DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10; rule 13)

PROCESS FOR PURIFICATION OF FLURALANER

HIKAL LIMITED, an Indian Company of 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411 057, Maharashtra, India

The following specification describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION

The present invention relates to a process for purification of Fluralaner of formula (I). The present invention further relates to a process for purification of Fluralaner of formula (I) with purity more than 99%, in simple, economic and commercially viable manner.

(I)
BACKGROUND OF THE INVENTION

Fluralaner, 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, is systemic insecticide and acaricide, used against ticks and fleas. The US Patent no. 7,662,972B2 discloses the isoxazoline-substituted benzamide compounds such as Fluralaner and process for preparation thereof. Another US Patent no. 8,796,464B2 discloses a process for preparation of crystal form of Fluralaner.

The US Patent no. 9,062,010B2 discloses S-isomer of Fluralaner and its purification by using preparative chromatography which is highly expensive and not commercially viable in industrial scale.

The purification of Fluralaner by conventional approach was not discussed in prior arts and it was purified by either column or preparative chromatography. These methods are highly expensive and not commercially viable in industrial scale. The process for the preparation of Fluralaner involves certain impurities. In accordance, the present process also involve certain impurities such as 2-methyl-4-(2,2,2-trifluoroacetyl)benzoic acid, 3,5-Dichloro-benzoic acid, 4-[5-(3,5-Dichloro-phenyl)-3-hydroxy-5-trifluoromethyl-isoxazolidin-3-yl]-2-methyl-N-[(2,2,2-trifluoroethylcarbamoyl)-methyl]-benzamide. Hence, the purification is inevitable to meet the regulatory standard. Considering the disadvantages associated with the prior art processes, there is a need to develop a simple, economic and commercially scalable process for purification of Fluralaner.

SUMMARY OF THE INVENTION

One aspect of the present invention providesa process for purification of Fluralaner of formula (I) with purity greater than 99%.

In another aspect of the present invention provides a process for purification of Fluralaner of formula (I) with purity greater than 99% which is obtained from taking a crude compound having purity at least 95%.

In another aspect of the present invention provides a process for purification of Fluralaner of formula (I) with purity greater than 99%, which comprises the steps of:

(I)

a) treatingcrude Fluralaner formula (I) in a suitable solvent;
b) heating the reaction mixture;
c) treating reaction mixture with a charcoal;
d) filtering and cooling the reaction mixture to obtain slurry;
e) filtering the solid and washing with solvent.

In one embodiment, the present invention provides a process for purification of Fluralaner of formula (I) with purity greater than 99% having single maximum impurity less than 1%.

In another embodiment, the present invention provides a process for purification of Fluralaner of formula (I) with purity greater than 99% having single maximum impurity less than 0.5%.

In another embodiment, the present invention provides a process for purification of Fluralaner of formula (I) with purity greater than 99% having single maximum impurity less than 0.1%.

In another embodiment, the present invention provides a process for purification of Fluralaner of formula (I) with purity greater than 99% having single maximum impurity less than 1%, preferably less than 0.5% where the said purity is obtained from crude compound having purity at least 95%.

In yet another embodiment,the present invention provides a process for purification of Fluralaner of Formula (I) with purity greater than 99% having single maximum impurity less than 1%, preferably less than 0.5% where the said purity is obtained from a crude compound having purity at least 95%by following the process mentioned herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more detail 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. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

The term ‘solvent’ used herein, refers to the single solvent or mixture of solvents.

The term ‘impurity’ used herein, refers toone or more of the following compounds:
a) 4-Acetyl-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide,

b) 4-[(Z)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide

c) 4-[5-(3,5-Dichloro-phenyl)-3-hydroxy-5-trifluoromethyl-isoxazolidin-3-yl]-2-methyl-N-[(2,2,2-trifluoroethylcarbamoyl)-methyl]-benzamide.

In an embodiment, the present invention provides a process for purification of Fluralaner of formula (I) with purity greater than 99% having single maximum impurity less than 1%, preferably less than 0.5%, less than 0.1%.

In another embodiment, the present invention, wherein the suitable solvent used in step (a) is selected from the group consisting of alcoholic solvents such as methanol, ethanol, isopropanol; acetate solvents such as ethyl acetate, isopropyl acetate and the like or mixture of solvents thereof.

In another embodiment, the present invention, wherein the step (a) is carried out at temperature between 20°C to 40°C.

In another embodiment, the present invention, wherein the step (b) & (c) is carried out at temperature between ambient temperature to reflux temperature.

