 shows the Raman spectra of DMAc and NMP solvates. [Figure 7] Figure 7 shows the IR spectrum of the DMAc solvate. [Figure 8] Figure 8 shows the IR spectrum of the NMP solvate. [Modes for carrying out the invention]

[0019] The starting point for preparing the crystalline form of the compound of formula (I) above by this method is the above formula (I) The compounds are N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl Formanilide, N-methyl-2-pyrrolidone, N-methylcaprolactam and hexa Selected from the group of methylphosphoramides, and very preferably N,N-dimethylacet At least one amide solution selected from the group consisting of amides and N-methyl-2-pyrrolidone. The presence of a reaction mixture dissolved in a medium. In a more preferred embodiment of the present invention, one The amide solvent is present, but the mixture of the aforementioned amide solvents is not.

[0020] Using N,N-dimethylacetamide, the compounds of formula (I) described below are further expressed. Crystalline N,N-dimethylacetamide solvate (DMAc solvate) is obtained. Using -2-pyrrolidone, the crystalline N-methyl of the compound of formula (I) described below is obtained. The ru-2-pyrrolidone solvate (NMP solvate) is obtained.

[0021] Compared to the crystalline compound of formula (I), DMAc solvate and NMP solvate are, It exhibits significantly improved filtration characteristics (see Table 5). The filtration resistance α measured in Table 5 is equal to the pressure. Filtration was measured by recording the filtration curve. The filtration test followed VDI guideline 2762. (Manufacturer: BHS Sonthofen, Model: Pocket Measuring Device KPL TMG) The filtration resistivity (α value) was determined in an apparatus according to 400). To measure the amount of precipitate in the filtrate (mother liquor), the suspension to be measured is introduced into the apparatus, and the amount of precipitate in the filtrate (mother liquor) is measured by applying a pressure difference. The volume was measured continuously. The filtrate volume V is recorded as a function of time t (filtrate curve). t / V By plotting against V, the filtration resistivity (m -2 Determining the alpha value (W. Beckmann: Crystallization - Basic Co) ncepts and Industrial Applications, Wiley (See also VCH, 2013, Chapter 14.2.3).

[0022] At least one amide solvent is preferably 2 to 20 times based on the compound of formula (I). It is used in excess by weight, particularly preferably 3 to 10 times excess by weight, in the reaction mixture.

[0023] The compound of formula (I) in at least one amide solvent is subjected to the addition of at least one poor solvent. Without doing so, the solvate can be obtained by lowering the temperature to allow crystallization. In this case, the temperature decrease is preferably slow, and particularly preferably in the range of 1 to 10°C / hour. More preferably, the procedure is carried out in the range of 1 to 5°C / hour, and further specified in the temperature range below. The compound of formula (I) in at least one amide solvent is, in this case, preferably homogeneous. It exists in a single mixture, which can be achieved, for example, by stirring.

[0024] With respect to the method described by the present invention, in preferred embodiments of the present invention, dissolution is essentially achieved. To reduce the degree and achieve a higher yield of the solvate, at least one poor solvent is used. It is used. Then, crystallization to obtain the solvate is carried out without lowering the temperature, or Overall, even higher process temperatures can be achieved. Particularly preferred in this invention In the embodiment, the presence of at least one poor solvent is required for crystallization to obtain the solvate. Alternatively, the addition and (preferably the subsequent) temperature reduction are combined. Poor solvents include water, acetonitrile, C1-C6 alcohols, toluene, and xylene. , esters of C1-C4 alcohols and formic acid, and esters of C1-C4 alcohols and acetic acid A poor solvent selected from the group of is preferably used. Particularly preferably, water, acetonitrile Toluene, methanol, ethanol, isopropanol, 1-butanol, toluene, and acetic acid. At least one poor solvent selected from the group of ethyls is used. A more preferred method of this invention In one embodiment, there is one type of poor solvent, and no mixture of the above-mentioned poor solvents.

[0025] In a more preferred embodiment of the present invention, at least one amide solvent and at least one The weight ratio of the poor solvent to the poor solvent is 10:1 to 1:1, particularly preferably 5:1 to 2:1, and very preferably The ratio is approximately 4:1.

[0026] At least one amide solvent is also required, and the solvent used must be inert under the reaction conditions. Before the crystallization of the mediator, for example, by increasing the temperature in a corresponding manner, a homogeneous state can be reached. The reaction mixture is already diluted with at least one poor solvent and a compound according to formula (I). It's fine if you do that.

