Process for the preparation of 2-chloro-n - (1-cyanocyclopropyl) - 5 - [2 ' - methyl-5 ' - (pentafluoroethyl) - 4 ' - (trifluoromethyl) - 2 ' h-1, 3 ' - bipyrazol-4-yl] benzamide

Abstract

To provide an advantageous crystal form such as being thermodynamically stable at room temperature.SOLUTION: The present invention relates to a crystalline form of 2-chloro-N - (1-cyanocyclopropyl) - 5 - [2 ' - methyl-5 ' - (pentafluoroethyl) - 4 ' - (trifluoromethyl) - 2 ' H-1, 3 ' - bipyrazol-4-yl] benzamide, i.e. a compound of formula (I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to 2-chloro-N-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'H-1,3'-bipyrazol-4-yl]benzamide, i.e., the compound of formula (I), and to a process for purifying the compound of formula I. The present invention further relates to a new crystalline form of the compound of formula I.

[0002] [ka] [Background technology]

[0003] The compound of formula (I) has an INN tigolanel. The compound is disclosed in WO 2014 / 122083, which also describes the preparation of the compound of formula I by Pd-catalyzed coupling of suitable structural units. Regarding the purification method, purification by column chromatography on silica gel is described for two comparable compounds.

[0004] WO 2015 / 078846, WO 2015 / 078847, WO 2015 / 181139, and WO 2016 / 026789 disclose the preparation of compounds of formula I according to the following reaction equation:

[0005] [ka] A drawback of the synthesis described in the examples in these patents is the low overall yield, which after purification is only about 49% of the theoretical value. The purification method described is by column chromatography on silica gel.

[0006] A further drawback is that, according to the examples in WO 2015 / 078846, WO 2015 / 078847, WO 2015 / 181139 and WO 2016 / 026789, structural units of formula II prepared according to the following reaction equation:

[0007] [ka] The high purchase cost of the highly fluorinated raw material of formula IV means that it is less favorable for commercial production. Summary of the Invention

[0008] The object was therefore to find a simplified process with improved yields for the compound of formula I which can be carried out reliably, advantageously on an industrial scale and which leads to an active substance of high purity.

[0009] Provided herein is a process for preparing a compound of formula (I), comprising:

[0010] [ka] Compound of formula (VI)

[0011] [ka] [In the formula, A, A boronic acid radical of the formula:

[0012] [ka] Trifluoroborates of the formula:

[0013] [ka] wherein M is an alkali metal salt, preferably sodium or potassium; and boronic esters of the formula:

[0014] [ka] [In the formula, R 1 and R 2 are independently C1-C6 alkyl or C3-C6 cycloalkyl, or R 1 and R 2 together form a C1-C6 alkylene group optionally substituted by one or more C1-C4 alkyl groups, Compound of formula (VII)

[0015] [ka] wherein X is a reactive group selected from bromine, iodine, and the radical -O-SO2-Y, wherein Y is a C1-C8 perfluoroalkyl; A method has been developed by reacting in the presence of a base and a catalyst.

[0016] In a further aspect, the present invention relates to a method for purifying the compound of formula I, wherein it is crystallized from an aromatic hydrocarbon.

[0017] The reactive group A is preferably a boronic acid or a boronic ester, more preferably a boronic ester.

[0018] R 1 and R 2 R preferably combines with each other to form a C1-C6 alkylene group, more preferably a C1-C4 alkylene group. 1 and R 2The alkylene group formed from may preferably be substituted with one or two C1-C2 alkyl groups. More specifically, R 1 and R 2 together form a group of formula -C(CH3)2-C(CH3)2- or -CH2-C(H)(CH3)-CH2-.

[0019] The reactive group -X is, according to the invention, bromine, iodine, or -O-SO2-Y, where the radical -Y is C1-C8 perfluoroalkyl, preferably linear C1-C4 perfluoroalkyl, more preferably trifluoromethyl, pentafluoroethyl, or nonafluorobutyl. X is, according to the invention, bromine or iodine.

[0020] The term "C1-C6 alkyl" refers to a straight-chain or branched, saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl, or 1,3-dimethylbutyl group, or an isomer thereof. The group is more specifically a group having 1, 2, 3, or 4 carbon atoms. and more particularly, having 1, 2, or 3 carbon atoms ("C1-C3 alkyl"), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl groups.

[0021] The term "C3-C6 cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, or 6 carbon atoms. A C3-C6 cycloalkyl group is, for example, a monocyclic hydrocarbon ring, such as a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, or a bicyclic hydrocarbon ring. The cycloalkyl ring can optionally contain one or more double bonds, for example, in a cycloalkenyl group such as a cyclobutenyl, cyclopentenyl, or cyclohexenyl group, and these double bond-containing cycloalkyl groups are attached to the remainder of the molecule through any desired carbon atom, whether saturated or unsaturated.

[0022] The term "alkylene" refers to a hydrocarbon chain, preferably having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, said chain having two bonds to the rest of the molecule or part thereof, and which may itself be formed singly or multiple times from the following groups: -CH2- ("methylene"); e.g., -C(CH3)2-), -CH2-CH2- ("ethylene", "dimethylene"); e.g., -C(CH3)2-C(CH3)2-), -CH2-CH2-CH2- ("propylene", and -CH-C(H)(CH)-CH-, -CH-C(CH)-CH-, -CH-C(CH)-CH-, -CH-CH-CH- ("butylene", "tetramethylene"), -CH-CH-CH-CH-CH- ("pentylene", "pentamethylene"), or -CH-CH-CH-CH-CH-CH-CH- ("hexylene", "hexamethylene"). Alkylene chains having 1, 2, 3, 4, or 5 carbon atoms, more particularly 1 or 2 carbon atoms, are preferred.

