Method for producing tetrazole-substituted anthranilic acid diamide derivatives

Abstract

The present invention relates to a method for preparing tetrazole-substituted anthranilic acid diamide derivatives according to formula (I) in crystalline form using solvate crystals with high purity and yield.The present invention also relates to the preparation of novel solvate crystals in crystalline form, which are characterized by improved filtration properties in contrast to the tetrazole-substituted anthranilic acid diamide derivatives according to formula (I) above. TIFF2023540965000022.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] The present invention relates to a method for producing tetrazole-substituted anthranilic acid diamide derivatives. The present invention also relates to a novel solvent-solvate crystal characterized by improved filtration properties compared to the crystalline form of the tetrazole-substituted anthranilic acid diamide derivative according to the above formula (I). [Background technology]

[0003] WO2011 / 157664A1 describes a method for producing tetrazole-substituted anthranilic acid diamide derivatives, particularly the derivative according to formula (I) above. WO2011 / 157664A1 also describes a method for preparing the crystalline form of the tetrazole-substituted anthranilic acid diamide derivative according to formula (I) above, which, due to its physicochemical properties, allows for the production of a stable formulation that is easy to handle.

[0004] The drawback of the method described in WO2011 / 157664A1 lies in its filtration properties and the physical characteristics of the crystalline form of the tetrazole-substituted anthranilic acid diamide derivative according to formula (I) above. According to the method described in WO2011 / 157664A1, the compound according to formula (I) above precipitates in a fine, needle-like form during isolation by filtration, resulting in a long filtration time and a high residual moisture content in the filter cake. The high residual moisture content in the filter cake further leads to a long drying time for the wet substance. Due to the problems described, the method described in WO2011 / 157664A1 for preparing the tetrazole-substituted anthranilic acid diamide derivative according to formula (I) above is not suitable for large-scale industrial production. [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 provide a novel method for preparing tetrazole-substituted anthranilic acid diamide derivatives according to the above formula (I) in crystalline form with high purity and high yield, which is also advantageous in large-scale industrial production considering economic factors.

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

[0008] [ka] This was achieved by the present invention, which is a method for preparing a compound of formula (I) in crystalline form, characterized by dissolving the compound 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, and then filtering and drying it.

[0009] The present invention also relates to solvent-solvate crystals of formula (I) formed by the method according to the present invention, characterized by improved filtration properties compared to tetrazole-substituted anthranilic acid diamide derivatives of formula (I) described in WO2011 / 157664A1. Therefore, the formation of solvent-solvate crystals of the compound of formula (I) is important for the economic feasibility of the method according to the present invention and its feasibility on an industrial production scale.

[0010] WO2011 / 157664A1 does not describe solvent-solvate crystals, nor the possibility of their formation, nor their favorable properties. Although amide solvents are known to be good solvents for compounds of formula (I), it was surprisingly possible to obtain solvent-solvate crystals from amide solvents in the course of the method according to the present invention.

[0011] Furthermore, what is particularly remarkable is that, in the process of the method according to the present invention, the compound of formula (I) can be obtained in its thermodynamically stable crystalline form by drying the solvate crystal.

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

[0013] Similarly preferably, the method of the present invention provides a compound of formula (I) in a crystalline form having a characteristic powder X-ray diffractogram, Raman spectrum, and IR spectrum (Tables 1 and 2, Figures 1, 2, and 3). This crystalline form of the compound of formula (I) is characterized in that its powder X-ray diffractogram using CuKα radiation at a temperature of 25°C has at least the following reflectances (2θ): 5.8°, 6.4°, 11.6°, 17.5°, 19.8°, 20.8°, 23.5°, and 24.2° (each ±0.2°). Preferably, the powder X-ray diffractogram of the crystalline form using CuKα radiation at 25°C has at least the following further reflectances (2θ): 10.2°, 12.8°, 16.7°, 19.0°, 25.3°, 27.5°, and 29.4° (each ±0.2°). In a more preferred variant of the present invention, a powder X-ray diffractogram of a crystalline form using CuKα radiation at a temperature of 25°C 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 Raman spectrum of the crystalline form 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 ±2 ocm -1 ) It has. In a more particularly preferred embodiment of the present invention, the IR spectrum of the crystalline form essentially corresponds to the spectrum shown in FIG. 3.

