DESC:FIELD OF THE INVENTION
The present invention relates to novel catalysts and their use in preparation of optically enriched isoxazoline compounds. The present invention relates to novel quinine, quinidine, cinchonine or cinchonidine based chiral catalysts and their use in preparation of optically enriched isoxazoline compounds.
BACKGROUND OF THE INVENTION
It is known in the field that isoxazoline compounds have a chiral quaternary carbon atom such as the carbon atom adjacent to the oxygen on the isoxazoline ring of the compounds have at least two optical isomer (enantiomers) that are mirror images of each other. Furthermore, it is sometimes the case with biologically active compounds that one of the enantiomers is more active than the other enantiomer. In addition, it is sometimes the case that one enantiomer of a biologically active compound is less toxic than the other enantiomer.
Therefore, with optically active compounds it is desirable to utilize the enantiomer that is most active and less toxic. However, isolating the most active enantiomer from a mixture can be costly and result in waste of up to half of the racemic mixture prepared.
Processes to prepare certain isoxazoline compounds enriched in an enantiomer using some cinchona alkaloid-derived phase transfer catalysts have been described. For example, US 2014/0206633, US 2014/0350261, WO 2013/116236, WO 2014/081800 and WO2022/020585 (incorporated herein by reference) describe the synthesis of certain isoxazoline active agents enriched in an enantiomer using cinchona alkaloid-based chiral phase transfer catalysts. Further Matoba et al., Angew. Chem. 2010, 122, 5898-5902 describes the chiral synthesis of certain pesticidal isoxazoline active agents. However, these documents do not describe the processes and certain catalysts described herein.

The aim of the present invention is to develop novel catalysts and their use in preparation of optically enriched isoxazoline compounds with improved enantio selectivity of the desired isomer as well as chemical yield and also providing an economical and industrially applicable manufacturing process for optically enriched compounds.
SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparing optically enriched isoxazoline compounds of formula (I)

wherein:
R1 is independently hydrogen, halogen, cyano, nitro, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, haloalkylthio, haloalkylsulfinyl, alkylcarbonyl, haloalkylsulfonyl, alkoxyalkyl, haloalkylcarbonyl, haloalkoxycarbonyl or alkoxycarbonyl;
n is from 0 to 5;
B1, B2 are each CR5, or B1 and B2 together form a sulfur or oxygen or nitrogen atom;
R5 is independently selected from the meaning as mentioned for R1 or two R5 bonded to adjacent carbon atoms may form a five- or six membered saturated, partially or fully unsaturated carbocyclic ring optionally substituted with N, O or S;
R2, R3 and R4 is independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, haloalkylthio, haloalkylsulfinyl, alkylcarbonyl, haloalkylsulfonyl, alkoxyalkyl, haloalkylcarbonyl, haloalkoxycarbonyl or alkoxycarbonyl; or
R2 is T-NR6R7 or -COOR8;
T is (CH2)n, C(=O) or C(=S); wherein n is as defined above;
R6, R7 and R8 are each independently selected from hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, each optionally substituted with one or more substituents independently selected from R9;
each R9 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 amino, cyano or nitro;
wherein the asterisk represents that the carbon atom is a chiral quaternary carbon atom; comprising reacting compound of formula (II)

wherein R1, R2, R3, R4, B1, B2 and n are as defined above, with hydroxylamine, a base, solvent(s) and a chiral catalyst of formula (IIIa) or (IIIb):

wherein R is phenyl group which is substituted with one or more group independently selected from the group consisting of thioalkyl; cyano; –COOH; -COOR’ wherein R’ is alkyl; and aryl group which is unsubstituted or substituted with 1 to 5 substituents selected from nitro, halogen, amino, cyano, alkylamino, dialkylamino, trifluoromethyl, alkyl, alkoxy, and benzyloxy;
X is selected from hydrogen or methoxy group; Z is selected from ethyl or vinyl group and Y is an anion; and isolating the compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION:
Definitions
The term "alkyl" as used herein and in the alkyl moieties of alkylamino, dialkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl and alkoxyalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, prefer ably 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl and like.
The term “halogen” denotes in each case fluorine, bromine, chlorine, or iodine, in particular fluorine, chlorine, or bromine.
The term "haloalkyl" as used herein and in the haloalkyl moieties of haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy, haloalkylaminocarbonyl and haloalkoxyalkyl, denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Preferred haloalkyl moieties are selected from C1-C4-haloalkyl, more preferably from C1-C3-haloalkyl or C1-C2-haloalkyl, in particular from C1-C2-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
The term "alkoxy" as used herein denotes in each case a straight chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert-butyloxy, and the like.

