FIELD OF THE INVENTION
The present invention relates to a process for preparation of 2,3,6-trihalobenzyl alkyl ketones of Formula I and intermediates thereof. These compounds are used in a wide variety of applications.

Formula I
wherein X independently represents a chloro or fluoro group and R represents an alkyl group.

BACKGROUND OF THE INVENTION
The 2,3,6-trihalobenzyl alkyl ketones, especially, 2,3,6-trifluorobenzylmethyl ketone is a valuable intermediate for synthesis of active agrochemical and pharmaceutical ingredients.
WO2013169348A1 discloses a process for preparation l-(2,3,6-trifluorophenyl)propan-2-one by reacting N-methoxy-N-methyl-2-(2,3,6-trifluorophenyl)acetamide with a methylmagnesium chloride in presence of cerium(III) chloride in tetrahydrofuran at 16°C.
The intermediate N-methoxy-N-methyl-2-(2,3,6-trifluorophenyl)acetamide and the reagent like cerium chloride are expensive and not easily available therefore makes the process costlier at commercial scale.
The methods reported in literature use expensive reagents therefore the present invention aims to provide a preparation of 2,3,6-trihalobenzyl alkyl ketones from easily available and less expensive perhalobenzoic acid.

OBJECT OF THE INVENTION
The main object of present invention is to provide an economical and industrially applicable process for preparation of 2,3,6-trihalobenzyl alkyl ketones of Formula I and intermediates thereof.

SUMMARY OF THE INVENTION
In first aspect, the present invention provides a process for preparation of a compound of Formula I,

Formula I
wherein X independently represents a chloro or fluoro and R represents an alkyl group,
comprising the steps of:
a) de-halogenating a compound of Formula VI,

Formula VI
wherein X independently represents a chloro or fluoro,
with zinc in the presence of a catalyst to give a compound of Formula V;

Formula V
wherein X is defined above,
b) alkylating the compound of V in the presence of a base to obtain a compound of Formula IV;

Formula IV
wherein X is defined above,

c) reacting the compound of Formula IV with a nucleophile of Formula VII,

Formula-VII
wherein R1 represents CN, CONH2, COOH, COOR, R represents C1-C4 alkyl,
in the presence of a base to obtain a compound of Formula III,

Formula III
wherein X, R, and R1 are as defined above,
d) hydrolyzing the compound of Formula III to a compound of Formula II, and

Formula II
wherein X and R are as defined above,
e) de-carboxylating the compound of Formula II to obtain the compound of Formula I.
In a second aspect, the present invention provides a compound of Formula II,

Formula II
wherein X independently represents a chloro or fluoro and R represents an alkyl group.
In a third aspect, the present invention provides a compound of Formula III,

