Process for preparation of compounds of formula (I)

Abstract

The present invention relates to a 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, i.e., a compound of formula (I), and to a process for the purification of said compound of formula I. The invention also relates to a novel crystal form of the compound shown in the formula I. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with the application date of May 26, 2021, the application number of 202180035472.9, and the invention title of "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". Technical Field

[0002] The present invention relates to a 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, i.e., the compound of formula (I), and a process for the purification of the compound of formula I. The present invention also relates to a new crystalline form of the compound of formula I.

[0003] Background Art

[0004] The compound of formula (I) has the INN tigolaner. The compound is disclosed in WO 2014 / 122083; the preparation of the compound of formula I by Pd-catalyzed coupling of suitable structural units is also described therein. Regarding the purification method, purification by silica gel column chromatography is described for two comparable compounds.

[0005] WO 2015 / 078846, WO 2015 / 078847, WO 2015 / 181139 and WO 2016 / 026789 disclose the preparation of the compound of formula I according to the following reaction scheme.

[0006]

[0007] The disadvantage of the synthesis described in the examples of these patents is the low overall yield of only about 49% in theory after purification. The described purification method is purification by silica gel column chromatography.

[0008] Another disadvantage is that, according to the examples in patents WO 2015 / 078846, WO 2015 / 078847, WO 2015 / 181139 and WO 2016 / 026789, the structural unit of formula II prepared according to the following reaction scheme

[0009]

[0010] is obtained in a yield of only about 24% in theory. The high purchase price of the highly fluorinated starting material of formula IV means that this is very disadvantageous for industrial production.

[0011] Accordingly, the aim is to find a simplified method with improved yields of the compounds of formula I, which can advantageously be carried out reliably and also on an industrial scale and which provides the active substance in high purity. SUMMARY OF THE INVENTION

[0012] A process for preparing a compound of formula (I) by reacting a compound of formula (VI) has now been developed

[0013]

[0014] wherein

[0015] A is a boron-containing substituent selected from:

[0016] a boronic acid group of the following formula

[0017]

[0018] a trifluoroborate of the following formula

[0019] -BF3M,

[0020] wherein M is an alkali metal salt, preferably sodium or potassium,

[0021] and a boronic ester of the following formula

[0022]

[0023] wherein 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,

[0024] reacting with a compound of formula (VII)

[0025]

[0026] wherein X is a reactive group selected from: bromine, iodine and the group -O-SO2-Y, where Y is a C1-C8 perfluoroalkyl group,

[0027] in the presence of a base and a catalyst.

[0028] In another aspect, the invention relates to: a process for purifying a compound of formula I, wherein the compound is crystallized from an aromatic hydrocarbon.

[0029] The reactive group A is preferably a boronic acid or a boronic ester, more preferably a boronic ester.

[0030] R 1 and R 2Preferably, they together form a C1-C6 alkylene group, more preferably a C1-C4 alkylene group. The alkylene group formed by R 1 and R 2 may preferably be substituted by one or two C1-C2 alkyl groups. More specifically, R 1 and R 2 together form a group of the formula -C(CH3)2-C(CH3)2- or -CH2-C(H)(CH3)-CH2-.

[0031] According to the present invention, the reactive group -X is bromine, iodine or -O-SO2-Y, where the group -Y is a C1-C8 perfluoroalkyl group, preferably a straight-chain C1-C4 perfluoroalkyl group, more preferably trifluoromethyl, pentafluoroethyl or nonafluorobutyl. According to the present invention, X is bromine or iodine.

[0032] The term "C1-C6 alkyl" refers to a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as 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 groups or their isomers. More specifically, the group has 1, 2, 3 or 4 carbon atoms ("C1-C4 alkyl"), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl, and more specifically has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), such as methyl, ethyl, n-propyl or isopropyl groups.

[0033] The term "C3-C6 cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. C3-C6 cycloalkyl groups are, for example, monocyclic hydrocarbon rings (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups) or bicyclic hydrocarbon rings. The cycloalkyl ring may optionally have one or more double bonds, such as in cycloalkenyl groups, such as cyclobutenyl, cyclopentenyl or cyclohexenyl groups, and these double-bond-containing cycloalkyl groups are attached to the rest of the molecule through any desired saturated or unsaturated carbon atoms.

[0034] The term "alkylene" preferably refers to a hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, said chain having two bonds with the rest of the molecule or a part thereof and being itself mono- or polysubstituted by C1-C4 alkyl, such as 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", "trimethylene"), e.g. -CH2-C(H)(CH3)-CH2-, -CH2-C(CH3)2-CH2-), -CH2-CH2-CH2-CH2- ("butylene", "tetramethylene"), -CH2-CH2-CH2-CH2-CH2- ("pentylene", "pentamethylene") or -CH2-CH2-CH2-CH2-CH2-CH2- ("hexylene", "hexamethylene"). Preferred is an alkylene chain having 1, 2, 3, 4 or 5 carbon atoms, more specifically 1 or 2 carbon atoms.