[0023] The compound of formula VI is used in an amount of 0.7 to 1.3 molar equivalents, preferably 0.9 to 1.1 molar equivalents, more preferably 0.95 to 1.05 molar equivalents, based on the structural unit of formula VII.

[0024] Compounds of formula VI can be prepared by reaction of a highly fluorinated pyrazole of formula VIa with a boron-substituted pyrazole of formula VIb:

[0025] [ka] wherein substituent A is as defined herein for compounds of formula VI. The preparation of compounds of formula VIa is disclosed in WO 2014 / 012975, WO 2015 / 078846, WO 2015 / 078847, WO 2015 / 181139, and WO 2016 / 026789. Compounds of type formula VIb are available in the chemical trade.

[0026] Compounds of formula VII can be prepared in a manner known per se, e.g. by reacting compounds of formula VIIa

[0027] [ka] of the acid chloride, The acid chloride can be prepared by reaction with an amine of formula VIIb. In formula VIIa, the substituent X is as defined herein for the compound of formula VII. The amine of formula VIIb can also be used in the form of a salt, for example, hydrochloride, hydrobromide, hydrogen sulfate, or sulfate, and in this case, an additional base can be added to neutralize the acid that forms the salt. The acid chloride can be prepared by a method known per se, for example, by reaction of the parent carboxylic acid with thionyl chloride or oxalyl chloride. The parent carboxylic acid is commercially available. The amine of formula VIIb is commercially available in the form of its salt.

[0028] The reaction according to the invention for preparing compounds of formula (I) is carried out in industrially conventional solvents such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, open-chain or cyclic ethers, preferably having 4 to 8 carbon atoms, such as dimethoxyethane, diethoxyethane, dioxane, or THF, or in C1-C6 alkyl-derived alcohols, such as methanol, ethanol, propanol, butanol, pentanol, isopropanol, 2-butanol, tert-butanol, or isoamyl alcohol, preferably C1-C4 alkyl-derived alcohols, such as methanol, ethanol, propanol, butanol, isopropanol, or 2-butanol. Among the aforementioned solvents, those that are miscible with water are preferred. Mixtures of the aforementioned solvents can also be used. Aliphatic alcohols having 1 to 4 carbon atoms, in particular ethanol, propanol, or isopropanol, are particularly preferred.

[0029] Water can also be used as an additional solvent. The proportion of water based on the solvent or solvent mixture used is usually 80% by weight or less, preferably 50% by weight or less, more preferably 30% by weight or less, and typically ranges from 1% to 80% by weight, preferably 5% to 50% by weight, more preferably 10% to 30% by weight.

[0030] The reaction according to the present invention is carried out in the presence of a base. Suitable bases are alkali metal or alkaline earth metal carbonates or bicarbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, lithium bicarbonate, sodium bicarbonate, or potassium bicarbonate, or alkali metal phosphates or bihydrogen phosphates, such as lithium phosphate, sodium phosphate, potassium phosphate, sodium bihydrogen phosphate, or potassium dihydrogen phosphate, or alkali metal fluorides, such as sodium fluoride, potassium fluoride, or cesium fluoride. Sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium bihydrogen phosphate, potassium dihydrogen phosphate, sodium fluoride, or potassium fluoride are preferred. It is also possible to use a mixture of the listed bases. As the base, alkali metal carbonates and alkali metal bicarbonates, especially sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate, are particularly preferred.

[0031] The amount of base employed, as enumerated, is, according to the present invention, 1 to 10 equivalents, preferably 2 to 5 equivalents, and more preferably 2.5 to 3.5 equivalents, based on the starting material of formula VI.

[0032] The reaction according to the present invention is carried out in the presence of a catalyst. The catalyst used is usually a palladium catalyst. In addition to the palladium-containing component, a phosphorus-containing component may also be optionally used.

[0033] Palladium-containing components which can be used in the reaction according to the invention are generally known to those skilled in the art and are extensively described in the general chemical literature, only selected examples of which can be listed below.

[0034] Palladium-containing components that may be used include Pd(OAc)2, PdCl2, Pd2(dba)3 (tris(dibenzylideneacetone)dipalladium(0)), Pd(dba)2 (bis(dibenzylideneacetone)palladium(0)), PdCl2(PPh3)2 (dichlorobis(triphenylphosphine)palladium(II)), PdCl(PPh3)3 (chlorotris(triphenylphosphine)palladium(I), Pd( Palladium salts or complexes such as PPh3)4 (tetrakis(triphenylphosphine)palladium(0)), PdCl2(dppf) (1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride), PdCl2(dppf) dichloromethane complex, and PdCl2(amphos)2 (bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II)).

[0035] Phosphorus-containing components that can be used in the reaction according to the invention are generally known to those skilled in the art and are extensively described in the general chemical literature, only selected examples of which can be listed below.

[0036] Phosphorus-containing components that can be used include triphenylphosphine, tris(o-tolyl)phosphine, tris(2-furyl)phosphine, dppp (1,3-bis(diphenylphosphino)propane), dppb (1,3-bis(diphenylphosphino)butane), dppf (1,1′-bis(diphenylphosphino)ferrocene), X-Phos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), S-Phos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl), Dave-Phos (2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl), amphos (di-tert-butyl(4-dimethylaminophenyl)phosphine), and the like.

[0037] When the palladium-containing component itself does not contain any phosphorus-containing ligand, a mixture of the palladium-containing component and the phosphorus-containing component is used according to the present invention. For example, the palladium-containing component Pd(OAc)2, PdCl2, Pd2(dba)3, Pd(dba)2, etc. is used in a mixture with the aforementioned phosphorus-containing component. The palladium-containing component already containing the phosphorus-containing component can be used without additional phosphorus-containing component. However, it is also possible to use a palladium-containing component already containing a phosphorus-containing ligand in a mixture with the phosphorus-containing component.

