EA041013B1 - METHOD FOR PRODUCING ENANTIOMERICALLY ENRICHED ISOXAZOLINE COMPOUNDS - Google Patents

Description

The field of technology to which the invention belongs

The present invention describes stereoselective methods for obtaining isoxazoline compounds enriched in one enantiomer. The present invention also describes new quinine chiral phase transfer catalysts and methods for preparing new catalysts.

Prior Art

Animals such as mammals and birds are often susceptible to parasitic infestations/infections. Such parasites can be ectoparasites such as insects and endoparasites such as nematodes and other worms. Domesticated animals such as cats and dogs are often infected with one or more of the following ectoparasites:

fleas (eg Ctenocephalides spp. such as Ctenocephalides felis and the like);

parasitiform mites (eg Rhipicephalus spp., Ixodes spp., Dermacentor spp., Amblyoma spp., etc.);

acariform mites (eg Demodex spp., Sarcoptes spp., Otodectes spp., etc.);

lice (eg Trichodectes spp., Cheyletiella spp., Linognathus spp., etc.);

mosquitoes (Aedes spp., Culex spp., Anopheles spp., etc.);

flies (Hematobia spp., Musca spp., StomoKCiis spp., Dermatobia spp., Cochliomyia spp., etc.).

Fleas are a particular problem because not only do they negatively affect the health of the animal or person, but they also cause great psychological stress. Moreover, fleas also transmit pathogenic agents such as tapeworm (Dipylidium caninum) to animals and humans.

Similarly, ticks are also harmful to the physical and/or psychological health of an animal or human. However, the most serious problem associated with ticks is that they are carriers of pathogenic agents that affect both humans and animals. Major diseases that can be transmitted by ticks include borreliosis (Lyme disease caused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused by Babesia spp.) and rickettsiosis (eg Rocky Mountain spotted fever). Ticks also release toxins that cause inflammation or paralysis in the host. Sometimes these toxins can be fatal to the host.

Similarly, farm animals are also susceptible to parasitic infestations. For example, cattle can become victims of a large number of parasites. The dominant parasite of cattle are ticks of the genus Rhipicephalus (Boophilus), especially those of the species microplus (ringed tick), decoloratus and annulatus. Ticks such as Rhipicephalus (Boophilus) microplus are difficult to control because they live in pastures for farm animals.

Animals and humans also suffer from endoparasitic infections, including, for example, helminthiasis, caused by a group of parasitic worms classified as cestodes (tapeworms), nematodes (roundworms) and flukes (flatworms or flukes). These parasites negatively affect animal nutrition and cause great economic losses in raising pigs, sheep, horses and cattle, as well as negatively affecting domestic animals and poultry. Other parasites found in the gastrointestinal tract of animals and humans include members of the genus Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichiris, Enterobius, and parasites that are found in the blood or other tissues and organs, such as filarial worms and additional intestinal stages of Strogyloides, Toxocara and Trichinella.

Recently, isoxazole- and isoxazoline-containing compounds have been shown to be effective against parasites that infect animals. For example, US Pat. Nos. 7,964,204 and 8,410,153 (DuPont, both incorporated herein by reference) describe isoxazoline compounds having the following formula (I) that exhibit activity against ectoparasites.

A particularly active isoxazoline compound, 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2 ,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide, known by the generic name afoxolaner. Afoxolaner has the following chemical structure:

- 1 041013

Other isoxazoline compounds that have shown high activity against parasitic insects and arachnids are known under the patent names fluralaner (see US patent 7662972, which is incorporated herein by reference), sarolaner (see US patent 846615, which is incorporated herein by reference). ) and Lotilaner (see, for example, US Pat. No. 8,383,659, which is incorporated herein by reference). The structures of these compounds are shown below:

Lotilaner

In addition, published patent applications US 2010/0254960 A1, WO 2007/070606 A2, WO 2007/123855 A2, WO 2010/003923 A1, US 7951828 & US 7662972, US 2010/0137372 A1, US 2010/017 US 2011/0086886 A2, US 2011/0059988 A1, US 2010/0179195 A1 and WO 2007/075459 A2, and US Pat. No. 7,951,828 (all incorporated herein by reference) describe various other parasiticidal isoxazoline compounds.

It is known in the art that isoxazoline compounds containing a chiral quaternary carbon atom, such as the carbon atom adjacent to the oxygen in the isoxazoline ring of the compounds described above, have at least two optical isomers (enantiomers) that are mirror images of each other. In addition, in the case of biologically active compounds, sometimes one of the enantiomers is more active than the other enantiomer. In addition, in the case of biologically active compounds, sometimes one of the enantiomers is less toxic than the other enantiomer. Therefore, in the case of optically active compounds, it is desirable to use the enantiomer that is more active and less toxic (eutomer). However, isolating the most active enantiomer from the mixture can be expensive and result in the disposal of up to half of the resulting racemic product.

Methods are described for the preparation of certain enantiomer-enriched isoxazoline compounds using certain phase transfer catalysts based on cinchon alkaloids. For example, US 2014/0206633 A1, US 2014/0350261 A1, WO 2013/116236 Al and WO 2014/081800 A1 (incorporated herein by reference) describe the synthesis of certain enantiomer-rich isoxazoline active ingredients using phase transfer catalysts based on cinchona

- 2 041013 alkaloids. In addition, Matoba et al., Angew. Chem. 2010, 122, 5898-5902 describes the chiral synthesis of certain pesticidal isoxazoline active ingredients. However, these documents do not describe the methods and catalysts described in this text.

Inclusion by reference

Any of the aforementioned applications and all documents cited in or in the course of their consideration (documents cited in the application), and all documents or references in documents cited in the application, and all documents cited or referred to in this document (“documents cited in this document"), and all documents cited or referenced in documents cited herein, together with all manufacturer's instructions, descriptions, datasheets and product data sheets for any products cited in this document or in any document included by reference herein are incorporated herein by reference and may be used in the practice of the invention.

Citation or mention of any document in this application is not an admission that such document is considered prior art for the present invention.

Brief description of the invention

The present invention relates to processes for the preparation of enantiomerically enriched antiparasitic isoxazoline compounds and novel phase transfer catalysts that can be used in these processes. In one embodiment, the present invention describes a process for preparing an isoxazoline compound having the following formula (I) that is enriched in one enantiomer

(I) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined herein and where the asterisk means that the carbon atom is a chiral quaternary carbon atom;

comprising the reaction of a compound having the formula (II)

(P) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a base and a chiral phase transfer catalyst having formula (IIIa) or (IIIb )

(Sha) (Wh) where R is aryl or heteroaryl substituted with one or more aralkoxy, amino, alkylamino or dialkylamino groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl; and X is a counterion, including a halogen, mesylate, tosylate, triflate, brosylate, nonylate, tresylate counterion, and the like.

It has been shown that the (S)-enantiomer of antiparasitic compounds having formula (I) is more

- 3 041013 is more active against ectoparasites (eg fleas and ticks) than the (R)-enantiomer. The (S)-enantiomer of the compounds described herein is formed as the main product when using a phase transfer catalyst having formula (IIIa), and the (R)-enantiomer is formed as the main product when using (IIIb).

In another embodiment of the present invention, the present invention describes a method for producing an isoxazoline compound having formula IA, where X ¹ , X ² and X ³ each independently represent H, halogen, C ₁ -C ₃ -alkyl or C ₁ -C ₃ -haloalkyl, which is enriched in the (S) enantiomer

comprising the reaction of a compound having the formula (IIA)

water, a water-immiscible organic solvent, a base, and a chiral phase transfer catalyst having the formula (IIIa)

where R is aryl or heteroaryl optionally substituted with one or more C1C ₃ alkoxy groups, amino groups, alkylamino groups, dialkylamino groups or aralkoxy groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group , W is ethyl or vinyl, and X is an anion.

In other embodiments, the present invention describes methods for preparing the following compounds enriched in the (S)-enantiomer using a chiral phase transfer catalyst having formula (IIIa)

- 4 041013

ci(S)-ID-l

In another embodiment of the present invention, isoxazoline compounds having formula (I) enriched in the (S)-enantiomer obtained using a chiral phase transfer catalyst having formula (IIIa) are purified and further enriched in the (S)-enantiomer by crystallization using aromatic solvent, including (but not limited to), toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, and mesitylene.

In other embodiments, the present invention describes parasiticidal veterinary compositions comprising compounds having formula (I) enriched in the (3)-enantiomer, and methods and uses of said compounds and compositions for the treatment and prevention of parasitic infestations and infections in animals. Also within the scope of the present invention are agricultural compositions, methods and uses comprising compounds of formula (I) enriched in the (3)-enantiomer for controlling animal pests and protecting crops and plants from these pests.

In another embodiment, the present invention describes a novel and innovative phase transfer catalyst having formula (IIIa-13-1), formula (IIIa-13-2), formula (IIIa-13-3), or formula ( Sha-13-4), or a mixture of any of these catalysts

where X is a counterion. In one embodiment of the catalysts having the formula (IIIa13-1), (IIIa-13-2), (IIIa-13-3) or (IIIa-13-4), X is a halogen counterion such as chloride.

In another embodiment, the present invention describes novel and innovative methods for preparing the chiral phase transfer catalysts described herein.

It is the object of the present invention not to include any previously known product, method of preparation or method of using a product in the present invention, so Applicants retain and waive rights to any previously known product, method or method. It should also be noted that the present invention does not include within its scope any product, method of making a product, or method of using a product that does not conform to the written description and requirements of the USPTO (35 U.S.C. §112, first paragraph) or EPO (Article 83 in EPC) so that Applicants retain and waive rights to any previously known product, method of making a product, or method of using a product.

These and other embodiments are described in, or appear to follow from, the following detailed description.

Brief description of the drawings

The following detailed description, given by way of example and not limiting the present invention to the particular embodiments described, will be better understood in conjunction with the accompanying drawings.

Fig. 1 is the 1H NMR spectrum of the chiral phase transfer catalyst (IIIa-131) prepared in Example 1.

Fig. 2 is the LCMS (HPLC-Mass) spectrum of the chiral phase transfer catalyst (IIIa-13-1) prepared in Example 1.

Fig. 3 is the 1H NMR spectrum of the (S)-afoxolaner-toluene solvate prepared in Example 7 in DMSO-I6.

Fig. 4 is the 1H NMR spectrum of afoxolaner (racemic) in DMSO-66.

Fig. 5 is a chiral HPLC chromatogram of afoxolaner using the HPLC method described in Example 3.

Fig. 6 is a chiral HPLC chromatogram of the (S)-αfoxolanerα obtained in Example 7, recorded using the HPLC method described in Example 3.

In FIG. 7 shows the combined TGA and DSC profiles of the (S)afoxolaner-toluene crystalline solvate described in Example 12.

In FIG. 8 shows an X-ray powder diffraction pattern for the crystalline (S)-afoxolaner toluene solvate described in Example 12.

In FIG. 9 shows the structure of the crystalline solvate of (S)-afoxolaner-toluene determined by X-ray diffraction analysis.

In FIG. 10 shows the molecular structure of (S)-afoxolaner obtained using the Cerius 2 program.

Detailed description

In the first aspect, the present invention describes a method for producing an isoxazoline compound having the following formula (I) which is enriched in one enantiomer

Where

B ¹ , B ² , B ³ 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;

R ¹ is C ₁ -C ₃ alkyl or C ₁ -C ₃ haloalkyl;

Y is optionally substituted phenylene, naphthylene, indanylene, 5- or 6-membered heteroarylene, or 8-10-membered fused heterobicyclylene, where the optional substituents are selected from the group consisting of halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy groups, alkylthio groups, haloalkylthio groups, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino groups, dialkylamino groups, -CN or -NO2 and NH2-C(=S)-;

Q is T-NR2R ³ , (-CH ₂ -)(-CH ₂ -)NR ³ , OH, NH2, alkoxy, haloalkoxy, alkylamino, haloalkylamino, dialkylamino, halodialkylamino a group, a thiol, an alkylthio group, a haloalkylthio group, an alkylsulfinyl, a haloalkylsulfinyl, an alkylsulfonyl, a haloalkylsulfonyl, or an optionally substituted 5- or 6-membered carbocyclyl, heterocyclyl, or heteroaryl ring;

T is (ODp, CH(CH3), CH(CN), C(=O) or C(=S);

R ² is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;

R ³ is H, OR ⁷ , NR8R ⁹ or Q ¹ ; or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl, each of which is optionally substituted with one or more substituents independently selected from R ⁴ ; or

R ² and R ³ are combined with the nitrogen atom to which they are attached to form a ring containing 2-6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, where the specified ring is optionally substituted with 1- 4 substituents independently selected from the group consisting of alkyl, halogen, -CN, -NO ₂ and alkoxy;

each R ⁴ is independently halogen; alkyl, cycloalkyl, alkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, haloalkylamino, dialkylamino, dihaloalkylamino, cycloalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl, dihaloalkylaminocarbonyl, hydroxy, -NH ₂ , -CN or -NO ₂ ; or Q ² ;

each R ⁵ is independently halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, -CN, or -NO ₂ ;

each R ⁶ is independently halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, -CN , -NO ₂ , phenyl or pyridinyl;

R ⁷ is H; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more halogen atoms;

R ⁸ is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;

R ⁹ is H; ^Q3 ; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more substituents independently selected from R ⁴ ; or

R ⁸ and R ⁹ are combined with the nitrogen atom to which they are attached to form a ring containing 2-6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, where the specified ring is optionally substituted with 1- 4 substituents independently selected from the group consisting of alkyl, halogen, -CN, -NO ₂ and alkoxy;

Q ¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-, or 10-membered fused bicyclic system optionally containing 1-3 heteroatoms selected from up to 1 O atom, up to 1 S atom, and up to 3 atoms N, each ring or ring system is optionally substituted with one or more substituents independently selected from R ⁵ ;

Q ² is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring is optionally substituted with one or more substituents independently selected from R ⁶ ;

Q ³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring is optionally substituted with one or more substituents independently selected from R ⁶ ; and n is 1, 2 or 3;

where the asterisk means that the given carbon atom is a quaternary carbon atom;

comprising the reaction of a compound having the formula (II)

(P) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a base and a chiral phase transfer catalyst having formula (IIIa) or (IIIb )

- 8 041013

(Sha) (IIb) where R is aryl or heteroaryl substituted with one or more aralkoxy, amino, alkylamino or dialkylamino groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl; and X is an anion. In the structures (IIIa) and (IIIb) 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 counterion, and the like.

In one embodiment, the present invention describes a process for preparing an isoxazoline compound having formula (I) above that is enriched in one enantiomer, which comprises reacting a compound having formula (II) above with hydroxylamine in the presence of water, a base, and a chiral catalyst. interfacial transfer having the formula (IIIa) or (IIIb); and isolating the product by crystallization.

In another embodiment, the present invention describes a process for preparing an isoxazoline compound having the above formula (I) which is enriched in one enantiomer, which comprises reacting a compound having the above formula (II) with hydroxylamine in the presence of water, a base and a chiral catalyst. interfacial transfer having the formula (IIIa) or (IIIb); and isolating the product by crystallization from the aromatic solvent or solvent mixture containing the aromatic solvent.

In another embodiment, the present invention describes a process for preparing an isoxazoline compound having the above formula (I) which is enriched in one enantiomer, which comprises reacting a compound having the above formula (II) with hydroxylamine in the presence of water, a base and a chiral catalyst. interfacial transfer having the formula (IIIa) or (IIIb); and isolating the product by crystallization from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene, or combinations thereof, or from a solvent mixture containing one or more of said solvents.

The chiral phase transfer catalyst having formula (IIIa) or (IIIb) used in the present invention is a very important factor in achieving the highest possible enrichment in the target enantiomer. It has been unexpectedly found that when R in formula (IIIa) or (IIIb) is an aryl substituent, including a phenyl group, the type of substituent and the degree of substitution have a significant effect on the stereoselectivity of the reaction. Although quinine phase transfer catalysts are known and have been used to prepare chiral isoxazoline compounds (see, for example, WO 2011/104089 A1, which is incorporated herein by reference), it has been surprisingly found that certain substituents unexpectedly improve reaction selectivity. It has been found that electron-donating substituents, such as alkoxy groups, on the aryl or heteroaryl group R increase the selectivity in favor of the (S)-enantiomer when (IIIa) is used. In addition, multiple substitution of the aryl or heteroaryl group R with electron donor groups further increases the selectivity of the reaction in favor of the (S)-enantiomer. Of course, if the stereochemistry of the chiral catalyst is reversed and (IIIb) is used, the selectivity is in favor of the (R)-enantiomer.

Those skilled in the art will appreciate that, in some circumstances, mixtures of the phase transfer catalysts described herein can be used to produce enantiomerically enriched isoxazoline compounds. In addition, it should be understood that a certain catalyst (for example, corresponding to formula (IIIa-13-1)) may contain small amounts of other catalysts having a different W (ethyl or vinyl) or R' group (for example, a methoxy group or an atom hydrogen). However, the presence of small amounts of catalysts substituted with other W and R' groups is still acceptable for the preparation of the enantiomerically enriched isoxazoline compounds described herein.

It has been found that by using a quinine phase transfer catalyst having formula (IIIa) or (IIIb) wherein R is a phenyl group thrice substituted with aralkoxy groups, an unexpectedly high selectivity for the formation of chiral isoxazolines is achieved.

- 9 041013 compounds, compared with known quinine phase transfer catalysts, even superior to quinine catalysts in which the group corresponding to R is an aryl group substituted with one or more alkoxy groups. Thus, phase transfer catalysts having formula (IIIa) or (IIIb) where R is a phenyl group substituted with 1, 2, 3, 4, or 5 aralkoxy groups have been found to provide unexpected selectivity in the formation of chiral isoxazoline compounds, having the formula (I), in comparison with known quinine catalysts of phase transfer. In one preferred embodiment, the chiral quinine phase transfer catalysts are substituted with 1, 2, 3, 4 or 5 benzyloxy groups (-OCH ₂ Ph). In a particularly preferred embodiment, the present invention describes chiral quinine phase transfer catalysts having the formula (IIIa), where W is ethyl or vinyl, R' is a methoxy group or a hydrogen atom, and R is 3,4,5 -tris(benzyloxy)phenyl. These catalysts have been shown to provide unexpectedly improved selectivity in the reaction for the preparation of isoxazoline compounds having formula (I) enriched in (S)-enantiomers.

Accordingly, in one embodiment, the present invention describes a process for the enantioselective synthesis of an antiparasitic isoxazoline compound having formula (I) enriched in the enantiomer

(I) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined above, including the reaction of a compound having formula (II)

2 1 ^(P) where B ¹ , B ² , B ³ , R ¹ , Y and Q have the meanings indicated for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst, having the formula (IIIa) or (IIIb)

(Sha) (Wh) where R is aryl or heteroaryl which is substituted with one or more aralkoxy, amino, alkylamino or dialkylamino groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl and X is an anion; and isolating said 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 counterion, or the like. In a preferred embodiment, the compound having formula (I) is isolated by crystallization from an aromatic solvent or solvent mixture containing an aromatic solvent. In one embodiment, a compound having formula (I) is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the compound having formula (I) is crystallized from toluene or from a solvent mixture containing toluene.

- 10 041013

In another embodiment, the present invention describes a process for preparing a mixture of iso-

where the mixture is enriched with (S)-l; And

B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined above for formula (I); comprising the reaction of a compound having formula (II):

where B ¹ , B ² , B ³ , R ¹ , Y and Q have the meanings given for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (Sha) :

where R is aryl or heteroaryl substituted with one or more aralkoxy, amino, alkylamino or dialkylamino groups, R' is a hydrogen atom or a C iC ₃ -alkoxy group, W is ethyl or vinyl, and X is an anion; and isolating said compound. In a preferred embodiment, a compound having formula (I) enriched in the (8)-enantiomer is isolated by crystallization from an aromatic solvent or solvent mixture containing an aromatic solvent. In one embodiment, a compound having formula (I) enriched in the (8)-enantiomer is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a mixture of solvents, containing one of the indicated solvents. In a preferred embodiment, a compound having formula (I) enriched in the (8)-enantiomer is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment, the present invention describes a process for preparing a mixture of isoxazoline compounds having the following formulas (S)-I and (R)-I

- I 041013

where the mixture is enriched with (R)-I, and

B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined above for formula (I); comprising the reaction of a compound having the formula (II)

where B ¹ , B ² , B ³ , R ¹ , Y and Q have the meanings given for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having formula (IIIb)

where R is aryl or heteroaryl substituted with one or more aralkoxy, amino, alkylamino or dialkylamino groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment, the present invention describes a process for preparing a mixture of isoxazoline compounds having the following formulas (S)-I and (R)-I

- 12 041013 where the mixture is enriched with (S)-I; And

B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined above for formula (I); comprising the reaction of a compound having the formula (II)

(II) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

(Sha) where R is aryl or heteroaryl substituted with one or more benzyloxy groups (-OCH ₂ Ph), amino groups, C ₁ -C ₃ alkylamino groups or di-C ₁ -C ₃ alkylamino groups; R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment, the present invention describes a process for synthesizing a mixture of enantiomers having formulas (S)-I and (R)-I, wherein the mixture is enriched in an enantiomer in a weight ratio of from about 55:45 to about 99.9:0.1, (S)- I to (R)-I. In another embodiment, the present invention describes a method for synthesizing a mixture of (S)-I and (R)-I enantiomers that is enriched in (S)-I in a weight ratio of from about 65:35 to about 99:1, (S)- I to (R)-I. In another embodiment, the present invention describes a method for synthesizing a mixture of (S)-I and (R)-I enantiomers, wherein the mixture is enriched in (S)-I in a weight ratio of from about 70:30 to about 99:1, from about 80 :20 to about 99:1, or from about 90:10 to about 99:1, (S)-I to (R)-I.

In another embodiment, the present invention describes a process for synthesizing a mixture of (S)-I and (R)-I enantiomers, wherein the mixture is enriched in (S)-I in a weight ratio of about 85:15 to about 95:5, (S) -I to (R)-I. In another embodiment, the present invention describes a process for synthesizing a mixture of (S)-I and (R)-I enantiomers, wherein the mixture is enriched in (S)-I in a weight ratio of from about 87:13 to about 93:7, (S) -I to (R)-I. In another embodiment, the present invention describes a process for synthesizing a mixture of (S)-I and (R)-I enantiomers, wherein the mixture is enriched in (S)-I in a weight ratio of 95:5 to 99:1, (S)-I to (R)-I.

In another embodiment, the present invention describes a process for preparing an isoxazoline compound having the formula (S)-I in substantially pure enatiomeric form (>99:1, (S)-I to (R)-I)

(5)-1

- 13 041013 where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined above for formula (I); comprising the reaction of a compound having the formula (II)

(II) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

(Sha) where R is aryl or heteroaryl substituted with one or more benzyloxy (OCH ₂ Ph) groups, W is ethyl or vinyl, R' is a hydrogen atom or a C1C ₃ alkoxy group, and X is an anion; and isolating the product by crystallization from the aromatic solvent or solvent mixture containing the aromatic solvent. In one embodiment, a compound having formula (S)-I is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. . In a preferred embodiment, the compound having formula (S)-I is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment, isolation of the product by crystallization from the aromatic solvent results in the isolation of the crystalline solvate solid form of the desired enantiomer with the aromatic solvent, which provides an unexpected isolation of the desired enantiomer in pure form from the reaction mixture, since the racemic compound does not form a solvate form.

