DESC:
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

“A PROCESS FOR THE PREPARATION OF ISOXAZOLINE-SUBSTITUTED AMIDE COMPOUNDS AND ITS INTERMEDIATES THEREOF”

HIKAL LIMITED, an Indian company, of 3A & 3B, International Biotech Park, Hinjewadi, Pune- 411057, Maharashtra, India

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

RELATED APPLICATION:
This application claims the benefit of Indian Provisional Application No. IN202321021207, filed on March 24, 2023, the contents of which are incorporated by reference herein.

FILED OF THE INVENTION:
The present invention relates to a process for the preparation of isoxazoline-substituted amide compounds and its intermediates thereof.
The present invention, particularly, relates to a process for the preparation of isoxazoline-substituted amide compounds such as Fluralaner, Afoxolaner or Lotilaner and its intermediates thereof.

BACKGROUND OF THE INVENTION:
The isoxazoline-substituted amide compounds such as Fluralaner, Afoxolaner and Lotilaner (laner compounds) exhibit antiparasiticidal activity with potent inhibitory activity on glutamate- and gamma-aminobutyric acid (GABA)-gated chloride channels in invertebrates, has good selectivity than other classes against insect and parasite species, and generally have a high safety margin in vertebrates. These isoxazoline-substituted benzoic acid amide compounds are useful for functional materials such as medical drugs or agricultural chemicals.

One example of an isoxazoline-substituted amide compound is Fluralaner [Bravecto®, Merck)] which is chemically known as 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]benzamide and structurally represented by compound of formula (I') as mentioned below:

PCT publications WO2005285216A1, WO2007074789A1, WO2009001942A1, WO2010005048A1, WO2023012821A1 disclosed the preparation of Fluralaner and/or its intermediates, which are incorporated herein for reference.

Another example of an isoxazoline-substituted amide compound is Afoxolaner [NexGard®, Boehringer Ingelheim] which chemically known as 4-[5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoro ethyl)amino]ethyl] -1-naphthamide and structurally represented by compound of formula (I'') as mentioned below:

PCT publications WO2009002809A2, WO2009025983A2, WO2009126668A2, and WO2012047543A1 disclosed the preparation of Afoxolaner and/or its intermediates, which are incorporated herein for reference.

Yet another example of an isoxazoline-substituted amide compound is Lotilaner [Credelio®, Elanco)] which is chemically known as (5S) isomer of 5-[4,5-dihydro-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide and structurally represented by compound of formula (I''') as mentioned below:

PCT publications WO2010070068A2, WO2014090918A1, WO2022016490A1 and WO2022020585A1 disclosed the preparation of Lotilaner and/or its intermediates, which are incorporated herein for reference.

Though various prior arts disclosed the preparation of isoxazoline-substituted amide compounds such as Fluralaner, Afoxolaner and Lotilaner (laner compounds), there is still need of a simple, economic, environment-friendly and high yielding alternative method for synthesizing these laner compounds.

SUMMARY OF THE INVENTION:
The present invention provides a process for preparation of an isoxazoline-substituted amide compound of formula (I)

wherein

comprising: reacting an isoxazoline-substituted compound of formula (II)

wherein A and B are the same as defined above,
with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein, X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base.

The present invention also provides a process for preparation of an isoxazoline-substituted amide compound of formula (I)

wherein

comprising:
i) reacting an aromatic ketone compound of formula (IV)

wherein A is the same as defined above,
with a substituted acetophenone compound of formula (V)

wherein R is CN or COOH, and

in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI)

wherein A and R are the same as defined above, and

ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI) to obtain 3-substituted-2-propen-1-one compound of formula (VII)

wherein A and R are the same as defined above, and

iii) reacting 3-substituted-2-propen-1-one compound of formula (VII) with hydroxylamine or its salt, in presence of
a. organic base and solvent, or
b. inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII)

wherein A and R are the same as defined above, and

iv) treating intermediate isoxazoline-substituted compound of formula (VIII)
a. when R= CN, in acidic or basic conditions, or
b. when R= COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II).

wherein

v) reacting an isoxazoline-substituted compound of formula (II) with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein, X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base to obtain isoxazoline-substituted amide compound of formula (I).

The present invention further provides a process for preparing an isoxazoline-substituted compound of formula (II) used for preparation of an isoxazoline-substituted amide compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION:
The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements.

The compounds of the formula (I), (I'), (I'') or (I''') obtained by the process of the present invention has an optically active substance generated by the presence of one or more asymmetric carbon atom(s), and includes all of optically active substances, racemic bodies, and mixtures of the optically active substances in any mixing ratio.

As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having" or any other variation thereof, are intended to cover a non-exclusive inclusion. Also, as used herein, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

As used herein, the terms ‘reacting’, ‘treating’ and ‘condensing’ are generally interchangeable and used in their ordinary meaning as they are in the field of the invention, unless otherwise specifically described.

As used herein, the terms ‘isolating’, ‘obtaining’ and ‘purifying’ are generally interchangeable and include but not specifically limited to extraction, evaporation, crystallization, filtration, recrystallization or chromatographic operations.

As used herein, the term “halo”, “halogen” include fluorine, chlorine, bromine and iodine.
As used herein, the term “solvent” used herein, refers to the single solvent or mixture of solvents.

The product(s) obtained may further be purified to obtain them in purer forms and may further be converted to any other physical forms thereof which includes but not specifically limited to salt(s), solvate(s), hydrate(s), co-crystal(s) and solid dispersion(s) in either crystalline or amorphous forms.

Accordingly, the present invention provides a process for the preparation of an isoxazoline-substituted amide compound of formula (I)

wherein

comprising: reacting an isoxazoline-substituted compound of formula (II)

wherein A and B are the same as defined above,
with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein, X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base.

In one embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted amide compound of formula I' (Fluralaner),

comprising: reacting an isoxazoline-substituted compound of formula (II')

with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein, X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base.

