FIELD OF THE INVENTION
The present invention provides a process for preparation of a compound of formula 1,

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine

BACKGROUND OF THE INVENTION
The compound of formula 1 i.e., halogen substituted pyridines are important intermediates for preparation of 2-(4-((5-chloro(or bromo)-3-fluoro)pyridinyl-2-oxy)phenoxy propionic acid and agriculturally acceptable derivatives thereof, for example, salts, esters and amides, which are known herbicidal agents. These compounds are also useful in the synthesis of various agrochemicals and medicines.
Various methods are known in the art for the preparation of these herbicide intermediates e.g., U.S. Patent No. 4,822,887 discloses a process for preparation of 5-halo-2,3-difluoropyridine by fluorinating 2,3,5-trichloropyridine using potassium fluoride in presence of sulfolane solvent. It took 33 hours to complete the reaction. After completion of the reaction, the reaction mixture was cooled and subjected to vacuum distillation at 140°C to get crude liquid product with a selectivity of 33% by GC analysis. The crude liquid product was further stirred at 190°C for 20 hours and subjected to distillation to get the desired product with a yield of 24%.
Thus the above process prepares 5-halo-2,3-difluoropyridine compound of formula 1 with a selectivity of 33% only. Moreover, it took 53 hours to complete the reaction.
It is a very well-known fact that high selectivity will lead to conversion of more reactant into the product which will reduce the cost of the process at industrial scale.
Moreover it is very important for a chemical reaction to have less reaction time. Less reaction time will not only provide a simple process at industrial scale but it will also reduce the possibility of formation of undesired impurities.
Thus there is need to develop a process for preparation of 5-halo-2,3-difluoropyridine with higher selectivity and lesser reaction time.
Surprisingly, the inventors of the present invention found that 5-halo-2,3-difluoropyridine can be prepared with a minimum selectivity of 45% and within a reaction time of 8 to 16 hours.

OBJECT OF THE INVENTION
The object of the present invention is to provide a cost effective and economical process for preparation of a compound of formula 1,

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparation of a compound of formula 1,

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine,
comprising the steps of:
a) drying potassium fluoride (KF) in a reactor at 130 to 250°C;
b) adding solution of a compound of formula 2 in a polar aprotic solvent to dried KF and heating to 180 to 250°C;

wherein X and X1 is a halogen selected independently from chlorine, bromine, iodine and fluorine
c) stirring the reaction mixture of step b) at 180 to 250°C for 8 to 16 hours;
d) distilling the reaction mixture of step c) to obtain crude compound of formula 1;
e) recycling the compound of formula 2 to step a) reactor; and
f) isolating pure compound of formula 1, having purity more than 97%,
wherein the compound of formula 1 is obtained with a yield of at least 75%, and wherein the compound of formula 2 is converted into compound of formula 1 with at least 45% selectivity.
In another aspect, the present invention provides a process for preparation of a compound of formula 1,

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine,
comprising the steps of:
a) drying potassium fluoride in a reactor at 130 to 250°C;
b) adding solution of a mixture of compound of formula 2a and 2b in a polar aprotic solvent to dried KF and heating to 180 to 250°C;