[0035] Based on the structural unit of formula VII, the compound of formula VI is used in an amount of 0.7 equivalent to 1.3 equivalents, preferably 0.9 molar equivalent to 1.1 molar equivalents, more preferably 0.95 molar equivalent to 1.05 molar equivalents.

[0036] The compound of formula VI can be prepared by reacting a highly fluorinated pyrazole of formula VIa

[0037]

[0038] with a boron-substituted pyrazole of formula VIb, wherein the substituent A is as defined herein for the compound of formula VI. The preparation of the compound of formula VIa is disclosed in WO 2014 / 012975, WO 2015 / 078846, WO 2015 / 078847, WO 2015 / 181139 and WO 2016 / 026789. Compounds of the type of formula VIb are commercially available.

[0039] The compound of formula VII can be prepared by methods known per se, for example by reacting an acyl chloride of formula VIIa

[0040]

[0041] React with the amine of formula VIIb. In formula VIIa, the substituent X is as defined herein for the compounds of formula VII. The amine of formula VIIb can also be used in the form of a salt, such as a hydrochloride, hydrobromide, bisulfate or sulfate, in which case an additional base can be added to neutralize the acid forming the salt. The acyl chloride can be prepared by methods known per se, by reaction of the parent carboxylic acid, by reaction with, for example, thionyl chloride or oxalyl chloride. The parent carboxylic acid is commercially available. The amine of formula VIIb can be commercially available in the form of its salt.

[0042] The reaction according to the invention for the preparation of the compounds of formula (I) is carried out in industrially commonly used solvents, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, open-chain ethers or cyclic ethers (preferably having 4 to 8 carbon atoms), such as dimethoxyethane, diethoxyethane, di ane or THF, or in an alcohol derived from a C1-C6 alkyl group, such as methanol, ethanol, propanol, butanol, pentanol, isopropanol, 2-butanol, tert-butanol, isopentanol, etc., preferably in an alcohol derived from a C1-C4 alkyl group, such as methanol, ethanol, propanol, butanol, isopropanol or 2-butanol. Among the above solvents, those that are miscible with water are preferred. Mixtures of the above solvents can also be used. Particularly preferred are aliphatic alcohols having 1 to 4 carbon atoms, especially ethanol, propanol or isopropanol.

[0043] Water can also be used as an additional solvent. Based on the solvent or solvent mixture used, the proportion of water generally does not exceed 80% by weight, preferably does not exceed 50% by weight, more preferably does not exceed 30% by weight; the general range is 1% by weight to 80% by weight, preferably 5% by weight to 50% by weight, more preferably 10% by weight to 30% by weight.

[0044] The reaction according to the invention is carried out in the presence of a base. Suitable bases are alkali metal or alkaline earth metal carbonates and bicarbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or alkali metal phosphates or dihydrogen phosphates, such as lithium phosphate, sodium phosphate, potassium phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, or alkali metal fluorides, such as sodium fluoride, potassium fluoride or cesium fluoride. Preferred are sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium fluoride or potassium fluoride. Mixtures of the said bases can also be used. As the base, alkali metal carbonates and alkali metal bicarbonates are particularly preferred, especially sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.

[0045] According to the invention, the amount of the base used is 1 equivalent to 10 equivalents, preferably 2 equivalents to 5 equivalents, and more preferably 2.5 equivalents to 3.5 equivalents based on the starting material of formula VI.

[0046] The reaction according to the present invention is carried out in the presence of a catalyst. The catalyst used is generally a palladium compound. In addition to the palladium-containing component, a phosphorus-containing component may optionally be used.

[0047] The palladium-containing components that can be used in the reaction according to the present invention are generally known to those skilled in the art and are described in a large number in general chemical literature. Only the selected examples are listed below as possible.

[0048] The palladium-containing components that can be used are salts or complexes of palladium, such as Pd(OAc)2, PdCl2, Pd2(dba)3 (bis(tri(dibenzylideneacetone)) dipalladium(0)), Pd(dba)2 (bis(dibenzylideneacetone) palladium(0)), PdCl2(PPh3)2 (bis(triphenylphosphine) palladium(II) dichloride), PdCl(PPh3)3 (tris(triphenylphosphine) palladium(I) chloride), Pd(PPh3)4 (tetrakis(triphenylphosphine) palladium(0)), PdCl2(dppf) (1,1'-bis(diphenylphosphino) ferrocene palladium(II) dichloride), PdCl2(dppf) dichloromethane complex, and PdCl2(amphos)2 (bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) palladium(II) dichloride), etc.

[0049] The phosphorus-containing components that can be used in the reaction according to the present invention are generally known to those skilled in the art and are described in a large number in general chemical literature. Only the selected examples are listed below as possible.

[0050] The phosphorus-containing components that can be used are 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), etc.

[0051] 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 components Pd(OAc)2, PdCl2, Pd2(dba)3, Pd(dba)2, etc. are used in a mixture with the above-mentioned phosphorus-containing components. The palladium-containing components that already contain a phosphorus-containing component can be used without an additional phosphorus-containing component. However, the palladium-containing components that already contain a phosphorus-containing ligand in a mixture with a phosphorus-containing component can also be used.

