FIELD OF THE INVENTION

The present invention provides an improved process for preparation of fluorinated benzene sulfonyl fluoride of formula I.

Formula I
wherein n=1-5

BACKGROUND OF THE INVENTION
Fluorinated aromatic sulfonyl fluorides are very useful in agrochemical and pharmaceutical industry.
US4,369,145 provides a process for preparation of 2,4-difluoro-benzenesulfonyl fluoride by reacting metal fluoride and 2,4-dichloro-benzenesulfonylchloride in presence of tris(3,6,9-trioxadecyl)amine as sequestering agent and large excess of solvent. The yield reported for the process is 65%. It states that process without using tris(3,6,9-trioxadecyl)amine gives yield below 40%. The weight ratio of solvent to 2,4-difluorobenzenesulfonyl fluoride is very high for this process which is increasing cost of process. Hence, the process is not economical and industrially applicable.
US20030232859 provides a process for preparation of halogenated benzene sulfonyl fluoride. The process comprising reacting halogenated aniline with sodium nitrite/hydrogen chloride, followed by reaction with sulphur dioxide in presence of copper chloride to prepare halogenated benzene sulfonyl chloride. Further, it was reacted with potassium fluoride to form halogenated sulfonyl fluoride.
Thus, there remains an urgent need to develop an economical and industrially applicable process for preparation of fluorinated benzene sulfonyl derivatives.
SUMMARY OF THE INVENTION
In first aspect, the present invention provides an improved process for preparation of a compound of formula I,

Formula I
wherein n=1-5
comprising the step of fluorinating a compound of formula II with fluoride source to obtain a compound of formula I, wherein process is carried out in absence of sequestering agent,

Formula II

wherein X is selected from –F, -Cl, -Br or –I, provided at least one X is not -F and n=1-5.

In second aspect, the present invention provides an improved process for preparation of a compound of formula I,

Formula I
wherein n=1-5
comprising the step of fluorinating a compound of formula II with preheated fluoride source to obtain compound of formula I, wherein process is carried out in absence of sequestering agent,

Formula II
wherein X is selected from –F, -Cl, -Br or –I, provided at least one X is not -F and n=1-5.

OBJECT OF THE INVENTION
The main object of present invention is to provide an economic and industrially applicable process for preparation of fluorinated benzene sulfonyl fluoride by improving reaction parameters and eliminating use of sequestering agent.

Formula I
wherein n=1-5
DETAILED DESCRIPTION OF THE INVENTION
As used herein, “inert atmosphere” refers to the atmosphere containing substantial amount of nitrogen, helium or argon.
As used herein, the term “polar aprotic solvent” refer to sulfolane, dimethyl sulfoxide, dimethyl formamide or N-methyl pyrrolidine or like.
As used herein “sequestering agent” refers to the sequestering agent defined in US4,369,145 selected from tris(3-oxaheptyl)amine, tris(3,6-dioxaheptyl)amine, tris(3,6,9-trioxadecyl)amine, tris(3,6-dioxa.octyl)amine, tris(3,6,9-trioxaundecyl)amine, tris(3,6-dioxanonyl)amine, tris(3,6,9-trioxadodecyl)amine, tris(3,6-dioxadecyl)amine, tris(3,6,9-trioxatridecyl)amine, tris(3,6-dioxa-4-methylheptyl)amine, tris(3,6-dioxa-2,4-dimethylheptyl)amine or like and mixture thereof.
In an embodiment, the present invention provides an improved process for preparation of a compound of formula I,

Formula I
wherein n=1-5
comprising the step of fluorinating a compound of formula II with fluoride source to obtain compound of formula I, wherein process is carried out in absence of sequestering agent;

