TRIFLUORO ACETOPHENONE”

RELATED APPLICATION

This application claims the benefit to Indian Provisional Application No. 202021021840, filed on May 25, 2020, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of intermediate 3,5- dichloro-2,2,2-trifluoroacetophenone of formula (I). The present invention further provides an improved process for the preparation of Fluralaner using 3,5-dichloro-2,2,2- trifluoroacetophenone of formula (I) obtained by a process described herein.

BACKGROUND OF THE INVENTION

The 3,5-dichloro-2,2,2-trifluoroacetophenone is a key intermediate for preparing veterinary APIs such as Fluralaner, Lotilaner, Afoxolaner. The 3,5-dichloro-2,2,2-trifluoroacetophenone is disclosed in a Journal of Physical Organic Chemistry ,(1989), Vol.2 (4), Pg.363-366, wherein it is synthesized from corresponding aryl halides via. Grignard reaction with trifluoroacetic anhydride at lower temperature (-70°C).

The Chinese patent application no. CN107353189; (henceforth ‘189) discloses a method for producing 3,5-dichloro-2,2,2-trifluoroacetophenone by reacting 3,5-dichlorobromobenzene with unstable trifluoroacetic anhydride in presence of expensive tert-butyllithium at -78°C. The above reaction not only involves expensive reagents but also drastic reaction conditions and result into low reaction yield (41%). The Ί89 patent application also disclosed the use of 3,5-dichlorobromobenzene and 1 -trifluoroacetyl piperidine in presence of tert-butyl lithium at -78°C for isolation of 3,5-dichloro-2,2,2-trifluoroacetophenone after high vacuum distillation resulting in low chemical yield (37%). The above reaction involved costly reagents, multiple purifications including high vacuum distillation, thus increases overall cost.

International (PCT) publication no. W02010/125130 (henceforth ‘130) discloses a method for producing a 3,5-dichloro-2,2,2-trifluoroacetophenone by reacting 3,5- dichlorobromobenzene and ethyl trifluoroacetate in presence of diisobutylaluminium hydride, magnesium metal at 0°C. The above reaction involves expensive reagents to produce low reaction yield (36%) with low purity (70%). It requires further purification and therefore the overall production cost increases.

The prior-art process(es) involve one or more process steps and/or reasons where the overall production cost increases in the production of an intermediate 3,5-dichloro-2,2,2- trifluoroacetophenone and consequently of Fluralaner.

The application of intermediate of formula (I) for preparation of fluralaner is as shown below.

Wherein T and Y each independently represent a substituted aryl or a substituted heteroaryl, X represents a hydrogen atom or a halogen atom.

The inventors of instant invention have developed an improved process for the preparation of 3,5-dichloro-2,2,2-trifluoroacetophenone to overcome the limitations of the prior arts in cost effective and industrially convenient way in high yield (70%) in less cycle time with greater chemical purity (99%). The instant two-step process performed on industrial scale by using commercially available key raw materials such as piperidine and 3,5-dichloroaniline. The instant process involve the simple reactions such as Sandmeyer reaction for preparation of 3.5-dichlorobromobenzene from 3,5-dichloroaniline and coupling of 3,5- dichlorobromobenzene with 1 -trifluoroacetyl piperidine in presence of Grignard reagent to obtain 3,5-dichloro-2,2,2-trifluoroacetophenone (I), which is further utilized for the preparation of Fluralaner as disclosed in Nissan’s PCT application WO 2013/021949 A1.

OBJECTIVES OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of a 3,5-dichloro-2,2,2-trifluoroacetophenone formula (I) using key raw materials piperidine and 3,5-dichloroaniline.

Another objective of the present invention is to provide a process for preparation of 3,5- dichloro-2,2,2-trifluoroacetophenoneformula (I) by reacting compound of formula (II) and compound of formula (IV).

Yet another objective of the present invention is to provide an improved process for the preparation of Fluralaner by using 3,5-dichloro-2,2,2-trifluoroacetophenone formula (I) which is obtained by a process of an instant invention.