[0052] Mixtures of different palladium salts, different palladium complexes, and different phosphorus-containing ligands can also be used.

[0053] According to the present invention, it is preferred to use Pd(OAc)2, PdCl2, Pd2(dba)3, Pd(dba)2 together with 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), preferably triphenylphosphine, dppf (1,1'-bis(diphenylphosphino)ferrocene), X-Phos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), S-Phos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl), and more preferably triphenylphosphine, dppf (1,1'-bis(diphenylphosphino)ferrocene) as the phosphorus-containing component.

[0054] According to the present invention, it is also preferred to use PdCl2(PPh3)2 (bis(triphenylphosphine)palladium(II) dichloride), PdCl(PPh3)3 (tris(triphenylphosphine)palladium(I) chloride), Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0)), PdCl2(dppf) (1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride), PdCl2(dppf) dichloromethane complex, and more preferably PdCl2(PPh3)2 (bis(triphenylphosphine)palladium(II) dichloride) or Pd(PPh3)4.

[0055] When using Pd(PPh3)4, according to the present invention, it is also preferred to additionally add the phosphorus-containing component triphenylphosphine. Based on the starting material of formula VI, the amount of the palladium-containing component used can be 0.01 mol% to 10 mol% according to the present invention, preferably 0.1 mol% to 2.5 mol%, and more preferably 0.50 mol% to 1 mol%.

[0056] Based on the starting material of formula VI, the amount of the catalytic dosage of the phosphorus-containing component used can be 0.025 mol% to 25 mol% according to the present invention, preferably 0.5 mol% to 10 mol%, and more preferably 2 mol% to 5 mol%.

[0057] The reaction can be carried out from room temperature to the boiling point of the solvent mixture used. The reaction temperature is generally in the range of 20°C to 150°C, preferably 50°C to 100°C.

[0058] After the reaction, the reaction mixture can be processed in a manner commonly used industrially. For example, the undissolved inorganic salts can be filtered out, or in the case where the solvent is slightly soluble in water, the undissolved inorganic salts can be removed by washing with water and optionally adding salts to the wash water.

[0059] 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 out and further wet-treated or dried.

[0060] In principle, it is also possible to separate the product of formula I by evaporating off the solvent.

[0061] The product of formula I obtained in the above-mentioned common manner can be further purified.

[0062] In one aspect of the present invention, the product of formula I can be purified by crystallization from an aromatic hydrocarbon in a further step, and can be specifically purified by precipitation or recrystallization from an aromatic hydrocarbon.

[0063] The aromatic hydrocarbon used can be a benzene derivative, such as toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, cumene or mesitylene, preferably toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, more preferably toluene. A mixture of the above solvents can also be used.

[0064] In the purification step, based on the crude product of formula I to be purified, the aromatic hydrocarbon or hydrocarbon mixture is used in an amount of 100% to 2000% by weight, preferably 200% to 1000% by weight.

[0065] It is also possible to add activated carbon during purification by recrystallization. Based on the crude product of formula I to be purified, the amount of activated carbon is usually at most 10% by weight, preferably at most 5% by weight. Adding activated carbon during purification is preferred.

[0066] Before crystallization of the pure product, the added activated carbon is removed from the mixture by filtration. In one embodiment, the mixture containing activated carbon is hot-filtered, where the product crystallizes out during cooling. In another embodiment, an additional solvent in which the crude product has a higher solubility can be added to prevent premature crystallization of the pure product and filtration together with the activated carbon, resulting in a loss of yield. 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 is carried out from the distillation residue containing mainly only the aromatic hydrocarbon as the solvent. It is preferred to use acetone and 2-butanone, more preferably acetone as the additional solvent.

[0067] Based on the amount of aromatic hydrocarbon used, the amount of the additional solvent is from 10% to 200% by weight, preferably from 20% to 100% by weight, more preferably from 30% to 70% by weight.

[0068] To achieve complete precipitation, before separating the purified solid of formula I, it is cooled to a temperature range of 0 °C - 35 °C, preferably cooled to a standard temperature such as 20 °C - 30 °C.

[0069] The product can be separated in a standard manner, for example, by means of common separation equipment such as a suction filter or a centrifuge. To remove the mother liquor, during separation, the product can be washed with a pharmaceutically acceptable solvent, which is preferably the same solvent as used previously. Then the product thus obtained can be dried.

[0070] The method according to the invention offers different advantages over the prior art. Particularly surprisingly, compared with the prior art, the novel and inventive conversion rate of the structural units of formula VI and formula VII provides a significant increase in yield.

[0071] The compound of formula I can be purified according to the novel method, preferably purified with an aromatic hydrocarbon. This step can follow the method for preparing the compound of formula I described herein. This purification step allows for achieving a very high purity even without using chromatographic purification. Surprisingly, a high-purity product can be obtained only by precipitation, recrystallization, or a combination of both. This allows for achieving a purity of the active substance suitable, for example, for veterinary drugs, as a low residual content of organic secondary components and palladium can be achieved.