Formula II
wherein X is selected from –F, -Cl, -Br or –I, provided at least one X is not -F and n=1-5.
In a preferred embodiment, process of present invention is carried out in absence of any sequestering agent.
As used herein, the term “fluoride ion source” refers to a compound containing fluoride ion.
The fluoride ion source for present invention is selected from a group consisting of metal fluoride such as sodium fluoride, potassium fluoride, cesium fluoride, lithium fluoride, zinc fluoride, aluminium fluoride, nickel fluoride and organic fluoride selected from tetramethylammonium fluoride, trimethylethylammonium fluoride, triethylmethylammonium fluoride or like or mixture thereof.
The benzene sulfonyl chloride compounds are sensitive to water and degrade in presence of moisture. Therefore, anhydrous conditions are used for the process.
In an embodiment, the fluoride source is initially dried at a temperature of 90 to 160°C to remove moisture content and maintained at same temperature. Further, inert atmosphere is used to prevent atmospheric moisture during the process. Inert gas for present invention may be selected from nitrogen, argon and xenon.
The drying and maintaining of fluoride source at high temperature helps to prevent moisture that can result in the impurities during the reaction. It is observed by the present inventors that maintaining fluoride source in hot condition also helps in improving the yield of the process.
In one embodiment, fluoride source is pre-heated at a temperature range selected from 90-160°C in the present invention. A solution of compound of formula II is added to hot fluoride source to form a reaction mixture.
In one embodiment, the reaction mixture is heated in a temperature range selected from 150-200°C, preferably in the range selected from 170-190°C and more preferably in the range selected from 175-180°C.
In one embodiment, present invention provides a process for preparation of a compound of formula I comprising;
a) heating potassium fluoride under reduced pressure;
b) adding a solution of a compound of formula II in a polar aprotic solvent to hot potassium fluoride of step-a) to obtain a reaction mixture;
c) heating the reaction mixture of step b) to obtain the compound of formula I.
In one embodiment, product of present invention was isolated through fractional distillation up to 220°C.
In another embodiment, the addition of a compound of formula II to fluoride source is carried out under inert atmosphere.
In another embodiment, the reaction mass was filtered before the work up to remove chloride salts and unreacted fluoride source.
In another embodiment, the solvent is recovered and reused in the process.
The present invention also provides an economical process for preparation of compound of formula I by limiting quantity of solvent.
In an embodiment of present invention, the process is carried out in presence of solvent, wherein the weight ratio of the solvent to the compound of formula II is less than 5.
The compound of formula II is used in solution form prepared using polar aprotic solvent.
The preferred solvents for present invention are the solvent having boiling in the range 150-300°C.
The purity of compound of formula I for present invention is greater than 95%. More preferably, the purity of compound of formula I is greater than 99%.
The yield of compound of formula I of present invention is greater than 75%.
The reagents used for present invention are anhydrous.
The compound of formula I may be isolated or can be used in situ for preparation pharmaceutical compounds for agrochemical industry.
The compound of formula II may be prepared by methods available in art. The preferred X for formula II are chloro and fluoro.
The compound of Formula I is isolated by any method 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.
The reagents used in the above process are obtained commercially.
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 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 2,6-difluorobenzenesulfonyl fluoride.
Potassium fluoride (425g) was charged in 5-litre round bottom flask and dried for 1 hour at 140-150°C under nitrogen atmosphere. A solution of 2,6-dichlorobeneznesulfonyl chloride (400g) in sulfolane (1700g) was charged to hot potassium fluoride at 140°C under nitrogen atmosphere. Mass temperature was increased to 180°C and maintained for 10 hours (check point: chlorofluorobenzenesulfonyl fluoride less than 2%). Reaction mass was analysed on gas chloromatography.
Reaction mass was cooled to room temperature and filtered. The by-product potassium chloride and unreacted potassium fluoride was filtered and washed with dichloromethane (800g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation using 1 metre column under vaccum 10-20mm Hg at 160-190°C.
Purity: 99%; Yield: 70%
Example 2: Preparation of 2,4-difluorobenzenesulfonyl fluoride
In a 5-litre round bottom flask, potassium fluoride (55g) was charged and dried for 1 hour at 150°C under nitrogen atmosphere. The 2,4-dichlorobenzenesulfonyl chloride (50g) was dissolved in dimethylformamide (220g) and added slowly to hot potassium fluoride at 150°C under nitrogen atmosphere. Mass temperature was increased to 150°C and maintained for 10 hours. Reaction mass sample was analysed on gas chloromatography (check point: chlorofluorobenzenesulfonyl chloride less than 2%). The reaction mass was cooled to room temperature and filtered to remove by product potassium chloride and unreacted potassium fluoride and washed with dichloromethane (100g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation under vaccum 10-20mm Hg.
Purity: 99.5%; Yield: 85%
Example 3: Preparation of 2,6-difluorobenzenesulfonyl fluoride
Potassium fluoride (85g) was charged in 5-litre round bottom flask and dried for 1 hour at 145°C under nitrogen atmosphere. Prepared a solution of 2,6-dichlorobenzenesulfonyl chloride (100.5g) in dimethylsulfoxide (450g) and charged to hot potassium fluoride at 140°C under nitrogen atmosphere. Mass temperature was increased to 180°C and maintained for 10 hours. Reaction mass was analysed on gas chloromatography (check point: chlorofluorosulfonyl chloride less than 2%). After reaction completed, reaction mass was cooled slowly to room temperature and filtered to remove byproduct potassium chloride and residual potassium fluoride. The solid byproduct was washed with dichloromethane (200g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation using 1 metre column under vaccum 10-20mm Hg.
Purity: 99.8%; Yield: 88%
Example 4: Preparation of 2-fluorobenzenesulfonyl fluoride
Potassium fluoride (81g) was charged in 5-litre round bottom flask and dried for 1 hour at 151°C under nitrogen atmosphere. Prepared a solution of 2-chlorobenzenesulfonyl chloride (60g) in dimethylsulfoxide (250g) and charged to hot potassium fluoride at 140°C under nitrogen atmosphere. Mass temperature was increased to 180°C and maintained for 9 hours. Reaction mass was analysed on gas chloromatography. After reaction completed, reaction mass was cooled slowly to room temperature and filtered to remove byproduct potassium chloride and residual potassium. The solid byproduct was washed with dichloromethane (130g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation using 1 metre column under vaccum 10-20mm Hg.
Purity: 99.1%; Yield: 90%
Example 5: Preparation of 2,4,6-trifluorobenzenesulfonyl fluoride
In a 5-litre round bottom flask, potassium fluoride (100g) was charged and dried for 1 hour at 148°C under nitrogen atmosphere. A solution of 2,4,6-trichlorobenzenesulfonyl chloride (80g) was dissolved in sulfolane (320g) and added to hot potassium fluoride at 150°C under nitrogen atmosphere. Mass temperature was increased to 180°C and maintained for 10 hours. Reaction mass sample was analysed on gas chloromatography (check point chlorodifluorobenzene sulfonyl fluoride less than 2%). The reaction mass was cooled to room temperature and filtered to remove unreacted potassium fluoride and by-product potassium chloride and washed with dichloromethane (160g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation under vaccum 10-20mmHg.
Purity: 99.2%; Yield: 87%
Example 6: Preparation of 4-fluorobenzenesulfonyl fluoride
Potassium fluoride (110g) was charged in 5-litre round bottom flask and dried for 1 hour at 140°C under nitrogen atmosphere. Prepared a solution of 4-chlorobenzenesulfonyl chloride (100g) in sulfolane (450g) and charged to hot potassium fluoride at 140°C under nitrogen atmosphere. Mass temperature was increased to 180°C and maintained for 10 hours. Reaction mass was analysed on gas chloromatography (check point: 4-chlorobenzenesulfonyl chloride less than 2%). After reaction completed, reaction mass was cooled slowly to room temperature and filtered to remove by product potassium chloride and un reacted potassium fluoride. The solid byproduct was washed with dichloromethane (200g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation using 1 metre column under vaccum upto 220°C.
Purity: >99%; Yield: 89%
Example 7: Preparation of 2,4,6-trifluorobenzenesulfonyl fluoride
Potassium fluoride (75g) was charged and dried for 1 hour at 140°C under nitrogen atmosphere. A solution of 2,4,6-trifluorbenzenesulfonyl chloride (60g) was prepared in sulfolane (250g) and added to hot potassium fluoride at 150°C under nitrogen atmosphere. Mass temperature was increased to 180°C and maintained for 10 hours. Reaction mass sample was analysed on gas chloromatography (check point: chlorodifluorobenzenesulfony fluoride less than 2%). The reaction mass was cooled to room temperature and filtered to remove Potassium chloride formed as byproduct and residual potassium fluoride. The filtered solid was washed with dichloromethane (30g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation under vaccum 10-20mm Hg.
Purity: >99%; Yield: 89%
Example 8: Preparation of 2,6-difluorobenzenesulfonyl fluoride
In a 5-litre round bottom flask potassium fluoride (42gm) was charged and dried for 1 hour at 153°C under nitrogen atmosphere. A solution of 2,6-difluorobenzenesulfonyl chloride (50g) was prepared in dimethylsulfoxide (400g) and added to hot potassium fluoride at 150°C under nitrogen atmosphere. Mass temperature was increased to 180°C and maintained for 10hr. Reaction mass sample was analysed on gas chloromatography.The reaction mass was cooled to room temperature and filtered to remove unreacted potassium fluoride and by product potassium chloride was washed with dichloromethane (50g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation under vaccum 10-20mm Hg.
Purity: 99%; Yield: 85%
Example 9: Preparation of 2,4,6-trifluorobenzenesulfonyl fluoride
Potassium fluoride (75g) was charged and dried for 1 hour at 150°C under nitrogen atmosphere. A solution of 2,4,6-trifluorbenzenesulfonyl chloride (60g) was prepared in dimethylsulfoxide (250g) and added to hot potassium fluoride at 150°C under nitrogen atmosphere. Mass temperature was increased to 180°C and maintained for 10hr. Reaction mass sample was analysed on gas chloromatography.The reaction mass was cooled to room temperature and filtered to remove unreacted potassium fluoride and potassium chloride was washed with dichloromethane (10g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation under vaccum 10-20mmHg.
Purity: 98%; Yield: 93%
Example 10: Preparation of 4-fluorobenzenesulfonyl fluoride
Potassium fluoride (110gm) was charged in 5-litre round bottom flask and dried for 1 hour at 140°C under nitrogen atmosphere. Prepared a solution of 4-chlorobenzenesulfonyl chloride (100g) in dimethylformamide (450g) and charged to hot potassium fluoride at 140°C under nitrogen atmosphere. Mass temperature was increased to 155°C and maintained for 10 hours. Reaction mass was analysed on gas chloromatography. After reaction completed, reaction mass was cooled slowly to room temperature and filtered to remove by product potassium chloride and unreacted potassium fluoride. The solid was washed with dichloromethane (200g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation using 1 metre column under vaccum 10-20mm Hg upto 210°C.
Purity: 99%; Yield: 85%

