Process for the preparation of tetrazole substituted anthranilic acid diamide derivatives

Abstract

The present invention relates to a process for the preparation of tetrazole substituted anthranilic acid diamide derivatives of formula (I) in crystalline form with high purity and high yield using solvate crystals. The present invention also relates to the preparation of new solvate crystals characterized by improved filtration properties compared to tetrazole substituted anthranilic acid diamide derivatives according to formula (I) above in crystalline form.

Description

[0001] This invention relates to a method for preparing crystalline tetrazolium-substituted anthranilic acid diamide derivatives of formula (I) in high purity and high yield via solvate crystals. The invention further relates to novel solvent-solvate crystals characterized by improved filtration properties compared to crystalline tetrazolium-substituted anthranilic acid diamide derivatives of formula (I) described above.

[0002]

[0003] WO2011 / 157664A1 discloses a method for preparing, in particular, tetrazolium-substituted anthranilic acid diamide derivatives according to formula (I) above. WO2011 / 157664A1 also discloses a method for preparing crystalline tetrazolium-substituted anthranilic acid diamide derivatives according to formula (I) above, which are easy to handle and can be used to prepare stable formulations due to their physicochemical properties.

[0004] A drawback of the method described in WO2011 / 157664A1 is the physical properties of the tetrazolium-substituted anthranilic acid diamide derivative according to formula (I) in terms of its filtration properties. According to the method described in WO2011 / 157664A1, the compound according to formula (I) precipitates as fine needles, resulting in long filtration times and high residual moisture content in the filter cake during the separation process. The high residual moisture content in the filter cake also leads to prolonged drying times for the wet material. Due to these problems, the method described in WO2011 / 157664A1 for preparing the tetrazolium-substituted anthranilic acid diamide derivative according to formula (I) is unsuitable for large-scale industrial production.

[0005] Therefore, the object of the present invention is to provide a novel method for preparing crystalline tetrazolium-substituted o-aminobenzoic acid diamide derivatives according to the above formula (I) in high purity and high yield, which is also advantageous for large-scale industrial production taking into account economic factors.

[0006] According to the present invention, this objective is achieved by a method for preparing a compound of formula (I) in crystalline form.

[0007]

[0008] The solvate is characterized by dissolving the compound of formula (I) in at least one amide solvent and crystallizing it in the presence of at least one antisolvent and / or by lowering the temperature, followed by filtration and drying.

[0009] The present invention further relates to a solvent-solvent crystal of formula (I) formed in the method of the present invention, characterized in that it has improved filtration properties compared with the tetrazolium-substituted anthranilic acid diamide derivative of formula (I) in the crystalline form described in WO2011 / 157664A1. Therefore, the formation of solvent-solvent crystals of the compound of formula (I) is crucial to the economic feasibility of the method of the present invention and its feasibility on an industrial scale.

[0010] WO2011 / 157664A1 does not describe solvent-solvent crystals, nor the possibility of their formation, nor their advantageous properties. Unexpectedly, in the process of the method of the present invention, solvent-solvent crystals can be obtained from amide solvents, even though amide solvents are known to be good solvents for compounds of formula (I).

[0011] What is particularly surprising is that, in the process of the method of the present invention, the compound of formula (I) can be obtained in its thermodynamically stable crystalline form by drying solvate crystals.

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

[0013] Also preferably, the method of the present invention provides a crystalline form of the compound of formula (I) having a characteristic X-ray powder diffraction pattern, 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 X-ray powder diffraction pattern, when irradiated with Cu Kα at a temperature of 25°C, has 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). Preferably, the X-ray powder diffraction pattern of the crystalline form, when irradiated with Cu Kα at a temperature of 25°C, has at least the following further reflections (2θ): 10.2°, 12.8°, 16.7°, 19.0°, 25.3°, 27.5°, and 29.4° (±0.2° in each case). In another preferred variant of the invention, the X-ray powder diffraction pattern of the crystalline form at a temperature of 25°C and using Cu Kα radiation substantially corresponds to the diffraction pattern depicted in Figure 1.

