BR112018070663B1 - PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY ENRICHED ISOXAZOLINE COMPOUNDS - CRYSTALLINE TOLUENE SOLVATE OF (S)-AFOXOLANER - Google Patents

Abstract

This invention relates to processes for the preparation of antiparasitic isoxazoline compounds enriched in one enantiomer using quinine-based chiral phase transfer catalysts. The invention also relates to new phase transfer catalysts based on quinine and to a crystalline form of (S)-afoxolaner toluene solvate.

Description

FIELD OF INVENTION

[001] The present invention provides stereoselective processes for the preparation of isoxazoline compounds enriched in one enantiomer. Also provided is a new crystalline toluene solvate of (S)afoxolaner prepared by the processes of the invention. The invention also provides novel quinine-based chiral phase transfer catalysts and processes for preparing the novel catalysts.

CROSS REFERENCE TO RELATED ORDERS

[002] This application claims the benefit of priority to US Provisional Application No. 62/319,207, filed on April 6, 2016, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

[003] Animals such as birds and mammals are often sensitive to parasite infestations / infections. These parasites can be ectoparasites, such as insects, and endoparasites, such as filariae and other worms. Domesticated animals, such as dogs and cats, are often infested with one or more of the following ectoparasites:

[004] - fleas (for example, Ctenocephalides spp., such as Ctenocephalides felis and the like);

[005] - ticks (e.g., Rhipicephalus spp, Ixodes spp, Dermacentor spp, Amblyomma spp, and the like);

[006] - mites (for example, Demodex spp, Sarcoptes spp, Otodectes spp, and the like);

[007] - lice (for example, Trichodectes spp, Cheiletiella spp, Linognathus spp and the like);

[008] - mosquitoes (Aedes spp, Culex spp, Anopheles spp and the like); It is

[009] - flies (Haematobia spp, Musca spp, Stomoxis spp, Dermatobia spp, Cochliomyia spp and others).

[0010] Fleas are a particular problem, not only because they negatively affect the health of the animal or human being, but they also cause a great deal of psychological stress. Furthermore, fleas are also vectors of pathogens in animals and humans, such as the canine tapeworm (Dipilidium caninum).

[0011] Likewise, ticks are also harmful to the physical and psychological health of the animal or human. However, the most serious problem associated with ticks is that they are the vector of pathogens in humans and animals. Major diseases that are caused by ticks include borreliosis (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia spp.), and rickettsioses (also known as Rocky Mountain fever). Ticks also release toxins that cause inflammation or paralysis in the host. Occasionally, these toxins are fatal to the host.

[0012] Likewise, farm animals are also susceptible to parasite infestation. For example, cattle are affected by a large number of parasites. A parasite that is very prevalent among farm animals is the tick genus Rhipicephalus (Boophilus), especially those of the species microplus (cattle tick), atus decolor and annulatus. Ticks, such as Rhipicephalus {Boophilus) microplus, are particularly difficult to control because they live in grassland where farm animals graze.

[0013] Animals and humans also suffer from endoparasite infections including, for example, helminthiasis which is most often caused by a group of parasitic worms categorized as cestodes (tapeworm), nematodes (roundworm) and trematodes (flatworm or flounder). These parasites adversely affect animal nutrition and cause serious economic losses in pigs, sheep, horses and cattle, as well as affecting domestic animals and poultry. Other parasites that occur in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongiloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris, Enterobius, and parasites that are found in the blood or other tissues and organs, such as filarial worms and the extra-intestinal stages of Strongiloides, Toxocara and Trichinella.

[0014] Recently, isoxazole and isoxazoline-containing compounds have been shown to be effective against parasites that harm animals. For example, US 7,964,204 and US 8,410,153 (DuPont, both incorporated herein by reference) describe isoxazoline compounds according to Formula (I) below, which are active against ectoparasites.

[0015] A particularly active isoxazoline compound, 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[ 2-oxo-2-[(2,2,24rifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide, is known by the non-proprietary name afoxolaner. Afoxolaner has the following chemical structure:

[0016] Other isoxazoline compounds that have been found to be highly active against parasitic insects and arachnids are known by the names unprotected fluralaner (see US 7662972, which is incorporated herein by reference), sarolaner (see US 8466, 15, incorporated herein by reference). reference) and lotilaner (see, for example, US 8383659, incorporated herein by reference). The structures of these compounds are presented below:

[0017] Additionally, published in patent applications. US 2010/0254960 Al, WO 2007/070606 A2, WO 2007/123855 A2, WO 2010/003923 Al, US7951828 and US7662972, US 2010/0137372 Al, US 2010/0 179194 A2, US 2011/0086886 A2, US 2011/0059988 Al, US 2010/0179195 Al and WO 2007/075,459 A2 and US Patent No. 7951828 (all incorporated herein by reference) describe several other parasiticidal isoxazoline compounds.

[0018] It is known in the art that isoxazoline compounds that have a chiral quaternary carbon atom, such as the carbon atom adjacent to the oxygen atom in the isoxazoline ring of the compounds described above, have at least two optical isomers (enantiomers) that they are mirror images of each other. Furthermore, it is sometimes the case with biologically active compounds that one of the enantiomers is more active than the other enantiomer. Furthermore, it is sometimes the case that one enantiomer of a biologically active compound is less toxic than the other enantiomer.

[0019] Therefore, with optically active compounds, it is desirable to use the enantiomer that is most active and least toxic (eutomer). However, isolating the most active enantiomer from a mixture can be expensive and result in the loss of up to half of the prepared racemic mixture.

[0020] Processes for preparing certain isoxazoline compounds enriched in one enantiomer using some cinchona alkaloid-derived phase transfer catalysts have been described. For example, US 2014/0206633 Al, US 2014/0350261 Al, WO 2013/116236 Al and WO 2014/081800 Al (incorporated herein by reference) describe the synthesis of certain isoxazoline active agents enriched in a chiral enantiomer using the alkaloid-based cinchona phase transfer catalysts. Furthermore, Matoba et al., Angew. Chem. 2010, 122, 5898-5902 describes the chiral synthesis of certain pesticide isoxazoline active agents. However, these documents do not describe the processes and certain catalysts described herein.

INCORPORATION BY REFERENCE

[0021] Any previous requests, and all documents cited herein or during their processing ("application of cited documents") and all documents cited or referenced in the application of cited documents, and all documents cited or referred to in this text ( "documents cited herein"), and all documents cited or referenced in documents cited herein, together with any manufacturer's instructions, descriptions, product specifications, and product inserts for all products herein or in any document incorporated herein by reference, are incorporated herein by reference mentioned, and may be employed in the practice of the invention.

[0022] Citation or identification of any document in this patent application is not an admission that such document is available as prior art to the present invention.

SUMMARY OF THE INVENTION

[0023] The present invention relates to processes for the preparation of enantiomerically enriched antiparasitic isoxazoline compounds and to new phase transfer catalysts useful for these processes. In one embodiment, the invention provides a process for preparing an isoxazoline compound of formula (I) below, which is enriched in one enantiomer: wherein B1, B2, B3, R1, Y and Q are defined herein and wherein the asterisk represents that the carbon atom is a chiral quaternary carbon atom; comprising reacting the compound of formula (II) wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a base and a chiral phase transfer catalyst of formula (IIIa) or (IIIb): wherein R is aryl or heteroaryl substituted with one or more aralkoxy, amino, alkylamino or dialkylamino, R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X is a counterion, including halogen, mesylate, tosylate , triflate, brosylate, nonylate, tresylate and the like.

[0024] The (S)-enantiomer of anti-parasitic compounds of formula (I) have been shown to be more active against ectoparasites (for example, fleas and ticks) than the (R)-enantiomer. The (S) enantiomer of the compounds is produced as the major product when a phase transfer catalyst with formula (IIIa) is used and the (R) enantiomer is produced as the major product when (IIIb) is used.

[0025] In another embodiment of the invention, the invention provides a process for preparing an isoxazoline compound of formula IA, wherein X1, X2 and X3 are each independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl, which is enriched in the (S) enantiomer:

[0026] comprising reacting a compound of formula (IIA):

[0027] wherein X1, X2 and X3 having the meanings described above for Formula IA, with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a phase transfer catalyst of formula ( IIIa): wherein R is aryl or heteroaryl optionally substituted with one or more C1-C3alkoxy, amino, alkylamino, dialkylamino or aralkoxy groups, R' is hydrogen or C1-C3alkoxy, W is ethyl or vinyl, and X- is an anion.

[0028] In other embodiments, the invention provides processes for the preparation of the following compounds enriched in the (S) enantiomer, using a chiral phase transfer catalyst of formula (IIIa):

[0029] In another embodiment of the invention, the isoxazoline compounds of formula (I) enriched in the (S)-enantiomer configuration, which are prepared using the chiral phase transfer catalyst of formula (Illa), is purified and enriched in the (S)-enantiomer by crystallization using an aromatic solvent including, but not limited to, toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole and mesitylene.

[0030] In another embodiment, the invention provides a crystalline toluene solvate form of (S)-afoxolaner prepared by crystallization of the compound from toluene or a mixture containing solvent toluene. Other solvates of the (S) enantiomers of the isoxazoline compounds of formula (I) of the invention with aromatic solvents, such as ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole and mesitylene are also foreseen.

[0031] In other embodiments, the invention provides parasiticidal veterinary compositions comprising compounds of formula (I) enriched in the (S)-enantiomer and methods and uses of the compounds and compositions for the treatment and prevention of infestations or infections of parasites in animals . Also included are methods and uses comprising compounds of formula (I) enriched in the (S)-enantiomer for combating animal pests and protecting crops and plants against these pests.

[0032] In another embodiment, the invention provides a new and inventive phase transfer catalyst of formula (IIIa-13-1), formula (IIIa-13-2), formula (IIIa-13-3) or formula (IIIa -13-4), or a mixture of any of these catalysts: where X is a counterion. In an embodiment of formula (IIIa-13-1), (IIIa-13-2), (IIIa-13-3) or (IIIa-13-4), X is a halogen counterion, such as chloride.

[0033] In yet another embodiment, the invention provides new and inventive processes for preparing the chiral phase transfer catalysts described herein.

[0034] It is an object of the invention to not include within the scope of the invention any previously known product, product manufacturing process, or method of using the product, such that applicants reserve the right and hereby disclose a notice of any previously known product, process or method. It is further noted that the invention is not intended to include within the scope of the invention any product, process, or making of the product or method of using the product, which does not meet the written description and qualification requirements of the USPTO ( 35 USC §112, first paragraph) or EPO (EPC Article 83), such that applicants reserve the right to hereby disclose notice of any previously described product, process of manufacturing the product, or method of using the product.

[0035] These and other embodiments are disclosed or are obvious from, and covered by, the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The following detailed description, given by way of example, but is not intended to limit the invention only to the specific embodiments described, can be better understood in conjunction with the attached drawings, in which:

[0037] Figure 1 is the 1H NMR spectrum of chiral phase transfer catalyst (IIIa-13-1) prepared in Example 1.

[0038] Figure 2 is the LCMS spectrum (FIPLC-mass spectrum) of chiral phase transfer catalyst (IIIa-13-1) prepared in Example 1.

[0039] Figure 3 represents the 1H NMR spectra of (S)-afoxolaner-toluene solvate prepared in Example 7 in DMSO-de.

[0040] Figure 4 represents the 1H NMR spectra of afoxolaner (racemic) in DMSO-d6.

[0041] Figure 5 represents the chiral HPLC chromatogram of afoxolaner using the HPLC method described in Example 3.

[0042] Figure 6 is the chiral FIPLC chromatogram of (S)-afoxolaner prepared in Example 7, using the HPLC method described in Example 3.

[0043] Figure 7 shows the combined TGA and DSC profiles of crystalline toluene solvate (S)-afoxolaner as described in Example 12.

[0044] Figure 8 shows the X-Ray Powder Diffraction pattern of the crystalline toluene solvate of (S)-afoxolaner as described in Example 12.

[0045] Figure 9 shows an X-ray single crystal structure of the crystalline solvate of toluene (S)-afoxolaner.

[0046] Figure 10 shows the molecular structure of (S)-afoxolaner determined using the Cerius 2 software.

DETAILED DESCRIPTION OF THE INVENTION

[0047] In a first aspect, the present invention provides a process for the preparation of an isoxazoline compound of formula I) below, which is enriched in one enantiomer: where: B1, B2, B3, are each, independently, CR or N; each R is independently H, halogen, cyano, -NO2, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino or alkoxycarbonyl; R1 represents C1-C3 alkyl or C1-C3 haloalkyl; Y is an optionally substituted phenylene, naphthylene, indanylene, a 5- or 6-membered heteroarylene or an 8-10 membered fused heterobicyclylene, wherein the optional substituents are selected from the group consisting of halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl , alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, -CN or -NO2 and H2-C(=S)-; Q is T-NR2R3, the group (-CH2-)(-CH2-)N-R3, OH, NH2, alkoxy, haloalkoxy, alkylamino, haloalkylamino, dialkylamino, halodialkylamino, thiol, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, or an optionally substituted 5- or 6-carbocyclyl, heterocyclyl or heteroaryl ring members; T is (CH2)n, CH(CH3), CH(CN), C(=O) or C(=S); R2 represents H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl; R3 represents H, OR7, R8R9 or Q1; or an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, each optionally substituted with one or more substituents independently selected from R4; or R2 and R3 are taken together with the nitrogen to which they are bonded to form a ring containing 2 to 6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, halogen, -CN, -NO2 and alkoxy; each R4 independently represents halogen; alkyl, cycloalkyl, alkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, haloalkylamino, dialkylamino, dihaloalkylamino, cycloalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl, loalkylaminocarbonyl, hydroxy, -NH2, - CN or -N02; or Q2; each R5 independently represents halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, -CN or -NO2; each R6 independently represents halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, -CN, -N02, phenyl or pyridinyl; R7 is H; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionally substituted with one or more halogen; R8 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl; R9 represents H; Q3; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R4; or R8 and R9 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, halogen, -CN, -N02 and alkoxy; Q1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or a fused 8-, 9- or 10-membered bicyclic ring system optionally containing one to three heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, each ring or ring system optionally substituted with one or more substituents selected independently of R5; Q2 is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R6; Q3 represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R6; en is 0, 1 or 2; wherein the asterisk represents that the carbon atom is a chiral quaternary carbon atom; comprising reacting a compound formula (II): wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a base and a chiral phase transfer catalyst of formula (IIIa) or (IIIb): wherein R is aryl or heteroaryl substituted with one or more aralkoxy, amino, alkylamino or dialkylamino groups; R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X- is an anion; and isolates the compound. In the structures of (Illa) and (Illb) indicated above, the stereochemistry is shown for clarity. In one embodiment, X- is a halogen counterion. In another embodiment, X- is chloride or bromide. In another embodiment, X- is a tosylate, mesylate, triflate, brosylate, nosylate or tresylate counter ion and the like.

[0048] In one embodiment, the invention provides a process for the preparation of an isoxazoline compound of formula (I) indicated above, which is enriched in an enantiomer, which comprises reacting the compound of formula (II) as defined above, with hydroxylamine , in the presence of water, a base and a chiral phase transfer catalyst of formula (IIIa) or (IIIb); and isolating the product by crystallization.

[0049] In another embodiment, the invention provides a process for the preparation of an isoxazoline compound of formula (I) indicated above, which is enriched in an enantiomer, which comprises the reaction of the compound of formula (II) as defined above, with hydroxylamine, in the presence of water, a base and a chiral phase transfer catalyst of formula (IIIa) or (IIIb); and isolating the product by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent.

[0050] In yet another embodiment, the invention provides a process for the preparation of an isoxazoline compound of formula (I) indicated above, which is enriched in an enantiomer, which comprises the reaction of the compound of formula (II) as defined above, with hydroxylamine, in the presence of water, a base and a chiral phase transfer catalyst of formula (IIIa) or (IIIb); and isolating the product by crystallization from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a combination thereof, or a mixture of solvents comprising one or more of these solvents.

[0051] The transfer of chiral phase of formula (IIIa) or (IIIb) used in the process is a very important factor in achieving the best possible enrichment of the desired enantiomer. It has surprisingly been found that when the symbol R in formula (IIIa) or (IIIb) is a substituted aryl group, including a phenyl group, the type of substituent and the degree of substitution have a pronounced effect on the stereoselectivity of the reaction. Although quinine phase transfer catalysts are known and have been used for the preparation of chiral isoxazoline compounds (see, for example, WO 2011/104089 A1, which is incorporated herein by reference), it has surprisingly been discovered that certain substituents have improved unexpectedly selectivity of the reaction. It has been found that electron-donating substituents such as alkoxy groups in which the aryl or heteroaryl group R improve selectivity for the (S)-enantiomer if (IIIa) is used. Furthermore, multiple substitution of the aryl or heteroaryl group R with further electron-donating groups improves the selectivity of the reaction for the (S) enantiomer. It is clear that if the stereochemistry of the chiral catalyst is inverted and (IIb) is used, the selectivity is for the (R) enantiomer.

[0052] Those skilled in the art will understand that, in some circumstances, the mixtures of phase transfer catalysts described herein can be used to obtain enantiomerically enriched isoxazoline compounds. Furthermore, it should be understood that a given catalyst (e.g., Formula (IIIa-13-1) may contain small amounts of another catalyst having a different group W (or vinyl acetate) or R' (e.g., methoxy or hydrogen). However, the presence of small amounts of catalysts substituted with other W and R' groups will still be useful for the preparation of the enantiomerically enriched isoxazoline compounds described here.

[0053] It was found that using a quinine phase transfer catalyst of formula (Illa) or (Illb), wherein R is a phenyl group with trisubstituted aralkoxy groups, a surprisingly high selectivity for the formation of compounds of Chiral isoxazoline compared to known quinine phase transfer catalysts is achieved even superior to quinine catalysts in which the corresponding group R is an aryl group substituted with one or more alkoxy groups. Thus, phase transfer catalysts of formula (Illa) or (Illb) wherein R is a phenyl group substituted with, 2, 3, 4 or 5 aralkoxy groups have been found to provide surprising selectivity in the formation of chiral isoxazoline compounds. of formula (I) compared to known quinine phase transfer catalysts. In a preferred embodiment, the chiral quinine phase transfer catalysts are substituted with 1, 2, 3, 4 or 5 (-OCH2Ph) benzyloxy groups. In a particularly preferred embodiment, the invention provides chiral quinine phase transfer catalysts of formula (IIIa) wherein W is ethyl or vinyl, R' is methoxy or hydrogen and R is 3,4,5-tris(benzyloxy)phenyl3 ,4,5-tris(benzyloxy)phenyl. These catalysts have been shown to provide surprisingly better selectivity in the reaction to prepare isoxazoline compounds of formula (I) enriched in the (S)-enantiomers.

[0054] Therefore, in one embodiment, the invention provides a process for the asymmetric synthesis of an antiparasitic isoxazoline compound of formula (I) enriched in one enantiomer: wherein B1, B2, B3, R1, Y and Q are as defined above, comprising the reaction of a compound of formula (II): wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (IIIa) or (IIIb):

[0055] wherein R is aryl or heteroaryl that is substituted with one or more aralkoxy, amino, alkylamino or dialkylamino, R' is hydrogen or C1-C3 - alkoxy, W is ethyl or vinyl, and X¯ is an anion; and isolation of the compound. In one embodiment, X¯ is a halide anion. In another embodiment, X is chloride or bromide. In another embodiment, X¯ is a tosylate, mesylate, triflate, brosylate, nosylate or tresylate counter ion, or the like. In a preferred embodiment, the compound of formula (I) is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the compound of formula (I) is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the compound of formula (I) is crystallized from toluene or a mixture of solvents comprising toluene.

[0056] In another embodiment, the invention provides a process for preparing a mixture of isoxazoline compounds of formula (S)-I and (R)-1 below: wherein the mixture is enriched in (S)-le; B1, B2, B3, R1, Y and Q have the same meanings as for formula (I) above;

[0057] comprising the reaction of a compound of formula (II) wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (IIIa):

[0058] wherein R is aryl or heteroaryl substituted with one or more aralkoxy, amino, alkylamino or dialkylamino, R' is hydrogen or C1-C3alkoxy, W is ethyl or vinyl, and X- is an anion; and isolation of the compound. In a preferred embodiment, the compound of formula (I) enriched in the (S)-enantiomer is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the compound of formula (I) enriched in the (S)-enantiomer is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the compound of formula (I) enriched in the (S)-enantiomer is crystallized from toluene or a mixture of solvents comprising toluene.

[0059] In another embodiment, the invention provides a process for preparing a mixture of isoxazoline compounds of formula (S)-I and (R)-I below: wherein the mixture is enriched in (R)-I; It is

[0060] B1, B2, B3, R1, Y and Q have the same meanings as for formula (I) above;

[0061] comprising the reaction of a compound of formula (II):

[0062] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (IIIb):

[0063] wherein R is aryl or heteroaryl substituted with one or more aralkoxy, amino, alkylamino or dialkylamino, R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[0064] In another embodiment, the invention provides a process for preparing a mixture of isoxazoline compounds of formula (S)-I and (R)-1 below: wherein the mixture is enriched in (S)-l and B1, B2, B3, R1, Y and Q have the same meanings as for formula (I) above;

[0065] comprising the reaction of a compound of formula (II):

[0066] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a transfer chiral phase catalyst of formula (IIIa):

[0067] wherein R is aryl or heteroaryl substituted with one or more benzyloxy (OCH2Ph), amino, C1-C3alkylamino or di-C1-C3-alkylamino groups; R' is hydrogen or Ci-C3alkoxy, W is ethyl or vinyl, and X- is an anion; and isolation of the compound. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[0068] In one embodiment, the invention provides a process for the synthesis of a mixture of enantiomers of formula (S)-I and (R)-I, in which the mixture is enriched in one enantiomer in a weight-to-weight ratio of about from 55:45 to about 99.9:0.1, (S)-I -to (R)-I. In another embodiment, the invention provides a process for the synthesis of a mixture of (S)-I and (R)-I enantiomers, which is enriched in the (S)-I enantiomer in a weight to weight ratio of about 65 :35 to about 99:1, (S)-I to (R)-I. In yet another embodiment, the invention provides a process for the synthesis of a mixture of (S)-I and (R)-I enantiomers, wherein the mixture is enriched in (S) in a weight to weight ratio of about 70 :30 to about 99:1, about 80:20 to about 99:1, or about 90:10 to about 99:1, (S)-I to (R)-I.

[0069] In another embodiment, the invention provides a process for the synthesis of a mixture of enantiomers of (S)-I and (R)-I, in which the mixture is enriched in (S)-I in a proportion by weight weight from about 85:15 to about 95:5, (S)-I to (R)-I. In yet another embodiment, the invention provides a process for the synthesis of a mixture of enantiomers of (S)-I and (R)-I, wherein the mixture is enriched in (S)- at a weight-to-weight ratio of about from 87:13 to about 93:7, (S)-I to (R)-I. In another embodiment, the invention provides a process for the synthesis of a mixture of (S)-I and (R)-I enantiomers, wherein the mixture is enriched in (S) in a 95:5 weight-to-weight ratio. 99:1, (S)-I to (R)-I.

[0070] In yet another embodiment, the invention provides a process for preparing an isoxazoline compound of formula (S)-I in substantially pure enantiomeric form (> 99:1, (S)-I to (R)-I ):

[0071] wherein B1, B2, B3, R1, Y and Q have the same meanings as for formula (I) above;

[0072] comprising the reaction of a compound of formula (II):

[0073] presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (IIIa):

[0074] where R is aryl or heteroaryl substituted with one or more benzyloxy groups (-OCH2Ph), W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the compound of formula (S)-I is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the compound of formula (S)-I is crystallized from toluene or a mixture of solvents comprising toluene.

[0075] In one embodiment, isolation of the product by crystallization from an aromatic solvent group results in the isolation of a solid solvate crystalline of the desired enantiomer, with the aromatic solvent resulting in a surprising purification of the desired enantiomer from the mixture reaction, because the racemic compound does not form the solvate form.

[0076] In one embodiment of the process, R in formula (Illa) or (Illb) represents an aryl or heteroaryl group substituted with an aralkoxy group. In another embodiment, R is aryl or heteroaryl substituted with two aralkoxy groups. In yet another embodiment, R is aryl or heteroaryl substituted with three aralkoxy groups. In yet another embodiment, R is aryl or heteroaryl substituted with four aralkoxy groups. In another embodiment, R is aryl or heteroaryl substituted with five aralkoxy groups.

[0077] In another embodiment of the process, R in formula (Illa) or (Illb) represents an aryl or heteroaryl group substituted with a benzyloxy group (OCH 2 Ph) and R' is hydrogen or methoxy. In another embodiment, R is aryl or heteroaryl substituted with two benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is aryl or heteroaryl substituted with three benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is aryl or heteroaryl substituted with four benzyloxy groups and R' is hydrogen or methoxy. In another embodiment, R is aryl or heteroaryl substituted with five benzyloxy groups and R' is hydrogen or methoxy.