[0016] All powder X-ray diffraction data of the crystalline form were obtained at 25 °C using the following acquisition parameters: Diffractometer type: PANalytic X’Pert PRO Anode material: Copper Radiation: CuKα1 Wavelength: 1.54060 Å Scan mode: Transmittance Scan type: 2θ: Omega Range: 2θ (peak maximum) ±0.2° The Raman spectrum of the crystalline form was recorded at 25 °C and a laser wavelength of 1064 nm and a resolution of 2 cm -1 using an FT Raman spectrometer from Bruker (e.g., RFS100 type or MultiRam type).

[0017] The IR spectrum of the crystalline form was recorded at 25 °C using a Bruker IR spectrometer (e.g., Tensor 37 type) having a universal diamond ATR unit with a resolution of 4 cm -1 .

Brief Description of the Drawings

[0018] [Figure 1] FIG. 1 shows the powder X-ray diffractogram of the crystalline form. [Figure 2] FIG. 2 shows the Raman spectrum of the crystalline form. [Figure 3] FIG. 3 shows the IR spectrum of the crystalline form. [Figure 4] FIG. 4 shows the powder X-ray diffractogram of the DMAc solvate. [Figure 5] FIG. 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 compound of formula (I) by this method is the presence of a reaction mixture in which the compound of formula (I) is dissolved in at least one amide solvent selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methyl-2-pyrrolidone, N-methylcaprolactam, and hexamethylphosphoramide, and very preferably selected from the group consisting of N,N-dimethylacetamide and N-methyl-2-pyrrolidone. In a more preferred embodiment of the present invention, there is one amide solvent and no mixture of the above amide solvents.

[0020] Using N,N-dimethylacetamide, a crystalline N,N-dimethylacetamide solvate (DMAc solvate) of the compound of formula (I) described below is obtained. Using N-methyl-2-pyrrolidone, a crystalline N-methyl-2-pyrrolidone solvate (NMP solvate) of the compound of formula (I) described below is obtained.

[0021] Compared to the crystalline compound of formula (I), DMAc solvates and NMP solvates exhibit significantly improved filtration properties (see Table 5). The filtration resistance α measured in Table 5 was determined by recording a pressure filtration curve. Filtration tests were performed in an apparatus for determining the filtration resistivity (α value) according to VDI guideline 2762 (manufacturer: BHS Sonthofen, model: pocket measuring instrument KPL TMG 400). For this purpose, the suspension to be measured was introduced into the apparatus, and the amount of precipitate in the filtrate (mother liquor) was continuously measured by applying a pressure difference. The filtrate volume V was recorded as a function of time t (filtrate curve). By plotting t / V against V, the filtration resistivity (m -2 The alpha value can be determined (see also W. Beckmann: Crystallization - Basic Concepts and Industrial Applications, Wiley-VCH, 2013, Chapter 14.2.3).

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

[0023] The compound of formula (I) in at least one amide solvent can be crystallized by lowering the temperature to obtain a solvate without adding at least one poor solvent. In this case, the temperature decrease is preferably carried out slowly, particularly preferably in the range of 1 to 10°C / hour, more preferably in the range of 1 to 5°C / hour, and further specified below. In this case, the compound of formula (I) in at least one amide solvent is preferably present in a homogeneous mixture, which can be achieved, for example, by stirring.