[0038] It is also possible to use mixtures of different palladium salts and different palladium complexes with different phosphorus-containing ligands.

[0039] According to the present invention, Pd(OAc)2, PdCl2, Pd2(dba)3, and Pd(dba)2 are used in combination with a phosphorus-containing component, such as triphenylphosphine, tris(o-tolyl)phosphine, tris(2-furyl)phosphine, dppp (1,3-bis(diphenylphosphino)propane), dppb (1,3-bis(diphenylphosphino)butane), dppf (1,1')-bis(diphenylphosphino)ferrocene), X-Phos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), S-Phos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl), and Dave- It is preferred to use Phos (2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl), amphos (di-tert-butyl(4-dimethylaminophenyl)phosphine), preferably triphenylphosphine, dppf (1,1'-bis(diphenylphosphino)ferrocene), X-Phos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), S-Phos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl), more preferably triphenylphosphine, dppf (1,1'-bis(diphenylphosphino)ferrocene).

[0040] Likewise, according to the invention, it is preferred to use PdCl2(PPh3)2 (dichlorobis(triphenylphosphine)palladium(II)), PdCl(PPh3)3 (chlorotris(triphenylphosphine)palladium(I)), Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0)), PdCl2(dppf) (1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride), PdCl2(dppf) dichloromethane complex, and also more preferably PdCl2(PPh3)2 (dichlorobis(triphenylphosphine)palladium(II), or Pd(PPh3)4.

[0041] When using Pd(PPh3)4, it is likewise preferred according to the invention to further add the phosphorus-containing component triphenylphosphine.

[0042] The amount of palladium-containing component used may, according to the present invention, be 0.01 to 10 mol %, preferably 0.1 to 2.5 mol %, more preferably 0.50 to 1 mol %, based on the starting material of formula VI.

[0043] The applied catalytic amount of phosphorus-containing component used can be 0.025 to 25 mol %, preferably 0.5 to 10 mol %, more preferably 2 to 5 mol %, based on the starting material of formula VI.

[0044] The reaction can be carried out at room temperature up to the boiling point of the solvent mixture used. The reaction temperature is usually within the range of 20 to 150°C, preferably 50 to 100°C.

[0045] After the reaction, the reaction mixture can be treated in an industrially customary manner, for example, undissolved inorganic salts can be filtered off or, in the case of solvents that are poorly soluble in water, removed by washing with water, optionally by adding salt to the washing water.

[0046] The product of formula I can be precipitated from the reaction mixture by adding water or a suitable solvent. After precipitation, the product can be filtered off and further treated by wetting or dried.

[0047] Isolation of the product of formula I by evaporating the solvent is likewise possible in principle.

[0048] The product of formula I obtained in the usual manner described above can be further purified.

[0049] In one aspect of the invention, the product of formula I can be purified in a further step by crystallization from an aromatic hydrocarbon, specifically by precipitation or recrystallization from an aromatic hydrocarbon.

[0050] The aromatic hydrocarbons used are toluene, ethylbenzene, ortho-xylene, meta-xylene, para-xylene, cumene, or mesitylene, preferably toluene, ethylbenzene, ortho-xylene, meta-xylene, para-xylene, cumene, or mesitylene. The solvent may be a benzene derivative such as benzene, ortho-xylene, meta-xylene, para-xylene, or more preferably toluene. It is also possible to use mixtures of the aforementioned solvents.

[0051] In the purification step, the aromatic hydrocarbon or hydrocarbon mixture is used in an amount of 100% to 2000% by weight, preferably 200% to 1000% by weight, based on the crude product of formula I to be purified.

[0052] It is also possible to add activated carbon during purification by recrystallization. The amount of activated carbon is usually up to 10% by weight, preferably up to 5% by weight, based on the crude product of formula I to be purified. It is preferred to add activated carbon during purification.

[0053] The added activated carbon is removed from the mixture by filtration prior to crystallization of the pure product. In one embodiment, the activated carbon-containing mixture is filtered at a high temperature, and the product crystallizes during cooling. In another embodiment, to prevent the pure product from prematurely crystallizing and being filtered off with the activated carbon, thereby resulting in a loss of yield, an additional solvent in which the crude product has a higher solubility can be added. Examples of such solvents include dichloromethane, methanol, ethanol, propanol, isopropanol, acetone, or 2-butanone. After filtration, the additional solvent is removed by distillation, and crystallization occurs from the distillation residue, which primarily contains only aromatic hydrocarbons as solvent. It is preferred to use acetone and 2-butanone as the additional solvent, more preferably acetone.

[0054] The amount of additional solvent based on the amount of aromatic hydrocarbon used is 10% by weight to 200% by weight, preferably 20% by weight to 100% by weight, more preferably 30% by weight to 70% by weight.

[0055] To achieve complete precipitation, isolation of the purified solid of formula I is preceded by cooling to a standard temperature within the range of 0-35°C, preferably, for example, 20-30°C.

[0056] The product can be isolated in a standard manner using conventional isolation equipment, such as a suction filter or a centrifuge. During isolation, the product can be washed with a pharmaceutically acceptable solvent, preferably the same solvent as before, to remove the mother liquor. The product thus obtained can then be dried.

[0057] The process according to the invention offers clear advantages over the prior art. What was particularly surprising was that the novel inventive modifications of the structural units of formula VI and formula VII resulted in a substantial increase in yield compared to the prior art.

