FIELD OF THE INVENTION
The present invention provides a process for preparation of trihalobenzenes and intermediates thereof.
BACKGROUND OF THE INVENTION
Trihalobenzenes are intermediates for complex organic molecules in the pharmaceutical and agricultural industries.
The following methods have been conventionally known for the preparation of trihalobenzenes.
RSC Adv., 2015, 5, 15354-15358 discloses a process for the preparation of trifluorobenzene by silver-catalysed deboronation of arylboronic acids and esters in the presence of a base.
CN101817724 discloses a process for preparation of 1,2,4-trifluoro-benzene from 3,4-difluoroaniline.
USH992H discloses a process for preparation of 1,2,4-trifluorobenzene by decarboxylation of 2,4,5-trifluorobenzoic acid in presence of copper (II) oxide and N-methyl-2-pyrrolidone. The process is performed in the absence of a ligand. The inventors of the present invention reproduced the process to obtain only 55% of product along with considerable amount of other impurities.
The method reported in the literature use expensive reagents. Therefore, the inventors of the present invention have evolved a cost-effective process of preparation of trihalobenzenes.

OBJECT OF THE INVENTION
The main object of present invention is to provide a cost-effective and a scalable process for preparation of trihalobenzenes by using pentahalobenzomtrile.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of a compound of formula I,
x
Formula I wherein X independently represents a fluoro or chloro
comprising the steps;
a) hydrolysing a compound of formula V,

Formula V wherein X independently represents a fluoro or chloro to give a compound of formula IV;

*N^

H2ISL ^-0

Formula IV
b) dehalogenating the compound of formula IV with zinc in the presence of a catalyst to give a compound of formula III;
A
yr ^r "x
X Formula III c) hydrolysing the compound of formula III to give a compound of formula II;
HOy°
x' ^r "x
X Formula II
d) decarboxylating a compound of Formula II, with a metal oxide in the presence of a ligand to obtain the compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, present invention provides a process for the preparation of a compound of formula I,
x
Formula I
wherein X independently represents a fluoro or chloro
comprising the steps of;
a) hydrolysing a compound of formula V,
CN
x Formula V wherein X independently represents a fluoro or chloro to give a compound of formula IV;
X" "Y" "X X
Formula IV

b) dehalogenating the compound of formula IV with zinc in the presence of a catalyst to give a compound of formula III;
H2N^O
>r ^-r "x
X Formula III c) hydrolysing the compound of formula III to give compound of formula II;
HOy°
x" ^r" "x x
Formula II
d) decarboxylating the compound of Formula II, with a metal oxide in the presence of a ligand to obtain the compound of formula I.
In an embodiment, present invention provides a process for selective preparation of 3,4,5-trihalobenzamides of formula III,
H,I\L /O

X" ^ "X
X
Formula III
wherein X independently represents a fluoro or chloro,

comprising the steps of dehalogenating a compound of Formula IV,
H2Nk ^O

Formula IV
using zinc in a solvent in the presence of a catalyst.
In an embodiment, present invention provides a process for the preparation of compound of formula I,
r^%

Formula I wherein X independently represents a chloro or fluoro group, comprising the step of decarboxylating a compound of Formula II,
HO^O
rr^

Formula II
with a metal oxide in a polar organic solvent in presence of a ligand.

In an embodiment, the hydrolysis of compound of formula V is carried out in the presence of an acid. The acid is selected from inorganic acid such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid or an organic acid such as glacial acetic acid, formic acid, propionic acid, citric acid, oxalic acid, methanesulfonic acid and p-toluenesulfonic acid or the like. Preferably, the hydrolysis is carried out in presence of an acid selected from a group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid.
In an embodiment, the hydrolysis of compound of formula V is carried out at a temperature of 110°C to 115°C using acid in the range of 5 to 10 equivalents.
In another embodiment, the step of dehalogenation is carried out in presence of zinc and water in a ratio ranging from 1:3 to 1:5.
In another embodiment, the step of dehalogenation is carried out in presence of a solvent selected from water, polar organic solvent or a mixture thereof.
The 'polar organic solvent' selected from a group consisting of water immiscible polar solvent and polar aprotic solvent. The examples of water immiscible polar solvent include ethylacetate, methylacetate, butylacetate, ethylpentonoate, propylacetate, pentylacetate, methylbutyrate, isobutylacetate, methylbenzoate, ethylbenzoate, methyl tetrahydrofuran, toluene, benzonitrile or a mixture thereof. The examples of polar aprotic solvents includes dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, N-vinylpyrrolidone, hexamethyl phosphoramide, tetrahydrofuran, acetonitrile and sulfolane or a mixture thereof.
Preferably, the step of dehalogenation is carried out in water and a water immiscible polar organic solvent. The product isolation and selectivity are enhanced in water immiscible polar organic solvents such as ethylacetate and are therefore most preferred.
In another embodiment of the present invention, the solvent used is recovered, recycled and reused.