[0014] Particularly preferably, the Raman spectrum of this crystalline form has at least the following bands [cm] -1 ]:2927,1663,1386,1334,1022,638 (±2°cm in each case) -1 In another particularly preferred embodiment of the invention, the Raman spectrum of the crystalline form substantially corresponds to the spectrum depicted in Figure 2.

[0015] Particularly preferably, the IR spectrum of this crystalline form has at least the following bands [cm] -1 ]:3286,1662,1219,1181,1154,1055 (±2°cm in each case) -1 In another particularly preferred embodiment of the invention, the IR spectrum of the crystalline form substantially corresponds to the spectrum depicted in Figure 3.

[0016] X-ray powder diffraction data for all crystalline forms were obtained at 25°C using the following acquisition parameters:

[0017] Diffractometer type: PANalytic X'Pert PRO

[0018] Anode material: Cu

[0019] Radiation: Cu Kα1

[0020] wavelength:

[0021] Scanning mode: Transmission

[0022] Scan type: 2θ:Omega

[0023] Range: 2θ (peak maximum value) ± 0.2°

[0024] At 25°C, an FT Raman spectrometer from Bruker (e.g., using model RFS100 or MultiRam) was used with a laser wavelength of 1064 nm and a 2 cm⁻¹ diameter. -1 The resolution records the Raman spectra of the crystalline form.

[0025] At 25°C, using a Bruker IR spectrometer with a universal diamond ATR unit (e.g., a Tensor 37 model), at a wavelength of 4 cm⁻¹, the image was analyzed. -1 The resolution records the IR spectrum of the crystalline form.

[0026] Figure 1 shows the X-ray powder diffraction pattern of the crystalline form.

[0027] Figure 2 shows the Raman spectrum of the crystalline form.

[0028] Figure 3 shows the IR spectrum of the crystalline form.

[0029] Figure 4 shows the X-ray powder diffraction pattern of the DMAc solvate.

[0030] Figure 5 shows the X-ray powder diffraction pattern of the NMP solvate.

[0031] Figure 6 shows the Raman spectra of DMAc and NMP solvates.

[0032] Figure 7 shows the IR spectrum of the DMAc solvate.

[0033] Figure 8 shows the IR spectrum of the NMP solvate.

[0034] The starting point for preparing the crystalline form of the compound of formula (I) according to the method of the present invention is the presence of a reactant mixture, wherein the compound of formula (I) is dissolved in at least one amide solvent selected from the following: N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methyl-2-pyrrolidone, N-methylcaprolactam, and hexamethylphosphoramide, very particularly preferably selected from N,N-dimethylacetamide and N-methyl-2-pyrrolidone. In a further preferred embodiment of the invention, an amide solvent is present, rather than a mixture of the above-mentioned amide solvents.

[0035] Using N,N-dimethylacetamide, crystalline N,N-dimethylacetamide solvates (DMAc solvates) of compounds of formula (I) further described below are obtained. Using N-methyl-2-pyrrolidone, crystalline N-methyl-2-pyrrolidone solvates (NMP solvates) of compounds of formula (I) further described below are obtained.

[0036] Compared to the crystalline form of the 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 used to determine the specific resistance (α value) of the filtration, according to VDI Guide 2762 (manufacturer: BHS Sonthofen, model: pocket measuring device KPL TMG 400). For this purpose, the suspension to be tested was introduced into the apparatus, and the amount of sediment in the filtrate (mother liquor) was continuously measured by applying a pressure differential. The relationship between the filtrate volume V and time t was recorded (filtrate curve). By plotting t / V against V, the specific resistance of the filtration (in m³) can be determined. -2 (α value in units) (See also W. Beckmann: Crystallization–Basic Concepts and Industrial Applications, Wiley-VCH, 2013, Chapter 14.2.3).

[0037] Based on the compound of formula (I), the at least one amide solvent is preferably used in the reactant mixture in an excess of 2 to 20 times by weight, and particularly preferably in an excess of 3 to 10 times by weight.

[0038] The compound of formula (I) in at least one amide solvent can be crystallized by lowering the temperature to obtain a solvate without the addition of at least one antisolvent. In this case, the lowering of the temperature is preferably carried out slowly within the temperature range further listed below, particularly preferably at 1 to 10 °C / hour, and even more preferably at 1 to 5 °C / hour. In this case, the compound of formula (I) in at least one amide solvent is preferably present as a homogeneous mixture, which can be achieved, for example, by stirring.