[0058] The compound of formula I can be purified according to a novel method, preferably using an aromatic hydrocarbon. This step can be continued from the method for preparing the compound of formula I described herein. This purification step allows for very high purity to be achieved without the use of chromatographic purification. Surprisingly, very pure products can be obtained simply by purification using precipitation, recrystallization, or a combination of these two. Since low residual contents of organic secondary components and palladium can be achieved, this allows for the achievement of an active substance purity suitable for use in, for example, veterinary medicine.

[0059] The following secondary components may be specifically mentioned herein by way of example:

[0060] Amide N1:

[0061] [ka]

[0062] Deschloro Compound N2:

[0063] [ka]

[0064] Bispyrazoloboronic ester N3 (compound of formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl):

[0065] [ka]

[0066] Bispyrazoloboronic acid N4:

[0067] [ka]

[0068] Chloriodobenzamide N5 (compound of formula VII, where X=I):

[0069] [ka]

[0070] The content of these secondary components in the final product should in each case preferably be less than 2% by weight, more preferably less than 1% by weight, particularly preferably less than 0.7% by weight, in particular less than 0.5% by weight. In the case of secondary components N3, N4 and N5, the content in the final product should very particularly preferably be less than 0.2% by weight.

[0071] A low palladium content in the final product is further desirable: it should be less than 100 ppm (w / w), preferably less than 50 ppm (w / w), more preferably less than 20 ppm (w / w).

[0072] The sum of all impurities in the final product should be less than 5% by weight, preferably less than 3% by weight, and more preferably less than 2.0% by weight.

[0073] The method is technically reliable in its implementation and allows for commercial scale production.

[0074] Novel crystalline forms of the compound of formula (I) have been found, in particular modification I, modification II, and an ethanol-water inclusion complex. The compound of formula (I) may also exist in amorphous form.

[0075] The terms modification, polymorph, and polymorphic form have the same meaning in the context of this application. In addition to polymorphs, the term "crystalline form" also encompasses pseudopolymorphic forms such as crystalline solvates. Polymorphs, pseudopolymorphic forms, and amorphous forms are different solid forms of the compound of formula (I).

[0076] Modification I of the compound of formula (I) is the thermodynamically stable form at room temperature. It is a stable, non-hygroscopic, easily prepared and easily handled crystalline form.

[0077] Modification I is therefore suitable for the pharmaceutical sector (including veterinary medicine), in particular for the production of drugs, preferably for animal use. The use of modification I prevents undesired transformation of the compound of formula (I) into other forms. This contributes to the quality and safety of formulations and drugs comprising the compound of formula (I).

[0078] In one embodiment, the medicament according to the invention comprises a compound of formula (I) in the form of modification I and also, optionally, further pharmaceutically acceptable excipients.

[0079] In a preferred embodiment, the medicament essentially comprises modification I and substantially free of other forms of the compound of formula (I), and also optionally comprises further pharmaceutically acceptable excipients.

[0080] In medicaments containing modification I, preferably at least 85% by weight, particularly preferably at least 90% by weight, very particularly preferably at least 95% by weight of the compound of formula (I) is present in the form of modification I used in the medicament, the said percentages being based on the total amount of the compound of formula (I) in the medicament concerned.

[0081] Modification I of the compound of formula (I) is characterized, inter alia, by its X-ray powder diffraction pattern and IR spectrum, which makes it distinguishable from the other forms of the compound (see Tables 1 and 2 and Figures 1 and 2 to 8).

[0082] Modification I of the compound of formula (I) can be prepared by crystallization from various solvents, and in particular from diisopropyl ether, toluene, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, acetonitrile, isopropanol, ethanol, or methanol. It can be manufactured.

[0083] Modification II can be prepared by crystallization from solketal (isopropylideneglycerol).

[0084] The ethanol-water inclusion complex can be obtained by crystallization from a 1:1 mixture of ethanol and water.

[0085] The usual procedure for crystallization is to dissolve the compound of formula (I) in a hot solvent and then cool to room temperature. If this does not result in precipitation, the solution can be cooled to a lower temperature or concentrated.

[0086] The compound of formula (I) modification I has useful pharmaceutical properties and can be used in particular for the treatment of animals. The compound of formula (I) modification I is particularly suitable for use in the control of parasites, especially ectoparasites, in animals.

[0087] In the field of animal health, i.e. in the field of veterinary medicine, the crystalline forms described herein, in particular modification I of the compound of formula (I), are used for the control of parasitic infestations in animals, in particular for the control of ectoparasitic infestations. Ectoparasites are typically and preferably arthropods, in particular flies (pasture flies, stable flies, horseflies or It is effective against pests such as Musca autumnalis and house fly (Musca domestica). insects such as blood-sucking flies and flies with sponge-like mouthparts, such as annoying or irritating flies), parasitic fly larvae (e.g., botflies, warble flies, blowfly larvae), sucking lice, biting lice, bird lice, fleas; or arachnids (order Acari), e.g. For example, ticks such as hard ticks or soft ticks, or These include mites such as mange mites, harvest mites, and poultry mites.

[0088] Parasites, especially ectoparasites, include, for example, the following insects and acarines:

[0089] From the order Anoplura, for example, Haematopinus spp., Linognathus spp., Pediculus spp., Pthirus spp., and Solenopotes spp., with particular mention of the dog louse (Linognathus setosus), cattle louse (Linognathus vituli), sheep louse (Linognathus ovillus), Linognathus oviformis, Linognathus pedalis, goat louse (Linognathus stenopsis), Haematopinus asini macrocephalus, cattle louse (Haematopinus eurysternus), pig lice (Haematopinus suis), head lice (Pediculus humanus capitis), body lice (Pediculus humanus corporis), Phylloxera vastatrix, pubic lice (Pthirus pubis), woolly cow lice (Solenopotes capillatus); Order Mallophaga, and suborder Amblycera and Slenderhorn From the suborder Ischnocera, for example, Trimenopon spp. , Menopon spp., Trinoton spp. , Bovicola spp., Werneckiella spp., Lepikentron spp., Damalinia spp., Trichodectes spp., and Felicola spp., with the following worthy of special mention: Bovicola bovis, Bovicola ovis, Bovicola limbata, Damalinia b ovis), dog louse (Trichodectes canis), cat louse (Felicola subrostratus ), goat louse (Bovicola caprae), Lepikentron ovis, Werneckiella equi; From the order Diptera and the suborders Nematocera and Brachycera For example, Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eucimium spp. species (Eusimulium spp.), sandflies (Phlebotomus spp.), Lutzomyia spp. Lutzomyia spp., Culicoides spp., deer flies Chrysops spp., Odagmia spp., Wilhelmia spp. Wilhelmina spp., Hybomitra spp., Atirostrum spp. Atylotus spp., Tabanus spp., Haematopota spp., Philipomyia spp., Braula spp., Musca spp., Hydrotaea spp., Stomoxys spp., Haematobia spp., Morellia spp., Fannia spp., Glossina spp., Calliphora spp., Lucilia spp.), Chrysomya spp., Wohlfahrtia spp., Sarcophaga spp. ), Oestrus spp., Hypoderma spp., Gasterophilus spp., Hippobosca spp., Lipofy flies, Lipotena spp., Melophagus spp., Rhinoestrus spp., Tipula spp., and other The following deserve special mention: Aedes aegypti, Aedes albopictus, Aedes taeniorhynchus, Anopheles gambiae, Anopheles maculipennis, Calliphora erythrocephala, Chrysozona pluvialis, Culex quinquefasciatus, Culex pipiens, Culex tarsalis, Fannia canicularis, Sarcophaga carnaria, Stomoxys calcitrans, Tipula paludosa, Sheep blowfly (Lucilia cuprina), Broad-headed blowfly (Lucilia sericata), Simulium reptans, Phlebotomus papatasi, Long-horned sandfly (Phlebotomus longipalpis), Odagmia ornata, Horsefly (Wilhelmina equina), Boophthora erythrocephala, Tabanus bromius, Tabanus spodopterus, Tabanus atratus, Tabanus sudeticus, Hybomitra ciurea), Chrysops caecutiens, Chrysops relic Chrysops relictus, Haematopota pluvialis, Haematopota italica, Musca autumnalis, Musca domestica, Horn fly (Haematobia irritans irritans), Horn fly (Haematobia irritans exigua), Haematobia stimulans, Hydrotaea irritans, White-spotted sting fly (Hydrotaea albipuncta), Chrysomya chloropyga, Screwworm fly (Chrysomya bezziana), Oestrus ovis, Hypoderma bovis, Hypoderma lineatum, Przhevalskiana silenus, Dermatobia hominis, Melophagus ovinus, Lipotena capreoli, Lipotena cervi, Hippobosca variegata, Hippobosca equina, Gasterophilus intestinalis, Gasterophilus haemorroidalis, Gasterophi lus inermis, Gasterophilus nasalis, Gasterophilus nigricornis, Gasterophilus pecorum, Braula coeca; From the order Siphonaptera, for example, Pulex spp., Ctenocephalides spp., Tunga spp., Xenopsylla spp., Ceratophyllus spp., the following are worthy of special mention: : Dog flea (Ctenocephalides canis), Cat flea (Ctenocephalides felis), Human flea (Pulex irritans), Sand flea (Tunga penetrans), Cheops' rat flea (Xenopsylla cheopis); From the Heteroptera, for example, Cimex spp., Triatoma spp., Rhodnius spp., Panstrongylus spp.; From the order Blattaria, for example, the Asian cockroach (Blatta orientalis), the American cockroach (Periplaneta americana), the German cockroach (Blattella germanic), Supella spp. (e.g., Supella longipalpa); From the subclass Acari (Acarina) and the suborder Metastigmata and Mesostigmata, for example, Argas spp., Ornithodorus spp., Otobius spp., Ixodes spp. Ixodes spp., Amblyomma spp., Ixodes spp. Rhipicephalus (Boophilus) spp., Dermacentor spp., Haemaphysalis spp., Hyalomma spp., Dermanyssus spp., Rhipicephalus spp. (the original genus of multi-host ticks), Ornithonyssus spp., Pneumonyssus spp., Raillietia spp., Sternostoma spp., Varroa spp., Acara spp. Acarapis spp.; specific examples are: Argas persicus, Argas reflexus, Ornithodorus moubata ), Otobius megnini, Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) annulatus, Rhipicephalus (Boophilus) calceratus, Hyalomma anatolicum, Hyalomma aegypticum, Hyalomma marginatum, Hyalomma transiens, Rhipicephalus evertusi evertsi), Ixodes ricinus, Ixodes hexago Eggplant (Ixodes hexagonus), Ixodes canisuga, Ixodes spiro Ixodes pilosus, Ixodes rubicundus, Black-legged Ixodes scapularis, Ixodes holocyclus, Haemaphysalis concinna, Haemaphysalis punctata, Haemaphysalis cinnabarina, Haemaphysalis Haemaphysalis otophila, Haemaphysalis leachi, Haemaphysalis longicorni, Dermacentor marginatus, Dermacentor reticulatus, Dermacentor pictus, Dermacentor albipictus, Dermacentor andersoni, American Dermacentor variabilis, Hyalomma urticaricum mauritanicum), Brown dog tick (Rhipicephalus sanguineus), Rhipicephalus Rhipicephalus bursa, Rhipicephalus appendiculatus appendiculatus), Rhipicephalus capensis, Rhipiceph Rhipicephalus turanicus, Rhiphicephalus zambesiensis picephalus zambeziensis), Amblyomma americanum, Amblyomma variegatum, Amblyomma maculatum, Amblyomma hebraeum, Amblyomma Amblyomma cajennense, Germanyssus gallinae, Ornithonyssus bursa, Ornithonyssus silviarum sylviarum), Varroa destructor mite (Varroa jacobsoni); From the orders Actinedida (suborder Prostigmata) and Acaridida (suborder Astigmata), for example, Acarapis spp., Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Psorergates spp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp. spp.), Hypodectes spp., Pterolichus spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp. Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Cytodites spp., Laminosioptes spp.; specific examples are: Cheyletiella yasguri, Cheyletiella blakei, Demodex canis, Demodex bovis, Demodex ovis, Demodex caprae, Demodex equi, Demodex caballi, Demodex suis, Neotrombicula autumnalis, Neotrombicula desaleri, Neoschongastia xerothermobia, Trombicula akamushi, Otodectes cynotis, Notoedres cati, Sarcoptes canis, Sarcoptes bovis (Sarcoptes bovis), Sarcoptes ovis, Sarcoptes rpicap Sarcoptes rupicaprae (=S. caprae), Sarcoptes equi, Sarcoptes suis, Psoroptes ovis, Psoroptes cuniculi, Psoroptes equi, Chorioptes bovis, Psorergates ovis, Pneumonyssoidic mange, and Anser punctata (Pneumonyssoides caninum), Acarindani (Acarapis woodi).