Formula III
wherein X independently represents a chloro or fluoro; R independently represents an alkyl group and R1 represents CN, CONH2, COOH, COOR.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “alkyl” may be selected from a group comprising methyl, ethyl, propyl and isopropyl or the like.
As used herein, “nucleophile of Formula VII” may be selected from a group comprising of alkyl acetoacetate, acetoacetic acid, acetyl acetonitrile, acetyl acetamide or the like.
In an embodiment of the present invention, the step of de-halogenation is carried out using zinc in presence of a catalyst in a solvent. The catalyst comprises a metal complex selected from a group consisting of nickel chloride hexahydrate along with a ligand such as 2,2´-bipyridine; morpholine; tetramethylethylenediamine; 1,10-phenanthroline and derivatives thereof.
The solvent used in the step of de-halogenation is selected from a group consisting of water and an organic solvent. The examples of organic solvent include ethyl acetate, methyl acetate, butyl acetate, ethyl pentonoate, propyl acetate, pentyl acetate, methyl butyrate, isobutyl acetate, methyl benzoate, ethyl benzoate, methyl tetrahydrofuran, toluene and benzonitrile or a mixture thereof.
The organic solvent also includes polar aprotic solvents selected from a group consisting of dimethylsulfoxide, N,N-dimethyl formamide, N-methylpyrrolidone, N,N-dimethyl acetamide, N-vinylpyrrolidone, hexamethyl phosphoramide, tetrahydrofuran, acetonitrile and sulfolane or a mixture thereof.
In another embodiment of the present invention, the solvent used is recovered, recycled and reused.
In another embodiment, the step of de-halogenation is carried out in the presence of nickel salt and the ligand in the ratio of 1 to 3.
In another embodiment, the step of de-halogenation is carried out at a temperature range of 30 to 60°C.
In another embodiment, the mole equivalents of zinc used in the step of de-halogenation is in the range of 2 to 3 molar equivalents.
In an embodiment, the step b) of alkylating the compound of Formula V to obtain a compound of Formula IV is carried out in presence of a base and an alkylating agent in a solvent. The alkylating agent is selected from dimethylsulphate, methyl iodide, generated in-situ by reacting methanol with sulphuric acid.
In another embodiment, the alkylation and the reaction of compound of Formula IV with a nucleophile of Formula VII are performed in-situ, without isolation of the compounds of Formula IV.
In another embodiment, the step c) of reacting a compound of Formula IV with a nucleophile is carried out at a temperature in the range from 40 to 70°C.
In another embodiment, the molar ratio of the compound of Formula IV with respect to a nucleophile used in step c) is in the range of 0.9- 1.0.
In another embodiment, the ‘base’ used in alkylation and the reaction of compound of Formula IV with a nucleophile of Formula VII is selected from a group consisting of a metal hydride, metal borohydride, alkali metal carbonate or the like. The example of the base includes sodium hydride, potassium hydride, sodium butoxide, potassium butoxide, lithium (hexamethylsilyl)amide, potassium (hexamethylsilyl)amide, butyl lithium, sodium metal, potassium metal, sodium ethoxide and sodium methoxide, alkali carbonate such as sodium carbonate, potassium carbonate, cesium carbonate and magnesium carbonate or the like.
The ‘solvent’ used in alkylation and the reaction of compound of Formula IV with a nucleophile of Formula VII is selected from a group consisting of a polar aprotic solvent selected from a group consisting of acetone, ethylacetate, dimethylsulfoxide (DMSO), dimethyl sulfide (DMS), N,N-dimethylformamide (DMF), acetonitrile, N-methylpyrrolidone (NMP), tetrahydrofuran, hexamethylphosphoric triamide (HMPT), dichloroethane N,N-dimethylacetamide, sulfolane, methyl tetrahydrofuran, 1,4-dioxane and1,3-dimethyl-2-imidazolidinone or a mixture thereof.
In an embodiment, the hydrolysis of the compound of Formula III is carried out using an acid selected from sulphuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid p-toluenesulphonic acid, or the like.
In another embodiment, the hydrolysis of a compound of Formula III is carried out at a temperature range of 120 to 140°C using an acid in the range of 5 to 10 equivalents.
In an embodiment, the step of de-carboxylating a compound of Formula II is carried out using a metal salt in the presence of organic solvent.
The metal salt is selected from metal oxide, metal hydroxide or metal carbonate. The metal salt includes copper oxide, silver oxide and calcium oxide, calcium hydroxide or the like. The de-carboxylation is preferably carried out in presence of cupric oxide.
The ‘organic solvent’ used in the step of de-carboxylation is selected from a group consisting of a polar aprotic organic solvent such as, sulpholane, N-methyl-2-pyrrolidone, benzonitrile, N-vinylpyrrolidone, hexamethylphosphoramide, dimethylsulfoxide, N,N-dimethyl formamide and N,N-dimethyl acetamide or a mixture thereof. N-methyl-2-pyrrolidone is preferred as a solvent for the step of de-carboxylation.
In another embodiment the step of de-carboxylation involves recycling and reusing the solvent.
In an embodiment, the step of de-carboxylation is carried out at a temperature range of 120 to 140°C.
In an embodiment, the mole equivalent of metal oxide used in the present invention is 0.05-0.5 molar equivalent.
In an embodiment, the present invention provides a process for preparation of 1-(2,3,6-trifluorophenyl)propan-2-one, comprising the steps of:
a) de-halogenating pentafluorobenzoic acid using zinc powder in presence of nickel chloride complex in water and an organic solvent to obtain 2,3,4,5-tetrafluorobenzoic acid;
b) reacting 2,3,4,5-tetrafluorobenzoic acid with dimethyl sulphate followed by reaction with methyl acetoacetate in presence of a base to obtain methyl 2,3,5-trifluoro-4-(1-methoxy-1,3-dioxobutan-2-yl)benzoate;
c) hydrolysing 2,3,5-trifluoro-4-(1-methoxy-1,3-dioxobutan-2-yl)benzoate using sulphuric acid to obtain 2,3,5-trifluoro-4-(2-oxopropyl)benzoic acid; and
d) de-carboxylating 2,3,5-trifluoro-4-(2-oxopropyl)benzoic acid using a metal oxide or metal hydroxide to obtain 1-(2,3,6-trifluorophenyl)propan-2-one.
In an embodiment, the present invention provides a process for preparation of a compound of Formula I, comprising a step of de-carboxylating a compound of Formula II.
In another embodiment, the present invention provides a process for preparation of 1-(2,3,6-trifluorophenyl)propan-2-one, comprising a step of de-carboxylating 2,3,5-trifluoro-4-(2-oxopropyl)benzoic acid using a metal oxide or metal hydroxide.