[0039] In a preferred embodiment of the method described in this invention, at least one antisolvent is used primarily to reduce solubility and obtain a higher yield of the solvate. The crystallization process to obtain the solvate can also be carried out without lowering the temperature, or even generally at a higher processing temperature. In a particularly preferred embodiment of the invention, the presence or addition of at least one antisolvent is combined with (preferably subsequently) a decrease in temperature for the crystallization process to obtain the solvate. Preferably, the antisolvent is selected from the group consisting of: water; acetonitrile; C1-C6 alcohols; toluene; xylene; esters of formic acid and C1-C4 alcohols; and esters of acetic acid and C1-C4 alcohols. Particularly preferred is the use of at least one antisolvent selected from: water, acetonitrile, methanol, ethanol, isopropanol, 1-butanol, toluene, and ethyl acetate. In another preferred embodiment of the invention, an antisolvent is present instead of a mixture of the above antisolvents.

[0040] In another preferred embodiment of the invention, the weight ratio of the at least one amide solvent to the at least one antisolvent is 10:1 to 1:1, particularly preferably 5:1 to 2:1, and very particularly preferably about 4:1.

[0041] The at least one amide solvent may also have been diluted with at least one antisolvent in the reactant mixture and a compound according to formula (I), provided that the solvent used is inert under the reaction conditions and has reached a homogeneous state by, for example, raising the temperature accordingly before the solvate crystallizes.

[0042] Before adding at least one antisolvent to the reactant mixture, those inert solvents that also enter the reaction mixture, for example, along with a solution of the compound of formula (II), may optionally be removed under reduced pressure by a suitable manner (e.g., by distillation).

[0043] The solvate crystallization according to the method of the present invention 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.

[0044] However, as an alternative, the reaction can also be carried out in an autoclave under vacuum or high pressure. Depending on the batch size, one or more amide solvents, one or more antisolvents, and temperature, the reaction time can be selected from one hour to several hours. Filtration can be performed using filtration devices known to those skilled in the art, such as pressure suction filters or centrifuges. Drying can be performed using drying equipment known to those skilled in the art, such as horizontal or vertical mixing dryers or suction dryers. Drying is carried out at a temperature range of 20 to 100°C, preferably in the range of 60 to 80°C. Drying is carried out at a pressure range of 1 to 100 mbar, preferably in the range of 5 to 20 mbar.

[0045] Preferably, the reactant mixture consisting of the compound of formula (I) and at least one amide solvent used in the above method is prepared by a method wherein the compound of formula (II) is used.

[0046]

[0047] Compounds of formula (III)

[0048]

[0049] The reaction is carried out in the presence of an amide solvent.

[0050] The coupling reaction can optionally be carried out in the presence of a catalyst. Examples include 4-dimethylaminopyridine or 1-hydroxybenzotriazole. No additional acid-binding agent is required for this reaction.

[0051] The coupling reaction is further preferably carried out such that the compound of formula (III) in the amide solvent is first added in an equimolar amount or a slightly excess of 1.0-1.2 molar equivalents based on the compound of formula (II). Then, the compound of formula (II) is metered in 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, very particularly preferably 10 to 30°C, for a time period preferably 1 to 10 hours, preferably 2 to 5 hours. The reaction is typically carried out under standard pressure. However, alternatively, it can also be carried out in an autoclave under vacuum or high pressure. After the make-up reaction time, the inert solvent is preferably removed, as described above.

[0052] The same amide solvent used for this coupling reaction is used as the one used for the reactant mixture described above.

[0053] The compound of formula (II) can be used as a solid or as a melt in this coupling reaction. However, it is preferred to use the compound of formula (II) dissolved in an inert organic solvent. In this document, the compound of formula (II) is dissolved in an inert organic solvent, preferably selected from aliphatic, alicyclic, and aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, and naphthane; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, tetrachloromethane, dichloroethane, and trichloroethane; and ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, and methyl tert-amyl ether. Ethers, 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-butyronitrile, isobutyronitrile, or benzyl nitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone, and hexamethylphosphoramide, and mixtures thereof. Toluene is particularly preferred.