In one embodiment of this process, R in formula (IIIa) or (IIIb) is aryl or heteroaryl substituted with one aralkoxy group. In another embodiment, R is aryl or heteroaryl substituted with two aralkoxy groups. In another embodiment, R is aryl or heteroaryl substituted with three aralkoxy groups. In 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.

In another embodiment of this method, R in formula (IIIa) or (IIIb) is aryl or heteroaryl substituted with one benzyloxy group (-OCH2Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is aryl or heteroaryl substituted with two benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is aryl or heteroaryl substituted with three benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is aryl or heteroaryl substituted with four benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is aryl or heteroaryl substituted with five benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

In another embodiment of this process, R in formula (IIIa) or (IIIb) is phenyl substituted with one aralkoxy group. In another embodiment, R is phenyl substituted with two aralkoxy groups. In another embodiment, R is phenyl substituted with three aralkoxy groups. In another embodiment, R is phenyl substituted with four aralkoxy groups. In another embodiment, R is phenyl substituted with five aralkoxy groups.

- 14 041013

In another embodiment of said method, R in formula (IIIa) or (IIIb) is

In another embodiment of this method, R in formula (IIIa) or (IIIb) is phenyl substituted with one benzyloxy group (-OCH2Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with two benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with three benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with four benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with five benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

In another embodiment of this process, R in formula (IIIa) or (IIIb) is naphthyl substituted with one aralkoxy group. In another embodiment, R is naphthyl substituted with two aralkoxy groups. In another embodiment, R is naphthyl substituted with three aralkoxy groups. In another embodiment, R is naphthyl substituted with four aralkoxy groups. In another embodiment, R is naphthyl substituted with five aralkoxy groups.

In another embodiment of this method, R in formula (IIIa) or (IIIb) is naphthyl substituted with one benzyloxy group (-OCH2Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is naphthyl substituted with two benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is naphthyl substituted with three benzyloxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is naphthyl substituted with four benzyloxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is naphthyl substituted with five benzyloxy groups and R' is a hydrogen atom or a methoxy group.

In another embodiment of this process, R in formula (IIIa) or (IIIb) is anthracenyl substituted with one aralkoxy group. In another embodiment, R is anthracenyl substituted with two aralkoxy groups. In another embodiment, R is anthracenyl substituted with three aralkoxy groups. In another embodiment, R is anthracenyl substituted with four aralkoxy groups. In another embodiment, R is anthracenyl substituted with five aralkoxy groups.

In another embodiment of this method, R in formula (IIIa) or (IIIb) is anthracenyl substituted with one benzyloxy group (-OCH2Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is an anthracenyl substituted with two benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is an anthracenyl substituted with three benzyloxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is an anthracenyl substituted with four benzyloxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is an anthracenyl substituted with five benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

In another embodiment of this process, R in formula (IIIa) or (IIIb) is pyridyl substituted with one aralkoxy group. In another embodiment, R is pyridyl substituted with two aralkoxy groups. In another embodiment, R is pyridyl substituted with three aralkoxy groups. In another embodiment, R is pyridyl substituted with four aralkoxy groups. In another embodiment, R is pyridyl substituted with five aralkoxy groups.

In another embodiment of this method, R in formula (IIIa) or (IIIb) is pyridyl substituted with one benzyloxy group (-OCH2Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is pyridyl substituted with two benzyloxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is pyridyl substituted with three benzyloxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is pyridyl substituted with four benzyloxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is pyridyl substituted with five benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

In another embodiment of this process, R in formula (IIIa) or (IIIb) is pyrimidinyl substituted with one aralkoxy group. In another embodiment, R is pyrimidinyl substituted with two aralkoxy groups. In another embodiment, R is pyrimidinyl substituted with three aralkoxy groups. In another embodiment, R is pyrimidinyl substituted with four aralkoxy groups. In another embodiment, R is pyrimidinyl substituted with five aralkoxy groups.

In another embodiment of this method, R in formula (IIIa) or (IIIb) is pyrimidinyl substituted with one benzyloxy group (-OCH2Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is a pyrimidinyl substituted with two benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is a pyrimidinyl substituted with three benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is a pyrimidinyl substituted with four benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is a pyrimidinyl substituted with five benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

In another embodiment of this process, R in formula (IIIa) or (IIIb) is quinolinyl substituted with one aralkoxy group. In another embodiment, R is quinolinyl substituted with two aralkoxy groups. In another embodiment, R is quinolinyl substituted with three aralkoxy groups. In another embodiment, R is quinolinyl substituted with four aralkoxy groups. In another embodiment, R is quinolinyl substituted with five aralkoxy groups.

In another embodiment of this method, R in formula (IIIa) or (IIIb) is quinolinyl substituted with one benzyloxy group (-OCH2Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is quinolinyl substituted with two benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is quinolinyl substituted with three benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is quinolinyl substituted with four benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is quinolinyl substituted with five benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

In another embodiment of said method, R in formula (IIIa) or (IIIb) is quinolin-4yl substituted with one aralkoxy group. In another embodiment, R is quinolin-4-yl substituted with two aralkoxy groups. In another embodiment, R is quinolin-4-yl substituted with three aralkoxy groups. In 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.

In another embodiment of this method, R in formula (IIIa) or (IIIb) is quinolin-4yl substituted with one benzyloxy group (-OCH ₂ Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is quinolin-4-yl substituted with two benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is quinolin-4-yl substituted with three benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is quinolin-4-yl substituted with four benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is quinolin-4-yl substituted with five benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

In another embodiment of this process, R in formula (IIIa) or (IIIb) is isoquinolinyl substituted with one aralkoxy group. In another embodiment, R is isoquinolinyl substituted with two aralkoxy groups. In another embodiment, R is isoquinolinyl substituted with three aralkoxy groups. In another embodiment, R is isoquinolinyl substituted with four aralkoxy groups. In another embodiment, R is isoquinolinyl substituted with five aralkoxy groups.

In another embodiment of this method, R in formula (IIIa) or (IIIb) is isoquinolinyl substituted with one benzyloxy group (-OCH2Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is isoquinolinyl substituted with two benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is isoquinolinyl substituted with three benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is isoquinolinyl substituted with four benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is isoquinolinyl substituted with five benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

- 16 041013

In another embodiment of this process, R in formula (IIIa) or (IIIb) is acridinyl substituted with one aralkoxy group. In another embodiment, R is acridinyl substituted with two aralkoxy groups. In another embodiment, R is acridinyl substituted with three aralkoxy groups. In another embodiment, R is acridinyl substituted with four aralkoxy groups. In another embodiment, R is acridinyl substituted with five aralkoxy groups.

In another embodiment of this method, R in formula (IIIa) or (IIIb) is acridinyl substituted with one benzyloxy group (-OCH2Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is an acridinyl substituted with two benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is an acridinyl substituted with three benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is an acridinyl substituted with four benzyloxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is an acridinyl substituted with five benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

In another embodiment of this process, R in formula (IIIa) or (IIIb) is acridine-9yl substituted with one aralkoxy group. In another embodiment, R is acridin-9-yl substituted with two aralkoxy groups. In another embodiment, R is acridin-9-yl substituted with three aralkoxy groups. In 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.

In another embodiment of this method, R in formula (IIIa) or (IIIb) is acridine-9yl substituted with one benzyloxy group (-OCH2Ph) and R' is a hydrogen atom or a methoxy group. In another embodiment, R is acridin-9-yl substituted with two benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is acridin-9-yl substituted with three benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is acridin-9-yl substituted with four benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is acridin-9-yl substituted with five benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

In another embodiment of said process, R in formula (IIIa) or (IIIb) is phenyl, naphthyl, anthracenyl, pyridyl, pyrimidinyl, quinolinyl, quinolin-4-yl, isoquinolinyl, acridinyl, or acridin-9-yl substituted with one amino- group, C ₁ -C ₃ -αkylamino group or di-C ₁ -C ₃ -alkylamino group, and R' represents a hydrogen atom or a methoxy group. In another embodiment, R is phenyl, naphthyl, anthracenyl, pyridyl, pyrimidinyl, quinolinyl, quinolin-4-yl, isoquinolinyl, acridinyl, or acridin-9-yl substituted with two amino groups, C ₁ -C ₃ alkylamino groups, or di-C ₁ -C3-alkylamino groups, and R' represents a hydrogen atom or a methoxy group. In another embodiment, R is phenyl, naphthyl, anthracenyl, pyridyl, pyrimidinyl, quinolinyl, quinolin-4-yl, isoquinolinyl, acridinyl, or acridin-9-yl substituted with three amino groups, C ₁ -C ₃ -alkylamino- groups or di-C ₁ -C ₃ -alkylamino groups, and R' represents a hydrogen atom or a methoxy group. In another embodiment, R is phenyl, naphthyl, anthracenyl, pyridyl, pyrimidinyl, quinolinyl, quinolin-4-yl, isoquinolinyl, acridinyl, or acridin-9-yl substituted with four amino groups, C ₁ -C ₃ -alkylamino- groups or di-C ₁ -C ₃ alkylamino groups, and R' represents a hydrogen atom or a methoxy group. In another embodiment, R is phenyl, naphthyl, anthracenyl, pyridyl, pyrimidinyl, quinolinyl, quinolin-4-yl, isoquinolinyl, acridinyl, or acridin-9-yl substituted with five amino groups, Ο ₁ -Ο ₃ alkylamino groups or di-C ₁ -C ₃ -alkylamino groups, and R' represents a hydrogen atom or a methoxy group.

In another embodiment of said process, R in formula (IIIa) or (IIIb) is phenyl substituted with one amino group, C ₁ -C ₃ alkylamino or di-C ₁ -C ₃ alkylamino, and R ' represents a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with two amino groups, C ₁ -C ₃ -alkylamino groups or du-C ₁ -C ₃ alkylamino groups, and R' represents a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with three amino groups, C ₁ -C ₃ alkylamino groups, or di-C ₁ -C ₃ alkylamino groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with four amino groups, C ₁ -C ₃ alkylamino groups, or di-C ₁ -C ₃ alkylamino groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with five amino groups, C ₁ -C ₃ alkylamino groups, or di-C ₁ -C ₃ alkylamino groups, and R' is a hydrogen atom or a methoxy group.

In one embodiment of the present invention, B ¹ , B ² , B ³ in compounds having formula (I) or formula (II) are CR and each R is independently H,

- 17 041013 halogen, C1-C6 alkyl or C1-C ₆ haloalkyl. In another embodiment, B ¹ , B ² , B ³ in formula (I) or formula (II) are CR and each R is independently H, halo, C1-C3 alkyl, or C1-C3 haloalkyl. In one embodiment, B ¹ , B ² , B ³ in formula (I) or formula (II) are CR and each R is independently H, Cl, F, C1-C3 alkyl or C1C ₃ fluoroalkyl. In another embodiment, B ¹ , B ² , B ³ in formula (I) or formula (II) are CR and each R is independently H, Cl, F, or CF3.

In one embodiment of the present invention, Y in formula (I) and formula (II) is an optionally substituted phenylene. In another embodiment, Y is an optionally substituted 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 another embodiment, Y is an optionally substituted bicyclic heteroarylene containing 1, 2 or 3 atoms selected from S, N and O.

In another embodiment of said method of the present invention, Y is selected from Y-1, Y-2, Y-3, Y4, where Z is a nitrogen atom or CH, Y-5 or Y-6

In one embodiment of the present invention, the Q group in formula (I) or formula (II) is T-NR2R ³ . In another embodiment, Q is T-NR ² R ³ where R ² is H or C1-C3 alkyl and R ³ is C1-C3 alkyl optionally having an R ⁴ substituent. In another embodiment, Q is T-NR2R ³ where R ² is H and R ³ is C1-C3 alkyl optionally substituted with 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 where R ² is H and R ³ is C1-C3 alkyl optionally substituted with alkylthio, haloalkylthio, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylaminocarbonyl, or dihaloalkylaminocarbonyl . In another embodiment, Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ . In another embodiment, Q is -C(O)CH ₂ S(O) ₂ CH ₃ . In another embodiment, Q is -C(O)NHCH ₂ CH ₂ SCH ₃ . In another embodiment, Q is a (-CH2-)(-CH2-)N(CO)CH2S(O)2CH3 group.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3;

B ² represents CH, C-Cl or CF;

R ¹ is CF3,

Y is Y-l, Y-2, Y-4 or Y-5; And

Q is -C(O)-NR ² R ³ where R ² is H and R ³ is C1-C ₃ alkyl optionally substituted with alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylaminocarbonyl or dihaloalkylaminocarbonyl; comprising the reaction of a compound having the formula (II)

- 18 041013

(Π) where B ¹ , B ² , B ³ , R ¹ , Y and Q have the meanings given for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

(Sha) where R is aryl or heteroaryl substituted with one or more benzyloxy (OCH ₂ Ph) groups, W is ethyl or vinyl, R' is a hydrogen atom or a C ₁ C ₃ alkoxy group, and X is anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3;

B ² represents CH, C-Cl or CF; R ¹ is CF ₃ ,

Y is Y-1, Y-2, Y-4 or Y-5; And

Q is -C(O)-NR ² R ³ , where R ² is H and R ³ is C1-C ₃ alkyl optionally substituted with C _g C ₃ alkylthio, C ₁ -C ₃ haloalkylthio -group, C1- _C3 alkylsulfinyl, _C1 - _C3 haloalkylsulfinyl, C1- _C3 alkylsulfonyl, _C1 - _C3 haloalkylsulfonyl, C1- _C3 alkylaminocarbonyl, C1- _C3 dialkylaminocarbonyl, C1- _C3 haloalkylaminocarbonyl or C ₁ -C ₃ dihaloalkylaminocarbonyl; comprising the reaction of a compound having the formula (II)

(II) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

- 19 041013

(Sha) where R is 3,4,5-tris(benzyloxy)phenyl;

W is ethyl or vinyl, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3;

B ² represents CH, C-Cl or CF; R ¹ is CF3;

Y is Y-1, Y-2, Y-4 or Y-5; And

Q is -C(O)CH2S(O)2CH3, -C(O)NHCH2CH2SCH3 or -C(O)NHCH2C(O)NHCH2CF3; comprising the reaction of a compound having the formula (II)

(II) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

(Sha) where R is aryl or heteroaryl substituted with one or more benzyloxy (-OCH ₂ Ph) groups, W is ethyl or vinyl, R' is a hydrogen atom or a C ₁ -C ₃ -alkoxy group, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

- 20 041013

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3;

B ² represents CH, C-Cl or CF; R ¹ is CF ₃ ,

Y is Y-1, Y-2, Y-4 or Y-5; And

Q is -C(O)CH ₂ S(O) ₂ CH ₃ , -C(O)NHCH ₂ CH ₂ SCH ₃ , or -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ ; comprising the reaction of a compound having the formula (II)

(II) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

(Sha) where R is 3,4,5-tris(benzyloxy)phenyl;

W is ethyl or vinyl, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3;

B ² is CH or CF;

R ¹ is CF ₃ ;

Y is Y-2; And

Q is -C(O)-NR ² R ³ where R ² is H and R ³ is C ₁ -C ₃ alkyl optionally substituted with alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl , alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylaminocarbonyl or dihaloalkylaminocarbonyl; comprising the reaction of a compound having the formula (II)

(II) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

- 21 041013

where R is aryl or heteroaryl substituted with one or more benzyloxy (-OCH ₂ Ph) groups, W is ethyl or vinyl, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, and X is an anion ; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3; B ² is CH or CF;

R ¹ is CF ₃ ,

Y is Y-2; And

Q is -C(O)-NR ² R ³ where R ² is H and R ³ is C ₁ -C ₃ alkyl optionally substituted with alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl , alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylaminocarbonyl, which reacts a compound having formula (II), or dihaloalkylaminocarbonyl; including

where B ¹ , B ² , B ³ , R ¹ , Y and Q have the meanings given for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having formula (IIIa)

where R is aryl or heteroaryl substituted with one or more C1- _C3 alkoxy groups, W is ethyl or vinyl, R' is a hydrogen atom or a C1- _C3 alkoxy group, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3;

B ² is CH or CF;

R ¹ is CF ₃ ,

Y is Y-2; And

Q is -C(O)-NR ² R ³ where R ² is H and R ³ is C1-C ₃ alkyl optionally substituted with C ₁ -C ₃ alkylthio, C ₁ -C ₃ - haloalkylthio, C1- _C3 alkylsulfinyl, _C1 - _C3 haloalkylsulfinyl, C1- _C3 alkylsulfonyl, C1- _C3 haloalkylsulfonyl, _C1 - _C3 alkylaminocarbonyl, C1- _C3 dialkylaminocarbonyl, _C1 -C ₃ -haloalkylaminocarbonyl or C1- _C3 dihaloalkylaminocarbonyl; comprising the reaction of a compound having the formula (II)

(II) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

(Sha) where R is 3,4,5-tris(benzyloxy)phenyl;

W is ethyl or vinyl, R' is a hydrogen atom or a C1- _C3 alkoxy group, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3;

B ² is CH or CF;

R ¹ is CF ₃ ,

Y is Y-2; And

Q is -C(O)-NR ² R ³ where R ² is H and R ³ is C1-C ₃ alkyl optionally substituted with C ₁ -C ₃ alkylthio, C ₁ -C ₃ - haloalkylthio, CpC ₃ alkylsulfinyl, C 1 -C ₃ haloalkylsulfinyl, C ₁ -C ₃ -alkylsulfonyl, C 1 -C ₃ haloalkyl sulfonyl, C 1 -C ₃ alkylaminocarbonyl, C 1 -C ₃ dialkylaminocarbonyl, C 1 -C ₃ haloalkylaminocarbonyl or C 1 - With ₃ dihaloalkylaminocarbonyl; comprising the reaction of a compound having the formula (II)

- 23 041013 where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

where R is a phenyl ring independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups;

W is ethyl or vinyl, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3;

B ² is CH or CF;

R ¹ is CF ₃ ,

Y is Y-2; And

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

comprising the reaction of a compound having the formula (II)

^R1-

Q (P) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having formula (IIIa)

- 24 041013

where R is aryl or heteroaryl substituted with one, two or three C ₁ -C ₃ alkoxy groups, W is ethyl or vinyl, R' is a hydrogen atom or a C 1 -Q alkoxy group, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3;

B ² is CH or CF;

R ¹ is CF ₃ ,

Y is Y-2; And

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

comprising the reaction of a compound having the formula (II)

G ¹ o

II

--Q

B ³ ^ (II) where B ¹ , B ² , B ³ , R ¹ , Y and Q have the meanings given for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

(Sha) where R is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups;

W is ethyl or vinyl, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF ₃ ;

B ² is CH or CF;

R ¹ is CF ₃ ,

Y is Y-2; And

Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ ;

comprising the reaction of a compound having the formula (II)

^R1-

Q (P) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having formula (IIIa)

where R is aryl or heteroaryl substituted with one, two or three benzyloxy (OCH ₂ Ph) groups, W is ethyl or vinyl, R' is a hydrogen atom or a C1C ₃ alkoxy group, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment of the present invention, a method for synthesizing a compound having formula (I) enriched in the (S)-enantiomer is described, wherein

B ¹ and B ³ are independently C-Cl or C-CF3;

B ² is CH or CF;

R ¹ is CF ₃ ,

Y is Y-2; And

Q is -C(O)NHCH ₂ C(O)NHCH ₂ CF ₃ or -C(O)NHCH ₂ CH ₂ SCH ₃ ;

comprising the reaction of a compound having the formula (II)

^R1 ~

Q (P) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having formula (IIIa)

- 26 041013

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

W is ethyl or vinyl, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

As described above, the antiparasitic compounds afoxolaner, fluralaner, sarolaner and lotilaner all have an asymmetric quaternary carbon atom in the isoxazoline ring. One of the enantiomers of each of these compounds is significantly more active against ectoparasites such as fleas and ticks than the other enantiomer. In the case of afoxolaner, the (S)-enαantiomer is the more active enantiomer. Sarolaner is the pure (3)-enantiomer, lotilaner is the pure (3)-enantiomer, and the (S)-enantiomer of fluralaner is considered to be the more active enantiomer.

Thus, in a second aspect, the present invention describes a process for preparing an isoxazoline compound having the formula IA, wherein X ¹ , X ² and X ³ are each independently H, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ -haloalkyl, which is enriched in the (S)-enantiomer

comprising the reaction of a compound having the formula (IIA)

water, a water-immiscible organic solvent, a base, and a chiral phase transfer catalyst having the formula (IIIa)

- 27 041013

where R is aryl or heteroaryl optionally substituted with one or more C ₁ -C ₃ alkoxy or aralkoxy groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In another embodiment, the present invention describes a process for preparing an isoxazoline compound having the formula IA, wherein X ¹ , X ² and X ³ are each independently H, chlorine, fluorine, or CF3 that is enriched in the (S)-enantiomer

comprising reacting a compound having the formula (IIA) wherein X ¹ , X ² and X ³ are H, chlorine, fluorine, or CF3 with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base, and a chiral phase transfer catalyst having the formula ( IIIa)

where R is aryl or heteroaryl optionally substituted with one or more C ₁ -C ₃

- 28 041013 alkoxy or aralkoxy groups, R' represents a hydrogen atom or a C ₁ -C ₃ -alkoxy group, W represents ethyl or vinyl, and X represents an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment of the process for preparing (S)-IA, R in the catalyst of formula (IIIa) is aryl or heteroaryl substituted with one or more C1- _C6 alkoxy groups. In another embodiment, R is aryl or heteroaryl substituted with 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 with one or more benzyloxy groups.

In another embodiment of the process for preparing a compound of formula IA enriched in the (S) enantiomer, R in the catalyst of formula (IIIa) is phenyl substituted with 1, 2, or 3 C1- _C6 alkoxy groups, and R' is is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy or ethoxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment of the process for preparing a compound of formula IA enriched in the (S) enantiomer, R in the catalyst of formula (IIIa) is phenyl independently substituted at positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group, and W represents a vinyl. In another embodiment, R is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' is a hydrogen atom and W is vinyl. In another embodiment, R is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group, and W represents ethyl. In another embodiment, R is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a hydrogen atom, and W represents ethyl.

In another embodiment of the process for preparing a compound of formula IA enriched in the (S) enantiomer, R in the catalyst of formula (IIIa) is phenyl substituted with 1, 2, or 3 benzyloxy groups, and R' is hydrogen or methoxy. -group. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment of the process for preparing a compound of formula IA enriched in the (S)enantiomer, R in the catalyst of formula (IIIa) is 3,4,5tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents a vinyl. In another embodiment, R is 3,4,5-tris(benzyloxy)phenyl; R' is a hydrogen atom and W is vinyl. In another embodiment, R is 3,4,5 tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents ethyl. In another embodiment, R is 3,4,5-tris(benzyloxy)phenyl; R' represents a hydrogen atom, and W represents ethyl.

