DESC:FIELD OF DISCLOSURE
The present disclosure relates to a process for preparing halogenated aromatic compounds. Particularly, the present disclosure relates to a process for fluorinating aromatic compounds.
BACKGROUND
Fluoro-aromatic compounds are vital for material science, life science and agricultural science. Introduction of fluorine atom in the aromatic compound has a significant impact on the properties of the aromatic compound because of its strong electro-negativity and ability of long range coupling with protons present in the aromatic compound.
Introduction of fluorine in the aromatic compound can be affected by two ways i.e., electrophilic substitution reaction and nucleophilic substitution reaction.
Electrophilic substitution reaction is carried out using reagents that provide fluorine cation whereas the nucleophilic substitution reaction is carried out using reagents that provide fluorine anion.
Conventionally, fluorine is introduced into the aromatic compound by a process involving a diazotization reaction by nucleophilic substitution reaction. This process involving a diazotization reaction often have low product yield and therefore are unsatisfactory for commercialization.
Another process in which the salts of hydrofluoric acid are used to replace fluorine with nitro group also gives low product yield.
Attempts were made to improve the yield of product via nucleophilic substitution reaction. US4568781 discloses a process for introducing fluoro group in an aromatic compound by replacing activated nitro group of the aromatic compound which is known as denitro fluorination reaction. The denitro fluorination reaction is affected using alkali salt of hydrofluoric acid in the presence of an acid halide. The drawback associated with the process of US4568781 is that the process cannot be employed for aromatic compounds in which single nitro group is present.
The articles titled “Tetra-phenyl phosphonium Bromide catalyzed fluoro-denitrations and fluoro-desulfonylations. Efficient synthesis of m-fluoroaromatic compounds” published in Chemistry Letters pp. 2213-2216, 1989 and “General and highly efficient syntheses of m-fluoro arenes using potassium fluoride exchange method” published in Bull. Chem Soc. Jpn., 63, 2010-2017, 1990, discloses the use of tetra-phenyl phosphonium bromide as a phase transfer catalyst for denitro-fluorination reaction in the presence of potassium fluoride & phthaloyl dichloride (an acid halide).
Another article titled “A general procedure for the fluoro-denitration of aromatic substances” published in J. Org. Chem. 1990, 56, 6406-6411, discloses a process for the synthesis of several fluoroaromatics using fluoro-denitration using a nitrite ion trapping agent such as phthaloyl difluoride and tetra-fluoro phthaloyl difluoride.
The limitation of these processes is that they cannot be applied for all the nitro-aromatic compounds. For instance, less than 10 % yield was observed for the synthesis of 3, 4-difluorobenzoyl chloride from 4-fluoro-3-nitro-benzoyl chloride by using the process disclosed in J. Org. Chem.
In view of this, there is a need for a process for preparing halogenated aromatic compounds. Further, there is a need for a process that can be applied for introducing fluorine group in almost all the nitro aromatic compounds in high yield. Furthermore, there is also a need for a process for denitro-fluorinating aromatic compounds that is amenable at large scale. Accordingly, the inventors of the present invention envisaged a process that is not only applicable for denitro-fluorination of substantial aromatic compounds in high yield but also easily amenable at large scale.

OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies are as follows:
It is an object of the present disclosure to provide a process for preparing halogenated aromatic compounds.
It is another object of the present disclosure to provide a process for denitro-halogenating aromatic compounds.
It is yet another object of the present disclosure to provide a simple and economic process for denitro-halogenating aromatic compounds.
It is still another object of the present disclosure to provide a process for denitro-halogenating aromatic compounds in high yield and purity.
It is yet another object of the present disclosure to provide a process for denitro-halogenating aromatic compounds which is amenable at large scale.
It is a further of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.
Other objects and advantages of the present disclosure will be more apparent from the following description when read in conjunction with the accompanying figures, which are not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure provides a process for preparing halogenated aromatic compounds. The process comprising the following steps:
a) mixing at least one alkali salt of a hydro-halo acid, at least one solvent, at least one phase transfer catalyst, at least one aromatic acid dihalide, and at least one nitro-aromatic compound to form a reaction mixture; and
b) heating the reaction mixture in the temperature range of 40 ºC to 250 ºC for a time period ranging from 6 hours to 24 hours to obtain the halogenated aromatic compounds.
The present disclosure provides at least one reaction facilitating component which is optionally mixed in the reaction mixture.
The present disclosure also provides a halogenated aromatic compound prepared by the process mentioned hereinabove.
In accordance with the present disclosure, the halogenated aromatic compound is 3, 4-difluorobenzoic acid.