SUMMARY OF THE INVENTION

In one aspect of the present invention provides an improved process for the preparation of

3.5-dichloro-2,2,2-trifluoroacetophenone of formula (I) which comprises the steps of: a) reacting piperidine andethyl triflu oroacetate to obtain compound of formula (II); b) obtaining compound of formula (I) by reacting compound of formula (II) and compound of formula (IV) with Grignard reagent in presence of solvent, wherein compound of formula (IV) is obtained by preparing a diazonium salt of compound formula (III) in presence of copper halide or potassium halide, acid and aqueous hydrogen bromide; c) optionally, purifying compound of formula (I).

The above process is illustrated in the following general synthetic scheme:

In another aspect of the present invention provides an improved process for the preparation of Fluralaner using 3,5-dichloro-2,2,2-trifluoroacetophenone of formula (I) obtained by a process described herein, where the process for preparation of Fluralaner is followed by a skilled person as illustrated in WO 2013021949. DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more fully hereinafter. As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains" or "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, a mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. Further, unless expressly stated to the contrary, "or" refers to an inclusive or and not to an exclusive. As used in the specification, and in the appended claims, indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive regarding the number of instances (i.e. occurrences) of the element or component. Therefore "a" or "an" should be read to include one or at least one, and the singular word form of the element or component also includes the plural unless the number is obviously meant to be singular indicates otherwise.

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

In accordance with the objectives, wherein the present invention provides the process for preparation of 3,5-dichloro-2,2,2-trifluoroacetophenone of formula (I), which comprises the step(a) of reacting a piperidine and ethyl triflu oroacetate to obtain compound of formula (II) without using any solvent and reagent (neat reaction). In another embodiment of the present invention, wherein the step (a) is performed at temperature 25 °C to 90°C and for 4-6 hours.

In another embodiment of the present invention, wherein compound of step (a) is obtained by distillation under vacuum of 15 to20 Torr at temperature 80°C to90°C.

In accordance with the objectives, wherein compound of formula (I) instep (b) is obtained by reacting a compound of formula (II) with compound of formula (IV) in presence of Grignard reagent in solvent such as tetrahydrofuran; wherein the Grignard reagent is prepared by using suitable alkyl magnesium halide in presence of suitable initiator in suitable solvent or mixture of solvents thereof.

In another embodiment of the present invention, wherein suitable alkyl magnesium halide is prepared by reacting alkyl halide with magnesium metal in suitable solvents at 10°C to 30°C.

In another embodiment of the present invention, wherein suitable alkyl halide is selected from isopropyl bromide, isopropyl chloride, methyl bromide and the like.

In another embodiment of the present invention, wherein suitable initiator is Iodine.

In another embodiment of the present invention, wherein suitable solvents of step (b) is ethereal solvent and hydrocarbon solvent.

In another embodiment of the present invention, wherein ethereal solvent is selected from tetrahydrofuran, diethyl ether, dibutyl ether, 2 -methyl tetrahydrofuran, tert -butyl methyl ether and the like; preferably tetrahydrofuran.

In another embodiment of the present invention, wherein hydrocarbon solvent is selected from toluene, hexane, and the like.

In another embodiment of the present invention, wherein the compound of formula (IV) is obtained from 3,5-dichloroaniline of formula (III) by Sandmeyer reaction in presence of suitable copper halide or potassium halide in aqueous hydrogen bromide with diazonium salt of 3,5-dichloroaniline in presence of suitable solvent..

In another embodiment of the present invention, wherein diazonium salt is prepared by reacting 3,5-dichloroaniline of formula (III) with sodium nitrite in a suitable acid; wherein suitable acid is selected from hydrobromic acid, hydrochloric acid, concentrated sulfuric acid, acetic acid and the like; preferably hydrochloric acid.

In another embodiment of the present invention, wherein suitable solvent used for preparation of diazonium salt is selected from water, acetonitrile, polyethylene glycol and the like; preferably water.

In another embodiment of the present invention, wherein suitable Copper halide is selected from Copper (I) bromide, Copper (I) chloride, Copper (I) iodide and suitable potassium halide is Potassium Iodide.