[0024] With respect to the methods described by the present invention, in preferred embodiments of the present invention, at least one poor solvent is used to essentially reduce solubility and achieve a higher yield of the solvate. Crystallization to obtain the solvate can then be carried out without lowering the temperature, or even at a higher process temperature overall. In particularly preferred embodiments of the present invention, the presence or addition of at least one poor solvent and (preferably subsequent) temperature reduction are combined for crystallization to obtain the solvate. Preferably, the at least one poor solvent is selected from the group consisting of water, acetonitrile, C1-C6 alcohols, toluene, xylene, esters of C1-C4 alcohols and formic acid, and esters of C1-C4 alcohols and acetic acid. Particularly preferred, at least one poor solvent is selected from the group consisting of water, acetonitrile, methanol, ethanol, isopropanol, 1-butanol, toluene, and ethyl acetate. In even more preferred embodiments of the present invention, one poor solvent is present, and no mixture of the above poor solvents is present.

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

[0026] At least one amide solvent may also be already diluted with at least one poor solvent and a compound according to formula (I) in the reaction mixture, provided that the solvent used is inert under the reaction conditions and reaches a homogeneous state before crystallization of the solvate, for example by correspondingly increasing the temperature.

[0027] Prior to the addition of at least one poor solvent to the reaction mixture, the inert solvent, which is also passed through the reaction mixture with, for example, a solution of the compound of formula (II), can be removed by appropriate means, for example, by distillation, and possibly under reduced pressure.

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

[0029] However, the reaction can also be carried out under vacuum or high pressure in an autoclave. The reaction time can be selected from 1 hour to several hours, depending on the batch size, amide solvent, poor solvent, and temperature. Filtration can be carried out using filtration equipment known to those skilled in the art, such as a pressurized suction filter or a centrifuge. Drying can be carried out using drying equipment known to those skilled in the art, such as a horizontal or vertical mixer dryer or a suction dryer. Drying can be carried out in a temperature range of 20 to 100°C, preferably 60 to 80°C. Drying can be carried out in a pressure range of 1 to 100 mbar, preferably 5 to 20 mbar.

[0030] Preferably, the reactant mixture used in the above method, consisting of the compound of formula (I) above, together with at least one amide solvent, is in the presence of the 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] The coupling reaction may be carried out in the presence of a catalyst, such as 4-dimethylaminopyridine or 1-hydroxybenzotriazole. Further acid binders are not required for this reaction.

[0034] The coupling reaction is carried out so that the compound of formula (III) in an amide solvent is initially added in equimolar amounts based on the compound of formula (II), or in a slightly excess amount of 1.0 to 1.2 molar equivalents. The compound of formula (II) is then metered and supplied as a solvent, preferably in an inert organic solvent, or as a melt, at a temperature preferably -10 to +50°C, particularly preferably 0 to 40°C, and very particularly preferably 10 to 30°C, over a period of preferably 1 to 10 hours, preferably 2 to 5 hours. This reaction is generally carried out under standard pressure. However, it is also possible to carry it out under vacuum or high pressure in an autoclave. After the reaction time is complete, it is preferable to remove the inert solvent as described above.

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

[0036] The compound of formula (II) can be used as a solid or a molten material for this coupling reaction. However, the use of the compound of formula (II) dissolved in an inert organic solvent is preferred. In this context, the compound of formula (II) is preferably an inert organic solvent selected from the group of aliphatic, alicyclic, and aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, and decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane, and trichloroethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-butyl ether, and methyl tert-butyl ether. It is soluble in t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, and anisole; ketones, such as acetone, butanone, methyl isobutyl ketone, and cyclohexanone; nitriles, such as acetonitrile, propionitrile, n- or isobutyronitrile, or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, and hexamethylphosphoramide, and mixtures thereof. The use of toluene is particularly preferred.

[0037] The compound of formula (III) is known or can be prepared by common synthetic methods (see, for example, Baker et al., J. Org. Chem. 1952, 149-153; G. Reissenweber et al., Angew. Chem 1981, 93, 914-915; P.J. Montoya-Pelaez, J. Org. Chem. 2006, 71, 5921-5929; F. Sheibley, J. Org. Chem. 1938, 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 compound is prepared by reacting it with an acid halide-forming agent selected from the group consisting of phosgene, phosphorus tribromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and thionyl chloride, in the presence of an inert organic solvent.