In an embodiment, the present invention provides a process for preparation of a compound of Formula II by hydrolysing a compound of Formula III.
In another embodiment, the present invention provides a process for preparation of 2,3,5-trifluoro-4-(2-oxopropyl)benzoic acid comprising the step of hydrolysing 2,3,5-trifluoro-4-(1-methoxy-1,3-dioxobutan-2-yl)benzoate using an acid.
In an embodiment, the present invention provides a process for preparation of a compound of Formula III by reacting a compound of Formula IV with an alkylating agent followed by a nucleophile in presence of a base.
In another embodiment, the present invention provides a process for preparation of methyl 2,3,5-trifluoro-4-(1-methoxy-1,3-dioxobutan-2-yl)benzoate, comprising a step of reacting 2,3,4,5-tetrafluorobenzoic acid with an alkylating agent followed by a nucleophile in presence of a base.
In an embodiment, the present invention provides a process of preparation of a compound of Formula IV by de-halogenating pentahalobenzoic acid.
In another embodiment, the present invention provides a process for preparation of 2,3,4,5-tetrafluorobenzoic acid, comprising a step of de-halogenating pentafluorobenzoic acid using zinc powder in presence of nickel chloride complex in water and an organic solvent.
In another embodiment, the compounds of Formula II, Formula III, and Formula IV are isolated and are used in the next step.
In another embodiment, the compounds of Formula II, Formula III, and Formula IV can be purified by crystalizing in a solvent selected from hexane, heptane, diethylether, acetone or the mixture thereof.
In another embodiment, the compounds of Formula II, Formula III, and Formula IV are not isolated and are used in situ for the next step.
The compound of Formula III of present invention is isolated in a purity of greater than 95%.
The compound of Formula II of present invention is isolated in a purity of greater than 90%
In an embodiment, the present invention provides a process for preparation of compound of Formula I, having selectivity greater than 75%, having yield greater than 80% and purity greater than 80%.
The compound as a starting material represented by the chemical Formula V and reagents used in the present invention are commercially available and can be easily obtained.
The isolation of compound of Formula I of the present invention may be carried out by any method selected from evaporation, distillation, column chromatography, filtration or like.
Unless stated to the contrary, any of the words “comprising”, “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The completion of the reaction can be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC) and alike.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES
Example 1: Preparation of 2,3,4,5-tetrafluorobenzoic acid.
Nickel chloride hexahydrate (0.2 M), 2,2´-bipyridine (0.2 M), N,N-dimethylformamide (200 ml) and water (100 ml) were added to a reactor equipped with a condenser and stirred at 60-70°C for 2-3 hours. A solution of pentafluorobenzoic acid (200 g) in N,N-dimethylformamide (200 ml) was added to the reaction mixture in 30 minutes. Zinc dust (2 M) was added lot-wise to the reaction mixture and the reaction temperature was maintained at 60-70°C for 12-15 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, pH of the reaction mass was adjusted using hydrochloric acid (6 M) at 10-20°C, the reaction mass was extracted using ethyl acetate (300 ml X 2) and washed with brine solution to obtain solid residue. The residue was crystallised using heptane at 60-70°C to obtain 2,3,4,5-tetrafluorobenzoic acid (yield: 80% and purity: 90%).
Example 2: Preparation of methyl 2,3,5-trifluoro-4-(1-methoxy-1,3-dioxobutan-2-yl)benzoate.
2,3,4,5-tetrafluorobenzoic acid (1.0 M), dimethylsulfoxide (600 ml) and potassium carbonate (1.15 M) were added to a reactor equipped with condenser and gradually dimethyl sulphate (1.1 M) was added to it and heated for 2-3 hours at 60-70°C. The mixture was cooled to 40-50°C and potassium carbonate (2.35 M) was added to the reaction mixture. Then methyl acetoacetate (1.1 M) was added to the reaction mixture and maintained the reaction at 60-70°C for 4-5 hours Thereafter, the progress of the reaction was monitored using HPLC. After the completion of the reaction, pH of the reaction mass was adjusted using hydrochloric acid (6 M) at 10-20°C, extracted the reaction mass using toluene (300 ml X 2) and washed with brine solution to obtain a solid residue. The residue was crystallised using a mixture of heptane and acetone at 10-70°C to obtain titled compound (yield: 90%; purity: 95%).
Example 3: Preparation of 2,3,5-trifluoro-4-(2-oxopropyl)benzoic acid.
Methyl 2,3,5-trifluoro-4-(1-methoxy-1,3-dioxobutan-2-yl)benzoate (200 g; obtained in above example) was slowly added to a solution of sulphuric acid (30%, 5 M) in a reactor equipped with condenser at a room temperature and heated at 120-130°C for 20-24 hours. After completion of the reaction, the mixture was cooled to 10-15°C and then filtered to get wet cake. 2-Methyltetrahydrofuran (300 g) was added to the wet cake and washed twice with water (150 ml X 2). The excess 2-methyltetrahydrofuran was distilled to get titled compound (yield: 85%; purity 95%).
Example 4: Preparation of 1-(2,3,6-trifluorophenyl)propan-2-one.
2,3,5-Trifluoro-4-(2-oxopropyl)benzoic acid (100 g, obtained in above example) and N-methyl-2-pyrrolidone (100 g) was taken in a reactor equipped with a condenser. Copper oxide (0.1 M) was added to the reaction mixture and heated mixture to 150-160°C. Thereafter, the progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 20-25°C and an aqueous solution of potassium carbonate (20%) was added dropwise to it in an hour to adjust the pH 8-9. Activated carbon (10 g) was added to the reaction mixture and filtered. The filtrate was extracted thrice with toluene (100 g x 3). An aqueous solution of sodium metabisulfite (40%, 1.5 M) was added into toluene layer and stirred at a temperature of 50-60°C for an hour and thereafter, gradually cooled to 20-30°C for 8-10 hours. The reaction mass was filtered under reduced pressure, wet caked was washed twice with dichloromethane (100 ml X 2) and dried for an hour. The dried cake was added to a reactor and heptane (100 g) and an aqueous solution of sodium hydroxide (20-30%, 2 M) was added to it at 40-50°C for 4-5 hours. The layers were separated, the organic layer was washed with water (100 g X 2) and heptane was completely removed under reduced pressure to get pure 1-(2,3,6-trifluorophenyl)propan-2-one (yield: 80%; purity 99.2%).