[0027] Before adding at least one poor solvent to the reaction mixture, dissolve, for example, the compound of formula (II) The inert solvent, which is also passed through the reaction mixture with the liquid, is removed by appropriate means, for example, by distillation. It can be removed under reduced pressure by combining these substances.

[0028] The crystallization of the solvate by the above-described method of the present invention is preferably carried out at a temperature of -20 to +30°C. The process is carried out, particularly preferably at a temperature of -10 to +20°C, and generally under standard pressure.

[0029] However, it can also be carried out under vacuum or high pressure in an autoclave. It is possible. The reaction time depends on the batch size, amide solvent, poor solvent, and temperature, and is 1 hour. It can be selected within a range of several hours. Filtration is performed using filtration devices known to those skilled in the art, for example, This can be done in a pressurized suction filter or a centrifuge. Drying is done by drying methods known to those skilled in the art. This can be done in a drying apparatus, such as a horizontal or vertical mixer dryer or a suction dryer. Drying is carried out in a temperature range of 20 to 100°C, preferably 60 to 80°C. Drying is carried out in a pressure range of 1 to 100 mbar, preferably 5 to 20 mbar. It can be done.

[0030] Preferably, the above consists of the compound of formula (I) together with at least one amide solvent. The reactant mixture used in the method is, in the presence of an amide solvent, formula (II)

[0031] [ka]

[0032] The compound is given by formula (III) [ka] It is prepared by reacting it with the compound.

[0033] Coupling reactions can sometimes be carried out in the presence of a catalyst. For example, 4- Examples include dimethylaminopyridine or 1-hydroxybenzotriazole. An acid binder is not required for this reaction.

[0034] The coupling reaction is more preferably carried out by a compound of formula (III) in an amide solvent. II) Based on the compound, in equimolar amounts, or in a slightly excess of 1.0 to 1.2 molar equivalents This is carried out so that it is added first. Then, the compound of formula (II) is added, preferably 1 to 1 For 0 hours, preferably 2 to 5 hours, use a solvent, preferably an inert organic solvent. , or as a molten material, preferably -10 to +50°C, particularly preferably 0 to 40°C, very It is particularly preferably metered and supplied at a temperature of 10-30°C. This reaction generally takes place under standard pressure. This is done. However, or, working under vacuum or high pressure in an autoclave. This is also possible. After the reaction time is complete, it is preferable to remove the inert solvent as described above. It seems so.

[0035] The same amide solvent is used as the amide solvent for this coupling reaction in the reaction mixture. And it is used as described above.

[0036] The compound of formula (II) is used as a solid or molten material for this coupling reaction. It can be used. However, the compound of formula (II) dissolved in an inert organic solvent The use of a substance is preferred. In this context, the compound of formula (II) is preferably an aliphatic, lipid compound. An inert organic solvent selected from the group of cyclic and aromatic hydrocarbons, e.g., petroleum ether, he Xane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xy Len and decalin; halogenated hydrocarbons, e.g., chlorobenzene, dichlorobenzene , dichloromethane, chloroform, tetrachloromethane, dichloroethane and trichloro Roethane; ethers, e.g., diethyl ether, diisopropyl ether, methyl ether rt-butyl ether, methyl tert-amyl ether, dioxane, tetrahydroph Lan, 1,2-dimethoxyethane, 1,2-diethoxyethane, and anisole; ketones Similar substances, such as acetone, butanone, methyl isobutyl ketone, and cyclohexanone; nitrates Lyle compounds, such as acetonitrile, propionitrile, n- or isobutyronitrile, Benzonitriles; amides, such as N,N-dimethylformamide, N,N-dimethyl Acetamide, N-methylformanilide, N-methylpyrrolidone, and hexamethylhol It is dissolved in sforamide and mixtures thereof. The use of toluene is particularly preferred. be.

[0037] The compound of formula (III) is either known or prepared by a common synthetic method. This is possible (for example, Baker et al., J. Org. Chem. 1952, 149-153; G. Reissenweber et al., Angew. Chem 1981, 93, 914-9 15, PJ Montoya-Pelaez, J.Org.Chem.2006, 71 , 5921-5929;FESheibley, J.Org.Chem.1938, See 3, 414-423, WO2006023783A1).

[0038] In a preferred embodiment of the present invention, the compound of formula (II) is of formula (IV).

[0039] [ka] The compounds were subjected to the action of phosgene, phosphorus tribromide, phosphorus trichloride, and phosphorus pentachloride in the presence of an inert organic solvent. It reacts with an acid halide forming agent selected from the group consisting of phosphorus oxychloride and thionyl chloride. It is prepared by doing so.

