DESC:TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to a process for preparation of 2-Bromo-5-fluoro benzotrifluoride. More particularly, the present invention relates to a process for preparation of 2-Bromo-5-Fluoro benzotrifluoride by bromination of 1-Fluoro-3-trifluoromethylbenzene without using any solvent.
BACKGROUND OF THE INVENTION
2-Bromo-5-fluoro-benzotrifluoride is used, as an organic reagent and pharmaceutical intermediate. Several processes for obtaining 2-Bromo-5-fluoro-benzotrifluoride are known in the art.
CN104311386 relates to a method of preparation of 2-Bromo-5-fluorobenzotrifluoride comprising the steps of: mixing sulfuric acid with Fluorobenzotrifluoride and further adding brominating agent to obtain mixture at 0-80 °C to react and thereby finally obtaining 2-Bromo-5-fluorobenzotrifluoride.
US 3,845,146 relates to bromination of benzene, lower alkylbenzene, phenol, biphenyl and diphenyl oxide with the help of bromine chloride in the presence of a catalyst under essentially autogenous pressure to obtain polybromination of the aromatic nucleus. CN201410652217 also teaches a method of preparation of 2-bromo-5-fluoro-benzotrifluoride using an organic solvent.
From the above discussion it is evident that the known processes use solvents for facilitating the reaction, wherein their post processing removal from the reaction mixture is difficult, adds to the reaction cost and leaves residual reaction waste which poses threat to the environment. Therefore, there is a need in the art to develop solvent-less and economical process for manufacturing of 2-bromo-5-fluoro-benzotrifluoride.
OBJECTS OF THE INVENTION
A basic object of the present invention is to overcome the disadvantages and drawbacks of the known art.
An object of the present invention is to provide a process for preparing 1-Bromo-4-fluoro-2-trifluoromethylbenzene without any solvent.
Another objective of the present invention is to provide a process for preparing 1-Bromo-4-fluoro-2-trifluoromethylbenzene that results in formation of fewer by-products.Another object of the present invention is to provide a process for preparing 1-Bromo-4-fluoro-2-trifluoromethylbenzene that reduces the use of bromine up to 50% in comparison to commonly known brominating reagents.
An object of the present invention is to provide an economical process for preparing 1-Bromo-4-fluoro-2-trifluoromethylbenzene with high purity and yield.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparation of 2-Bromo-5-fluoro benzotrifluoride by bromination of 1-Fluoro-3-trifluoromethylbenzene without using any solvent.
In accordance with an embodiment of the invention, there is provided a process for preparing 2-Bromo-5-fluorobenzotrifluoride, said process comprising the steps of:
(a) brominating 1-Fluoro-3-trifluoromethylbenzene with a brominating reagent in the presence of a Friedel Craft’s catalyst;
(b) treating the reaction mixture with sodium metabisulphite solution to neutralize residual bromine;
(c) separating the organic layer comprising 2-Bromo-5-fluorobenzotrifluoride and drying to obtain crude 2-Bromo-5-fluorobenzotrifluoride; and
(d) fractional distillation of crude 2-Bromo-5-fluorobenzotrifluoride to obtain 2-Bromo-5-fluorobenzotrifluoride with a purity of =98.5%;
wherein the process is carried out in the absence of an added organic solvent.
In accordance with another embodiment of the invention, the brominating reagent is selected from the group consisting of N-bromo succinimide, 1,3-Dibromo-5,5-dimethylhydantoin, N-bromo phthalamide, and bromomonochloride (BrCl).
Preferably, the brominating reagent is bromomonochloride, wherein the bromomonochloride is prepared in-situ by the reaction of chlorine gas and bromine at temperatures in the range of -5 to 0 °C. The molar ratio between 1-Fluoro-3-trifluoromethyl-benzene and bromomonochloride is at least stoichiometric. Preferably, the molar ratio between 1-Fluoro-3-trifluoromethyl-benzene and bromomonochloride ranges from 1:1.1 to 1:2.
In accordance with yet another embodiment of the invention, the Friedel Craft’s catalyst is selected from the group consisting of aluminium chloride, aluminium bromide, ferric chloride, ferric bromide and combinations thereof.