COMPARATIVE EXAMPLES:
Example 1: : Preparation of 4-fluorobenzenesulfonyl fluoride
In a 1-litre round bottom flask equipped with mechanical stirrer, potassium fluoride (110g), 4-chlorobenzenesulfonyl chloride (100g) and sulfolane (450g) were charged and slowly heated to 180°C up to 10 hours. Reaction mass sample was analysed on gas chloromatography. After reaction completed, reaction mass was cooled slowly to room temperature and filtered to remove by product potassium chloride and unreacted potassium fluoride. The solid was washed with dichloromethane (200g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation using 1 metre column under vaccum 10-20mm Hg upto 210°C.
Purity: 85%; Yield: 40%
Example 2: Preparation of 2,4-difluorobenzenesulfonyl fluoride
In 5-litre round bottom flask equipped with mechanical stirrer, potassium fluoride (55g), 2,4-dichlorobenzene sulfonyl chloride (50g) and dimethyl formamide (220g) were charged and heated to 175°C under nitrogen atmosphere. Reaction mass was maintained for 10 hours at 175°C. The reaction mass sample was analysed on gas chloromatography. After reaction completed, the reaction mass was cooled to room temperature and filtered to remove byproduct potassium chloride and unreacted potassium fluoride and washed with dichloromethane (100g). Dichloromethane was recovered from filtrate and crude product was carried forward for fractional distillation under vaccum.
Purity: 82%; Yield: 38%