[0072] The following secondary components can be specifically mentioned by the following examples:

[0073] Amide N1:

[0074]

[0075] Dechlorinated compound N2:

[0076]

[0077] Bipyrazole borate N3 (compound of formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl):

[0078]

[0079] Bipyrazole boronic acid N4:

[0080]

[0081] Chloroiodobenzamide N5 (compound of formula VII, where X = I):

[0082]

[0083] The content of these secondary components in the final product should preferably be less than 2% by weight, more preferably less than 1% by weight, particularly preferably less than 0.7% by weight, especially less than 0.5% by weight in each case. In the case of secondary components N3, N4 and N5, the content in the final product should be very particularly preferably less than 0.2% by weight.

[0084] A low palladium content in the final product is additionally desired. This should be less than 100 ppm (w / w), preferably less than 50 ppm (w / w), more preferably less than 20 ppm (w / w).

[0085] The sum of all impurities in the final product should be less than 5% by weight, preferably less than 3% by weight, more preferably less than 2.0% by weight.

[0086] The method is technically reliable in its implementation and allows production on a commercial scale.

[0087] Novel crystal forms of the compound of formula (I) have been found, in particular form I, form II and ethanol-water inclusion complexes. The compound of formula (I) can also exist in amorphous form.

[0088] The terms form, polymorph and polymorphic form have the same meaning in the context of the present application. In addition to polymorphs, the term "crystal 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):

[0089] Form I of the compound of formula (I) is the thermodynamically stable form at room temperature. It is a stable, non-hygroscopic, easily preparable and easily processable crystal form.

[0090] Therefore, form I is suitable for the pharmaceutical field (including veterinary medicine), especially for the production of pharmaceuticals, preferably for the production of pharmaceuticals for animals. The use of form I prevents unwanted conversion to other forms of the compound of formula (I). This contributes to the quality and safety of formulations and pharmaceuticals containing the compound of formula (I).

[0091] In one embodiment, the pharmaceutical according to the invention comprises the compound of formula (I) in form I and optionally further pharmaceutically acceptable excipients.

[0092] In a preferred embodiment, the pharmaceutical essentially comprises form I and does not contain a significant proportion of other forms of the compound of formula (I) and optionally further pharmaceutically acceptable excipients.

[0093] In a medicament comprising polymorph I, there is 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) in the form of polymorph I for use in medicaments, said percentages being based on the total amount of the compound of formula (I) in the medicament in question.

[0094] Polymorph I of the compound of formula (I) is in particular characterized by its X-ray powder diffraction pattern and IR spectrum and can be distinguished from other forms of the compound (see Tables 1 and 2 and Figure 1 and Figures 2 - 8 ).

[0095] Polymorph I of the compound of formula (I) can be prepared by crystallization from various solvents and in particular, especially, diisopropyl ether, toluene, tetrahydrofuran, 1,4-dioxane, acetone, ethyl acetate, acetonitrile, isopropanol, ethanol or methanol.

[0096] Polymorph II can be prepared by crystallization from acetone glycerol (isopropylidene glycerol).

[0097] The ethanol-water clathrate complex can be obtained by crystallization from a 1:1 mixture of ethanol and water.

[0098] 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.

[0099] Polymorph I of the compound of formula (I) has useful pharmacological properties and can be used in particular for treating animals. Polymorph I of the compound of formula (I) is particularly suitable for controlling parasitic organisms in animals, especially ectoparasites.

[0100] In the field of animal health, i.e. veterinary medicine, the crystalline forms described herein, in particular polymorph I of the compound of formula (I), are used for controlling parasitic infestations in animals, especially ectoparasite infestations. Ectoparasites are generally and preferably arthropods, especially insects, such as flies (blood-sucking flies and flies with sponging mouthparts, such as pasture flies, stable flies, horse flies, or other annoying or irritating flies, such as Musca autumnalis, Musca domestica), parasitic fly larvae (e.g. horse flies, warble flies, blowfly larvae), sucking lice, biting lice, bird lice, fleas, etc.; or arachnids (Acari), such as ticks, e.g. hard ticks or soft ticks, or mites, such as Sarcoptes scabiei, Dermatophagoides farinae, Dermanyssus gallinae, etc.

[0101] Parasitic organisms, especially ectoparasites, include for example the following insects and Acari.