[0078] In yet another embodiment of the process, R in formula (Illa) or (Illb) represents a phenyl group substituted with an aralkoxy group. In another embodiment, R is phenyl substituted with two aralkoxy groups. In yet another embodiment, R is phenyl substituted with three aralkoxy groups. In yet another embodiment, R is phenyl substituted with four aralkoxy groups. In another embodiment, R is phenyl substituted with five aralkoxy groups.

[0079] In another embodiment of the process, R in formula (Illa) or (Illb) is:

[0080] In another embodiment of the process, R in formula (Illa) or (Illb) represents a phenyl group substituted with a benzyloxy group (OCH2Ph) and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted with two benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is phenyl substituted with three benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is phenyl substituted with four benzyloxy groups and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted with five benzyloxy groups and R' is hydrogen or methoxy.

[0081] In yet another embodiment of the process, R in formula (Illa) or (Illb) is naphthyl substituted with an aralkoxy group. In another embodiment, R is naphthyl substituted by two aralkoxy groups. In yet another embodiment, R is naphthyl substituted with three aralkoxy groups. In yet another embodiment, R is naphthyl substituted with four aralkoxy groups. In another embodiment, R is naphthyl substituted with five aralkoxy groups.

[0082] In another embodiment of the process, R in formula (Illa) or (Illb) is naphthyl substituted with a benzyloxy group (OCH2Ph) and R' is hydrogen or methoxy. In another embodiment, R is naphthyl substituted by two benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is naphthyl substituted with three benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is naphthyl substituted with four benzyloxy groups and R' is hydrogen or methoxy. In another embodiment, R is naphthyl substituted with five benzyloxy groups and R' is hydrogen or methoxy.

[0083] In yet another embodiment of the process, R in formula (Illa) or (Illb) is anthracenyl substituted with an aralkoxy group. In another embodiment, R is anthracenyl substituted with two aralkoxy groups. In yet another embodiment, R is anthracenyl substituted with three aralkoxy groups. In yet another embodiment, R is anthracenyl substituted with four aralkoxy groups. In another embodiment, R is anthracenyl substituted with five aralkoxy groups.

[0084] In another embodiment of the process, R in formula (Illa) or (Illb) is anthracenyl substituted with a benzyloxy group (OCH2Ph) and R' is hydrogen or methoxy. In another embodiment, R is anthracenyl substituted with two benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is anthracenyl substituted with three benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is anthracenyl substituted with four benzyloxy groups and R' is hydrogen or methoxy. In another embodiment, R is anthracenyl substituted with five benzyloxy groups and R' is hydrogen or methoxy.

[0085] In yet another embodiment of the process, R in formula (Illa) or (Illb) is pyridyl substituted with an aralkoxy group. In another embodiment, R is pyridyl substituted with two aralkoxy groups. In yet another embodiment, R is pyridyl substituted with three aralkoxy groups. In yet another embodiment, R is pyridyl substituted with four aralkoxy groups. In another embodiment, R is pyridyl substituted with five aralkoxy groups.

[0086] In another embodiment of the process, R in formula (Illa) or (Illb) is pyridyl substituted with a benzyloxy group (OCH2Ph) and R' is hydrogen or methoxy. In another embodiment, R is pyridyl substituted with two benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is pyridyl substituted with three benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is pyridyl substituted with four benzyloxy groups and R' is hydrogen or methoxy. In another embodiment, R is pyridyl substituted with five benzyloxy groups and R' is hydrogen or methoxy.

[0087] In yet another embodiment of the process, R in formula (Illa) or (Illb) is pyrimidinyl substituted with an aralkoxy group. In another embodiment, R is pyrimidinyl substituted with two aralkoxy groups. In yet another embodiment, R is pyrimidinyl substituted with three aralkoxy groups. In yet another embodiment, R is pyrimidinyl substituted with four aralkoxy groups. In another embodiment, R is pyrimidinyl substituted with five aralkoxy groups.

[0088] In another embodiment of the process, R in formula (Illa) or (Illb) is pyrimidinyl substituted with a benzyloxy group (OCH2Ph) and R' is hydrogen or methoxy. In another embodiment, R is pyrimidinyl substituted with two benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is pyrimidinyl substituted with three benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is pyrimidinyl substituted with four benzyloxy groups and R' is hydrogen or methoxy. In another embodiment, R is pyrimidinyl substituted with five benzyloxy groups and R' is hydrogen or methoxy.

[0089] In yet another embodiment of the process, R in formula (Illa) or (Illb) is quinolinyl substituted with an aralkoxy group. In another embodiment, R is quinolinyl substituted with two aralkoxy groups. In yet another embodiment, R is quinolinyl substituted with three aralkoxy groups. In yet another embodiment, R is quinolinyl substituted with four aralkoxy groups. In another embodiment, R is quinolinyl substituted with five aralkoxy groups.

[0090] In another embodiment of the process, R in formula (Illa) or (Illb) is quinolinyl substituted with a benzyloxy group (OCH 2 Ph) and R' is hydrogen or methoxy. In another embodiment, R is quinolinyl substituted with two benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is quinolinyl substituted with three benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is quinolinyl substituted with four benzyloxy groups and R' is hydrogen or methoxy. In another embodiment, R is quinolinyl substituted with five benzyloxy groups and R' is hydrogen or methoxy.

[0091] In yet another embodiment of the process, R in formula (Illa) or (Illb) is replaced with a quinolin-4-yl aralkoxy group. In another embodiment, R is quinolin-4-yl substituted with two aralkoxy groups. In yet another embodiment, R is quinolin-4-yl substituted with three aralkoxy groups. In yet another embodiment, R is quinolin-4-yl substituted with four aralkoxy groups. In another embodiment, R is quinolin-4-yl substituted with five aralkoxy groups.

[0092] In another embodiment of the process, R in formula (Illa) or (Illb) is replaced with a benzyloxy quinolin-4-yl group (-OCH2Ph) and R' is hydrogen or methoxy. In another embodiment, R is substituted with two benzyloxy quinolin-4-yl groups and R' is hydrogen or methoxy. In yet another embodiment, R is substituted with three benzyloxy quinolin-4-yl groups and R' is hydrogen or methoxy. In yet another embodiment, R is substituted with four benzyloxy quinolin-4-yl groups and R' is hydrogen or methoxy. In another embodiment, R is substituted with five benzyloxy quinolin-4-yl groups and R' is hydrogen or methoxy.

[0093] In yet another embodiment of the process, R in formula (Illa) or (Illb) is isoquinolinyl substituted with an aralkoxy group. In another embodiment, R is isoquinolinyl substituted with two aralkoxy groups. In yet another embodiment, R is isoquinolinyl substituted with three aralkoxy groups. In yet another embodiment, R is isoquinolinyl substituted with four aralkoxy groups. In another embodiment, R is isoquinolinyl substituted with five aralkoxy groups.

[0094] In another embodiment of the process, R in formula (Illa) or (Illb) is isoquinolinyl substituted with a benzyloxy group (OCH 2 Ph) and R' is hydrogen or methoxy. In another embodiment, R is isoquinolinyl substituted with two benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is isoquinolinyl substituted with three benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is isoquinolinyl substituted with four benzyloxy groups and R' is hydrogen or methoxy. In another embodiment, R is isoquinolinyl substituted with five benzyloxy groups and R' is hydrogen or methoxy.

[0095] In yet another embodiment of the process, R in formula (Illa) or (Illb) is acridinyl substituted with an aralkoxy group. In another embodiment, R is acridinyl substituted with two aralkoxy groups. In yet another embodiment, R is acridinyl substituted with three aralkoxy groups. In yet another embodiment, R is acridinyl substituted with four aralkoxy groups. In another embodiment, R is acridinyl substituted with five aralkoxy groups.

[0096] In another embodiment of the process, R in formula (Illa) or (Illb) is acridinyl substituted with a benzyloxy group (OCH2Ph) and R' is hydrogen or methoxy. In another embodiment, R is acridinyl substituted with two benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is acridinyl substituted with three benzyloxy groups and R' is hydrogen or methoxy. In yet another embodiment, R is acridinyl substituted with four benzyloxy groups and R' is hydrogen or methoxy. In another embodiment, R is acridinyl substituted with five benzyloxy groups and R' is hydrogen or methoxy.

[0097] In yet another embodiment of the process, R in formula (Illa) or (Illb) is acridin-9-yl substituted with an aralkoxy group. In another embodiment, R is acridin-9-yl substituted with two aralkoxy groups. In yet another embodiment, R is acridin-9-yl substituted with three aralkoxy groups. In yet another embodiment, R is acridin-9-yl substituted with four aralkoxy groups. In another embodiment, R is acridin-9-yl substituted with five aralkoxy groups.

[0098] In another embodiment of the process, R in formula (Illa) or (Illb) is acridin-9-yl substituted with a benzyloxy group (OCH 2 Ph) and R' is hydrogen or methoxy. In another embodiment, R is substituted with two benzyloxy acridin-9-yl groups and R' is hydrogen or methoxy. In yet another embodiment, R is substituted with three benzyloxy acridin-9-yl groups and R' is hydrogen or methoxy. In yet another embodiment, R is substituted with four benzyloxy acridin-9-yl groups and R' is hydrogen or methoxy. In another embodiment, R is substituted with five benzyloxy acridin-9-yl groups and R' is hydrogen or methoxy.

[0099] In another embodiment of the process, R in formula (Illa) or (Illb) represents a phenyl, naphthyl, anthracenyl, pyridyl, pyrimidinyl, quinolinyl, quinolin-4-yl, isoquinolinyl, acridinyl or acridin-9-yl group substituted with an amino, C1-C3alkylamino or di-C1-C3-alkyl amino groups and R' is hydrogen or methoxy. In another embodiment, R is phenyl, naphthyl, anthracenyl, pyridyl, pyrimidinyl, quinolinyl, quinolin-4-yl, isoquinolinyl, acridinyl or acridin-9-yl substituted with two aminos, C1-C3alkylamino or amino di-C1-C3-alkyl groups and R' is hydrogen or methoxy. In yet another embodiment, R is phenyl, naphthyl, anthracenyl, pyridyl, pyrimidinyl, quinolinyl, quinolin-4-yl, isoquinolinyl, acridinyl or acridin-9-yl substituted with three amino, CI-

[00100] C3alkylamino or di-C1-C3-alkyl amino groups and R' is hydrogen or methoxy. In yet another embodiment, R is phenyl, naphthyl, anthracenyl, pyridyl, pyrimidinyl, quinolinyl, quinolin-4-yl, isoquinolinyl, acridinyl or acridin-9-yl substituted with four amino, C1-C3 alkylamino or di-C1-C3 groups amino-alkyl and R' is hydrogen or methoxy. In another embodiment, R is phenyl, naphthyl, anthracenyl, pyridyl, pyrimidinyl, quinolinyl, quinolin-4-yl, isoquinolinyl, acridinyl or acridin-9-yl substituted with five amino, C1-C3 alkylamino or di-C1-C3 amino groups - alkyl and R' is hydrogen or methoxy.

[00101] In another embodiment of the process, R in formula (Illa) or (Illb) represents a phenyl group substituted with an amino, C1-C3 alkylamino or di-C1-C3 alkyl amino groups and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted with two amino, C1-C3 alkylamino or di-C1-C3 amino-alkyl groups and R' is hydrogen or methoxy. In yet another embodiment, R is phenyl substituted with three amino, C1-C3 alkylamino or di-C1-C3 amino-alkyl groups and R' is hydrogen or methoxy. In yet another embodiment, R is phenyl substituted with four amino, C1-C3 alkylamino or di-C1-C3 amino-alkyl groups and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted with five amino, C1-C3 alkylamino or di-C1-C3 amino-alkyl groups and R' is hydrogen or methoxy.

[00102] In one embodiment of the invention, B1, B2, B3, in compounds of Formula (I) or Formula (II) are CR and each R is independently H, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In another embodiment, B1, B2, B3 in Formula (I) or Formula (II) are C-R and each R is independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl. In one embodiment, B1, B2, B3 in Formula (I) or Formula (II) are CR and each R is independently H, Cl, F, C1-C3 alkyl or C1-C3 fluoroalkyl. In another embodiment, B1, B2, B3 in Formula (I) or Formula (II) are CR and each R is independently H, Cl, F or CF3.

[00103] In one embodiment of the invention, Y in formula (I) and formula (II) is optionally substituted phenylene. In another embodiment, Y is optionally substituted for naphthylene. In another embodiment, Y is an optionally substituted 5- or 6-membered heteroarylene containing 1, 2 or 3 atoms selected from S, N and O. In yet another embodiment, Y is an optionally substituted bicyclic heteroarylene containing 1, 2 or 3 atoms selected from S, N and O.

[00104] In another embodiment of the process of the invention, Y is selected from Il, Y-2, Y-3, Y-4 where Z is nitrogen or CH, Y-5 or Y-6:

[00105] In one embodiment of the invention, the Q group in Formula (I) or Formula (II) is T-NR2R3. In another embodiment, Q is T-NR2R3 wherein R2 is H or C1-C3 alkyl and R3 is C1-C3 alkyl optionally substituted by R4. In yet another embodiment, Q is T-NR2R3, where R2 is H and R3 is C1C3 alkyl optionally substituted by alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl or dihaloalkylaminocarbonyl. In another embodiment, Q is t-NR 2 R 3 wherein R 2 H and R 3 is C1-C3 alkyl optionally substituted by alkylthio, haloalkylthio, alkylaminocarbonyl, dialkylaminocarbonyl, or haloalkylaminocarbonyl dihaloalkylaminocarbonyl. In yet another embodiment, Q is -C(O)NHCH2C(O)NHCH2CF3. In yet another embodiment, Q is -C(O)CH2S(O)2CH3. In another embodiment, Q is --C(O)NHCH2CH2SCH3. In another embodiment, the symbol Q represents the group (CH2-)(-CH2-)N(CO)CH2S(O)2CH3.

[00106] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which: B1 and B3 are, independently, C-Cl or C-CF3; B2 represents a CH, C-Cl or CF group; R1 represents CF3; Y is Il, Y-2, 4-Y or Y-5; and Q is -C(O)-NR2R3 wherein R2 is H and R3 is C1-C3 alkyl optionally substituted by alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylaminocarbonyl or dihaloalkylaminocarbonyl;

[00107] comprising the reaction of a compound of formula II):

[00108] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a transfer chiral phase catalyst of formula (IIIa): wherein R is aryl or heteroaryl substituted with one or more benzyloxy groups (-OCH2Ph), W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00109] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which: B1 and B3 are, independently, C-Cl or C-CF3; B2 represents a CH, C-Cl or CF group; R1 represents CF3; Y is Il, Y-2, Y-Y-4 or 5; and Q is -C(O)-NR2R3 wherein R2 is H and R3 represents C1-C3 alkyl optionally substituted by C1-C3 alkylthio, C1-C3 haloalkylthio, C1-C3 alkylsulfinyl, C1-C3 haloalkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 haloalkylsulfonyl, C1-C3 alkylaminocarbonyl, C1-C3 dialkylaminocarbonyl, C1-C3 haloalkylaminocarbonyl or C1-C3dihaloalkylaminocarbonyl;

[00110] comprising the reaction of a compound of formula (II):

[00111] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a transfer chiral phase catalyst of formula (IIIa): wherein R is 3,4,5-tris(benzyloxy)phenyl;

[00112] W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00113] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which: B1 and B3 are, independently, C-Cl or C-CF3; B2 represents a CH, C-Cl or CF group; R1 represents CF3; Y is Il, Y-2, YY-4 or 5; and Q is -C(O)CH2S(O)2CH3, -C(O)NHCH2CH2SCH3 or -C(O)NHCH2C(O)NHCH2CF3; comprising the reaction of a compound of formula (II):

[00114] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a transfer chiral phase catalyst of formula (IIIa):

[00115] wherein R is aryl or heteroaryl substituted with one or more benzyloxy groups (-OCH2Ph), W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00116] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which:

[00117] B1 and B3 are, independently, C-Cl or C-CF3;

[00118] B2 represents a CH, C-Cl or CF group;

[00119] R1 represents CF3;

[00120] Y is Il, Y-2, Y-Y-4 or 5; It is

[00121] Q is -C(O)CH2S(O)2CH3, -C(O)NHCH2CH2SCH3 or -C(O)NHCH2C(O)NHCH2CF3;

[00122] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula ( IIIa):

[00123] where R is 3,4,5-tris (benzyloxy) phenyl;

[00124] W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00125] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which:

[00126] B1 and B3 are, independently, C-Cl or C-CF3; B2 is C-H or CF;

[00127] R1 represents CF3;

[00128] Y is Y-2; It is

[00129] Q is -C(O)-NR2R3 where R 2 H and R 3 is C1-C3 alkyl optionally substituted by alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or haloalkylaminocarbonyl dihaloalkylaminocarbonyl;

[00130] comprising the reaction of a compound of formula II):

[00131] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a transfer chiral phase catalyst of formula (IIIa):

[00132] wherein R is aryl or heteroaryl substituted with one or more benzyloxy groups (-OCH2Ph), W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00133] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which:

[00134] B1 and B3 are, independently, C-Cl or C-CF3; B2 is CH or CF;

[00135] R1 represents CF3;

[00136] Y is Y-2; It is

[00137] Q is -C(O)-NR2R3 where R2 is H and R3 is C1-C3 alkyl optionally substituted by alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or haloalkylaminocarbonyl dihaloalkylaminocarbonyl;

[00138] comprising the reaction of a compound of formula (II):

[00139] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, an organic solvent that is not miscible with water, a base and a transfer catalyst chiral phase of formula (IIIa):

[00140] wherein R is aryl or heteroaryl substituted with one or more C1-C3 alkoxy groups, W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00141] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which:

[00142] B1 and B3 are, independently, C-Cl or C-CF3; B2 is CH or CF;

[00143] R1 represents CF3;

[00144] Y is Y-2; It is

[00145] Q is -C(O)-NR2R3 where R2 is H and R3 is C1-C3 alkyl optionally substituted by C1-C3 alkylthio, C1-C3 haloalkylthio, C1-C3 alkylsulfinyl, C1-C3 haloalkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 haloalkylsulfonyl, C1-C3 alkylaminocarbonyl, C1-C3 dialkylaminocarbonyl, C1-C3 haloalkylaminocarbonyl or C1C3 dihaloalkylaminocarbonyl;

[00146] comprising the reaction of a compound of formula (II):

[00147] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (IIIa): wherein R is 3,4,5-tris(benzyloxy)phenyl;

[00148] W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00149] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which:

[00150] B1 and B3 are, independently, C-Cl or C-CF3; is CH or CF;

[00151] R1 represents CF3;

[00152] Y is Y-2; It is

[00153] Q is -C(O)-NR2R3 where R2 is H and R3 is C1-C3 alkyl optionally substituted by C1-C3 alkylthio, C1-C3 haloalkylthio, C1-C3 alkylsulfinyl, C1-C3 haloalkylsulfinyl, C1-C3 alkylsulfonyl, C1-C3 haloalkylsulfonyl, C1-C3 alkylaminocarbonyl, C1-C3 dialkylaminocarbonyl, C1-C3 haloalkylaminocarbonyl or C1C3 dihaloalkylaminocarbonyl;

[00154] comprising the reaction of a compound of formula (II):

[00155] wherein B1, B2, B3, R1, Y are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a phase transfer chiral catalyst of formula (IIIa):

[00156] wherein R is a phenyl ring independently substituted in the 3-, 4- and 5-position with methoxy, ethoxy or isopropoxy;

[00157] W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00158] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which:

[00159] B1 and B3 are, independently, C-Cl or C-CF3; B2 is CH or CF;

[00160] R1 represents CF3;

[00161] Y is Y-2; It is

[00162] Q is -C(O)NHCH2C(O)NHCH2CF3 or -C(O)NHCH2CH2SCH3;

[00163] comprising the reaction of a compound of formula (II):

[00164] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a transfer chiral phase catalyst of formula (IIIa):

[00165] wherein R is aryl or heteroaryl substituted with one, two or three C1-C3 alkoxy groups, W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00166] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which:

[00167] B1 and B3 are, independently, C-Cl or C-CF3; B2 is CH or CF;

[00168] R1 represents CF3;

[00169] Y is Y-2; It is

[00170] Q is -C(O)NHCH2C(O)NHCH2CF3 or -C(O)NHCH2CH2SCH3;

[00171] comprising the reaction of a compound of formula (II): Wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (IIIa):

[00172] wherein R is phenyl independently substituted in the 3, 4 and 5 positions with methoxy, ethoxy or isopropoxy;

[00173] W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00174] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which:

[00175] B1 and B3 are, independently, C-Cl or CCF3; B2 is CH or CF;

[00176] R1 represents CF3;

[00177] Y is Y-2; It is

[00178] Q is -C(O)NHCH2C(O)NHCH2CF3 or -C(O)NHCH2CH2SCH3;

[00179] comprising the reaction of a compound of formula (II):

[00180] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a transfer chiral phase catalyst of formula (IIIa):

[00181] where R is aryl or heteroaryl substituted with one, two or three benzyloxy (-OCH 2 Ph groups), W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00182] In another embodiment of the invention, a process is provided for the synthesis of a compound of formula (I) enriched in the (S)-enantiomer in which:

[00183] B1 and B3 are, independently, C-Cl or C-CF3; B2 is CH or CF;

[00184] R1 represents CF3;

[00185] Y is Y-2; It is

[00186] Q is -C(O)NHCH2C(O)NHCH2CF3 or -C(O)NHCH2CH2SCH3;

[00187] comprising the reaction of a compound of formula (II):

[00188] wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a transfer chiral phase catalyst of formula (IIIa):

[00189] where R is 3,4,5-tris (benzyloxy) phenyl;

[00190] W is ethyl or vinyl, R' is hydrogen or C1-C3 alkoxy, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00191] As described above, the antiparasitic compounds afoxolaner, fluralaner, sarolaner and lotilaner all have an asymmetric quaternary carbon atom in the isoxazoline ring. One enantiomer of each of these compounds is substantially more active against ectoparasites such as fleas and ticks than the other enantiomer. With respect to afoxolaner, the (A) enantiomer is the most active enantiomer. Saronaler is the pure (S)-enantiomer, lotilaner is the (S)-enantiomer, and it is believed that the (S)-enantiomer fluralaner is also the (S)-enantiomer. more active.

[00192] Thus, in a second aspect, the invention provides a process for preparing an isoxazoline compound of formula IA, wherein X1, X2 and X3 are each independently H, halogen, C1-C3 alkyl or C1-C3 haloalkyl , which is enriched in the (S)-enantiomer:

[00193] comprising the reaction of a compound of formula (IIA):

[00194] wherein X1, X2 and X3 have the meanings described above for Formula IA, with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (IIIa):

[00195] wherein R is aryl or heteroaryl optionally substituted with one or more C1-C3 alkoxy or aralkoxy groups, R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00196] In another embodiment, the invention provides a process for preparing an isoxazoline compound of formula IA, wherein X 1, X2 and X3 are each independently H, chlorine, fluorine or CF3, which is enriched in ( S)-enantiomer:

[00197] comprising the reaction of a compound of formula (IIA):

[00198] where X1, IIIa):

[00199] wherein R is aryl or heteroaryl optionally substituted with one or more Ci-C3alkoxy or aralkoxy groups, R' is hydrogen or Ci-C3alkoxy, W is ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00200] In one embodiment of the process for the preparation of (<S) -IA, R in which the catalyst of formula (Illa) is aryl or heteroaryl substituted by one or more C1C6 alkoxy. In another embodiment, R is aryl or heteroaryl substituted by one or more methoxy, ethoxy, -propoxy, isopropoxy, -butoxy, isobutoxy, sec-butoxy or tert-butoxy groups. In another embodiment, R is aryl or heteroaryl substituted by one or more benzyloxy.

[00201] In another embodiment of the process for the preparation of Formula IA enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is phenyl substituted by, 2 or 3 C1-C6 alkoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by one, two or 3 methoxy, ethoxy or isopropoxy groups, and R 'is hydrogen or methoxy. In another embodiment, R is phenyl substituted with, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is vinyl. in yet another embodiment, R is phenyl substituted with, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R 'represents a methoxy group and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 methoxy or ethoxy groups, R' is hydrogen and W is ethyl.

[00202] In another embodiment of the process for the preparation of Formula IA enriched in the (S)-Enantiomer, R in which the catalyst of formula (Illa) is phenyl substituted independently in the 3, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is methoxy and W is vinyl. In another embodiment, R is phenyl independently substituted in the 3-, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is vinyl. In another embodiment, R is phenyl substituted independently in the 3-, 4- and 5-positions. positions with methoxy, ethoxy or isopropoxy; R' is methoxy and W is ethyl. In another embodiment, R is phenyl independently substituted in the 3-, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is ethyl.

[00203] In yet another embodiment of the process for the preparation of Formula IA enriched in the enantiomer (S), R in which the catalyst of formula (Illa) is phenyl substituted by, 2 or 3 benzyloxy, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted with, 2 or 3 benzyloxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by benzyloxy, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted with, 2 or 3 benzyloxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is hydrogen and W is ethyl.

[00204] In another embodiment of the process for the preparation of Formula IA enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is 3,4,5-tris benzyloxy) phenyl (; R' is methoxy and W is vinyl. In another embodiment, R is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen, and W is vinyl. phenyl; R' is methoxy and W is ethyl. In yet another embodiment, R is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen and W is ethyl.