In another embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted amide compound of formula I" (Afoxolaner),

comprising: reacting an isoxazoline-substituted compound of formula (II")

with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein, X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base.

In another embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted amide compound of formula I'" (Lotilaner),

comprising: reacting an isoxazoline-substituted compound of formula (II'")

with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein, X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base.

In an embodiment, in the reaction of the isoxazoline-substituted compound with N-(2,2,2-trifluoroethyl)acetamide compound, the solvent is alcoholic solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; hydrocarbon solvent selected from n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene; ethereal solvent selected from diethyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, acetonitrile; or mixtures thereof.

In an embodiment, the reaction of isoxazoline-substituted compound with N-(2,2,2-trifluoroethyl)acetamide compound is optionally carried out in presence of base, wherein, the base is alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide, caesium hydroxide, ammonium hydroxide; carbonate selected from potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate, calcium carbonate, magnesium carbonate, caesium carbonate, ammonium carbonate; bicarbonate selected from potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, magnesium bicarbonate, caesium bicarbonate, ammonium bicarbonate; alkoxide selected from methoxide, ethoxide, tert-butoxide of sodium, potassium, lithium, barium, calcium, magnesium, caesium, ammonium; hydride selected from sodium hydride, potassium hydride, lithium hydride, barium hydride, calcium hydride, magnesium hydride, caesium hydride; amide selected from sodium amide, potassium amide, lithium amide, Lithium bis(trimethylsilyl)amide, calcium amide, magnesium amide, caesium amide; alkyl lithium selected from methyllithium, n-butyllithium, tert-butyllithium, phenyllithium; or mixtures thereof.

The amount of N-(2,2,2-trifluoroethyl)acetamide used for this reaction is in general, from 0.75 to 10, more preferably from 0.9 to 3 times by mole per mole of isoxazoline-substituted compound. The solvent volumes are, in general, from 2 to 50 volumes, more preferably from 3 to 15 volumes. The base which is optional is not particularly limited, however, the amount is usually used 0.01 to 100 times by mole, preferably 0.05 to 50 times by mole, particularly preferably 0.05 to 10 times by mole per mole of isoxazoline-substituted compound.

In an embodiment, the preparation of preparation of isoxazoline-substituted amide compound of formula I' (Fluralaner) is carried out at a temperature 0°C to 200°C., more preferably from 20°C to 150°C.

In one embodiment, the present invention provides a process for preparation of an isoxazoline-substituted amide compound of formula (I)

wherein

comprising:
i) reacting an aromatic ketone compound of formula (IV)

wherein A is the same as defined above,
with a substituted acetophenone compound of formula (V)

wherein R is CN or COOH, and

in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI)

wherein A and R are the same as defined above, and

ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI) to obtain 3-substituted-2-propen-1-one compound of formula (VII)

wherein A and R are the same as defined above, and

iii) reacting 3-substituted-2-propen-1-one compound of formula (VII) with hydroxylamine or its salt, in presence of
a. organic base and solvent, or
b. inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII)

wherein A and R are the same as defined above, and

iv) treating intermediate isoxazoline-substituted compound of formula (VIII)
a. when R= CN, in acidic or basic conditions, or
b. when R= COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II).

wherein

v) reacting an isoxazoline-substituted compound of formula (II) with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein, X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base to obtain isoxazoline-substituted amide compound of formula (I).

In another embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (I’) (Fluralaner)

comprising:
i) reacting an aromatic ketone compound of formula (IV')

with a substituted acetophenone compound of formula (V')

wherein R is CN or COOH,
in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI')

wherein R is the same as defined above,
ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI') to obtain 3-substituted-2-propen-1-one compound of formula (VII')

wherein R is the same as defined above,
iii) reacting 3-substituted-2-propen-1-one compound of formula (VII') with hydroxylamine or its salt, in presence of
a. organic base and solvent, or
b. inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII')

wherein R is the same as defined above,
iv) treating intermediate isoxazoline-substituted compound of formula (VIII')
a. when R= CN, in acidic or basic conditions, or
b. when R= COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II').

v) reacting an isoxazoline-substituted compound of formula (II') with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein, X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base to obtain isoxazoline-substituted amide compound of formula (I').

In another embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (I") (Afoxolaner)

comprising:
i) reacting an aromatic ketone compound of formula (IV'')

with a substituted acetophenone compound of formula (V'')

wherein R is CN or COOH,
in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI'')

wherein R is the same as defined above,
ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI'') to obtain 3-substituted-2-propen-1-one compound of formula (VII'')

wherein R is the same as defined above,
iii) reacting 3-substituted-2-propen-1-one compound of formula (VII'') with hydroxylamine or its salt, in presence of
a. organic base and solvent, or
b. inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII'')

wherein R is the same as defined above,
iv) treating intermediate isoxazoline-substituted compound of formula (VIII'')
a. when R= CN, in acidic or basic conditions, or
b. when R= COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II'').

v) reacting an isoxazoline-substituted compound of formula (II'') with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein, X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base to obtain isoxazoline-substituted amide compound of formula (I'').

In another embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (I"') (Lotilaner)

comprising:
i) reacting an aromatic ketone compound of formula (IV''')

with a substituted acetophenone compound of formula (V''')

wherein R is CN or COOH,
in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI''')

wherein R is the same as defined above,
ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI''') to obtain 3-substituted-2-propen-1-one compound of formula (VII''')

wherein R is the same as defined above,
iii) reacting 3-substituted-2-propen-1-one compound of formula (VII''') with hydroxylamine or its salt, in presence of
a. organic base and solvent, or
b. inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII''')

wherein R is the same as defined above,
iv) treating intermediate isoxazoline-substituted compound of formula (VIII''')
a. when R= CN, in acidic or basic conditions, or
b. when R= COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II''').

v) reacting an isoxazoline-substituted compound of formula (II''') with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein, X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base to obtain isoxazoline-substituted amide compound of formula (I''').