wherein X1 is a halogen selected from chlorine, bromine, iodine and fluorine
c) stirring the reaction mixture of step b) at 180 to 250°C for 8 to 16 hours;
d) distilling the reaction mixture of step c) to obtain crude compound of formula 1, and recycling back the unreacted mixture of compound of formula 2a and 2b to step a) reactor; and
e) isolating pure compound of formula 1, having purity more than 97%,
wherein the compound of formula 1 is obtained with an yield of at least 75%, and wherein the mixture of compound of formula 2a and 2b is converted into compound of formula 1 with at least 45% selectivity.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the compound of formula 1 refers to 2,3,5-trifluoropyridine, 5-chloro-2,3-difluoropyridine, 5-bromo-2,3-difluoropyridine and 5-iodo-2,3-difluoropyridine.
The potassium fluoride (KF) used as fluorinating agent in the present invention is commercially available. Substantially anhydrous and finely-divided potassium fluoride is preferred. Amorphous or spray-dried forms are particularly preferred. Substantially anhydrous KF can be prepared, for example, by drying in vacuum at 130°-250°C for several hours.
In an embodiment of the present invention, the KF is dried under inert atmosphere. The inert atmosphere is created using nitrogen or argon.
The polar aprotic solvent used in step b) is selected from a group consisting of sulfolane, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide or a mixture thereof.
In an embodiment, the compound of formula 2 was dissolved in sulfolane. The solvent used is 4 to 10 times with respect to the compound of formula 2.
In a preferred embodiment, the present invention provides a process for preparation of 5-chloro-2,3-difluoropyridine, comprising the steps of:
a) drying potassium fluoride at 130 to 250°C;
b) adding solution of 2,3,5-trichloropyridine in sulfolane to dried KF and heating to 180 to 250°C;
c) stirring the reaction mixture of step b) at 180 to 250°C for 8 to 16 hours;
d) distilling the reaction mixture of step c) to obtain crude 5-chloro-2,3-difluoropyridine, and recycling back 3,5-dichloro-2-fluoropyridine to step a) reactor; and
e) isolating pure 5-chloro-2,3-difluoropyridine, having purity more than 97%,
wherein 5-chloro-2,3-difluoropyridine is obtained with an yield of at least 75%, and selectivity of at least 45%.
In another preferred embodiment, the present invention provides a process for preparation of 5-chloro-2,3-difluoropyridine, comprising the steps of:
a) drying potassium fluoride at 130 to 250°C;
b) adding a solution of 3,5-dichloro-2-fluoropyridine in sulfolane to dried KF and heating to 180 to 250°C;
c) stirring the reaction mixture of step b) at 180 to 250°C for 8 to 16 hours;
d) distilling the reaction mixture of step c) to obtain crude 5-chloro-2,3-difluoropyridine, and recycling 3,5-dichloro-2-fluoropyridine back to step a) reactor; and
e) isolating pure compound of 5-chloro-2,3-difluoropyridine, having purity more than 97%,
wherein 5-chloro-2,3-difluoropyridine is obtained with an yield of at least 75%, and selectivity of at least 45%.
As used herein, the term “isolating” refers to the method used to isolate the compound from the reaction mixture. The isolation is carried out using any of the process consisting of extraction, distillation, filtration, decantation, washing, dryings or combination thereof.
In a preferred embodiment, the compound of the formula 1 is isolated using fractional distillation technique at a pressure range of 200mmHg – 10mmHg and at a temperature range of 100°C - 180°C.
The isolation of the compound of formula 1 can also be done by crystallization or recrystallization using non-polar solvent selected from a group consisting of hexane, heptane, pentane, butane, propane, iso-propane and the like.
In a preferred embodiment, the compound of formula 1 is recrystallized using hexane.
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” and includes 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 compound of formula 2 which is used herein as starting material can be prepared by any of the methods known in the art i.e., or can be obtained commercially.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES
Example 1: Preparation of 5-chloro-2, 3-difluoropyridine (CDFP) from 2,3,5-trichloropyridine (TCP)
Potassium fluoride (576g) was taken into 1litre round bottom flask (RBF) at 140°C under nitrogen atmosphere and it was dried for 1hour at same temperature. 2,3,5-trichloropyridine (565g) in (2.79kg) of sulfolane was added to hot potassium fluoride at 140°C and mass was heated to 220°C and was stirred for 16 hours.
CDFP selectivity: 46%
The mixture was cooled and subjected to vacuum distillation to remove crude liquid composition. The mixture was further subjected to column distillation to separate 5-chloro-2, 3-difluoropyridine from unreacted 2,3,5-trichloropyridine and 2-fluoro-3,5-dichloropyridine (by-product). The unreacted TCP and by-products were recycled back to the reactor. The Separated 5-chloro-2, 3-difluoropyridine crude liquid was fractionally distilled to obtain pure CDFP.
Yield: 75%
Purity: 97.5%
Example 2: Preparation of 5-chloro-2,3-difluoropyridine from 2-fluoro-3,5-dichloropyridine
Potassium fluoride (394g) was taken into 1 litre RBF at 140°C under nitrogen atmosphere and it was dried for 1 hour at same temperature. (565g of 2-fluoro-3,5-dichloropyridine in 2.79 kg of sulfolane was added to hot potassium fluoride at 140°C and mass was heated to 220°C and was stirred for 16 hours.
CDFP selectivity: 46%
The mixture was cooled and subjected to vacuum distillation to remove crude liquid composition. The mixture was further subjected to column distillation to separate CDFP. The unreacted 2-fluoro-3,5-dichloropyridine was recycled back to the reactor. Separated CDFP crude was fractionally distilled to obtain pure CDFP.
Yield: 78%
Purity: 98%
Example 3: Preparation of 5-chloro-2, 3-difluoropyridine from a mixture of 2-fluoro-3,5-dichloropyridine (DCFP) and 2,3,5-trichloropyridine (TCP)
Potassium fluoride (63.7 g) was taken into 1 litre RBF at 140°C under nitrogen atmosphere and it was dried for 1 hour at same temperature. 2,3,5-trichloropyridine (50g) and 2,3-dichloro-5-fluoropyridine (45.5g) in 530 g of sulfolane was added to hot potassium fluoride at 140°C and mass was heated to 220°C and held for 16 hours.
CDFP selectivity: 48%
The mixture was cooled and subjected to vacuum distillation to remove crude liquid mixture containing CDFP and DCFP. The mixture was further subjected to column distillation to separate CDFP. The unreacted DCFP was recycled back to the reactor. Separated CDFP crude was recrystallized using hexane (300ml) at temperature -50 to -40°C to obtain pure CDFP.
Yield: 80%
Purity: 98%