[0040] The acid halogen-forming agent is preferably from the group consisting of phosgene, mesyl chloride, and thionyl chloride. The following are selected. Thionyl chloride is particularly preferred.

[0041] The reaction mixture starts with compounds of formulas (II) and (III) as the inert organic solvent. The above-mentioned inert organic solvents are used for the preparation of the product. Particularly preferred is toluene. It is for use.

[0042] This process step is preferably carried out at a temperature of +20 to +100°C, and particularly preferably at +50°C. The process is carried out at a temperature of ~+75°C, generally under standard pressure. Batch size, reactants used. Depending on the quality and temperature, the reaction time is in the range of 1 to 5 hours, preferably 1 to 3 hours. It is located there.

[0043] The pyrazolecarboxylic acid of formula (IV) is known or can be obtained by known methods. This is possible (see, for example, WO2011 / 157664A1). Due to the tetrazole group In general, pyrazole carboxylic acid of formula (IV) exists as a mixture of different positional isomers. do.

[0044] Another subject of the present invention is powder X-ray diffractometry at a temperature of 25°C using CuKα radiation. In Gram, it has at least the following reflectances: 8.3, 8.9, and 14.6, and is particularly preferred It has at least the following reflections: 8.3, 8.9, 10.4, 14.6, 15.5, and extremely Particularly preferred are reflections of at least the following values: 8.3, 8.9, 10.4, 12.7, and 14. Equation (I) has 6, 15.5, 27.6 (specified as 2θ / ° value ±0.2°)

[0045] [ka] This invention relates to the crystalline N,N-dimethylacetamide solvate of the compound. Preferably, Crystalline N,N-dimethylacetamide solvate (DMAc solvate) of the compound of formula (I) The DMAc solvate powder X-ray spectroscopy (abbreviated as ) has the reflection (2θ) specified in Table 3. The diffractogram is also shown in Figure 4.

[0046] A further subject of this invention is powder X-ray diffusion at a temperature of 25°C using CuKα radiation. The ctogram has at least the following reflectances: 8.3, 8.9, 14.6, and is particularly preferred. Or at least the following reflectances: 8.3, 8.9, 10.5, 14.6, 15.4, Very preferably, the following reflections: 8.3, 8.9, 10.5, 12.7, 1 Equations (I) have values ​​of 4.6, 15.4, and 27.6 (specified as 2θ / ° values ​​±0.2°). )

[0047] [ka] This relates to the crystalline N-methyl-2-pyrrolidone solvate of the compound. Preferably, the present invention The crystalline N-methyl-2-pyrrolidone solvate of the compound of formula (I) (abbreviated as NMP solvate) The NMP solvate powder X-ray diffraction has the reflection (2θ) specified in Table 3. The togram is also shown in Figure 5.

[0048] Powder X-ray diffraction data for DMAc and NMP solvates were all obtained at 25°C with a wavelength of 1.54 Using 18 Å CuKα radiation, the Bruker D2 with a LynxEye detector... Measurements were taken using a PHASER diffractometer. Data were obtained from horizontal Bragg-B measurements at 5–30° (2θ). With rentano(θ / 2θ) geometry, 0.0264119° steps in 0.5 seconds. Recorded in / step. The X-ray tube was operated at 30kV and 10mA. All X-ray reflections were recorded. This is identified as the 2θ (theta) value (maximum peak) with a resolution of ±0.2°.

[0049] The crystalline N,N-dimethylacetamide solvate and crystalline N-methyl-2-pyrrolidone solvate of the compound of formula (I) can be further characterized by IR and Raman spectroscopy. The corresponding Raman and IR spectra are shown in FIGS. 6, 7 and 8. All Raman spectra of the solvates were recorded at 25 °C with a Kaiser Raman RXN2 spectrometer using a fiber optic probe for in-situ detection. The system used had an MR probe for non-contact measurement. A NIR Kaiser Invictus Laser (785 nm) with 450 mW emission was used. The spectral range of this system extended from +100 to +3425 cm at a resolution of 4 cm. Mettler Toledo's iC Raman software was used for instrument configuration, data recording and data evaluation. The IR spectra of the solvates were recorded by FT-IR analysis in the spectral range of 400 - 4000 cm at a resolution of 4 cm using a Bruker Platinum ATR tensor II. Bruker's Opus software was used for instrument configuration, data recording and data evaluation.