[00205] In another embodiment, the invention provides a process for the preparation of afoxolaner enriched in the (S)-enatiomer:

[00206] comprising the reaction of a compound of formula (IIA-1):

[00207] with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a transfer catalyst (IIIa):

[00208] wherein R is aryl or heteroaryl optionally substituted with one or more C1-C3 alkoxy or aralkoxy groups, R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00209] In an embodiment of the synthesis of afoxolaner enriched in the (<S) enantiomer, R in which the catalyst of formula (Illa) is aryl or heteroaryl substituted by one or more C1-C6 alkoxy. In another embodiment, R is aryl or heteroaryl substituted by one or more methoxy, ethoxy, -propoxy, isopropoxy, -butoxy, isobutoxy, sec-butoxy or tert-butoxy groups. In another embodiment, R is aryl or heteroaryl substituted by one or more benzyloxy.

[00210] In another embodiment of the synthesis of afoxolaner enriched in the (S) enantiomer, R in which the catalyst of formula (Illa) is phenyl substituted by 2 or 3 C1-C6 alkoxy groups and R' is hydrogen or methoxy. In another embodiment R is phenyl substituted by, 2 or 3, methoxy or ethoxy and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted with, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted with, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen and W is ethyl.

[00211] In another embodiment of the synthesis of afoxolaner enriched in the (S) enantiomer, R in which the catalyst of formula (Illa) is phenyl independently substituted in the 3, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is methoxy and W is vinyl. In another embodiment of the synthesis of afoxolaner enriched in the (S) enantiomer, R in which the catalyst of formula (Illa) is phenyl independently substituted in the 3, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is vinyl. In another embodiment of the synthesis of afoxolaner enriched in the (S) enantiomer, R in which the catalyst of formula (Illa) is phenyl independently substituted in the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is methoxy and W is ethyl. In another embodiment of the synthesis of afoxolaner enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is phenyl independently substituted in the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is ethyl.

[00212] In yet another embodiment of the synthesis of afoxolaner enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is phenyl substituted by 2 or 3 benzyloxy and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is vinyl. In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is hydrogen and W is ethyl.

[00213] In another embodiment of the synthesis of afoxolaner enriched in the (S) enantiomer, R in which the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy and W is vinyl. In another embodiment of the synthesis of afoxolaner enriched in the (<S) enantiomer, R in which the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen, and W is vinyl. In another embodiment of the synthesis of afoxolaner enriched in the (S) enantiomer, R in which the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy and W is ethyl. In another embodiment of the synthesis of afoxolaner enriched in the (<S) enantiomer, R in which the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen and W is ethyl.

[00214] In another embodiment, the invention provides a process for preparing an isoxazoline compound of formula IB enriched in the (S)-enantiomer:

[00215] wherein X1, X2 and X3 are each independently H, chlorine, fluorine or CF3;

[00216] comprising the reaction of a compound of formula (IIB):

[00217] wherein X1, X2 and X3 are H, chlorine, fluorine or CF3, with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula ( Illa):

[00218] wherein R is aryl or heteroaryl optionally substituted with one or more C1-C3 alkoxy, amino, C1-C3 - alkylamino, C1-C3 dialkylamino or aralkoxy groups, R' is hydrogen or C1-C3 alkoxy, W is acetate or vinyl and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00219] In one embodiment of the process for the preparation of (S)-IB, R in which the catalyst of formula (Illa) is aryl or heteroaryl substituted by one or more C1C6 alkoxy. In another embodiment, R is aryl or heteroaryl substituted by one or more methoxy, ethoxy, -propoxy, isopropoxy, -butoxy, isobutoxy, sec-butoxy or tert-butoxy groups. In another embodiment, R is aryl or heteroaryl substituted by one or more benzyloxy.

[00220] In another embodiment of the process for the preparation of (S) -IB, R in which the catalyst of formula (Illa) is phenyl substituted by 2 or 3 C1-C6 alkoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy, ethoxy or isopropoxy groups, and R' is hydrogen or methoxy, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted with, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted with, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen and W is ethyl. In another embodiment for the preparation of (<S)-IB, R wherein the catalyst of formula (Illa) is phenyl independently substituted in the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is methoxy or hydrogen; and W is vinyl or ethyl.

[00221] In yet another embodiment of the process for the preparation of (S)-IB, R in which the catalyst of formula (Illa) is phenyl substituted by 2 or 3 benzyloxy, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted with, 2 or 3 benzyloxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is hydrogen and W is ethyl. In another embodiment for the preparation of (<S)-IB, R wherein the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy or hydrogen; and W is vinyl or ethyl.

[00222] In another embodiment, the invention provides a process for the preparation of fluralaner enriched in the (S)-enatiomer:

[00223] comprising the reaction of a compound of formula (IIB):

[00224] with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (Illa):

[00225] wherein R is aryl or heteroaryl optionally substituted with one or more C1-C3 alkoxy or aralkoxy groups, R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00226] In an embodiment of the synthesis of fluralaner enriched in the (S) enantiomer, R in which the catalyst of formula (IIIa) is aryl or heteroaryl substituted by one or more C1-C6 alkoxy. In another embodiment, R is aryl or heteroaryl substituted by one or more methoxy, ethoxy, -propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy groups. In another embodiment, R is aryl or heteroaryl substituted by one or more benzyloxy.

[00227] In another embodiment of the process for the preparation of fluralaner enriched in the (S) enantiomer, R in which the catalyst of formula (IIIa) is phenyl substituted by 2 or 3 C1-C6 alkoxy groups. In another embodiment, R is phenyl substituted by 2 or 3 methoxy, ethoxy or isopropoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted with, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen and W is ethyl.

[00228] In another embodiment of the synthesis of fluralaner enriched in (S), R in which the catalyst of formula (Illa) is phenyl independently substituted in the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is methoxy and W is vinyl. In another embodiment of the synthesis of fluralaner enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is phenyl independently substituted in the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is vinyl. In another embodiment of the synthesis of fluralaner enriched in the (S) enantiomer, R wherein the catalyst of formula (IIIa) is phenyl independently substituted in the 3, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is methoxy and W is ethyl in another embodiment of the synthesis of fluralaner enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is phenyl substituted independently in positions 3, 4 and. 5-position with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is ethyl.

[00229] In yet another embodiment of the synthesis of fluralaner enriched in the (S) enantiomer, R is phenyl substituted by 2 or 3 benzyloxy, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted with, 2 or 3 benzyloxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted with, 2 or 3 benzyloxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is hydrogen and W is ethyl.

[00230] In another embodiment of the synthesis of fluralaner enriched in (S), R in which the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy and W is vinyl. In another embodiment of the synthesis of fluralaner enriched in the (S) enantiomer, R in which the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen, and W is vinyl. In another embodiment of the synthesis of fluralaner enriched in the (S) enantiomer, R in which the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy and W is ethyl. In another embodiment of the synthesis of fluralaner enriched in the (S) enantiomer, R in which the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen and W is ethyl.

[00231] In another embodiment, the invention provides a process for preparing an isoxazoline compound of structural formula (S)-IC, wherein X1, X2 and X3 are each independently H, chlorine, fluorine or CF, which is enriched in the (S)-enantiomer: Understanding reacting a compound of formula (IIC):

[00232] wherein X1, X2 and X3 are H, chlorine, fluorine or CF3, with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula ( IIIa):

[00233] wherein R is aryl or heteroaryl optionally substituted with one or more C1-C3 alkoxy or aralkoxy groups, R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00234] In one embodiment of the process for the preparation of (S)-IC, R in which the catalyst of formula (IIIa) is aryl or heteroaryl substituted by one or more C1C6 alkoxy. In another embodiment, R is aryl or heteroaryl substituted by one or more methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy groups. In another embodiment, R is aryl or heteroaryl substituted by one or more benzyloxy.

[00235] In another embodiment of the process for the preparation of Formula (S)-IC, R in which the catalyst of formula (Illa) is phenyl substituted by 2 or 3 C1-C6 alkoxy groups. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen and W is ethyl. In another embodiment for the preparation of (S)-IC, R wherein the catalyst of formula (Illa) is phenyl independently substituted at positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy; R' is methoxy or hydrogen; and W is vinyl or ethyl.

[00236] In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted with, 2 or 3 benzyloxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is hydrogen and W is ethyl. In another embodiment for the preparation of (S)-IC, R wherein the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy or hydrogen; and W is vinyl or ethyl.

[00237] In another embodiment of the invention, a process for preparing sarolaner is provided:

[00238] Understanding reacting a compound of formula (IIC-1):

[00239] with hydroxylamine, in the presence of water, a base and a chiral phase transfer catalyst of formula (IIIa):

[00240] wherein R is aryl or heteroaryl optionally substituted with one or more C1-C3 alkoxy or aralkoxy groups, R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00241] In one embodiment of the sarolaner synthesis, R in which the catalyst of formula (Illa) is aryl or heteroaryl substituted by one or more C1-C6 alkoxy. In another embodiment, R is aryl or heteroaryl substituted by one or more methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy groups. In another embodiment, R is aryl or heteroaryl substituted by one or more benzyloxy.

[00242] In another embodiment, R is phenyl substituted with, 2 or 3 C1-C6 alkoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen and W is ethyl.

[00243] In another embodiment of the sarolaner synthesis, R in which the catalyst of formula (IIIa) is phenyl independently substituted in the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is methoxy and W is vinyl. In another embodiment of the sarolaner synthesis, R wherein the catalyst of formula (IIIa) is phenyl independently substituted in the 3-, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is vinyl. In another embodiment of the sarolaner synthesis, R wherein the catalyst of formula (IIIa) is phenyl independently substituted in the 3-, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is methoxy and W is ethyl. In another embodiment of the sarolaner synthesis, R wherein the catalyst of formula (Illa) is phenyl independently substituted in the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is ethyl.

[00244] In yet another embodiment in the synthesis of sarolaner, R in which the catalyst of formula (Illa) is phenyl substituted by 2 or 3 benzyloxy, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is hydrogen and W is ethyl.

[00245] In another embodiment of the sarolaner synthesis, R in which the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy and W is vinyl. In another embodiment of the sarolaner synthesis, R wherein the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen, and W is vinyl. In another embodiment of the sarolaner synthesis, R wherein the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy and W is ethyl. In another embodiment of the sarolaner synthesis, R wherein the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen and W is ethyl.

[00246] In another embodiment, the invention provides a process for preparing an isoxazoline compound of formula ID, wherein X1, X2 and X3 are each independently H, chlorine, fluorine or CF, which is enriched in (S) -enantiomer:

[00247] comprising the reaction of a compound of formula (IID):

[00248] wherein X1, X2 and X3 are H, chlorine, fluorine or CF3, with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula ( IIIa):

[00249] wherein R is aryl or heteroaryl optionally substituted with one or more Ci-C3alkoxy or aralkoxy groups, R' is hydrogen or Ci-C3alkoxy, W is ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00250] In one embodiment of the process for the preparation of (S)-ID, R in which the catalyst of formula (Illa) is aryl or heteroaryl substituted by one or more C1C6 alkoxy. In another embodiment, R is aryl or heteroaryl substituted by one or more methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy groups. In another embodiment, R is aryl or heteroaryl substituted by one or more benzyloxy.

[00251] In another embodiment, R is phenyl substituted by 2 or 3 C1-C6 alkoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen and W is ethyl. In another embodiment for the preparation of (S)-ID, R wherein the catalyst of formula (Illa) is phenyl independently substituted at the 3-, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is methoxy or hydrogen; and W is vinyl or ethyl.

[00252] In yet another embodiment of the process for the preparation of Formula ID enriched in the enantiomer (S), R in which the catalyst of formula (IIIa) is phenyl substituted by, 2 or 3 benzyloxy, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is hydrogen and W is ethyl. In another embodiment for the preparation of (<S) -ID, R wherein the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy or hydrogen; and W is vinyl or ethyl.

[00253] In another embodiment, the invention provides a process for preparing lotilaner:

[00254] comprising the reaction of a compound of formula (IID-1):

[00255] with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (IIIa):

[00256] wherein R is aryl or heteroaryl optionally substituted with one or more Ci-C3alkoxy or aralkoxy groups, R' is hydrogen or Ci-C3alkoxy, W is ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00257] In one embodiment of the process for the preparation of lotilaner, R in which the catalyst of formula (Illa) is aryl or heteroaryl substituted by one or more C1-C6 alkoxy. In another embodiment, R is aryl or heteroaryl substituted by one or more methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy groups. In another embodiment, R is aryl or heteroaryl substituted by one or more benzyloxy.

[00258] In another embodiment of the process for the preparation of lotilaner, R in which the catalyst of formula (Illa) is phenyl substituted by 2 or 3 C1-C6 alkoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted with, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen and W is ethyl.

[00259] In another embodiment of the lotilaner synthesis, R in which the catalyst of formula (Illa) is phenyl independently substituted in the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is methoxy and W is vinyl. In another embodiment of the lotilaner synthesis, R wherein the catalyst of formula (Illa) is phenyl independently substituted in the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is vinyl. In another embodiment of the lotilaner synthesis, R wherein the catalyst of formula (IIIa) is phenyl independently substituted in the 3-, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is methoxy and W is ethyl. In

[00260] another embodiment of lotilaner synthesis, R in which the catalyst of formula (Illa) is phenyl independently substituted in the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is ethyl.

[00261] In yet another embodiment of the process for preparing lotilaner, R in which the catalyst of formula (IIIa) is phenyl substituted by 2 or 3 benzyloxy, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is hydrogen and W is ethyl.

[00262] In another embodiment of the lotilaner synthesis, R in which the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy and W is vinyl. In another embodiment of the lotilaner synthesis, R wherein the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen, and W is vinyl. In another embodiment of the lotilaner synthesis, R wherein the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy and W is ethyl. In another embodiment of the lotilaner synthesis, R wherein the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen and W is ethyl. In another embodiment, the invention provides a process for preparing an isoxazoline compound of general formula Ie, wherein X1, X2 and X3 are each independently H, chlorine, fluorine or CF3, which is enriched in the (S)-enantiomer :

[00263] comprising the reaction of a compound of formula (IIA):

[00264] wherein X1, X2 and X3 are H, chlorine, fluorine or CF3, with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula ( IIIa):

[00265] wherein R is aryl or heteroaryl optionally substituted with one or more C1-C3 alkoxy or aralkoxy groups, R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00266] In one embodiment of the process for the preparation of (S)-IE, R in which the catalyst of formula (Illa) is aryl or heteroaryl substituted by one or more C1C6 alkoxy. In another embodiment, R is aryl or heteroaryl substituted by one or more methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy groups. In another embodiment, R is aryl or heteroaryl substituted by one or more benzyloxy.

[00267] In another embodiment of the process for the preparation of Formula IE enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is phenyl substituted by 2 or 3 C1-C6 alkoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy, ethoxy or isopropoxy groups, R' is methoxy and W is vinyl. In yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is ethyl. in yet another embodiment, R is phenyl substituted with, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen and W is ethyl. In another embodiment for the preparation of (<S) -IE, R wherein the catalyst of formula (IIIa) is independently phenyl substituted at one of the 3-, 4- and 5-positions with methoxy, ethoxy or isopropoxy; R' is methoxy or hydrogen; and W is vinyl or ethyl.

[00268] In yet another embodiment of the process for the preparation of Formula IE enriched in the enantiomer (S), R in which the catalyst of formula (Illa) is phenyl substituted by, 2 or 3 benzyloxy, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted with benzyloxy, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted with, 2 or 3 benzyloxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted with 2 or 3 benzyloxy groups, R' is hydrogen and W is ethyl. In another embodiment for the preparation of (<S) -IE, R wherein the catalyst of formula (IIIa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy or hydrogen; and W is vinyl or ethyl.

[00269] In another embodiment, the invention provides a process for preparing an isoxazoline compound of general formula Ie-1, which is enriched in the (S)-enantiomer:

[00270] comprising the reaction of a compound of formula (IIA):

[00271] with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (Illa):

[00272] wherein R is aryl or heteroaryl optionally substituted with one or more C1-C3 alkoxy or aralkoxy groups, W represents ethyl or vinyl, and X- is an anion; and isolating the product. In a preferred embodiment, the product is isolated by crystallization. In another preferred embodiment, the product is isolated by crystallization from an aromatic solvent or a mixture of solvents comprising an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or a mixture thereof, or a mixture of solvents comprising one of these solvents. In a preferred embodiment, the product is crystallized from toluene or a mixture of solvents comprising toluene.

[00273] In one embodiment of the process for the preparation of (S)-IE-1, R in which the catalyst of formula (Illa) is aryl or heteroaryl substituted by one or more C1C6 alkoxy. In another embodiment, R is aryl or heteroaryl substituted by one or more methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy groups. In another embodiment, R is aryl or heteroaryl substituted by one or more benzyloxy.

[00274] In another embodiment, R is phenyl substituted with, 2 or 3 C1-C6 alkoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted with, 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted by 2 or 3 methoxy groups, ethoxy or isopropoxy groups, R' is hydrogen and W is ethyl.

[00275] In another embodiment of the synthesis of Formula IE-1 enriched in the (S)-enatiomer, R in which the catalyst of formula (Illa) is phenyl independently substituted in the 3-, 4- and 5-position with methoxy, ethoxy or isopropoxy; R' is methoxy and W is vinyl. In another embodiment of the synthesis of Formula IE-1 enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is phenyl independently substituted in the 3, 4 and 5 positions with methoxy, ethoxy or isopropoxy; R' is hydrogen and W is vinyl. In another embodiment of the synthesis of formula IE-1 enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is phenyl substituted independently in positions 3, 4 and 5 - positions with methoxy, ethoxy or isopropoxy; R' is methoxy and W is ethyl in another embodiment of the synthesis of Formula IE-1 enriched in (S)-enantiomer, R in which the catalyst of formula (Illa) is phenyl independently substituted in positions 3, 4 and 5 positions with methoxy , ethoxy or isopropoxy; R' is hydrogen and W is ethyl.

[00276] In yet another embodiment, R is phenyl substituted by 2 or 3 benzyloxy, and R' is hydrogen or methoxy. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is vinyl. Yet another embodiment, R is phenyl substituted with benzyloxy, R' is hydrogen, and W is vinyl. In another embodiment, R is phenyl substituted by 2 or 3 benzyloxy groups, R' is methoxy and W is ethyl. In yet another embodiment, R is phenyl substituted with 2 or 3 benzyloxy groups, R' is hydrogen and W is ethyl.

[00277] In another embodiment of the synthesis of Formula IE-1 enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy and W is vinyl.

[00278] In another embodiment of the synthesis of Formula IE-1 enriched in the enantiomer (S), R in which the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen, and W is vinyl. In another embodiment of the synthesis of Formula IE-1 enriched in the (S)-enantiomer, R in which the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is methoxy and W is ethyl. In another embodiment of the synthesis of formula IE-1 enriched in the (A -enantiomer, R in which the catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl; R' is hydrogen and W is ethyl.

[00279] In any of the embodiments of the invention described above, the chiral phase transfer catalyst of formula (IIIa) may have the structures of formulas (Ilia-1) to (III-A-38) in Table 1 below, wherein W is ethyl or vinyl, X is a halogen, mesylate, tosylate, triflate, brosylate, nosylate or tresylate ion counter; each R is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, ZSO-butyl, tert-butyl or CH 2 Ph; R' is hydrogen or C1-C3-alkoxy; Z is halogen, C1-C3 alkyl or C1-C3 haloalkyl; n is 0, 1, 2, 3 or 4; m is 1 or 2; p is 1 or 2; and R1, R2, R3 and R4 are independently H or C1-C3 alkyl. Table 1: The chiral phase transfer catalysts of formula (IlIa-1) to (IIIa-38):

[00280] In another embodiment, the invention provides chiral phase transfer catalysts of formula (IIIb-1) to (IIIb-38) in which the compounds have the structures shown in Table 1 above, with the exception that the compounds have the opposite stereochemistry shown in the carbon atom bearing the hydroxy group and the carbon atom adjacent to the nitrogen atom of the quinuclidine nucleus.

[00281] In another embodiment, the invention provides chiral phase transfer catalysts of formula (IIIa-39) to (IIIa-76), wherein the chiral phase transfer catalysts have the formulas of compounds of formula (IIIa-1 ) to (IIIa-38), except that the OR groups are replaced with the -NHR groups where R has the same meaning.

[00282] In another embodiment, the invention provides chiral phase transfer catalysts of formula (IIIa-77) to (IIIa-114), wherein the chiral phase transfer catalysts have the formulas of compounds of formula (IIIa-1 ) to (IIIa-38), except that the OR groups are replaced with the NRaRb groups where Ra and Rb have the same meaning as R in Table 1.

[00283] In one embodiment, the invention provides a chiral phase transfer catalyst of formula (IIIa-13-1), (IIIa-13-2), (IIIa-13-3) or mixture of (IIIa-13- 4), or one of these, where X- is a counterion, or a mixture of two or more of the catalysts:

[00284] In another embodiment, the invention provides a chiral phase transfer catalyst of formula (IIIa-13-1), (IIIa-13-2), (IIIa-13-3) or (IIIa-13-4) , where X- is a counterion halogen. In another embodiment, X- is a chloride counterion. In yet another embodiment, X- is a mesylate, tosylate, triflate, brosylate, nosylate or tresylate ion counter. The novel phase transfer catalyst can be used to prepare enantiomerically enriched antiparasitic isoxazolines as described herein; however, the skilled artisan will also understand that this catalyst can be used to catalyze other phase transfer reactions to prepare enantiomerically enriched compounds.

Synthesis of chiral phase transfer catalysts

[00285] The chiral phase transfer catalysts of the invention can be prepared by reacting appropriately substituted arylmethyl or heteroarylmethyl intermediates having a suitable leaving group on the methyl moiety with quinine or dihydroquinine in a solvent. Representative reaction examples for preparing other quinine-based chiral phase transfer catalysts can be found in, for example, US 2014/0206633 Al, US 2014/0350261 Al, both incorporated herein by reference. Additional examples of preparation and use of quinine-based chiral phase transfer catalysts are found in Angew. Chem. Int. Ed. 2007, 46, 4222-4266; Tetrahedron Letters 1998, 8775; and Chem. Common. 2009, 7090. For example, aryl or substituted heteroaryl-chloromethyl intermediates can be reacted with quinine to produce the desired catalysts. Scheme 1 below provides an example of the preparation of quinine-based chiral phase transfer catalysts that can be used in the process of the invention, wherein R is C1-C3 alkyl or aralkyl and LG is a suitable leaving group such as halogen ( for example, chloride, iodide, etc.), mesylate, tosylate, triflate and the like. Scheme 1

[00286] It will be appreciated by those skilled in the art that other phase transfer catalysts, for example, react other cinchona alkaloids with intermediate 1-3. Other cinchona alkaloids that can be used include cinchonidine, cinchonine and quinidine. Likewise, dihydroquinine, dihydrocinchonidine, dihydrocinchonine and dihydroquinidine can be reacted with intermediate 13 to produce the corresponding chiral phase transfer catalyst 1-5.

[00287] Furthermore, those skilled in the art will understand that reduction of the 1-1 to 1-2 alcohol intermediate can be achieved with a variety of suitable reducing agents and reducing conditions known in the art, as this is a reaction very general in organic chemistry. For example, the 1-1 reduction can be carried out by a variety of reducing agents, such as sodium borohydride (NaBH4), sodium triacetoxy borohydride, aluminum bis(2-methoxyethoxy) hydride (Red-Al), aluminum and lithium (LiAlH4), and the like. Furthermore, the reduction can advantageously be conducted using a combination of a reducing agent with a Lewis acid, such as NaBH4/AlCl3, and others (see, for example, Advanced Organic Chemistry, Reactions, Mechanisms and Structure, 3rd Edition, by Jerry March, John Wiley & Sons, New York, 1985 ("March").

[00288] Furthermore, it should be understood that the halogenation of alcohols is also a very well-known transformation in organic chemistry (e.g., thionyl chloride (SOCl2), see March) and various reagents and conditions are well known to the skilled artisan. in art. The reaction of quinine with a halomethyl-substituted aromatic group is achieved by heating the reactants in an inert organic solvent such as toluene at elevated temperatures (see, for example, US 2014/0206633 Al, US 2014/0350261 Al).

[00289] It will also be appreciated by those skilled in the art that quinine can react with appropriately substituted aryl or heteroaryl groups that contain other leaving groups on the arylmethyl or heteroarylmethyl group. This includes, for example, tosylates, triflate mesylates and the like.

[00290] The preparation of compounds of formula (II) is known in the art. For example, in US patent 8,217,180; 8,952,175 and publication nos. US 2014/0206633 and WO 2014/081800 (all incorporated herein by reference), among others, provide methods for the synthesis of these compounds. Furthermore, those skilled in the art based on the methods described in these publications and others in combination with the current state of the art will be easily able to make more compounds of formula (II) with different substitution patterns.