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

[0041] As inert organic solvents, the inert organic solvents already described above are used for the preparation of reaction mixtures starting from the compounds of formulas (II) and (III). Toluene is particularly preferred.

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

[0043] The pyrazole carboxylic acids of formula (IV) are known or can be obtained by known methods (see, for example, WO2011 / 157664A1). Due to the tetrazole group, the pyrazole carboxylic acids of formula (IV) generally exist as mixtures of different positional isomers.

[0044] Another subject of the present invention is formula (I) having at least the following reflectances in a powder X-ray diffractogram at a temperature of 25°C using CuKα radiation: 8.3, 8.9, 14.6, particularly preferably at least the following reflectances: 8.3, 8.9, 10.4, 14.6, 15.5, and most particularly preferably at least the following reflectances: 8.3, 8.9, 10.4, 12.7, 14.6, 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, the crystalline N,N-dimethylacetamide solvate (abbreviated as DMAc solvate) of the compound of formula (I) of the present invention has the reflectance (2θ) specified in Table 3. The powder X-ray diffractogram of the DMAc solvate is also shown in Figure 4.

[0046] A further subject of the present invention is formula (I) having at least the following reflectances in a powder X-ray diffractogram at a temperature of 25°C using CuKα radiation: 8.3, 8.9, 14.6, particularly preferably at least the following reflectances: 8.3, 8.9, 10.5, 14.6, 15.4, and most particularly preferably at least the following reflectances: 8.3, 8.9, 10.5, 12.7, 14.6, 15.4, 27.6 (specified as 2θ / ° value ±0.2°).

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

[0048] Powder X-ray diffraction data for DMAc and NMP solvates were all measured using CuKα radiation at a wavelength of 1.5418 Å at 25°C on a Bruker D2 PHASER diffractometer with a LynxEye detector. Data were recorded at 0.0264119° steps and 0.5 sec / step on a horizontal Bragg-Brentano(θ / 2θ) geometry of 5–30°(2θ). The X-ray tube was operated at 30 kV and 10 mA. All X-ray reflections are identified as 2θ (theta) values ​​(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.

[0050] 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 was equipped with an MR probe for non-contact measurements. A NIR Kaiser Invictus Laser (785 nm) with an emission of 450 mW was used. The spectral range of this system was +100 to +3425 cm -1 with a resolution of 4 cm -1 . Mettler Toledo's iC Raman software was used for instrument configuration, data recording and data evaluation.

[0051] The IR spectra of the solvates were recorded by FTIR analysis in the spectral range of 400 to 4000 cm -1 with a resolution of 4 cm -1 using a Bruker Platinum ATR tensor II. Bruker's Opus software was used for instrument configuration, data recording and data evaluation.

[0052] The IR and Raman spectra of the DMAc and NMP solvates contain the bands listed in Table 4.

[0053] Preferably, the Raman spectrum of the DMAc solvate has at least the following characteristic bands: 3126, 1685, 1340, particularly preferably the following bands: 3126, 3026, 1685, 1340, 1306, very particularly preferably the following bands: 3126, 3026, 2972, 1685, 1340, 1306, 963 (bands [cm -1 specified as; each ±2 cm -1 ).

[0054] Preferably, the IR spectrum of the DMAc solvate has at least the following characteristic bands: 3234, 1525, 926, particularly preferably the following bands: 3234, 3124, 1525, 1496, 926, and very preferably the following bands: 3234, 3124, 3078, 1525, 1496, 1016, 926 (bands [cm²] -1 ] is 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, particularly preferably the following bands: 3125, 3024, 1684, 1342, 1305, and very preferably the following bands: 3125, 3024, 2973, 1684, 1342, 1305, 963 (band [cm] -1 ] is identified as; each ±20cm -1 ) has.