[0054] The compounds of formula (III) are 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; PJ Montoya-Pelaez, J. Org. Chem. 2006, 71, 5921-5929; FE Sheibley, J. Org. Chem. 1938, 3, 414-423, WO2006023783A1).

[0055] In a preferred embodiment of the invention, the compound of formula (II) is prepared by reacting the compound of formula (IV) with an acyl halide forming agent in the presence of an inert organic solvent.

[0056]

[0057] The acyl halide forming agent is selected from phosgene, phosphorus tribromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and thionyl chloride.

[0058] The acyl halide forming agent is preferably selected from phosgene, methanesulfonyl chloride, and thionyl chloride. Thionyl chloride is particularly preferred.

[0059] As an inert organic solvent, the inert organic solvent mentioned above for preparing reactant mixtures from compounds of formulas (II) and (III) is used. Toluene is particularly preferred.

[0060] The process steps are typically 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, the reactants used, and the temperature, the reaction time is from 1 hour to 5 hours, preferably from 1 hour to 3 hours.

[0061] Pyrazole carboxylic acids of formula (IV) are known or can be obtained by known methods (see, for example, WO2011 / 157664A1). Due to the tetrazolium group, pyrazole carboxylic acids of formula (IV) are usually present as a mixture of different regioisomers.

[0062] Another object of the present invention relates to crystalline N,N-dimethylacetamide solvates of compounds of formula (I).

[0063]

[0064] Its X-ray powder diffraction pattern using Cu Kα radiation at 25°C has at least the following reflectances: 8.3, 8.9, 14.6, particularly preferably at least the following reflectances: 8.3, 8.9, 10.4, 14.6, 15.5, and very particularly preferably at least the following reflectances: 8.3, 8.9, 10.4, 12.7, 14.6, 15.5, 27.6 (expressed as 2θ / ° values ​​± 0.2°). Preferably, the crystalline N,N-dimethylacetamide solvate of the compound of formula (I) of the present invention (abbreviated as DMAc solvate) has the reflectance (2θ) shown in Table 3. The X-ray powder diffraction pattern of the DMAc solvate is also shown in Figure 4.

[0065] Another object of the present invention relates to crystalline N-methyl-2-pyrrolidone solvates of compounds of formula (I).

[0066]

[0067] The X-ray powder diffraction pattern of the compound at 25°C using Cu Kα radiation has at least the following reflections: 8.3, 8.9, 14.6, particularly preferably at least the following reflections: 8.3, 8.9, 10.5, 14.6, 15.4, and very particularly preferably at least the following reflections: 8.3, 8.9, 10.5, 12.7, 14.6, 15.4, 27.6 (expressed as 2θ / ° values ​​± 0.2°). Preferably, the crystalline N-methyl-2-pyrrolidone solvate of the compound of formula (I) of the present invention (abbreviated as NMP solvate) has the reflections (2θ) shown in Table 3. The X-ray powder diffraction pattern of the NMP solvate is also shown in Figure 5.

[0068] All X-ray powder diffraction data for DMAc and NMP solvates were obtained on a Bruker D2 PHASER diffractometer equipped with a LynxEye detector at 25°C using wavelengths of [wavelength missing]. Cu Kα radiation measurements were performed. Data were recorded at 0.5 s / steps in horizontal Bragg-Brentano (θ / 2θ) geometry between 5 and 30° (2θ). The X-ray tube was operated at 30 kV and 10 mA. All X-ray reflections were expressed as 2θ (theta) values ​​(peak maximum) with a resolution of ±0.2°.

[0069] The crystalline N,N-dimethylacetamide solvate and the crystalline N-methyl-2-pyrrolidone solvate of the compounds of formula (I) can be further characterized by IR and Raman spectroscopy. The corresponding Raman and IR spectra are shown in Figures 6, 7 and 8.

[0070] All Raman spectra of the solvates were recorded at 25 °C using a Kaiser Raman RXN2 spectrometer with a fiber-coupled probe for in-situ detection. The system was equipped with an MR probe for non-contact measurements. A 450 mW NIR Kaiser Invictus laser (785 nm) was used. The spectral range of this system was within 4 cm⁻¹. -1 Coverage from +100 to +3425cm at resolutions -1 The iC Raman software from Mettler Toledo is used for instrument configuration, data logging, and data evaluation.