Preparation of Chiral Isoxazoline Compounds

[00291] The preparation of isoxazoline active agents of formula (I) by reacting compounds of formula (II) with hydroxylamine and a base in the presence of a chiral phase transfer catalyst of formula (Illa) or (Illb) can be carried out in a two-phase mixture of water and a suitable inert organic solvent, which is not miscible with water. In some embodiments where the compound of formula (II) forms a water-immiscible liquid phase in an organic solvent, it may not be necessary. In certain other embodiments in which the reaction can work in a single phase, the reaction can be carried out without water or with a smaller amount of water. Preferably, the process is conducted in a two-phase mixture of water in an organic solvent that is not miscible with water.

[00292] Suitable organic solvents include, but are not limited to, aromatic solvents, aliphatic solvents and halogenated aliphatic solvents, ethereal solvents and the like. Preferred solvents will not be miscible with water and will have low solubility in water. In one embodiment, an aromatic solvent will be used in the process of the invention, including, but not limited to, toluene, xylenes, fluorobenzene, chlorobenzene, o-dichlorobenzene, anisole and mesitylene. In a preferred embodiment, aliphatic solvents optionally substituted with halogen can be used for the reaction of the compound of formula (II) with hydroxylamine, in the presence of a chiral phase transfer catalyst of formula (Illa) or (Illb). Aliphatic solvents, optionally substituted with halogen, include, but are not limited to, n-pentane, n-hexane, heptane, octane, cyclopentane, cyclohexane, dichloromethane, chloroform, and 1,2-dichloroethane and methylcyclohexane. In a preferred embodiment, the reaction of a compound of formula (II) with hydroxylamine in the presence of a chiral phase transfer catalyst is conducted in a halogenated aliphatic solvent such as dichloromethane or an aromatic solvent such as toluene.

[00293] In some embodiments, ether solvents can be used in the process to prepare enantiomerically enriched isoxazoline compounds, including, but not limited to, diethyl ether, diisopropyl ether, di-butyl ether, methyl cyclopentyl ether. , t-butyl methyl - « ethyl ether and t-butyl ether. In some embodiments, tetrahydrofuran, dimethoxyethane, dioxane, tetrahydropyran, of these, methyltetra may be used including 2-methyltetrahydrofuran, diethoxy methane, acetonitrile, or a combination. In various embodiments, a combination of solvents described above may be used.

[00294] The amount of organic solvent used in the reaction is not critical and depends on the available equipment used for the process as long as the amount of solvent is sufficient to provide the desired reaction at a reasonable rate. However, it will be appreciated that the use of smaller volumes of an organic solvent will be beneficial from an economic and environmental point of view. In some embodiments of the invention, the reaction of a compound of formula (II) with a chiral phase transfer catalyst of formula (Illa) or (Illb) may utilize a volume of an organic solvent of from about 1 to about 100 volumes based on the amount of the starting quantity of the compound of formula (II), assuming a density of lg/mL (excluding water in the reaction medium). For example, if 100 g of the compound of formula (II) is used in the reaction, 10 volumes of solvent would equal 1,000 mL. In other embodiments, the reaction can be carried out with between about 1 to about 80 volumes of solvent. In another embodiment, the reaction can be carried out with between about 1 to about 50 volumes of solvent. In yet another embodiment, the reaction can be carried out with between about 1 to about 30 volumes of solvent, or between about 1 to about 20 volumes of solvent. In another embodiment, the reaction can be carried out with about 1 to about 15 or about 5 to about 15 volumes of solvent. In another embodiment, the reaction of the compound of formula (II) with hydroxylamine in the presence of a base and a chiral phase transfer catalyst of formula (Illa) or (Illb) to form the compound of formula (I) will utilize about 10 volumes of solvent.

[00295] The reaction can be carried out at temperatures of between about -78°C to about 60°C, depending on the solvents used and other factors. More typically, the reaction to form the isoxazoline compounds of formula (I) is carried out at a temperature of between about -30°C to about 40°C. In one embodiment, the reaction is carried out between about -20°C. C to about 25°C. In yet another embodiment, the reaction is carried out at a temperature of about -15°C to about 20°C. In yet another embodiment, the reaction is carried out at a temperature of about - 15°C to about 10°C or about -15°C to about 5°C. In another embodiment, the reaction can be carried out at a temperature range of about -15°C to about -5°C. °C. In another embodiment, the reaction is carried out at a temperature of about -15°C to about 0°C or about -10° to about 0°C. In yet another embodiment, the reaction is carried out at a temperature of about -13°C to about 3°C.

[00296] Of course, the reaction may take a shorter or longer time depending on the temperature and concentration of the reaction mixture. The extent of the reaction can be monitored by measuring the amount of remaining starting material (e.g. compound of formula (II)) using chromatographic methods such as thin layer chromatography (tlc) or HPLC, and the reaction can be stopped when proper conversion is achieved. In some embodiments, the reaction will be carried out from about 30 minutes to about 48 hours. In one embodiment, the reaction will be allowed to stand for about 1 hour to about 48 hours or about 1 hour to about 24 hours. In other embodiments, the reaction will be aged from about 1 hour to about 10 hours. In some embodiments, the reaction is aged for about 1 hour to about 5 hours. In another embodiment, the reaction is aged for about 10 to about 30 hours. In another embodiment, the reaction is aged for about 15 hours to about 25 hours to obtain the desired reaction conversion.

[00297] In some embodiments of the invention, hydroxylamine can be used in excess in relation to the compound of formula (II), including between about 1 and about 50 molar equivalents (as a free base). In one embodiment, the amount of hydroxylamine can be between about 1 to about 20 equivalents. In another embodiment, an amount of from about 1 to about 15 equivalents of hydroxylamine may be used. In another embodiment, from about 1 to about 10 equivalents of hydroxylamine may be used. In another embodiment, from about 1 to about 5 equivalents, or from about 1 to about 6 equivalents of hydroxylamine may be used. In other embodiments, from about 4 to about 8 equivalents of hydroxylamine may be used. In yet another embodiment, from about 5 to about 7 equivalents of hydroxylamine may be used. In another embodiment, about 5 or about 6 equivalents of hydroxylamine may be used. In another embodiment, from about 1 to about 3 molar equivalents of hydroxylamine may be used. In yet another embodiment, from about 1.5 to about 3 or from about 1.5 to about 2.5 molar equivalents of hydroxylamine per mole of the compound of formula (II) can be used. In a particular embodiment, (II) about 2.2 molar equivalents of hydroxylamine (as free base) will be used per mole of the formula compound.

[00298] Hydroxylamine can be as the free base or can be used as an acid salt such as hydroxylamine sulfate salt, hydrochloride salt, phosphate, oxalate, nitrate or acetate. However, because hydroxylamine is dangerous as a free base, it may be beneficial to store and use it as a salt and produce the free base in situ by adding a base. However, the molar equivalents of hydroxylamine relative to the compound of formula (II) will be calculated as a free base.

[00299] In some embodiments, the hydroxylamine reagent will be used as a solution in water. The concentration of the aqueous solution of hydroxylamine (either as a free base or as a salt) is not limited. However, lower safe concentrations may be desired, including about 50% (W/W) or lower. In some embodiments, the process of the present invention will utilize an aqueous solution of hydroxylamine of between 5 to about 50% (W/W). In another embodiment, the concentration of hydroxylamine used will range from about 10 to about 30% (W/W) or about 15 to about 25% (W/W). In another embodiment, the concentration of hydroxylamine is between about 15 to about 20%) (W/W). In one embodiment, the concentration of the hydroxylamine (free base or as a salt) used will be about 18% (W/W) or about 20% (W/W).

[00300] Any suitable base can be used in the reaction including, but not limited to, alkali metal hydroxides or alkoxides, or alkaline earth hydroxides or alkoxides. In some embodiments, alkali metal carbonates or bicarbonates may be used. In one embodiment, the reaction is carried out with an alkali metal hydroxide, including, but not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide. In one embodiment, the base is in the form of an aqueous solution.

[00301] In other embodiments, an organic base can be used in the reaction. Organic bases include, but are not limited to, amine bases such as triethylamine, tributylamine, diisopropylethylamine, 1,5,7-triazabicyclo (4.4.0) dec-5-ene (TBD), 7-Methyl-1,5 ,7 - triazabicyclo (4.4.0) dec-5-ene (MTBD), l,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5 - ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), quinuclidine, 2,2,6,6-tetramethylpiperidine (TMP), Pempidine (PMP), 1,4-diazabicyclo [2.2.2] octane (TED), collidine, 2,6-lutidine (2,6-dimethylpyridine), N, N, N', N'-tetramethyl-1, 8-naphthalenediamine (Proton Sponge ® ), and the like. In another embodiment, phosphazene bases can be used in the process of the invention.

[00302] The base can be used in an amount of about 1 and 100 molar equivalents based on the compound of formula (II). Typically, an excess of base is used relative to the hydroxylamine reagent, especially if an acid salt of hydroxylamine is used. In other embodiments, between about 1 and about 50 equivalents of base is used relative to the compound of formula (II). In still other embodiments, between about 1 to about 30 or between 1 to about 20 equivalents of base is used. More typically, it is used in an amount of about 1 to about 10 base equivalents. In yet another embodiment, about 2 to about 8 equivalents of base is used in the reaction. In another embodiment, about 3 to about 6 equivalents of base are used. In another embodiment, about five equivalents or 6 equivalents of base are used. In yet another embodiment, between about 3 to about 5 equivalents of base is used. In another embodiment, about 4 to about 5 equivalents of base are used in the process. In yet another embodiment, about 4.4 equivalents of base is used.

[00303] In one embodiment, the chiral phase transfer catalyst of formula (III) can be used in an amount of from about 0.1 mole% to about 20 mole% per mole of the compound of formula (II) ( for example, from 0.001 mole to about 0.2 mole per mole). In another embodiment, the chiral phase transfer catalyst is used in an amount of about 0.5 mole % to about 10 mole % per mole of formula (II). In yet another embodiment, the amount of catalyst used is from about 0.5 to about 10 mole% or from about 0.5 mole% to about 5 mole% per mole of the compound of formula (II). In yet another embodiment, the amount of chiral phase transfer catalyst is between about 1 mole % to about 5 mole % per mole of the compound of formula (II). In another embodiment, the amount of chiral phase transfer catalyst is between about 3 mole % to about 7 mole %. In another embodiment, the amount of chiral phase transfer catalyst used is between about 1 mole% to about 3 mole% or between about 2 mole% to about 4 mole% per mole of the compound of formula (II ). In another embodiment, the amount of chiral phase transfer catalyst used is about 1 mole%, about 1.5 mole%, about 3 mole%, about 5 mole%, or about 10 mole% per mole. of the compound of formula (II).

[00304] Once the reaction has progressed to a suitable point, the reaction can be processed by procedures known to those skilled in the art. For example, water and an aqueous acid solution can be added to the reaction mixture and the resulting mixture can be slightly heated with stirring. Addition of a dilute acidic solution neutralizes the base to achieve a slightly neutral mixture (target pH 7-8). Any suitable acid can be used to neutralize the basic reaction mixture, including dilute hydrohalides (e.g., HC1), carboxylic acids/carboxylates (e.g., acetic acid, citric acid, formic acid, etc.), ammonium salts. (e.g., ammonium chloride), monobasic phosphates (e.g., KH2PO4), hydrogen bisulfate salts (e.g., KHSO4), and the like. The two-phase mixture can be resolved and the organic phase separated and washed with a dilute acid solution (e.g., KH2P04 or similar) to further neutralize the mixture. The reaction mixture can be further washed with brine and the two layers allowed to stand and separate. A final wash with water can be done. The organic layer can be collected as a crude product mixture, which can be further purified before isolation.

[00305] The product can be purified from the crude mixture using methods known in the art. In one embodiment, a solution of the reaction mixture can be crystallized from a suitable solvent to produce the purified product. The pure product may be crystallized or re-crystallized by methods known in the art including, but not limited to, cooling a solution of the crude product in a suitable solvent (or mixture of solvents) until the product begins to crystallize, adding of an anti-solvent (or mixture of solvents) in which the product has a low solubility, and the like. In one embodiment, the product may be crystallized by adding the desired crystallization solvent to the crude product mixture while distilling the mixture, optionally under vacuum, to exchange the reaction solvent for the crystallization solvent until a sufficient amount of the reaction solvent/solvent mixture has been removed and replaced with the desired crystallization solvent (or solvent mixture). The mixture can then be concentrated further until a suitable concentration is reached. As is known in the art, it is desirable to adjust the concentration of the product in the crystallization solvent/solvent mixture so that the concentration is greater than the saturation concentration at the temperature at which the product is to be crystallized (e.g., after cooling). , but below the saturation concentration at an elevated temperature (e.g. in solution). Once a sufficient amount of crystallization solvent is present and the product concentration is appropriate, seed crystal product can be added to the mixture at a suitable temperature to induce crystallization when the mixture is cooled. These processes are well known in the art to those skilled in the art.

[00306] In one embodiment, the product can be crystallized or recrystallized from an aromatic solvent. Various aromatic solvents can be used to crystallize or re-crystallize the product. These solvents include aromatic solvents known in the art to be acceptable for use in the manufacture of pharmaceutical active agents including, but not limited to, toluene, ethylbenzene, chlorobenzene, xylenes (mixture of isomers or pure isomers), anisole, and the like. In a preferred embodiment, the product may be crystallized or recrystallized from toluene. In one embodiment, the product may be crystallized or recrystallized from benzene acetate. In yet another embodiment, the product may be crystallized or recrystallized from chlorobenzene. In another embodiment, the product is crystallized or recrystallized from anisole. In another embodiment, the product is crystallized or recrystallized from xylenes. It may also be possible to crystallize the product from benzene, although this is not preferred because of the toxicity problems associated with this solvent.

[00307] In one embodiment, the product can be crystallized or recrystallized from a mixture of solvents comprising a polar solvent in which the product is soluble and a non-polar solvent in which the product is not very soluble. In another embodiment, the product may be crystallized or recrystallized from hexanes, heptane, cyclohexane and the like. In one embodiment, the re-crystallization of the isolated product in the form of a solvate with an aromatic solvent (e.g. toluene solvate) can be re-crystallized with a polar/non-polar solvent combination to further purify the product and/or to remove the aromatic solvent component of the solvate. In yet another embodiment, the product may be crystallized or recrystallized from a mixture of solvents including a mixture comprising an aromatic solvent, an aliphatic solvent, an alcohol solvent, an ethereal solvent, an ester solvent, and the like, or a mixture of the same. Suitable alcohols include, but are not limited to, C1-C6 aliphatic alcohols, such as ethanol, isopropanol, 1-propanol, 1-butanol, sec-butanol, and the like.

[00308] In one embodiment, the product can be crystallized or recrystallized from a mixture of an aromatic solvent and an aliphatic solvent. In another embodiment, the product can be crystallized or recrystallized from a mixture of an aliphatic solvent and an alcohol solvent. In yet another embodiment, the product may be crystallized or recrystallized from a mixture of an aromatic solvent and an alcohol solvent. In one embodiment, the product may be crystallized or recrystallized from a mixture of a cycloalkyl solvent and an alcohol solvent. . In another embodiment, the product can be crystallized or recrystallized from a mixture of a solvent and a C1-C6 cycloalkyl alcohol solvent. In one embodiment, the product may be crystallized or recrystallized from a mixture of hexane/ethanol, toluene/cyclohexane, toluene/hexanes, toluene/heptane, cyclohexane/ethanol, or toluene/ethanol, and the like. It will be apparent to those skilled in the art that the proportion of each solvent in the solvent combinations will be adjusted to obtain a solvent combination in which the product is reasonably soluble at higher temperatures, but not very soluble when the mixture is cooled. The solvent ratio can be adjusted to decrease the solubility of the product at the appropriate time. For example, an additional amount of the lean solvent in a mixture can be added once the solid has dissolved to bring the solution closer to the saturation point. Of course, it will be apparent to one skilled in the art that the product can be recrystallized one or more times from a suitable solvent/solvent mixture to improve the purity of the product, if necessary.

[00309] In one embodiment of the invention, the (S)-enantiomer afoxolaner prepared by the process of the invention is crystallized from toluene to produce crystals of very high purity. It was surprisingly found that the (S)-enantiomer afoxolaner forms a crystalline solvate with toluene (see example 12), while racemic afoxolaner does not. Due to this feature, crystallization of the desired (S)-enantiomer from toluene resulted in a significant improvement of the enantiomeric purity of the product, compared to the ratio of enantiomers in the completed reaction mixture. selective crystallization of (S)-afoxolaner with other aromatic solvents has also been carried out (e.g. anisole, chlorobenzene, etc.). This is surprising because normally one enantiomer will not be enriched over the other enantiomer unless crystallization is conducted using a chiral system in which there is a preference for one enantiomer over the other. Crystallizations of this type are known, using, for example, chiral bases when the chiral product is an acid. However, it is very surprising that crystallization of an enantiomer from a non-chiral solvent such as toluene results in not only the purification of the product (e.g., the removal of non-chiral reaction impurities and starting), but also results in the enrichment of the desired enantiomer.

[00310] Crystallization of the desired enantiomerically pure isoxazoline compounds of the invention from a suitable solvent, including, but not limited to, those described above can be achieved by a solvent exchange from the reaction solvent to the solvent used for crystallization to an appropriate volume by distillation, optionally, under vacuum, as is known to those skilled in the art. In one embodiment, the processed reaction mixture can be concentrated to a volume, such as between about 0.5 to 30 volumes based on the compound of formula (II). More typically, the processed reaction mixture can be concentrated to a volume of between about 1 and about 20 or between about 2 and 10 volumes. In other embodiments, the reaction mixture is concentrated to between about 1 to about 5 volumes, about 1 to about 3 volumes, or between about 1 to about 2 volumes.

[00311] Once a suitable amount of the reaction solvent has been removed, a suitable amount of the crystallization solvent is added and the volume of the mixture is adjusted by means of distillation (optionally, under vacuum) to a suitable volume (optionally with the adding more crystallization solvent), so that the product crystallizes from solution after cooling. In principle, the volume from which the product is produced is not critical, however, having too much solvent in the crystallization can result in higher losses of product in the mother liquor. On the other hand, product crystallization from a mixture that is too concentrated can result in lower quality products. The volume of the pre-crystallization mixture depends on the solubility of the product in the crystallization solvent. In one embodiment, the pre-crystallization volume may be between about 1 volume to about 30 volumes. In some embodiments, the volume of the pre-crystallization mixture may be between about 1 volume and about 20 volumes, or between about 1 volume and about 10 volumes. More typically, the volume of the pre-crystallization mixture may be from about 2 volumes to about 10 volumes, about 3 volumes to about 8 volumes, or about 4 volumes to about 7 volumes. In one embodiment, the pre-crystallization volume may be about 5-6 volumes, before cooling the mixture.

[00312] When the pre-crystallization mixture is cooled slowly the desired product will crystallize from solution and can be isolated by filtration. Since there is always a certain amount of the unwanted enantiomer, it is possible with certain isoxazoline compounds that the unwanted enantiomer or racemic compound may crystallize from solution more quickly than the desired enantiomer. For example, it was found that in one embodiment of the invention for the synthesis of (S)-afoxolaner that racemic afoxolaner crystallized (unsolvated) from toluene solution faster than the pure (S)-enantiomer. The crystals of the racemic afoxolaner have a higher melting point than the crystals of the (S)-enantiomer solvate. Thus, crystals of the racemic compound can be removed by adjusting the temperature of the mixture to a temperature at which the racemic compound crystallizes from solution and then by filtering the solid to provide the desired enantiomer in solution. seed of the unwanted enantiomer or the racemic compound to induce crystallization of these compounds can be added. Once most of the racemic compound is removed, the volume of the filtrate can be adjusted further (e.g., by distillation or by adding more crystallization solvent) and the solution cooled to induce crystallization of the desired compound.

[00313] In one embodiment, crystallization of the racemic compound can be accomplished by seeding with crystals of the racemic compound at a low temperature to induce crystallization of the compound, aging the mixture for an appropriate time, heating to dissolve most of the desired enantiomer, aging at the highest temperature and filtering the mixture to remove the solid. In one embodiment, the seeding and crystallization of the racemic compound is carried out at a temperature of between about -10°C to about 30°C. In other embodiments, the seeding step is conducted between about 0°C to about from 20°C, about 0°C to about 15°C, or about 5°C to about 15°C. In another embodiment, seeding and crystallization is accomplished by seeding with the racemic compound at a temperature of about 7°C to about 13°C and aging for an appropriate time to ensure that the majority of the racemic compound has been crystallized.

[00314] The mixture is then heated to a higher temperature to dissolve the desired enantiomer while maintaining the crystals of the racemic compound. In one embodiment, the mixture is heated to a temperature of about 30°C to about 100°C. More typically, the mixture is heated to about 30°C to about 80°C and aged for a time. suitable for dissolving the desired enantiomer while maintaining the racemic compound in solid form. Even more typically, the mixture is heated to a temperature of between about 40°C to about 70°C, about 50°C to about 70°C, or about 55°C to about 65°C. In yet another embodiment, the mixture is heated to about 57°C to about 63°C and aged for a suitable period of time. The mixture is then filtered to remove the solid comprising the unwanted racemic compound.

[00315] The resulting filtrate is crystallized by further adjusting the volume to the desired volume using distillation and/or addition of more crystallization solvent and then slowly cooling to a suitable temperature to induce crystallization of the desired enantiomer. In one embodiment, the mixture is cooled to a temperature of about -10°C to about 30°C. In other embodiments, the seeding step is conducted between about 0°C to about 20°C, about 0°C to about 15°C or about 5°C to about 15°C. In another embodiment, the mixture is cooled to a temperature of about 7°C to about 13°C. At the desired temperature, the mixture can be seeded with crystals of the desired enantiomer and aged for a suitable time. The product is isolated by filtration or centrifugation and the cake is washed with the crystallization solvent. The resulting solid is then dried, optionally under vacuum.

[00316] In some embodiments, the product can be re-crystallized using the same crystallization solvent or an alternative solvent to further purify the material. A similar process as described above can be used with the exception that pre-crystallization of the unwanted enantiomer or racemic compound will probably not be necessary. In one embodiment, the desired enantiomer of the isoxazoline compound can be recrystallized from a mixture of an aliphatic solvent and an alcohol solvent. In another embodiment, the isoxazoline compound can be re-crystallized from a mixture of an aliphatic solvent and a C1-C6 alcohol solvent. In another embodiment, the isoxazoline compound can be recrystallized from a mixture of a solvent and a C1-C6 cycloalkyl alcohol solvent. In yet another embodiment, the isoxazoline compound can be recrystallized from a cyclohexane/ethanol mixture.

[00317] In one embodiment using a solvent combination of an aliphatic hydrocarbon and an alcohol solvent, the mixture containing the solid product and the crystallization solvent is heated to dissolve the solid and then cooled to a temperature suitable for seeding the solution. with product seed crystals, if desired. Seeding the crystallization mixture is optional, but may be desired to form larger crystal of the desired shape. In another embodiment, the product is first dissolved in the solvent in which the compound is most soluble (e.g., alcohol solvent) and the other solvent is added at an elevated temperature.

[00318] In one embodiment, in which a solvent mixture of an alcoholic solvent and an aliphatic solvent is used for crystallization of the product, in a volume ratio of about 1:10 to 1:99, the volume of alcohol to volume of aliphatic solvent. More typically, a volume ratio of about 1:5 to about 1:40 or about 1:5 to about 1:30 volume of alcohol to volume of aliphatic solvent may be used. In another embodiment , the volume ratio of an alcohol solvent and aliphatic solvent in a mixture may be from about 1:5 to about 1:15, from about 1:8 to about 1:13, or from about 1:10 to about 1:13, volume of alcohol to volume of aliphatic solvent. In another embodiment, the volume ratio of an alcohol solvent to aliphatic solvent in a solvent mixture can be from about 1:10 to about 1:30 or about 1:15 to about 1:25. In yet another embodiment, the volume ratio of an alcohol solvent to aliphatic solvent in a solvent mixture can be from about 1:20.

[00319] The amount of aliphatic solvent used in the crystallization of the isoxazoline compounds of the invention, when part of a solvent system with an alcoholic solvent, will also depend on the specific aliphatic solvent used and the specific isoxazoline compound. In one embodiment, the amount of aliphatic solvent used can be from about 5 to about 30 volumes based on the volume of re-crystallized product or on the volume of starting material crystallized from the synthesis sequence. In other embodiments, from about 5 to about 20 volumes of an aliphatic solvent may be used. More typically, between about 10 to about 20 volumes of an aliphatic solvent may be suitable. In one embodiment, from about 13 to about 16 volumes of an aliphatic solvent can be used.

[00320] In one embodiment, the mixture is heated to a temperature of between about 40°C to about 70°C to dissolve the solid. More typically, the mixture is heated to a temperature of between about 50°C to about 70°C or between about 55°C to about 65°C. In one embodiment, the mixture is heated to a temperature of between about 57°C to about 63°C to dissolve the solid.

[00321] Once the solid has dissolved, additional solvent can be added to bring the mixture to a point at or just above saturation. Typically, the solvent that is added is the one in which the product is least soluble. The resulting mixture may be cooled slightly to bring the mixture to the saturation point and then optionally seeded with crystals of the desired enantiomer. The mixture is then slowly cooled further to an appropriate temperature and then aged. The product is isolated by filtration or centrifugation and the product is dried, optionally under vacuum.