[0050] The IR and Raman spectra of the DMAc and NMP solvates contain the bands listed in Table 4. Preferably, the Raman spectrum of the DMAc solvate has at least the following characteristic bands -1 -1

[0051] -1 -1

[0052]

[0053] ​​​​​​​​​​​​​​​​D: 3126, 1685, 1340, especially preferably the following bands: 3126, 3026 , 1685, 1340, 1306, and very preferably the following bands: 3126, 30 26, 2972, 1685, 1340, 1306, 963 (band [cm -1 ] as a special Determined; ±20cm each -1 ) has.

[0054] Preferably, the IR spectrum of the DMAc solvate has at least the following characteristic bands. :3234, 1525, 926, especially preferably the following bands:3234, 3124, 1 525, 1496, 926, and very preferably the following bands: 3234, 3124, 3078, 1525, 1496, 1016, 926 (band [cm -1 Identified as ] Each ±20cm -1 ) has.

[0055] Preferably, the Raman spectrum of the NMP solvate has at least the following characteristic bands. :3125, 1684, 1342, especially preferably the following bands:3125, 3024, 1684, 1342, 1305, and very preferably the following bands: 3125, 302 4, 2973, 1684, 1342, 1305, 963 (band [cm -1 ] as identified They are done; each by ±20cm -1 ) has.

[0056] Preferably, the IR spectrum of the NMP solvate has at least the following characteristic bands: 3234, 1525, 926, especially preferably the following bands: 3234, 3124, 15 25, 926, 848, and very preferably the following bands: 3234, 3124, 30 78, 1525, 1016, 926, 848 (band [cm) -1 ] is identified as; Each ±20cm -1 ) has. [Examples]

[0057] The present invention relates to the methods of the present invention, particularly to novel crystalline DMAc and NMP solvents of the compound of formula (I). The methods by which Japanese goods can be obtained are described in more detail below: Preparation example The following preparation examples are illustrative and not limiting to the present invention.

[0058] Example 1 1-(3-chloropyridine-2-yl)-3-[(5-(trifluoromethyl)-2H -Tetrazole-2-yl)methyl]-1H-pyrazole-5-carbonyl chloride (main isomers) and 1-(3-chloropyridine-2-yl)-3-{[5-(trifluoromethyl )-1H-tetrazol-1-yl]methyl}-1H-pyrazole-5-carbonylchloro Isomer mixture of lid (a minor component) 50.0g of 1-(3-chloropyridine-2-yl)-3-[(5-(trifluoromethyl [Tyl)-2H-tetrazol-2-yl)methyl]-1H-pyrazole-5-carboxylic acid and 1-(3-chloropyridine-2-yl)-3-{[5-(trifluoromethyl)- 1H-tetrazole-1-yl]methyl}-1H-pyrazole-5-carboxylic acid, 95 The 5 isomer mixture was first added to 200.0 g of toluene and heated to 75°C. 17.1 g of thionyl chloride was weighed and added within 1 hour, followed by stirring the mixture at 75°C for 1 hour. After the reaction was complete, the excess thionyl chloride was removed at 70°C and 150 mbar. The ene was removed by distillation along with a portion of it (distillate 27.0 g). This solution was then used to create a 95:5 isomer mixture. To obtain a solution of approximately 20% by weight of the product, use fresh toluene to prepare 240.0 g of The total weight was adjusted and used in the next step.

[0059] Example 2 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(meth Lucarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazo [Lu-2-yl)methyl]-1H-pyrazole-5-carboxamide (main isomer) and 1 -(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methyl cyano-2- [Rubamoyl)phenyl]-3-{[5-(trifluoromethyl)-1H-tetrazole- Isomer mixture of 1-ylmethyl}-1H-pyrazole-5-carboxamide (a minor component) a) 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6- (methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetra Razole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomers Preparation of solutions in N,N-dimethylacetamide (DMAc) 25.3g of 2-amino-5-cyano-N-3-dimethylbenzamide to 123.0g Dissolve in DMAc, then distill off with 20.0 g of DMAc at 65°C and 20 mbar. The mixture was cooled to 10-15°C, and the pre-prepared 1-(3-chloropyridine-2-I) was used. (Lu)-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl] -1H-pyrazole-5-carbonyl chloride and a 20% solution of its isomers should be prepared within 1 hour. After measuring and supplying the mixture, the mixture was stirred at 10-15°C for 3 hours once the addition was complete. Subsequently, the torrent was added. The ene was removed by distillation at 45-50°C and 30 mbar, thereby obtaining 1-( 3-Chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarb [(moyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2- [Iyl(methyl)]-1H-pyrazole-5-carboxamide and approximately 35 of its corresponding isomers A %w / w solution was obtained.