The term "alkoxyalkyl" as used herein refers to alkyl usually comprising 1 to 10, frequently 1 to 4, preferably 1 to 2 carbon atoms, wherein 1 carbon atom carries an alkoxy radical usually com prising 1 to 4, preferably 1 or 2 carbon atoms as defined above. Examples are methoxymethyl, 2-(methoxy)ethyl, and 2-(ethoxy)ethyl and the like.

The term "haloalkoxy" as used herein denotes in each case a straight-chain or branched alkoxy group having from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C1-C4-haloalkoxy, in particular C1-C2-fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoro-methoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and the like.
The term “alkylthio” as used herein refers to a straight-chain or branched saturated alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (C1-C4-alkylthio), more preferably 1 to 3 carbon atoms, which is attached via a sulfur atom.
The term "alkylsulfinyl" as used herein refers to a straight chain or branched saturated alkyl group (as mentioned above) having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (C1-C4-alkylsulfinyl), more preferably 1 to 3 carbon atoms bonded through the sulfur atom of the sulfinyl group at any position in the alkyl group.
The term "alkylsulfonyl" as used herein refers to a straight chain or branched saturated alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (C1-C4-alkylsulfonyl), preferably 1 to 3 carbon atoms, which is bonded via the sulfur atom of the sulfonyl group at any position in the alkyl group.
The term "alkylcarbonyl" refers to an alkyl group as defined above, which is bonded via the carbon atom of a carbonyl group (C=O) to the remainder of the molecule.
The term "alkoxycarbonyl" refers to an alkylcarbonyl group as defined above, which is bonded via an oxygen atom to the remainder of the molecule.

The term "alkenyl" as used herein denotes in each case a singly unsaturated hydrocarbon radical having usually 2 to 10, frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl and the like.

The term "alkynyl" as used herein denotes in each case a singly unsaturated hydrocarbon radical having usually 2 to 10, frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. ethynyl, propargyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylprop-2-yn-1-yl), 2-butyn-1-yl, 3-butyn-1-yl and the like.

The term "cycloalkyl" as used herein and in the cycloalkyl moieties of cycloalkoxy and cycloalkylthio denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The term "halocycloalkyl" as used herein and in the halocycloalkyl moieties of halocycloalkoxy and halocycloalkylthio denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 C atoms or 3 to 6 C atoms, wherein at least one, e.g. 1, 2, 3, 4 or 5 of the hydrogen atoms, are replaced by halogen, in particular by fluorine or chlorine. Examples are 1- and 2-fluo-rocyclopropyl, 1,2-, 2,2- and 2,3-difluorocyclopropyl, 1,2,2-trifluorocyclopropyl, 2,2,3,3-tetrafluo-rocyclpropyl, 1- and 2-chlorocyclopropyl, 1,2-, 2,2- and 2,3-dichlorocyclopropyl, 1,2,2-trichloro-cyclopropyl and the like.

The term "cycloalkenyl" as used herein and in the cycloalkenyl moieties of cycloalkenyloxy and cycloalkenylthio denotes in each case a monocyclic singly unsaturated non-aromatic radical having usually from 3 to 10, e.g. 3 or 4 or from 5 to 10 carbon atoms, preferably from 3 to 8 carbon atoms. Examples of cycloalkenyl groups include cyclopropenyl, cycloheptenyl and the like.

The term “carbocyclyl” or “carbocyclic” includes in general a 3 to 12-membered, preferably a 3 to 8-membered or a 5 to 8-membered, more preferably a 5 or 6-membered mono-cyclic, aromatic or non-aromatic ring optionally substituted with heteroatom S, O or N.