In another embodiment, the present invention describes a process for producing afoxolaner enriched in the (S)-enantiomer

- 29 041013

(5)-afoxolaner comprising the reaction of a compound having the formula (IIA-1)

(PA-1) with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base, and a chiral phase transfer catalyst having the formula (IIIa)

(Sha) where R is aryl or heteroaryl optionally substituted with one or more C ₁ -C ₃ alkoxy or aralkoxy groups, R' is a hydrogen atom or a C 1 -C ₃ alkoxy group, W is ethyl or vinyl , and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment of the synthesis of afoxolaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is aryl or heteroaryl substituted with one or more C ₁ -C 6 alkoxy groups. In another embodiment, R is aryl or heteroaryl substituted with 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 with one or more benzyloxy groups.

In another embodiment for the synthesis of afoxolaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 C1-C6 alkoxy groups and R' is hydrogen or methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy or ethoxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment for the synthesis of (S)-enangiomer-enriched afoxolaner, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group, and W represents a vinyl. In another embodiment for the synthesis of afoxolaner enriched in the (S) enantiomer, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' is a hydrogen atom and W is vinyl. In another embodiment for the synthesis of afoxolaner enriched in the (3)-enantiomer, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group, and W represents ethyl. In another embodiment for the synthesis of afoxolaner enriched in the (3)-enantiomer, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a hydrogen atom, and W represents ethyl.

In another embodiment for the synthesis of afoxolaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 benzyloxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment for the synthesis of afoxolaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents a vinyl. In another embodiment for the synthesis of afoxolaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' is a hydrogen atom and W is vinyl. In another embodiment for the synthesis of afoxolaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents ethyl. In another embodiment for the synthesis of afoxolaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is 3,4,5tris(benzyloxy)phenyl; R' represents a hydrogen atom, and W represents ethyl.

In another embodiment, the present invention describes a process for preparing an isoxazoline compound having formula IB enriched in the (S)-enantiomer o

(W where X ¹ , X ² and X ³ are each independently H, chlorine, fluorine or CF ₃ ; comprising the reaction of a compound having formula (IIB) o

x ³ (IV) where X ¹ , X ² and X ³ represent H, chlorine, fluorine or CF ₃ , with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having formula (IIIa)

- 31 041013

(Sha) where R is aryl or heteroaryl optionally substituted with one or more C1C ₃ alkoxy amino groups, C ₁ -C ₃ alkylamino groups, C ₁ -C ₃ dialkylamino groups or aralkoxy groups, R ' represents a hydrogen atom or a C ₁ -C ₃ alkoxy group, W represents ethyl or vinyl, and X represents an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment of the process for preparing (S)-IB, R in the catalyst having formula (IIIa) is aryl or heteroaryl substituted with one or more C1-C6 alkoxy groups. In another embodiment, R is aryl or heteroaryl substituted with 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 with one or more benzyloxy groups.

In another embodiment of the process for preparing (S)-IB, R in the catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 C1-C6 alkoxy groups and R' is a hydrogen atom or a methoxy group . In another embodiment, R is phenyl substituted with 1, 2 or 3 methoxy, ethoxy or isopropoxy groups and R' is a hydrogen atom or a methoxy group and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is ethyl. In another embodiment of (S)-IB, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group or a hydrogen atom; and W is vinyl or ethyl.

In another embodiment of the process for preparing (S)-IB, R in the catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is ethyl. In another embodiment of (S)-IB, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a methoxy group or a hydrogen atom; and W is vinyl or ethyl.

In another embodiment, the present invention describes a process for producing fluralaner enriched in the (S)-enantiomer

- 32 041013

ABOUT

Cl

Cl(5)-fluralaner comprising the reaction of a compound having the formula (IIB)

with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base, and a chiral phase transfer catalyst having the formula (IIIa)

where R is aryl or heteroaryl optionally substituted with one or more C1-C3 alkoxy or aralkoxy groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment of the synthesis of fluralaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is aryl or heteroaryl substituted with one or more C1-C6 groups. In another embodiment, R is aryl or heteroaryl substituted with 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 with one or more benzyloxy groups.

In another embodiment of the process for preparing fluralaner enriched in the (3)-enantiomer, R in the catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 C1-C6 alkoxy groups. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is ethyl. In a different

- 33 041013 embodiment, R is phenyl substituted with 1, 2 or 3 methoxy, ethoxy or isopropoxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment for synthesizing fluralaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group, and W represents a vinyl. In another embodiment for synthesizing fluralaner enriched in the (S)enantiomer, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' is a hydrogen atom and W is vinyl. In another embodiment for the synthesis of a fluralaner enriched in the (3)-enantiomer, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group, and W represents ethyl. In another embodiment for synthesizing fluralaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a hydrogen atom, and W represents ethyl.

In another embodiment for synthesizing fluralaner enriched in the (S)-enantiomer, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment for synthesizing fluralaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents a vinyl. In another embodiment for synthesizing fluralaner enriched in the (3)-enantiomer, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' is a hydrogen atom and W is vinyl. In another embodiment for synthesizing fluralaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents ethyl. In another embodiment for synthesizing fluralaner enriched in the (S)-enantiomer, R in the catalyst having formula (IIIa) is 3,4,5tris(benzyloxy)phenyl; R' represents a hydrogen atom, and W represents ethyl.

In another embodiment, the present invention describes a process for preparing an isoxazoline compound having the formula IC, where X ¹ , X ² and X ³ are each independently H, chlorine, fluorine, or CF ₃ that is enriched in the (3)-enantiomer (5) -1C comprising the reaction of a compound having the formula (IIC) cf ₃ o where X ¹ , X ² and X ³ are H, chlorine, fluorine or CF ₃ with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral catalyst interfacial transfer having the formula (IIIa)

- 34 041013

(Sha) where R is aryl or heteroaryl optionally substituted with one or more C1C ₃ alkoxy or aralkoxy groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment of the process for preparing (S)-IC, R in the catalyst having formula (IIIa) is aryl or heteroaryl substituted with one or more C1- _C6 groups. In another embodiment, R is aryl or heteroaryl substituted with 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 with one or more benzyloxy groups.

In another embodiment of the process for preparing a compound having formula (S)-IC, R in the catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 C1- _C6 groups. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is ethyl. In another embodiment of (S)-IC, R in the catalyst having formula (IIIa) is phenyl independently substituted at positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group or a hydrogen atom; and W is vinyl or ethyl.

In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is ethyl. In another embodiment of (S)-IC, R in the catalyst having formula (IIIa) is 3,4,5 tris(benzyloxy)phenyl; R' represents a methoxy group or a hydrogen atom; and W is vinyl or ethyl.

In another embodiment, the present invention describes a method for producing sarolaner

- 35 041013

with hydroxylamine in the presence of water, a base and a chiral phase transfer catalyst having the formula (IIIa) comprising the reaction of a compound having the formula (IIC-1)

where R is aryl or heteroaryl optionally substituted with one or more C1C3 alkoxy or aralkoxy groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment of the synthesis of sarolaner, R in the catalyst having formula (IIIa) is aryl or heteroaryl substituted with one or more C ₁ -C 6 alkoxy groups. In another embodiment, R is aryl or heteroaryl substituted with 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 with one or more benzyloxy groups.

In another embodiment, R is phenyl substituted with 1, 2 or 3 C1-C6 alkoxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment of the synthesis of sarolaner, R in a catalyst having formula (IIIa),

- 36 041013 is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group, and W represents a vinyl. In another embodiment for the synthesis of sarolaner, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' is a hydrogen atom and W is vinyl. In another embodiment for the synthesis of sarolaner, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group, and W represents ethyl. In another embodiment for the synthesis of sarolaner, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a hydrogen atom, and W represents ethyl.

In another embodiment of the synthesis of sarolaner, R in the catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment for synthesizing sarolaner, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents a vinyl. In another embodiment for synthesizing sarolaner, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' is a hydrogen atom and W is vinyl. In another embodiment for synthesizing sarolaner, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents ethyl. In another embodiment for synthesizing sarolaner, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a hydrogen atom, and W represents ethyl.

In another embodiment, the present invention describes a process for preparing an isoxazoline compound having the formula ID, where X ¹ , X ² and X ³ are each independently H, chlorine, fluorine, or CF ₃ that is enriched in the (S)-enantiomer

comprising the reaction of a compound having the formula (IID)

(PO) where X ¹ , X ² and X ³ are H, chlorine, fluorine, or CF ₃ , with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base, and a chiral phase transfer catalyst having formula (IIIa)

- 37 041013

(Sha) where R is aryl or heteroaryl optionally substituted with one or more C1C ₃ alkoxy or aralkoxy groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment of the process for preparing (S)-ID, R in the catalyst having formula (IIIa) is aryl or heteroaryl substituted with one or more C1-C6 groups. In another embodiment, R is aryl or heteroaryl substituted with 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 with one or more benzyloxy groups.

In another embodiment, R is phenyl substituted with 1, 2 or 3 C1-C6 alkoxy groups and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is ethyl. In another embodiment of (S)-ID, R in the catalyst having formula (IIIa) is phenyl independently substituted at positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group or a hydrogen atom; and W is vinyl or ethyl.

In another embodiment of the process for preparing a compound of formula ID enriched in the (S) enantiomer, R in the catalyst of formula (IIIa) is phenyl substituted with 1, 2, or 3 benzyloxy groups, and R' is hydrogen or methoxy. -group. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is ethyl. In another embodiment of (S)-ID, R in the catalyst having formula (IIIa) is 3,4,5 tris(benzyloxy)phenyl; R' represents a methoxy group or a hydrogen atom; and W is vinyl or ethyl.

In another embodiment, the present invention describes a method for producing lotilaner

- 38 041013

Lotilaner comprising the reaction of a compound having the formula (IID-1)

(ISH-1) with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base, and a chiral phase transfer catalyst having the formula (IIIa)

(Sha) where R is aryl or heteroaryl optionally substituted with one or more C1C ₃ alkoxy or aralkoxy groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment of the Lotilaner process, R in the catalyst having formula (IIIa) is aryl or heteroaryl substituted with one or more C1- _C6 groups. In another embodiment, R is aryl or heteroaryl substituted with 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 with one or more benzyloxy groups.

In another embodiment of the Lotilaner production process, R in the catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 C1- _C6 groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment of the synthesis of lotilaner, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy-, ethoxy- or isopro

- 39 041013 poxy groups; R' represents a methoxy group, and W represents a vinyl. In another embodiment for the synthesis of lotilaner, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' is a hydrogen atom and W is vinyl. In another embodiment for the synthesis of lotilaner, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group, and W represents ethyl. In another embodiment for the synthesis of lotilaner, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a hydrogen atom, and W represents ethyl.

In another embodiment of the Lotilaner production process, R in the catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment for the synthesis of lotilaner, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents a vinyl. In another embodiment for the synthesis of lotilaner, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' is a hydrogen atom and W is vinyl. In another embodiment for the synthesis of lotilaner, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents ethyl. In another embodiment for the synthesis of lotilaner, R in the catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a hydrogen atom, and W represents ethyl. In another embodiment, the present invention describes a process for preparing an isoxazoline compound having the formula IE, where X ¹ , X ² and X ³ are each independently H, chlorine, fluorine, or CF3, which is enriched in the (S)-enαantiomer:

comprising the reaction of a compound having the formula (IIA) o. /----a (NOT) where X ¹ , X ² and X ³ represent H, chlorine, fluorine or CF3, with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base and a chiral phase transfer catalyst having the formula ( IIIa)

- 40 041013

(Sha) where R is aryl or heteroaryl optionally substituted with one or more C1C ₃ alkoxy or aralkoxy groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment of the process for preparing (S)-IE, R in the catalyst having formula (IIIa) is aryl or heteroaryl substituted with one or more C1-C6 groups. In another embodiment, R is aryl or heteroaryl substituted with 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 with one or more benzyloxy groups.

In another embodiment of the process for preparing a compound of formula III enriched in the (S) enantiomer, R in the catalyst of formula (IIIa) is phenyl substituted with 1, 2, or 3 C1-C6 groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is ethyl. In another embodiment of (S)-IE, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy or isopropoxy groups; R' represents a methoxy group or a hydrogen atom; and W is vinyl or ethyl.

In another embodiment of the process for preparing a compound of formula III enriched in the (S) enantiomer, R in the catalyst of formula (IIIa) is phenyl substituted with 1, 2, or 3 benzyloxy groups, and R' is hydrogen or methoxy. -group. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is ethyl. In another embodiment of (S)-IE, R in the catalyst having formula (IIIa) is 3,4,5 tris(benzyloxy)phenyl; R' represents a methoxy group or a hydrogen atom; and W is vinyl or ethyl.

In another embodiment, the present invention describes a process for preparing an isoxazoline compound having the formula IE-1 that is enriched in the (S)-enantiomer

- 41 041013

comprising the reaction of a compound having the formula (IIA)

hydroxylamine immiscible in the presence of water, with water an organic solvent, a base and a chiral phase transfer catalyst having the formula (IIIa)

where R is aryl or heteroaryl optionally substituted with one or more C1C ₃ alkoxy or aralkoxy groups, W is ethyl or vinyl, and X is an anion; and isolating said 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 solvent mixture containing an aromatic solvent. In one embodiment, the product is crystallized from toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, or mesitylene, or from a mixture thereof, or from a solvent mixture containing one of said solvents. In a preferred embodiment, the product is crystallized from toluene or from a solvent mixture containing toluene.

In one embodiment of the process for preparing (S)-IE-1, R in the catalyst having formula (IIIa) is aryl or heteroaryl substituted with one or more C1- _C6 alkoxy groups. In another embodiment, R is aryl or heteroaryl substituted with 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 with one or more benzyloxy groups.

In another embodiment, R is phenyl substituted with 1, 2 or 3 C1- _C6 alkoxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 methoxy, ethoxy, or isopropoxy groups, R' is a hydrogen atom, and W is ethyl.

- 42 041013

In another embodiment of the synthesis of a compound having the formula IE-1 enriched in the (S) enantiomer, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy-, ethoxy- or isopropoxy- groups; R' represents a methoxy group, and W represents a vinyl. In another embodiment of the synthesis of a compound having formula IE-1 enriched in the (3)-enantiomer, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy-, ethoxy- or isopropoxy -groups; R' is a hydrogen atom and W is vinyl. In another embodiment of the synthesis of a compound having formula IE-1 enriched in the (B)-enantiomer, R in the catalyst having formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy-, ethoxy- or isopropoxy -groups; R' represents a methoxy group, and W represents ethyl. In another embodiment of the synthesis of a compound of formula IE1 enriched in the (3)-enantiomer, R in the catalyst of formula (IIIa) is phenyl independently substituted in positions 3, 4 and 5 with methoxy, ethoxy, or isopropoxy groups. ; R' represents a hydrogen atom, and W represents ethyl.

In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, and R' is a hydrogen atom or a methoxy group. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is vinyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is methoxy, and W is ethyl. In another embodiment, R is phenyl substituted with 1, 2, or 3 benzyloxy groups, R' is a hydrogen atom, and W is ethyl.

In another embodiment for synthesizing a compound having formula IE-1 enriched in the (S)enantiomer, R in the catalyst having formula (IIIa) is 3,4,5tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents a vinyl. In another embodiment for synthesizing a compound of formula IE-1 enriched in the (3)-enantiomer, R in the catalyst of formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl;

R' is a hydrogen atom and W is vinyl. In another embodiment for synthesizing a compound of formula IE-1 enriched in the (S)-enantiomer, R in the catalyst of formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a methoxy group, and W represents ethyl. In another embodiment for synthesizing a compound of formula IE-1 enriched in the (B)-enantiomer, R in the catalyst of formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl; R' represents a hydrogen atom, and W represents ethyl.

In any of the above embodiments of the present invention, the chiral phase transfer catalyst having formula (IIIa) may have structures corresponding to formulas (IIIa-1) to (IIIa-38) in Table 1 below, where W is ethyl or vinyl, X is a halogen, mesylate, tosylate, triflate, brosylate, nosylate, or tresylate counterion; each R is independently methyl, ethyl, n-propyl, isopropyl, nbutyl, sec-butyl, iso-butyl, t-butyl, or CH ₂ Ph; R' represents a hydrogen atom or a C1- _C3 alkoxy group; Z is halo, 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 R ¹ , R ² , R ³ and R ⁴ are independently H or C1-C ₃ alkyl.

Table 1. Chiral phase transfer catalysts having formulas (IIIa-1)-(IIIa-38)

- 43 041013

W ^H "s (Sha-4) ^W and '71 (1Pa-5) _W n (Sha-6) _W and ; i : OR (Sha-7) OR (Sha-8) (Sha-9) (Sha-10) :% (Sha-i) w n 7% (Sha-12) OR (Sha-13) OR (IIIa-14) w n %& (Sha-15) w and (Sha-16) ! / , OR (IIIa-17) _{w n} s-1: (Sha-18)

- 44 041013

(Z) „ (Sha-19) _{w n} U G (P1a-20) UGG OR (Sha-21) w and A# (Sha-22) /G: (Sha-23) w and YES: Z (Sha-24) /G/: OR (Sha-25 '/U (Sha-26) w n yes Z (Sha-27 /GU OR (Sha-28) _w to OR (Sha-29) _w n OR (Sha-30)

- 45 041013

In another embodiment, the present invention describes chiral phase transfer catalysts having formulas (IIIb-1)-(IIIb-38) wherein the compounds have the structures shown in Table 1 above, except that these compounds have reverse stereochemistry. relative to that shown for the carbon atom bearing the hydroxy group and for the carbon atom adjacent to the nitrogen atom in the quinuclidine nucleus.

In another embodiment, the present invention describes chiral phase transfer catalysts having the formulas (IIIa-39)-(IIIa-76), where the chiral phase transfer catalysts have the formulas of compounds having the formula (IIIa-1)-(IIIa-38) , except that the OR groups are changed to -NHR groups, where R has the same meaning.

In another embodiment, the present invention describes chiral phase transfer catalysts having the formulas (IIIa-77)-(IIIa-114), where the chiral phase transfer catalysts have the formulas of compounds having the formula (IIIa-1)-(IIIa-38) , except that the OR groups are replaced by groups -NR ^a R ^b , where R ^a and R ^b have the same meaning as R in table. 1.

In one embodiment, the present invention describes a chiral phase transfer catalyst having the formula (IIIa-13-1), (IIIa-13-2), (IIIa-13-3) or (IIIa-13-4), or their a mixture where X is a counterion, or a mixture of two or more of the catalysts

- 46 041013

OCH ₂ Ph (Sha-13-4)

In another embodiment, the present invention describes a chiral phase transfer catalyst having the formula (IIIa-13-1), (IIIa-13-2), (IIIa-13-3) or (IIIa-13-4), where X is a halogen counterion. In another embodiment, X is a chloride counterion. In another embodiment, X is a mesylate, tosylate, triflate, brosylate, nosylate, or tresylate counterion. The novel phase transfer catalyst can be used to prepare enantiomerically enriched antiparasitic isoxazolines as described herein; however, the skilled artisan will also appreciate that the catalyst can be used to catalyze other phase transfer reactions to produce enantiomerically enriched compounds. Synthesis of Chiral Phase Transfer Catalysts The chiral phase transfer catalysts of the present invention can be prepared by reacting suitably substituted arylmethyl or heteroarylmethyl intermediates having a suitable leaving

- 47 041013 a common group on a methyl fragment, with quinine or dihydroquinine in a solvent. Representative examples of this reaction for preparing other quinine chiral phase transfer catalysts can be found, for example, in US 2014/0206633 A1, US 2014/0350261 A1, both of which are incorporated herein by reference. Additional examples of the preparation and use of quinine chiral phase transfer catalysts can be found in Angew. Chem. Int. Ed. 2007, 46, 4222-4266; Tetrahedron Letters 1998, 8775; and Chem. commun. 2009, 7090. For example, chloromethyl-substituted aryl or heteroaryl intermediates can be reacted with quinine to give the desired catalysts. Scheme 1 below is an example of the preparation of quinine-based chiral phase transfer catalysts that can be used in the process of the present invention, wherein R is C1-C3 alkyl or aralkyl and LG is a suitable leaving group such as halogen (e.g., chloride, iodide, etc.), mesylate, tosylate, triflate, and the like.

Scheme 1

Those skilled in the art will appreciate that other phase transfer catalysts can be prepared, for example, by reacting cinchon alkaloids with intermediate 1-3. Other useful cinchon alkaloids include cinchonidine, cinchonine and quinidine. Similarly, dihydroquinine, dihydrocinchonidine, dihydrocinchonin and dihydroquinidine can be reacted with intermediate 1-3 to give the corresponding chiral phase transfer catalyst 1-5.

In addition, those skilled in the art will appreciate that reduction of intermediate 1-1 to alcohol 1-2 can be carried out with a wide range of suitable reducing agents and under conditions known in the art, as this is a very common reaction in organic chemistry. For example, reduction 1-1 can be carried out with a number of reducing agents such as sodium borohydride (NaBH4), sodium triacetoxyborohydride, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), lithium aluminum hydride (LiAlH4), and the like. In addition, reduction can be carried out using a combination of a reducing agent with a Lewis acid such as NaBH4/AlCl ₃ and others (see, for example, Advanced Organic Chemistry, Reactions, Mechanisms and Structure, ^3rd edition, by Jerry March, John Wiley & Sons , New York, 1985 (March).

In addition, it should be understood that the halogenation of alcohols is also a well-known transformation in organic chemistry (for example, with thionyl chloride (SOCl ₂ ), see March), and various reagents and conditions are known to those skilled in the art. The reaction of quinine with a halomethyl-substituted aromatic group proceeds by heating the reactants in an inert organic solvent such as toluene at elevated temperatures (see, for example, US 2014/0206633 A1, US 2014/0350261 A1).

Those skilled in the art will also appreciate that quinine can react with suitably substituted aryl or heteroaryl groups containing other leaving groups on the arylmethyl or heteroarylmethyl group. They include, for example, tosylates, mesylates, triflates, and the like.

The preparation of compounds having formula (II) is known in the art. For example, US Pat. Nos. 8,217,180; 8,952,175 and US 2014/0206633 and WO 2014/081800 (all incorporated herein by reference), among others, describe methods for the synthesis of these compounds. Except

- 48 041013 In addition, those skilled in the art, based on the methods described in these and other publications, in combination with the prior art, can easily obtain other compounds having formula (II) with different arrangements of substituents.

Preparation of chiral isoxazoline compounds

The preparation of isoxazoline active compounds having formula (I) by reacting compounds having formula (II) with hydroxylamine and a base in the presence of a chiral phase transfer catalyst having formula (IIIa) or (IIIb) can be carried out in a two-phase mixture of water and a suitable inert organic solvent that is immiscible with water. In some embodiments, when a compound having formula (II) forms an immiscible liquid phase with water, an organic solvent may not be required. In some other embodiments, where the reaction can operate in a single phase, the reaction can be carried out without water or with a small amount of water. Preferably, the process is carried out in a two-phase mixture of water and a water-immiscible organic solvent.