The yield on purity of the halogenated aromatic compounds ranges from 44 % to 54 %.
DETAILED DESCRIPTION
The present disclosure provides a process for preparing halogenated aromatic compounds. In accordance with one embodiment, the present disclosure provides a process for denitro-fluorinating aromatic compounds.
The process of the present disclosure is described herein after.
In the first step, at least one alkali salt of a hydro-halo acid, at least one solvent, at least one phase transfer catalyst, at least one aromatic acid dihalide, component, and at least one nitro-aromatic compound are mixed to form a reaction mixture.
In the second step, the reaction mixture formed in the first step is heated in the temperature range of 40 ºC to 250 ºC for a time period ranging from 6 hours to 24 hours to obtain the halogenated aromatic compounds.
The present disclosure provides at least one reaction facilitating component which is optionally mixed in the reaction mixture that is obtained in the first step.
In accordance with one embodiment, the reaction facilitating component used is a plurality of Stainless Steel (SS) balls.
The reaction facilitating component satisfies at least one of the following criteria:
a) improves yield of the product;
b) enhances rate of the reaction;
c) reduces impurity generation;
d) facilitates amenability of the reaction at large scale;
e) facilitates the application of moderate reaction conditions; and
f) reduces the proportion of at least one reagent and/or catalyst with respect to the reactant/s.
In accordance with one embodiment, at least one alkali salt of hydro-halo acid, at least one solvent, at least one phase transfer catalyst, at least one aromatic acid halide, at least one nitro-aromatic compound, and at least one reaction facilitating component can be mixed in any order to obtain the desired result.
In accordance with an exemplary embodiment, at least one hydro-halo acid and at least one solvent can be mixed and heated at elevated temperature followed by addition of at least one aromatic acid dihalide, at least one phase transfer catalyst, at least one nitro-aromatic compound, and at least one reaction facilitating component to obtain the desired result.
Examples of the suitable alkali component in the alkali salt include at least one component selected from the group consisting of lithium, sodium, potassium, rubidium, cesium, and francium.
Examples of the suitable halo component in the hydro-halo acid include at least one component selected from the group consisting of fluorine, chlorine, bromine, and iodine.
In accordance with one embodiment, the alkali salt of hydro-halo acid is potassium fluoride.
In accordance with one embodiment, the solvent used is sulfolane.
Examples of the suitable phase transfer catalyst include at least one catalyst selected from the group consisting of tetra-phenyl phoshonium bromide, tetra-methyl ammonium chloride, benzyl tri-methyl ammonium chloride, and tri ethyl ammonium bromide.
In accordance with one embodiment, the phase transfer catalyst is tetra-phenyl phoshonium bromide.
Examples of the suitable aromatic acid dihalide include at least one dihalide selected from the group consisting of phthaloyl dichloride, phthaloyl dibromide, phthaloyl difluoride, and phthaloyl di-iodide.
In accordance with one embodiment, the aromatic acid dihalide is phthaloyl dichloride.
Examples of the suitable nitro-aromatic compound include at least one compound selected from the group consisting of 4-chloro-3-nitrobenzoyl chloride, and 4-fluoro-3-nitro-benzoyl chloride.
In accordance with the present disclosure, the yield on purity of the halogenated aromatic compounds ranges from 44 % to 54 %.
The present disclosure also provides a halogenated aromatic compound prepared by the process as described herein above.
In accordance with the present disclosure, the halogenated aromatic compound is 3, 4-difluorobenzoic acid.
The present disclosure is further described in light of the following non-limiting examples which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure.
Example 1
175 gms of commercial potassium fluoride were added into 700 ml of sulfolane to obtain a dispersion. 195 ml of sulfolane was distilled out from the dispersion under vacuum at 165 °C to remove moisture content from the dispersion so as to obtain colorless slurry. The colorless slurry was cooled to 140 °C and further 112 gms of phthaloyl dichloride, 21 gms of tetra-phenyl phosphonium bromide, and 110 gms of 4-chloro-3-nitrobenzoyl chloride were added in the colorless slurry while stirring to obtain a reaction mass. The reaction mass was heated to 150°C to obtain a heated reaction mass. The temperature (150°C) of the heated reaction mass was maintained for 6 hrs. The heated reaction mass was further heated to 200°C while vigorous stirring and the same temperature was maintained for 24 hrs. Gas-Liquid chromatography (GLC) analysis of the heated reaction mass depicted 87% of 3, 4-difluorobenzoic acid. The heated reaction mass was cooled to 35°C and filtered to obtain a filtrate. The filtrate was then washed twice with 500 ml of dichloromethane. The filtrate and washings were mixed and concentrated to recover the concentration of dichloromethane initially at atmospheric pressure and later under vacuum to distil out 59 ml of dichloromethane as distillate. Gas-Liquid chromatography (GLC) analysis of the distillate depicted 74% pure 3, 4-difluorobenzoic acid. Yield on purity of 3, 4-difluorobenzoic acid is 54%.