The term “anion” as it relates to Y refers to a negatively charged organic or inorganic group. For example, Y can be tosylate, brosylate, mesylate, nosylate, triflate, acetate, and the like or can be halide, sulfate, phosphate, hydroxide, boron tetrafluoride, and the like. In one embodiment, Y is a halide. In one embodiment Y is chloride or bromide.
The term “enantiomerically pure” as used herein refers to R or an S isomer that is present in greater than 80%, preferably over 90% or more preferably over 95%.
The term "optically enriched" as used herein refers to the presence of an enantiomeric excess of either an R or an S isomer at a given stereocenter of a molecule in a composition.
The term optically enriched mixture have an enantiomeric excess of over 0%, preferably over 20%, preferably over 40%, preferably over 70%, more preferably over 80%, more preferably over 90% or more preferably over 98% of one enantiomer in relation to the other enantiomer.

In first embodiment, the present invention relates to a process for preparing optically enriched isoxazoline compounds of formula (I)

wherein:
R1 is independently hydrogen, halogen, cyano, nitro, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, haloalkylthio, haloalkylsulfinyl, alkylcarbonyl , haloalkylsulfonyl, alkoxyalkyl, haloalkylcarbonyl, haloalkoxycarbonyl or alkoxycarbonyl;
n is from 0 to 5;
B1, B2 are each CR5, or B1 and B2 together form a sulfur or oxygen or nitrogen atom;
R5 is independently selected from the meaning as mentioned for R1 or two R5 bonded to adjacent carbon atoms may form a five- or six membered saturated, partially or fully unsaturated carbocyclic ring optionally substituted with N, O or S;
R2, R3 and R4 is independently selected from hydrogen, halogen, cyano, nitro, amino, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, haloalkylthio, haloalkylsulfinyl, alkylcarbonyl, haloalkylsulfonyl, alkoxyalkyl, haloalkylcarbonyl, haloalkoxycarbonyl or alkoxycarbonyl; or
R2 is T-NR6R7, -COOR8 or an optionally substituted 5- or 6- membered carbocyclyl, heterocyclyl or heteroaryl ring;
T is (CH2)n, C(=O) or C(=S); wherein n is as defined earlier;
R6, R7 and R8 are each independently selected from hydrogen, C1-C4alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, each optionally substituted with one or more substituents independently selected from R9;
each R9 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 amino, cyano or nitro;
wherein the asterisk represents that the carbon atom is a chiral quaternary carbon atom; comprising of reacting compound of formula (II)

wherein R1, R2, R3, R4, B1, B2 and n are as defined as above with hydroxylamine, a base, solvent(s) and a chiral catalyst of formula (IIIa) or (IIIb):

wherein R is phenyl group substituted (i.e. at ortho, meta or para position) with one or more groups consisting of thioalkyl; -CN; –COOH; -COOR’ wherein R’ is alkyl; phenyl which is further optionally substituted with 1 to 5 substituents selected from nitro, halogen, amino, cyano, alkylamino, dialkylamino, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, and benzyloxy;
X is selected from hydrogen or methoxy group;
Z is selected from ethyl or vinyl group and Y is an anion selected from F, Cl, Br, I; and isolating the compound of formula (I).
In second embodiment, the present invention particularly relates to a process for preparing optically enriched isoxazoline compounds of formula (I’)

wherein R1 and n are as defined above; and R10 is independently selected from the meaning as mentioned for R2; wherein the asterisk represents that the carbon atom is a chiral quaternary carbon atom; comprising of reacting compound of formula (II’)

wherein R1, R10 and n are as defined above with hydroxylamine, a base, solvent(s) and a chiral catalyst of formula (IIIa) or (IIIb):

wherein R, X, Z, and Y are as defined above; and isolating the compound of formula (I’).
In third embodiment, the present invention particularly relates to a process for preparing optically enriched isoxazoline compounds of formula (I”)

wherein R10 is independently selected from the meaning as mentioned for R2; wherein the asterisk represents that the carbon atom is a chiral quaternary carbon atom; comprising reacting compound of formula (II”)

wherein R10 is as defined above with aqueous solution of hydroxylamine, a base, solvent(s) and a chiral catalyst of formula (IIIa) or (IIIb):