In an embodiment, the step of dehalogenation is carried out in presence of a catalyst comprising a metal complex selected from group consisting of a nickel chloride hexahydrate along with a ligand such as 2,2'-bipyridine or 1,10-phenanthroline and derivatives thereof.
In another embodiment, the step of dehalogenation is carried out in presence of nickel salt and the ligand in the ratio of 1:1 to 1:4.
The use of complex of nickel chloride hexahydrate with 1,10-phenanthroline monohydrate has been found to be a good and versatile medium for the highly selective dehalogenation of pentahalobenzamide by zinc under unprecedentedly mild conditions.
The use of a catalyst, solvent and ligand of the present invention leads to regioselective dehalogenation.
In an embodiment, the step of dehalogenation is carried out at a temperature range of 60°C to 95°C, preferably in a temperature range from 65°C to 70°C.
In a preferred embodiment, the present invention provides a process for preparation of 3,4,5-trifluorobenzamide, comprising the step of reacting 2,3,4,5,6-pentafluorobenzamide with zinc and water in presence of nickel chloride hexahydrate and 1,10-phenanthroline monohydrate in a solvent.
In an embodiment, the mole equivalent of zinc used in the step of dehalogenation is in the range of 3 to 5 molar equivalent.
The preparation of 3,4,5-trihalobenzamides involves generation of dihalobenzamides as side products that are recovered and recycled.
The preparation of 3,4,5-trifluorobenzamide involves generation of 3,5-difluorobenzamide/3,4-difluorobenzamide as side product that is recovered.
In an embodiment, the step of dehalogenation has selectivity greater than 95%. provides yield greater than 90%.

In an embodiment, the hydrolysing of compound of formula III is carried out in the presence of an acid or a base. The acid is selected from inorganic acid such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid or an organic acid such as glacial acetic acid, formic acid, propionic acid, citric acid, oxalic acid, methanesulfonic acid and p-toluenesulfonic acid or the like. Preferably, the hydrolysis is carried out in presence of an acid selected from a group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid.
In an embodiment, the hydrolysis of compound of formula III is carried out at a temperature range of 140°C to 150°C using acid in the range of 4 to 7 equivalents.
In an embodiment, the step of decarboxylating a compound of Formula II is carried out using a metal oxide in the presence of a ligand. The metal oxide is selected from copper oxide, silver oxide and calcium oxide, preferably cupric oxide.
In an embodiment, the step of decarboxylation is carried out in presence of a ligand selected from group consisting of 1,10-phenonthroline monohydrate and its derivatives, morpholine, 2,2'-bipyridine and tetramethylethylenediamine.
In an embodiment, the step of decarboxylation is carried out in presence of a polar
aprotic organic solvent such as, sulfolane, N-methyl-2-pyrrolidone, benzonitrile, N-
vinylpyrrolidone, hexamethylphosphoramide, dimethylsulfoxide, N,N-
dimethylformamide and N,N-dimethylacetamide or a mixture thereof. N-methyl-2-pyrrolidone is preferred as a solvent for the step of decarboxylation.
In another embodiment the step of decarboxylation involves recycling and reusing the solvent.
In an embodiment, the step of decarboxylation is carried out at a temperature range of 150°Ctol60°C.
In an embodiment, the mole equivalent of cupric oxide used in the present invention is 0.20 molar equivalent.