In one embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (II)

wherein

comprising
i) reacting an aromatic ketone compound of formula (IV)

wherein A is the same as defined above,
with a substituted acetophenone compound of formula (V)

wherein R is CN or COOH, and

in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI)

wherein A and R are the same as defined above, and

ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI) to obtain 3-substituted-2-propen-1-one compound of formula (VII)

wherein A and R are the same as defined above, and

iii) reacting 3-substituted-2-propen-1-one compound of formula (VII) with hydroxylamine or its salt, in presence of
a. organic base and solvent, or
b. inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII)

wherein A and R are the same as defined above, and

iv) treating intermediate isoxazoline-substituted compound of formula (VIII)
a. when R= CN, in acidic or basic conditions, or
b. when R= COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II)

In another embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (II') (Fluralaner intermediate)

comprising
i) reacting an aromatic ketone compound of formula (IV')

with a substituted acetophenone compound of formula (V')

wherein R is CN or COOH,
in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI')

wherein R is the same as defined above,
ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI') to obtain 3-substituted-2-propen-1-one compound of formula (VII')

wherein R is the same as defined above,
iii) reacting 3-substituted-2-propen-1-one compound of formula (VII') with hydroxylamine or its salt, in presence of
a. organic base and solvent, or
b. inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII')

wherein R is the same as defined above,
iv) treating intermediate isoxazoline-substituted compound of formula (VIII')
a. when R= CN, in acidic or basic conditions, or
b. when R= COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II').

In another embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (II'') (Afoxolaner intermediate)

comprising
i) reacting an aromatic ketone compound of formula (IV'')

with a substituted acetophenone compound of formula (V'')

wherein R is CN or COOH,
in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI'')

wherein R is the same as defined above,
ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI'') to obtain 3-substituted-2-propen-1-one compound of formula (VII'')

wherein R is the same as defined above,
iii) reacting 3-substituted-2-propen-1-one compound of formula (VII'') with hydroxylamine or its salt, in presence of
a. organic base and solvent, or
b. inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII'')

wherein R is the same as defined above,
iv) treating intermediate isoxazoline-substituted compound of formula (VIII'')
a. when R= CN, in acidic or basic conditions, or
b. when R= COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II'').

In another embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (II''') (Lotilaner intermediate)

comprising
i) reacting an aromatic ketone compound of formula (IV''')

with a substituted acetophenone compound of formula (V''')

wherein R is CN or COOH,
in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI''')

wherein R is the same as defined above,
ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI''') to obtain 3-substituted-2-propen-1-one compound of formula (VII''')

wherein R is the same as defined above,
iii) reacting 3-substituted-2-propen-1-one compound of formula (VII''') with hydroxylamine or its salt, in presence of
a. organic base and solvent, or
b. inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII''')

wherein R is the same as defined above,
iv) treating intermediate isoxazoline-substituted compound of formula (VIII''')
a. when R= CN, in acidic or basic conditions, or
b. when R= COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II''').

In an embodiment, in reaction of an aromatic ketone with substituted acetophenone, the base is selected from inorganic base or organic base; inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, caesium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, magnesium bicarbonate, caesium bicarbonate, ammonium bicarbonate, potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate, calcium carbonate, magnesium carbonate, caesium carbonate, ammonium carbonate; organic base is selected from methylamine, ethylamine, propylamine, butylamine, di-methylamine, di-ethylamine, di-isopropyl amine, di-isopropyl ethylamine, trimethylamine, triethylamine, tri-benzylamine, pyridine, 4-dimethylaminopyridine, pyrrolidine, piperidine, N-Methyl-Piperidine, piperazine, morpholine, imidazole, 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN), tetramethylguanidine, triazabicyclodecene; or mixtures thereof. The solvent for this reaction is hydrocarbon solvent selected from n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene; chlorinated solvent selected from methylene chloride, ethylene chloride, chlorobenzene; ethereal solvent selected from diethyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether; ester solvent selected from methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate; nitrile solvent selected from acetonitrile, propionitrile, butyronitrile, benzonitrile; alcohol solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, acetonitrile; or mixtures thereof.

The amount of base used in reaction of an aromatic ketone with substituted acetophenone is not particularly limited, however, the amount is usually 0.01 to 100 times by mole, preferably 0.05 to 50 times by mole, particularly preferably 0.05 to 10 times by mole per mole of an aromatic ketone. The solvent volumes are, in general, from 0.1 to 50 volumes, more preferably from 3 to 15 volumes and the reaction can be carried out at a temperature of from 20°C to 200°C, more preferably from 30°C to 150°C.

In an embodiment, the dehydration is performed using dehydrating agent selected from acetic anhydride, propionic anhydride, benzoic anhydride, trifluoro acetic anhydride, hydrochloric acid, phosphoric acid, trifluoroacetic acid, citric acid, sulfuric acid, p-toluenesulfonic acid, acetyl chloride, thionyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, aluminium oxide;.

The amount of dehydrating agent used is usually 0.1 to 100 times by mole, preferably 0.5 to 50 times by mole, particularly preferably 1 to 15 times by mole per mole of the 1,3-bis(substituted phenyl)-3-substituted-3-hydroxypropan-1-one compound obtained by reaction of an aromatic ketone with substituted acetophenone. The solvent volumes are, in general, from 0.1 to 50 volumes, more preferably from 3 to 15 volumes and the reaction can be carried out at a temperature of from 20°C to 200°C, more preferably from 30°C to 150°C.

In an embodiment, in the preparation of intermediate isoxazoline-substituted compound, the organic base is selected from methylamine, ethylamine, propylamine, butylamine, di-methylamine, di-ethylamine, di-isopropyl amine, di-isopropyl ethylamine, trimethylamine, triethylamine, tri-benzylamine, pyridine, 4-dimethylaminopyridine, pyrrolidine, piperidine, N-Methyl-Piperidine, piperazine, morpholine, imidazole, 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN), tetramethylguanidine, triazabicyclodecene; and the solvent is other than water and selected from hydrocarbon solvent selected from n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene; chlorinated solvent selected from methylene chloride, ethylene chloride, chlorobenzene; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; or mixtures thereof.