CLAIMS:

WE CALIM
1. A process for preparation of a compound of Formula I,

Formula I
wherein X independently represents a chloro or fluoro and R represents an alkyl group,
comprising the steps of:
a) de-halogenating a compound of Formula VI,

Formula VI
wherein X independently represents a chloro or fluoro,
with zinc in presence of a catalyst to give a compound of Formula V;

Formula V
wherein X is defined above,
b) alkylating the compound of V in the presence of a base to obtain a compound of Formula IV;

Formula IV
wherein X is defined above,
c) reacting the compound of Formula IV with a nucleophile of Formula VII,

Formula-VII
wherein R1 represents CN, CONH2, COOH, COOR, R represents C1-C4 alkyl,
in the presence of a base to obtain a compound of Formula III,

Formula III
wherein X, R, and R1 are as defined above,
d) hydrolyzing the compound of Formula III to a compound of Formula II, and

Formula II
wherein X and R are as defined above,
e) de-carboxylating the compound of Formula II to obtain the compound of Formula I.
2. A compound of Formula II,

Formula II
wherein X independently represents a chloro or fluoro and R represents an alkyl group.
3. A compound of Formula III,

Formula III
wherein X independently represents a chloro or fluoro; R independently represents an alkyl group and R1 represents CN, CONH2, COOH, COOR.
4. The process as claimed in claim 1, wherein the step of de-halogenation is carried out using zinc in presence of a catalyst comprising a metal complex selected from a group consisting of nickel chloride hexahydrate with a ligand selected from the group consisting of 2,2´-bipyridine; morpholine; tetramethylethylenediamine and 1,10-phenanthroline.
5. The process as claimed in claim 1, wherein the “nucleophile of Formula VII” is selected from a group consisting of alkyl acetoacetate, acetoacetic acid, acetyl acetonitrile and acetyl acetamide.
6. The process as claimed in claim 1, wherein the reaction of the compound of Formula IV with a nucleophile of Formula VII is carried out at a temperature in the range from 40 to 70°C.
7. The process as claimed in claim 1, wherein the hydrolysis of the compound of Formula III is carried out using an acid selected from sulphuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid and p-toluene sulphonic acid.
8. The process as claimed in claim 1, wherein the hydrolysis of the compound of Formula III is carried out at a temperature range of 120 to 140°C using an acid in the range of 5 to 10 equivalents.
9. The process as claimed in claim 1, wherein the ‘base’ used in alkylation and the reaction of compound of Formula IV with a nucleophile of Formula VII is selected from a group consisting of a metal hydride, metal borohydride and alkali metal carbonates.
10. The process as claimed in claim 1, wherein the alkylation reaction and the reaction of compound of Formula IV with a nucleophile of Formula VII is performed in-situ, without isolation of the compounds of Formula IV.