In an embodiment, the present invention provides a process for preparation of 1,2,3-trifluorobenzene, comprising the step of:
a) hydrolysing pentahalobenzonitrile to obtain 2,3,4,5,6-pentafluorobenzamide;
b) dehalogenating 2,3,4,5,6-pentafluorobenzamide in presence of zinc, water and
catalyst in a polar organic solvent to obtain 3,4,5-trifluorobenzamide;
c) hydrolysing 3,4,5-trifluorobenzamide to obtain 3,4,5-trifluorobenzoic acid;
d) decarboxylating 3,4,5-trifluorobenzoic acid in presence of cupric oxide and a ligand in a polar organic solvent to obtain 1,2,3-trifluorobenzene.
In another embodiment, the steps a) to d) are carried out without isolation of intermediate at any stage.
In another preferred embodiment, the step of dehalogenation of 2,3,4,5,6-pentafluorobenzamide is carried out in a mixture of water and an ester solvent. The ester solvent is selected from ethylacetate, methylacetate, butylacetate, ethylpentonoate, propyl acetate, pentyl acetate, methylbutyrate, isobutyl acetate, methylbenzoate, ethylbenzoate. Most preferably, the step of dehalogenation is carried out in a mixture of water and ethylacetate. The mixture of an ester and water enables hassle free separation of the product and provides better yield and selectivity towards 3,4,5-trifluorobenzamide.
In an embodiment, the present invention provides a process for preparation of compound of Formula I, having selectivity greater than 97%.
In an embodiment, the present invention provides a process for preparation of compound of Formula I, having yield greater than 85%.
In an embodiment, the present invention provides a process for preparation of compound of Formula I, having purity greater than 90%.

The reactants used in the present invention i.e., compound of formula V along with reagents and solvents are commercially available.
The compound of the present invention can be isolated using various isolation techniques known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
The completion of the reaction may 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), liquid chromatography (LC) and alike.
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: Process for the preparation of 2,3,4,5,6-pentafluorobenzamide
2,3,4,5,6-pentafluorobenzonitrile (50.0 gm), sulfuric acid (233.0 gm) and water (4.67 gm) were charged into the round bottom flask and heated the reaction mixture at 110-115°C for 3-4 hours. After completion of the reaction, recovered the 2,3,4,5,6-pentafluorob enzami de.
Purity: >95 %; Yield: 94-95 %
Example 2: Process for the preparation of 3,4,5-trifluorobenzamide
N-methyl-2-pyrrolidone (70.40 gm), nickel chloride hexahydrate (0.85 gm), 1,10-phenanthroline monohydrate (1.41 gm) and water (5.0 gm) were charged into the round bottom flask and heated the reaction mixture at a temperature of 90-95°C for an hour. Zinc (5.0 eq.) was added to the reaction mixture and stirred the mixture for 10-15 minutes. 2,3,4,5,6-pentafluorobenzamide (15 gm) (obtained in example 1) was added to the reaction mixture and stirred the mixture for 4-6 hours. After completion of the reaction, the reaction mixture was filtered and extracted with dichloromethane. The solvent was removed to recover solid product.
Purity: >97-98 %; Yield: 80-85 %; Selectivity of 3,4,5-trifluorobenzamide: 97-98 %
Example 3: Process for the preparation of 3,4,5-trifluorobenzamide
Water (160 gm), ethylacetate (20 gm), nickel chloride hexahydrate (1.13 gm) and 1,10-phenanthroline monohydrate (0.94 gm) were charged into the round bottom flask and heated the mixture at a temperature of 55-60°C for an hour. Zinc (3.0 eq.) was added into the reaction mixture and stirred the mixture for 10-15 minutes. 2,3,4,5,6-pentafluorobenzamide (20 gm) was added to the reaction mixture and stirred the mixture for 6-7 hours. Zinc (1.0 eq.) was added in two parts to the reaction mixture