,CLAIMS:WE CLAIM:
1. A process for preparation of a compound of formula 1,

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine,
comprising the steps of:
a) drying potassium fluoride (KF) in a reactor at 130 to 250°C;
b) adding solution of a compound of formula 2 in a polar aprotic solvent to dried KF and heating to 180 to 250°C;

wherein X and X1 is a halogen selected independently from chlorine, bromine, iodine and fluorine
c) stirring the reaction mixture of step b) at 180 to 250°C for 8 to 16 hours;
d) distilling the reaction mixture of step c) to obtain crude compound of formula 1,
e) recycling the compound of formula 2 to step a) reactor; and
f) isolating pure compound of formula 1, having purity more than 97%.
wherein the compound of formula 1 is obtained with a yield of at least 75%, and selectivity of at least 45%.

2. A process for preparation of a compound of formula 1,

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine,
comprising the steps of:
a) drying potassium fluoride in a reactor at 130 to 250°C;
b) adding solution of a mixture of compound of formula 2a and 2b in a polar aprotic solvent to dried KF and heating to 180 to 250°C;

wherein X is a halogen selected from chlorine, bromine, iodine and fluorine
c) stirring the reaction mixture of step b) at 180 to 250°C for 8 to 16 hours;
d) distilling the reaction mixture of step c) to obtain crude compound of formula 1, and recycling back the unreacted mixture of compound of formula 2a and 2b to step a) reactor; and
e) isolating pure compound of formula 1, having purity more than 97%.
wherein the compound of formula 1 is obtained with an yield of at least 75%, and selectivity of at least 45%.
3. The process as claimed in claim 1 and claim 2, wherein the polar aprotic solvent is selected from a group consisting of sulfolane, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide or a mixture thereof.
4. The process as claimed in claim 1 and claim 2, wherein the compound of formula 1 is isolated using fractional distillation technique at a pressure range of 200mmHg – 10mmHg and at a temperature range of 100°C-180°C.
5. The process as claimed in claim 1 and claim 2, wherein the compound of formula 1 is isolated by crystallization or recrystallization or combination thereof using non-polar solvent.
6. The process as claimed in claim 5, wherein the non-polar solvent is selected from a group consisting of hexane, heptane, pentane, butane, propane and iso-propane or a mixture thereof.
7. The process as claimed in claim 1 and claim 2, wherein the potassium fluoride used is in the form selected from anhydrous, finely-divided, amorphous and spray-dried or a combination thereof.
Dated this 30th September, 2019.