Preferably, the Friedel Craft’s catalyst is aluminium chloride, wherein the Friedel Craft’s catalyst is present in an amount ranging from 1 mol% to 6 mol% with respect to 1-Fluoro-3-trifluoromethyl-benzene, preferably from 3 mol% to 6 mol%.
In accordance with still another embodiment of the invention, the added organic solvent is any solvent that comprises a C atom and can dissolve either the reactant, 1-Fluoro-3-trifluoromethylbenzene or the product, 2-Bromo-5-fluorobenzotrifluoride or both.
Preferably the reaction of step (a) is carried out at a temperature below 0 °C. More preferably, the reaction of step (a) is carried out at a temperature between -5 to 0 °C.
In accordance with a further embodiment of the invention, step (c) comprises washing the organic layer comprising 2-Bromo-5-fluorobenzotrifluoride with sodium bicarbonate solution. Preferably, the organic layer comprising 2-Bromo-5-fluorobenzotrifluoride is washed with 10% sodium bicarbonate solution.
In accordance with still yet another embodiment of the invention, step (b) comprises adding sodium metabisulphite solution to the reaction mixture at a temperature in the range of -5 to 20 °C, till the colour of the reaction mixture changes from brown to colourless.
DESCRIPTION OF THE INVENTION
Discussed below are some representative embodiments of the present invention. The invention in its broader aspects is not limited to the specific details and representative methods. Illustrative examples are described in this section in connection with the embodiments and methods provided.
It is to be noted that, as used in the specification, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
The expression of various quantities in terms of “%” or “% w/w” means the percentage by weight of the total solution or composition unless otherwise specified.

All cited references are incorporated herein by reference in their entireties. Citation of any reference is not an admission regarding any determination as to its availability as prior art to the claimed invention.
The present invention, in all its aspects, is described in detail as follows: The terms “1-Bromo-4-Fluoro-2-trifluoromethylbenzene” and “2-Bromo-5-fluorobenzotrifluoride” mean the same thing and can be used interchangeably.
The present invention relates to the process for preparation of 1-Bromo-4-fluoro-2-trifluoromethylbenzene, said process comprising the steps of:
(a) brominating 1-Fluoro-3-trifluoromethyl-benzene with a brominating reagent in the presence of a Friedel Craft’s catalyst;
(b) treating the reaction mixture with sodium metabisulphite solution to neutralize residual bromine;
(c) separating the organic layer comprising 2-Bromo-5-fluorobenzotrifluoride and drying to obtain crude 2-Bromo-5-fluorobenzotrifluoride; and
(d) fractional distillation of crude 2-Bromo-5-fluorobenzotrifluoride to obtain 2-Bromo-5-fluorobenzotrifluoride with a purity of =98.5%;
wherein the process is carried out in the absence of an added organic solvent.
The term “added organic solvent” used herein refers to an organic solvent containing at least one C atom that can dissolve either the reactant, 1-Fluoro-3-trifluoromethylbenzene; the product, 2-Bromo-5-fluorobenzotrifluoride or both during the bromination reaction. Non-limiting examples of organic solvents, include but not limited to, carbon tetrachloride, nitrobenzene, acetonitrile, tetrahydrofuran, acetic acid and so forth.
The accordance with an embodiment, the process comprises of bromination of 1-Fluoro-3-trifluoromethyl-benzene with BrCl, in presence of AlCl3, in the absence of a solvent, to obtain 1-Bromo-4-fluoro-2-trifluoromethylbenzene and is represented by following reaction scheme:

The instant process relates to bromination of 1-Fluoro-3-trifluoromethylbenzene in an electrophilic substitution reaction in presence of Friedel Craft’s catalyst such as aluminium chloride, aluminium bromide, ferric chloride, ferric bromide etc. In a preferred embodiment, the Friedel Craft’s catalyst is Aluminium Chloride, wherein the Friedel Craft’s catalyst is present in an amount ranging from 1 mol% to 6 mol% with respect to 1-Fluoro-3-trifluoromethylbenzene, preferably from 3 mol% to 6 mol%.