after 3 hours of reaction progression. After completion of the reaction, the reaction mixture was filtered at 25-30°C to obtain the desired product.
Purity: >97-98 % Yield: >95 %; Selectivity of 3,4,5-trifluorobenzamide: >97 %
Example 4: Process for the preparation of 3,4,5-trifluorobenzoic acid
3,4,5-trifluorobenzamide (50.0 gm), sulfuric acid (171.5 gm) and water (63.9 gm) were charged into the round bottom flask and heated the reaction mixture at 140-150°C for 3-4 hours. After completion of the reaction, recovered the 3,4,5-trifluorobenzoic acid.
Purity: >90 %; Yield: 88-90 %
Example 5: Process for the preparation of 1,2,3-trifluorobenzene
N-methyl-2-pyrrolidone (50.0 gm) and 3,4,5-trifluoro benzoic acid (20.0 gm) were charged into round bottom flask equipped with mechanical stirrer to form a reaction mixture. Cupric oxide (0.45 gm) and 1,10-phenanthrolinemonohydrate (1.13 gm) were added into the reaction mixture and heated the mixture to 150-160°C and stirred for 4-6 hours. After completion of the reaction, recovered the 1,2,3-trifluorobenzene.
Purity: >90 %; Yield: 88-90 %; Selectivity of 1,2,3-trifluorobenzene: >97%
Example 6: Process for the preparation of 1,2,3-trifluorobenzene
N-methyl-2-pyrrolidone (50.0 gm) and 3,4,5-trifluoro benzoic acid (20.0 gm) were charged into round bottom flask equipped with mechanical stirrer to form a reaction mixture. Cupric oxide (0.45 gm) and morpholine (0.49 gm) were added into the reaction mixture and heated to a temperature of 150-160°C and stirred for 4-6 hours. After completion of the reaction, recovered the 1,2,3-trifluorobenzene with yield of 75%.

Example 7: Process for the preparation of 1,2,3-trifluorobenzene
N-methyl-2-pyrrolidone (50.0 gm) and 3,4,5-trifluoro benzoic acid (20.0 gm) were charged into round bottom flask equipped with mechanical stirrer to form a reaction mixture. Cupric oxide (0.45 gm) and tetramethylethylenediamine (0.65 gm) were added into the reaction mixture, heated the mixture to 150-160°C and stirred for 4-6 hours.
After completion of the reaction, recovered the 1,2,3-trifluoro benzene.
Yield: 90%; Selectivity of 1,2,3-trifluorobenzene: 95 %

WE CLAIM:

1. A process for preparation of a compound of formula I,
X
Formula I wherein X independently represents a fluoro or chloro, comprising the steps of;
a) hydrolysing a compound of formula V,
CN x. J*, y.
x y^ x x
Formula V
wherein X independently represents a fluoro or chloro
to give a compound of formula IV;
H2ISL ^-0
N^

x^

,x

X" ^T "X X
Formula IV

b) dehalogenating the compound of formula IV with zinc in the presence of a catalyst
to give a compound of formula III;
H2N^O
(11
X Formula III
c) hydrolysing the compound of formula III to give a compound of formula II;
HOy°
x^^^x
X Formula II
d) decarboxylating a compound of Formula II with a metal oxide in the presence of a
ligand to obtain the compound of formula I.
2. The process as claimed in claim 1, wherein the hydrolysis is carried out in the presence of an acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid.
3. The process as claimed in claim 1, wherein the hydrolysis of step a) is carried out at a temperature of 110°C to 115°C.
4. The process as claimed in claim 1, wherein the dehalogenation is carried out in water and a polar organic solvent selected from a group consisting of ethylacetate, methylacetate, butylacetate, ethylpentonoate, propyl acetate, pentylacetate, methylbutyrate, isobutyl acetate, methylbenzoate, ethylbenzoate, methyl

tetrahydrofuran, toluene, dimethylsulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylacetamide, N-vinylpyrrolidone, hexamethyl phosphoramide, tetrahydrofuran, acetonitrile and sulfolane.
5. The process as claimed in claim 1, wherein the dehalogenation is carried out in presence of a catalyst comprising a metal complex such as nickel chloride hexahydrate with a ligand such as 2,2'-bipyridine or 1,10-phenanthroline and derivatives thereof.
6. The process as claimed in claim 1, wherein the dehalogenation is carried out at a temperature range of 60°C to 95°C.
7. The process as claimed in claim 1, wherein the hydrolysis of step c) is carried out at a temperature range of 140°C to 150°C.
8. The process as claimed in claim 1, wherein the decarboxylation is carried out using a metal oxide selected from a group consisting of cupric oxide, silver oxide and calcium oxide.
9. The process claimed in claim 1, wherein the decarboxylation is carried out in presence of a ligand selected from a group consisting of 1,10-phenonthroline monohydrate, morpholine, 2,2'-bipyri dine, tetramethylethylenediamine and derivatives thereof.

10. The process as claimed in claim 1, wherein the decarboxylation is carried out in a polar organic solvent selected from a group consisting of sulfolane, N-methyl-2-pyrrolidone, benzonitrile, N-vinylpyrrolidone, hexamethylphosphoramide, dimethylsulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide or the like.