Suitable organic solvents include, but are not limited to, aromatic solvents, aliphatic solvents and halogenated aliphatic solvents, ether solvents, and the like. Preferred solvents are immiscible with water and have low water solubility. In one embodiment, an aromatic solvent is used in the process of the present invention, including but not limited to toluene, xylene, fluorobenzene, chlorobenzene, o-dichlorobenzene, anisole, and mesitylene. In one preferred embodiment, aliphatic solvents optionally substituted with halogen can be used to react a compound having formula (II) with hydroxylamine in the presence of a chiral phase transfer catalyst having formula (IIIa) or (IIIb). Aliphatic solvents optionally substituted with halogen include, but are not limited to, n-pentane, n-hexane, n-heptane, n-octane, cyclopentane, cyclohexane, dichloromethane, chloroform, 1,2-dichloroethane, and methylcyclohexane. In a preferred embodiment, the reaction of a compound having formula (II) with hydroxylamine in the presence of a chiral phase transfer catalyst is carried out in a halogenated aliphatic solvent such as dichloromethane or an aromatic solvent such as toluene.

In some embodiments, ether solvents can be used in the process of the present invention to prepare enantiomerically enriched isoxazoline compounds, including (but not limited to), diethyl ether, diisopropyl ether, di-n-butyl ether, cyclopentyl methyl ether, tert-butyl -methyl ether and tert-butyl ethyl ether. In some embodiments, tetrahydrofuran, dimethoxyethane, dioxane, tetrahydropyran, methyltetrahydrofuran, including 2-methyltetrahydrofuran, diethoxymethane, acetonitrile, or a combination thereof can be used. In various embodiments, a combination of the solvents described above can be used.

The amount of organic solvent used in the reaction is not critical and depends on the available equipment used for the process, provided that the amount of solvent is sufficient to carry out the desired reaction at a reasonable rate. However, it is clear that the use of smaller volumes of organic solvent is preferable from an economic and environmental point of view. In some embodiments of the present invention, in the reaction of a compound having formula (II) with a chiral phase transfer catalyst having formula (IIIa) or (IIIb), a volume of organic solvent from about 1 to about 100 volumes relative to the amount of the initial amount of the compound can be used having formula (II), assuming a density of 1 g/ml (excluding water in the reaction mixture). For example, if 100 g of a compound having formula (II) is used in the reaction, 10 volumes of solvent is 1000 ml. In other embodiments, implementation, the reaction can be carried out with the amount of solvent from about 1 to about 80 volumes. In another embodiment, the reaction can be carried out with about 1 to about 50 volumes of solvent. In another embodiment, the reaction can be carried out with an amount of solvent from about 1 to about 30 volumes, or from about 1 to about 20 volumes. 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 a compound having formula (II) with hydroxylamine in the presence of a base and a chiral phase transfer catalyst having formula (IIIa) or (IIIb) to form a compound having formula (I) is carried out with about 10 volumes solvent.

The reaction can be carried out at temperatures from about -78°C to about 60°C, depending on the solvents used and other factors. In a more typical case, the reaction with the formation of isoxazoline compounds having formula (I) is carried out at a temperature of from about -30°C to about 40°C. In one embodiment, the reaction is carried out at a temperature of from about -20°C to about 25°C. In another embodiment, the reaction is carried out at a temperature of from about -15°C to about 20°C. In another embodiment, the reaction is carried out at a temperature

- 49 041013 from about -15°C to about 10°C, or from about -15°C to about 5°C. In another embodiment, the reaction can be carried out at a temperature of from about -15°C to about -5°C. In another embodiment, the reaction is carried out at a temperature of from about -15°C to about 0°C, or from about -10° to about 0°C. In another embodiment, the reaction is carried out at a temperature of from about -13°C to about 3°C.

Of course, the reaction may take less or more time, depending on the temperature and concentration of the reaction mixture. The progress of the reaction can be monitored by determining the amount of the remaining starting compound (eg, a compound having formula (II)) by chromatographic methods such as thin layer chromatography (TLC) or HPLC, and the reaction can be stopped after reaching an acceptable degree of conversion. In some embodiments, the reaction is carried out for a period of time from about 30 minutes to about 48 hours. In one embodiment, the reaction is carried out for a period of time from about 1 to about 48 hours, or from about 1 to about 24 hours. In others embodiments, the reaction is carried out over a period of time from about 1 to about 10 hours. In some embodiments, the reaction is carried out over a period of time from about 1 to about 5 hours. In another embodiment, the reaction is carried out over a period of time from about 10 up to about 30 hours. In another embodiment, the reaction is carried out for a period of time from about 15 to about 25 hours to achieve the target conversion.

In some embodiments, implementation of the present invention, hydroxylamine can be used in excess relative to the compounds having formula (II), including the range from about 1 and about 50 molar equivalents (in terms of free base). In one embodiment, the amount of hydroxylamine may be from about 1 to about 20 equivalents. In another embodiment, hydroxylamine can be used in an amount of from about 1 to about 15 equivalents. In another embodiment, hydroxylamine can be used in an amount of from about 1 to about 10 equivalents. In another embodiment, hydroxylamine can be used in an amount of from about 1 to about 5 equivalents, or from about 1 to about 6 equivalents. In other embodiments, hydroxylamine can be used in an amount of from about 4 to about 8 equivalents. In another embodiment, hydroxylamine can be used in an amount of from about 5 to about 7 equivalents. In another embodiment, hydroxylamine can be used in an amount of about 5 or about 6 equivalents. In another embodiment, hydroxylamine can be used in an amount of from about 1 to about 3 mole equivalents. In another embodiment, hydroxylamine can be used in an amount of from about 1.5 to about 3, or from about 1.5 to about 2.5 molar equivalents per mole of the compound having formula (II). In a particular embodiment, about 2.2 mole equivalents of hydroxylamine (in terms of free base) are used per mole of the compound having formula (II).

Hydroxylamine can be used in free base form or can be used as an acid salt such as hydroxylamine sulfate, hydrochloride salt, phosphate salt, oxalate, nitrate or acetate. However, since hydroxylamine is dangerous as a free base, it may be preferable to store and use it as a salt and generate the free base in situ by adding a base. However, the number of mole equivalents of hydroxylamine relative to the compound having the formula (II) is calculated based on the free base.

In some embodiments, the hydroxylamine is used as a solution in water. The concentration of the aqueous solution of hydroxylamine (as a free base or as a salt) is not limited. However, lower concentrations are preferred for safety, including concentrations of about 50% (w/w) or lower. In some embodiments, the method of the present invention uses an aqueous solution of hydroxylamine at a concentration of from 5% to about 50% (w/w). In another embodiment, the concentration of hydroxylamine is from about 10% to about 30% (w/w), or from about 15% to about 25% (w/w). In another embodiment, the concentration of hydroxylamine is from about 15% to about 20% (w/w). In one embodiment, the concentration of hydroxylamine (free base or salt) is about 18% (w/w) or about 20% (w/w).

Any suitable base may be used in the reaction in question, including but not limited to alkali metal hydroxides or alkoxides, or alkaline earth metal hydroxides or alkoxides. In some embodiments, alkali metal carbonates or bicarbonates can 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.

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- 50 041013 triazabicyclo(4.4.0)dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5diazabicyclo[4.3.0]non-5- ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), quinuclidine, 2,2,6,6tetramethylpiperidine (TMP), pempidine (PMP), 1,4-diazabicyclo[2.2.2]octane (TED) , collidine, 2,6lutidine (2,6-dimethylpyridine), N,N,N',N''-tetramethyl-1,8-naphthaleneduamine (Proton Sponge®) and the like. In another embodiment, phosphazene bases can be used in the process of the present invention.

The base can be used in an amount of from about 1 to 100 mole equivalents relative to the compound having formula (II). Typically, an excess of base relative to the hydroxylamine reagent is used, especially if an acid salt of hydroxylamine is used. In other embodiments, about 1 to about 50 base equivalents are used relative to the compound having formula (II). In other embodiments, from about 1 to about 30, or from 1 to about 20 base equivalents, is used. More typically, about 1 to about 10 base equivalents are used. In another embodiment, about 2 to about 8 equivalents of base are used in the reaction. In another embodiment, about 3 to about 6 base equivalents are used. In another embodiment, about 5 equivalents or 6 equivalents of base are used. In another embodiment, about 3 to about 5 equivalents of base are used. In another embodiment, about 4 to about 5 equivalents of base are used. In another embodiment, about 4.4 base equivalents are used.

In one embodiment, a chiral phase transfer catalyst having formula (III) may be used in an amount of from about 0.1 mole % to about 20 mole % per mole of compound having formula (II) (e.g., 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 from about 0.5 mole % to about 10 mole % per mole of the compound having formula (II). In another embodiment, the amount of catalyst used is from about 0.5 to about 10 mol%, or from about 0.5 mol% to about 5 mol%, per mol of compound having formula (II). In another embodiment, the amount of chiral phase transfer catalyst is from about 1 mole % to about 5 mole % per mole of the compound having formula (II). In another embodiment, the amount of chiral phase transfer catalyst is from about 3 mol% to about 7 mol%. In another embodiment, the amount of chiral phase transfer catalyst used is from about 1 mol% to about 3 mol%, or from about 2 mol% to about 4 mol%, per mol of compound having formula (II). In another embodiment, the amount of chiral phase transfer catalyst used is from about 1 mol% to about 1.5 mol%, about 3 mol%, about 5 mol%, or about 10 mol% per mole of a compound having the formula ( II).

After the reaction has gone to a sufficient extent, the reaction mixture is processed according to methods known to those skilled in the art. For example, water and an aqueous acid solution are added to the reaction mixture, and the resulting mixture is slightly heated while stirring. The addition of dilute acid neutralizes the base, giving a roughly neutral mixture (target pH 7-8). Any suitable acid may be used to neutralize the main reaction mixture, including dilute hydrogen halides (e.g. HCl), carboxylic acids/carboxylates (e.g. acetic acid, citric acid, formic acid, etc.), ammonium salts (e.g. ammonium chloride) , monobasic phosphates (eg KH ₂ PO ₄ ), hydrosulfate salts (eg KHSO4) and the like. The biphasic mixtures are allowed to settle, the organic phase is separated and washed with a dilute acidic solution (eg KH2PO4 or similar) to further neutralize the mixture. The reaction mixture can then be washed with saturated sodium chloride solution, allowed to stand and the two layers separated. Can be rinsed with water at the end. The organic layer is collected as a crude product mixture, which can be further purified prior to isolation.

The product can be isolated from the mixture in pure form by methods known in the art. In one embodiment, the reaction mixture solution can be crystallized from a suitable solvent to give a purified product. The pure product can be crystallized or recrystallized by known methods, including (but not limited to) cooling a solution of the crude product in a suitable solvent (or solvent mixture) until the product crystallizes, adding an anti-solvent (or solvent mixture) in which the product has low solubility, and so on. In one embodiment, the product may be crystallized by adding the desired crystallization solvent to the crude product mixture while distilling the mixture, optionally in vacuo, to replace the reaction solvent with the crystallization solvent, until sufficient reaction solvent/solvent mixture has been removed and replaced with the desired crystallization solvent (or mixture of solvents). The resulting mixture can then be further concentrated to a suitable concentration. As is known in the art, it is desirable to create a concentration of product in the crystallization solvent/solvent mixture such that the concentration is above the saturation concentration at a temperature at which

- 51 041013 the product will crystallize (eg after cooling) but below saturation concentration at elevated temperature (eg in solution). When sufficient crystallization solvent is present and the product concentration is appropriate, a seed crystal can be added to the mixture at a suitable temperature to induce crystallization as the mixture cools. These methods are well known to those skilled in the art.

In one embodiment, the product can be crystallized or recrystallized from an aromatic solvent. Various aromatic solvents can be used to crystallize or recrystallize the product. These solvents include aromatic solvents known in the art for use in the manufacture of pharmaceutical active ingredients, including but not limited to toluene, ethylbenzene, chlorobenzene, xylene (mixed isomers or pure isomers), anisole, and the like. In one preferred embodiment, the product can be crystallized or recrystallized from toluene. In one embodiment, the product can be crystallized or recrystallized from ethylbenzene. In another embodiment, the product can be crystallized or recrystallized from chlorobenzene. In another embodiment, the product can be crystallized or recrystallized from anisole. In another embodiment, the product can be crystallized or recrystallized from xylene. It is also possible to crystallize the product from benzene, although this is not the preferred option due to toxicity issues associated with this solvent.

In one embodiment, the product can be crystallized or recrystallized from a solvent mixture containing a polar solvent in which the product is soluble and a non-polar solvent in which the product does not dissolve very well. In another embodiment, the product may be crystallized or recrystallized from hexane, heptane, cyclohexane, and the like. In one embodiment, the product isolated as an aromatic solvent solvate (e.g., toluene solvate) can be recrystallized from a combination of polar and non-polar solvents to further purify the product and/or to remove the aromatic solvent that is a component of the solvate. In another embodiment, the product may be crystallized or recrystallized from a mixture of solvents, including a mixture containing an aromatic solvent, an aliphatic solvent, an alcoholic solvent, an ether solvent, an ester solvent, and the like. or their mixture. 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.

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 alcoholic solvent. In another embodiment, the product may be crystallized or recrystallized from a mixture of an aromatic solvent and an alcoholic solvent. In one embodiment, the product may be crystallized or recrystallized from a mixture of a cycloalkyl solvent and an alcoholic solvent. In another embodiment, the product can be crystallized or recrystallized from a mixture of a cycloalkyl solvent and a C ₁ -C ₆ alcohol solvent. In one embodiment, the product can be crystallized or recrystallized from a mixture of hexane/ethanol, toluene/cyclohexane, toluene/hexane, toluene/heptane, cyclohexane/ethanol or toluene/ethanol, and the like. Those skilled in the art will appreciate that the proportion of each solvent in the solvent combination should be selected to produce a solvent combination in which the product is markedly soluble at elevated temperatures but not very soluble when the mixture is cooled. The ratio of solvents can be adjusted to reduce the solubility of the product at the right time. For example, you can add more bad solvent to the mixture when the solid has dissolved to bring the solution closer to the saturation point. Of course, the skilled person will understand that the product can be recrystallized one or more times from a suitable solvent/solvent mixture to increase the purity of the product, if necessary.

In one embodiment of the present invention, the (S)-enantiomer of afoxolaner obtained by the method of the present invention is crystallized from toluene to obtain crystals of very high purity. It was unexpectedly found that the (S)-enantiomer of afoxolaner forms a crystalline solvate with toluene (see example 12) while racemic afoxolaner does not. Due to these properties, crystallization of the target (S)-enantiomer from toluene leads to a significant increase in the enantiomeric purity of the product, compared with the ratio of enantiomers in the reaction mixture after completion of the reaction. Selective crystallization of (S)afoxolaner with other aromatic solvents (eg anisole, chlorobenzene, etc.) has also been achieved. This is unexpected since there is typically no enrichment of one enantiomer relative to the other enantiomer, unless the crystallization is carried out using a chiral system in which there is a preference for one of the enantiomers over the other. Crystallization of this type is known, for example, in the case of chiral bases, when the chiral product is an acid. However, it is very surprising that crystallization of one enantiomer from a non-chiral solvent such as toluene results not only in purification of the product (eg, removal of non-chiral reactive impurities and starting compound), but also in enrichment of the target enantiomer.

Crystallization of the desired enantiomerically pure isoxazoline compounds of the present invention from a suitable solvent, including but not limited to those described above, can be accomplished by changing the solvent from the reaction solvent to the solvent used for crystallization in the proper volume by distillation, optionally under vacuum, as is known qualified professionals in this field. In one embodiment, the reaction mixture to be treated can be evaporated to a volume, for example, from about 0.5 to 30 volumes relative to the compound having formula (II). More typically, the reaction mixture to be treated can be evaporated to about 1 to about 20 volumes, or about 2 to 10 volumes. In other embodiments, the reaction mixture is evaporated to a volume of from about 1 to about 5 volumes, from about 1 to about 3 volumes, or from about 1 to about 2 volumes.

After removing the proper amount of reaction solvent, the required amount of crystallization solvent is added and the volume of the mixture is adjusted by distillation (optionally in vacuo) to the desired volume (optionally with additional addition of crystallization solvent) so that the product crystallizes from solution upon cooling. In principle, the volume from which the product is crystallized is not critical; however, the presence of too much solvent during crystallization can lead to increased losses of product in the mother liquor. On the other hand, crystallization of a product from a mixture with too high a concentration may lead to a lower product quality. The volume of the mixture before crystallization depends on the solubility of the product in the crystallization solvent. In one embodiment, the volume of the mixture prior to crystallization may be from about 1 volume to about 30 volumes. In some embodiments, the volume of the mixture prior to crystallization may be from about 1 volume to about 20 volumes, or from about 1 volume to about 10 volumes. More typically, the volume of the mixture prior to crystallization may be from about 2 volumes to about 10 volumes, from about 3 volumes to about 8 volumes, or from about 4 volumes to about 7 volumes. In one embodiment, the volume of the mixture before crystallization (before cooling the mixture) may be about 5-6 volumes.

When the mixture to be recrystallized is cooled slowly, the target product crystallizes out of solution and can be separated by filtration. Since some undesired enantiomer is always present, it is possible for some isoxazoline compounds that the undesired enantiomer or racemic compound crystallizes out of solution faster than the desired enantiomer. For example, in one embodiment of the synthesis of the (S)-afoxolaner of the present invention, racemic afoxolaner crystallizes (unsolvated) from a toluene solution faster than the pure (S)-enantiomer. The racemic afoxolaner crystals have a higher melting point than the (S)-enantiomer solvate crystals. Thus, the crystals of the racemic compound can be removed by bringing the temperature of the mixture to a temperature at which the racemic compound crystallizes from solution, and then filtering off the solid precipitate to obtain the desired enantiomer in solution. Seed crystals of the undesired enantiomer or racemic compound may be added to promote crystallization of these compounds. After most of the racemic compound has been removed, the volume of the filtrate can be further changed (eg, by distillation or adding more crystallization solvent) and the solution can be cooled to promote crystallization of the target compound.

In one embodiment, crystallization of a racemic compound can be carried out by adding seeds of the racemic compound at a low temperature to induce crystallization of the compound, holding the mixture for the desired amount of time, heating to dissolve most of the desired enantiomer, holding at elevated temperature, and filtering the mixture to remove insoluble precipitate . In one embodiment, the addition of seed crystals and crystallization of the racemic compound is carried out at a temperature of from about -10°C to about 30°C. In other embodiments, seeding is carried out at a temperature of from about 0°C to about 20°C, from about 0°C to about 15°C, or from about 5°C to about 15°C. In another embodiment, the addition of seeds and crystallization is carried out by adding seeds of the racemic compound at a temperature of from about 7° C. to about 13° C. and holding for a time sufficient for most of the racemic compound to crystallize.

The mixture is then heated to an elevated temperature to dissolve the desired enantiomer while keeping the crystals of the racemic compound undissolved. In one embodiment, the mixture is heated to a temperature of from about 30°C to about 100°C. More typically, the mixture is heated to about 30°C to about 80°C and held for

- 53 041013 time sufficient to dissolve the target enantiomer, while maintaining the racemic compound in solid form. More typically, the mixture is heated to a temperature of from about 40°C to about 70°C, from about 50°C to about 70°C, or from about 55°C to about 65°C. In another embodiment, the mixture is heated to a temperature of from about 57°C to about 63°C and maintained for the desired amount of time. The resulting mixture is then filtered to remove the solid phase containing the unwanted racemic compound.

The resulting filtrate is crystallized by bringing the volume of the solution back to the desired volume using distillation and/or adding more crystallization solvent, followed by slow cooling to the desired temperature to induce crystallization of the desired enantiomer. In one embodiment, the mixture is cooled to a temperature of from about -10°C to about 30°C. In other embodiments, the step of adding seed crystals is carried out at a temperature of from about 0°C to about 20°C, from about 0°C to about 15°C, or from about 5°C to about 15°C. In another embodiment, the mixture is cooled to a temperature of from about 7°C to about 13°C. When the mixture reaches the target temperature, seeds of the target enantiomer can be added to the mixture and allowed to stand for the desired amount of time. The product is isolated by filtration or centrifugation and the precipitate is washed with crystallization solvent. The solid product obtained is then dried, if necessary under vacuum.

In some embodiments, the product may be recrystallized using the same crystallization solvent or an alternative solvent to further purify the product. A method similar to that described above can be used, except that no pre-crystallization of the undesired enantiomer or racemic compound is required. In one embodiment, the target enantiomer of the isoxazoline compound can be recrystallized from a mixture of an aliphatic solvent and an alcoholic solvent. In another embodiment, the isoxazoline compound can be recrystallized 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 cycloalkyl solvent and a C1-C6 alcohol solvent. In another embodiment, the isoxazoline compound can be recrystallized from a cyclohexane/ethanol mixture.

In one embodiment, using a combination of an aliphatic and an alcoholic solvent, a mixture containing a solid product and a crystallization solvent is heated to dissolve the solid product, and then cooled to a suitable temperature to seed the product solution, if necessary. The addition of seed crystals is optional, but may be desirable to form larger crystals of the desired shape. In another embodiment, the product is first dissolved in a solvent in which the compound is more soluble (eg, an alcoholic solvent) and the remaining solvent is added at elevated temperature.

In one embodiment, in which a solvent mixture consisting of an alcoholic solvent and an aliphatic solvent is used to crystallize the product, a volume ratio of from about 1:10 to 1:99, volumes of alcohol relative to volumes of aliphatic solvent, can be used. More typically, a volume ratio of from about 1:5 to about 1:40, or from about 1:5 to about 1:30, volumes of alcohol relative to volumes of aliphatic solvent can be used. In another embodiment, the ratio of the volumes of alcohol solvent to aliphatic solvent in the 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, volumes of alcohol relative to the volumes of the aliphatic solvent. In another embodiment, the ratio of the volumes of alcoholic solvent to aliphatic solvent in the solvent mixture may be from about 1:10 to about 1:30, or from about 1:15 to about 1:25. In another embodiment, the ratio of the volumes of alcohol solvent to aliphatic solvent in the solvent mixture may be about 1:20.

The amount of aliphatic solvent used in the crystallization of the isoxazoline compounds of the present invention as part of the alcohol solvent system also depends on the specific aliphatic solvent used and the nature of the isoxazoline compound. In one embodiment, the amount of aliphatic solvent may be from about 5 to about 30 volumes relative to the volume of the recrystallized product or the volume of the starting compound if the crude synthesis product is crystallized. In other embodiments, from about 5 to about 20 volumes of aliphatic solvent may be used. More typically, about 10 to about 20 volumes of aliphatic solvent may be used. In one embodiment, about 13 to about 16 volumes of aliphatic solvent may be used.

In one embodiment, the mixture is heated to a temperature of from about 40°C to about 70°C to dissolve the solid. More typically, the mixture is heated to a temperature of

- 54 041013 about 50°C to about 70°C, or from about 55°C to about 65°C. In one embodiment, the mixture is heated to a temperature of from about 57°C to about 63°C to dissolve the solid.

After the solid has dissolved, additional solvent may be added to bring the mixture to or slightly above saturation point. Usually a solvent is added in which the product is less soluble. The resulting mixture can be cooled slightly to bring the mixture to saturation point, and then, if necessary, seed crystals of the desired enantiomer are added. The resulting mixture is then slowly cooled to the required temperature and maintained for the required time. The product is isolated by filtration or centrifugation and then the resulting product is dried under vacuum if necessary.