It involves one-pot synthesis of 1-Bromo-4-fluoro-2-trifluoromethylbenzene from 1-fluoro-3-trifluoromethylbenzene with bromo-monochloride in presence of aluminium chloride at -5 to 0 °C, where the brominating reagent bromo-monochloride is formed in-situ by reaction of chlorine gas and bromine at low temperatures. The molar ratio between 1-Fluoro-3-trifluoromethylbenzene and bromomonochloride is at least stoichiometric or greater than stoichiometric, bromomonochloride being in a stoichiometrically greater quantity. Preferably, the molar ratio between 1-Fluoro-3-trifluoromethyl-benzene and bromomonochloride ranges from 1:1.1 to 1:2.
After the bromination is complete, the reaction mass is treated with sodium metabisulphite solution to neutralize the residual bromine remaining in the reaction mixture. The organic layer comprising 1-Bromo-4-fluoro-2-trifluoromethylbenzene and the aqueous layer comprising sodium metabisulphite are allowed to settle and are separated. The organic layer comprising 1-Bromo-4-fluoro-2-trifluoromethylbenzene is washed with sodium bicarbonate solution, more preferably 10% sodium bicarbonate solution. Thereafter, the organic layer comprising 1-Bromo-4-fluoro-2-trifluoromethylbenzene is dried to obtain crude Bromo-4-fluoro-2-trifluoromethylbenzene.
The term “dried” used herein relates to the removal of water from the organic layer comprising 1-Bromo-4-fluoro-2-trifluoromethylbenzene. A person skilled in the art of synthetic organic chemistry is well aware of the various techniques that can be used for drying the organic layer, which is obtained after washing with aqueous solution. As a non-limiting example, drying of the organic layer can be achieved by adding anhydrous salts such as sodium sulfate and magnesium sulfate into the organic layer and allowing to stand for a specified time.
After drying, the crude 1-Bromo-4-fluoro-2-trifluoromethylbenzene is purified by fractional distillation to obtain 1-Bromo-4-fluoro-2-trifluoromethylbenzene with a Gas Chromatography (GC) purity of more than 98.5%.
Further, the use of bromomonochloride as a brominating reagent reduces the use of bromine by 50% as compared to the reagents commonly used for bromination such as N-bromo succinimide, 1,3-Dibromo-5,5-dimethylhydantoin, N-bromo phthalamide, etc., and hence results in a very cost effective process.
The invention is now illustrated by way of following non-limiting examples:
The present invention is more particularly described in the following examples that are intended as illustration only, since numerous modifications and variations within the scope of the present invention will be apparent to those of skill in the art. Unless otherwise noted, all parts, percentages, and ratios reported in the following example are on a weight basis, and all reagents used in the examples were obtained or are available from the chemical suppliers.
The following examples illustrate the basic methodology and versatility of the present invention.
Example 1:
In order to prepare 2-Bromo-5-fluorobenzotrifluoride, first Bromo monochloride, BrCl, solution was prepared. A 2.0 L, 4 neck round bottom flask was arranged on a cooling bath in reflux condition and thermopocket, sensor and chlorine purging system were set up. Thereafter, 1400 g (1-Fluoro-3-trifluoromethylbenzene) FBTF was charged and the mass was cooled up to -5 °C.
After that, lot 1, aluminum chloride (20 g) was charged, chlorine gas was purged and 820 g of bromine was added in 7.5 h, through dropping funnel at -5 to 0 oC. Chlorine was purged till reaction complies. 460 g of Chlorine gas was required for reaction completion.
The reaction mass was stirred at -5 to 0 °C for 2 h. The colour of the reaction mass changes from dark brown to light brown.
Thereafter lots 2 and 3 of aluminum chloride, 5g each, were charged, after 3.5 h and 7 h of starting bromine addition. Reaction mass was stirred at -5 to 0 °C for 2 h. Samples were sent for GC every 2 h, after addition of bromine.
Optionally, if reaction didnot complete, then lot 4, aluminum chloride, 5 g, was charged and sample was sent for Gas Chromatography (GC) analysis after 2 hrs. After reaction completion, 1050 g of 20% Sodium metabisulphite solution was added at -5 to 20 °C till the color of reaction mass changes from brown to colorless. The organic layer comprising 2-Bromo-5-fluorobenzotrifluoride, and the aqueous layer were allowed to settle and separate at room temperature. Weight of organic layer was recorded as 2045 g and weight of aqueous layer was recorded as 1362 g. Thereafter, organic layer was washed with 400 g of 10% sodium bicarbonate solution and dried to obtain crude 2-Bromo-5-fluorobenzotrifluoride. Reaction yield was 87% and GC purity after fractional distillation of crude 2-bromo-5-fluorobenzotrifluoride was more than 99%.