[0090] Preferably, the following ectoparasites may be mentioned: Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp., Pulex spp., Hyalomma spp., Rhipicephalus spp., Boophilus spp., Amblyomma spp., Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argas spp., Ornithodorus spp., Otobius spp., dog ear mites (Otodectes cynotis), cats Notoedres cati.

[0091] The compounds of formula (I) in crystalline form described herein are suitable for the prevention and treatment of animals suffering from arthropod infestations, including mammals such as agricultural livestock, e.g., sheep, goats, horses, donkeys, camels, buffalo, rabbits, reindeer, fallow deer, and especially cattle and pigs, or poultry such as turkeys, ducks, geese, and especially chickens.

[0092] These animals also include animals kept as pets, for example mammals such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets, and especially dogs and cats; and caged birds and reptiles.

[0093] In certain embodiments, the compounds of formula (I) are used / administered for the treatment of a mammal.

[0094] The use of the compounds of formula (I) for the control of animal parasites is intended to reduce or prevent disease, mortality and loss of production (meat, milk, wool, hides, eggs, honey, etc.), thereby making animal rearing more economical and easier and improving animal well-being.

[0095] For example, it is desirable to prevent parasites from taking blood from a host animal. Parasite control can also help prevent the transmission of infection.

[0096] In the animal health or veterinary medicine context of the present invention, the term "treatment" includes prophylactic, metaphylactic, or therapeutic treatment.

[0097] As used herein in the field of animal health, the term "control" means that the active substance reduces the number of parasites in the infested animal, preferably to a harmless level. More precisely, "control" means that the active substance kills the parasites concerned, inhibits their growth, or prevents their reproduction.

[0098] The compounds of formula (I) in crystalline form described herein preferably have -For mite control -For flea control -To dogs -Used in cats.

[0099] The compounds of formula (I) in crystalline form described herein may in principle be administered by any conventional route of administration, preferably oral administration.

[0100] Modification I of the compound of formula (I) can also be used in combination with other suitable active substances.

[0101] The preparation of modification I of the compound of formula (I) and the pharmaceutical forms suitable for its production are generally known to those skilled in the art.

[0102] When used in animals, the compound of formula (I) is generally used in an amount of 1 to 100 mg per kg body weight (mg / kgBW), preferably 5 to 30 mg / kgBW, more preferably 10 to 20 mg / kgBW.

[0103] The present invention also encompasses any desired combination of the preferred and particularly preferred embodiments described above.

[0104] The present invention will be illustrated by, but not limited to, the following examples. [Example]

[0105] A: Method Example The following examples illustrate compounds of formula VI, wherein -A is 4,4,5,5-tetramethyl-1,3,2 The present invention discloses a method for the synthesis of phenylalanine, which uses the structural unit of formula II (which is 2-dioxaborolan-2-yl). The synthesis results in substantially better yields than known syntheses based on the known structural unit of formula II.

[0106] Example 1 30.0 g of water, 120.0 g of isopropanol, and 9.2 g of 2'-methyl-5'-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(trifluoromethyl)-2'H-1,3'-bipyrazole (a compound of Formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. To this was added 6.0 g of 2-chloro-N-(1-cyanocyclopropyl)-5-bromobenzamide (a compound of Formula VII, where -X is bromine) and 5.0 g of sodium bicarbonate. Finally, 1.16 g of tetrakis(triphenylphosphine)palladium was added, and the mixture was heated under reflux for 5 hours. The solids present in the reaction mixture were filtered off with suction and washed with 30 g of isopropanol. The filtrate was slightly concentrated to about 75%, and the distillation residue was weighed into 200 ml of water. The precipitated solids were filtered off with suction, washed with water, and dried under reduced pressure. This gave 11.3 g of material with a content of 93.2 area %. Without taking into account the content, the calculated yield was 102.2% of the theoretical value due to the content of secondary components. With the content taken into account, it was 95.3% of the theoretical value.