wherein R, X, Z, and Y are as defined above; and isolating the compound of formula (I’).
The “base” as used herein is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, sodium methoxide, potassium hydroxide, potassium t-butoxide, and mixtures thereof.
The “chiral catalyst” as used herein is preferably in a molar ratio of 0.001 to 10, more typically 0.01 to 1, even more typically 0.05 to 0.5.
The “solvent(s)’ as used herein is selected from chlorinated solvents like dichloromethane, chloroform; ether solvents like tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl-t-butyl ether, t-amyl methyl ether, ethyl-t-butyl ether, water and mixture thereof.
In fourth embodiment, the present invention relates to chiral catalyst of formula (IIIa) or (IIIb) as below:

wherein R, X, Z, and Y are as defined above.
In another embodiment compound of Formula (IIIa) or (IIIb) is selected from quinine, quinidine, cinchonine and cinchonidine based chiral catalyst preferably quinine or cinchonidine based chiral catalyst.
In fifth embodiment, the present invention particularly relates to chiral catalyst as below:

In sixth embodiment, the present invention provides general process of preparing chiral catalyst of formula (IIIa) or (IIIb) as below:

wherein R, X, Z, and Y are as defined above; L in compound of formula (A) is suitable leaving group selected from halogens such as F, Cl, Br or I; mesylate; tosylate; triflate and the like.
In seventh embodiment, the present invention particularly provides process for preparing chiral catalyst as shown in below scheme: wherein X, Y & Z are as defined above and the reaction occurs in presence of suitable solvent selected from but not limited to aromatic hydrocarbon such as toluene, xylene and like; ketone solvents such as acetone, 1-propanone, 2-butanone and the like; nitrile solvents such as acetonitrile and like.
In eight embodiment, the present invention process is illustrated by below general scheme.
wherein R1, R2, R3, R4, B1, B2 and n are as defined above.
In ninth embodiment, the present invention process is further illustrated by below general scheme.

wherein R1, R3, R4, B1, B2 and n are as defined above.
Above process describes a cinchona alkaloid directed asymmetric hydroxylamine/enone cascade reaction using a compound of formula (II) with hydroxyl amine and an appropriate base and solvent(s) in the presence of chiral catalyst of formula (IIIa) or (IIIb) to give an optically enriched or enantiomerically pure compound of formula (I) or (Ia).
The reaction is typically carried out at temperatures of from -50°C to 50°C, more typically - 40°C to 0°C, more typically -40°C to -10°C, and even more typically -30°C to -20°C, and generally required from 1 to 48 hours.
The person of skill in the art will appreciate that a compound of formula (II) exists as geometric isomers. In the compound of formula (II) the bond from the double bond to the CF3 group denotes such geometric isomers, including an E-isomer, a Z-isomer and mixtures thereof and the present invention encompasses the use of the E-isomer, the Z-isomer and mixtures thereof in any ratio.
Wherever applicable in the embodiment or example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The suitable techniques that can be used for the removal of solvent or for isolation of product include but not limited to distillation, distillation under vacuum, evaporation, flash evaporation, simple evaporation, decantation, trituration followed by filtration by gravity or suction, evaporation of the solvent, concentrating the solution centrifugation, filtration and the like, and optionally washing with a solvent or any other suitable technique known in the art. The drying may be carried at normal pressure or under reduced pressure.
The invention is further described in general procedure, which is illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples:
Reference example-1: Preparation of methyl 3-methyl-5-[(E/Z)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate

To a stirred solution of methyl 5-acetyl-3-methyl thiophene-2-carboxylate (1 mol) in MDC (7.5 vol) was added 2,2,2-trifluoro-1-(3,4,5-trichlorophenyl) ethenone (1.05 mol) followed by addition of triethyl amine (3.03 mol). The reaction mass was heated to 40oC for about 2 hours and further cooling to 0oC and thionyl chloride (1.54 mol) was added to it at same temperature. The reaction mass was stirred for about 3 hours at room temperature. The reaction mass was neutralized with sodium bicarbonate solution and organic layer was separated. MDC was distilled out and methanol (2 vol) was added to it. The solid was filtered and dried to obtain product.
Reference example-2: Preparation of methyl 3-methyl-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylate

To the product obtained in reference example-1 was added MDC (10 vol) and cooled to -6oC followed by addition of aq. NaOH solution (3.5 mol) and aq. NH2OH solution (3 mol). The reaction mass was stirred for about 4 hours at -6oC. Dilute HCl solution was added to reaction mass and the organic layer was separated and distilled out to obtain product.
Reference example-3: Preparation of 3-methyl-5-[5-(3.4.5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid

To the product obtained in reference example-2 was added THF (6.5 vol), water (2.5 vol) and aq. NaOH solution (1.7 mol) with stirring. The reaction mass was heat it to 60oC and stirred for about 5 hours. The reaction mass was cooled to 25oC and dil. HCl was added to it followed by addition of ethyl acetate. The organic layer was separated and distilled out to obtain the product.
Reference example-4: Enantiomeric separation of racemic isoxazoline thiophene carboxylic acid and collection of the S-enantiomer

To the product obtained in reference example-3 was added acetonitrile (9.5 vol), 2-butanol (2.3 vol), water (0.4 vol) and (R)-(+)-1-Methyl phenyl ethyl amine (0.9 mol) with stirring. The reaction mass was heat it to 60oC and stirred for about 2 hours and further cooled to 25oC. The reaction mass was filtered to obtain wet cake. The wet cake was added to acetonitrile (8 vol) and heated to 80oC followed by addition of water (6 vol) and stirred for about 2 hours and filtered. The wet cake obtained was again added to acetonitrile (4 vol) and heated to 80oC followed by addition of water (3 vol) and stirred for about 2 hours, filtered and dried to obtain prouduct.
Reference example-5: Preparation of Lotilaner

To the product obtained in reference example-4 was added toluene (10 vol) followed by addition of dil. HCl (3 vol) with stirring. Organic layer was separated and distilled out to obtain residue.
To above residue in DMF was added HBTU (0.8 mol), 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (1.2 mol) and triethyl amine (3.5 mol) with stirring at room temperature. Water (10 vol) was added to the reaction mass and filtered. The filtrate was separated and acidified with dil. HCl and stirred for about 6 hours at room temperature. The solid was filtered and dried to obtain crude product. The crude product was purified using cumene and n-heptane and again purified using methanol and water.

Reference example-6: Preparation of pure Lotilaner
To the product obtained in reference example-5 was added methanol (5 vol). The solution obtained was filtered followed by addition of water (3.3 vol). The reaction mass was cooled, filtered and dried to obtain product.
General procedure for the enantioselective synthesis of trifluoromethyl 2-isoxazolines compounds:
To a stirred solution of trifluoromethylated enones compound of general formula (II) or (II’) and catalyst in dichloromethane was added the aqueous solution of hydroxylamine, aqueous solution of sodium hydroxide at low temperature and stirred under nitrogen atmosphere. After completion of the reaction, it was quenched with saturated aqueous solution of aqueous ammonium chloride. Aqueous layer was extracted with dichloromethane and the combined organic layers were washed with brine, and concentrated under reduced pressure to obtain enriched isoxazoline compounds of formula (I) or (I’).

Example 1: Preparation of (5S)-3-(5-bromo-4-methyl-2-thienyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole

To a stirred solution of (Z/E)-l-(5-bromo-4-methyl-2-thienyl)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-2-en-l-one (1.0 g) in dichloromethane (100 ml) under nitrogen was added (R)-[(2S)-l-[[4- thiomethylphenyl] methyl]-5-vinyl-quinuclidin-l-ium-2-yl]-(6-methoxy-4-quinolyl)methanol bromide (135 mg) and solution was cooled between -15°C to -10°C followed by addition of solution of hydroxylamine in water (0.386 ml) and sodium hydroxide (0.70 ml) at -10°C. The reaction mixture was stirred for about 6 to 7 hours at same temperature and further stirred for about 10 to 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel using ethyl acetate and hexane solvent system. The solvent was removed from the product containing fractions under reduced pressure to obtain product. (Chiral HPLC purity: S-isomer: 91.33%; R-isomer: 8.67%)
Example 2: Preparation of Methyl 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carbo xylate