Example 2:
Arrange 2.0 L, 4 neck, round bottom flask on cooling bath in reflux condition, along with themopocket, sensor, chlorine purging system etc. Charge Bromine, 974.3 g, and cool the mass up to -5 to 0 °C. Start purging of chlorine gas in bromine up to 214 g. Charge aluminium chloride, 15 g, in above bromomonochloride solution and start addition of FBTF, 1000 g, using addition funnel at -5 to 0 °C. After addition of 285 g of FBTF, add 7.0 g aluminium chloride. Addition of FBTF continues at -5 to 0°C. After addition of another 285 g of FBTF, add 7.0 g aluminium chloride. Addition of FBTF continues at -5 to 0°C. After complete addition of FBTF, 428.6 g, add 7.0 g aluminium chloride at -5 to 0 °C. Stir for 2.0 h at -5 to 0 °C. Send sample for GC monitoring. After completion of reaction, add 20% Sodium metabisulphite solution, 2140 g, at -5 to 10 °C till the reaction mass is free from bromine and becomes colourless. Let the aqueous and organic layers settle and then separate them. The organic layer primarily comprises of 2-Bromo-5-fluorobenzotrifluoride. The organic layer was washed with 10% sodium bicarbonate solution, 428 g. Again, let the aqueous and organic layers settle, and separate them. Collect the organic layer and dry it, and then proceed for fractional distillation. Reaction yield was 83%, and after fractional distillation 2-bromo-5-fluorobenzotrifluoride was obtained in a GC purity of more than 98.5%.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive.
,CLAIMS:1. A process for preparing 2-Bromo-5-fluorobenzotrifluoride, said process comprising the steps of:
(a) brominating 1-Fluoro-3-trifluoromethylbenzene with a brominating reagent in the presence of a Friedel Craft’s catalyst;
(b) treating the reaction mixture with sodium metabisulphite solution to neutralize residual bromine;
(c) separating the organic layer comprising 2-Bromo-5-fluorobenzotrifluoride and drying to obtain crude 2-Bromo-5-fluorobenzotrifluoride; and
(d) fractional distillation of crude 2-Bromo-5-fluorobenzotrifluoride to obtain 2-Bromo-5-fluorobenzotrifluoride with a purity of =98.5%;
wherein the process is carried out in the absence of an added organic solvent.
2. The process as claimed in claim 1, wherein the brominating reagent is bromomonochloride, prepared in-situ by the reaction of chlorine gas and bromine at temperatures in the range of -5 to 0 °C, and wherein the molar ratio between 1-Fluoro-3-trifluoromethyl-benzene and bromomonochloride ranges from 1:1.1 to 1:2 .
3. The process as claimed in claims 1 and 2, wherein the Friedel Craft’s catalyst is selected from the group consisting of aluminium chloride, aluminium bromide, ferric chloride, ferric bromide and combinations thereof.
4. The process as claimed in claims 1 to 3, wherein the Friedel Craft’s catalyst is aluminium chloride, and wherein the Friedel Craft’s catalyst is present in an amount ranging from 1 mol% to 6 mol% with respect to 1-Fluoro-3-trifluoromethyl-benzene, preferably from 3 mol% to 6 mol%.
5. The process as claimed in claims 1 to 4, wherein the said organic solvent is any solvent that comprises a C atom, and can dissolve either 1-Fluoro-3-trifluoromethyl-benzene or 2-Bromo-5-fluorobenzotrifluoride.
6. The process as claimed in claims 1 to 5, wherein the reaction of step (a) is carried out at a temperature below 0 °C.
7. The process as claimed in claims 1 to 6, wherein the reaction of step (a) is carried out at a temperature between -5 to 0 °C.
8. The process as claimed in claims 1 to 7, wherein step (c) comprises washing the organic layer with sodium bicarbonate solution.
9. The process as claimed in claims 1 to 8, wherein step (c) comprises washing the organic layer with 10% sodium bicarbonate solution.
10. The process as claimed in claims 1 to 9, wherein step (b) comprises adding sodium metabisulphite solution to the reaction mixture at a temperature in the range of -5 to 20 °C, till the colour of the reaction mixture changes from brown to colourless.