The temperature at which the mixture is seeded (if applicable) depends on the isoxazoline compound and the solvents used for crystallization. In one embodiment, seeding the mixture during crystallization is carried out at a temperature of from about 10°C to about 80°C, or from about 20°C to about 70°C. In one embodiment, the introduction of seed crystals in the mixture during crystallization is carried out at a temperature of from about 40°C to about 65°C. In other embodiments, seeding the mixture during crystallization is carried out at a temperature of from about 45°C to about 65°C, or from about 50°C to about 60°C. In one embodiment, the mixture is seeded with the desired product at a temperature of from about 52° C. to about 58° C. and stirred for the required amount of time. In one embodiment, the seeded mixture is heated for at least 30 minutes or at least 1 hour.

After seeding the desired product, in some embodiments, the mixture is cooled to an intermediate temperature (eg, between the final crystallization temperature and the seeding temperature) and allowed to stand. The resulting mixture can also be reheated to a temperature close to or slightly higher than the temperature at which the mixture is seeded and then slowly cooled. This process is carried out so that the resulting crystals grow before the final cooling and crystallization.

The seeded mixture is then finally 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 from about 10°C to about 30°C. In other embodiments, the seeding step is carried out at a temperature of from about 0°C to about 20°C, from about 0°C to about 15°C, or from about 5°C to about 15°C. In another embodiment, the mixture is cooled to a temperature of from about 7°C to about 13°C. In another embodiment, the seeded mixture is cooled to a temperature below about 20° C. or below about 15° C. and held to complete crystallization of the product. The resulting mixture is kept, and then the solid precipitate is separated by filtration or centrifugation. The product is dried, optionally under vacuum, to give the expected product.

Those skilled in the art will appreciate that the cooling rate is very important in the crystallization process. If the cooling rate is too fast, the solubility of the compound in the solvent will drop too quickly and the crystals will not be able to grow and give the product in the desired crystalline form and quality. In some embodiments, the crystallizable mixture is cooled at a rate of from about 20° C./h to 1° C./h so that the desired product crystals can grow at a suitable rate to ensure product purity. More typically, the crystallizable mixture is cooled at a rate of from about 15°C/h to 1°C/h, or from about 10°C/h to 5°C/h. In one embodiment, the crystallizable mixture is cooled to the target temperature at a rate of from about 8°C/h to 3°C/h.

The product is dried at a temperature from about room temperature to 80°C, optionally under vacuum. In other embodiments, the product is dried at a temperature of from about 30°C to about 70°C, optionally under vacuum. In other embodiments, the product is dried at a temperature of from 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.

In another embodiment, the crude product may be purified by chromatography to obtain a pure product. Purification techniques using chiral stationary phases are well known in the art. For example, the desired enantiomer of a 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 techniques are well known in the art.

In one embodiment of the present invention, a chiral phase transfer catalyst having formula (IIIa) or (IIIb) can be attached to a polymer support so that the catalyst can be easily separated from the reaction mixture and reused. A catalyst having formula (IIIa) or (IIIb) can be attached to a suitable polymer at several points, including points in the aryl or heteroaryl group R, in the W group, or in the quinoline group, as shown below for formula (IIIa-13)

OR (Sha-13)

The catalyst can be attached to a suitable polymeric support at the substituted phenyl group, for example by reacting the hydroxyl group in the original catalyst with an electrophile. Other catalyst addition methods include, for example, reacting a quinine catalyst in which W is a vinyl group by olefin metathesis or other methods that involve the reactivity of the vinyl group.

In another embodiment, the catalyst can be attached to a suitable polymer at the quinoline group via free hydroxyl group protection, demethylation, and polymer addition alkylation.

In the present description and in the claims, terms such as contains, containing, having, and the like have the meanings assigned to them in the US Patent Law, i.e. can mean includes including and the like; terms consisting principally of and consisting principally of also have the meaning prescribed in patent law, and these terms are non-exclusive, allowing the presence of more than what is listed, provided that the essential or new characteristics of what is listed are not changed by the presence of more than listed, but excluding options known in the prior art.

It should also be noted that in the present description and in the claims, the compounds of the present invention include all stereoisomers and crystalline forms (which include hydrated forms, polymorphic forms and amorphous forms).

Definitions

The terms used in this text have the generally accepted meaning in this field, unless otherwise indicated. The organic moieties referred to in the definitions of the variables present in formula (I) are, as a term, halogen-collective terms for lists of individual group members. The prefix Cn-Cm in each case indicates the possible number of carbon atoms in the group.

The term animal is used in this text to include all mammals, birds and fish, and also includes all vertebrates. Animals include, but are not limited to, cats, dogs, cattle, chickens, cows, deer, goats, horses, llamas, pigs, sheep, and yaks. They also include the individual animal at all stages of development, including the embryonic and intrauterine stages. In some embodiments, animal means non-human animals.

The term aliphatic solvent, as used herein, means 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 mixtures thereof. As used herein, the term aliphatic solvent does not include aromatic solvents such as toluene.

The term aromatic solvent, as used herein, means solvents consisting of hydrocarbon molecules having an aromatic character, optionally substituted with halogens. Common aromatic solvents include, but are not limited to, benzene, toluene, o-xylene, p-xylene, or a mixture thereof (xylene), fluorobenzene, chlorobenzene, dichlorobenzene, anisole, and mesitylene, a mixture thereof.

The term alkyl refers to saturated linear, branched, primary, secondary or tertiary hydrocarbons, including hydrocarbons containing from 1 to 20 atoms. In some embodiments, the alkyl groups include C ₁ -C ₁₂ , C ₁ -C _1o , C ₁ -C ₈ , C ₁ -C ₆ , or C ₁ -C ₄ alkyl groups. Examples of C ₁ -C ₁₀ alkyls include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-56 041013 methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2dimethylbutyl, 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, 1-ethyl-2methylpropyl, 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.

Cyclic alkyl groups or cycloalkyl, which are included in the term alkyl, include groups with 3-10 carbon atoms containing one or more fused rings. In some embodiments, the cycloalkyl groups include C4-C7 or _C3 - _C4 cyclic alkyl groups. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

Terms that include the term alkyl, such as alkylcycloalkyl, cycloalkylalkyl, alkylamino, or dialkylamino, are to be understood as containing an alkyl group as defined above linked to another functional group, wherein said group is linked to the remainder of the compound via the last listed groups, as will be understood by a person skilled in the art.

The term alkenyl refers to straight and branched carbon chains containing at least one carbon-carbon double bond. In some embodiments, alkenyl groups may include C ₂ -C ₂₀ alkenyl groups. In other embodiments, the alkenyl comprises C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ , or C ₂ -C ₄ alkenyl groups. In one version of alkenyl, the number of double bonds is 1-3, in another version of alkenyl, the number of double bonds is one or two. Other numbers of carbon-carbon double bonds and carbon atoms are also included in the definition of this term, depending on the location of the alkenyl fragment in the molecule. C ₂ -C ₁₀ alkenyl groups may contain 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, 1methyl- 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, 3methyl-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-dimethyl2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-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, 2ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl -3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl .

The term alkynyl refers to straight and branched carbon chains containing at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1-3; in another version of alkynyl, the number of triple bonds is one or two. In some embodiments, the alkynyl groups include C ₂ -C ₂₀ alkynyl groups. In other embodiments, alkynyl groups may include C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ , or C ₂ -C ₄ alkynyl groups. Other numbers of carbon-carbon triple bonds and carbon atoms are also included in the definition of this term, depending on the location of the alkynyl moiety in the molecule. C ₂ -C ₁₀ alkynyl as used herein refers to linear or branched unsaturated hydrocarbon groups containing from 2 to 10 carbon atoms 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-yl, n-but -2-in-1-yl, n-pent-1-in-1-yl, n-pent-1-in-3-yl, n-pent-1-in-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-yl -3-yl, 3methylbut-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-6yl, 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-yn2-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, 4methylpent-1-yn-1-yl , 4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and the like.

The term haloalkyl refers to an alkyl group, as defined herein, that is substituted with one or more halogen atoms. For example, C ₁ -C ₄ haloalkyl includes, but is not limited to, chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1fluoroethyl, 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, etc.

The term haloalkenyl refers to an alkenyl group as defined herein.

- 57 041013 text, which is substituted by one or more halogen atoms.

The term haloalkynyl refers to an alkynyl group, as defined herein, that is substituted with one or more halogen atoms.

The term alkoxy refers to the group alkyl-O-, where alkyl has the above meaning. Similarly, the terms alkenyloxy, alkynyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, and halocycloalkenyloxy refer to the groups alkenyl-O-, alkynyl-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-, (CH ₃ ) ₂ CHO-, n-butoxy, C ₂ H ₅ CH(CH ₃ )O-, (CH ₃ ) 2CH-CH2O-, (CH ₃ ) ₃ CO-, n-pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethyl-propoxy , 1-ethylpropoxy, n-hexoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1,2dimethylbutoxy, 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.

The term alkylthio refers to the group alkyl-S-, where alkyl is as defined above. Similarly, the terms haloalkylthio, cycloalkylthio, and the like are refer to the groups haloalkyl-S- and cycloalkyl-S-, where haloalkyl and cycloalkyl have the meanings given above.

The term alkylsulfinyl refers to the group alkyl-S(O)-, where alkyl is as defined above. Similarly, the term haloalkylsulfinyl refers to the group haloalkyl-S(O)-, where haloalkyl has the same meaning as defined above.

The term alkylsulfonyl refers to the group alkyl-S(O) ₂ -, where alkyl has the above meaning. Similarly, the term haloalkylsulfonyl refers to the group haloalkyl-S(O)2-, where haloalkyl has the same meaning as defined above.

The terms alkylamino and dialkylamino refer to the groups alkyl-NH- and (alkyl) ₂ N-, where alkyl is as defined above. Similarly, the term haloalkylamino refers to the group haloalkyl-NH-, where haloalkyl has the same meaning as defined above.

The terms alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl and dialkylaminocarbonyl refer to the groups alkyl-C(O)-, alkoxy-C(O)-, alkylamino-C(O)- and dialkylamino-C(O)-, where alkyl, alkoxy, alkylamino and dialkylamino have the above meanings. Similarly, the terms haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl, and dihaloalkylaminocarbonyl refer to the haloalkyl-C(O)-, haloalkoxy-C(O)-, haloalkylamino-C(O)-, and dihaloalkylamino-C(O)- groups, where haloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are as defined above.

The term aryl refers to a monovalent carbocyclic group containing from 6 to 14 carbon atoms, having one ring or more fused rings. In some embodiments, the aryl groups include C ₆ -C ₁₀ aryl groups. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. Aryl groups may be unsubstituted or be substituted with one or more substituents selected from the following: halogen atom, cyano group, nitro group, hydroxy group, mercapto group, amino group, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkenyl, alkoxy group, alkenyloxy group, alkynyloxy group, haloalkoxy group, haloalkenyloxy group, haloalkynyloxy group, cycloalkoxy group, cycloalkenyloxy group, halocycloalkoxy group, halocycloalkenyloxy group, alkylthio group, haloalkylthio group, cycloalkylthio group, halocycloalkylthio group, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, haloalkylsulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, alkylamino-amino group, alkenyl-amino group group, di(alkyl)amino- group, di(alkenyl)amino group, di(alkynyl)amino group or trialkylsilyl.

The term aralkyl refers to an aryl group that is linked to the remainder of the compound via a diradical alkylene bridge, (-CH ₂ -) _p , where n is 1-12 and where aryl is as defined above.

The term heteroaryl refers to a monovalent aromatic group containing 1-15 carbon atoms, preferably 1 to 10 carbon atoms, containing one or more oxygen, nitrogen and sulfur heteroatoms in the ring, preferably 1-4 heteroatoms or 1-3 heteroatoms. The nitrogen and sulfur heteroatoms may optionally be oxidized. Such heteroaryl groups may have one ring (eg, pyridyl or furyl) or multiple fused rings, provided that the point of attachment is on a heteroaryl ring atom. Preferred heteroaryls include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, cynolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,2,3-benzotriazinyl, 1,2,4-benzotriazinyl, furanyl , thienyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, pyrazolyl, benzofuranyl and benzothienyl. Heteroaryl rings may be unsubstituted or substituted with one or more of the moieties defined above for the term aryl.

The terms heterocyclyl, heterocyclic or heterocyclo refers to fully saturated or unsaturated cyclic groups, for example, 3-7 membered monocyclic or 4-7 membered monocyclic, 7-11 membered bicyclic or 10-15 membered tricyclic systems, which may contain at least one heteroatom in a ring containing at least one carbon atom. Each cycle of a heterocyclic group containing a heteroatom may contain 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom in the ring or ring system, and may be unsubstituted or substituted with one or more substituents as described above for aryl groups.

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

Examples of 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, cinnolinyl, quinoxalinyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2b]pyridinyl] or furo[2,3-Npyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo- quinazolinyl), tetrahydroquinolinyl, and the like.

Examples of tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

The term halogen means fluorine, chlorine, bromine and iodine atoms. The designation halogen (for example, as in the term haloalkyl) refers to all degrees of substitution from single substitution to perhalogen substitution (for example, can be illustrated for methyl: chloromethyl (-CH ₂ Cl), dichloromethyl (-CHCl ₂ ), trichloromethyl (-CCl ₃ )).

The term amorphous in relation to afoxolaner in the present text refers to a solid state in which the molecules of afoxolaner are in a random environment and do not form a pronounced crystal lattice or unit cell. When analyzed by X-ray diffraction analysis, amorphous afoxolaner does not show any characteristic crystalline peaks.

The term chemical purity means the total content of the target product. If the compound is present in enantiomeric forms, the chemical purity, in the context of the present invention, includes both enantiomeric forms when calculating the total content of the desired product. If the compound is present in solvate form, chemical purity, in the context of the present invention, includes the solvate in the calculation of the total content of the desired product. The impurities may be in the form of, for example, unwanted process reactants, intermediates, degradation products, or oxidation products. In particular embodiments, the chemical purity is high, ie the chemical purity is above 90%, especially above 92.5%, 95%, 96%, 97%, 98%, 99% and includes 100%. Purity can be determined by various methods, including HPLC analysis.

The terms enantiomer and enantiomeric mean a molecule that is not aligned with its specular reflection and therefore has optical activity, where the enantiomer rotates the plane of polarized light in one direction, and the compound that is its specular reflection rotates the plane of polarized light in the opposite direction.

The term enantiomeric excess or ee, as used herein, means the difference between the amount of one enantiomer and the amount of the other enantiomer present in a mixture of products. The enantiomeric excess value given below in each example indicates the relative content of each enantiomer. This value is defined as the difference between the relative percentages of the two enantiomers. For example, when the percentage of the (S)-enantiomer of the compound of the present invention is 97.5% and the percentage of the (R)-enantiomer is 2.5%, the enantiomeric excess of the (S)-enantiomer is 95%.

As used herein, the term chiral purity or enantiomeric purity means the percentage of HPLC peak area for the enantiomer of a compound in question relative to the HPLC peak area for the combination of both enantiomers in a mixture, as analyzed by chiral HPLC, excluding other compounds and impurities. For example, the chiral purity of the (S)- 59 041013 enantiomer of afoxolaner is calculated by the equation S/(S+R)x100%, where S and R are the areas of the peaks corresponding to (S)-afoxolaner and (R)-afoxolaner, respectively, when analyzed chiral method

HPLC.

The term isolated, when used herein in relation to solid forms of afoxolaner of the present invention, refers to solid forms of afoxalaner physically separated from the reaction mixture in which they were formed.

The term non-solvate polymorph or non-solvate crystalline form means a crystalline form that does not contain solvent molecules bound in a crystal lattice. However, the crystals may contain a trace amount of solvent unbound in the crystal lattice.

The term polymorph, as used herein, refers to the various crystal structures (solvated or non-solvated forms) in which a compound can crystallize.

The term racemic or racemate and other similar terms refer to equimolar ratios of two enantiomers of a compound. For example, afoxolaner is a racemate containing equimolar amounts of the (S)- and (R)-enantiomers of this compound.

The term seed, as used herein, can be used as a noun to describe one or more crystals of a crystalline compound (eg, racemic afoxolaner) used to induce crystallization of the compound. For example, if crystalline afoxolaner (racemic) is desired, racemic afoxolaner crystals can serve as seed crystals to enhance the crystallization process. The term seeding may also be used to refer to the act of introducing said one or more crystals of a compound into a medium (including, but not limited to, for example, a solution, mixture, suspension, or dispersion), resulting in the formation of more of these the same crystals of the compound (eg, the formation of racemic afoxolaner).

The term hydrate, hydrate polymorph, or hydrated crystalline form refers to the crystalline form of a compound that contains one or more water molecules bound in a crystal lattice.

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

Stereoisomers and polymorphic forms

Those skilled in the art will appreciate that some compounds may exist and be isolated as optically active and racemic forms. Compounds having one or more chiral centers, such as the isoxazoline active ingredients of the present invention, may be present as single enantiomers or diastereomers, or as mixtures of enantiomers and/or diastereomers. Chiral centers in a molecule may include a sulfur atom. For example, it is well known that sulfoxide compounds may be optically active and may exist as single enantiomers or racemic mixtures. In addition, the compounds of the present invention may include other chiral centers, in addition to the chiral carbon atom in the isoxazoline ring, which lead to the existence of a theoretical number of optically active isomers. Where the compounds in the compositions of the present invention include n chiral centers, the compounds may have up to 2 ⁿ optical isomers. The present invention encompasses the particular enantiomers or diastereomers of each compound, as well as mixtures of different enantiomers and/or diastereomers of the compounds of the present invention that have the useful properties described herein.

The compounds in the compositions of the present invention may also be present in various solid forms, such as various crystalline forms or amorphous solid form. The present invention encompasses various crystalline forms as well as amorphous forms of the compounds of the present invention. In addition, the compounds in the compositions of the present invention may exist as hydrates or solvates in which certain stoichiometric amounts of water or solvent are associated with the molecule in crystalline form. Compositions of the present invention may include hydrates and solvates of the active ingredients.

In one embodiment, the present invention encompasses a crystalline solvated solid form of the isoxazoline compounds having formula (I) with an aromatic solvent. In a particularly preferred embodiment, the present invention encompasses a crystalline solvated solid form of (S)-afoxolaner with an aromatic solvent. In a particularly preferred embodiment, the present invention describes a crystalline (S)-afoxolaner solvate toluene. As described above, crystallization of the (S)-enantiomer of afoxolaner from a mixture of (S)- and (R)-enantiomers of afoxolaner enriched in the (S)-enantiomer obtained by reacting compound (IIA-1) with hydroxylamine in the presence of a base and a chiral catalyst

- 60 041013 phase transfer, having the formula (Na-13-1), leads to an unexpected purification of the product and enrichment of the target (S)-enantiomer. Depending on the intended use of the solid form of afoxolaner, the process may involve the preferred isolation of a particular solid form or a particular combination of such solid forms. The use of a solvated crystalline form, such as a crystalline toluene solvate form, instead of unsolvated forms in the composition can eliminate the processing step, namely desolvation, for processes that would otherwise involve desolvation of the solvated crystalline form. E. Shelter and T. Higuchi measured the relative dissolution rates of several crystalline solvated and unsolvated forms of important pharmaceutical compounds, see J. Pharm. Sci., 52 (8), (1963), 781-91.

The crystalline toluene solvate of (S)-afoxolaner was found to contain two molecules of the compound and two molecules of toluene, as shown in FIG. 9 and described in Example 12. (S)-afoxolaner toluene solvate can be prepared by crystallizing (S)-afoxolaner from pure toluene or from a solvent mixture containing toluene (e.g., cyclohexane/toluene) by methods known in the art, including methods described in examples 7, 8 and 12. Crystallization can also be carried out by dissolving (S)-afoxolaner or a sample of (S)-enantiomer-enriched afoxolaner in toluene or in a solvent mixture containing toluene at a concentration which ensures the formation of a suspension at a temperature , at which the compound crystallizes (eg, room temperature or below), and a solution at an elevated temperature, followed by slow cooling to the target temperature to promote crystallization of the target toluene solvate (S)afoxolaner.

In one embodiment, the (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, the (S)-afoxolaner is dissolved in toluene or in a solvent mixture containing toluene by heating the resulting combination to a temperature of about 30° C. to the boiling point of the solvent. In another embodiment, the (S)-afoxolaner is dissolved in toluene or in a solvent mixture containing toluene by heating the resulting combination to a temperature of from about 30°C to about 100°C. More typically, (S)afoxolaner is dissolved in toluene or in a solvent mixture containing toluene by heating the resulting combination to a temperature of from about 30°C to about 80°C, from about 50°C to about 80°C, from about 40°C to about 70°C, or from about 50°C to about 70°C. In another embodiment, the mixture is heated to a temperature of from about 55°C to about 65°C, or from about 50°C to about 60°C. In another embodiment, the mixture is heated to a temperature of from about 30°C to about 50°C.

After solution of the mixture of (S)-afoxolaner in toluene or in a solvent mixture containing toluene, a crystalline toluene solvate of (S)-afoxolaner is obtained by slowly cooling the mixture. In one embodiment, the mixture is cooled to a temperature below about 30°C or below about 20°C. In other embodiments, the mixture is slowly cooled to a temperature below about 15°C or below about 10°C. In another embodiment, the mixture is cooled to a temperature below about 5°C.

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

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

Once the (S)-afoxolaner crystalline toluene solvate has been formed, it can be isolated by filtration or other methods known in the art (eg centrifugation) and dried, optionally under vacuum, to remove excess solvent.

The source of (S)-afoxolaner for crystallization can be another solid form of (S)-61 041013 afoxolaner (for example, amorphous or other crystalline form) or a solution containing (S)-afoxolaner in another solvent, as in examples 7 and 8. Can be used other crystallization methods known in the art.

In one embodiment, the present invention describes a crystalline (3)-afoxolaner solvate toluene (structure shown below)

characterized by powder X-ray diffraction (XRPD) and/or differential scanning calorimetry (DSC) as described in Example 12.

In one embodiment, the present invention describes a crystalline toluene solvate of (3)-afoxolaner having one or more of the characteristic peaks, expressed in degrees 2-theta (2θ)±0.2, as shown in Table 2 below and in FIG. 8 and obtained by the method described in example 12.

table 2

Corner 2-theta ⁰ 1 4.859 2 8.516 3 8.823 4 9.735 5 10.778 6 11.644 7 12.161 8 12.746 9 14.591 10 15.136 AND 16.694 12 16.999 13 17.616 14 18.411 15 18.838 16 19,540 17 19.894 18 20.937 19 21.484 20 21.859 21 22.236 22 22.985 23 23.431 24 24,540 25 25.291 26 25.643 27 26.359 28 27.143 29 28.472 thirty 29.223 31 29.776 32 30.638 33 32.865 34 33.120 35 33.782 36 34.529 37 37.046 38 38.405 39 39.648

-62041013

In another embodiment, the present invention describes a crystalline (S)-afoxolaner toluene solvate having one or more characteristic peaks expressed in degrees

2-theta (2θ)±0.2 shown in Table 3 below and in FIG. 8 and obtained by the method described in example 12.