In an embodiment, in the preparation of intermediate isoxazoline-substituted compound in presence of water, the inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, caesium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, magnesium bicarbonate, caesium bicarbonate, ammonium bicarbonate, potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate, calcium carbonate, magnesium carbonate, caesium carbonate, ammonium carbonate; the phase-transfer catalyst is selected from tetra-butylammonium bromide, tetra-butylammonium chloride, tetra-butylammonium iodide, tetra-butylammonium hydroxide, tetra-methylammonium bromide, tetra-methylammonium chloride, tetra-methylammonium iodide, tetra-methylammonium hydroxide, tetra-butylammonium hydrogen sulfate, 18-crown-6, 15-crown-5; and the solvent is ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; alcohol solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; or mixtures thereof.

The amount of organic or inorganic base used in preparation of intermediate isoxazoline-substituted compound is usually 0.0001 to 10 times by mole, and preferably 0.0005 to 1 times by mole per mole of the substituted-3-hydroxypropan-1-one compound and amount of phase-transfer catalyst used is usually 0.0001 to 10 times by mole, and preferably 0.0005 to 1 times by mole per mole of the substituted-3-hydroxypropan-1-one compound. The solvent volumes, in general, from 2 to 50 volumes, more preferably from 3 to 15 volumes and the reaction can be carried out at a temperature of from 0°C to 200°C, more preferably from 20°C to 150°C.

Hydroxylamine may be used in the form of its salt, such as acid salt selected from hydrochloride, sulfate or acetate, or may also be used as an aqueous solution of adequate concentration. The amount of hydroxylamine used is usually 0.5 to 100 times by mole, preferably 1 to 10 times by mole, particularly preferably 1 to 3 times by mole per mole of the substituted-3-hydroxypropan-1-one compound.

In an embodiment, intermediate isoxazoline-substituted compound (when R= CN) under acidic conditions is converted into isoxazoline-substituted compound, wherein, acidic conditions involve treating intermediate isoxazoline-substituted compound with an acid optionally in solvent at a temperature of from 40°C to 100°C, more preferably from 50°C to 80°C. The acid used is selected from acetic acid, sulphuric acid, hydrochloric acid; and the solvent used is alcoholic solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; water or mixtures thereof. The solvent volumes are, in general, from 2 to 50 volumes, more preferably from 3 to 15 volumes.

In an embodiment, intermediate isoxazoline-substituted compound (when R= CN) under basic conditions is converted into isoxazoline-substituted compound, wherein, basic conditions involve treating intermediate isoxazoline-substituted compound with an inorganic base in solvent at a temperature of from 30°C to 150°C, more preferably from 70°C to 120°C, wherein base is in an amount usually 0.5 to 3 times by mole, and preferably 1 to 2 times by mole per mole of intermediate isoxazoline-substituted compound (R= CN). The base used is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, caesium hydroxide. The solvent used in acidic or basic conditions is alcoholic solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; water or mixtures thereof. The solvent volumes are, in general, from 2 to 50 volumes, more preferably from 3 to 15 volumes.

In an embodiment, intermediate isoxazoline-substituted compound (when R= COOH) is converted into isoxazoline-substituted compound by treating it with acid activating agent, followed by treatment with ammonia source in solvent. The acid activating agent used is selected from thionyl chloride, thionyl bromide, oxalyl chloride, pivaloyl chloride, tosyl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, phosphorus tribromide, phosphorus triiodide, triphosgene, acetic anhydride, N,N-dicyclohexylcarbodiimide (DCC), 1,1-carbonyldiimidazole (CDI), 3-(ethyliminomethyleneamino)-N, N-dimethylpropan-1-amine (EDC); the ammonia source is selected from ammonia gas, ammonium hydroxide, liquor ammonia and methanolic ammonia and the solvent used is hydrocarbon solvent selected from n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene; chlorinated solvent selected from methylene chloride, ethylene chloride, chlorobenzene; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; or mixtures thereof. The reaction can be carried out at a temperature of from 0°C to 200°C, more preferably from 20°C to 150°C. The solvent volumes, in general, from 2 to 50 volumes, more preferably from 3 to 15 volumes.

In an alternate embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (II)

wherein

comprising,
i) treating intermediate isoxazoline-substituted nitrile compound of formula (VIII-a)

wherein A is the same as defined above and

under controlled, acidic conditions optionally in solvent or in basic conditions in solvent to obtain isoxazoline-substituted compound of formula (II), or
ii) treating intermediate isoxazoline-substituted nitrile compound of formula (VIII-a)

wherein A is the same as defined above and

under acidic conditions optionally in solvent or basic conditions in solvent to obtain intermediate isoxazoline-substituted acid compound of formula (VIII-b);

wherein

reacting intermediate isoxazoline-substituted acid compound of formula (VIII-b) with an acid activating agent, followed by ammonia source in solvent to obtain isoxazoline-substituted compound of formula (II).

In another alternate embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (II') (Fluralaner intermediate)

comprising,
i) treating intermediate isoxazoline-substituted nitrile compound of formula (VIII'-a)

under controlled, acidic conditions optionally in solvent or in basic conditions in solvent to obtain isoxazoline-substituted compound of formula (II), or
ii) treating intermediate isoxazoline-substituted nitrile compound of formula (VIII'-a)

under acidic conditions optionally in solvent or basic conditions in solvent to obtain intermediate isoxazoline-substituted acid compound of formula (VIII'-b);

reacting intermediate isoxazoline-substituted acid compound of formula (VIII'-b) with an acid activating agent, followed by ammonia source in solvent to obtain isoxazoline-substituted compound of formula (II').