[0056] Preferably, the IR spectrum of the NMP solvate has at least the following characteristic bands: 3234, 1525, 926, particularly preferably the following bands: 3234, 3124, 1525, 926, 848, and very preferably the following bands: 3234, 3124, 3078, 1525, 1016, 926, 848 (bands [cm] -1 ] is identified as; each ±20cm -1 ) has. [Examples]

[0057] The methods of the present invention, in particular, the means by which novel crystalline DMAc and NMP solvates of the compound of formula (I) are 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 A mixture of isomers of 1-(3-chloropyridine-2-yl)-3-[(5-(trifluoromethyl)-2H-tetrazol-2-yl)methyl]-1H-pyrazole-5-carbonyl chloride (main isomer) and 1-(3-chloropyridine-2-yl)-3-{[5-(trifluoromethyl)-1H-tetrazol-1-yl]methyl}-1H-pyrazole-5-carbonyl chloride (minor component). 50.0 g of 1-(3-chloropyridine-2-yl)-3-[(5-(trifluoromethyl)-2H-tetrazole-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 as a 95:5 isomer mixture was first added to 200.0 g of toluene and heated to 75°C. 17.1 g of thionyl chloride was added by weighing within 1 hour, and the mixture was subsequently stirred at 75°C for 1 hour. After the reaction was complete, the excess thionyl chloride was removed by distillation at 70°C and 150 mbar along with a portion of the toluene (distillate 27.0 g). This solution was prepared to a total weight of 240.0 g using fresh toluene to obtain a solution of approximately 20% by weight of the product as a 95:5 isomer mixture, and was thus used in the next step.

[0059] Example 2 A mixture of isomers of 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazol-2-yl)methyl]-1H-pyrazole-5-carboxamide (main isomer) and 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-{[5-(trifluoromethyl)-1H-tetrazol-1-yl]methyl}-1H-pyrazole-5-carboxamide (minor component). a) Preparation of solutions of 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomer in N,N-dimethylacetamide (DMAc) 25.3 g of 2-amino-5-cyano-N-3-dimethylbenzamide was dissolved in 123.0 g of DMAc, followed by distillation off with 20.0 g of DMAc at 65°C and 20 mbar. The mixture was cooled to 10-15°C, and a pre-prepared 20% solution of 1-(3-chloropyridine-2-yl)-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carbonyl chloride and its isomer was weighed and added within 1 hour. After the addition was complete, the mixture was stirred at 10-15°C for 3 hours. Next, toluene was removed by distillation at 45-50°C and 30 mbar, thereby obtaining approximately 35% w / w solutions of 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carboxamide and the corresponding isomers in DMAc.

[0060] b) Preparation of 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomer DMAc solvates A roughly 35% w / w solution of 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carboxamide in DMAc 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 over 2 hours, followed by stirring for 1 hour. Crystallographic samples of the suspension showed lozenge-shaped DMAc solvate crystals under an optical microscope. The obtained DMAc solvate exhibited XRPD reflectances as described in Table 3 and Figure 4, as well as Raman and IR spectra as specified in Table 4 and Figures 6 and 7.

[0061] c) Isolation and drying of 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomer DMAc solvates To ensure a complete yield, 30.0 g of water was added to the suspension within 10 minutes, followed by stirring at 0–5°C for 1 hour. The solid was filtered using a suction filter and washed with a mixture of 50.0 g of DMAc and 50.0 g of water at 0–5°C. The moistened filter cake was dried at 80°C and 10 mbar. 66.0 g of the product (89% yield) was obtained as a 95:5 isomer mixture with a purity of 95% and in crystalline form. The resulting crystalline forms were shown in characteristic powder X-ray diffractograms identified in Table 1 and Figure 1, as well as in Raman and IR spectra identified in Table 2 and Figures 2 and 3.