The preparation of the starting materials and reagents used in the present invention are well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

Experimental

Example 1: Preparation of 4-acetyl-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-benzamide (a)

In clean and dry RBF equipped with mechanical stirrer, 2L dichloromethane (DCM) and 100.0 g (0.5612 moles) 4-acetyl-2-methyl benzoic acid were charged at 20°C to 40°C and stirred for about 15min. The reaction mixture was cooled to 0°C to 10°C.

To the reaction mixture, 161.4 g (0.8418moles) of 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and 118.9 g (0.6173 moles) of 2-amino-N-(2,2,2-trifluoroethyl) acetamide hydrochloride were lot wise added at 0°C to 10°C. To the reaction mixture 3.43 g (0.0280 moles) of 4-dimethylaminopyridine (DMAP) was added at 0°C to 10°C. Further, 108.8 g (0.8418 moles) of diisopropyl ethyl amine was drop wise added for 30 to 60min at 0°C to 10°C and the temperature of reaction mixture was maintained at 20°C to 35°C for 4 to 6 hrs. After completion of reaction, sodium bicarbonate solution (100.0 g in 1L of water) was drop wise added to the reaction mixture at 20°C to 40°C and stirred for 30 to 40 min at 20°C to 40°C. The organic layer and aqueous layer were separated. 200.0 mL (4.0V) of dichloromethane was added to the aqueous layer and the solution was stirred for about 30 to 40 min at 20°C to 40°C. The organic layer and aqueous layer were separated. The organic layer fractions were combined, and sodium chloride solution was added. The reaction mass was stirred for about 30 to 40 min at 20°C to 40°C. The organic layer and aqueous layer were separated.10.0 g(10%) of activated carbon was added to the organic layer and stirred for about 30 to 40 min at 20°C to 40°C. The reaction mixture was filtered, washed the bed with dichloromethane and distilled the solvent.To the reaction mass, 400.0 mL (4.0V) of toluene was charged and maintained at 60°C to 75°C for 1 to 3 hrs. The reaction mass was cooled to 20°C to 40°C and stirred the solid slurry for 2 to 4 hrs. The solid slurry was filtered, washed with toluene and dried for 1 to 3 hrs. The wet material was dried to obtain 140 g of compound (a) (% yield - 80%).

Example 2: Preparation of4-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-2-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-benzamide (b)

In clean and dry RBF equipped with mechanical stirrer, 3L (20.0V) of isopropyl acetate, 150.0 g (1.0 eq) of compound (a) was charged and stirred for 15 to 20 min at 20°C to 40°C. 121.0g (1.05 eq) of 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanone, 32.77g (0.5 eq.) of potassium carbonate (lot1) and 4.8g (0.1 eq) triethyl amine (lot 1) were added at 20°C to 40°C. The reaction mixture was heated to reflux temperature and maintained for 3 to 4hrs. The addition of same quantities of potassium carbonate and triethyl amine in 3 lots were added at same previous reaction conditions. Again 32.77 g (0.5 eq) of potassium carbonate (lot 5) and 4.8 g (0.1 eq) triethyl amine (lot 5) at were added at 20°C to 40°C. The reaction mixture was heated to reflux temperature and maintained for 8 to 9 hrs. Again 32.77 g (0.5 eq) of potassium carbonate (lot6) and 4.8 g (0.1 eq) triethyl amine (lot6) at were added at 20°C to 40°C. The reaction mixture was heated to reflux temperature, maintained for 12 to 14 hrs and 5 to 6V of isopropyl acetate was distilled out. The reaction mixture was cooled to 20°C to 40°C.750.0 mL (5.0V) of water was added to reaction mixtureand stirredfor 30 to 40 min at 20°C to 40°C. The organic layer and aqueous layer were separated. 750.0 mL of 10% sodium chloride was added to the organic layer and the solution was stirred for 30 to 40 min at 20°C to 40°C. The organic layer and aqueous layer were separated. 15.0 g (10%) of activated carbon and 150.0 g of Silica were added to the organic layer and stirred for about 1 hr at 20°C to 40°C. The reaction mixture was filtered, washed the bed with isopropyl acetate and distilled the solvent.300.0 mL (2.0V) of isopropyl acetate was added to reaction mixture and solvent mixture was distilled out. The residual mass was cooled to temperature below 50°C and 600.0 mL (4.0 V) of diisopropyl ether was charged. The reaction mixture was cooled to 20°C to 35°Cand the solid slurry was stirred for 2 to 4hrs. The solid slurry was filtered, washed with diisopropyl ether and dried for 1 to 3 hrs. 1800.0 mL (12.0 V) of toluene was charged to the wet material and the reaction mixture was heated to 90°C to 100°C for 30 to 40 min.15.0 g (10%) of activated carbon was added to the reaction mass and stirred at 90°C to 100°C for 30 to 40 min. The reaction mixture was filtered, washed with toluene and the filtrate was cooled to 20°C to 35°C with stirring for 24 to 26 hrs. The solid slurry was filtered, washed with toluene and dried for 1 to 3 hrs. The wet material was dried to obtain 100 g of compound (b) (% yield – 38.80%).