In another alternate embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (II'') (Afoxolaner intermediate)

comprising,
i) treating intermediate isoxazoline-substituted nitrile compound of formula (VIII''-a)

under controlled, acidic conditions optionally in solvent or in basic conditions in solvent to obtain isoxazoline-substituted compound of formula (II), or
ii) treating intermediate isoxazoline-substituted nitrile compound of formula (VIII''-a)

under acidic conditions optionally in solvent or basic conditions in solvent to obtain intermediate isoxazoline-substituted acid compound of formula (VIII''-b);

reacting intermediate isoxazoline-substituted acid compound of formula (VIII''-b) with an acid activating agent, followed by ammonia source in solvent to obtain isoxazoline-substituted compound of formula (II'').

In another alternate embodiment, the present invention provides a process for the preparation of an isoxazoline-substituted compound of formula (II''') (Lotilaner intermediate)

comprising,
i) treating intermediate isoxazoline-substituted nitrile compound of formula (VIII'''-a)

under controlled, acidic conditions optionally in solvent or in basic conditions in solvent to obtain isoxazoline-substituted compound of formula (II), or
ii) treating intermediate isoxazoline-substituted nitrile compound of formula (VIII'''-a)

under acidic conditions optionally in solvent or basic conditions in solvent to obtain intermediate isoxazoline-substituted acid compound of formula (VIII'''-b);

reacting intermediate isoxazoline-substituted acid compound of formula (VIII'''-b) with an acid activating agent, followed by ammonia source in solvent to obtain isoxazoline-substituted compound of formula (II''').

In an embodiment, under controlled acidic conditions, intermediate isoxazoline-substituted nitrile compound is converted into isoxazoline-substituted compound, wherein, acidic conditions involve treating intermediate isoxazoline-substituted nitrile compound with an acid optionally in solvent at a temperature of from 40°C to 100°C, more preferably from 50°C to 80°C. The acid used is selected from acetic acid, sulphuric acid, hydrochloric acid; and the solvent used is alcoholic solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; water or mixtures thereof. The solvent volumes are, in general, from 2 to 50 volumes, more preferably from 3 to 15 volumes.

In an embodiment, under controlled basic conditions, intermediate isoxazoline-substituted nitrile compound is converted into isoxazoline-substituted compound, wherein, basic conditions involve treating intermediate isoxazoline-substituted compound with an inorganic base in solvent at a temperature of from 30°C to 150°C, more preferably from 70°C to 120°C, wherein base is in an amount usually 0.5 to 3 times by mole, and preferably 1 to 2 times by mole per mole of intermediate isoxazoline-substituted nitrile compound. The base used is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, caesium hydroxide. The solvent used in acidic or basic conditions is alcoholic solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; water or mixtures thereof. The solvent volumes are, in general, from 2 to 50 volumes, more preferably from 3 to 15 volumes.

In an embodiment, under acidic conditions, intermediate isoxazoline-substituted nitrile compound is converted into isoxazoline-substituted acid compound, wherein, acidic conditions involve treating intermediate isoxazoline-substituted nitrile compound with an acid optionally in solvent at a higher temperature of from 40°C to 200°C, more preferably from 70°C to 140°C. The acid used is selected from acetic acid, sulphuric acid, hydrochloric acid; and the solvent used is alcoholic solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; water or mixtures thereof. The solvent volumes are, in general, from 2 to 50 volumes, more preferably from 3 to 15 volumes.

In an embodiment, under basic conditions, intermediate isoxazoline-substituted nitrile compound is converted into isoxazoline-substituted acid compound, wherein, basic conditions involve treating intermediate isoxazoline-substituted nitril compound with an inorganic base in solvent at a temperature of from 30°C to 150°C, more preferably from 70°C to 120°C, wherein base is in an excess amount usually 2 to 40 times by mole, and preferably 15 to 25 times by mole per mole of intermediate isoxazoline-substituted nitrile compound. The base used is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, caesium hydroxide. The solvent used in acidic or basic conditions is alcoholic solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; water or mixtures thereof. The solvent volumes are, in general, from 2 to 50 volumes, more preferably from 3 to 15 volumes.

In an embodiment, intermediate isoxazoline-substituted acid compound is converted into isoxazoline-substituted compound by reacting it with acid activating agent, followed by treatment with ammonia source in solvent. The acid activating agent used is selected from thionyl chloride, thionyl bromide, oxalyl chloride, pivaloyl chloride, tosyl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, phosphorus tribromide, phosphorus triiodide, triphosgene, acetic anhydride, N,N-dicyclohexylcarbodiimide (DCC), 1,1-carbonyldiimidazole (CDI), 3-(ethyliminomethyleneamino)-N, N-dimethylpropan-1-amine (EDC); the ammonia source is selected from ammonia gas, ammonium hydroxide, liquor ammonia and methanolic ammonia and the solvent used is hydrocarbon solvent selected from n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene; chlorinated solvent selected from methylene chloride, ethylene chloride, chlorobenzene; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; or mixtures thereof. The reaction can be carried out at a temperature of from 0°C to 200°C, more preferably from 20°C to 150°C. The solvent volumes, in general, from 2 to 50 volumes, more preferably from 3 to 15 volumes.

A process for the preparation of isoxazoline-substituted amide compounds and its intermediates according to the present invention is substantially as same as that depicted in Scheme-I.

The solvents, reagents, catalysts, temperature pressure conditions, work up mechanism, mode of addition along with examples provided herein are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way. Any modifications, extrapolation or any design around shall be the part of the present invention.

Examples:
Example 1: Preparation of substituted-2-propen-1-one compound (VII', wherein R= CN)

To a mixture of 4-acetyl-2-methylbenzonitrile (150.0g, 0.942 mol) in toluene (900 mL), added potassium per carbonate (188.7g, 1.365 mol) and p-toluenesulfonic acid monohydrate (53.8g, 0.283 mol). To this reaction mixture added 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethan-1-one (263.3g, 1.084 mol) in dimethylformamide (30 mL), heated the reaction mixture to reflux for 10-14 hours and water removed. After completion of reaction, the reaction mass was cooled at 20-30°C, THF (900 mL) and water (1350 mL) were charged, stirred for 30 min, separated the organic layer and the organic layer carried forward as such for next conversion.
HPLC purity: 92%.