[00322] The temperature at which the crystallization mixture is seeded (if done) depends on the isoxazoline compound and the solvents used for crystallization. In one embodiment, seeding of the precrystallization mixture is conducted at a temperature of between about 10°C to about 80°C or between about 20°C to about 70°C. The crystallization premix is made at a temperature of between about 40°C to about 65°C.

[00323] In other embodiments, the pre-crystallization mixture is seeded at a temperature of between about 45°C to about 65°C or between about 50°C to about 60°C. In one embodiment, the The mixture is seeded with crystals of the desired product at a temperature of about 52°C to about 58°C and stirred for a suitable time. In one embodiment, the seed mixture is heated for at least 30 minutes, or at least one hour.

[00324] After seeding with seed crystals of the desired product, in some embodiments, the mixture may be cooled to an intermediate temperature (e.g., between the final crystallization temperature and the seeding temperature) and aged. The mixture may also be reheated to a temperature close to or slightly above the temperature at which the mixture was seeded and then slowly recooled. This process is conducted to allow the formed crystals to grow before cooling and final crystallization.

[00325] The mixture is seeded then finally slowly cooled to a lower temperature to complete the crystallization process. In one embodiment, the seeded mixture is cooled to a temperature below about 30°C to crystallize the desired product. In one embodiment, the mixture is cooled to a temperature of between about -10°C to about 30°C. In other embodiments, the seeding step is conducted between about 0°C to about 20°C, about from 0°C to about 15°C or about 5°C to about 15°C. In another embodiment, the mixture is cooled to a temperature of about 7°C to about 13°C. In another embodiment, the seed mixture is cooled to below about 20°C or below about 15°C and aged to complete crystallization of the product. The mixture is aged and then the solid is isolated by filtration or centrifugation. The product is optionally dried under vacuum to provide the desired product.

[00326] It will be appreciated by those skilled in the art that the rate of cooling is very important in the crystallization process. If the cooling rate is too rapid, the solubility of the compound in the solvent will drop too quickly and the crystals will not be able to grow to produce the product in the desired crystal form and quality. In some embodiments, the crystallization mixture is cooled at a rate of between about 20°C/hour and 1°C/hour to ensure that crystals of the desired product can grow at a rate suitable to ensure product purity. More typically, the crystallization mixture is cooled at a rate of between about 15°C/hour and 1°C/hour or about 10°C/hour and 5°C/hour. In one embodiment, the crystallization mixture is cooled at a rate of about 8°C/hour and 3°C/hour to the target temperature.

[00327] The product is dried at a temperature of between about room temperature and 80 ° C, optionally under vacuum. In other embodiments, the product is dried at a temperature of between about 30°C to about 70°C, optionally under vacuum. In still other embodiments, the product is dried at a temperature of between about 40°C to about 60°C, optionally under vacuum. In one embodiment, the product is dried at a temperature of from about 45°C to about 55°C, optionally under vacuum.

[00328] In another embodiment, the raw product mixture can be purified by chromatography to produce the product. Purification methods using chiral stationary phases are well known in the art. For example, the desired enantiomer of the compound of formula (I) can be isolated using preparative HPLC with a chiral stationary phase, such as a Chiralpak® AD column. Other chiral columns and chromatographic methods are well known in the art.

[00329] In one embodiment of the invention, the chiral phase transfer catalyst of formula (IIIa) or (IIIb) can be attached to a polymer support so that the catalyst can be easily recovered from the reaction mixture and reused . The catalyst of formula (IIIa) or (IIIb) may be linked to a suitable polymer at various locations, including on the aryl or heteroaryl group of R, on the W group or on the quinoline group, as shown below for formula (IIIa-13 ):

[00330] The catalyst may be linked to a suitable polymeric support for the substituted phenyl group, for example, by reacting a hydroxyl group in the catalyst starting material with an electrophile in the catalyst. Other methods for attaching the catalyst include, for example, reacting a quinine-based catalyst where W is a vinyl group using an olefin metathesis reaction or other methods that can react with the vinyl group.

[00331] In another embodiment, the catalyst can be anchored to a suitable polymer in the quinoline group by protection of the free hydroxyl group, demethylation and alkylation to the polymer.

[00332] In the present specification and the claims, terms such as "comprises", "comprising", "containing" and "having" and the like, may have the meaning assigned to them in U.S. Patent law and may mean " includes", "including," and similar; "Consisting essentially of or 'essentially consists' also has the meaning assigned in U.S. Patent law and the term is open-ended, allowing for the presence of more than what is recited as long as basic or novel features of what is recited is not altered by the presence of more than what is recited, but excludes concretizations of prior art.

[00333] It is also to be noted that in the present specification and in the claims and/or paragraphs, the compounds of the invention are intended to include all stereoisomers and crystalline forms (which include hydrated forms, polymorphic forms and amorphous forms.

Definitions

[00334] Terms used herein will have their usual meaning in the art, unless otherwise specified. The organic moieties mentioned in the definitions of the variables of formula (I) are - like the term "halogen" - collective terms for individual listings of the individual members of the group. The prefix C n -C m indicates in each case the possible number of carbon atoms in the group.

[00335] The term "animal" is used herein to include all mammals, birds and fish and also to include all vertebrate animals. Animals include, but are not limited to, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep and yaks. It also includes an individual animal at all stages of development, including embryonic and fetal stages. In some embodiments, the animal will be a non-human animal.

[00336] The term "aliphatic solvent" as used herein refers to solvents consisting of linear, branched, cyclic, primary, secondary or tertiary hydrocarbons. Common aliphatic solvents include, but are not limited to, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, and the like, and a mixture thereof. As used herein, "aliphatic solvent" does not include aromatic solvents such as toluene.

[00337] The term "aromatic solvent", as used herein refers to solvents consisting of hydrocarbon molecules with an aromatic character, optionally substituted by halogen. Common aromatic solvents include, but are not limited to, benzene, toluene, o-xylene, A-xylene or a mixture thereof (xylenes), fluorobenzene, chlorobenzene, o-dichlorobenzene, anisole and mesitylene, and a mixture thereof.

[00338] The term "alkyl" refers to primary, straight-chain, branched, cyclic, secondary or tertiary saturated hydrocarbons, including those having 1 to 20 atoms. In some embodiments, the alkyl groups include C1-C12, C1-C10 alkyl, C1-C8, C1-C6 or C1-C4 alkyl groups. Examples of C1-C10 alkyl include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 1,2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, l-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and their isomers. C1-C4 alkyl means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.

[00339] Cyclic alkyl groups or "cycloalkyl" which are covered by alkyl include those with 3 to 10 carbon atoms and which have single or multiple condensed rings. In some embodiments, cycloalkyl groups include C4-C7 cyclic alkyl or C3-C4 cycloalkyl groups. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[00340] The alkyl groups described herein may be unsubstituted or substituted with one or more radicals selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- or dialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine, thiother, thioether, oxide halide, anhydride, oxime , hydrazine, carbamate, phosphoric acid, phosphate, phosphonate, or any other viable functional group that does not inhibit the biological activity of the compounds of the invention, whether unprotected or protected as necessary, as known to those skilled in the art, for example, as taught in Greene , et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Third Edition, 1999, incorporated herein by reference.

[00341] Terms including the term "alkyl" such as "alkylcycloalkyl", "cycloalkylalkyl", "alkylamino" or "dialkylamino" will be understood to include an alkyl group as defined above, attached to the other functional group, where the group is attached to the compound via the last listed group, as understood by those skilled in the art.

[00342] The term "alkenyl" refers to linear and branched carbon chains that have a double bond, at least one carbon-carbon bond. In some embodiments, the alkenyl groups may include C2-C20 alkenyl groups. In other embodiments, it includes C2-C12, C2-C10, C2-C8, C2-C6 or C2-C4 alkenyl. In one embodiment of alkenyl, the number of double bonds is 13, in another embodiment of alkenyl, the number of double bonds is one or two. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated, depending on the location of the alkenyl moiety on the molecule. "C2-C10-alkenyl" groups may include more than one double bond in the chain. Examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1 -propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl- 2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3 - pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1, 1-dimethyl-2-butenyl, 1, 1-dimethyl- 3-butenyl, 1,2-dimethyl- 1-butenyl, 1,2-dimethyl- 2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-l-butenyl, 1, 3-dimethyl- 2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl- 3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2- ethyl- 1-butenyl, 2-ethyl-2-butenyl, 2-ethyl- 3-butenyl, l, l, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, l-ethyl- 2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

[00343] "Alkynyl" refers to linear and branched carbon chains that have a triple bond, at least one carbon-carbon bond. In an alkynyl embodiment, the number of triple bonds is 1-3; in another embodiment of alkynyl, the number of triple bonds is one or two. In some embodiments, alkynyl groups may include C2-C20 alkynyl groups. In other embodiments, alkynyl groups may include C2-C12, C2-C10, C2-C8, C2-C6, or C2-C4 alkynyl groups. Other ranges of carbon-carbon triple bonds and carbon numbers are also contemplated, depending on the location in the molecule of the alkenyl moiety. For example, the term "C2-C10-alkynyl" as used herein refers to a branched unsaturated hydrocarbon group of carbon atoms having 2 to 10 and containing at least one triple bond, such as ethynyl, prop-1- yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl, n-but-1- yn-3-yl, n-but-1-yn-4- il, n-but-2-yn-1-yl, n-pent-1-yn-1-yl, n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl, n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3- methylbut-1-yn-3-yl, 3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl, n-hex- 1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1- yn-6-yl, n-hex-2-yn-1-yl, n-hex-2- yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl, n-hex-3-yn- 2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl, 3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5- yl, 4-methylpent-1-yn-1-yl, 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and the like.

[00344] The term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted by one or more halogen atoms. For example C1-C4, haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl , 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl , pentafluoroethyl and the like.

[00345] The term "haloalkenyl" refers to an alkenyl group, as defined herein, that is substituted by one or more halogen atoms.

[00346] The term "haloalkynyl" refers to an alkynyl group, as defined herein, that is substituted by one or more halogen atoms.

[00347] "Alkoxy" refers to alkyl-O-, where alkyl is as defined above. Likewise, the terms

[00348] "alkenyloxy," alkynyloxy, ""haloalkoxy," "haloalkenyloxy," "haloalkynyloxy," "cycloalkoxy," "cycloalkenyloxy," "halocycloalkoxy," and "halocycloalkenyloxy" refer to alkenyl-0-, alkynyl- groups O-, haloalkyl-O-, haloalkenyl-O-, haloalkynyl-O-, cycloalkyl-O-, cycloalkenyl-O-, halocycloalkyl-O-, and halocycloalkenyl-O-, respectively, wherein alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, and halocycloalkenyl are as defined above. Examples of C1-C6 alkoxy include, but are not limited to, methoxy, ethoxy, C2H5-CH2O-, (CH3)2CHO-, n-butoxy, C2H5-CH(CH3)O-, (CH3)2CH-CH2O-, (CH3)3CO-, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1, 1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, n-hexoxy, 1 - methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy and the like.

[00349] The term "alkylthio" refers to alkyl-S-, where alkyl is as defined above. Likewise, the terms "haloalkylthio," "cycloalkylthio," and the like, refer to haloalkyl-S- and cycloalkyl-S-, where haloalkyl and cycloalkyl are as defined above.

[00350] The term "sulfinyl alkyl" refers to alkyl-S(O)-, where alkyl is as defined above. Likewise, the term "haloalkylsulfinyl" refers to haloalkyl-S(O) - where haloalkyl is defined as above.

[00351] The term "alkylsulfonyl" refers to alkyl-S(0)2-, where alkyl is as defined above. Likewise, the term "haloalkylsulfonyl" refers to haloalkyl-S(0)2 - where haloalkyl is as defined above.

[00352] The terms alkylamino and dialkylamino refer to alkyl-H- and (alkyl)2N-, where alkyl is as defined above. Likewise, the terms "haloalkylamino" refers to haloalkyl-H- where haloalkyl is defined as above.

[00353] The terms "alkylcarbonyl", "alkoxycarbonyl", "alkylaminocarbonyl", and

[00354] "Dialkylaminocarbonyl refers to alkyl-C(O)-, alkoxy-C(O)-, alkyl-C(O)-, and dialkylamino-C(O)-. Wherein alkyl, alkoxy, alkylamino and dialkylamino are as defined above. Similarly, the terms "haloalkylcarbonyl," "haloalkoxycarbonyl," "haloalkylaminocarbonyl," and "dihaloalkylaminocarbonyl" refer to the groups haloalkyl-C(o)-, haloalkoxy-C(o)-, haloalkylamino- C(o)- and dihaloalkylamino-C(O)- where haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are as defined above.

[00355] "Aryl" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring or multiple condensed rings. In some embodiments, the aryl groups include C6-C10 aryl. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indanyl and phenylcyclopropyl. Aryl groups may be unsubstituted or substituted by one or more radicals selected from halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, halocycloalkylthium, sulfinyl alkyl, alkenylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, yl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkyl - sulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, alkylamino, alkenylamino, alkynylamino, di (alkyl) amino, di (alkenyl)-amino, di (alkynyl) amino or trialkylsilyl.

[00356] The term "aralkyl" refers to an aryl group that is linked to the parent compound through a di-radical alkylene bridge, (-CH 2 -) n, where n is 1-12 and where "aryl " is as defined above.

[00357] "Heteroaryl" refers to a monovalent aromatic group of from 1 to 15 carbon atoms, preferably from 1 to 10 carbon atoms, having one or more oxygen, nitrogen, and sulfur heteroatoms within the ring, of preferably 1 to 4 heteroatoms, or 1 to 3 heteroatoms. Nitrogen and sulfur heteroatoms can optionally be oxidized. Such heteroaryl groups may have a single ring (e.g., pyridyl or furyl) or multiple fused rings, as long as the point of attachment is through a heteroaryl ring atom. Preferred heteroaryls include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, quinoxalinnyl, phthalazinyl, 1,2,3-benzotriazinyl, 1,2,4-benzotriazinyl, furanyl, thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadazolyl, benzofuranyl pyrazolyl, and benzothienyl. Heteroaryl rings may be unsubstituted or substituted by one or more radicals as described for aryl above.

[00358] "Heterocyclyl", "heterocyclic" or "heterocycle" refers to completely saturated or unsaturated cyclic groups, for example, 3 to 7 membered monocyclic or 4 to 7 membered monocyclic; 7 to 11 bicyclic members, or 10 to 15 tricyclic member ring systems, which have one or more oxygen, sulfur or nitrogen atoms in the ring, preferably 1 to 4 or 1 to 3 heteroatoms. Nitrogen and sulfur heteroatoms can optionally be oxidized and nitrogen heteroatoms can optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system and may be unsubstituted or substituted by one or more radicals as described for the aryl groups above.

[00359] Illustrative cyclic heterocyclic groups include, but are not limited to, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolidinyl, , furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

[00360] Exemplary bicyclic heterocyclic groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinolinyl, quinoxalinyl, indazolyl, pyridyl pyrrole, furopyridinyl (such as fur[2,3-c] pyridinyl, fur[3,2-b] pyridinyl] or fur[2,3-b] pyridinyl), dihydroisoindolyl, di - hydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like.

[00361] Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[00362] Halogen means the atoms of fluorine, chlorine, bromine and iodine. The designation "halo" (e.g. as illustrated in the term haloalkyl) refers to all degrees of substitution from a single substitution to a per-halo substitution (e.g. as illustrated with methyl as chloromethyl (CH2C1) , dichloromethyl (-CHC12) , trichloromethyl (-CC13)).

[00363] The term "amorphous" as applied to afoxolaner here refers to a solid state in which the afoxolaner molecules are present in a disordered arrangement and do not form a distinguishable crystalline lattice or unit cell. When subjected to X-ray powder diffraction, amorphous afoxolaner does not produce any characteristic crystalline peaks.

[00364] The term "chemical purity" refers to the general level of a desired product. If a compound is present in enantiomeric forms, "chemical purity" as used herein should include both enantiomeric forms in calculating the overall level of the desired product. If a compound is present in solvate forms, "chemical purity" as used herein should include the solvate in calculating the overall level of the desired product. Impurities can be in the form of, for example, the presence of unwanted process reactants, process intermediates, degradation products or oxidation products. In particular embodiments the chemical purity is high, which is greater than 90% chemical purity, especially above 92.5%, 95%, 96%, 97%, 98%, 99% and includes 100%.

[00365] Purity can be measured from a variety of techniques, including HPLC analysis.

[00366] The terms "enantiomers" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and is therefore optically active in that the enantiomer rotates the plane of polarized light in one direction and its compound Mirror image rotates the plane of polarized light in the opposite direction.

[00367] The term "enantiomeric excess" or "e.e.", as used herein refers to a difference between the amount of one enantiomer and the amount of the other enantiomer that is present in the product mixture. The enantiomeric excess value in each example given below gives an indication of the relative amount of each enantiomer. The value is defined as the difference between the relative percentages for the two enantiomers. Thus, for example, when the percentage of the (S) enantiomer of the compound of the invention is 97.5% and the percentage for the (R) enantiomer is 2.5%), the enantiomeric excess for the (S) enantiomer is 95%. %.

[00368] As used herein, the term "chiral purity" or "enantiomeric purity" refers to the percentage of HPLC area of the subject enantiomer of the compound relative to the HPLC area of the combination of both enantiomers in the mixture measured by HPLC chiral, excluding other compounds or impurities. For example, the chiral purity of the (S)-enantiomer of afoxolaner is calculated by the equation S/(S+P)x100%>, with S and R representing peak areas of (S)-afoxolaner and (R)-afoxolaner , respectively, determined by chiral HPLC.

[00369] The term "isolated", as used herein, in reference to solid state forms of afoxolaner of the present disclosure corresponds to a solid state form of afoxolaner that is physically separated from the reaction mixture in which it is formed.

[00370] The term "polymorphic non-solvate" or "non-solvate crystal form" refers to a crystal form that does not have a solvent molecule attached to the crystal lattice. However, crystals may contain trace amounts of unbound solvate in the crystal lattice.

[00371] The term "polymorph", as used herein, refers to different crystal structures (of solvated or unsolvated forms) in which a compound can crystallize.

[00372] The term "racemic" or "racemate", and other similar terms generally refer to equimolar proportions two enantiomers of a compound. For example, afoxolaner is a racemate containing equamolar amounts of the (S)- and (R)-enantiomers of the compound.

[00373] The term "seed" as used herein can be used as a noun to describe one or more crystals of a crystalline compound (e.g., racemic afoxolaner) used to induce crystallization of the compound. For example, if it is desired to produce crystalline (racemic) afoxolaner, the seed crystals to be used to enhance the crystallization process may be racemic afoxolaner crystals. The term "seed" or "seeding" may also be used as a verb to describe the act of introducing said one or more crystals of a compound into an environment (including, but not limited to, e.g., a solution, a mixture, a suspension, or a dispersion) thus resulting in the formation of more of the same crystals of the compound (e.g., the formation of the racemic afoxolaner compound).

[00374] The term or "hydrate", "hydrate polymorph" or "hydrate crystalline form" refers to a crystalline form of a compound that has one or more water molecules bound in the crystal lattice.

[00375] The term "solvate", "polymorph solvate" or "crystalline form of solvate" refers to a crystalline form of a compound that has one or more molecules of a solvent bound in the crystal lattice.

Stereoisomers and polymorphic forms

[00376] As discussed above, it will be appreciated by those skilled in the art that there may be certain compounds that can be isolated as optically active and racemic forms. Compounds that have one or more chiral centers, such as the isoxazoline active agents of the present invention, may be present as individual enantiomers or diastereomers, or as mixtures of enantiomers and/or diastereomers. Chiral centers in molecules can include a sulfur atom. For example, it is well known in the art that sulfoxide compounds can be optically active and can exist as individual enantiomers or racemic mixtures. Furthermore, the compounds of the invention may include other chiral centers in addition to the chiral carbon atom in the isoxazoline ring, which results in a theoretical number of optically active isomers. When compounds within the compositions of the present invention include n chiral centers, the compounds may comprise up to 2 n optical isomers. The present invention encompasses the enantiomers or diastereomers of each specific compound, as well as mixtures of different enantiomers and/or diastereomers of the compounds of the invention that have the properties described here.

[00377] The compounds within the compositions of the present invention may also be present in different solid forms, such as different crystalline forms or in the form of an amorphous solid. The present invention encompasses different crystalline forms, as well as amorphous forms of the compounds of the invention. Furthermore, compounds within the compositions of the present invention may exist in the form of hydrates or solvates, wherein a certain stoichiometric amount of water or a solvent is associated with the molecule in crystalline form. The compositions of the invention may include hydrates and solvates of the active agents.

[00378] In one embodiment, the present invention encompasses a solvated crystalline solid form of the isoxazoline compounds of formula (I) with an aromatic solvent. In a particularly preferred embodiment, the present invention encompasses a solvated crystalline form of solid (A)-afoxolaner with an aromatic solvent. In a particularly preferred embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner. As discussed above, the crystallization of the (S)-enantiomer of afoxolaner from a mixture of (S)-enantiomers and (R)-afoxolaner enriched in the (S)-enantiomer obtained from the reaction of the compound (IIA-1) with hydroxylamine, in the presence of a base and a chiral phase transfer catalyst of formula (IIIa-13-1) results in a surprising product purification and enrichment of the A. Depending on the intended use for the solid state form of afoxolaner, desired processing considerations ( enantiomer may favor the selection of a specific solid state form or a specific combination of such solid state forms. The use of a solvated crystalline form, such as a toluene crystalline solvate form, rather than the unsolvated forms of a composition may favor. eliminate a processing step, i.e., desolvation, for processes that would otherwise proceed by desolvation of a solvated crystalline form. E. Shefter T. Higuchi and measured the relative dissolution rates of various crystalline solvated and unsolvated forms of important drugs, J. Pharrn. Sci., 52(8), (1963), 781-91.

[00379] The crystalline toluene solvate of (S)-afoxolaner was found to contain two molecules of the compound and two molecules of toluene as shown in Figure 9 and described in Example 12. The toluene solvate of (S)-afoxolaner is can be prepared by crystallization of (S)-afoxolaner from pure toluene or from a toluene-containing solvent mixture (e.g., cyclohexane/toluene) by methods known in the art, including the processes described in Examples 7, 8 and 12. Crystallization may also be carried out by dissolving the (e.g., (S)-afoxolaner or a sample of afoxolaner enriched in the (S)-enantiomer in toluene or a solvent mixture containing toluene, at a concentration that is a suspension at a temperature at which the compound will be crystallized (e.g., room temperature or lower) and a solution at an elevated temperature and then slowly cooling to the target temperature to induce crystallization of the desired (S)-afoxolaner toluene solvate.

[00380] In one embodiment, (S)-afoxolaner is dissolved in toluene (optionally in the presence of a second solvent) at an elevated temperature and then cooled to induce crystallization. In another embodiment, (S)-afoxolaner is dissolved in toluene or a solvent mixture comprising toluene by heating the combination to a temperature of about 30°C to the boiling point of the solvent. In another embodiment, (S)-afoxolaner is dissolved in toluene or a solvent mixture comprising toluene by heating the combination to a temperature of between about 30°C to about 100°C. More typically, (S)-afoxolaner is dissolved in toluene or a mixture of solvents comprising toluene by heating the combination to a temperature of between about 30°C to about 80°C, between about 50°C to about 80°C, between about 40°C C to about 70°C or between about 50°C to about 70°C. In another embodiment, the mixture is heated to a temperature of between about 55°C to about 65°C or between about 50°C to about 60°C. In another embodiment, the mixture is heated to a temperature of between about 30°C to about 50°C.

[00381] Once the mixture of (S)-afoxolaner in toluene or a mixture of solvents comprising toluene is in solution, the toluene solvate of the crystalline (S)-afoxolaner is obtained by slowly cooling the mixture. In one embodiment, the mixture is cooled to a temperature of less than about 30°C or less than about 20°C. In other embodiments, the mixture is slowly cooled to less than about 15°C or less than about 10°C. In yet another embodiment, the mixture is cooled to less than about 5°C.

[00382] When crystallization is conducted in the presence of a second solvent, the ratio of toluene and the second solvent can be from about 20:80 to about 99:1 of toluene to the second solvent, by volume. In other embodiments, the volume ratio of toluene to the second solvent may be between about 30:70 to about 99:1, between about 40:60 to about 99:1, or between about 50:50 to about 99:1. In other embodiments, the ratio of toluene to the second solvent may be between about 40:60 to about 90:10, between about 50:50 to about 90:10, or between about 50:50 to about 80:20. In other embodiments, the ratio may be from about 40:60 to about 80:20, about 50:50 to about 75:25, toluene to the second solvent, by volume. In one embodiment, the second solvent will be an aliphatic solvent including, but not limited to, pentane, hexane, heptane, octane, cyclopentane, cyclohexane and the like.