Example 2
598 gms of commercial potassium fluoride, 84 gms of tetra-phenyl phosphonium bromide, 2400 gms of stainless steel (SS) balls (diameter approximately equal to ¼ inch), and 1600 ml of sulfolane were added in a 3.5 litre integrated reactor to obtain a dispersion. 125 ml of sulfolane was distilled out from the dispersion under vacuum at 140°C to remove traces of moisture from the dispersion so as to obtain colorless slurry. The colorless slurry was cooled to 45 °C, 435 gms of phthaloyl dichloride, and 397 gms 4-fluoro-3-nitrobenzoyl chloride were added to the colorless slurry while stirring to obtain a reaction mass. The reaction mass was heated at 200°C to obtain a heated reaction mass. The temperature (200°C) of the heated reaction mixture was maintained for 12 hrs. Gas-Liquid chromatography (GLC) analysis of the heated reaction mass depicted 59% of 3, 4-difluorobenzoic acid. The reaction mass was then cooled to 35°C and filtered to obtain a filtrate. The filtrate was washed twice with 500 ml of dichloromethane. The filtrate and washings were mixed and concentrated to recover the concentration of dichloromethane initially at atmospheric pressure and later under vacuum to distil 178 ml of dichloromethane as distillate. Gas-Liquid chromatography (GLC) analysis of the distillate depicted 77% pure 3, 4-difluorobenzoic acid. Yield on purity of 3, 4-difluorobenzoic acid is 44%.
The process of the present disclosure described herein above shows that overcomes the drawbacks associated with the conventional processes.
TECHNICAL ADVANCEMENT
The present disclosure relates to the process for preparing halogenated aromatic compounds. The process has several technical advancements:
• the process can be applied for all nitro-aromatic compounds;
• yield of the halogenated aromatic compound obtained from the process is high;
• purity of the halogenated aromatic compound obtained from the process is high;
• the process is amenable at large scale; and
• the process is simple and economic.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.
The numerical values given for various physical parameters, dimensions and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary. ,CLAIMS:1. A process for preparing halogenated aromatic compounds, said process comprising the following steps:
c) mixing at least one alkali salt of a hydro-halo acid, at least one solvent, at least one phase transfer catalyst, at least one aromatic acid dihalide, component, and at least one nitro-aromatic compound to form a reaction mixture; and
d) heating said reaction mixture in the temperature range of 40 ºC to 250 ºC for a time period ranging from 6 hours to 24 hours to obtain said halogenated aromatic compounds.
2. The process as claimed in claim 1, wherein at least one reaction facilitating component is optionally mixed in said reaction mixture.
3. The process as claimed in claim 1, wherein the alkali component in said alkali salt is at least one selected from the group consisting of lithium, sodium, potassium, rubidium, cesium, and francium.
4. The process as claimed in claim 1, wherein said alkali salt of hydro-halo acid is potassium fluoride.
5. The process as claimed in claim 1, wherein said solvent is sulfolane.
6. The process as claimed in claim 1, wherein said phase transfer catalyst is at least one selected from the group consisting of tetra-phenyl phoshonium bromide, tetra-methyl ammonium chloride, benzyl tri-methyl ammonium chloride, and tri ethyl ammonium bromide.
7. The process as claimed in claim 1, wherein said phase transfer catalyst is tetra-phenyl phoshonium bromide.
8. The process as claimed in claim 1, wherein said aromatic acid dihalide is at least one selected from the group consisting of phthaloyl dichloride, phthaloyl dibromide, phthaloyl difluoride, and phthaloyl di-iodide.

9. The process as claimed in claim 1, wherein said aromatic acid dihalide is phthaloyl dichloride.
10. The process as claimed in claim 1, wherein said nitro-aromatic compound is at least one selected from the group consisting of 4-chloro-3-nitrobenzoyl chloride, and 4-fluoro-3-nitro-benzoyl chloride.
11. The process as claimed in claim 1, wherein said reaction facilitating component is a plurality of Stainless Steel (SS) balls.
12. The process as claimed in claim 1, wherein the yield on purity of said halogenated aromatic compounds ranges from 44 % to 54 %.
13. A halogenated aromatic compound prepared by the process as claimed in claims 1 to 11.