Example 2: Preparation of substituted-2-propen-1-one compound (VII', wherein R= COOH)

To the mixture of 4-acetyl-2-methylbenzoic acid (50.0g, 0.28 mol) in toluene (300 mL) added triethylamine (42.6g, 0.42 mol), 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethan-1-one (75.0g, 0.31 mol), and the reaction mixture heated at 60°C for 10-14 hours. After completion of reaction, the reaction mass filtered. To the filtrate added DMAP (3.4g, 0.03 mol) followed by acetic anhydride (57.3g, 0.56 mol) and the reaction mixture heated at 60 °C for 6-10 hours. After completion of reaction, added water and ether (300 mL), stirred for 30 min, separated the organic layer and the organic layer carried forward as such for next conversion.
HPLC purity: 87%.

Example 3: Preparation of intermediate isoxazoline-substituted compound (VIII', wherein R= CN)
1. presence of organic base and solvent:

To the compound VII' (0.942 mol) obtained in example 1 added hydroxyl amine hydrochloride (98.2g, 1.42 mol) and 1,8-Diazabicyclo(5.4.0)undec-7-ene (301.2g, 1.98 mol) at 0-10°C and maintained the reaction for 2-4 hours. After completion of reaction, added water (750 mL), separated the organic layer, solvent removed under vacuum. Stirred the crude mass in isopropanol (750 mL) and filtered to give intermediate isoxazoline-substituted compound.
Yield: 316.0g, 84%; HPLC purity: 88%.

2. Presence of inorganic base, phase-transfer catalyst, solvent, and water:

To the compound VII' (0.942 mol) obtained in example 1 added hydroxyl amine hydrochloride (98.2g, 1.42 mol), sodium hydroxide (79.1g, 1.98 mol) in water (360 mL) at 0-10°C and maintained the reaction for 2-4 hours. After completion of reaction, organic layer separated, solvent removed under vacuum, stirred the crude mass in isopropanol (750 mL) and filtered to give intermediate isoxazoline-substituted compound.
Yield: 331.0g, 88%; HPLC purity: 90%.
1H NMR (400 MHz, DMSO-d6): d 2.52 (s, 3H), 4.30 – 4.44 (m, 2H), 7.61 (s, 2H), 7.67 – 7.72 (d, J = 8.4, 1H), 7.82 (d, J = 0.8, 2H), 7.90 – 7.92 (d, J = 8.0, 1H)
Example 4: Preparation of intermediate isoxazoline-substituted compound (VIII', wherein R= COOH)

To the mixture of compound VII' (0.28 mol) obtained in example 2 added DBU (85.25g, 0.56 mol), aq. solution of NaOH (11.2g, 0.28 mol in water 25 mL), aq. solution of hydroxylamine hydrochloride (23.35g, 0.336 mol in water 25 mL) at 0-10°C and maintained the reaction for 2-4 hours. After completion of reaction, added aq. HCl (92 mL) to adjust pH to 1-2, stirred for 15 min, separated the organic layer and solvent removed under vacuum. The crude mass stirred in n-heptane (150 mL) and filtered to give intermediate isoxazoline-substituted compound.
Yield: 80g, 68%; HPLC purity: 86%.
1H NMR (400 MHz, DMSO-d6): d 2.53 (s, 3H), 4.26 (m, 2H), 7.61-7.63 (m, 4H), 7.78 (d, J = 11.2, 1H), 7.87 (d, J = 8, 1H), 13.09 (s, 1H)

Example 5: Preparation of isoxazoline-substituted compound of formula (II')
1. Acidic conditions:

To the compound VIII' (300g, 0.752 mol) obtained in example 3 added acetic acid (1500 mL), sulphuric acid (60 mL) and heated to 50 to 80°C for 12 hours. After completion of reaction, added water (3000 mL), and filtered to get crude product. Crude product stirred with acetonitrile (1500 mL) and filtered to give isoxazoline-substituted compound.
Yield: 254.0g, 81%; HPLC purity:86%.

2. Basic Conditions:

To the compound VIII' (300g, 0.752 mol) obtained in example 3 added sodium hydroxide (60.1g, 1.5 mol) in water (1500 mL) and isopropyl alcohol (750 mL). The reaction mixture heated to 70-120°C for 8 hours. After completion of reaction, added water (1500 mL), and filtered to get crude product. Crude product stirred with acetonitrile (1500 mL) and filtered to give isoxazoline-substituted compound.
Yield: 272.8g, 87%; HPLC purity:84%.
1H NMR (400 MHz, CDCl3): d 2.38 (s, 3H), 4.25 – 4.38 (m, 2H), 7.42 (d, J = 7.6, 1H), 7.48 (s, 1H), 7.52 – 7.61 (m, 4H), 7.80 (s, 2H)

Example 6: Preparation of isoxazoline-substituted compound of formula (II')

To the compound VIII' (50g, 0.120 mol) obtained in example 4 added thionyl chloride (750 mL). The reaction mixture heated to 70-120°C for 2-3 hours. After completion of reaction, concentrated the reaction mass and added dichloromethane (1000 mL). Purged the ammonia gas at 0-15°C. After completion of reaction, distilled out solvent under vacuum at 35-40°C up to stirrable volumes, stripped out with acetonitrile (500 mL) to get crude product. Crude mass stirred with acetonitrile (1250 mL) and filtered to give isoxazoline-substituted compound.
Yield: 42.9g, 86%; HPLC purity:84%.

Example 7: Preparation of isoxazoline-substituted amide compound of formula (I') (Fluralaner)

To the compound (1 mole) obtained in example 5 or example 6, added THF (1000mL) at 0-10°C, followed by sodium hydride (60% suspension in oil) (40.26g, 1.0 mol) and N-(2,2,2-Trifluoroethyl)chloroacetamide (126.23g, 0.719 mol). The reaction mixture heated to 30 to 40°C for 5 hours. After completion of reaction, added water (1750 mL) and extracted with ethyl acetate (1250mL), separated the organic layer, solvent removed under vacuum. The crude mass stirred with toluene (1250mL) and filtered to give isoxazoline-substituted amide compound (Fluralaner).