Table 3

Corner 2-theta ⁰ 1 4.859 2 22.236 3 18.838 4 8.516 5 25.643 6 25.291 7 21.859 8 18.411 9 19.894 10 12.746 AND 23.431 12 16.999 13 10.778 14 14.591 15 27.143 16 12.161 17 17.616 18 15.136 19 9.735 20 11.644

In another embodiment, the present invention describes a crystalline (S)-afoxolaner toluene solvate having one or more of the characteristic peaks, expressed in 2-theta (2θ) ± 0.2 degrees, as shown in Table 4 below and in FIG. 8 and obtained by the method described in example 12.

Table 4

Corner 2-theta ⁰ 1 4.859 2 22.236 3 18.838 4 8.516 5 25.643 6 25.291 7 21.859 8 18.411 9 19.894 10 12.746

In another embodiment, the present invention describes a crystalline toluene solvate of (3)-afoxolaner having at least seven of the characteristic peaks, expressed in degrees 2-theta (2θ)±0.2, in one or more of the positions given above in table. 2, Table 3 or Table 4 and FIG. 8 and obtained by the method described in example 12.

In another embodiment, the present invention describes a crystalline (S)-afoxolaner toluene solvate having at least five of the characteristic peaks, expressed in degrees 2-theta (2θ)±0.2, at one or more of the positions given above in Table 1. 2, Table 3 or Table 4 and FIG. 8 and obtained by the method described in example 12.

In another embodiment, the present invention describes a crystalline (S)-afoxolaner toluene solvate having at least three of the characteristic peaks, expressed in degrees 2-theta (2θ)±0.2, at one or more of the positions given above in Table 1. 2, Table 3 or Table 4 and FIG. 8 and obtained by the method described in example 12.

In another embodiment, the present invention describes a crystalline (3)-afoxolaner toluene solvate having an endotherm ranging from about 70°C to about 90°C as described in Example 12 and shown in FIG. 7.

In another embodiment, the present invention describes a crystalline (3)-afoxolaner toluene solvate having an endotherm ranging from about 75°C to about 90°C as described in Example 12 and shown in FIG. 7.

In another embodiment, the present invention describes crystalline toluene

- 63 041013 (S)-afoxolaner solvate having an endotherm ranging from about 80°C to about 90°C as described in Example 12 and shown in FIG. 7.

In another embodiment, the present invention describes a crystalline (S)-afoxolaner toluene solvate having an endotherm ranging from about 83°C to about 87°C as described in Example 12 and shown in FIG. 7.

In another embodiment, the present invention describes a crystalline (S)-afoxolaner toluene solvate having an endotherm at about 85°C as described in Example 12 and shown in FIG. 7.

In another embodiment, the present invention describes a crystalline (S)-afoxolaner toluene solvate having an endotherm at about 84.7°C as described in Example 12 and shown in FIG. 7.

In another embodiment, the present invention describes a crystalline toluene solvate of (S)-afoxolaner, wherein at least 90% of the solid form is the crystalline toluene solvated form.

In another embodiment, the present invention describes a crystalline (S)-afoxolaner toluene solvate wherein at least 80% of the solid form is the crystalline toluene solvated form.

In another embodiment, the present invention describes a crystalline (S)-afoxolaner toluene solvate wherein at least 70% of the solid form is the crystalline toluene solvated form.

In another embodiment, the present invention describes a crystalline (S)-afoxolaner toluene solvate wherein at least 60% of the solid form is the crystalline toluene solvated form.

In another embodiment, the present invention describes pesticide or parasiticide compositions containing the crystalline toluene solvated form of (S)afoxolaner alone or in combination with other active ingredients, together with agricultural or pharmaceutically acceptable carriers or diluents.

In another embodiment, the present invention describes pesticidal or parasiticide compositions comprising (S)-afoxolaner crystalline toluene solvate alone or in combination with one or more additional active ingredients, and agricultural or pharmaceutically acceptable carriers or diluents, wherein at least 80 % solid form (S)-afoxolaner is a crystalline toluene solvated form of (S)-afoxolaner.

In another embodiment, the present invention describes pesticidal or parasiticide compositions comprising (S)-afoxolaner crystalline toluene solvate alone or in combination with one or more additional active ingredients, and agricultural or pharmaceutically acceptable carriers or diluents, wherein at least 70 % solid form (S)-afoxolaner is a crystalline toluene solvated form of (S)-afoxolaner.

In another embodiment, the present invention describes pesticidal or parasiticide compositions comprising (S)-afoxolaner crystalline toluene solvate alone or in combination with one or more additional active ingredients, and agricultural or pharmaceutically acceptable carriers or diluents, wherein at least 60 % solid form (S)-afoxolaner is a crystalline toluene solvated form of (S)-afoxolaner.

salt

Also within the scope of the present invention are acid and base salts of the compounds described herein, where applicable.

The term acid encompasses all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. In one embodiment, the acids are linear or branched, saturated or unsaturated C1- _C20 aliphatic carboxylic acids which are optionally substituted with halogens 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, methanesulfonic 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 containing from 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butanoic acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and phenylstearic acid. Other acids include gluconic acid, glucoheptonic acid and lactobionic acid.

The term base embraces all pharmaceutically acceptable inorganic or organic bases, including alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates. Salts formed with such bases include, for example, alkali or alkaline earth metal salts, including (but not limited to) lithium, sodium, potassium, magnesium, or calcium salts. Salts formed with organic bases include salts with commonly known hydrocarbon and heterocyclic amines, which include, for example, ammonium (NH ₄ ⁺ ), alkyl- and dialkylammonium salts, and salts with cyclic amines such as morpholine and piperidine salts.

Veterinary Compositions

Compounds having formula (I) enriched in the (S)-enantiomer and compositions containing these compounds can be used to prevent and treat parasitic infestations/infections in animals. The compositions of the present invention contain an effective amount of at least one isoxazoline compound having 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 inactive excipients and optionally in combination with one or more additional active ingredients. In a preferred embodiment, the veterinary parasiticide compositions of the present invention comprise an effective amount of isoxazoline having the above formula IA, enriched in the (S)-enantiomer, or a pharmaceutically acceptable salt thereof, wherein X ¹ , X ² and X ³ are H, chlorine, fluorine or CF ₃ . In another preferred embodiment, the present invention describes veterinary parasiticide compositions containing afoxolaner enriched in the (S)enantiomer as described above.

The compositions may be in various solid and liquid forms suitable for various routes of administration to the animal. For example, veterinary compositions containing the compounds of the present invention may be in compositions suitable for oral administration, injection administration, including subcutaneous and parenteral administration, and topical application (eg, spot application or douche). The compositions are intended for administration 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, alpacas, pigs, horses, donkeys, dogs, cats, and other farm or domestic animals. Examples of birds include turkeys, chickens, ostriches, and other farm or domestic birds. The use of compounds having formula (I) enriched in the (S)-enantiomer is particularly useful in protecting companion animals such as dogs and cats and farm animals such as cattle and sheep from ectoparasites.

Agricultural compositions

In another embodiment, the present invention describes agricultural compositions containing compounds having formula (I), formula IA, enriched in the (S)-enantiomer, including (S)-afoxolaner. The compositions can be used to control pests that damage plants, plant propagation material and crops, or wood-based materials. According to the present invention, compounds having formula (I) enriched in the (S)-enantiomer can be incorporated into common types of formulations such as, for example, solutions, emulsions, suspensions, powders, powders, pastes, granules and spray solutions directly onto processed area. The form of application depends on the specific purpose and route of administration. The type of preparation and method of administration in each case are selected so as to achieve a fine and uniform distribution of the compound having the formula (I) of the present invention.

The present invention also describes an agricultural composition for controlling animal pests, which contains such an amount of at least one compound having formula (I), formula IA, where X ¹ , X ² and X ³ represent H, chlorine, fluorine or CF ₃ enriched in the (S) enantiomer, including (S)-afoxolaner, or an agriculturally acceptable salt thereof, and at least one inert liquid and/or solid agriculturally acceptable carrier that exerts a pesticidal effect, and, if desired, at least one surface-active substance. Such a composition may contain a single active ingredient of formula (I) enriched in the (S)-enantiomer, or a salt thereof, or a mixture of several active ingredients of formula (I) enriched in the (S)-enantiomer, or salts thereof, according to the present invention.

The compositions are prepared in a known manner (see, for example, US 3060084, EP-A 707445 (for liquid concentrates), Browning, Agglomeration, Chemical Engineering, Dec. 4, 1967, 147-48, Perry's Chemical

- 65 041013

Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57; , 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. D. A. Knowles, Chemistry and Technology of Agrochemical Formulations, Kluwer Academic Publishers, Dordrecht, 1998 (ISBN 0-7514-0443-8, which are all included herein by reference), e.g. by diluting the active ingredient with auxiliary components suitable for agrochemical compositions, such as solvents and/or carriers, if necessary, emulsifiers, surfactants and dispersants, preservatives, defoamers, additives to lower the freezing point , and in sl teaching compositions for seed treatment - optionally dyes and/or binders and/or gelling agents.

Application and methods of treatment in veterinary medicine

As described above, compounds having formula (I) enriched in the (S)-enantiomer are effective against ectoparasites and can be used to treat and prevent infestation by parasites in animals or on animal skins. In one embodiment, the present invention describes a method of treating or preventing ectoparasitic infestation in animals or on the integument of animals (e.g., mammals or birds), comprising administering to the animal an ectoparasitically effective amount of a compound having formula (I) enriched in the (S)-enantiomer, or its pharmaceutically acceptable salts, or a composition containing said compound. In another embodiment, the methods of the present invention comprise administering to an animal an effective amount of a compound having formula IA wherein X ¹ , X ² and X ³ are H, chlorine, fluorine, or CF3 enriched in the (S)-enantiomer, or a pharmaceutically acceptable thereof salt. In a preferred embodiment, the methods of the present invention comprise administering to the animal an effective amount of the (S)-enantiomer enriched afoxolaner, or a pharmaceutically acceptable salt thereof.

In another embodiment, when compounds having formula (I) or IA enriched in (S)-enantiomers, including (S)-afoxolaner, are administered in combination with other compounds active against endoparasites, the present invention describes a method for the treatment or prevention of endoparasitic infections and infestations with ectoparasites in the animal or on the integument of the animal. This method comprises administering to an animal a composition comprising an effective amount of a compound having formula (I), IA or an (S)-enantiomer enriched afoxolaner, in combination with an effective amount of at least one second active ingredient, or pharmaceutically acceptable salts thereof.

Mammals that may 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 present invention, the treated animals are humans, cats or dogs.

In one embodiment of the present invention, compositions of the present invention comprising a compound, a compound having formula (I) or IA enriched in the (S)enantiomer, in combination with an additional compound active against endoparasites, are effective against endoparasites resistant to the active substances from the class of macrocyclic lactones. In one embodiment, the compounds and compositions of the present invention are effective against Haemonchus contortus, Ostertagia circumcincta and Trichostrongylus colubriformis in mammals or birds.

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

In one treatment against ectoparasites, the ectoparasites belong to the genus Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Amblyomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes, Trichodectes, and Felicola. Ectoparasites to be treated include, but are not limited to, fleas, ticks, itchs, mosquitoes, flies, lice, blowflies, and combinations thereof. Particular examples include (but are not limited to) cat and dog fleas (Ctenocephalides felis, genus Ctenocephalides, etc.), parasitiform mites (genus Rhipicephalus, Ixodes, Dermacentor, Amblyomma, etc.), and acariform cleft 66 041013 cabbage soup (genus Demodex, Sarcoptes, Otodectes, etc.), lice (genus Trichodectes, Cheyletiella, Linognathus, etc.), mosquitoes (genus Aedes, Culex, Anopheles, etc.) and flies (genus Haematobia , Musca, Stomoxys, Dermatobia, Cochliomyia, etc.). In another treatment option for ectoparasites, the ectoparasite is a flea and/or a tick.

Additional examples of ectoparasites that can be controlled with compounds of formula (I) and IA enriched in (S)-enantiomers include, but are not limited to, Rhipicephalus microplus mite, Rhipicephalus decoloratus, and Rhipicephalus annulatus; myiases such as Dermatobia hominis and Cochliomyia hominivorax (green carrion); sheep myiases such as Lucilia sericata, Lucilia cuprina (known as the carrion fly in Australia, New Zealand and South Africa), flies proper, namely those whose adult forms are parasitic, such as Haematobia irritans (small cow's stallion); lice such as Linognathus vituli and the like; and acariform mites such as Sarcoptes scabiei and Psoroptes ovis. The above list is not exhaustive and other ectoparasites are well known in the art to be dangerous to animals and humans. They include, for example, migrating Diptera larvae.

In one embodiment, when administered with another compound active against endoparasites, the compounds and compositions of the present invention can be used to treat or prevent endoparasitic infection of the following parasites:

Anaplocephala (Anoplocephala) Ancylostoma Necator , Haemonchus, Metastrongylus, Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia, Oxyuris, Parascaris, Schistosoma, Strongylus, Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris, Trichostrongylus, Truodntophorus, Uncinaria, Wuchereria, and combinations thereof . In another embodiment of the present invention, the parasite is Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battus, Dirofilaria immitis, and combinations thereof.

Non-Veterinary Uses and Methods

Due to their excellent activity, compounds having formula (I) enriched in the (S) enantiomer, and especially compounds having formula IA, where X ¹ , X ² and X ³ are H, chlorine, fluorine or CF3, including (S)-afoxolaner can be used to control pests that damage crops, plants and wood-based materials. Accordingly, the present invention also describes a method for controlling animal pests, comprising treating the pests, their food, their habitat or breeding grounds, or crop plants, plant propagation material (such as seeds), soil, area, material or environment, in which pests grow or may grow, or materials, crop plants, plant propagation material (such as seeds), soil, surfaces or spaces to be protected from pest attack or pest infestation, with a pesticidally effective amount of a compound having formula (I) , formula IA, where X ¹ , X ² and X ³ represent H, chlorine, fluorine or CF3, including (S)-afoxolaner, or its salts, or compositions containing the specified connection.

In one embodiment, the method of the present invention serves to protect the plant propagation material (such as seeds) and the plant that grows therefrom from attack or infestation by animal pests, and comprises treating the plant propagation material (such as seeds) with a pesticidally effective the amount of a compound having formula (I), formula IA, where X ¹ , X ² and X ³ represent H, chlorine, fluorine or CF ₃ , including (S)-afoxolaner, or its agriculturally acceptable salt as described above, or pesticidally an effective amount of the agricultural composition described above and below. The method of the present invention is not limited to protecting the substrate (plant, plant propagation material, soil, etc.) that is treated according to the present invention, but also has a preventive effect, such as protecting a plant that grows from the treated material for plant propagation (such as seeds) without the plant itself being treated.

In one embodiment of the present invention relating to agricultural use, animal pests means arthropods and nematodes, more preferably harmful insects, arachnids and nematodes, and even more preferably harmful insects, mites and nematodes.

Examples

The present invention is further described with the help of the following non-limiting examples, which further illustrate the invention, but do not limit, and should not be interpreted as limiting, the scope of the present invention.

All temperatures are in degrees Celsius; room temperature corresponds to a temperature of 20 to 25°C. Reagents were purchased from commercial suppliers or obtained according to literature methods. Chiral purity was determined by HPLC analysis using a chiral column. The indication of the volume of solvent or reagent is based on the volume of the parent compound, assuming the density

- 67 041013 for 1 g/ml.

Bn = benzyl

DXM = dichloromethane

DMF = dimethylformamide

ACN = acetonitrile equiv. = molar equivalents

HPLC = High Performance Liquid Chromatography PE = Petroleum Ether

Red-Al = sodium bis(2-methoxyethoxy)aluminum hydride rt = room temperature

TEA = triethylamine

THF= tetrahydrofuran min. = minutes h = hours rev. = volume of solvent relative to volume of parent compound, calculated assuming a density of 1 gram per milliliter.

Example 1. Obtaining a catalyst.

A chiral phase transfer catalyst having the formula (Ha-131a) was prepared according to the embodiment shown in Scheme 2 below.

Scheme 2

Mol. weight 184.15 GPa-13-1-1

Step 1: Synthesis of IIIa-13-1-1.

Mol. weight 184.15 H1a-13-1-1

1. Load dimethylformamide (DMF, 7.0 L, 10 volumes) into a 20 L 4-necked flask.

2. Load the original compound (700.0 g, 1.0 equiv.) into the flask.

3. Load K ₂ CO ₃ (2622.9 g, 5.0 equiv.) into the flask.

4. BnBr (2250.3 g, 3.5 equiv.) is added dropwise to the mixture at 0~20°C.

5. The reaction mixture is heated to 60±5°C.

6. Stir the reaction mixture for 12 hours at 60±5°C.

7. Monitor the progress of the reaction until the content of the starting compound is <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 off the product (solid) and wash the filter cake with 5.0 l of water.

11. Dry the product in vacuo at 60°C.

12. After drying, 1500 g of product is obtained. The HPLC purity of the product is 99.0% and the yield is 88.0%.

- 68 041013

Step 2: Synthesis of Sha-13-1-2.

Oh Oh

ORp

Red-AI toluene

H1a-13-1-1 llla-13-1-2

1) Load toluene (21.0 L, 10 volumes) into the 50 L reactor.

2) Load IIIa-13-1-1 (2045 g, 1.0 equiv.) into the reactor.

3) Cool the mixture to 0-10°C.

4) Sodium bis(2-methoxyethoxy)aluminum hydride (Red-A1, 3000 g, 2.3 eq.) was added dropwise to the mixture at 0-10° C. with stirring.

5) The reaction mixture is stirred for 5 hours at 15-20°C.

6) Monitor the progress of the reaction by HPLC until the content of the starting compound is <0.5%.

7) After reaching complete conversion (<0.5% of the starting compound), the reaction mixture was poured into 20.0 L of 10% NaOH solution at 10~20°C.

8) The resulting mixture is stirred for 2 hours at 10~15°C and then filtered through a pad of diatomaceous earth (eg Celite).

9) The filter cake is washed with 10.0 L of ethyl acetate and the solvent washings are combined with the filtrate.

10) The combined organic phases are washed with water (10 L) and saturated sodium chloride solution (5.0 L) once.

11) The organic phase is evaporated to about 2 volumes.

12) The concentrated organic phase is then diluted with petroleum ether (PE, 20 L).

13) The diluted organic phase is again evaporated to about 2 volumes and then filtered.

14) The filter cake is washed with 5.0 L of PE and then dried in vacuum at 30-40°C to obtain

1660 g IIIa-13-1-2 (86.0% yield) with a purity of 98.7%.

Step 3: Synthesis of IIIa-13-1-3.

HE

Mol.weight 42S.5

H1a-13-1-2

CI socb D yes ¹ VpoA^OVp

ORp

Mol.weight 444.95 llla-13-1-3

1) Load dichloromethane (DCM, 29.0 L, 10 volumes) into the 50 L reactor.

2) Load IIIa-13-1-2 (2.9 kg, 1.0 equiv.) into a 50-liter reactor and cool to a temperature of about -5 to 0°C.

3) Load SOCl ₂ (900 g, 1.1 equiv.) into the reactor at -5~0°C.

4) Stir the reaction mixture for 5 hours at -5~5°C.

5) Monitor the progress of the reaction by TLC until complete.

6) Evaporate the mixture to 2 volumes.

7) Dilute the residue with petroleum ether (20 L).

8) Evaporate the mixture again to 2 volumes.

9) Dilute the concentrated residue with petroleum ether (20 L).

10) Evaporate the mixture again to 2 volumes.

11) Filter the mixture and wash the filter cake with petroleum ether (5.0 L).

12) Dry the filter cake under vacuum at 30-40°C to give 2.9 kg of product (93.0% yield). Step 4: Synthesis of IIIa-13-1.

1) Charge toluene (15 L, 10 volumes) into a 50 L 4-necked flask.

2) Load quinine (1500 g, 1.0 equiv.) into the reactor.

3) Load IIIa-13-1-3 (2472 g, 1.2 eq.) into the reactor.

- 69 041013

4) Stir the reaction mixture for 12 hours at 60-65°C.

5) Monitor the progress of the reaction by HPLC until the content of the starting compound is <2.0%.

6) After the completion of the reaction according to HPLC, cool the mixture to 25~35°C.

7) Filter the reaction mixture and wash the precipitate on the filter with 10.0 l of toluene.

8) Dry the product in vacuum at 40~45°C to obtain the target product (2.4 kg, 94.9% purity, 67.5% yield).

Proton NMR spectra and LCMS analysis of the product confirm the structure of IIIa-13-1. In FIG. 1 shows the 1H NMR spectrum of the product in DMSO-d ₆ and FIG. 2 shows the LCMS spectrum of the product. The purity of the product according to HPLC analysis is 94.9% by peak area, and the chiral purity according to chiral HPLC is 100% by peak area.

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

An alternative method according to scheme 2 was used to obtain a catalyst having the formula IIIa-13-1.

Step 1: Synthesis of IIIa-13-1-1.

1. 3,4,5-trihydroxybenzoate (9.6 kg, 1.0 eq.) and DMF (76.8 L) are charged into the reactor at 10-25°C.

2. K ₂ CO ₃ (25.1 kg, 3.5 eq.) is charged into the reactor at the same temperature.

3. Benzyl bromide (28.4 kg, 3.2 eq) is then slowly added to the mixture at 20-45°C and the mixture is held at about 60°C for about 4 hours.

4. Analysis of the reaction mixture showed that <1.0% of the starting compound remained.

5. The solid precipitate is filtered off and washed twice with DMF (1 vol.).

6. The filtered solution and washing solution are added to water (115 L) at 5°C and the mixture is stirred for 2 hours at 5-15°C.

7. The resulting mixture is filtered and the filter cake is washed with water.

8. The isolated solid is dried 12 hours in vacuo at 45° C. to give the product (22.6 kg off-white solid).

9. In this alternative method, IIIa-13-1-1 is obtained as an off-white solid with a purity of 99.4% and a yield of 95.4%.

Step 2: Synthesis of IIIa-13-1-2.

1. Tetrahydrofuran (177.6 L) is loaded into the reactor and AlCl ₃ (6.5 kg, 1.0 eq.) is added at 10-15°C.

2. Compound IIIa-13-1 (22.2 kg, 1.0 equiv.) and then NaBH ₄ (1.78 kg, 1.0 equiv.) are loaded into the resulting mixture at 10-25°C.

3. The resulting reaction mixture is kept for 10 hours at 20-30°C, then more NaBH ₄ (1.78 kg, 1.0 equiv.) is added, and the mixture is stirred for another 12 hours.

4. Add 2 more equivalents of NaBH ₄ , stand the reaction mixture (12-14 h), after which HPLC analysis showed that remained <2.5% of the original compound.

5. The reaction mixture is cooled to about 15°C and slowly add water (55.5 l).

6. After water is added, 2M HCl is added to the mixture and the resulting mixture is stirred for the required time at 20°C.

7. Separate the layers, separate the organic layer and re-extract the aqueous layer with ethyl acetate.

8. The combined organic layers are washed with 6% NaHCO ₃ solution and then with 20% saturated sodium chloride solution.

9. The combined organic layers are then evaporated to about 2.5 volumes in vacuo at 4050° C. and heptane (about 67 L) is charged.

10. The mixture is evaporated to about 3 volumes in vacuo.

11. The mixture is filtered and the filter cake washed with heptane.

12. The precipitate is dried in vacuo at 35-45° C. to give 20.1 kg of IIIa-13-1-2 as an off-white solid in 97.5% yield and 96.5% purity.