[00383] In some embodiments, the toluene solvate of the crystalline (S)-afoxolaner can be prepared by dissolving the compound in toluene or a mixture of solvents comprising toluene, and adding a solvent to the mixture, wherein (S )-afoxolaner has a low solubility (e.g. an anti-solvent). In one variant, crystallization of the crystalline toluene solvate (S)-afoxolaner can be induced by addition of an aliphatic solvent, such as those described above.

[00384] Once the toluene solvate of the crystalline (S)-afoxolaner is formed, it can be isolated by filtration or other methods known in the art (e.g., centrifugation) and optionally dried under vacuum to remove the excess solvent.

[00385] The source of (S)-afoxolaner for crystallization can be another solid form of (S)-afoxolaner (e.g. other crystalline or amorphous form) or a solution containing (S)-afoxolaner in another solvent such as in the Examples 7 and 8. Other crystallization methods known in the art can be used.

[00386] In one embodiment, the invention provides a crystalline solvate of toluene (S)-afoxolaner (structure shown below), as characterized by X-Ray Powder Diffraction (XRPD) and/or Differential Scanning Calorimetry (DSC) described in Example 12.

[00387] In one embodiment, the invention provides a crystalline solvate of toluene (A-afoxolaner which exhibits one or more of the characteristic peaks expressed in degrees 2-theta (2θ) ± 0.2 shown in Table 2 below and in Figure 8, as determined by the method described in Example 12. Table 2

[00388] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner that exhibits one or more of the characteristic peaks expressed in degrees 2-theta (2θ) ± 0.2 shown in Table 3 below and in Figure 8, as determined by the method described in Example 12. Table 3

[00389] In another embodiment, the invention provides a toluene crystal solvate line of (S)-afoxolaner that exhibits one or more of the characteristic peaks expressed in 2-theta degrees (2θ) ± 0.2 shown in Table 4 below and in Figure 8, as determined by the method described in Example 12. Table 4

[00390] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner that exhibits at least seven of the characteristic peaks expressed in degrees 2-theta (2θ) ± 0.2 in one or more of the positions indicated in Table 2, Table 3 or Table 4 above and in Figure 8, as determined by the method described in Example 12.

[00391] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner that exhibits at least five of the characteristic peaks expressed in degrees 2-theta (2θ) ± 0.2 in one or more of the positions shown in Table 2, Table 3 or Table 4 above and in Figure 8, as determined by the method described in Example 12.

[00392] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner that exhibits at least three of the characteristic peaks expressed in degrees 2-theta (2θ) ± 0.2 in one or more of the positions indicated in Table 2, Table 3 or Table 4 above and in Figure 8, as determined by the method described in Example 12.

[00393] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner that exhibits an endotherm between about 70 ° C and about 90 ° C, as described in Example 12 and shown in Figure 7.

[00394] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner that exhibits an endotherm between about 75 ° C and about 90 ° C, as described in Example 12 and shown in Figure 7.

[00395] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner that exhibits an endotherm between about 80 ° C and about 90 ° C, as described in Example 12 and shown in Figure 7.

[00396] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner that exhibits an endotherm between about 83 ° C and about 87 ° C, as described in Example 12 and shown in Figure 7.

[00397] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner that exhibits an endotherm of about 85 ° C, as described in Example 12 and shown in Figure 7.

[00398] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner that exhibits an endotherm of about 84.7 ° C, as described in Example 12 and shown in Figure 7.

[00399] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner, wherein at least 90% of the solid form is a crystalline form of toluene solvate.

[00400] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner, wherein at least 80% of the solid form is a crystalline form of toluene solvate.

[00401] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner, wherein at least 70% of the solid form is a crystalline form of toluene solvate.

[00402] In another embodiment, the invention provides a crystalline toluene solvate of (S)-afoxolaner, wherein at least 60% of the solid form is a crystalline form of toluene solvate.

[00403] In another embodiment, the invention provides pesticide or parasiticidal compositions comprising a crystalline form of toluene solvate (A-afoxolaner alone, or in combination with other active agents, together with agriculturally or pharmaceutically acceptable carriers or diluents.

[00404] In another embodiment, the invention provides pesticide or parasiticidal compositions comprising a crystalline solvate of toluene (S)-afoxolaner alone, or in combination with one or more additional active agents, and agriculturally or pharmaceutically acceptable carriers or diluents, wherein At least 80% of the solid form of (S)-afoxolaner is a crystalline solvate form of toluene (S)-afoxolaner.

[00405] In another embodiment, the invention provides pesticide or parasiticidal compositions comprising a crystalline solvate of toluene (S)-afoxolaner alone, or in combination with one or more additional active agents, and agriculturally or pharmaceutically acceptable carriers or diluents, wherein At least 70% of the solid form of (S)-afoxolaner is a crystalline solvate form of toluene (S)-afoxolaner.

[00406] In another embodiment, the invention provides pesticide or parasiticidal compositions comprising a crystalline solvate of toluene (S)-afoxolaner alone, or in combination with one or more additional active agents, and agriculturally or pharmaceutically acceptable carriers or diluents, wherein At least 60% of the solid form of (S)-afoxolaner is a crystalline solvate form of toluene (S)-afoxolaner. Salts

[00407] Also contemplated within the scope of the invention are salts of acids or bases, if applicable, of the compounds of the invention provided for herein.

[00408] The term "acid" encompasses all pharmaceutically acceptable inorganic or organic acids.

[00409] Inorganic acids include mineral acids such as halide acids, such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Organic acids all include pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. In one embodiment of the acids, the acids are straight-chain or branched, saturated or unsaturated, C1-C20 aliphatic carboxylic acids, which are optionally substituted by halogen or hydroxyl groups, or C6-C12 aromatic carboxylic acids. Examples of such acids are carbonic acid, formic acid, acetic acid, propionic acid, isopropionic acid, valeric acid, α-hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid and salicylic acid. Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid, fumaric acid, and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid. Other acids include gluconic acid, glycoheptonic acid and lactobiic acid.

[00410] The term "base" includes all pharmaceutically acceptable inorganic or organic bases, including hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals. Salts formed with such bases include, for example, alkali metal and alkaline earth metal salts, including, but not limited to, lithium, sodium, potassium, magnesium or calcium salts. Salts formed with organic bases include the common hydrocarbon and heterocyclic amine salts, which include, for example, ammonium salts (H4+), alkyl dialkyl ammonium salts, and cyclic amine salts, such as morpholine and piperidine salts.

Veterinary compositions

[00411] The compounds of formula (I) enriched in the (S)-enantiomer configuration and compositions comprising the compounds are useful for the prevention and treatment of parasite infestations / infections in animals. The compositions of the invention comprise an effective amount of at least one isoxazoline compound formula (I) enriched in the (S)-enantiomer, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier or diluent and optionally other non-active excipients and , optionally, in combination with one or more additional active agents. In a preferred embodiment, the veterinary parasiticidal compositions of the invention comprise an effective amount of an isoxazoline of formula IA as described above enriched in the (S)-enantiomer, or a pharmaceutically acceptable salt thereof, wherein X1, X2 and X3 are H , chlorine, fluorine or CF3. In another preferred embodiment, the invention provides veterinary compositions incorporating afoxolaner parasiticides enriched in the (S) enantiomer, as described above.

[00412] The compositions can be in a variety of solid and liquid forms, which are suitable for various forms of application or administration to an animal. For example, veterinary compositions incorporating the compounds of the invention may be in compositions suitable for oral administration, injectable administration, including subcutaneous administration and parenteral administration, and topical administration (e.g., spot-on or pour-on). The compositions are intended to be administered to an animal, including, but not limited to, mammals, birds and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpaca, pigs, horses, donkeys, dogs, cats and other domestic animals or mammals. Examples of birds include turkeys, chickens, ostriches, and other livestock or poultry. The use of compounds of formula (I) enriched in the (A-enantiomer) configuration to protect companion animals, such as dogs and cats, and farm animals, such as cattle and sheep, from ectoparasites is particularly useful. Agricultural compositions

[00413] In another embodiment, the invention provides agricultural compositions comprising compounds of formula (I), formula Ia enriched in the (S) enantiomer, including (S)-afoxolaner. The compositions can be used to combat pests that damage plants, plant and crop propagation material, or wood-derived material. According to the present invention, compounds of formula (I) enriched in the (S) enantiomer can be converted into usual compositions, for example, solutions, emulsions, suspensions, dusts, powders, pastes, granules and directly sprayable solutions. The form of application depends on the particular purpose and application method. The formulations and application methods are chosen to ensure in each case a fine and uniform distribution of the compound of formula (I) according to the present invention.

[00414] The invention further provides an agricultural composition for combating such animal pests, which comprises such an amount of at least one compound of formula (I), formula IA wherein X1, X2 and X3 are H, chlorine, fluorine or CF3 enriched in the (S)-enantiomer, including (S)-afoxolaner, or its agriculturally useful salts thereof, and at least one inert liquid and/or agriculturally acceptable solid carrier which has a pesticidal action and, if desired , at least one surfactant. Such a composition may contain a single active compound of formula (I) enriched in the (S)-enantiomer, or a salt thereof, or a mixture of several active compounds of formula (I) enriched in the (S)-enantiomer configuration, or salts thereof. , in accordance with the present invention.

[00415] The compositions are prepared in a known manner (see for example, by US evaluation 3060084, EP-A 707 445 (for liquid concentrates), Browning, "Agglomeration", Chemical Engineering, December 4, 1967, 147- 48, Perry Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and et seq. 180,587, US 5,232,701, US 5,208,030, G095558, US 3299566, Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, Hance et al., Weed Control Handbook, 8th Ed ., Blackwell Scientific Publications, Oxford, 1989 and Mollet, H., Grubemann, A., Formulation Technology, Wiley VCH Verlag GmbH, Weinheim (Germany), 2001, 2. dA Knowles, Chemistry and Technology of Agrochemical Formulations, Kluwer Academic Publishers, Dordrecht, 1998 (ISBN 0-7514-0443-8, all of which are incorporated herein by reference in their entirety), for example, by extending the active compound with adjuvants suitable for compounding agrochemicals, such as solvents and/or carriers, if desired emulsifiers, surfactants and dispersants, preservatives, anti-foaming agents, anti-freezing agents, for the seed treatment composition, also, optionally, colorants and/or binders and/or gelling agents. Veterinary Uses and Methods

[00416] As discussed above, compounds of formula (I) enriched in the (S)-enantiomer are effective against ectoparasites and can be used to treat and prevent parasite infestations in or on animals. In one embodiment, the present invention provides a method of treating or preventing an ectoparasite infestation in or on an animal (e.g., a mammal or a bird) comprising administering an ectoparasiticidally effective amount of a compound of formula (I) enriched in form (S) - enantiomer, or pharmaceutically acceptable salts thereof, or a composition comprising the compound, for the animal. In another embodiment, the methods of the invention comprise administering an effective amount of a compound of formula IA wherein X1, X2 and X3 are H, chlorine, fluorine or CF3 enriched in the (S) enantiomer, or a pharmaceutically acceptable salt thereof. , for the animal. In a preferred embodiment, the methods of the invention comprise administering an effective amount of afoxolaner enriched in the (S) enantiomer, or a pharmaceutically acceptable salt thereof, to the animal.

[00417] In another embodiment, when compounds of formula (I) or IA, enriched in the form (S)-enantiomers, including (S)-afoxolaner, are administered in combination with other compounds that are active against endoparasites, the invention provides a method for treating or preventing an endoparasitic infection and an ectoparasite infestation in and on an animal. The method comprises administering a composition comprising an effective amount of a compound of formula (I), IA or afoxolaner enriched in the (S) enantiomer, in combination with an effective amount of at least one second active agent, or pharmaceutically acceptable salts thereof. , for the animal.

[00418] Mammals that can be treated include, but are not limited to humans, cats, dogs, cattle, chickens, cows, bison, deer, goats, horses, llamas, camels, pigs, sheep and yaks. In one embodiment of the invention, mammals are treated humans, cats or dogs.

[00419] In one embodiment of the invention, compositions of the invention comprising a compound of formula (I) or IA enriched in the (S) enantiomer, in combination with an additional compound that is active against endoparasites are effective against endoparasites that are resistant active agents from the macrocyclic lactone class. In one embodiment, the compounds and compositions of the invention are effective for controlling Haemonchus contortus, Ostertagia circumcincta and Trichostrongilus colubriformis in mammals or birds.

[00420] In another embodiment, the invention provides a method for treating an infestation and/or parasitic infection in an animal, comprising administering an effective amount of a compound of formula (I) or IA enriched in the (S) enantiomer, including (S)-afoxolaner, in combination with an effective amount of invertebrate GABA receptor activators, including avermectin or milbemycin, to the animal in need thereof. Avermectins that can be used in combination with the compounds of the invention include, but are not limited to, abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, and selamectin. Milbemycin compounds that can be used in combination with the compounds of the invention include, but are not limited to, milbemectin, milbemycin D, milbemycin oxime, moxidectin and nemadectin. Also included are the 5-oxo and 5-oxime of said avermectins and milbemycins.

[00421] In one embodiment for treatment against ectoparasites, the ectoparasite is from the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes , Trichodectes, and Felicola. Treated ectoparasites include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, blowflies, and combinations thereof. Specific examples include, but are not limited to, dog and cat fleas {Ctenocephalides felis, Ctenocephalides spp. and the like), ticks (Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyomma spp., and the like), and mites (Demodex spp., Sarcoptes spp., Otodectes spp., and the like), lice ( Trichodectes spp., Cheiletiella spp., Linognathus spp., and the like), mosquitoes (Aedes spp., Culex spp., Anopheles spp., and the like), and flies (Haematobia spp., Musca spp., Stomoxis spp., Dermatobia spp., Cochliomyia spp., and so on). In yet another embodiment for treatment against ectoparasites, the ectoparasite is a flea and/or tick.

[00422] Other examples of ectoparasites that can be controlled with compounds of formula (I) or IA enriched in (S)-enantiomers include, but are not limited to, the tick Rhipicephalus microplus (cattle tick), Rhipicephalus decoloratus and Rhipicephalus annulatus; myiasis, such as Dermatobia hominis and Cochliomyia hominivorax (greenbottle); myiasis of sheep, such as Lucilia sericata, Lucilia cuprina (known as strike blowfly in Australia, New Zealand and South Africa) suitable fly, i.e. those whose adult constitutes the parasite, such as Haematobia irritans (horn fly); lice, such as Linognathus vitulorum, etc.; and mites such as Sarcoptes scabiei Psoroptes ovis and the above list is not exhaustive and other ectoparasites are well known in the art to be harmful to humans and animals. These include for example migratory dipteran larvae.

[00423] In one embodiment, when administered with another compound that is active against endoparasites, the compounds and compositions of the invention can be used to treat or prevent an endoparasitic infection of the following parasites: Anaplocephala (Anoplocephala), Ancylostoma, Necator, Ascaris, Brugia , Bunostomum, Capillaria, Chabertia, Cooperia, Cyathostomum, Cilicocyclus, Cilicodontophorus, Cilicostephanus, Craterostomum, Dictyocaulus, Dipetalonema, Dipilidium, Dirofilaria, Dracunculus, Echinococcus, Enterobius, Fasciola, oides filar, Habronema, Haemonchus, Metastrongilus, Moniezia, Necator, , Nippostrongilus, Oesophagostomum, Onchocerca, Ostertagia, Oxiuris, Parascaris, Schistosoma, Strongilus, Taenia, Toxocara, Strongiloides, Toxascaris, Trichinella, Trichuris, Trichostrongilus, Triodontophorus, Uncinaria, Wuchereria, and combinations thereof. In another embodiment of the invention, the parasite is Haemonchus contortus, Ostertagia circumcincta, Trichostrongilus axei, Trichostrongilus colubriformis, Cooperia curticei, Nematodirus battus, Dirofilaria immitis, and combinations thereof.

Veterinary Uses and Methods

[00424] Due to their excellent activity, compounds of formula (I) enriched in the enantiomer (S), and in particular compounds of formula IA in which X1, X2 and X3 are H, chlorine, fluorine or CF3, including (S) -afoxolaner, can be used to control pests that cause damage to crops, plants and materials made from wood. Accordingly, the present invention also provides a method for controlling animal pests, which method comprises treating the pest, its food source, its habitat or broth or a cultivated plant, plant propagation materials ( such as seed), the soil, area, material or environment in which the pests are growing or may grow, or the materials, cultivated plants, plant propagation materials (such as seeds), soils, surfaces or spaces to protect against pest attack or infestation with a pesticidally effective amount of a compound of formula (I), formula IA wherein X1, X2 and X3 are H, chlorine, fluorine or CF3, including (S)-afoxolaner, or one thereof salts, or a composition comprising the compounds.

[00425] In one embodiment, the method of the invention serves to protect plant propagation material (such as seed) and the plant growing therefrom from animal pest attack or infestation and comprises treating the plant propagation material. plants (such as seeds) with a pesticidally effective amount of a compound of formula (I), formula IA wherein X1, X2 and X3 are H, chlorine, fluorine or CF3, including (S)-afoxolaner, or an agricultural salt thereof acceptable amounts, as defined above, or with a pesticide effective amount of an agricultural composition, as defined above and below. The method of the invention is not limited to the protection of the "substrate" (plant, plant propagation materials, soil material, etc.) that has been treated in accordance with the invention, but also has a preventive effect, thus, by For example, under the protection of a plant that grows from a treated plant propagation material (such as seeds), the plant itself has not been treated.

[00426] In an embodiment of the present invention related to agricultural applications, "animal pests" refer to arthropods and nematodes, more preferably insects, arachnids and nematodes, and even more preferably insects, acarids and nematodes. EXAMPLES

[00427] The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended, nor should it be construed to, limit the scope of the invention.

[00428] All temperatures are given in degrees Celsius; Room temperature means 20 to 25 °C. Reagents were purchased from commercial sources or prepared following literature procedures. Chiral purity is determined by HPLC analysis using a chiral column. Reference to the volume of a solvent or reagent are based on the volume of the starting material using the density of 1 g/mL.

[00429] Bn = benzyl

[00430] DCM = dichloromethane

[00431] DMF = dimethylformamide

[00432] ACN = acetonitrile

[00433] eq = molar equivalents

[00434] HPLC = high pressure liquid chromatography

[00435] PE = petroleum ether

[00436] Red-Al = bis (2-methoxyethoxy) aluminum hydride

[00437] RT = ambient temperature

[00438] TEA = triethylamine

[00439] THF = tetrahydrofuran

[00440] min. = minute

[00441] h = hour

[00442] vol = volume of solvent relative to the volume of starting material, calculated assuming a density of 1 gram / millilier.

Example 1: Catalyst Preparation

[00443] The chiral phase transfer catalyst of formula (IIIa-13-la) was prepared according to an embodiment shown in scheme 2 below: Scheme 2 1. Load dimethylformamide (DMF, 7.0 L, 10 volumes) into a 20-liter 4-neck flask. 2. Load the starting material (700.Og, l.Oeq) into the flask. 3. Charge K 2 C0 3 (2622.9 g, 5.0 eq) to the balloon. 4. BnBr (2250.3 g, 3.5 eq) is added dropwise to the mixture at 0 ~ 20 ° C. 5. The reaction mixture is heated to 60 ± 5 ° C. 6. The reaction mixture 6 . Stir for 12 hours at 60 ± 5 ° C. 7. The reaction is monitored until the starting material content reaches 0.5%. 8. Pour the reaction mixture into 25.0 L of ice water. 9. Stir for 2 hours at 20 ± 5°C. 10. Filter the product (solid) and wash the filter cake with 5.0 L of water. 11. Dry the product under vacuum at 60 ° C. 12. After drying, 1,500 g of the product is obtained. The purity of the product by HPLC and the yield is 88.0%. Step 2: Synthesis of IIIa-13-1-2 1) Charge toluene (21.0 L, 10 volumes) to a 50 L reactor. 2) Charge IIIa-13-1-1 (2.045 g, 1.0 eq.) to the reactor. 3) Cool the mixture to 0~10°C. 4) Sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al, 3000 g, 2.3 eq.) is added dropwise to the mixture at 0- 10°C with stirring. 5) The reaction mixture is stirred for 5 h at 15-20°C. 6) The reaction is monitored by HPLC until the starting material content < 0.5%. 7) Once the conversion is complete (< 0.5% starting material), the reaction mixture is poured into 20.0 L of 10% NaOH at 10 ~ 20 ° C. 8) The resulting mixture is stirred for 2 hours at 10~15°C and then filtered through a bed of diatomaceous earth (e.g. Celite). 9) The filter cake is washed with 10.0 liters of ethyl acetate and the washings are combined with the filtrate. 10) The combined organic phase filtrate is washed with water (10 L) and brine (5.0 L) once each. 11) The organic phase is concentrated to about 2 volumes. 12) The concentrated organic phase is then diluted with petroleum ether (PE, 20 L). 13) The diluted organic phase is reconcentrated to about two volumes and then filtered. 14) The filter cake is washed with 5.0 L of PE and then dried under vacuum at 30-40 °C to give 660 g of Illa-13-1-2 yield (86.0%) with a purity of 98.7%.Step 3 - Synthesis of IIIa-13-1-3

[00444] 1) Charge dichloromethane (DCM, 29.0 L, 10 volumes) to a 50 L reactor. 2) Charge IIIa-13-1-2 (2.9 kg, 1.0 eq.) to the reactor 50 L and cool to about -5 ~ 0 °C. 3) Charge SOCl2 (900 g, 1.1 eq.) to the reactor at -5 ~ 0 C. 4) Stir reaction mixture for 5 h at -5 ~ 5°C. 5) The extent of the reaction is monitored by TLC until complete. 6) Concentrate the mixture to 2 volumes. 7) Dilute to residue with PE (20 L). 8) Re-concentrate the 2 volume mixture. 9) The concentrated residue was diluted with PE (20 L). 10) Re-concentrate the 2 volume mixture. 11) Filter the mixture and wash the filter cake with PE (5.0 L). 12) Dry the filter cake under vacuum at 30-40 °C to obtain 2.9 kg of product (yield 93.0%).

[00445] Step 4 - Synthesis of IIIa-13-1 1) Load toluene (15 L, 10 volumes) to a 50 L four-neck flask. 2) charge quinine (1,500 g, 1.0 eq.) to the reactor. 3) Charge IIIa-13-1-3 (2.472 g, 1.2 eq.) to the reactor. 4) Stir the reaction mixture for 12 h at 60-65 °C. 5) The reaction is monitored by HPLC until the starting material content is <2.0%. 6) Once the reaction is complete by HPLC, cool the mixture to 25-35°C. 7) Filter the reaction mixture and wash the filter cake with 10.0 L of toluene. 8) Dry the product under vacuum at 40~45°C to obtain the desired product (2.4 kg, purity 94.9%, 67.5% yield).

[00446] The proton NMR spectra and product CL are consistent with the structure of Illa-13-1. Figure 1 shows the 1H NMR spectra of the product in DMSO-d 6 and Figure 2 shows the LCMS of the product. Product purity by HPLC analysis was 94.9% by area and chiral purity by chiral HPLC was 100%) by area.

Example 2: Alternative Process for the Preparation of Chiral Phase Transfer Catalyst IIIa-13-1

[00447] An alternative process according to Scheme 2 was used to prepare the catalyst of synthesis formula IIIa-13-1-1. Step 1 - Synthesis of IIIa-13-1-1 1. 3,4,5-trihydroxybenzoate (9.6 kg, 1.0 eq.) and DMF (76.8 liters) are charged to a reactor at 10-25 °C. 2. K2C03 (25.1 kg, 3.5 eq.) at the same temperature is charged into the reactor. 3. Benzyl bromide (28.4 kg, 3.2 eq.) is then slowly added to the mixture at a temperature of 20-45°C and the mixture aged at about 60°C for about 4 hours. 4. Analysis of the reaction mixture shows that <1.0% starting material remains. 5. Solids are filtered and the cake is washed twice with DMF (1 vol.). 6. The filtered and washing solution is added to water (115 liters) at 5°C and the mixture was stirred for 2 hours at 5-15°C. 7. The resulting mixture was filtered and the cake washed with water. 8. The isolated solid was dried for 2 hours under vacuum at 45°C to obtain the product (22.6 kg, as an off-white solid. 9. In this alternative process IIIa-13-1-1 is obtained as an off-white solid with 99.4% purity and a yield of 95.4%.

[00448] Step 2: Synthesis of IIIa-13-1-2 1. Tetrahydrofuran (177.6 liters) is charged to a reactor and A1C13 (6.5 kg, 1.0 eq.) is charged to 1015 °C. 2. To the resulting mixture is charged compound Illa-13-1 (22.2 kg, 1.0 eq.) and then added NaBH4 (1.78 kg, 1.0 eq.) at 10- 25°C. 3. The resulting reaction mixture is aged for 10 hours at 20-30°C and then additional NaBH4 is charged (1.78 kg, 1.0 eq.) and the mixture is stirred for a additional 12 hours. 4. In addition, 2 equivalents of NaBH4 are charged with subsequent aging of the reaction mixture (1214 hours) where HPLC analysis shows that < 2.5% of the starting material remains. 5. The reaction mixture is cooled to about 15°C and water (55.5 liters) is added slowly. 6. After addition of water, 2M HCl was added to the mixture and the resulting mixture was stirred for an appropriate period of time at 20°C. 7. The layers are resolved, the organic layer is separated and the aqueous layer extracted back with ethyl acetate. 8. The combined organic layers are washed with 6% NaHC0 3 and then 20% brine. 9. The combined organic and wash layer is then concentrated to about 2.5 volumes under vacuum at 40-50°C and heptane is charged (approximately 67 liters). 10. The mixture is then concentrated to about 3 volumes under vacuum. 11. The mixture is filtered and the cake is washed with heptane. 12. The cake is dried under vacuum at 35-45°C to obtain 20.1 kg of IIIa-13-1-2 as an off-white sold in 97.5% yield and 96.5% purity.