[0071] FTIR analysis was performed in the range of 400 to 4000 cm⁻¹. -1 Within the spectral range, Bruker Platinum ATR tensor II was used at 4 cm⁻¹. -1 The instrument records the IR spectra of solvates at high resolution. Opus software from Bruker is used for instrument configuration, data logging, and data evaluation.

[0072] The IR and Raman spectra of DMAc and NMP solvates include the bands listed in Table 4.

[0073] Preferably, the Raman spectrum of the DMAc solvate has at least the following characteristic bands: 3126, 1685, 1340; particularly preferred are the following bands: 3126, 3026, 1685, 1340, 1306; and very particularly preferred are the following bands: 3126, 3026, 2972, 1685, 1340, 1306, 963 (in cm⁻¹). -1 [Indicates ±2°cm in each case] -1 ).

[0074] Preferably, the IR spectrum of the DMAc solvate has at least the following characteristic bands: 3234, 1525, 926; particularly preferred are the following bands: 3234, 3124, 1525, 1496, 926; and very particularly preferred are the following bands: 3234, 3124, 3078, 1525, 1496, 1016, 926 (in cm⁻¹). -1 [Indicates ±2°cm in each case] -1 ).

[0075] Preferably, the Raman spectrum of the NMP solvate has at least the following characteristic bands: 3125, 1684, 1342; particularly preferred are the following bands: 3125, 3024, 1684, 1342, 1305; and very particularly preferred are the following bands: 3125, 3024, 2973, 1684, 1342, 1305, 963 (in cm⁻¹). -1 [Indicates ±2°cm in each case] -1 ).

[0076] Preferably, the IR spectrum of the NMP solvate has at least the following characteristic bands: 3234, 1525, 926; particularly preferred are the following bands: 3234, 3124, 1525, 926, 848; and very particularly preferred are the following bands: 3234, 3124, 3078, 1525, 1016, 926, 848 (in cm⁻¹). -1 [Indicates ±2°cm in each case] -1 ).

[0077] The method of the present invention is described in more detail below, through which crystalline DMAc and NMP solvates of novel compounds of formula (I) are obtained in particular:

[0078] Preparation Examples

[0079] The following preparation examples illustrate the present invention but are not intended to limit the invention.

[0080] Example 1

[0081] A mixture of isomers of 1-(3-chloropyridin-2-yl)-3-[(5-(trifluoromethyl)-2H-tetrazol-2-yl)methyl]-1H-pyrazole-5-formyl chloride (major isomer) and 1-(3-chloropyridin-2-yl)-3-{[5-(trifluoromethyl)-1H-tetrazol-1-yl]methyl}-1H-pyrazole-5-formyl chloride (minor component).

[0082] First, 50.0 g of a 95:5 isomer mixture of 1-(3-chloropyridin-2-yl)-3-[(5-(trifluoromethyl)-2H-tetrazol-2-yl)methyl]-1H-pyrazole-5-carboxylic acid and 1-(3-chloropyridin-2-yl)-3-{[5-(trifluoromethyl)-1H-tetrazol-1-yl]methyl}-1H-pyrazole-5-carboxylic acid was added to 200.0 g of toluene and heated to 75 °C. 17.1 g of thionyl chloride was added metered over 1 hour, and the mixture was subsequently stirred at 75 °C for 1 hour. After the reaction was complete, excess thionyl chloride and a portion of toluene (27.0 g distillate) were distilled off together at 70 °C and 150 mbar. The solution was brought 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, which was used directly as is in the next step.

[0083] Example 2

[0084] A mixture of isomers of 1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazol-2-yl)methyl]-1H-pyrazole-5-carboxamide (major isomer) and 1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-{[5-(trifluoromethyl)-1H-tetrazol-1-yl]methyl}-1H-pyrazole-5-carboxamide (minor component).

[0085] a) Preparation of solutions of 1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazol-2-yl)methyl]-1H-pyrazole-5-carboxamide and its isomer in N,N-dimethylacetamide (DMAc).