Yield: 226.7g (68%); HPLC purity: 99%.
1H NMR (400 MHz, DMSO-d6): d 2.42 (s, 3H), 3.93 – 3.99 (m, 4H), 4.30 – 4.43 (m, 2H), 7.52 (d, J = 8.4, 1H), 7.63 (m, 4H), 7.82 (t, J = 1.6, 1.6, 1H), 8.63 (m, 2H).
,CLAIMS:We Claim:

1. A process for preparation of an isoxazoline-substituted amide compound of formula (I)

wherein
A is ,
B is ,
# indicates the attachment to the isoxazoline ring, and
* indicates the attachment to the carbonyl group
comprising reacting an isoxazoline-substituted compound of formula (II)

wherein A and B are the same as defined above,
with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein X is halogen, OMs, OTs, OTf
in solvent and optionally in presence of base.

2. The process according to claim 1, wherein isoxazoline-substituted amide compound of formula (I) is:
A) Fluralaner compound of formula (I')

the preparation of which comprises reacting an isoxazoline-substituted compound of formula (II')

with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein X is halogen, OMs, OTs, OTf ;
or
B) Afoxolaner compound of formula (I")

the preparation of which comprises reacting an isoxazoline-substituted compound of formula (II")

with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein X is halogen, OMs, OTs, OTf;
or
C) Lotilaner compound of formula (I'")

the preparation of which comprises reacting an isoxazoline-substituted compound of formula (II'")

with N-(2,2,2-trifluoroethyl)acetamide compound of formula (III)

wherein X is halogen, OMs, OTs, OTf;
in solvent and optionally in presence of base.

3. The process according to claim 1 or claim 2, wherein the solvent is alcoholic solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; hydrocarbon solvent selected from n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene; ethereal solvent selected from diethyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, acetonitrile; or mixtures thereof.

4. The process according to claim 1 or claim 2, wherein the base is alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide, caesium hydroxide, ammonium hydroxide; carbonate selected from potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate, calcium carbonate, magnesium carbonate, caesium carbonate, ammonium carbonate; bicarbonate selected from potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, magnesium bicarbonate, caesium bicarbonate, ammonium bicarbonate; alkoxide selected from methoxide, ethoxide, tert-butoxide of sodium, potassium, lithium, barium, calcium, magnesium, caesium, ammonium; hydride selected from sodium hydride, potassium hydride, lithium hydride, barium hydride, calcium hydride, magnesium hydride, caesium hydride; amide selected from sodium amide, potassium amide, lithium amide, Lithium bis(trimethylsilyl)amide, calcium amide, magnesium amide, caesium amide; alkyl lithium selected from methyllithium, n-butyllithium, tert-butyllithium, phenyllithium; or mixtures thereof.

5. A process for the preparation of an isoxazoline-substituted compound of formula (II)

wherein
A is ,
B is ,
# indicates the attachment to the isoxazoline ring, and
* indicates the attachment to the carbonyl group
comprising the steps of:
v) reacting an aromatic ketone compound of formula (IV)

wherein A is the same as defined above,
with a substituted acetophenone compound of formula (V)

wherein
B is ,
* indicates the attachment to the carbonyl group,
# indicates the attachment to the R group, and
R is CN or COOH,
in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI)

wherein A and R are the same as defined above,
B is ,
* indicates the attachment to the carbonyl group, and
# indicates the attachment to R group
vi) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI) to obtain 3-substituted-2-propen-1-one compound of formula (VII)

wherein A and R are the same as defined above, and
B is ,
* indicates the attachment to the carbonyl group, and
# indicates the attachment to R group
vii) reacting 3-substituted-2-propen-1-one compound of formula (VII) with hydroxylamine or its salt, in presence of
a. organic base and solvent, or
b. inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII)

wherein A and R are the same as defined above,
B is ,
* indicates the attachment to the isoxazoline ring, and
# indicates the attachment to the R group
viii) treating intermediate isoxazoline-substituted compound of formula (VIII)
a. when R= CN, in acidic or basic conditions, or
b. when R= COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II).

6. The process according to claim 5, wherein an isoxazoline-substituted compound of formula (II) is
A) Fluralaner intermediate compound of formula (I')

the preparation of which comprises:
i) reacting an aromatic ketone compound of formula (IV')

with a substituted acetophenone compound of formula (V')

wherein R is CN or COOH,
in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI')

wherein R is the same as defined above,
ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI') to obtain 3-substituted-2-propen-1-one compound of formula (VII')

wherein R is the same as defined above,
iii) reacting 3-substituted-2-propen-1-one compound of formula (VII') with hydroxylamine or its salt, in presence of
a) organic base and solvent, or
b) inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII')

wherein R is the same as defined above,
iv) treating intermediate isoxazoline-substituted compound of formula (VIII')
a) when R = CN, in acidic or basic conditions, or
b) when R = COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II');
or
B) Afoxolaner intermediate compound of formula (I")

the preparation of which comprises:
i) reacting an aromatic ketone compound of formula (IV'')

with a substituted acetophenone compound of formula (V'')

wherein R is CN or COOH,
in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI'')

wherein R is the same as defined above,
ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI'') to obtain 3-substituted-2-propen-1-one compound of formula (VII'')

wherein R is the same as defined above,
iii) reacting 3-substituted-2-propen-1-one compound of formula (VII'') with hydroxylamine or its salt, in presence of
a) organic base and solvent, or
b) inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII'')

wherein R is the same as defined above,
iv) treating intermediate isoxazoline-substituted compound of formula (VIII'')
a) when R = CN, in acidic or basic conditions, or
b) when R = COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II'');
or
C) Lotilaner intermediate compound of formula (I'")