[00449] Step 3 - Synthesis of IIIa-13-1 without isolation of IIIa-13-1-3 1. Toluene (148 liters, 10 vol.) and IIIa-13-1-2 (18.5 kg) were added , 1.0 eq.) are charged to a reactor and cooled to about 15°C. 2. SOCl2 (5.27 kg, 1.03 eq.) is charged, and the resulting mixture is stirred for 3 hours . 3. After confirming that the reaction is complete, water (111 liters, 6 vol.) is added to the reaction mixture slowly. 4. The layers are left to rest and the organic layer separated. 5. The organic layer is then washed with NaHC0 3 (8%) and then K2HP04 (5%). 6. The organic layer was washed and then washed twice with water and then with 20% brine twice. 7. To the washed organic layer quinine (11.3 kg, 0.8 eq.) is added at 15-25°C and the mixture was stirred for 24 hours at 60°C, after which HPLC analysis shows < 5% quinine remaining. 8. The mixture is cooled to 10°C slowly and then further stirred at this temperature for about 2 hours. 9. The mixture is filtered and the solid washed with toluene twice and then dried under vacuum at 40°C for 12 hours to obtain 20.1 kg of IIIa-13-1 as an off-white solid with a 79.4% yield and 96.6% purity by HPLC.

[00450] The 1H and LCMS MR spectra of the product were found to be consistent with the structure of the desired product.

[00451] Enantiomerically enriched isoxazoline compounds of formula (R)-IA and (S)-IA are prepared according to Examples 3 and 4, respectively, as shown in Scheme 3 below. The stereochemistry indicated in the title of the compound refers to the orientation of the quaternary carbon of the isoxazoline ring, whether it is shown in the chemical structure as wedges or not.

[00452] Scheme 3 Example 3: Synthesis of (R)-IA-2, in which the chiral carbon in the isoxazoline ring is in an (R) configuration. 1) Formula (II-2) (45.0g, l.Oeq) and dichloromethane (DCM, 1.35 L, 30 volumes) were placed in a 2 L reactor and stirred until the solid completely dissolved. 2) The mixture was cooled to 0°C. 3) Catalyst (IIIb-13-1) was added (1.8 g, 3 mol%) to the mixture. 4) The mixture was cooled to -10°C. 5) hydroxylamine (25.7 g, 5.0 eq., 50% in water) was added to a NaOH solution (18.7 g, 6.0 eq. , in 5 volumes of water) in the other reactor. 6) The solution was stirred for 30 min. 7) Hydroxylamine and a NaOH solution were added dropwise to the 2 L reactor in about 4 hours. 8) The resulting mixture was stirred for 16 h at -10 °C. 9) The reaction process was monitored by HPLC until the starting material content was <1.0%. 10) When the reaction was complete, the mixture was heated to 10°C. 11) 200 ml of water was added to the mixture and the mixture was stirred for 10 minutes. 12) The organic and aqueous phases were allowed to separate and the organic layer was collected. 13) The organic layer was washed with 200 ml of 15% KH2PO4. 14) The aqueous and organic phases were allowed to separate and the organic layer was collected. 15) The organic layer was further washed with 200 ml of brine and the organic layer was collected. 16) The resulting organic layer was concentrated under vacuum at 25-30°C to about 2 volumes. 17) Added toluene (450 ml, 10 volumes) was charged to the vessel and the mixture was further concentrated under vacuum at 45-50°C to about 3 volumes. Solvent exchange for toluene was repeated twice using this procedure. 18) After solvent exchange to toluene, the solution was heated to 55-60°C. 19) The mixture was cooled to 40°C over 1.5 hours and stirred at 40°C for 3 hours. 20) The mixture was further cooled to 25°C over 2 hours and stirred at 25°C for 3 hours. 21) The mixture was cooled to 5-10°C over 1 hour and stirred at 8°C for 12 hours. 22) After aging for 12 hours at 8°C, the solid was removed by filtration and the cake was washed with cold toluene (90 mL, 2 volumes). 23) The resulting solid was dried under vacuum at 85 ~ 90 ° C for 24 h to obtain the product as a white solid (24.0 g, chiral purity 98.4%, chemical purity 99.3%, yield 52. 1%).

[00453] The 1H NMR and LCMS of the product are consistent with the structure of (R) -IA-2. Furthermore, the chiral purity of the product was verified using a chiral HPLC method using a Chiralpak IA 4.6 x 150 mm, 5 mm column with a mobile phase of «-hexane and isopropanol (90:10) at a temperature of 30 °C with detection at 240 nm. The flow rate is 1.0 ml/min and the sample is prepared at a concentration of 2.0 mg/mL in ethanol. Example 4: Synthesis of (S)-IA, in which the chiral carbon in the isoxazoline ring is in the (S) configuration. 1) Formula (II-2) (23.0 g, 1.0 eq.) and DCM (690 ml, 30 volumes) were placed in a 1L reactor. The solid was completely dissolved. 2) The mixture was cooled to 0°C, at which point some starting material precipitated. 3) The catalyst of formula (Ilia-13-1) (0.92 g, 3 mol%) was added to the reactor and the mixture was cooled to -10 °C. 4) hydroxylamine (13.15 g, 5.0 eq., 50% in water) was added to a NaOH solution (9.56 g, 6.0 eq., in 5 volumes of water) in the other reactor. 5) The resulting solution was stirred for 30 min. 6) Hydroxylamine and NaOH solution was added dropwise to the reactor containing 1L Formula (IIA-2) over about 3 hours. 7) The resulting mixture was stirred for 16 h at -10 °C. 8) The extent of the reaction is monitored by HPLC until the starting material content is <1.0%. 9) Once the reaction is complete, the mixture was heated to 10°C and 100 ml of water was added and the resulting mixture was stirred for 10 minutes. 10) The aqueous and organic layers are allowed to separate and the organic layer is collected. 11) The organic layer was washed with 100 ml of 5% KH2PO4, the layers were allowed to separate and the organic layer was collected. 12) The organic layer was washed with 100 ml of brine, the layers were allowed to separate and the organic layer was collected. 13) The organic layer was concentrated under vacuum at 25~30°C to about 2 volumes. 14) Added toluene (230 ml, 10 volumes) was charged to the vessel and concentration under vacuum at 45 ~ 50 °C was continued until about 3 volumes. The solvent exchange process was repeated twice more. 15) Once the solvent exchange process was finished, the solution was heated to 55-60°C. 16) The mixture was then cooled to 40°C over 1.5 hours and stirred at 40°C for 3 hours. 17) The mixture was then cooled to 25°C over 2 hours and stirred at 25°C for 3 hours. 18) The mixture was then further cooled to 5-10°C over 1 hour and stirred at 8°C for 12 hours, at which point the solid was filtered. 19) The filter cake was washed with cold toluene (460 mL, 2 volumes) and then dried under vacuum at 85-90 °C for 24 hours to obtain the product as a solid (13.0 g, purity white chiral: 99.0% using the chiral HPLC method described in Example 3, chemical purity: 98.7% by area (HPLC), yield: 52.1%). The 1H and LCMS MR spectra are consistent with the product structure. Examples 5 and 6 describe the preparation of (R)-IA-3 and (S)-IA-3, respectively, as shown in Scheme 4 below.Scheme 4 Example 5: Synthesis of (R)-IA-3 using the chiral phase transfer catalyst (IIIb-13-1)

[00454] Step 1: Synthesis of intermediate 4-2. 1) The substituted starting material iodobenzene (SM) (200.0 g, 1.0 eq.) and THF (400 ml, 10 volumes) were placed in a 1 L reactor and the mixture was cooled to -10 to -5 2) i-PrMgCl (340 ml, 1.1 eq.) dropwise for 1.5 hours at -10 to -5 °C for mixing. 3) After the addition was complete, the mixture was stirred for 1 h at -10 to -5°C. 4) TLC analysis showed complete consumption of the SM (1 M HCl quench sample). 5) CF3COOMe (94.7 g, 1.2 eq.) was added for one hour at the temperature of -10 ~ -5 ° C and the reaction mixture. 6) The mixture was stirred for a further 12 hours -10 ~ -5°C. 7) TLC analysis showed almost complete consumption of intermediate 4-1 (quench with 1M HCl). 8) 1M HCl 1000ml was added dropwise to the reaction mixture slowly at 0~5°C over 2 hours. 9) The reaction mixture was extracted twice with hexane (1000 ml, 500 ml). 10) Add p-toluenesulfonic acid 1.0 g to the organic phase and then the mixture was refluxed for 30 min. 11) The resulting mixture was then concentrated under vacuum at 20~25°C to remove hexane. 12) Sodium bicarbonate (NaHC0 3 was added, 300 mg) and the mixture was distilled in vacuum to provide compound 4-2 at 80 ~ 82 ° C, as a red liquid (85.0 grams, purity was 92.5% by HPLC, and the yield was 47.0%). Step 2: Preparation of compound of Formula (IIA-3):

[00455] 1) Compound 4-2 (70.0 g, 1.0 eq.) and acetonitrile (ACN, 350 mL, 5 volumes) were placed in a 1 L reactor. The solid was completely dissolved. 2) Compound 4-1 (70.2 g, 1.2 eq.) was then added to the mixture, and the mixture was heated to 90-95 °C. 3) The water/ACN azeotrope, was removed by distillation ( boiling point 79°C). 4) K2CO3 (2.0 g, 0.1 eq.) was then added to the mixture. 5) Distillation was continued to remove ACN/water at 90~95°C for about 6 hours. 6) After this time, about 28% Compound 4-2 remained by HPLC. 7) The mixture was cooled to 15~20°C over 1.5 hours and solid precipitated. 8) Water (50 ml) was added and then the mixture was further cooled to 0°C over 40 min. 9) The mixture was then kept at 0°C for 40 minutes. 10) The mixture was filtered and the cake was washed with 100 ml of cold ACN/water (ACN/water, 25:6V/v) to obtain 75.0 g of a yellow solid, after drying (purity: 95 .1%; yield: 50.0%). Step 3: Preparation of (R)-IA-3 using the chiral phase transfer catalyst IIIb-13-1 1) the compound of formula IIA-3 (40.0 g, 1.0 eq) and DCM (1.2 L, 30 volumes) were placed in a 2 L reactor; the solid dissolved completely. 2) The mixture was cooled to 0°C and some starting material precipitated. 3) The catalyst of formula IIIb-13-1 (1.47 g, 3 mol%) was added to the mixture and the mixture was cooled to -10 °C. 4) hydroxylamine (21.0 g, 5.0 eq., 50% in water) was added to a NaOH solution (15.3 g, 6.0 eq., in 5 volumes of water) in another reactor and stirred for 30 minutes. 5) The hydroxylamine/NaOH solution was then added dropwise to the 2 liter reactor over about 4 hours. 6) The resulting reaction mixture was stirred for 16 h at a temperature of -10 ° C. 7) In the process samples were collected and analyzed by HPLC until the starting material content was <1.0%. 8) When the reaction was complete, the mixture was heated to 10°C and 200 ml of water was added. The mixture was stirred for 10 minutes. 9) After mixing, the mixture was allowed to stand to separate the aqueous phase and organic layers and the organic layer was collected. 10) The organic layer was washed with 200 ml of 5% KH2PO4. 11) The two layers were allowed to separate and the organic layer was collected. 12) The organic layer was then washed with 200 ml of brine, the two layers were allowed to separate and the organic layer was collected again. 13) The resulting organic layer was concentrated under vacuum at 25-30°C to about 2 volumes. 14) Toluene (400 ml, 10 volumes) was added to the vessel and concentration under vacuum was continued at 40 ~ 45 ° C at about 3 volumes. The solvent exchange was repeated twice more using the same procedure. 15) When the solvent exchange was complete, the solution was heated to 55-60°C. 16) The mixture was then cooled to 40°C over 1.5 hours and stirred at 40°C for 3 hours. 17) The mixture was then cooled to 25°C over 2 hours and stirred at 25°C for 3 hours. 18) The mixture was finally cooled to 5-10°C over 1 hour and stirred at 8°C for 12 hours. 19) After this time, the mixture was filtered and the filter cake was washed with cold toluene (80 mL, 2 volumes). 20) The product was dried under vacuum at 70 ~ 75 ° C for 12 h, to obtain a solid (22.0 g, white chiral purity: 98.0% by area using the chiral HPLC method described in Example 3, chemical purity: 97.1% by area (HPLC), yield: 48.8%). The 1H and LCMS MR spectra are consistent with the structure of the product. Example 6: Preparation of (S)-IA-3 using the chiral phase transfer catalyst Illa-13-1 1) The compound of Formula IIA-3 (11.6 g, 1.0 eq) and 360 ml of DCM, 30 volumes) were placed in a 1 L solid reactor and dissolved completely. 2) The mixture was cooled to 0°C and some starting material was separated by precipitation. 3) The catalyst (0.43 g, 3 mol%) was added to the resulting mixture, and the mixture was cooled to -10 °C. 4) Hydroxylamine (6.1 g, 5.0 eq., 50% in water ) was added to a NaOH solution (4.4 g, 6.0 eq., in 5 volumes of water) in another reactor, and the mixture was stirred for 30 minutes. 5) Hydroxylamine and a NaOH solution were added dropwise to the 1 L reactor over about 2 hours, after which the mixture was stirred for 16 h at -10 °C. 6) Samples were collected and analyzed by HPLC to monitor the extent of the reaction until the starting material content was <1.0%. 7) When the reaction was complete, the mixture was heated to 10°C and 50 ml of water was added. The mixture was stirred for 10 minutes. 8) The mixture was left to stand to separate the aqueous phase and organic layers and the organic layer was collected. 9) The organic layer was washed with 50 ml of 5% KH2PO4. 10) The mixture was allowed to separate and the organic layer was collected. 11) The organic layer was washed with 50 ml of brine and the organic layer was collected again. 12) The organic layer was concentrated under vacuum at 2530°C to about 2 volumes. 13) Toluene (230 ml, 10 volumes) was added and concentration under vacuum was continued at 40 ~ 45 ° C at about 3 volumes. The solvent exchange was repeated twice more using the same procedure. 14) After the solvent exchange was complete, the solution was heated to 55-60°C. 15) The mixture was then cooled to 40°C over 1.5 hours and stirred at 40°C for 3 hours. 16) The mixture was cooled to 25°C over 2 hours and stirred at 25°C for 3 hours. 17) Finally, the mixture was cooled to 5-10°C over 1 hour and stirred at 8°C for 12 hours, after which the mixture was filtered. 18) The filter cake was washed with cold toluene (25 mL, 2 volumes). 19) The product was dried under vacuum at 85~90°C for 24 hours, resulting in the product as a white solid (6.8 g, chiral purity: 98.7 area % using the chiral FTPLC method described in Example 3, chemical purity: 99.3% in area (FTPLC), yield: 52.1%). Example 7: Preparation of (S)-afoxolaner using chiral phase transfer catalyst (Ilia-13-1):

[00456] 1) Starting material (II-1) (200 g, 1.Oeq, 94.0%) and DCM (6 L, 30 volumes) were placed in a 10 L reactor, the solid was completely dissolved. 2) The mixture was cooled to 0°C, and some starting material precipitated. 3) Catalyst (Ilia-13-1) (7.56 g, 3 mol%, 95.0%) was added to the mixture and the resulting mixture was further cooled to -10 °C. 4) Hydroxylamine (64, 9 g, 3.0 eq, 50% solution in water) was added to a NaOH solution (52.5 g, 4.0eq, in 5v water) in a separate reactor and stirred for 30 minutes. 5) The resulting hydroxylamine/NaOH solution was then added dropwise to the 10 L reactor containing (IIA-1) over about 4 hours. 6) The resulting mixture was stirred for 12 hours at -10°C and monitored for the extent of the reaction until the amount of starting material was <1.0% by HPLC. 7) The mixture was then heated to 10°C, 1 liter of water was added and the mixture was stirred for 10 minutes. 8) The mixture was left to stand to separate the two phases, and the organic layer was collected. 9) The organic layer was then washed with 2 liters of water, the layers were allowed to separate again and the organic layer was collected. 10) The organic layer was washed with 1 liter of brine, the layers were allowed to separate and the organic layer was collected and dried over Na2SO4 (200 g). 11) The dried organic layer was concentrated under vacuum to about 2 volumes. 12) Added toluene (2 L, 10 volumes) was charged to the concentrated mixture and concentration under vacuum was continued at about 5 volumes. Solvent exchange was repeated twice more. 13) The resulting solution was placed in a 2.0 L reactor and heated to 55-60°C. 14) cyclohexane (300 ml, 1.5 volumes) was added at 55-60°C. 15) The mixture was then cooled to 40°C over 1.5 hours and then stirred at 40°C for 3 hours. 16) The mixture was then cooled to 25°C over 2 hours and stirred at 25°C for a further 3 hours. 17) The resulting mixture was cooled to 0-5°C over 1 hour and stirred at 5°C for 12 hours, at which point the mixture was filtered to isolate the product. 18) The filter cake was washed with cold toluene/cyclohexane (3:1, 1000 mL, 5 volumes). 19) The product was obtained as a white solid. (171.5g, chiral purity > 99.0% by area using the chiral HPLC method described in Example 3, chemical purity > 99.0% by area (HPLC), yield: 83.6%, assay purity: 92% ). The 1H NMR and LCMS spectra are consistent with the structure of (S)-afoxolaner as the toluene solvate. Figure 3 shows the 1H NMR spectra of (S)-afoxolaner in DMSO-d6 and Figure 4 shows the 1H NMR spectra of afoxolaner (racemic) for comparison. The chiral purity of the product was determined using the chiral HPLC method described in Example 3. Figure 5 shows the chiral HPLC chromatogram of afoxolaner (racemic) and Figure 6 shows the chiral HPLC chromatogram of the product (S)-afoxolaner which shows an enantiomer.

Example 8: Alternative process for preparing (S)-afoxolaner

[00457] An alternative process was carried out for the preparation of (S)-afoxolaner. Some of the main variations in the alternative process are noted below. 1. 1 kilogram of compound (IIA-1) (1 eq.) and 9 liters of DCM are charged into a reactor and stirred to dissolve the compound. 2. The mixture is cooled to about 0°C and 50 grams (5 mole %) of chiral phase transfer catalyst (Ilia-13-1) and 1 liter of DCM are charged and the resulting mixture is cooled to about of -13 ° C. 3. A 19% (W/W) solution of hydroxylamine sulfate (294 g, 1.1 eq.) (Prepared with 294 grams of (H 2 OH) H 2 S0 4 and 141 g of NaCl in 1112 mL of water) and 4.4 equivalents of NaOH as a 17.6% (W/W) solution (286 grams of NaOH and 158 grams of NaCl in 1180 mL of water) are charged to the reaction mixture at the same time. Same time. 4. The resulting reaction mixture was allowed to stand for about 20 hours at about -13°C and then checked for reaction conversion by HPLC (target <0.5% by area); 5. After completion of the reaction, water (3 vol.) was added at about 0°C. Then a solution of 709 g of KH 2 P0 4 to 4.2 liters of water are added to the mixture to adjust the pH (target 7/8) and the resulting mixture is stirred at about 20°C for 30 minutes. 6. The layers are allowed to settle, the aqueous phase is removed and the organic layer is washed with 3 liters of water twice. Crystallization of toluene solvate 1. After the extraction/washing phase, dichloromethane is removed by vacuum distillation to about 1-2 volumes and toluene (about 5-10 volumes) is added. 2. _The volume is adjusted by further distillation under vacuum and/or adding more toluene to about 5-6 volumes. The mixture is distilled, still maintaining volume to completely remove the dichloromethane reaction solvent. 3. The mixture is then cooled to about 10°C and seeded with afoxolaner (racemic compound) and stirred at the same temperature for at least 2 hours; 4. The mixture is heated to about 55-65°C, aged for at least 17 hours and then the solid is separated by filtration. The filtered solid is washed with toluene; 5. The combined and washed filtrate was adjusted to a volume of about 5-6 volumes by vacuum distillation and/or addition of toluene; 6. The resulting mixture is cooled to about 10°C and aged for at least 5 hours and then filtered. The cake is washed with toluene. 7. The cake is dried at 50°C under vacuum to obtain a toluene solvate of (S)-afoxolaner containing between about 6% and 8% toluene. Re-crystallization from cyclohexane/ethanol

[00458] The toluene solvate of (S)-afoxolaner was subsequently re-crystallized from a mixture of cyclohexane and ethanol, to remove the toluene and combined to further purify the product. 1. 591 grams of toluene (S)-afoxolaner solvate were charged into a vessel along with 709 mL of ethanol (1.2 vol.) and 1.773 mL of cyclohexane (3 vol.) and the mixture was heated to ca. 60°C. 2. To the resulting mixture was added an additional 6383 mL of cyclohexane with stirring. 3. The resulting mixture was cooled to about 30°C and then heated again to 60°C. This process was repeated once. 4. The mixture was slowly cooled to 10°C and stirred for at least 5 hours. 5. The resulting slurry was filtered and the cake was washed with cyclohexane. 6. The cake was dried at 50°C under vacuum to provide 453.7 grams of (S)-afoxolaner Example 9: Selectivity comparison of benzyloxy-substituted chiral phase transfer catalyst (Illa-13) with other chiral phase transfer based on cinchona alkaloids.

[00459] The selectivity of the formation of (S)-afoxolaner from the compound IIA-1, as shown above, was studied with sixteen chiral phase transfer catalysts (PTC) of different structures. The reaction was conducted using conditions similar to those in Example 7. The proportion of (S)-afoxolaner and (R)-afoxolaner in the reaction mixture was determined by chiral HPLC using the method described in Example 3. The results of the study are provided in Table 2 below. Table 2

[00460] As shown in the table, the catalyst in which the R group in the structure of formula (Illa) is phenyl 3,4,5-tribenzyloxy results in a surprising better selectivity for the (S)-enantiomer compared to another phase Quinine-based transfer catalysts in which the group corresponding to R in formula (Illa) is another group.

Example 10: Improvement of chiral purity of (<S)-afoxolaner by crystallization from toluene

[00461] A sample reaction mixture containing a ratio (HPLC area) of 92.1: 7.9, (S)-afoxolaner to (R)-afoxolaner, was concentrated to dryness and the residue was crystallized from from toluene and from ethanol/cyclohexane using a process similar to that described in Example 8. The isolated crystalline solid was analyzed using chiral HPLC to determine the relative amounts of (S)-afoxolaner and (R)-afoxolaner. (HPLC method: column - Chiralpak AD-3 150 mm x 4.6 mm x 3.0 μni, injection volume - 10 μ'l, temperature - 35 °C, flow - 0.8 mL/minute, phase mobile -89% hexane/10% isopropanol/1% methanol, detection - 312 nm.) The ratio of (S)-afoxolaner to (R)-afoxolaner in the solid isolated from toluene crystallization was found to be 99. .0:1.0, while the ratio of (S)-afoxolaner to (R)-afoxolaner in the solid crystallized from ethanol/cyclohexane was found to be 95.0:5.0.

[00462] The example shows that crystallization (S)-afoxolaner from an aromatic solvent such as toluene results in a significant improvement in the chiral purity of the product. This is very unexpected and surprising.

Example 11: Comparison of alkoxy-substituted chiral phase transfer catalyst selectivity vs. benzyloxy of Formula (IIIa-13)

[00463] Three chiral phase transfer catalysts of formula (III-13), in which the phenyl ring is substituted with three alkoxy groups and three benzyloxy groups (R = methyl, ethyl and benzyl); R '= OMe, W = vinyl and X = chlorine, were evaluated in the process to prepare (S)-IA from compound II-1 as shown below.