[0086] 25.3 g of 2-amino-5-cyano-N-3-dimethylbenzamide was dissolved in 123.0 g of DMAc, and then 20.0 g of DMAc was distilled off at 65 °C and 20 mbar. The mixture was cooled to 10-15 °C, and a 20% solution of the prepared 1-(3-chloropyridin-2-yl)-3-[(5-(trifluoromethyl)-2H-tetrazol-2-yl)methyl]-1H-pyrazole-5-carboxyl chloride and its isomer was added metered over 1 hour, followed by stirring at 10-15 °C for 3 hours after the addition was completed. Subsequently, toluene was distilled off at 45–50 °C and 30 mbar to give a solution of 1-(3-chloropyridin-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 isomer in DMAc at approximately 35% w / w.

[0087] b) Preparation of DMAc solvates of 1-(3-chloropyridin-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

[0088] A solution of 1-(3-chloropyridin-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 over 10 minutes. The mixture was cooled to 0-5 °C over a 2-hour period and then stirred for 1 hour. Crystalline samples of the suspension showed rhombic DMAc solvate crystals under an optical microscope. The obtained DMAc solvates exhibit XRPD reflectance as described in Table 3 and Figure 4, and Raman and IR spectra as shown in Table 4 and Figures 6 and 7.

[0089] c) Separation and drying of DMAc solvates of 1-(3-chloropyridin-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

[0090] To achieve the desired yield, 30.0 g of water was added to the suspension over 10 minutes, followed by stirring at 0–5 °C for 1 hour. The solid was filtered off using a suction filter, washed at 0–5 °C with a mixture of 50.0 g DMAc and 50.0 g water, and the wet filter cake was dried at 80 °C and 10 mbar. 66.0 g of product (89% yield) was obtained in crystalline form as a 95:5 isomer mixture with 95% purity. The resulting crystalline form is shown in the characteristic X-ray powder diffraction patterns in Table 1 and Figure 1, and the Raman and IR spectra in Table 2 and Figures 2 and 3.

[0091] Example 3

[0092] Using alternative antisolvents, and optionally without using an antisolvent, DMAc solvates of 1-(3-chloropyridin-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 are prepared.

[0093] A 35% w / w solution of 175.0 g of 1-(3-chloropyridin-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 DMAc, prepared according to Example 2a, was cooled to 30°C. Within 10 minutes, 27.0 g of one or a mixture of alternative solvents of the following: ethanol, 2-propanol, 1-butanol, toluene, xylene, ethyl acetate, or isopropyl acetate was added. Optionally, no antisolvent was added. The batch was then cooled to 0-5°C over 2 hours, followed by stirring for 1 hour. Optionally, crystallization was initiated by adding a small amount of solvate inoculum solution. Crystallized samples of the suspension also showed rhombic DMAc solvate crystals under an optical microscope. The obtained DMAc solvates show the XRPD reflectance described in Table 3 and Figure 4, as well as the Raman and IR spectra specified in Table 4 and Figures 6 and 7.

[0094] Example 4

[0095] Preparation and drying of 1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-[(5-(trifluoromethyl)-2H-tetrazole-2-yl)methyl]-1H-pyrazole-5-carboxamide and its NMP solvates

[0096] A 35% w / w solution of 114.0 g of 1-(3-chloropyridin-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 prepared according to Example 2a in NMP was cooled to 30 °C. 17.0 g of methanol was added over 10 minutes. The mixture was cooled to 0–5 °C over a 2-hour period and then stirred for 1 hour. Crystalline samples of the suspension showed rhombic NMP solvate crystals under an optical microscope. The obtained NMP solvates exhibit XRPD reflectance as described in Table 3 and Figure 5, and Raman and IR spectra as shown in Table 4 and Figures 6 and 8.

[0097] The solid was filtered out using a suction filter, and the wet filter cake was dried at 80 °C and 10 mbar. 31.4 g of the product was obtained as a crystalline form of a 95:5 isomer mixture. The obtained crystalline form is shown in the characteristic X-ray powder diffraction patterns in Table 1 and Figure 1, and the Raman and IR spectra in Table 2 and Figures 2 and 3.

[0098] Solvent samples for X-ray powder diffraction, IR and Raman analysis are provided according to methods known to those skilled in the art.