[0060] b) 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6- (methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetra Razole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomers Preparation of DMAc solvates 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl in DMAc -6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H Approximately 35% of -tetrazol-2-yl)methyl]-1H-pyrazole-5-carboxamide The %w / w solution was cooled to 25-30°C, and 27.0 g of methanol was added within 10 minutes. The mixture was cooled to 0-5°C for 2 hours, followed by stirring for 1 hour. Crystalline sample of the suspension. Under an optical microscope, it showed lozenge-shaped DMAc solvate crystals. The solvates are shown in Table 3 and Figure 4 for XRPD reflection, as well as in Table 4 and Figure 6 and Raman and IR spectra identified as 7 are shown.

[0061] c) 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6- (methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetra Razole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomers Isolation and drying of DMAc solvates To ensure a complete yield, add 30.0g of water to the above suspension within 10 minutes, then 0 The mixture was stirred at ~5°C for 1 hour. The solid was filtered off using a suction filter, and 50.0 g of DMA was added. Wash with a mixture of c and 50.0g of water at 0-5°C, then heat the wet filter cake at 80°C. It was then dried at 10 mbar. 66.0 g of the product (89% yield) was used to achieve a purity of approximately 95%. It was obtained as a 95:5 isomer mixture in crystalline form. The obtained crystalline forms are shown in Table 1 and Figure 1. Identified characteristic powder X-ray diffractograms, as well as those shown in Table 2 and Figures 2 and 3. The determined Raman and IR spectra were shown.

[0062] Example 3 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(meth Lucarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazo [Lu-2-yl]methyl-1H-pyrazole-5-carboxamide and its isomer DMA Preparation of c solvates using another poor solvent, and in some cases without using a poor solvent. 1-(3-chloropyridine-2-yl)- in DMAc prepared according to Example 2a N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5- (trifluoromethyl)-2H-tetrazol-2-yl)methyl]-1H-pyrazole Cool 175.0 g of a 35% w / w solution of -5-carboxamide and its isomer to 30°C. 27.0 g of one of the following solvents, or a mixture of the following solvents, within 10 minutes. Added: Ethanol, 2-propanol, 1-butanol, toluene, xylene, acetic acid Ethyl or isopropyl acetate. In some cases, a poor solvent was not added. Then batch The mixture was cooled to 0-5°C within 2 hours, followed by stirring for 1 hour. If necessary, crystallization was initiated. To achieve this, seed crystals were introduced into the solution by adding a small amount of solvate. The sample also showed lozenge-shaped DMAc solvate crystals under an optical microscope. The DMAc solvate is shown in Table 3 and Figure 4 for XRPD reflection, as well as in Table 4 and Figure 4. Raman and IR spectra identified as 6 and 7 are shown.

[0063] Example 4 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(meth Lucarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazo [Lu-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomer NMP Preparation and drying of solvates 1-(3-chloropyridine-2-yl)-N in NMP prepared according to Example 2a -[4-Cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-( Trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole- 114.0 g of a 35% w / w solution of 5-carboxamide and its isomer was cooled to 30°C. 17.0 g of methanol was added within 10 minutes. The mixture was left to stand for 2 hours at 0-5°C. The suspension was cooled and then stirred for 1 hour. The crystalline sample was observed in lozenge form under an optical microscope. The NMP solvate crystals were shown. The obtained NMP solvates are described in Table 3 and Figure 5. XRPD reflection, as well as Raman and IR spectral data specified in Table 4 and Figures 6 and 8. He showed Tor.

[0064] Use a suction filter to filter out the solids, and leave the moist filter cake at 80°C and 10°C. The product was dried at mbar. 31.4 g of the product was obtained as a crystalline 95:5 isomer mixture. The obtained crystal morphology is a characteristic powder X-ray diffractometer identified in Table 1 and Figure 1. Gram, as well as the Raman and IR spectra identified in Table 2 and Figures 2 and 3, are shown. did.

[0065] Solvate samples for powder X-ray diffraction, IR, and Raman analysis are prepared by methods known to those skilled in the art. Therefore, it was provided.