[00464] The amount of solvents and reagents and the reaction and isolation conditions were as described in Example 7 above. The same procedure was used for each catalyst tested. It was found that the selectivity of the tri-benzyloxy catalyst was surprisingly significantly better than the two alkoxy-substituted catalysts, as shown by the chiral purity of the product. Furthermore, it was found that using the tri-benzyloxy substituted phase transfer catalyst the resulting chemical purity was also much better. The superior selectivity of the benzyloxy-substituted catalyst is significant and surprising and cannot be predicted. Chiral phase transfer catalysts containing a phenyl group substituted with benzyloxy and alkoxy groups have been shown to be superior to catalysts substituted with other groups, such as electron withdrawing groups and alkyl groups. The chiral purity and chemical purity of the product produced from their respective phase transfer catalysts is shown in Table 3 below: Table 3

Example 12: Crystallization of (S)-afoxolaner to produce Crystalline toluene solvate:

[00465] The amount of (<S)-afoxolaner shown in Table 4 in powder form was placed in a glass tube and numbered accordingly. The crystallization solvent (Table 4) was then added into the tube. The volume of crystallization solvent (see Table 4) was adjusted to preferably obtain a suspension at room temperature and a clear solution at an elevated temperature. The tube was then tightly closed to prevent evaporation of the crystallization solvent and heated to high temperature (see Table 4), while the solution was vortexed at 400 rpm or stirred with a magnetic bar to dissolve the (S) -afoxolaner to induce crystallization of the product, the tube was then cooled at a rate and temperature given in Table 4. When crystals were suspected in the tube, the solution was then filtered under vacuum and the solid obtained was analyzed by X- Ray Powder Diffraction. When any crystals were not suspected in the tube, the aftertreatment mentioned in Table 4 was applied to the solution before X-Ray Powder Diffraction. All samples 1-5 were confirmed to be a crystalline toluene solvate of (<S)-afoxolaner. Table 4

[00466] The solid obtained from sample 2 in Table 4 was analyzed by thermogravimetric analysis (TGA) on a TA Instruments TGA Q500 instrument with the following parameters: atmosphere: nitrogen, with 60 ml flow / nm, standard pam: TA 901670-901 non-hermetic, lid standard: AT 901671 -901, speed: 10°C/minute. TGA analysis showed a mass loss of about 10.5% from room temperature up to 160°C, being particularly important in the temperature range of 70°C to 90°C. A large mass loss above 280° C was associated with the decomposition of the compound. The TGA trace is shown in Figure 7.

[00467] Solid analysis from sample 2 by Differential Scanning Calorimetry (DSC) was carried out on a TA Instruments Q200 device using the following parameters: atmosphere: nitrogen, with 60 ml flow / nm, standard pan: TA 901670-901 non-airtight, standard cap: TA 901671-901, rate: 10°C/minute. The thermal profile shows a large and narrow endothermic peak between 70 °C and 90 °C. The DSC profile is shown in Figure 7.

[00468] The solid isolated from sample 2 was analyzed by X-Ray Powder Diffraction using the following equipment and conditions: Apparatus: Bruker D8 Advance diffractometer, type: Bragg-Brentano; source CuKoci, À = 1.5406A and CuKoci , À 2 = 1.54439A; generator: 35 kV - 40 mA; Detector: Eye Lynx; Anton Paar TTK450 camera; Si sample holder; Angle range: 2° to 40° in 2-theta Bragg; variable divergence gap: 4 mm (V4); step size: 0.041°; step time: 1 second. Figure 8 shows the X-Ray Powder Diffraction pattern of the solid form. Table 6 below presents the grade 2-theta peaks identified from the analysis. Table 6

Example 13: Single Crystal X-ray Diffraction

[00469] A single crystal X-ray diffraction analysis was performed on a toluene solvate crystal produced by crystallization of (S)-afoxolaner made by the process of the invention according to Examples 7 and 8. The crystal structure of (S)-afoxolaner was resolved and refined to a final R factor of 5.5%. The structure was found to be a clinical tri-molecule that contains two independent toluene molecules and two (S)-afoxolaner. The crystal structure was found to be strongly disordered, as shown in Figure 9. Table 7 below outlines some information describing the crystal and molecular structure. According to the Cerius2 molecular simulation program, the absolute configuration of toluene solvate prepared by the process of the invention is (S). The structure of the molecular structure obtained from Cerius2 software is shown in Figure 10. Table 7

[00470] The invention is further described by the following numbered paragraphs:

[00471] Process for the preparation of an isoxazoline compound of the following formula (I), which is enriched in one enantiomer: where: 81, B2, B3, are each, independently, CR or N; each R is independently H, halogen, cyano, -NO2, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino or alkoxycarbonyl; R1 represents C1-C3 alkyl or C1-C3 haloalkyl; Y is an optionally substituted phenylene, naphthylene, indanylene, a 5- or 6-membered heteroarylene or an 8-10 membered fused heterobicyclylene, wherein the optional substituents are selected from the group consisting of halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl , alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, -CN or -NO2 and H2-C(=S)-; Q is T-NR2R3, the group (-CH2-)(-CH2-)N-R3, OH, NH2, alkoxy, haloalkoxy, alkylamino, haloalkylamino, dialkylamino, halodialkylamino, thiol, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, or an optionally substituted 5- or 6-carbocyclyl, heterocyclyl or heteroaryl ring members; T is (CH2)n, CH(CH3), CH(CN), C(=O) or C(=S); R2 represents H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl; R3 represents H, OR7, R8R9 or Q1; or an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, each optionally substituted with one or more substituents independently selected from R4; or R2 and R3 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, halogen, -CN, -NO2 and alkoxy; each R4 independently represents halogen; alkyl, cycloalkyl, alkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, haloalkylamino, dialkylamino, dihaloalkylamino, cycloalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl, loalkylaminocarbonyl, hydroxy, -NH2, - CN or -N02; or Q2; each R5 independently represents halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, -CN or -NO2; each R6 independently represents halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, -CN, -N02, phenyl or pyridinyl; R7 is H; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionally substituted with one or more halogen; R8 is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl; R9 represents H; Q3; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionally substituted with one or more substituents independently selected from R4; or R8 and R9 are taken together with the nitrogen to which they are attached to form a ring containing 2 to 6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, said ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkyl, halogen, -CN, -N02 and alkoxy; Q1 is a phenyl ring, a 5- or 6-membered heterocyclic ring, or a fused 8-, 9- or 10-membered bicyclic ring system optionally containing one to three heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, each ring or ring system optionally substituted with one or more substituents selected independently of R5; Q2 is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R6; Q3 represents a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring optionally substituted with one or more substituents independently selected from R6; en is 0, 1 or 2; wherein the asterisk represents that the carbon atom is a chiral quaternary carbon atom; comprising reacting a compound formula (II): wherein B1, B2, B3, R1, Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a base and a chiral phase transfer catalyst of formula (IIIa) or (IIIb): wherein R is aryl or heteroaryl substituted with one or more aralkoxy, amino, alkylamino or dialkylamino groups; R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X- is an anion; and isolates the compound.

[00472] 2. Process, according to claim 1, in which the compound of formula (I) enriched in an enantiomer is isolated by crystallization of the compound from an aromatic solvent or a mixture of solvents comprising an aromatic solvent.

[00473] 3. Process according to claim 2, wherein the aromatic solvent is selected from the group consisting of toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole and mesitylene or a combination thereof .

[00474] 4. Process, according to claim 3, in which the aromatic solvent is toluene.

[00475] 5. Process, according to any one of claims 1 to 4, wherein before isolating the compound of formula (I) enriched in one of its enantiomers, the process further comprises crystallizing the racemic compound of formula (I ) and remove the solid.

[00476] 6. Process according to any one of claims 1 to 5, wherein Y is where Z is N or CH.

[00477] 7. Process according to claim 1 or 6, wherein Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3, -C(O)NHCH2CH2SCH3 or ( -CH2-)(-CH2-)N(CO)CH2S(O)2CH3.

[00478] 8. Process according to any one of claims 1 to 7, wherein X- in the chiral phase transfer catalyst of formula (IIIa) or (IIIb) is a halogen counterion.

[00479] 9. Process according to claim 7, wherein X- is a chloride counterion.

[00480] 10. Process according to any one of claims 1 to 9, wherein R in the chiral phase transfer catalyst of formula (IIIa) or (IIIb) is a phenyl group that is substituted by 1, 2, 3 , 4 or 5 aralkoxy groups.

[00481] 11. Process according to claim 10, wherein the aralkoxy group is a benzyloxyl group.

[00482] 12. Process, according to claim 10, in which R is substituted with 3 aralkoxy groups.

[00483] 13. Process according to claim 12, wherein R is 3,4,5-tris (benzyloxy) phenyl.

[00484] 14. Process for the preparation of an isoxazoline compound which is of formula IA, wherein X1, X2 and X3 are each independently H, chlorine, fluorine or CF3, which is enriched in the (S) - enantiomer : comprising reacting a compound of formula (IIA): wherein X1, X2 and X3 are H, chlorine, fluorine or CF3, with hydroxylamine, in the presence of water, an organic solvent that is not miscible with water, a base and a chiral phase transfer catalyst of formula (IIIa): wherein R is aryl or heteroaryl optionally substituted with one or more C1-C3 alkoxy, amino, C1-C3 alkylamino, C1-C3 dialkylamino or aralkoxy groups, R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X- is an anion; and isolates the compound of formula (S)-IA.

[00485] 15. Process, according to claim 14, in which the compound of formula (S)-IA is isolated by crystallization of the compound from an aromatic solvent or a mixture of solvents comprising aromatic solvent.

[00486] 16. Process according to claim 15, wherein the aromatic solvent is selected from the group consisting of toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole and mesitylene.

[00487] 17. Process, according to claim 16, in which the aromatic solvent is toluene.

[00488] 18. Process, according to any one of claims 14 to 17, wherein before isolating the compound of formula (S)-IA, the process further comprises crystallizing the racemic compound of formula IA and removing the solid .

[00489] 19. Process according to claim 14, wherein R in the chiral phase transfer catalyst of formula (IIIa) is phenyl substituted by 1, 2 or 3 methoxy or ethoxy groups, and R' is hydrogen or methoxy .

[00490] 20. Process according to claim 14, wherein R in the chiral phase transfer catalyst of formula (IIIa) is phenyl substituted by 1, 2 or 3 benzyloxy groups, and R' is hydrogen or methoxy.

[00491] 21. Process according to claim 14, wherein R in the chiral phase transfer catalyst of formula (Illa) is 3,4,5-tris (benzyloxy) phenyl.

[00492] 22. Process according to claim 14, wherein X1 and X3 are independently chlorine or CF3 and X2 is H or fluorine.

[00493] 23. Process according to claim 14, wherein X1 is chlorine; X3 represents CF3 and X2 represents H.

[00494] 24. Process according to claim 14, wherein X1 and X3 are chlorine; and X2 represents H.

[00495] 25. Process according to claim 14, wherein X1 and X3 are chlorine and X2 is fluorine.

[00496] 26. Process according to claim 14, wherein X1 is chlorine; X3 represents CF3 and X2 is fluorine.

[00497] 27. Chiral phase transfer catalyst in which it is of formula (IIIa):

[00498] where R is aryl or heteroaryl substituted with one or more aralkoxy groups, R' is hydrogen or C1-C3 alkoxy, W is ethyl or vinyl, and X is an anion.

[00499] 28. Chiral phase transfer catalyst according to claim 27, wherein R is phenyl.

[00500] 29. Chiral phase transfer catalyst according to claim 27 or 28, wherein X is a halogen counterion.

[00501] 30. Chiral phase transfer catalyst according to claim 27, wherein R is phenyl substituted by one or more benzyloxy groups.

[00502] 31. Chiral phase transfer catalyst according to claim 30, wherein R is 3,4,5-tris (benzyloxy) phenyl.

[00503] 32. Chiral phase transfer catalyst according to claim 27, wherein W is vinyl and X is chloride.

[00504] 33. Chiral phase transfer catalyst according to claim 27, wherein

[00505] R is phenyl substituted by one or more benzyloxy groups;

[00506] R' is hydrogen or methoxy;

[00507] W is vinyl; It is

[00508] X is halogen.

[00509] 34. Chiral phase transfer catalyst according to claim 33, wherein R' is methoxy.

[00510] 35. Chiral phase transfer catalyst according to claim 27, wherein

[00511] R is phenyl substituted by one or more benzyloxy groups;

[00512] R' is hydrogen or methoxy;

[00513] W is ethyl; It is

[00514] X is halogen.

[00515] 36. Chiral phase transfer catalyst according to claim 35, wherein R' is methoxy.

[00516] 37. Chiral phase transfer catalyst according to claim 27, wherein the chiral phase transfer catalyst has the following formula (IIIa-13-1), (IIIa-13-2), (IIIa -13-3) or (IIIa-13- 4): where X is a halogen counterion.

[00517] 38. Chiral phase transfer catalyst according to claim 37, wherein X is chloride.

[00518] 39. Crystalline toluene solvate (S)- afoxolaner having the formula:

[00519] 40. The crystalline toluene solvate of claim 39, wherein an X-ray powder diffraction pattern comprising two or more of the 2-theta peaks selected from the group consisting of: ± 0.2 2-theta, as determined on a diffractometer using Cu-Kα radiation.

[00520] 41. Crystalline toluene solvate according to claim 39, wherein an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of: ±0.2 2-theta.

[00521] 42. Crystalline toluene solvate according to claim 39, wherein an X-ray powder diffraction pattern is substantially as shown in Figure 8.

[00522] 43. The crystalline toluene solvate of claim 39, wherein a differential scanning calorimetry (DSC) thermogram having an endotherm at a temperature of about 83° C to about 87° C, corresponding to toluene solvate.

[00523] 44. Crystalline toluene solvate according to claim 39, wherein by a differential scanning calorimetry (DSC) thermogram having an endotherm at a temperature of about 84.7 ° C, which corresponds to toluene solvate.

[00524] 45. Crystalline toluene solvate according to claim 39, wherein a differential scanning calorimetry thermogram is substantially as shown in Figure 7.

[00525] 46. The crystalline toluene solvate of claim 39, wherein a thermogravimetric analysis (TGA) thermogram, wherein the weight loss of about 10.5% from about about 26° C to about 160°C.

[00526] 47. Crystalline toluene solvate according to claim 39, wherein a thermogravimetric analysis thermogram is substantially as shown in Figure 7.

[00527] 48. Crystalline toluene solvate according to claim 39, wherein the unit cell parameters are substantially the same as the following:

[00528] 49. Crystalline toluene solvate according to claim 39, wherein the unit cell parameters are substantially the same as the following:

[00529] 50. Crystalline toluene solvate according to claim 39, wherein two or more of the following features: i) an X-ray powder diffraction pattern comprising at least three 2-theta values selected from of the group consisting of ± 0.2 2-theta; ii) an X-ray powder diffraction pattern substantially in accordance with the X-ray powder diffraction spectrum shown in Figure 8; iii) a differential scanning calorimetry (DSC) that has an endotherm at a temperature of between about 83°C to about 87°C; iv) a differential scanning calorimetry thermogram substantially as shown in Figure 7; and v) a thermogravimetric analysis (TGA) diagram substantially the same as that shown in Figure 7.

[00530] 51. Crystalline toluene solvate according to claim 39, wherein the molar ratio of (S)-afoxolaner to toluene is about 1:1.

[00531] 52. Crystalline toluene solvate, according to claim 39, wherein the crystalline toluene solvate (S)-afoxolaner is isolated.

[00532] 53. Crystalline toluene solvate according to claim 39, wherein at least 90% of (S)-afoxolaner by weight is in a crystalline toluene solvate form.

[00533] 54. Crystalline toluene solvate according to claim 39, wherein at least 80% of (S)-afoxolaner by weight is in a crystalline toluene solvate form.

[00534] 55. Crystalline toluene solvate according to claim 39, wherein at least 70% of (S)-afoxolaner by weight is a crystalline toluene solvate form.

[00535] 56. Crystalline toluene solvate according to claim 39, wherein at least 60% of (S)-afoxolaner by weight is in a crystalline toluene solvate form.

[00536] 57. Pesticide or parasiticide composition comprising crystalline toluene solvate as defined by claim 39, and at least one agriculturally or pharmaceutically acceptable carrier or excipient.

[00537] 58. Pesticide or parasiticide composition according to claim 57, wherein it comprises crystalline toluene solvate as defined by claim 36, wherein said crystalline toluene solvate is in admixture with one or more distinct polymorphic forms and / or an amorphous compound of (S) - afoxolaner.

[00538] 59. The pesticide or parasiticide according to claim 57, wherein at least 80% of (S) - afoxolaner is in a crystalline toluene solvate form.

[00539] 60. Pesticide or parasiticide composition according to claim 57, wherein the composition comprises at least 95% by weight of the crystalline toluene solvate as defined by claim 36 based on the total weight of compound (S )-afoxolaner in the composition.

[00540] 61. Pesticide or parasiticide composition according to claim 60, wherein the composition comprises at least 98%, by weight, of the crystalline toluene solvate as defined by claim 36 based on the total weight of compound (S )-afoxolaner in the composition.

[00541] 62. Process for preparing crystalline toluene solvate as defined by claim 39 wherein said process comprises crystallizing (S) - afoxolaner from toluene, optionally in the presence of a second solvent.

[00542] 63. Process, according to claim 62, comprising crystallizing (S)-afoxolaner from a mixture of toluene and cyclohexane.

[00543] 64. The process of claim 63, wherein the mixture of toluene and cyclohexane comprises from a ratio of about 50:50 to about 99:1 (v/v) of toluene to cyclohexane.

[00544] 65. Process according to claim 62 comprising: a) providing a solution of (S)-afoxolaner in toluene, optionally in the presence of a second solvent; b) obtain the crystalline solvate of (S)-afoxolaner from the solution from step a); and c) isolating the crystalline toluene solvate from (S) - afoxolaner.

[00545] 66. Process, according to claim 65, in which the solution of (S) -afoxolaner in toluene, optionally in the presence of a second solvent, is obtained by combining solid (S) -afoxolaner and toluene, optionally in the presence of a second solvent, and heating the combination.

[00546] 67. Process according to claim 66, in which the combination is heated to a temperature of between about 50° C and about 80° C.

[00547] 68. Process, according to claim 65, in which the crystalline toluene solvate of (S) -afoxolaner is obtained by cooling the solution from step a).

[00548] 69. Process according to claim 68, in which the solution from step a) is cooled to a temperature below about 20° C.

[00549] 70. Process according to claim 68, in which the solution from step a) is cooled to a temperature below about 15° C.

[00550] 71. Process, according to claim 68, in which the solution from step a) is cooled to a temperature of about 10° C.

[00551] Having thus described in detail several embodiments of the present invention, it is to be understood that the invention defined by the above paragraphs is not to be limited to the particular details set forth in the above description as many evident variations thereof are possible without departing from the spirit or scope of the present invention.

Claims (43)

1. Process for the preparation of an isoxazoline compound characterized by the fact that it is of formula IA, wherein X1, X2 and X3 are each independently H, chlorine, fluorine or CF3, which is enriched in the (S)-enantiomer : comprising reacting a compound of formula (IIA): wherein X1, X2 and -1): where X- is an anion; and isolates the compound of formula (S)-IA. 2. Process, according to claim 1, characterized by the fact that the compound of formula (S)-IA is isolated by crystallization of the compound from an aromatic solvent or a mixture of solvents comprising aromatic solvent. 3. Process according to claim 2, characterized in that the aromatic solvent is selected from the group consisting of toluene, ethylbenzene, xylenes, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole and mesitylene. 4. Process according to claim 3, characterized by the fact that the aromatic solvent is toluene. 5. Process according to any one of claims 1 to 47, characterized by the fact that, before isolating the compound of formula (S)-IA, the process further comprises crystallizing the racemic compound of formula IA and removing the solid. 6. Process according to claim 1, characterized by the fact that X1 and X3 are independently chlorine or CF3 and X2 is H or fluorine. 7. Process according to claim 1, characterized by the fact that X1 is chlorine; X3 represents CF3 and X2 represents H. 8. Process according to claim 1, characterized by the fact that X1 and X3 are chlorine; and X2 represents H. 9. Process according to claim 1, characterized by the fact that X1 and X3 are chlorine and X2 is fluorine. 10. Process according to claim 1, characterized by the fact that X1 is chlorine; X3 represents CF3 and X2 is fluorine. 11. Crystalline toluene solvate (S)-afoxolaner characterized by the fact that having the formula: 12. The crystalline toluene solvate of claim 11, wherein an X-ray powder diffraction pattern comprising two or more of the 2-theta peaks selected from the group consisting of: ± 0.2 2-theta, as determined on a diffractometer using Cu-Kα radiation. 13. The crystalline toluene solvate of claim 11, wherein an X-ray powder diffraction pattern comprising three or more peaks selected from the group consisting of: ±0.2 2-theta. 14. Crystalline toluene solvate according to claim 11, characterized in that an X-ray powder diffraction pattern is substantially as shown in Figure 8. 15. The crystalline toluene solvate of claim 11, wherein a differential scanning calorimetry (DSC) thermogram having an endotherm at a temperature of about 83° C. to about 87° C., corresponding to toluene solvate. 16. Crystalline toluene solvate according to claim 11, characterized in that by a differential scanning calorimetry (DSC) thermogram having an endotherm at a temperature of about 84.7° C, which corresponds to toluene solvate. 17. Crystalline toluene solvate according to claim 11, characterized in that a differential scanning calorimetry thermogram is substantially as shown in Figure 7. 18. Crystalline toluene solvate according to claim 11, characterized by the fact that a thermogravimetric analysis (TGA) thermogram, wherein the weight loss of about 10.5% from about about 26° C to about 160° C. 19. Crystalline toluene solvate according to claim 11, characterized in that a thermogravimetric analysis thermogram is substantially as shown in Figure 7. 20. Crystalline toluene solvate according to claim 11, characterized in that the unit cell parameters are substantially the same as the following: 21. Crystalline toluene solvate according to claim 11, characterized in that the unit cell parameters are substantially the same as the following: 22. Crystalline toluene solvate according to claim 11, characterized by having two or more of the following characteristics: i) an X-ray powder diffraction pattern comprising at least three 2-theta values selected from the group consisting of ± 0.2 2-theta; ii) an X-ray powder diffraction pattern substantially in accordance with the X-ray powder diffraction spectrum shown in Figure 8; iii) a differential scanning calorimetry (DSC) that has an endotherm at a temperature of between about 83°C to about 87°C; iv) a differential scanning calorimetry thermogram substantially as shown in Figure 7; and v) a thermogravimetric analysis (TGA) diagram substantially the same as that shown in Figure 7. 23. Crystalline toluene solvate according to claim 11, characterized in that the molar ratio of (S)-afoxolaner to toluene is about 1:1. 24. Crystalline toluene solvate according to claim 11, characterized in that the crystalline toluene solvate (S)-afoxolaner is isolated. 25. Crystalline toluene solvate according to claim 11, characterized in that at least 90% of (S)-afoxolaner by weight is in a crystalline toluene solvate form. 26. Crystalline toluene solvate according to claim 11, characterized in that at least 80% of (S)-afoxolaner by weight is in a crystalline toluene solvate form. 27. Crystalline toluene solvate according to claim 117, characterized in that at least 70% of (S)-afoxolaner by weight is a crystalline toluene solvate form. 28. Crystalline toluene solvate according to claim 11, characterized in that at least 60% of (S)-afoxolaner by weight is in a crystalline toluene solvate form. 29. Pesticide or parasiticide composition characterized by the fact that it comprises crystalline toluene solvate as defined by claim 11, and at least one agriculturally or pharmaceutically acceptable carrier or excipient. 30. Pesticide or parasiticide composition according to claim 29, characterized in that it comprises crystalline toluene solvate as defined by claim 11, wherein said crystalline toluene solvate is in admixture with one or more distinct polymorphic forms and / or an amorphous compound of (S) - afoxolaner. 31. Pesticide or parasiticide composition according to claim 29, characterized by the fact that at least 80% of (S) - afoxolaner is in a crystalline toluene solvate form. 32. Pesticide or parasiticide composition according to claim 29, characterized by the fact that the composition comprises at least 95%, by weight, of the crystalline toluene solvate as defined by claim 11 based on the total weight of compound (S )-afoxolaner in the composition. 33. Pesticide or parasiticide composition according to claim 32, characterized by the fact that the composition comprises at least 98%, by weight, of the crystalline toluene solvate as defined by claim 11 based on the total weight of compound (S )-afoxolaner in the composition. 34. Process for preparing crystalline toluene solvate as defined by claim 11 characterized by the fact that said process comprises crystallizing (S)-afoxolaner from toluene, optionally in the presence of a second solvent. 35. Process, according to claim 34, characterized by the fact that it comprises crystallizing the (S) -afoxolaner from a mixture of toluene and cyclohexane. 36. Process according to claim 35, characterized by the fact that the mixture of toluene and cyclohexane comprises from a ratio of about 50:50 to about 99:1 (v / v) of toluene to cyclohexane. 37. Process according to claim 34 characterized by the fact that it comprises: a) providing a solution of (S)-afoxolaner in toluene, optionally in the presence of a second solvent; b) obtain the crystalline solvate of (S)-afoxolaner from the solution from step a); and c) isolating the crystalline toluene solvate from (S) - afoxolaner. 38. Process according to claim 37, characterized by the fact that the solution of (S)-afoxolaner in toluene, optionally in the presence of a second solvent, is obtained by combining solid (S)-afoxolaner and toluene, optionally in the presence of a second solvent, and heating the combination. 39. Process according to claim 38, characterized by the fact that the combination is heated to a temperature of between about 50° C and about 80° C. 40. Process according to claim 37, characterized by the fact that the crystalline toluene solvate of (S) -afoxolaner is obtained by cooling the solution from step a). 41. Process according to claim 40, characterized by the fact that the solution from step a) is cooled to a temperature below about 20° C. 42. Process according to claim 40, characterized by the fact that the solution from step a) is cooled to a temperature below about 15° C. 43. Process according to claim 40, characterized by the fact that the solution from step a) is cooled to a temperature of about 10° C.