[0099] Table 1: X-ray powder diffraction

[0100]

[0101]

[0102] Table 2: IR and Raman bands

[0103]

[0104]

[0105]

[0106]

[0107] Table 3: X-ray powder diffraction

[0108]

[0109] Table 4: IR and Raman bands

[0110]

[0111]

[0112] Table 5: Filtering resistance α

[0113] Crystalline form DMAc solvates <![CDATA[Filter resistance α (in m -2 ):]]> <![CDATA[3.0–7.0*10 13 ]]> <![CDATA[3.8*10 11 ]]>

Claims

1. Crystalline N,N-dimethylacetamide solvate of the compound of formula (I) （I）， Its X-ray powder diffraction pattern using Cu Kα radiation at 25°C has at least the following reflections: 8.3, 8.9, 10.4, 12.7, 14.6, 15.5, 27.6 (expressed as °2θ values ​​± 0.2°).

2. The crystalline N,N-dimethylacetamide solvate of the compound of formula (I) according to claim 1, characterized in that, Its Raman spectrum has at least the following bands: 3126, 1685, 1340 (in cm⁻¹). -1 [Indicates ±2° cm in each case] -1 ).

3. Crystalline N-methyl-2-pyrrolidone solvate of the compound of formula (I) （I）， Its X-ray powder diffraction pattern using Cu Kα radiation at 25°C has at least the following reflections: 8.3, 8.9, 14.6 (expressed as °2θ values ​​± 0.2°).

4. The crystalline N-methyl-2-pyrrolidone solvate of the compound of formula (I) according to claim 3, characterized in that, Its Raman spectrum has at least the following bands: 3125, 1684, 1342 (in cm⁻¹). -1 [Indicates ± 2°cm in each case] -1 ).

5. A method for preparing compounds of formula (I) in crystalline form. （I）， Its features are, The solvate according to any one of claims 1 to 4 is obtained by dissolving the compound of formula (I) in at least one amide solvent and by crystallization in the presence of at least one antisolvent and by lowering the temperature, followed by filtration and drying; The at least one antisolvent is selected from acetonitrile; C1-C6 alcohols; toluene; xylene; esters of formic acid and C1-C4 alcohols and esters of acetic acid and C1-C4 alcohols; The weight ratio of the at least one amide solvent to the at least one antisolvent is 10:1 to 1:1; and The at least one amide solvent is selected from N,N-dimethylformamide and N-methyl-2-pyrrolidone.

6. The method according to claim 5, characterized in that, Solvent crystallization is carried out at temperatures ranging from -20°C to +30°C.

7. The method according to claim 5 or 6, characterized in that, Compound of formula (II) (II) Compounds of formula (III) (III) The compound of formula (I) is prepared by reacting in the presence of an amide solvent.

8. The method according to claim 5, characterized in that, The compound of formula (II) is prepared by reacting the compound of formula (IV) with an acyl halide forming agent in the presence of an inert organic solvent. (IV), The acyl halide forming agent is selected from phosgene, phosphorus tribromide, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and thionyl chloride.

9. Use of crystalline N,N-dimethylacetamide solvates of the compound of formula (I) according to claim 1 or 2 and / or crystalline N-methyl-2-pyrrolidone solvates of the compound of formula (I) according to claim 3 or 4 for the preparation of the compound of formula (I) in crystalline form.

10. The method according to any one of claims 5 to 8 or the use according to claim 9, wherein the compound of formula (I) is obtained in crystalline form, characterized in that, Its X-ray powder diffraction pattern at 25 °C using Cu Kα radiation has 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).

11. The method according to any one of claims 5 to 8 or the use according to claim 9, wherein the compound of formula (I) is obtained in crystalline form, characterized in that, Its Raman spectrum has at least the following bands [cm] -1 ]:2928, 1663,1386, 1334, 1022, 638 (± 2° cm in each case) -1 ).

12. The method according to any one of claims 5 to 8 or the use according to claim 9, wherein the compound of formula (I) is obtained in crystalline form, characterized in that, Its IR spectrum has at least the following bands [cm] -1 ]:3286, 1662,1219, 1181, 1154, 1055 (± 2° cm in each case) -1 ).

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