[0102] From the order Anoplura, such as the genera Haematopinus spp., Linognathus spp., Pediculus spp., Pthirus spp., and Solenopotes spp., the following are worth special mention: Linognathus setosus, Linognathus vituli, Linognathus ovillus, Linognathus oviformis, Linognathus pedalis, Linognathus stenopsis, Haematopinus asinimacrocephalus, Haematopinus eurysternus, Haematopinus suis, Pediculus humanus capitis, Pediculus humanus corporis, Phylloxera vastatrix, Pthirus pubis, Solenopotes capillatus;

[0103] From the order Mallophaga and the suborders Amblycera and Ischnocera, such as the genera Trimenopon spp., Menopon spp., Trinoton spp., Bovicola spp., Werneckiella spp., Lepikentron spp., Damalinia spp., Trichodectes spp., and Felicola spp., the following are worth special mention: Bovicola bovis, Bovicola ovis, Bovicola limbata, Damalinia bovis, Trichodectes canis, Felicola subrostratus, Bovicola caprae, Lepikentronovis, Werneckiella equi;

[0104] From the order Diptera, suborders Nematocera and Brachycera, such as Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Odagmia spp., Wilhelmina spp., Hybomitra 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., Lipoptena spp., Melophagus spp., Rhinoestrus spp., Tipula spp., among which the following are worth special mention: Aedes aegypti, Aedes albopictus, Aedes taeniorhynchus, Anopheles gambiae, Anopheles maculipennis, Calliphora erythrocephala, Chrysozona pluvialis, CulexCulex quinquefasciatus, Culex pipiens, Culex tarsalis, Fannia canicularis, Sarcophaga carnaria, Stomoxys calcitrans, Tipula paludosa, Lucilia cuprina, Lucilia sericata, Simulium reptans, Phlebotomus papatasi, Phlebotomus longipalpis, Odagmia ornata, Wilhelmina fly, Boophthora erythrocephala, Tabanus bromius, Tabanus spodopterus, Tabanus atratus, Tabanus sudeticus, Hybomitra ciurea, Chrysops caecutiens, Chrysops relictus, Haematopota pluvialis, Haematopota italica, Musca autumnalis, Musca domestica, Haematobia irritans irritans, Haematobia irritans exigua, Haematobia stimulans, Hydrotaea irritans, Hydrotaea albipuncta, Chrysomya chloropyga, Chrysomya bezziana, Oestrus ovis, Hypoderma bovis, Hypoderma lineatum, Przhevalskiana silenus, Dermatobia hominis, Melophagus ovinus, Lipoptena capreoli, Lipoptenacervi), Hippobosca variegata, Hippobosca equina, Gasterophilus intestinalis, Gasterophilus haemorroidalis, Gasterophilus inermis, Gasterophilus nasalis, Gasterophilus nigricornis, Gasterophilus pecorum, Braula coeca;

[0105] From the order Siphonaptera, such as the genera Pulex spp., Ctenocephalides spp., Tunga spp., Xenopsylla spp., Ceratophyllus spp., the following are worth special mention: Ctenocephalides canis, Ctenocephalides felis, Pulex irritans, Tunga penetrans, Xenopsylla cheopis;

[0106] From the suborder Heteroptera, such as the genera Cimex spp., Triatoma spp., Rhodnius spp. and Panstrongylus spp.;

[0107] From the order Blattaria, such as Blatta orientalis, Periplaneta americana, Blattella germanica and the genus Supella spp. (e.g., Supella longipalpa);

[0108] From the subclass Acari (order Acarina), and the suborders Metastigmata and Mesostigmata, such as Argas spp., Ornithodorus spp., Otobius spp., Ixodes spp., Amblyomma 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., 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 evertsi, Ixodes ricinus, Ixodes hexagonus, Ixodes canisuga, Ixodespilosus), Ixodes rubicundus, Ixodes scapularis, Ixodes holocyclus, Haemaphysalis concinna, Haemaphysalis punctata, Haemaphysalis cinnabarina, Haemaphysalis otophila, Haemaphysalis leachi, Haemaphysalis longicorni, Dermacentor marginatus, Dermacentor reticulatus, Dermacentor pictus, Dermacentor albipictus, Dermacentor andersoni, Dermacentor variabilis, Hyalomma mauritanicum, Rhipicephalus sanguineus, Rhipicephalus bursa, Rhipicephalus appendiculatus, Rhipicephalus capensis, Rhipicephalus turanicus, Rhipicephalus zambeziensis, Amblyomma americanum, Amblyomma variegatum, Amblyomma maculatum, Amblyomma hebraeum, Amblyomma cajennense, Dermanyssus gallinae, Ornithonyssus bursa, Ornithonyssus sylviarum, Varroa jacobsoni;

[0109] From the Actinedida (Prostigmata) and Acaridida (Astigmata), such as Acarapis spp., Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Psorergates spp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp., Pterolichus spp., Psoroptes spp., Chorioptes spp., Otodectes 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 ovis, Sarcoptes rupicaprae (= Sarcoptes caprae) (caprae), Sarcoptes equi, Sarcoptes suis, Psoroptes ovis, Psoroptes cuniculi, Psoroptes equi, Chorioptes bovis, Psorergates ovis, pneumonyssoidic mange, Pneumonyssoides caninum, Acarapis woodi.

[0110] The following ectoparasites are preferably mentioned: Ctenocephalides, Echidnophaga spp., Ceratophyllus, Pulex, Hyalomma, Rhipicephalus, Boophilus, Amblyomma, Haemaphysalis, Dermacentor, Ixodes, Argas, Ornithodoros, Otobius megnini, Otodectes cynotis, Otodectes felis.