[0107] Example 2 30.0 g of water, 120.0 g of isopropanol, and 9.2 g of 2'-methyl-5'-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(trifluoromethyl)-2'H-1,3'-bipyrazole (a compound of Formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. To this was added 6.9 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (a compound of Formula VII, where -X is iodine) and 5.0 g of sodium bicarbonate. Finally, 1.16 g of tetrakis(triphenylphosphine)palladium was added, and the mixture was heated under reflux for 5 hours. The solids present in the reaction mixture were filtered off with suction and washed with 30 g of isopropanol. The filtrate was slightly concentrated to about 75%, and the distillation residue was weighed into 200 ml of water. The precipitated solids were filtered off with suction, washed with water, and dried under reduced pressure. This gave 10.8 g of material with a content of 97.3 area %. Without taking into account the content, the calculated yield was 97.7% of the theoretical value due to the content of secondary components. With the content taken into account, it was 95.1% of the theoretical value.

[0108] Example 3 150 g of water, 600 g of isopropanol, and 46.0 g of 2'-methyl-5'-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(trifluoromethyl)-2'H-1,3'-bipyrazole (compound of formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. To this was added 34.7 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (compound of formula VII, where -X is iodine) and 25.20 g of sodium bicarbonate. Finally, 1.44 g of tetrakis(triphenylphosphine)palladium was added, and the mixture was heated under reflux for 3.5 hours. The solids present in the reaction mixture were filtered off with suction and washed with 100 g of isopropanol. The filtrate was slightly concentrated to about 50% and the distillation residue was cooled to room temperature. 1000 ml of water was metered into the cooled residue. The precipitated solids were filtered off with suction, washed with water and dried under reduced pressure. This gave 54.6 g of material with a content of 98.7 area %. Without taking the content into account, the calculated yield was 98.8% of the theoretical value due to the content of secondary components. When the content was taken into account, it was 97.5% of the theoretical value.

[0109] Example 4 10.6 g of the product obtained in the previous example was dissolved in 94.4 g of toluene in a reaction vessel at high temperature. The solution was cooled with stirring, and the solid was filtered off by suction, washed with toluene, and dried under reduced pressure. This gave 8.9 g of material (84.0% based on the starting material used) with a palladium content of 99.4 area % and below 100 ppm.

[0110] Example 5 37.5 g of water, 150 g of isopropanol, and 11.5 g of 2'-methyl-5'-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(trifluoromethyl)-2'H-1,3'-bipyrazole (a compound of Formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. To this was added 0.16 g of triphenylphosphine, 8.7 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (a compound of Formula VII, where -X is iodine), and 6.3 g of sodium bicarbonate. Finally, 0.2 g of tetrakis(triphenylphosphine)palladium was added, and the mixture was heated under reflux for 5 hours. The mixture was cooled, and any solids present were removed by filtration and washed with a small amount of isopropanol. 250 ml of water was weighed into the pooled filtrate, and the precipitated solid was filtered off and washed with water. The wet product was mixed with approximately 44 g of toluene and stirred at 70-75°C for 1 hour. The suspension was cooled to room temperature, and the solid was filtered off with suction, washed with toluene, and dried. This yielded 12.3 g (89.0% of theory) of a slightly yellowish solid with a content of >99 area % (area percent from HPLC chromatogram). The palladium content was below 50 ppm.

[0111] Example 6 In a reaction vessel, 11.1 g of the product obtained in the previous example was mixed with 198 g of toluene and 0.5 g of activated carbon and dissolved at elevated temperature under reflux. The activated carbon was filtered off at elevated temperature, and the resulting filtrate was concentrated to approximately 40%. This was cooled with stirring, and the resulting solid was filtered off, washed with toluene, and dried under reduced pressure. This yielded 10.0 g (90.1% based on the starting material used) of a colorless, finely crystalline powder with a content of >99.8 area % (area percent from HPLC chromatogram). None of the secondary components were present at a content greater than 0.10 area %. The palladium content was below 10 ppm.

[0112] The product prepared in Example 6 was investigated by TGA, which showed no mass loss up to 150°C.

[0113] The product prepared in Example 6 was analyzed by X-ray powder diffraction (measurement conditions as specified hereinbelow). The product crystallized in modification I, which is described in detail hereinbelow. The diffractogram of the product from Example 6 is shown in Figure 1.

[0114] Example 7 37.5 g of water, 150 g of isopropanol, and 11.5 g of 2'-methyl-5'-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(trifluoromethyl)-2'H-1,3'-bipyridine The benzole (a compound of Formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) was mixed in a reaction vessel. To this was added 0.16 g of triphenylphosphine, 8.7 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (a compound of Formula VII, where -X is iodine), and 6.3 g of sodium bicarbonate. Finally, 0.2 g of tetrakis(triphenylphosphine)palladium was added, and the mixture was heated under reflux for 5 hours. The mixture was cooled, and the solids present were removed by filtration and washed with 1.8 g of isopropanol. 250 ml of water was weighed into the filtrate, and the precipitated solids were filtered off, washed with water, and dried under reduced pressure. A 2.0 g preliminary sample of the water-wet product was taken and dried. This yielded 1.1 g of material (8.0% of theoretical). The remaining water-wet product was suspended in 300 g of toluene, and the water was removed by azeotropic distillation. Activated carbon was then added, and the mixture was stirred under reflux and filtered hot. Approximately 60% of the solvent was distilled from the clear filtrate, and the remaining residue was cooled. The precipitated solid in the mixture was filtered off by suction, washed with toluene, and dried under reduced pressure. This yielded 10.8 g of a crystalline solid (78.2% of theoretical). The analytical content of was 99.6 area % (area percent from HPLC chromatogram). The maximum secondary component was present at 0.11%. The palladium content was less than 100 ppm.