In another embodiment of the present invention, wherein the preparation of compound (IV) and compound (I) is performed at temperature 10°C to 90° C for 2-6 hours.

In another embodiment of the present invention, wherein the overall reaction time to obtain compound (I) is 20-24 hours.

In another embodiment of the present invention, wherein in step (c) pure compound (I) is obtained by high vacuum distillation using vacuum of 10-15 torr at 80°C to 90°C.

In another embodiment of the present invention, wherein the preparation of a compound of formula (II) and compound (IV) is performed in an in-situ manner.

In still another embodiment of the present invention wherein the one or more steps from (a) to (b) of the instant invention is performed in in-situ manner.

In another embodiment of the present invention, wherein all the crude compound may be used as such or may be purified by distillation or any other purification technique well understood by those skilled in the art.

The compound 3,5-dichloro-2,2,2-trifluoroacetophenone of formula (I) obtained by the process described herein is further used for the preparation of Fluralaner.

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 1-trifluoroacetyl piperidine (II)

The ethyl trifluoroacetate (1.0 to 1.2eq) was added into piperidine (l.Oeq) at 20°C to 30°C for 1-2 hours. The reaction mixture was heated at 75°C to 85°C and stirred for 3-4 hours. After completion of reaction, the reaction mixture was kept for simple distillation at 90 °C to 100°C for 3-4 hours and further distilled under vacuum of at 80°C to 90°Cto obtain the compound II (90% yield, GC purity: 99.9%).

Example 2: Preparation of 3,5-dichlorobromobenzene (IV)

To 3,5-dichloroaniline (l.Oeq), acetonitrile (IV) was charged and stirred at 20°C to 30°C for 15 min. Water (2V) and aqueous hydrobromic acid (3V) were added at 25°C to 35°C. The reaction mixture was cooled to 0°C to 5°C and aqueous sodium nitrite solution (70.26 g, 1.1 eq) was added slowly at 0°C to 5°C within 1-3 hours. The reaction mixture was stirred at 0°C to 5°C for 1 hour. The solution of Copper bromide (0.4 eq) in 48% hydrobromic acid (4.0eq) was added to reaction mixture at0°C to 15°C for 1-2 hours and the reaction temperature was raised to 20°C to 30°C and stirred for 2 hours and further heated to 70°C to 75°C for 2 hours. After completion of reaction, reaction mixture was cooled to 20°C to 30°C and quenched by adding water. The aqueous layer was extracted with dichloromethane and combined organic layer was washed with aqueous sodium bicarbonate and brine solution. The solvent was removed under vacuum to obtain the crude compound IV and the pure compound is obtained by high vacuum distillation (72% yield, HPLC purity: 98%).

Example 3: 3,5-dichloro-2,2,2-trifluoroacetophenone (I)

The magnesium turning (1.0 to 1.4 eq), tetrahydrofuran (IV) and Iodine (0.1 to0.4eq) were charged into a round bottom flask and stirred. To the reaction mixture a solution of isopropyl bromide (1 to 1.4 eq) in tetrahydrofuran (3V) was added and stirred at 20°C to 30°C for 1-2 hours. The reaction mixture was cooled to 0°C to 5°C and a solution of 3,5- dichlorobromobenzene (IV, l.Oeq) in tetrahydrofuran (2V) was added. The reaction temperature was raised to 0°C to 30°C and stirred for 1 hour. The reaction mixture was cooled to 0°C to 5°C and 1-trifluoroacetyl piperidine (II) was added. The reaction temperature was raised to 20°C to 30°C and stirred for 1-2 hours. After completion of reaction the reaction mixture was cooled to 0°C to 5°C and quenched by adding into aqueous hydrochloric acid. The reaction mass temperature was raised to 20°C to 30°C and stirred for 1-2 hours. The aqueous layer was extracted with methyl tert butyl ethyl and solvent was removed to obtain the crude compound (I, 90% yield, GC purity: 93%) and purified by distillation at 80 °C to 90°C under vacuum to obtain the pure compound (I, 70% yield, HPLC purity: 99%).