[0111] The compound of formula (I) in its crystalline form as described herein is suitable for the prevention and treatment of animals suffering from arthropod infestations. The animals include agricultural livestock, such as mammals such as sheep, goats, horses, donkeys, camels, water buffalo, rabbits, reindeer, wapiti, especially cattle and pigs, or poultry such as turkeys, ducks, geese, especially chickens.

[0112] The animals also include animals kept as pets, such as mammals such as hamsters, guinea pigs, rats, mice, chinchillas, ferrets, especially dogs and cats; and caged birds and reptiles.

[0113] In a specific embodiment, the compound of formula (I) is used / administered for the treatment of mammals.

[0114] The use of the compound of formula (I) for controlling animal parasites is intended to reduce or prevent diseases, mortality and production losses (production of meat, milk, wool, hides, eggs, honey, etc.), thus enabling a more economic and easier animal husbandry and improving the health of the animals.

[0115] For example, it is desirable to prevent the parasite from ingesting blood from the host animal. Parasite control can also help prevent the spread of infections.

[0116] In the context of animal health or veterinary medicine of the present invention, the term "treatment" encompasses prophylactic, metaphylactic or therapeutic treatment.

[0117] As used herein, the term "control" in the context of animal health means that the active substance reduces the parasite count in an infested animal, preferably to a harmless level. More precisely, "control" means that the active substance kills the relevant parasite, weakens its growth or prevents its reproduction.

[0118] Preferably, the compound of formula (I) in the crystalline form described herein is used:

[0119] - for controlling ticks

[0120] - for controlling fleas

[0121] - in dogs

[0122] - in cats.

[0123] The compound of formula (I) in the crystalline form described herein can in principle be administered by the commonly used routes of administration, preferably oral administration.

[0124] Variant I of the compound of formula (I) can also be used in combination with other suitable active substances.

[0125] Suitable pharmaceutical forms for formulating variant I of the compound of formula (I) and for its preparation are generally known to those skilled in the art.

[0126] When used in animals, the compound of formula (I) is generally used in an amount of 1 to 100 mg / kg body weight (mg / kg BW), preferably 5 to 30 mg / kg BW, more preferably 10 to 20 mg / kg BW.

[0127] The present invention also encompasses any desired combinations of the above-mentioned preferred and particularly preferred embodiments. Description of the Drawings

[0128] Figure 1 : X-ray powder diffraction pattern of variant I;

[0129] Figure 2 : X-ray powder diffraction pattern of variant II;

[0130] Figure 3 : X-ray powder diffraction pattern of the ethanol-water inclusion complex;

[0131] Figure 4 : X-ray powder diffraction pattern of the amorphous form;

[0132] Figure 5 : IR spectrum of variant I;

[0133] Figure 6 : IR spectrum of variant II;

[0134] Figure 7 : IR spectrum of the ethanol-water inclusion complex; and

[0135] Figure 8 : IR spectrum of the amorphous phase. Detailed implementation mode

[0136] The present invention is illustrated by the following examples, but is not limited thereto.

[0137] Example

[0138] A: Method Example

[0139] The following examples illustrate the method of the present invention using the structural unit of formula VI (where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl). This synthesis provides a substantially better yield than the known synthesis based on the known structural unit of formula II.

[0140] Example 1

[0141] Mix 30.0 g of water, 120.0 g of isopropyl alcohol and 9.2 g of 2'-methyl-5'-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-4'-(trifluoromethyl)-2'H-1,3'-bipyrazole (compound of formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl) in a reaction vessel. Add 6.0 g of 2-chloro-N-(1-cyanocyclopropyl)-5-bromobenzamide (compound of formula VII, where -X is bromine) and 5.0 g of sodium bicarbonate thereto. Finally, add 1.16 g of tetrakis(triphenylphosphine)palladium, and heat the mixture under reflux for 5 h. Filter out the solid present in the reaction mixture by suction and wash it with 30 g of isopropyl alcohol. Concentrate the filtrate slightly to about 75%, and meter the distillation residue into 200 ml of water. Filter out the precipitated solid by suction, wash it with water and dry it under reduced pressure. This gives 11.3 g of a material with a content of 93.2 area%. Without considering the content, due to the content of secondary components, the calculated yield is 102.2% of the theory; when considering the content, it is 95.3% of the theory.

[0142] Example 2

[0143] 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 (Compound of Formula VI, wherein -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. 6.9 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (Compound of Formula VII, wherein -X is iodine) and 5.0 g of sodium bicarbonate were added thereto. Finally, 1.16 g of tetrakis(triphenylphosphine)palladium was added, and the mixture was heated under reflux for 5 h. The solid present in the reaction mixture was filtered off by suction and washed with 30 g of isopropanol. The filtrate was concentrated slightly to about 75%, and the distillation residue was metered into 200 ml of water. The precipitated solid was filtered off by suction, washed with water and dried under reduced pressure. This gave 10.8 g of a material with a content of 97.3 area%. Without considering the content, due to the content of secondary components, the calculated yield was 97.7% of theory; when considering the content, it was 95.1% of theory.