[0066] Table 1: Powder X-ray diffraction [Table 1]

[0067] Table 2: IR and Raman bands [Table 2] TIFF2026053590000011.tif234157

[0068] Table 3: Powder X-ray diffraction [Table 3]

[0069] Table 4: IR and Raman bands [Table 4] TIFF2026053590000014.tif45127

[0070] Table 5: Filtration resistance α [Table 5]

Claims

1. Equation (I) 【Chemistry 1】 The compound is dissolved in at least one amide solvent, and in the presence of at least one poor solvent... , and / or by lowering the temperature, crystallization is performed to obtain a solvate, which is then filtered, A method for preparing a compound of formula (I) in crystalline form, characterized by drying.

2. For crystallization to obtain the solvate, at least one poor solvent is present, and temperature The method according to claim 1, characterized in that a decrease in starts.

3. The above at least one amide solvent is N,N-dimethylformamide, N,N-dimethyl Luacetamide, N-methylformanilide, N-methyl-2-pyrrolidone, N-methyl Characterized by being selected from the group consisting of caprolactam and hexamethylphosphoramide. The method according to any one of claims 1 to 2.

4. The above at least one poor solvent is water, acetonitrile, C １ -C ６ Alcohol, True N, xylene, C １ -C ４ Esters of alcohol and formic acid and C １ -C ４ Alcohol and vinegar The method described in any one of claims 1 to 3, characterized by being selected from the group of acid esters. The method.

5. The weight ratio of the at least one amide solvent to the at least one poor solvent is 10: The method according to any one of claims 1 to 4, characterized in that the ratio is 1 to 1:

1.

6. Claim 1, characterized in that the crystallization of the solvate is carried out at a temperature of -20 to +30°C. The method described in any one of items (5) above.

7. In the presence of an amide solvent, formula (II) 【Chemistry 2】 The compound of formula (III) 【Transformation 3】 This method is characterized by preparing the compound of formula (I) in an amide solvent by reacting it with the compound of [another compound]. The method according to any one of claims 1 to 6.

8. In the presence of an inert organic solvent, formula (IV) 【Chemistry 4】 The compounds include phosgene, phosphorus tribromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and salts. By reacting with an acid halide forming agent selected from the group of thionyl compounds, formula (II The method according to claim 7, characterized by preparing a compound of ).

9. In a powder X-ray diffractogram at 25°C using CuKα radiation, at least The following reflections are observed: 8.3, 8.9, 14.6 (specified as a °²θ value ±0.2°). ru, formula (I) 【Transformation 5】 The crystalline N,N-dimethylacetamide solvate of the compound.

10. The Raman spectrum shows at least the following bands: 3126, 1685, 1340 (band) do [cm －１ ] is identified as; each ±20 cm －１ ) characterized by having , a crystalline N,N-dimethylacetamide solvate of the compound of formula (I) according to claim 9.

11. In a powder X-ray diffractogram at 25°C using CuKα radiation, at least The following reflections are observed: 8.3, 8.9, 14.6 (specified as a °²θ value ±0.2°). ru, formula (I) 【Transformation 6】 The crystalline N-methyl-2-pyrrolidone solvate of the compound.

12. The Raman spectrum shows at least the following bands: 3125, 1684, 1342 (bands) cm －１ is specified as; ±2 cm each －１ characterized by having , a crystalline N-methyl-2-pyrrolidone solvate of the compound of formula (I) according to claim 11.

13. For the preparation of a compound of formula (I) in crystalline form, the formula (I) according to claim 9 or 10. The crystalline N,N-dimethylacetamide solvate of the compound and / or claim 11 if The use of the crystalline N-methyl-2-pyrrolidone solvate of the compound of formula (I) described in 12. 。

14. The compound of formula (I) undergoes powder X-ray diffractometry at a temperature of 25°C using CuKα radiation. Gram's reflections (2θ) are at least the following: 5.8°, 6.4°, 11.6°, 17.5° It has angles of 19.8°, 20.8°, 23.5°, and 24.2° (each with a tolerance of ±0.2°). The method according to any one of claims 1 to 8, characterized by obtaining a crystalline form, The use described in claim 13.

15. The compound of formula (I) has a Raman spectrum that shows at least the following bands [cm] －１ ]: 2928, 1663, 1386, 1334, 1022, 638 (each ±20 cm) －１ The crystalline form obtained is characterized by having the following characteristics, according to any one of claims 1 to 8. The method or use as described in claim 13.

16. The compound of formula (I) has an IR spectrum that contains at least the following bands [cm] －１ ]:3 286, 1662, 1219, 1181, 1154, 1055 (each ±20 cm) －１ The crystalline form obtained is characterized by having the following characteristics, according to any one of claims 1 to 8. The method or use as described in claim 13.

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