Step 3: Synthesis of IIIa-13-1 without isolation of IIIa-13-1-3.

1. Toluene (148 L, 10 vol.) and IIIa-13-1-2 (18.5 kg, 1.0 eq.) are loaded into the reactor and cooled to about 15°C.

2. Load SOCl ₂ (5.27 kg, 1.03 eq.) and the resulting mixture was stirred for 3 hours.

3. After confirming the end of the reaction, slowly add water (111 L, 6 vol.) to the reaction mixture.

4. The layers are left to separate and the organic layer is separated.

5. The organic layer is then washed with a solution of NaHCO ₃ (8%) and then K2HPO4 (5%).

6. The washed organic layers are then washed twice with water and then twice with 20% saturated sodium chloride solution.

7. Add quinine (11.3 kg, 0.8 equiv.) to the washed organic layer at 15-25°C, and the mixture is re-

- 70 041013 stirred for 24 hours at 60°C, after which HPLC analysis showed that <5% of quinine remained.

8. The mixture is slowly cooled to 10°C and then stirred at this temperature for about 2 hours.

9. The mixture is filtered, the precipitate is washed twice with toluene and then dried in vacuo at 40° C. for 12 hours to give 20.1 kg of IIIa-13-1 as an off-white solid in 79.4% yield and 96.6% purity by HPLC.

1H NMR and LCMS spectra of the product correspond to the structure of the target product.

Enantiomerically enriched isoxazoline compounds having formula (R)-IA and (S)-IA are prepared according to Examples 3 and 4, respectively, as shown in Scheme 3 below. cycle, regardless of whether it is depicted by wedge-shaped bonds or not.

Scheme 3

Example 3 Synthesis of (R)-IA-2, where the chiral carbon atom in the isoxazoline ring has (Reconfiguration.

1) Compound (IIA-2) (45.0 g, 1.0 eq.) and dichloromethane (DCM, 1.35 L, 30 vols) were placed in a 2 liter reactor and stirred until then. until the solid has completely dissolved.

2) The mixture was cooled to 0°C.

3) Catalyst (IIIb-13-1) (1.8 g, 3 mol %) was added to the mixture.

4) The mixture was cooled to -10°C.

5) Hydroxylamine (25.7 g, 5.0 eq, 50% solution in water) was added to NaOH solution (18.7 g, 6.0 eq, in 5 volumes of water) in another reactor.

6) The solution was stirred for 30 minutes.

7) A solution of hydroxylamine and NaOH was added dropwise to a 2 liter reactor over about 4 hours.

8) The resulting mixture was stirred for 16 hours at -10°C.

9) The reaction progress 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) Left to separate the aqueous and organic phases and separated the organic layer.

13) The organic layer was washed with 200 ml of 15% K ₂ HPO ₄ solution.

14) Left to separate the aqueous and organic phases and separated the organic layer.

15) The organic layer was washed again with 200 ml of saturated sodium chloride solution, the organic layer was collected.

16) The resulting organic layer was evaporated in vacuum at 25~30°C to about 2 volumes.

- 71 041013

17) Toluene (450 ml, 10 vols) was added and the mixture was evaporated in vacuo at 45~50° C. to about vol. This procedure for changing the solvent to toluene was repeated twice.

18) After replacing the solvent with toluene, the solution was heated to 55-60°C.

19) The mixture was cooled to 40°C for 1.5 hours and stirred at 40°C for 3 hours.

20) The mixture was cooled to 25°C for 2 hours and stirred at 25°C for 3 hours.

21) The mixture was cooled to 5~10°C for 1 hour and stirred at 8°C for 12 hours.

22) After 12 hours at 8° C., the precipitate is filtered off and washed on the filter with cold toluene (90 ml, 2 volumes).

23) The resulting solid was dried in vacuo at 85~90°C for 24 hours to give the product as a white solid (24.0 g, 98.4% chiral purity, 99.3% chemical purity, 52.1% yield).

1 H NMR and LCMS of the product were consistent with the structure of (R)-IA-2. In addition, the chiral purity of the product was checked by chiral HPLC using a Chiralpak IA 4.6x150 mm, 5 mm column, mobile phase: n-hexane and isopropanol (90:10), at a temperature of 30°C, a detector with a wavelength of 240 nm. The flow rate was 1.0 ml/min, the sample was prepared at a concentration of 2.0 mg/ml in ethanol.

Example 4 Synthesis of (S)-IA wherein the chiral carbon atom in the isoxazoline ring is in the (S) configuration.

ό CF ₃

1) Compound (IIA-2) (23.0 g, 1.0 eq.) and DCM (690 ml, 30 volumes) were placed in a 1 liter reactor. The solid was completely dissolved.

2) The mixture was cooled to 0°C, while some of the original substance precipitated.

3) Added to the reactor a catalyst having the formula (IIIa-13-1) (0.92 g, 3 mol.%), and the mixture was cooled to -10°C.

4) Hydroxylamine (13.15 g, 5.0 eq, 50% solution in water) was added to NaOH solution (9.56 g, 6.0 eq, in 5 volumes of water) in another reactor.

5) The resulting solution was stirred for 30 minutes.

6) A solution of hydroxylamine and NaOH was added dropwise to a 1 liter reactor containing compound (IIA-2) over about 3 hours.

7) The resulting mixture was stirred for 16 hours at -10°C.

8) Monitor the progress of the reaction by HPLC until the content of the starting compound is < 1.0%.

9) After the reaction was completed, the mixture was heated to 10°C, 100 ml of water was added and the resulting mixture was stirred for 10 minutes.

10) The aqueous and organic layers were allowed to separate, and the organic layer was separated.

11) The organic layer was washed with 100 ml of 5% K ₂ HPO ₄ solution, the layers were left to separate and the organic layer was separated.

12) The organic layer was washed with 100 ml of saturated sodium chloride solution, the layers were left to separate and the organic layer was separated.

13) The organic layer was evaporated in vacuum at 25~30°C to about 2 volumes.

14) Added toluene (230 ml, 10 volumes) and evaporated in vacuum at 45~50°C to about 3 volumes. The solvent exchange process was carried out two more times.

15) After the end of the solvent replacement process, the solution was heated to 55-60°C.

16) Then the mixture was cooled to 40°C for 1.5 h and stirred at 40°C for 3 h.

17) The mixture was then cooled to 25°C over 2 hours and stirred at 25°C for 3 hours.

18) The mixture was cooled further to 5-10°C over 1 hour and stirred at 8°C for 12 hours, after which the solid was filtered off.

19) The filter cake was washed with cold toluene (460 ml, 2 volumes) and then dried in vacuo at 85-90° C. for 24 hours to give the product as a white solid (13.0 g, chiral purity: 99.0% by chiral HPLC according to method described in Example 3, chemical purity: 98.7% by peak area (HPLC), yield: 52.1%). 1H NMR and LCMS spectra were consistent with the structure of the product.

Examples 5 and 6 describe the preparation of (R)-IA-3 and (S)-IA-3, respectively, as shown in Scheme 4 below.

- 72 041013

Scheme 4

Example 5 Synthesis of (R)-IA-3 using a chiral phase transfer catalyst (IIIL-13-1). Stage 1: synthesis of intermediate 4-2.

1) The starting compound, which is a substituted iodobenzene (200.0 g, 1.0 equiv.), and THF (400 ml, 10 volumes) were placed in a 1-liter reactor, and the mixture was cooled to a temperature between -10 and -5°C.

2) i-PrMgCl (340 ml, 1.1 equiv.) was added dropwise to the mixture over 1.5 h at a temperature between -10 and -5°C.

3) After the addition was complete, the mixture was stirred for 1 hour at a temperature between -10 and -5°C.

4) TLC analysis showed complete disappearance of the starting compound (the sample was quenched with 1M HCl solution).

5) CF ₃ COOMe (94.7 g, 1.2 equiv.) was added to the reaction mixture for one hour at a temperature of -10~-5°C.

6) The mixture was stirred for another 12 hours at -10~-5°C.

7) TLC analysis showed almost complete disappearance of intermediate 4-1 (sample was quenched with 1M HCl solution).

8) 1000 ml of 1M HCl solution was slowly added dropwise to the reaction mixture at 0~5°C for 2 hours.

9) The reaction mixture was extracted twice with hexane (1000 ml, 500 ml).

10) 1.0 g of p-toluenesulfonic acid was added to the organic layer, and then the mixture was boiled for 30 minutes.

11) The resulting mixture was evaporated in vacuum at 20~25°C to remove hexane.

12) Sodium bicarbonate (NaHCO ₃ , 300 mg) was added and the mixture was evaporated in vacuo to give compound 4-2 at 80~82°C as a red liquid (85.0 g, 92.5% purity according to HPLC, and the yield was 47.0 %).

Step 2: Obtaining a compound having the formula (IIA-3).

- 73 041013

1) Compound 4-2 (70.0 g, 1.0 eq.) and acetonitrile (ACN, 350 ml, 5 volumes) were placed in a 1 liter 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) ACN/water azeotrope was removed by distillation (bp 79°C).

4) K2COZ (2.0 g, 0.1 equiv.) was added to the mixture.

5) Continued distillation to remove the ACN/water mixture at 90~95°C for about 6 hours.

6) Approximately 28% of compound 4-2 remained after this, according to HPLC.

7) The mixture was cooled to 15~20°C for 1.5 h, a precipitate formed.

8) Water (50 ml) was added and the mixture was cooled to 0°C over 40 min.

9) The mixture was kept at 0°C for 40 min.

10) The mixture is filtered and the filter cake is washed with 100 ml of cold ACN/water (ACN/water, 25:6 v/v) to give 75.0 g of a yellow solid after drying (purity: 95.1%, yield: 50.0%).

Step 3: Preparation of (R)-IA-3 using a chiral phase transfer catalyst IIIb-13-1.

1) The compound having the formula IIA-3 (40.0 g, 1.0 eq.) and DCM (1.2 L, 30 volumes) were placed in a 2 liter reactor; the solid was completely dissolved.

2) The mixture was cooled to 0° C. and some starting material precipitated.

3) Added to the mixture a catalyst having the formula IIIb-13-1 (1.47 g, 3 mol.%), and the mixture was cooled to -10°C.

4) Hydroxylamine (21.0 g, 5.0 eq., 50% solution in water) was added to NaOH solution (15.3 g, 6.0 eq., in 5 volumes of water) in another reactor and stirred for 30 min.

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 -10°C.

7) During the process, samples were taken and analyzed by HPLC until the content of the original substance was <1.0%.

8) When the reaction was completed, the mixture was heated to 10°C and 200 ml of water was added. The resulting mixture was stirred for 10 minutes.

9) After stirring, the mixture was left to separate the aqueous and organic layers, and the organic layer was separated.

10) The organic layer was washed with 200 ml of 5% KH2PO4 solution.

11) Left to separate the layers and separated the organic layer.

12) The organic layer was then washed with 200 ml of saturated sodium chloride solution, left to separate the two layers, and the organic layer was separated again. 13). The resulting organic layer was evaporated in vacuum at 25~30°C to about 2 volumes.

14) Added to the reactor toluene (400 ml, 10 volumes) and continued evaporation in vacuum at 40~45°C to about 3 volumes. The solvent change was repeated two more times by the same procedure.

15) At the end of the solvent change, the solution was heated to 55-60°C.

16) Then the mixture was cooled to 40°C for 1.5 h and stirred at 40°C for 3 h.

17) The mixture was then cooled to 25°C over 2 hours and stirred at 25°C for 3 hours.

18) The mixture was cooled to 5~10°C for 1 hour and stirred at 8°C for 12 hours.

19) The mixture is then filtered and the filter cake washed with cold toluene (80 ml,

- 74 041013 volumes).

20) The product was dried in vacuo at 70~75°C for 12 hours to give a white solid (22.0 g, chiral purity: 98.0% by peak area according to chiral HPLC by the method described in Example 3, chemical purity: 97.1% by area peak (HPLC), yield: 48.8%). 1H NMR and LCMS spectra were consistent with the structure of the product.

Example 6 Preparation of (S)-IA-3 Using Chiral Phase Transfer Catalyst IIIa-13-1.

1) The compound having the formula IIA-3 (11.6 g, 1.0 eq.) and DCM (360 ml, 30 volumes) were placed in a 1-liter reactor; the solid was completely dissolved.

2) The mixture was cooled to 0° C. and some starting material precipitated.

3) 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% solution in water) was added to NaOH solution (4.4 g, 6.0 eq, in 5 volumes of water) in another reactor and the mixture was stirred for 30 min.

5) A solution of hydroxylamine and NaOH was added dropwise to a 1 liter reactor over about 2 hours, after which the mixture was stirred for 16 hours at -10°C.

6) Samples were taken and analyzed by HPLC to monitor the progress of the reaction until the content of the original substance was <1.0%.

7) When the reaction was complete, the mixture was heated to 10°C and 50 ml of water was added. The resulting mixture was stirred for 10 minutes.

8) The mixture was left to separate the aqueous and organic layer, and the organic layer was separated.

9) The organic layer was washed with 50 ml of 5% K ₂ HPO ₄ solution.

10) The mixture was left to separate the layers and the organic layer was separated.

11) The organic layer was washed with 50 ml of saturated sodium chloride solution and the organic layer was separated again.

12) The organic layer was evaporated in vacuum at 25-30°C to about 2 volumes.

13) Added toluene (230 ml, 10 volumes) and continued evaporation in vacuum at 40~45°C to about 3 volumes. The solvent change was repeated two more times using the same procedure.

14) After completing the solvent change, the solution was heated to 55-60°C.

15) The mixture was then cooled to 40°C for 1.5 hours and stirred at 40°C for 3 hours.

16) The mixture was cooled to 25°C for 2 hours and stirred at 25°C for 3 hours.

17) Finally, the mixture was cooled to 5~10°C for 1 hour and stirred at 8°C for 12 hours, then the mixture was filtered.

18) The filter cake was washed with cold toluene (25 ml, 2 volumes).

19) The product was dried in vacuo at 85~90°C for 24 hours to give the product as a white solid (6.8 g, chiral purity: 98.7% by peak area according to chiral HPLC by the method described in Example 3, chemical purity: 99.3 % by peak area (HPLC), yield: 52.1%).

Example 7 Preparation of (3)-afoxolaner using a chiral phase transfer catalyst (IIIa-13-1).

1) Starting material (IIA-1) (200 g, 1.0 eq., 94.0%) and DCM (6 L, 30 volumes) were placed in a 10 L reactor, the solid was completely dissolved.

- 75 041013

2) The mixture was cooled to 0° C. and some starting material precipitated.

3) Catalyst (IIIa-13-1) (7.56 g, 3 mol.%, 95.0%) was added to the mixture, and the resulting mixture was cooled to -10°C.

4) Hydroxylamine (64.9 g, 3.0 eq., 50% solution in water) was added to NaOH solution (52.5 g, 4.0 eq., in 5 volumes of water) in a separate reactor and stirred for 30 minutes.

5) The resulting hydroxylamine/NaOH solution was then dropped into a 10 liter reactor containing (IIA-1) over about 4 hours.

6) The resulting mixture was stirred for 12 h at -10°C and the progress of the reaction was monitored until the amount of starting material was <1.0% according to HPLC.

7) The mixture was then heated to 10° C., 1 L of water was added and the mixture was stirred for 10 minutes.

8) The mixture was left to separate the two phases and the organic layer was separated.

9) The organic layer was then washed with 2 L of water, the layers were allowed to separate and the organic layer was separated.

10) The organic layer was washed with 1 L saturated sodium chloride solution, the layers were allowed to separate and the organic layer was separated and dried over Na2SO4 (200 g).

11) The dried organic layer was evaporated in vacuo to about 2 volumes.

12) Toluene (2 L, 10 vols) was added to the concentrated mixture and evaporation continued in vacuo to about 5 vols. The solvent change was repeated two more times.

13) The resulting solution was placed in a 2.0-liter reactor and heated to 55-60°C.

14) Added cyclohexane (300 ml, 1.5 volumes) at 55-60°C.

15) Then the mixture was cooled to 40°C for 1.5 h and stirred at 40°C for 3 h.

16) The mixture was then cooled to 25°C for 2 hours and stirred at 25°C for another 3 hours.

17) The resulting mixture was cooled to 0~5°C for 1 hour and stirred at 5°C for 12 hours, after which the mixture was filtered to isolate the product.

18) The filter cake was washed with cold toluene/cyclohexane (3:1, 1000 ml, 5 vols).

19) The product was obtained as a white solid. (171.5 g, chiral purity >99.0% by peak area according to chiral HPLC as described in Example 3, chemical purity >99.0% by peak area (HPLC), yield: 83.6%, purity: 92%). 1H NMR and LCMS spectra were consistent with the structure of (S)-afoxolaner as a toluene solvate. In FIG. 3 shows the 1H NMR spectrum of (S)afoxolaner in DMSO-d ₆ FIG. 4 shows the 1H NMR spectrum of afoxolaner (racemic) for comparison. The chiral purity of the product was determined by chiral HPLC as described in Example 3. FIG. 5 shows a chiral HPLC chromatogram of afoxolaner (racemic) and FIG. 6 shows a chiral HPLC chromatogram of the (S)-afoxolaner product showing the presence of one enantiomer.

Example 8 An alternative method for the production of (S)-afoxolaner.

Implemented an alternative method for obtaining (S)-afoxolaner. Some key variations of the alternative method are described below.

1. 1 kg of compound (IIA-1) (1 eq) and 9 L of DCM are charged into a reactor and stirred to dissolve the compound.

2. The mixture is cooled to about 0°C, 50 g (5 mol.%) of chiral phase transfer catalyst (IIIa-13-1) and 1 l of DCM are added and the resulting mixture is cooled to about -13°C.

3. A solution of 19% (w/w) hydroxylamine sulfate (294 g, 1.1 eq.) (prepared from 294 g (NH ₂ OH)H ₂ SO ₄ and 141 g NaCl in 1112 ml water) and 4.4 equivalents of NaOH in in the form of a 17.6% (w/w) solution (286 g of NaOH and 158 g of NaCl in 1180 ml of water) is simultaneously loaded into the reaction mixture.

4. The resulting reaction mixture is incubated for about 20 hours at about -13°C and then check the degree of conversion in the reaction by HPLC (target value <0.5% peak area).

5. After completion of the reaction, water (3 vol.) was added at about 0°C. A solution of 709 g of K2HPO4 in 4.2 L of water is then added, adjusting the pH (target value 7-8), and the resulting mixture is stirred at about 20°C for 30 minutes.

6. The layers are allowed to separate, the aqueous layer is discarded and the organic layer is washed twice with 3 L of water.

Crystallization of toluene solvate

1. After the extraction/washing step, dichloromethane is removed by distillation in vacuo to about 1-2 volumes and toluene is added (about 5-10 volumes).

2. The volume is adjusted by further distillation in vacuo and/or by adding more toluene to about 5-6 volumes. The resulting mixture is distilled off further, maintaining the volume, to completely remove the reaction solvent - dichloromethane.

3. The mixture is cooled to about 10°C, 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, held for at least 17 hours and then solid

- 76 041013 the tooth is filtered. The filtered solid is washed with toluene.

5. The combined filtrates and washings are adjusted to about 5-6 volumes by stripping in vacuo and/or adding toluene.

6. The resulting mixture is cooled to about 10°C and incubated for at least 5 hours, then filtered. The filter cake is washed with toluene.

7. The solid product is dried at 50° C. in vacuo to give (S)-afoxolaner toluene solvate containing about 6 to 8% toluene.

Recrystallization from cyclohexane/ethanol

Toluene solvate of (B)-afoxolaner was further recrystallized from a mixture of cyclohexane and ethanol to remove bound toluene and further purify the product.

1. 591 g of (S)-afoxolaner toluene solvate were placed in a reactor along with 709 ml of ethanol (1.2 vol.) and 1773 ml of cyclohexane (3 vol.) and the mixture was heated to about 60°C.

2. An additional 6383 ml of cyclohexane was added to the resulting mixture with stirring.

3. The resulting mixture was cooled to about 30°C and then heated again to 60°C. This process was repeated once more.

4. The mixture was slowly cooled to 10°C and stirred for at least 5 hours.

5. The resulting suspension is filtered and the filter cake is washed with cyclohexane.

6. The solid product is dried at 50° C. under vacuum to give 453.7 grams of (3)-afoxolaner.

Example 9 Comparison of the selectivity of the benzyloxy-substituted chiral phase transfer catalyst (IIIa-13) with other chiral phase transfer catalysts based on cinchon alkaloids.

The selectivity of the above formation of (S)-afoxolaner from compound IIA-1 was studied with 16 chiral phase transfer catalysts (CMTs) having different structures. The reaction was carried out under the conditions described in example 7. The ratio of (S)-afoxolaner and (R)-afoxolaner in the reaction mixture was determined using chiral HPLC according to the method described in example 3. The results of the study are shown below in table.2.

- 77 041013

table 2

No. Chiral CMP (X)- and (R)afoxolaner ratio 1 ΜΧν ^{+ Ι ci} “ o Π L/^ovn X VoBn OBn 91.5% : 8.5% 2 '° and 62% : 38% 3 gC ^z \ ° \—/ \ 54% : 46% 4 0NG L/X.OPMB ^/O Y^OPMB OPMB PMB = irra-methoxybenzyl 90% : 10% 5 '^=< b c > o 90% : 10% 6 '^o< b J& ^/O M o o \ / 90% : 10%

- 78 041013

7 / \ o o '•A /r^p ABOUT\ 87% : 13% 8 O S h __ hh ~ o / aphids ^ζ \ V ^- ° \=/ \ 80% : 20% 9 °Ί 50% : 50% 10 / \ o o sJA^oir z=Z U O \=/ \ 70% : 30% AND / \ O O o—'C— o ^z \ V ^- ° \=/ \ 69% : 31% 12 o o /“7\S / ^z \ W ^- ° \=/ \ 64% : 35%

- 79 041013

As shown in the table, a catalyst in which the R group in the structure having formula (IIIa) is 3,4,5-tribenzyloxyphenyl results in an unexpectedly improved selectivity in favor of the (S)-enantiomer compared to other quinine phase transfer catalysts, in which the group corresponding to R in formula (IIIa) is another group.

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

A sample of the reaction mixture having an HPLC area ratio of 92.1:7.9 (S)-afoxolaner to (R)-afoxolaner was evaporated to dryness and the residue was recrystallized from toluene and from ethanol/cyclohexane in a manner similar to that described in Example 8. The isolated crystalline solid was analyzed by 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 μm, injection volume - 10 μl, temperature - 35°С, flow rate - 0.8 ml/min, mobile phase - 89% hexane/10% isopropanol/1% methanol, detection at 312 nm). The ratio of (S)-afoxolaner to (R)-afoxolaner in the solid product isolated after crystallization from toluene was 99.0:1.0, while the ratio of (3)-afoxolaner to (R)-afoxolaner in the solid product isolated after crystallization from ethanol/cyclohexane mixture was 95.0:5.0.

This example shows that crystallization of (B)-afoxolaner from an aromatic solvent such as toluene leads to a significant increase in the chiral purity of the product. This is a very unexpected fact.

Example 11 Comparison of the selectivity of benzyloxy and alkoxy-substituted chiral phase transfer catalyst having the formula (IIIa-13).