[0144] Example 3

[0145] 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, wherein -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. 34.7 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (Compound of Formula VII, wherein -X is iodine) and 25.20 g of sodium bicarbonate were added thereto. Finally, 1.44 g of tetrakis(triphenylphosphine)palladium was added, and the mixture was heated under reflux for 3.5 h. The solid present in the reaction mixture was filtered off by suction and washed with 100 g of isopropanol. The filtrate was concentrated slightly to about 50%, and the distillation residue was cooled to room temperature. 1000 ml of water was metered into the cooled residue. The precipitated solid was filtered off by suction, washed with water and dried under reduced pressure. This gave 54.6 g of a material with a content of 98.7 area%. Without considering the content, due to the content of secondary components, the calculated yield was 98.8% of theory; when considering the content, it was 97.5% of theory.

[0146] Example 4

[0147] The 10.6 g of product obtained in the previous example was dissolved thermally in 94.4 g of toluene in a reaction vessel. The solution was cooled while 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), which had a content of 99.4 area % and a palladium content of less than 100 ppm.

[0148] Example 5

[0149] 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 (compound of formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. 0.16 g of triphenylphosphine, 8.7 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (compound of formula VII, where -X is iodine) and 6.3 g of sodium hydrogen carbonate were added thereto. Finally, 0.2 g of tetrakis(triphenylphosphine)palladium was added, and the mixture was heated under reflux for 5 h. The mixture was cooled, and the solid present was removed by filtration and washed with a little isopropanol. 250 ml of water was metered into the combined filtrate, and the precipitated solid was filtered off and washed with water. The moist product was mixed with about 44 g of toluene and stirred at 70 °C - 75 °C for 1 h. The suspension was cooled to room temperature, and the solid was filtered off by suction, washed with toluene and dried. This gave 12.3 g (89.0% of theory) of a pale yellow solid with a content > 99 area % (area percentage from HPLC chromatogram). The palladium content was less than 50 ppm.

[0150] Example 6

[0151] 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 thermally under reflux. The activated carbon was filtered off hot, and the filtrate obtained was concentrated to about 40%. It was cooled while stirring, and the solid obtained was filtered off, washed with toluene and dried under reduced pressure. This gave 10.0 g (90.1%, based on the starting material used) of a colorless fine crystalline powder with a content > 99.8 area % (area percentage from HPLC chromatogram). No secondary component was present in a content higher than 0.10 area %. The palladium content was less than 10 ppm.

[0152] The product prepared in Example 6 was studied by TGA. This showed no mass loss up to 150 °C.

[0153] The product prepared in Example 6 was analyzed by X-ray powder diffraction (measurement conditions specified below). The product crystallized in Modification I, which is described in detail below. Figure 1 The diffraction pattern of the product from Example 6 is shown therein.

[0154] Example 7

[0155] 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 (Compound of Formula VI, wherein -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. 0.16 g of triphenylphosphine, 8.7 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (Compound of Formula VII, wherein -X is iodine) and 6.3 g of sodium bicarbonate were added thereto. Finally, 0.2 g of tetrakis(triphenylphosphine)palladium was added and the mixture was heated under reflux for 5 h. The mixture was cooled and the solid present was removed by filtration and washed with 1.8 g of isopropanol. 250 ml of water was metered into the combined filtrate and the precipitated solid was filtered off, washed with water and dried under reduced pressure. A reserved sample of 2.0 g of the water-wet product was taken and dried. This gave 1.1 g of material (8.0% of theory). The remaining water-wet product was suspended in 300 g of toluene and water was removed by azeotropic distillation. Then activated carbon was added and the mixture was stirred under reflux and hot-filtered. Approximately 60% of the solvent was distilled off from the clear filtrate and the remaining residue was cooled. The solid precipitated in the mixture was filtered off by suction, washed with toluene and dried under reduced pressure. This gave 10.8 g of crystalline solid (78.2% of theory). The assay was 99.6 area % (area percentage from HPLC chromatogram). The largest secondary component was present at 0.11%. The palladium content was less than 100 ppm.

[0156] Example 8

[0157] Charge 25.1 g of the crude product prepared in a manner analogous to Example 5 into a reaction vessel. Add 195.5 g of toluene, 80.0 g of acetone and 1.26 g of activated carbon thereto. Dissolve the crude product by heating under reflux. Filter off the activated carbon while hot, and concentrate the resulting filtrate by distillation under standard pressure to obtain approximately 167 g of a residue. Cool it while stirring (< approximately 54 °C) until crystallization is substantially complete. Heat the suspension to an internal temperature of approximately 95 °C and stir briefly at this temperature without allowing complete dissolution. Slowly cool the resulting hot suspension to 5 °C, stir further at this temperature, and filter off the obtained solid, wash it with toluene and dry it under reduced pressure. This gives 23.7 g (94.4%, based on the starting materials used) of a colorless, fine crystalline powder with a content > 99.8 area % (area percentage from an HPLC chromatogram). No secondary components are present in a content higher than 0.10 area %. The palladium content is below 1 ppm.

[0158] Example 9

[0159] Prepare the structural unit of formula C (corresponding to the structural unit of formula VI, where -A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl).