the preparation of which comprises:
i) reacting an aromatic ketone compound of formula (IV''')

with a substituted acetophenone compound of formula (V''')

wherein R is CN or COOH,
in the presence of base and solvent, to obtain substituted-3-hydroxypropan-1-one compound of formula (VI''')

wherein R is the same as defined above,
ii) dehydrating the substituted-3-hydroxypropan-1-one compound of formula (VI''') to obtain 3-substituted-2-propen-1-one compound of formula (VII''')

wherein R is the same as defined above,
iii) reacting 3-substituted-2-propen-1-one compound of formula (VII''') with hydroxylamine or its salt, in presence of
a) organic base and solvent, or
b) inorganic base, phase-transfer catalyst, solvent, and water
to obtain intermediate isoxazoline-substituted compound of formula (VIII''')

wherein R is the same as defined above,
iv) treating intermediate isoxazoline-substituted compound of formula (VIII''')
a) when R = CN, in acidic or basic conditions, or
b) when R = COOH, with an acid activating agent followed by ammonia source in solvent,
to obtain isoxazoline-substituted compound of formula (II''').

7. The process according to claim 5 or claim 6, wherein the base in step i) is selected from inorganic base or organic base, and wherein inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, caesium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, magnesium bicarbonate, caesium bicarbonate, ammonium bicarbonate, potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate, calcium carbonate, magnesium carbonate, caesium carbonate, ammonium carbonate; and organic base is selected from methylamine, ethylamine, propylamine, butylamine, di-methylamine, di-ethylamine, di-isopropyl amine, di-isopropyl ethylamine, trimethylamine, triethylamine, tri-benzylamine, pyridine, 4-dimethylaminopyridine, pyrrolidine, piperidine, N-Methyl-Piperidine, piperazine, morpholine, imidazole, 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN), tetramethylguanidine, triazabicyclodecene; or mixtures thereof.

8. The process according to claim 5 or claim 6, wherein the solvent in step i) is hydrocarbon solvent selected from n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene; chlorinated solvent selected from methylene chloride, ethylene chloride, chlorobenzene; ethereal solvent selected from diethyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether; ester solvent selected from methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate; nitrile solvent selected from acetonitrile, propionitrile, butyronitrile, benzonitrile; alcohol solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; polar aprotic solvent selected from dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane; or mixtures thereof.

9. The process according to claim 5 or claim 6, wherein the dehydration is performed using dehydrating agent selected from acetic anhydride, propionic anhydride, benzoic anhydride, trifluoro acetic anhydride, hydrochloric acid, phosphoric acid, trifluoroacetic acid, citric acid, sulfuric acid, p-toluenesulfonic acid, acetyl chloride, thionyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride, aluminium oxide.

10. The process according to claim 5 or claim 6, wherein the organic base in step iii) a) is selected from methylamine, ethylamine, propylamine, butylamine, di-methylamine, di-ethylamine, di-isopropyl amine, di-isopropyl ethylamine, trimethylamine, triethylamine, tri-benzylamine, pyridine, 4-dimethylaminopyridine, pyrrolidine, piperidine, N-Methyl-Piperidine, piperazine, morpholine, imidazole, 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN), tetramethylguanidine, triazabicyclodecene; and solvent is hydrocarbon solvent selected from n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene; chlorinated solvent selected from methylene chloride, ethylene chloride, chlorobenzene; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; or mixtures thereof.

11. The process according to claim 5 or claim 6, wherein the inorganic base in step iii) b) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, caesium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, magnesium bicarbonate, caesium bicarbonate, ammonium bicarbonate, potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate, calcium carbonate, magnesium carbonate, caesium carbonate, ammonium carbonate; phase-transfer catalyst is selected from tetra-butylammonium bromide, tetra-butylammonium chloride, tetra-butylammonium iodide, tetra-butylammonium hydroxide, tetra-methylammonium bromide, tetra-methylammonium chloride, tetra-methylammonium iodide, tetra-methylammonium hydroxide, tetra-butylammonium hydrogen sulfate, 18-crown-6, 15-crown-5; and solvent is ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; alcohol solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; or mixtures thereof.

12. The process according to claim 5 or claim 6, wherein the acidic conditions in step iv) a) involve treating intermediate isoxazoline-substituted compound of formula (VIII) or (VIII') or (VIII'') or (VIII''') with an acid selected from acetic acid, sulphuric acid, hydrochloric acid optionally in solvent selected from alcoholic solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; water or mixtures thereof.

13. The process according to claim 5 or claim 6, wherein the basic conditions in step iv) a) involve treating intermediate isoxazoline-substituted compound of formula (VIII) or (VIII') or (VIII'') or (VIII''') with an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, caesium hydroxide in solvent selected from alcoholic solvent selected from methanol, ethanol, isopropanol, butanol, ethylene glycol, poly ethylene glycol; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; water or mixtures thereof.

14. The process according to claim 5 or claim 6, wherein the acid activating agent in step iv) is selected from thionyl chloride, thionyl bromide, oxalyl chloride, pivaloyl chloride, tosyl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, phosphorus tribromide, phosphorus triiodide, triphosgene, acetic anhydride, N,N-dicyclohexylcarbodiimide (DCC), 1,1-carbonyldiimidazole (CDI), 3-(ethyliminomethyleneamino)-N, N-dimethylpropan-1-amine (EDC).

15. The process according to claim 5 or claim 6, wherein the ammonia source in step iv) b) is selected from ammonia gas, ammonium hydroxide, liquor ammonia and methanolic ammonia; and solvent is hydrocarbon solvent selected from n-pentane, n-hexane, n-heptane, cyclohexane, benzene, toluene, xylene; chlorinated solvent selected from methylene chloride, ethylene chloride, chlorobenzene; ethereal solvent selected from dimethyl ether, diethyl ether, ethyl methyl ether, di-isopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, diphenyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran; or mixtures thereof.