Example 3: Preparation of Fluralaner (I)

In clean and dry RBF equipped with mechanical stirrer, 975mL (15.0V) of DCM (lot 1) and 65.0 g (0.120 moles) of compound (b) were charged at 20°C to 40°C with stirring for about 15 to 20 min. The reaction mixture was cooled to 0 to 10°C and 5.80 g (0.018moles) of tetrabutyl ammonium bromide (TBAB) was added. The sodium hydroxide solution (63.89 g in 390.0 mL of water) was drop wise added to reaction mixture. 20.84 g (0.300moles) of hydroxyl amine hydrochloride was lot wise added to the reaction mixture at 0 to 5°C. The reaction mixture was maintained at 0°C to 10°C for 8 to 10 hrs. After completion of reaction, the temperature of reaction mixture was raised to 20°C to 35°C. The organic layer and aqueous layer were separated. 195.0 mL (3.0V) of dichloromethane was added to the aqueous layer and the reaction mass was stirred for 30 to 40 min at 20°C to 40°C. The organic layer and aqueous layer were separated. The organic layer fractions were combined, and sodium chloride solution was added. The reaction mass was stirred for about 30 to 40 min at 20°C to 40°C. The organic layer and aqueous layer were separated. The solvent of organic layer was distilled out. To the reaction mixture, 32.5 mL (0.5V) of methanol was charged at 60°C to 65°C. 650.0 mL (10.0V) of heptane was added to the reaction mixture at 60°C to 65°C. The reaction mixture was cooled to 0°C to 5°C and the solids slurry was stirred for 2 to 4 hrs. The solid slurry was filtered, washed with heptane and dried for 1 to 3 hrsto obtain 35 g of Fluralaner (% yield - 52%, purityby HPLC 98.29%)

Example 4: Purification of Fluralaner (I)

In clean and dry RBF equipped with mechanical stirrer, 97.2 ml (3.0V) of methanol and 32.5g (1.0 eq.) of crude fluralaner were charged at 20°C to 40°C and stirred for about 15 to 30min. The reaction mixture was heated to 60°C to 65°C.3.2g of activated carbon was added to the reaction mass and stirred for about 30 to 40 min at 60°C to 65°C. The reaction mixture was filtered and cooled to 0°C to 10°C. The solid slurry was stirred for 2 to 4 hr. The solid slurry wasfiltered and washed with methanol. The wet material was dried to obtain pure fluralaner (yield:80%, purity by HPLC >99%).
,CLAIMS:We Claim:

1. A process for purification of Fluralaner of formula (I) having purity greater than 99%, which comprises the steps of:

(I)
a) treatingcrude Fluralaner formula (I) in a suitable solvent;
b) heating the reaction mixture;
c) treating reaction mixture with a charcoal;
d) filtering and cooling the reaction mixture to obtain slurry;
e) filtering the solid and wash with solvent.

2. The process as claimed in claim 1, wherein the process provides Fluralaner of formula (I) with purity greater than 99% having single maximum impurity less than 1%.

3. The process as claimed in claim 1, wherein the process provides Fluralaner of formula (I) with purity greater than 99% having single maximum impurity less than 0.5%.

4. The process as claimed in claim 1, wherein the process provides Fluralaner of formula (I) with purity greater than 99% having single maximum impurity less than 0.1%.

5. The process as claimed in claim 1, wherein the process provides Fluralaner of formula (I) with purity greater than 99% having single maximum impurity less than 1%, or less than 0.5% or less than 0.1%, where the said purity is obtained from a crude compound having purity at least 95%.

6. The process as claimed in claim 1, whereinthe solvent used in step (a) is selected from the group consisting of alcoholic solvents such as methanol, ethanol, isopropanol; acetate solvents such as ethyl acetate, isopropyl acetate.

7. The process as claimed in claim 1, whereinthe step (a) is carried out at temperature between 20°C to 40°C.

8. The process as claimed in claim 1, wherein the step (b) & (c) is carried out at temperature between ambient temperature to reflux temperature.