To a stirred solution of methyl 3-methyl-5-[(E/Z)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl]thiophene-2-carboxylate (0.5 g) in toluene/methyl cyclohexane (1:1; 50 mL) under nitrogen was added (R)-[(2S)-l-[[4- thiomethylphenyl]methyl]-5-vinyl-quinuclidin-l-ium-2-yl]-(6-methoxy-4-quinol yl)methanol bromide (70 mg) and solution was cooled between -15°C to -10°C followed by addition of solution of hydroxylamine in water (0.223 ml) and sodium hydroxide (0.30 ml) at -10°C. The reaction mixture was stirred for about 24 hours at same temperature and further stirred for about 10 to 12 hours at room temperature. The reaction mixture was concentrated under reduced pressure and purified by chromatography on silica gel using ethyl acetate and hexane solvent system. The solvent was removed from the product containing fractions under reduced pressure to obtain product. (Chiral HPLC purity: S-isomer: 96.33%; R-isomer: 3.67%)
Example 3: Preparation of Lotilaner

To a stirred solution of (Z/E)-3-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-2-enoyl)thiophene-2-carboxamide (1 g) in dichloromethane (50 ml) under nitrogen was added (R)-[(2S)-l-[[4- thiomethylphenyl] methyl]-5-vinyl-quinuclidin-l-ium-2-yl]-(6-methoxy-4-quinolyl)methanol bromide (100 mg) and solution was cooled between -15°C to -10°C followed by addition of solution of hydroxylamine in water (0.25 ml) and sodium hydroxide (0.40 ml) at -10°C. The reaction mixture was stirred for about 5 to 6 hours at same temperature and further stirred for about 16 to 18 hours at room temperature. Water (50 ml) was added to reaction mixture. The organic phase was separated, evaporated under reduced pressure to obtain product. (Chiral HPLC purity: S-isomer: 91.78%; R-isomer: 8.22%)

Dated this: 14th day of April, 2025
Dr. S. Ganesan
Alembic Pharmaceutical Ltd

,CLAIMS:WE CLAIM:

1. A process for preparing optically enriched isoxazoline compound of formula (I’)

wherein
R10 is selected from
- halogen;
- -COOR8 wherein R8 is selected from hydrogen, C1-C4 alkyl;
- T-NR6R7 wherein T is C(=O) wherein
R6 and R7 are selected from hydrogen, C1-C4alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, optionally substituted with one or more substituents selected from R9;
R9 is selected from halogen; alkyl, cycloalkyl, alkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino, haloalkylamino, dialkylamino, dihaloalkylamino, cycloalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl, dihaloalkylaminocarbonyl, hydroxy amino, cyano or nitro;
wherein the asterisk represents that the carbon atom is a chiral quaternary carbon atom;
comprising of reacting compound of formula (II”)

with aqueous solution of hydroxylamine, base, solvent(s) and a chiral catalyst of formula

and isolating the compound of formula (I’).

2. The process as claimed in claim 1, wherein base used is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, sodium methoxide, potassium hydroxide and potassium t-butoxide and mixture thereof.

3. The process as claimed in claim 1, wherein chiral catalyst used is having a mole ratio between 0.01 to 1.

4. The process as claimed in claim 1, wherein solvent(s) used are selected from dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl-t-butyl ether, t-amyl methyl ether, ethyl-t-butyl ether, water and mixture thereof.

5. A process for preparing (5S)-3-(5-bromo-4-methyl-2-thienyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole of formula

comprising of reacting compound of formula

with aqueous solution of hydroxylamine, and (R)-[(2S)-l-[[4- thiomethylphenyl] methyl]-5-vinyl-quinuclidin-l-ium-2-yl]-(6-methoxy-4-quinolyl)methanol bromide.

6. A process for preparing methyl 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylate of formula

Comprising of reacting compound of formula

with aqueous solution of hydroxylamine and (R)-[(2S)-l-[[4- thiomethylphenyl] methyl]-5-vinyl-quinuclidin-l-ium-2-yl]-(6-methoxy-4-quinolyl)methanol bromide.

7. A process for preparing Lotilaner of formula

comprising of reacting compound of formula

with aqueous solution of hydroxylamine and (R)-[(2S)-l-[[4- thiomethylphenyl] methyl]-5-vinyl-quinuclidin-l-ium-2-yl]-(6-methoxy-4-quinolyl)methanol bromide.

Dated this: 14th April 2025
Dr. S. Ganesan
Alembic Pharmaceutical Ltd.