WE CLAIM:

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

Formula I
wherein n=1-5
comprising the step of fluorinating a compound of formula II with a fluoride source to obtain the compound of formula I, wherein the process is carried out without using any sequestering agent,

Formula II
wherein X is selected from –F, -Cl, -Br or –I, provided at least one X is not -F and n=1-5.
2. The process as claimed in claim 1, wherein the fluoride source is either a metal fluoride selected from a group consisting of sodium fluoride, potassium fluoride, cesium fluoride, lithium fluoride, zinc fluoride, aluminum fluoride, nickel fluoride or an organic fluoride selected from a group consisting of tetramethylammonium fluoride, trimethylethylammonium fluoride, triethylmethylammonium fluoride or a mixture thereof.
3. The process as claimed in claim 1, wherein fluoride source is pre-heated at a temperature of 90-160°C.
4. The process as claimed in claim 1, wherein the fluorination is carried out at a temperature of 150-200°C.
5. The process as claimed in claim 1, wherein the process is carried out in presence of a solvent, wherein the weight ratio of the solvent to the compound of formula II is less than 5.
6. The process as claimed in claim 5, wherein the solvent is a polar aprotic solvent selected from a group consisting of sulfolane, dimethyl sulfoxide, dimethyl formamide and N-methyl pyrrolidine or a mixture thereof.