[0160]

[0161] Mix 2.6 kg of structural unit B and 22.88 liters of acetonitrile in a reaction vessel at 22 °C. Add 2.78 kg of ground potassium carbonate, 3.64 kg of the structural unit of formula A and 1.91 kg of acetonitrile thereto. Stir the reaction mixture under reflux for 7 h and then cool it to room temperature. Filter off the solid in the reaction mixture and wash it with 4.03 kg of acetonitrile. Distill off 23.75 kg of the solvent from the combined filtrates. Mix the distillation residue with 7.53 kg of isopropanol, then meteringly add 47.85 kg of water at approximately 22 °C, cool the mixture to 3 °C - 5 °C and filter off the precipitated solid. Wash the solid with water and dry it under reduced pressure. This gives 4.99 kg of the product of formula C as a light yellow solid. This corresponds to 85.2% of theory. The analytical content is 99.6% ESTD (HPLC evaluation with an external standard).

[0162] B. Crystal Forms of the Compound of Formula (I)

[0163] B.1. Preparation of Polymorph I

[0164] Dissolve approximately 400 mg of the compound of formula (I) in each case by heating in one of the solvents specified in the specified volumes of the solvents below and filter while hot:

[0165] - 80 ml of diisopropyl ether + 5 ml of ethanol

[0166] -40 ml of toluene

[0167] -40 ml of tetrahydrofuran

[0168] -40 ml of acetone

[0169] -40 ml of ethyl acetate

[0170] -40 ml of acetonitrile

[0171] -40 ml of 2-propanol

[0172] -40 ml of ethanol

[0173] -40 ml of methanol

[0174] -40 ml of 1,4-dioxane

[0175] -40 ml of DMSO

[0176] Let the solution stand at room temperature until dry. Modification I is characterized by X-ray diffraction.

[0177] B.2. Preparation of Polymorph II

[0178] Dissolve approximately 400 mg of the compound of formula (I) in 4 ml of acetone glycerol by heating. Let the solution stand at room temperature until dry. Modification II is characterized by X-ray diffraction.

[0179] B.3. Preparation of Ethanol - Water Inclusion Complex

[0180] Dissolve approximately 400 mg of the compound of formula (I) in 100 ml of EtOH / H2O 1:1 by heating and filter hot. Let the solution stand until dry. The ethanol-water inclusion complex is characterized by X-ray diffraction.

[0181] B.4. Characterization of Crystal Forms

[0182] Table 1 XRPD Data of the Crystal Forms of the Compound of Formula (I)

[0183]

[0184]

[0185] Measurement conditions:

[0186] Figure 1 : X-ray powder diffraction pattern of Modification I

[0187] Figure 2 : X-ray powder diffraction pattern of Modification II

[0188] Figure 3 : X-ray powder diffraction pattern of ethanol-water clathrate complex Figure 4 : X-ray powder diffraction pattern of the amorphous form

[0189] Table 2 IR Spectral Data of the Crystal Forms of the Compound of Formula (I)

[0190]

[0191]

[0192] Measurement conditions:

[0193] The ATR IR spectra were recorded at room temperature in a Tensor 37 FT-IR spectrometer from Bruker using an ATR unit and without further sample preparation. The resolution was 4 cm -1 .

[0194] The spectra are shown in the figures:

[0195] Figure 5 : IR spectrum of variant I

[0196] Figure 6 : IR spectrum of variant II

[0197] Figure 7 : IR spectrum of ethanol-water clathrate complex

[0198] Figure 8 : IR spectrum of the amorphous phase.

Claims

1. The compound of formula (I) in crystalline form:

2. The compound of formula (I) according to claim 1, wherein, The crystalline form is polymorph I or an ethanol - water inclusion complex.

3. The compound of formula (I) according to claim 1, wherein, The crystalline form is polymorph II or an ethanol - water inclusion complex.

4. Use of the compound of formula (I) according to any one of claims 1 to 3 in the preparation of a medicament.

5. Use of the compound of formula (I) according to claim 4, wherein, The medicament is for animals.

6. Use of the compound of formula (I) according to claim 4 or 5, wherein, The medicament is for treating animals to prevent and control parasitic organisms, especially ectoparasites.

7. A pharmaceutical composition comprising the compound of formula (I) according to claim 1 or 2, and substantially comprising polymorph I of the compound of formula (I), free of significant proportions of other forms of the compound of formula (I), optionally comprising additional pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 7, wherein, There is at least 85% by weight, preferably at least 90% by weight, particularly preferably at least 95% by weight of polymorph I form of the compound of formula (I) for use in the medicament, said percentage being based on the total amount of the compound of formula (I) in the medicament concerned.

9. A method for preparing polymorph I of the compound of formula (I) according to claim 2 by crystallization from diisopropyl ether, toluene, tetrahydrofuran, 1,4 - dioxane, acetone, ethyl acetate, acetonitrile, isopropanol, ethanol or methanol.

10. A method for preparing polymorph II of the compound of formula (I) according to claim 3 by crystallization from isopropylidene glycerol.

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