[0062] Example 3 Preparation of 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomer DMAc solvates using another poor solvent, and in some cases without a poor solvent. 175.0 g of a 35% w / w solution of 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomers in DMAc, prepared according to Example 2a, was cooled to 30°C. 27.0 g of one of the following solvents, or a mixture of the following solvents, was added within 10 minutes: ethanol, 2-propanol, 1-butanol, toluene, xylene, ethyl acetate, or isopropyl acetate. In some cases, no poor solvent was added. The batch was then cooled to 0-5°C within 2 hours, followed by stirring for 1 hour. In some cases, seed crystals were added to the solution by adding a small amount of solvate to initiate crystallization. Crystallized samples of the suspension also showed lozenge-shaped DMAc solvate crystals under a light microscope. The obtained DMAc solvates exhibited XRPD reflectances as shown in Table 3 and Figure 4, as well as Raman and IR spectra as specified in Table 4 and Figures 6 and 7.

[0063] Example 4 Preparation and drying of 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomer NMP solvates. 114.0 g of a 35% w / w solution of 1-(3-chloropyridine-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomer in NMP, prepared according to Example 2a, was cooled to 30°C. 17.0 g of methanol was added within 10 minutes. The mixture was cooled to 0-5°C over 2 hours, followed by stirring for 1 hour. Crystallographic samples of the suspension showed lozenge-shaped NMP solvate crystals under an optical microscope. The obtained NMP solvate exhibited XRPD reflectances as described in Table 3 and Figure 5, as well as Raman and IR spectra as specified in Table 4 and Figures 6 and 8.

[0064] The solid was filtered off using a suction filter, and the moist filter cake was dried at 80°C and 10 mbar. 31.4 g of the product was obtained as a crystalline mixture of 95:5 isomers. The obtained crystalline forms were shown in characteristic powder X-ray diffractograms identified in Table 1 and Figure 1, as well as in Raman and IR spectra identified in Table 2 and Figures 2 and 3.

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

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

[0067] Table 2: IR and Raman bands [Table 2] TIFF0007834723000010.tif234157

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

[0069] Table 4: IR and Raman bands [Table 4] TIFF0007834723000013.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... By lowering the temperature, crystallization is performed to obtain a solvate, which is then filtered and dried. A method for preparing a compound of formula (I) in crystalline form, characterized by the following: Both are poor solvents, such as acetonitrile and C １ -C ６ Alcohol, Toluene, Xylene, C １ -C ４ Esters of alcohol and formic acid and C １ -C ４ A group of alcohol and acetic acid esters Selected from, the weight of the at least one amide solvent and the at least one poor solvent The method wherein the ratio is between 10:1 and 1:

1.

2. 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 claim 1.

3. Claim 1, characterized in that the crystallization of the solvate is carried out at a temperature of -20 to +30°C. Or the method described in 2.

4. In the presence of an amide solvent, formula (II) 【Chemistry 2】 The compound of formula (III) 【Transformation 3】 The method according to any one of claims 1 to 3, characterized in that a compound of formula (I) is prepared in an amide solvent by reacting it with a compound of the same name.

5. 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 4, characterized by preparing a compound of ).

6. 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.

7. The Raman spectrum shows at least the following bands: 3126, 1685, 1340 (band) do [cm －１ ] is identified as; ±2 cm each －１ ) characterized by having , a crystalline N,N-dimethylacetamide solvate of the compound of formula (I) according to claim 6.

8. 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.

9. The Raman spectrum shows at least the following bands: 3125, 1684, 1342 (bands) in [cm －１ and is specified as; each of ±2 cm －１ ), characterized by having , a crystalline N-methyl-2-pyrrolidone solvate of the compound of formula (I) as described in claim 8.

10. For the preparation of a compound of formula (I) in crystalline form, the formula (I) according to claim 6 or 7 Crystalline N,N-dimethylacetamide solvate of the compound and / or claim 8 or Use of the crystalline N-methyl-2-pyrrolidone solvate of the compound of formula (I) described in 9.

11. 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 5, characterized by obtaining a crystalline form, The use described in claim 10.

12. 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 ±2° cm) －１ The crystalline form obtained is characterized by having the following characteristics, according to any one of claims 1 to 5. The method or use according to claim 10.

13. 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 ±2°cm) －１ The crystalline form obtained is characterized by having the following characteristics, according to any one of claims 1 to 5. The method or use according to claim 10.

Images