[0115] Example 8 25.1 g of crude product prepared in a manner similar to Example 5 was charged to a reaction vessel. To this was added 195.5 g of toluene, 80.0 g of acetone, and 1.26 g of activated carbon. The crude product was dissolved at elevated temperature under reflux. The activated carbon was filtered off at elevated temperature, and the resulting filtrate was concentrated by distillation at standard pressure to a residue of approximately 167 g. This was cooled with stirring until crystallization was nearly complete (<approximately 54°C). The suspension was heated to an internal temperature of approximately 95°C and briefly stirred at this temperature without complete dissolution. The resulting hot suspension was slowly cooled to 5°C and further stirred at this temperature. The resulting solid was filtered off, washed with toluene, and dried under reduced pressure. This yielded 23.7 g (94.4% based on the starting material used) of a colorless, finely crystalline powder with a content of >99.8 area % (area percent from HPLC chromatogram). None of the secondary components were present at a content greater than 0.10 area %. The palladium content was below 1 ppm.

[0116] Example 9 Preparation of structural units of formula C (corresponding to structural units of formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl).

[0117] [ka] In a reaction vessel, 2.6 kg of structural unit B and 22.88 liters of acetonitrile were mixed at 22°C. To this was added 2.78 kg of ground potassium carbonate, 3.64 kg of structural unit of formula A, and 1.91 kg of acetonitrile. The reaction mixture was stirred under reflux for 7 hours and then cooled to room temperature. The solid in the reaction mixture was filtered off and washed with 4.03 kg of acetonitrile. 23.75 kg of solvent was distilled from the pooled filtrate. The distillation residue was mixed with 7.53 kg of isopropanol, after which 47.85 kg of water was metered in at approximately 22°C. The mixture was cooled to 3-5°C, and the precipitated solid was filtered off. The solid was washed with water and reduced. The solid was dried under vacuum to give 4.99 kg of the product of formula C as a pale yellow solid, which was equivalent to 85.2% of the theoretical value. The analytical content was 99.6% ESTD (HPLC evaluation with an external standard).

[0118] B. Crystalline Forms of the Compound of Formula (I) B.1. Preparation of Modification I Approximately 400 mg of compound of formula (I) was in each case dissolved hot in the indicated volume of one of the solvents specified below and filtered hot. - 80ml diisopropyl ether + 5ml ethanol - 40ml toluene - 40ml of tetrahydrofuran - 40ml acetone - 40ml ethyl acetate - 40ml acetonitrile - 40ml of 2-propanol - 40ml of ethanol - 40ml of methanol - 40ml of 1,4-dioxane - 40ml DMSO

[0119] The solution was left to dry at room temperature.Modification I was characterized by X-ray diffraction.

[0120] B.2. Preparation of Modification II Approximately 400 mg of the compound of formula (I) was dissolved in 4 ml of solketal at elevated temperature. The solution was left to dry at room temperature. Modification II was characterized by X-ray diffraction.

[0121] B.3. Preparation of Ethanol-Water Inclusion Complex Approximately 400 mg of the compound of formula (I) was dissolved in 100 ml of EtOH / H2O 1:1 at high temperature and filtered at high temperature. The solution was left to dry. The ethanol-water inclusion complex was characterized by X-ray diffraction.

[0122] B.4. Characterization of Crystalline Morphology

[0123] [Table 1-1]

[0124] [Table 1-2]

[0125] Measurement conditions: Anode material: Cu K-Alpha1[Å] 1.54060 Generator 40mA, 40kV Sample rotation: Yes Scan axis goniometer Starting position [°2 theta] 2.0066 End position [°2 theta] 37.9906 Figure 1: X-ray powder diffraction diagram of modification I Figure 2: X-ray powder diffraction diagram of modification II Figure 3: X-ray powder diffraction pattern of the ethanol-water inclusion complex Figure 4: X-ray powder diffraction diagram of the amorphous form

[0126] [Table 2]

[0127] Measurement conditions: ATR IR spectra were recorded at room temperature in a Tensor 37 FT-IR spectrophotometer from Bruker using an ATR unit without further sample preparation. The resolution was 4 cm. -1 It was.

[0128] The spectra are shown in the figure. Figure 5: IR spectrum of modification I Figure 6: IR spectrum of modification II Figure 7: IR spectrum of the ethanol-water inclusion complex Figure 8: IR spectrum of the amorphous phase [Brief explanation of the drawings]

[0129] [Figure 1] X-ray powder diffraction pattern of modification I [Figure 2] X-ray powder diffraction pattern of modification II [Figure 3] X-ray powder diffraction pattern of the ethanol-water inclusion complex [Figure 4] X-ray powder diffraction pattern of the amorphous form [Figure 5] IR spectrum of modification I [Figure 6] IR spectrum of modification II [Figure 7] IR spectrum of the ethanol-water inclusion complex [Figure 8] IR spectrum of the amorphous phase

Claims

1. A crystal of the compound of formula (I). 【Chemistry 1】

2. 2. The crystal according to claim 1, which is modification I or an ethanol-water inclusion complex.

3. 2. The crystal according to claim 1, which is modification II or an ethanol-water inclusion complex.

4. A drug comprising the crystal according to any one of claims 1 to 3.

5. The drug according to claim 4, which is a veterinary drug.

6. 6. A method according to claim 4 or 5 for controlling parasites, especially ectoparasites, in animals.

7. A pharmaceutical composition comprising the crystal of claim 1 or 2, essentially comprising modification I and substantially free of other forms of the compound of formula (I), and optionally further comprising a pharmaceutically acceptable excipient.

8. 8. The pharmaceutical composition according to claim 7, wherein at least 85% by weight, preferably at least 90% by weight, particularly preferably at least 95% by weight, of the compound of formula (I) is present in the form of modification I, said percentages being based on the total amount of the compound of formula (I).

9. 3. A process for the preparation of crystals according to claim 2, comprising crystallization from various solvents, in particular diisopropyl ether, toluene, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, acetonitrile, isopropanol, ethanol or methanol.

10. 4. A method for preparing the crystals of claim 3, comprising crystallization from isopropylideneglycerol.

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