Three chiral phase transfer catalysts having the formula (IIIa-13) wherein 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 investigated in the process shown below for preparing (S)-IA from compound IIA-1.

- 80 041013

The amount of solvent and reagents, as well as reaction and product isolation conditions, were as described above in Example 7. The same procedure was used for each catalyst tested. It has been found that the selectivity of the tri-benzyloxy catalyst unexpectedly greatly exceeds that of the two alkoxy-substituted catalysts, as judged by the chiral purity of the products. In addition, it was found that when using tri-benzyloxy substituted phase transfer catalyst, the chemical purity was also much higher. The higher selectivity of the benzyloxy-substituted catalyst is significant and unexpected and could not be predicted. Chiral phase transfer catalysts containing phenyl substituted with benzyloxy and alkoxy groups are superior to catalysts substituted with other groups such as electron withdrawing groups and alkyl groups. The chiral purity and chemical purity of the product provided by the respective phase transfer catalysts are summarized in Table 3 below.

Table 3

Catalyst Chiral purity (8)-afoxolaner Chemical purity (% area) R = methyl 86.4% 97.8% R = ethyl 89.0% 98.1 R = benzyl 99.1% 99.6%

Example 12 Crystallization of (S)-afoxolaner to give crystalline toluene solvate.

The amount of (S)-afoxolaner indicated in Table 4 in powder form was placed in a glass vial and numbered accordingly. Then the crystallization solvent was added to the tube (Table 4). The volume of crystallization solvent (see Table 4) was selected so as to obtain preferably a suspension at room temperature and a clear solution at high temperature. Then the tube was hermetically sealed to prevent evaporation of the crystallization solvent, and heated for 1 h at high temperature (see Table 4), stirring the solution on a vortex mixer at 400 rpm or on a magnetic stirrer to dissolve (S)-afoxolaner. To crystallize the product, the tube was then cooled at the rate and to the temperature indicated in Table 4. When crystals formed in the tube, the solution was vacuum filtered and the resulting precipitate was analyzed by powder X-ray diffraction. When there were no crystals in the tube, the additional treatment indicated in Table 4 was applied before X-ray diffraction was performed on the powder. All samples 1-5 were crystalline toluene solvate of (3)-afoxolaner.

Table 4

arr. (5)afoxolaner Crystallization solvent High temp. Cooling rate Cooling temperature Additional processing 1 8.0 mg 20 µl toluene 80°C 3°/h 5°С Filter 0.2µm, then drying 1h at 50°C 2 10 mg 200 µl toluene 50°C 3°/h 5°C Filter 0.2µm, then drying 1h at 50°C 3 10 mg 200 µl Toluene/Cyclohexane (50/50 v/v) 50°C 3°/h 5°С Filter 0.2µm, then drying 1h at 50°C 4 10 mg 200 µl Toluene/Cyclohexane (75/25 v/v) 50°С 3°/h 5°C Filter 0.2µm, then drying 1h at 50°C 5 30 mg 600 µl Toluene/Cyclohexane (75/25 v/v) 50°C 3°/h 5°C -

The solid product 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 a flow of 60 ml/min, standard cup: TA 901670-901 non-sealed, standard lid : TA 901671-901, speed: 10°C/min. TGA analysis showed a weight loss of approximately 10.5% from room temperature to 160°C, especially in the temperature range from 70°C to 90°C. A large weight loss above 280°C is associated with the decomposition of the compound. The TGA curve is shown in FIG. 7.

Solid Sample 2 was analyzed by differential scanning calorimetry (DSC) on a TA Instruments Q200 instrument with the following parameters: atmosphere: nitrogen with a flow of 60 ml/min, standard cup: TA 901670-901 leaky, standard lid: TA 901671-901, speed: 10°C/min. The thermal profile showed a large and narrow endothermic peak between 70 and 90°C. The DSC profile is shown in Fig. 7.

The solid product obtained from Sample 2 was analyzed by X-ray powder diffraction using the following equipment and conditions: instrument: Bruker D8-Advance diffractometer, type: Bragg-Brentano; source CuKa _b λ=1.5406Α, and CuKa _b λ=1.54439Α; generator: 35 kV - 40 mA; detector:

- 81 041013

Lynx Eye; cell Anton Paar TTK450; Si sample holder; angle range: 2° to 40° in 2-theta Bragg;

variable gap: 4 mm (V4); step size: 0.041°; step time: 1 s. In FIG. 8 shows an X-ray powder diffraction pattern for a solid form. Table 6 below shows the 2-theta peaks from the analysis.

Table 6

Corner d value Intensity Intensity % 2-theta ⁰ angstrom number % 4.859 18.17219 2531 100 8.516 10.37469 1375 54.3 8.823 10.01388 457 18.1 9.735 9.07796 298 I,8 10.778 8.20182 729 28.8 11.644 7.59373 272 10.7 12.161 7.27189 566 22.4 12.746 6.93963 1029 40.7 14.591 6.06596 654 25.8 15.136 5.84883 450 17.8 16.694 5.30627 538 21.3 16.999 5.21182 930 36.7 17.616 5.03058 493 19.5 18.411 4.81508 1113 44 18.838 4.70694 1403 55.4 19.54 4.53941 725 28.6 19.894 4.45942 1073 42.4 20.937 4.23955 383 15.1 21.484 4.13274 645 25.5 21.859 4.06265 1141 45.1 22.236 3.99476 1497 59.1 22.985 3.86627 657 26 23.431 3.79365 998 39.4 24,540 3.62465 466 18.4 25.291 3.51867 1218 48.1 25.643 3.4711 1367 54 26.359 3.37852 393 15.5 27.143 3.28268 625 24.7 28.472 3.13235 417 16.5 29.223 3.05358 425 16.8 29.776 2.99809 425 16.8 30.638 2.91563 449 17.7 32.865 2.72303 314 12.4 33.120 2.70265 300 I,9 33.782 2.65114 358 14.1 34.529 2.5955 402 15.9 37.046 2.42474 348 13.7 38.405 2.342 364 14.4 39.648 2.27137 358 14.1

Example 13. X-ray diffraction analysis of a single crystal.

Single crystal X-ray diffraction analysis was performed on a crystal of toluene solvate obtained by crystallization of (S)-afoxolaner obtained by the method of the present invention according to examples 7 and 8. The crystal structure of (S)-afoxolaner was determined and refined to a final R factor of 5.5%. The structure is triclinic, containing two independent (S)-afoxolaner molecules and two toluene molecules. The crystal structure was found to be highly disordered, as shown in FIG. 9. Table 7 below provides some information describing the crystal and molecular structure. According to the Cerius2 molecular modeling program, the absolute configuration of the toluene solvate obtained by the method of the present invention corresponds to (S). The molecular structure obtained using the Cerius2 program is shown in Fig. 10.

- 82 041013

Table 7

Crystal structure parameters Chemical formula C ₃₃ H ₂₅ C1F ₉ N ₃ O ₃ Volume 1561.42 A ³ Crystal system Triclinic space group P1 A 8.2010 A b 10.7031 A With 18.6462 A A 75.6862° β 84.2126° γ 80.592° Density (g/ ^cm3 ) 1.497 R-factor 5.5% Structural factor -0.03 Molecules in a cell 2 Theta Range at Data Collection 1.98°-26.44°

The present invention is further described in the following numbered paragraphs.

1. Process for producing an isoxazoline compound having the following formula (I) which is enriched in one enantiomer

(I) where

B ¹ , B ² , B ³ 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;

R ¹ is C ₁ -C ₃ alkyl or C _g C ₃ haloalkyl;

Y is optionally substituted phenylene, naphthylene, indanylene, 5- or 6-membered heteroarylene, or 8-10-membered fused heterobicyclylene, where the optional substituents are selected from the group consisting of halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy groups, alkylthio groups, haloalkylthio groups, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino groups, dialkylamino groups, -CN or -NO2 and NH ₂ -C(=S)-;

Q is T-NR2R ³ , (-CH ₂ -)(-CH ₂ -)NR ³ , OH, NH2, alkoxy, haloalkoxy, alkylamino, haloalkylamino, dialkylamino, halodialkylamino a group, a thiol, an alkylthio group, a haloalkylthio group, an alkylsulfinyl, a haloalkylsulfinyl, an alkylsulfonyl, a haloalkylsulfonyl, or an optionally substituted 5- or 6-membered carbocyclyl, heterocyclyl, or heteroaryl ring;

T is (C^n, CH(CH3), CH(CN), C(=O) or C(=S);

R ² is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;

R ³ is H, OR ⁷ , NR8R ⁹ or Q ¹ ; or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl, each of which is optionally substituted with one or more substituents independently selected from R ⁴ ; or

R ² and R ³ are combined with the nitrogen atom to which they are attached to form a ring containing 2-6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, where the specified ring is optionally substituted with 1- 4 substituents independently selected from the group consisting of alkyl, halogen, -CN, -NO2 and alkoxy;

each R ⁴ is independently halogen; alkyl, cycloalkyl, alkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, haloalkylamino, dialkylamino, dihaloalkylamino, cycloalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl,

- 83 041013 dihaloalkylaminocarbonyl, hydroxy, -NH2, -CN or -NO2; or Q2;

each R ⁵ is independently halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, -CN, or -NO2;

each R ⁶ is independently halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, -CN , -NO2, phenyl or pyridinyl;

R ⁷ is H; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more halogen atoms;

R ⁸ is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;

R ⁹ is H; ^Q3 ; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is optionally substituted with one or more substituents independently selected from R ⁴ ; or

R ⁸ and R ⁹ are combined with the nitrogen atom to which they are attached to form a ring containing 2-6 carbon atoms and optionally one additional atom selected from the group consisting of N, S and O, where the specified ring is optionally substituted with 1- 4 substituents independently selected from the group consisting of alkyl, halogen, -CN, -NO ₂ and alkoxy;

Q ¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-, or 10-membered fused bicyclic system optionally containing 1-3 heteroatoms selected from up to 1 O atom, up to 1 S atom, and up to 3 atoms N, each ring or ring system is optionally substituted with one or more substituents independently selected from R ⁵ ;

Q ² is independently a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring is optionally substituted with one or more substituents independently selected from R ⁶ ;

Q ³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ring is optionally substituted with one or more substituents independently selected from R ⁶ ; and n is 0, 1, or 2;

where the asterisk means that the given carbon atom is a chiral quaternary carbon atom;

comprising the reaction of a compound having the formula (II)

(P) where B ¹ , B ² , B ³ , R ¹ , Y and Q are as defined for formula (I), with hydroxylamine in the presence of water, a base and a chiral phase transfer catalyst having formula (IIIa) or (IIIb )

(Sha) (Wh) where R is aryl or heteroaryl substituted with one or more aralkoxy, amino, alkylamino or dialkylamino groups; R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is an anion; and isolating said compound.

2. The method according to claim 1, wherein the compound having formula (I) enriched in one enantiomer is isolated by crystallization of the compound from an aromatic solvent or solvent mixture containing an aromatic solvent.

3. The method according to claim 2, where the aromatic solvent is selected from the group consisting of toluene, ethyl-

- 84 041013 benzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole and mesitylene or mixtures thereof.

4. The method of claim 3 wherein the aromatic solvent is toluene.

5. The method according to any one of claims 1 to 4, wherein before isolating the enantiomer-enriched compound having formula (I), the method further comprises crystallizing the racemic compound having formula (I) and separating the solid phase.

6. The method according to any one of claims 1 to 5, where Y is

Y-4 Y-5 Y-6 where Z is N or CH.

7. The method according to claim 1 or 6, where Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(OhCH3, -C(O)NHCH2CH2SCH3 or (-CH2-)(-CH2- )N(CO)CH2S(O)2CH3.

8. The process according to any one of claims 1 to 7, wherein X in the chiral phase transfer catalyst having formula (IIIa) or (IIIb) is a halogen counterion.

9. The method of claim 8 wherein X is a chloride counterion.

10. The method according to any one of claims 1 to 9, wherein R in the chiral phase transfer catalyst having formula (IIIa) or (IIIb) is a phenyl group which is substituted with 1, 2, 3, 4 or 5 aralkoxy groups.

11. The method of claim 10 wherein the aralkoxy group is a benzyloxy group.

12. The method of claim 10 wherein R is substituted with 3 aralkoxy groups.

13. The method of claim 12 wherein R is 3,4,5-tris(benzyloxy)phenyl.

14. A process for the preparation of an isoxazoline compound having the formula IA wherein X ¹ , X ² and X ³ are each independently H, chlorine, fluorine, or CF ₃ which is enriched in the (S)-enantiomer o

x ³

GW comprising the reaction of a compound having the formula (IIA) o

x ³ (PA) where X ¹ , X ² and X ³ are H, chlorine, fluorine, or CF ₃ , with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base, and a chiral phase transfer catalyst having formula (IIIa)

- 85 041013

(Sha) where R is aryl or heteroaryl optionally substituted with one or more C1C ₃ alkoxy groups, amino groups, C ₁ -C ₃ alkylamino groups, C ₁ -C ₃ dialkylamino groups, or aralkoxy groups , R' is a hydrogen atom or a C ₁ -C ₃ -alkoxy group, W is ethyl or vinyl, and X ^- is an anion; and isolating a compound having formula (S)-IA.

15. The method of claim 14, wherein the compound having formula (S)-IA is isolated by crystallization of the compound from an aromatic solvent or solvent mixture containing an aromatic solvent.

16. The method of claim 15, wherein the aromatic solvent is selected from the group consisting of toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole, and mesitylene, or a combination thereof.

17. The method of claim 16 wherein the aromatic solvent is toluene.

18. The method according to any one of claims 14 to 17, wherein before isolating the compound having formula (S)-IA, the method further comprises crystallizing the racemic compound having formula IA and separating the solid phase.

19. The process of claim 14 wherein R in the chiral phase transfer catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 methoxy or ethoxy groups and R' is a hydrogen atom or a methoxy group .

20. The method of claim 14, wherein R in the chiral phase transfer catalyst having formula (IIIa) is phenyl substituted with 1, 2, or 3 benzyloxy groups, and R' is a hydrogen atom or a methoxy group.

21. The process of claim 14 wherein R in the chiral phase transfer catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl.

22. The method of claim 14 wherein X ¹ and X ³ are independently chlorine or CF3 and X ² is H or fluorine.

23. The method according to claim 14, where X ¹ represents chlorine; X ³ is CF3 and X ² is H.

24. The method according to claim 14, where X ¹ and X ³ represent chlorine; and X ² is H.

25. The method of claim 14 wherein X ¹ and X ³ are chlorine and X ² is fluorine.

26. The method according to claim 14, where X ¹ represent chlorine; X ³ is CF3 and X ² is fluorine.

27. Chiral phase transfer catalyst having the formula (IIIa)

(Sha) where R is aryl or heteroaryl substituted with one or more aralkoxy groups, R' is a hydrogen atom or a C ₁ -C ₃ alkoxy group, W is ethyl or vinyl, and X is an anion.

28. The chiral phase transfer catalyst of claim 27 wherein R is phenyl.

29. A chiral phase transfer catalyst according to claim 27 or 28, wherein X is a halogen counterion.

30. The chiral phase transfer catalyst of claim 27 wherein R is phenyl substituted with one or more benzyloxy groups.

31. The chiral phase transfer catalyst of claim 30, wherein R is 3,4,5-

- 86 041013 tris(benzyloxy)phenyl.

32. The chiral phase transfer catalyst of claim 27 wherein W is vinyl and X is chloride.

33. Chiral phase transfer catalyst according to claim 27, where

R is phenyl substituted with one or more benzyloxy groups;

R' represents a hydrogen atom or a methoxy group; W is vinyl; and X ^- represents halogen.

34. The chiral phase transfer catalyst of claim 33 wherein R' is a methoxy group.

35. Chiral phase transfer catalyst according to claim 27, where

R is phenyl substituted with one or more benzyloxy groups;

R' represents a hydrogen atom or a methoxy group; W is ethyl; and X ^- represents halogen.

36. The chiral phase transfer catalyst of claim 35, wherein R' is a methoxy group.

37. The chiral phase transfer catalyst of claim 27, wherein the chiral phase transfer catalyst has the formula (IIIa-13-1), (IIIa-13-2), (IIIa-13-3) or (IIIa-13-4)

OCH ₂ Ph , OCH ₂ Ph

_OCH2 Ph

-

Claims (26)

where X- is a halogen counterion. 38. The chiral phase transfer catalyst of claim 37 wherein X- is chloride. Despite the detailed description of the various embodiments of the present invention, it should be understood that the invention described above is not limited to the specific details given above in the description, since numerous variations are possible without departing from the essence and scope of the present invention. CLAIM 1. Process for producing an isoxazoline compound having the following formula (I) which is enriched in one enantiomer Where B ¹ , B ² , B ³ are each independently CR; each R is independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- _C6 haloalkoxy, C1- _C6 alkylthio, _C1 - _C6 -haloalkylthio group, C1C ₆ -alkylsulfinyl, C 1 -C ₆ -haloalkylsulfinyl, C 1 -C ₆ -alkylsulfonyl, C 1 -C ₆ -haloalkylsulfonyl, C1 -C ₆ -alkylamino group, di-C1 -C ₆ - an alkylamino group or C1- _C6 alkoxycarbonyl; R ¹ is C ₁ -C ₃ haloalkyl; Y is an optionally substituted phenylene, naphthylene, a 5- or 6-membered heteroarylene containing from 1 to 3 O, N or S heteroatoms, or an 8-10-membered fused heterobicyclic lylene containing from 1 to 3 O heteroatoms, N or S, where the optional substituents are selected from the group consisting of halogen, CrC ₆ alkyl, C 1 -C ₆ haloalkyl, C _{1 -C 6 alkoxy, C 1} -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio -groups, C ₁ -C ₆ haloalkylthio groups; Q is T-NR2R ³ ; T is C(=O) or C(=S); R ² is H, C1-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; R ³ is CrC ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, or C ₂ -C ₆ haloalkynyl, each of which is optionally substituted with one or more substituents independently selected from R ⁴ ; each R ⁴ is independently C 1 -C ₆ alkylcarbonyl, C 1 -C ₆ alkoxycarbonyl, C _g C ₆ alkylaminocarbonyl, di-C 1 -C ₆ alkylaminocarbonyl, C 1 -C ₆ haloalkylcarbonyl, C 1 -C ₆ haloalkoxycarbonyl, C ₁ -C ₆ haloalkylaminocarbonyl or di-C ₁ -C ₆ haloalkylaminocarbonyl; and n is 0, 1, or 2; where the asterisk means that the given carbon atom is a chiral quaternary carbon atom; comprising the reaction of a compound having the formula (II) where B ¹ , B ² , B ³ , R ¹ , Y and Q have the meanings given for formula (I), with hydroxylamine in the presence of water, base and a chiral phase transfer catalyst having formula (IIIa) or (IIIb) (Sha) (SHb) where R is phenyl substituted with one or more C₆-WITH₁₄-aralkoxy groups; R' represents a hydrogen atom or C₁-WITH₃-alkoxy group, W is ethyl or vinyl, and X is an anion; and isolating said compound. 2. The method according to claim 1, wherein the compound having formula (I) enriched in one enantiomer is isolated by crystallization of the compound from an aromatic solvent or solvent mixture containing an aromatic solvent. 3. The method of claim 2, wherein the aromatic solvent is selected from the group consisting of toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole and mesitylene, or a combination thereof. 4. The method of claim 3 wherein the aromatic solvent is toluene. 5. The method according to any one of claims 1 to 4, wherein before isolating the enantiomer-enriched compound having formula (I), the method further comprises crystallizing the racemic compound having formula (I) and separating the solid phase. 6. The method according to any one of claims 1 to 5, where Y is - 89 041013 Υ-4 Υ-5 Υ-6 where Z is N or CH. 7. The method according to claim 1 or 6, wherein Q is -C(O)NHCH2C(O)NHCH2CF3, -C(O)CH2S(O)2CH3 or -C(O)NHCH2CH2SCH3. 8. The process according to any one of claims 1 to 7, wherein X ⁱⁿ the chiral phase transfer catalyst having the formula (IIIa) or (IIIb) is a halogen counterion. 9. The method according to claim 7, where X ^- represents a chloride counterion. 10. The method according to any one of claims 1 to 9, wherein R in the chiral phase transfer catalyst having formula (IIIa) or (IIIb) is a phenyl group which is substituted with 1, 2, 3, 4, or 5 C ₆ -C ₁₄ aralkoxy groups. 11. The method of claim 10 wherein the C ₆ -C ₁₄ aralkoxy group is a benzyloxy group. 12. The method of claim 10 wherein R is substituted with 3 C ₆ -C ₁₄ aralkoxy groups. 13. The method of claim 12 wherein R is 3,4,5-tris(benzyloxy)phenyl. 14. A process for the preparation of an isoxazoline compound having the formula IA wherein X ¹ , X ² and X ³ are each independently H, chlorine, fluorine, or CF3 which is enriched in the (S)-enantiomer o x ³ (5)-1A comprising the reaction of a compound having the formula (IIA): O x ³ (PA) where X ¹ , X ² and X ³ are H, chlorine, fluorine, or CF3, with hydroxylamine in the presence of water, a water-immiscible organic solvent, a base, and a chiral phase transfer catalyst having formula (IIIa): - 90 041013 (Sha) where R is phenyl optionally substituted with one or more C ₁ -C ₃ alkoxy groups or C ₆ -C ₁₄ aralkoxy groups, R' is a hydrogen atom or C ₁ -C ₃ alkoxy group, W is ethyl or vinyl and X ^- is an anion; and isolating a compound having formula (S)-IA. 15. The method of claim 14, wherein the compound having formula (S)-IA is isolated by crystallization of the compound from an aromatic solvent or solvent mixture containing an aromatic solvent. 16. The method of claim 15 wherein the aromatic solvent is selected from the group consisting of toluene, ethylbenzene, xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole and mesitylene. 17. The method of claim 16 wherein the aromatic solvent is toluene. 18. The method according to any one of claims 14 to 17, wherein before isolating the compound having formula (S)-IA, the method further comprises crystallizing the racemic compound having formula IA and separating the solid phase. 19. The method of claim 14 wherein R in the chiral phase transfer catalyst having formula (IIIa) is phenyl substituted with 1, 2 or 3 methoxy or ethoxy groups and R' is a hydrogen atom or a methoxy group . 20. The method of claim 14, wherein R in the chiral phase transfer catalyst having formula (IIIa) is phenyl substituted with 1, 2, or 3 benzyloxy groups, and R' is a hydrogen atom or a methoxy group. 21. The process of claim 14 wherein R in the chiral phase transfer catalyst having formula (IIIa) is 3,4,5-tris(benzyloxy)phenyl. 22. The method of claim 14 wherein X ¹ and X ³ are independently chlorine or CF ₃ and X ² is H or fluorine. 23. The method according to claim 14, where X ¹ represents chlorine; X ³ is CF ₃ and X ² is H. 24. The method according to claim 14, where X ¹ and X ³ represent chlorine; and X ² is H. 25. The method of claim 14 wherein X ¹ and X ³ are chlorine and X ² is fluorine. 26. The method according to claim 14, where X ¹ represents chlorine; X ³ is CF ₃ and X ² is fluorine. -