1. A process for the preparation of 2-bromo-5-fluorobenzotrifluoride of Formula-I, comprising the steps of: a) reacting 3-fluorobenzotrifluoride of Formula-II, with brominating agent in the presence of antimony catalyst selected from antimony trichloride (SbCl3), antimony pentachloride (SbCl5) or mixture(s) thereof, at a temperature ranging between -5 °C to 5 °C to obtain 2-bromo-5-fluoro-benzotrifluoride of formula-I; and b) optionally, purifying the 2-bromo-5-fluoro-benzotrifluoride of formula-I.

2. The process as claimed in claim 1, wherein the brominating agent is selected from bromine monochloride, bromate(s), N-bromosuccinamide (NBS), dibromodimethylhydantoin (DBDMH), tribromoisocyanuric acid (TBCA), sodium bromate (NaBrO3), perbromide(s), dimethyl bromo sulphur (DMBS), pyridinium bromide perbromide or mixture(s) thereof.

3. The process as claimed in 1, wherein in reaction step a) antimony catalyst is used in the molar ration of 1: 0.001 to 1: 0.04 with respect to 3-fluorobenzotrifluoride of Formula-II.

4. The process as claimed in claim 1, wherein the product obtained in step a) has purity greater than 94% by Gas chromatography (GC).

5. The process as claimed in claim 1, wherein the product obtained in step a) has yield greater than 92.5%.

6. The process as claimed in claim 1, wherein pure product obtained in step b) after purification by fractional distillation.

7. The process as claimed in claim 1, wherein the purified product obtained in step b) after purification has purity greater than 98.5% GC purity.

Description:
FORM 2

THE PATENT ACT 1970 (39 OF 1970)
AND
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
A PROCESS FOR THE PREPARATION OF 2-BROMO-5-FLUOROBENZOTRIFLUORIDE (BFBTF)

2.APPLICANT(S)
(a) NAME: Gujarat Fluorochemicals Limited

(b) NATIONALITY: Indian

(c) ADDRESS: Gujarat Fluorochemicals Limited,
INOXGFL Towers, Plot no.17, Sector-16A,
Noida, Uttar Pradesh 201 301
India

3. PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed.

 
FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of 2-bromo-5-fluorobenzotrifluoride. More particularly, the present invention relates to bromination of 3-fluorobenzotrifluoride (FBTF) in the presence of brominating agent and antimony catalyst selected from antimony trichloride (SbCl3), antimony pentachloride (SbCl5) or mixture(s) thereof, to provide high purity 2-bromo-5-fluorobenzotrifluoride with high yield, which is not only cost-effective but also industrially scalable.
BACKGROUND OF THE INVENTION:
2-Bromo-5-fluorobenzotrifluoride is having a chemical structural Formula-I as given below:

2-bromo-5-fluorobenzotrifluoride has a wide range of uses, mainly for pharmaceutical
and pesticide intermediates. 2-bromo-5-fluorobenzotrifluoride can be used to synthesize 2-trifluoromethyl-4-aminobenzonitrile, which is a raw material and intermediate for synthesizing the anti-tumour drug bicalutamide. Several processes for preparation of 2-bromo-5-fluorobenzotrifluoride are known in the prior-art.
Chinese patent number CN 105152853 (herein after CN ‘853) discloses a process for preparation of 2-bromo-5-fluorobenzotrifluoride comprising, reacting 3-fluorobenzotrifluoride with bromine in presence of lithium bromide, ferric bromide, tetrabutylammonium bromide and concentrated sulfuric acid followed purification using vacuum distillation to obtain 2-bromo-5-fluorobenzotrifluoride. The major drawback of this process is used as expensive reagents and many impurities are generated, which is affecting overall yield of 2-bromo-5-fluorobenzotrifluoride. Therefore, process for preparation of 2-bromo-5-fluorobenzotrifluoride as disclosed in CN ‘853 is not suitable for large scale industrial production.
Chinese patent number CN 104610015 (herein after CN ‘015) discloses process for preparation of 2-bromo-5-fluorobenzotrifluoride comprising, reacting 3-fluorobenzotrifluoride with potassium bromate in presence 70 % sulfuric acid followed by purification using fractional distillation to obtain 2-bromo-5-fluorobenzotrifluoride. The major drawback of process is used expensive reagents, which is also not amenable for large scale industrial production.
Chinese patent number CN 107337576 (herein after CN ‘576) discloses process for preparation of 2-bromo-5-fluorobenzotrifluoride comprising, reacting 3-fluorobenzotrifluoride with bromine in presence of N-bromosuccinimide, tetrabutylammonium bromide and sulfuric acid followed by purification using fractional distillation to obtain 2-bromo-5-fluorobenzotrifluoride. The major drawback of process is used expensive reagents, which is also not a viable & cost-effective process for large scale industrial production.
To overcome the above prior art problems, Indian patent number IN 344902 (herein after IN ‘902) discloses a process for preparation of 2-bromo-5-fluorobenzotrifluoride comprising reacting 3-fluorobenzotrifluoride with bromo monochloride in presence of aluminum chloride as a catalyst followed by purification using fractional distillation to obtain 2-bromo-5-fluorobenzotrifluoride having 87 % yield. However, there are disadvantages of this process for preparation of 2-bromo-5-fluorobenzotrifluoride as disclosed in IN ‘902, such as requiring multiple lots addition of aluminum chloride catalyst and obtained 2-bromo-5-fluorobenzotrifluoride has lower yield and purity. Therefore, IN ‘902 process can be improvised in terms of bromine atom efficiency, yield and purity to make it industrially more cost effective and commercially viable.
Therefore, still there exist need in the prior art to develop improved and economically viable process for manufacturing of 2-bromo-5-fluorobenzotrifluoride which may overcomes drawbacks of the prior-art.
OBJECT OF THE INVENTION:
The main objective of the present invention is to provide a process for preparation of 2-bromo-5-fluorobenzotrifluoride with a higher yield and purity and advantageous for the industrial sector.
Another objective of the present invention is to provide a process for preparation of 2-bromo-5-fluorobenzotrifluoride having high purity.
SUMMARY OF THE INVENTION:
The present invention relates to an improved process for the preparation of 2-bromo-5-fluorobenzotrifluoride with a higher yield and quality, which is simple, eco-friendly, and commercially viable.
The present invention particularly relates to an improved process for preparation of 2-bromo-5-fluorobenzotrifluoride of Formula-I,

comprising the steps of:
a) reacting 3-fluorobenzotrifluoride of Formula-II,

with brominating agent in the presence of antimony catalyst selected from antimony trichloride (SbCl3), antimony pentachloride (SbCl5) or mixture(s) of thereof to obtain 2-bromo-5-fluoro-benzotrifluoride of formula-I; and
b) optionally, purifying the 2-bromo-5-fluoro-benzotrifluoride of formula-I.
 
DETAILED DESCRIPTION OF THE INVENTION:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used in this specification the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
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.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
While the following specification concludes with claims particularly pointing out and distinctly claiming the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description and by studying the included examples.
The best methods and materials of performing the present invention are described here.
The present invention provides an improved process for preparation of 2-bromo-5-fluorobenzotrifluoride of Formula-I can be summarized in the following schematic representation.

Scheme 1: Bromination of 3-fluorobenzotrifluoride to give 2-bromo-5-fluorobenzotrifluoride.
According to first embodiment, the present invention is to provides a process for the preparation of 2-bromo-5-fluorobenzotrifluoride of Formula-I,

comprising the steps of:
a) reacting 3-fluorobenzotrifluoride of Formula-II,

with brominating agent in the presence of antimony catalyst selected from antimony trichloride (SbCl3), antimony pentachloride (SbCl5) or mixture(s) thereof, to obtain 2-bromo-5-fluoro-benzotrifluoride of formula-I; and
b) optionally, purifying the step a) product of 2-bromo-5-fluoro-benzotrifluoride to obtain pure 2-bromo-5-fluoro-benzotrifluoride of formula-I.
In step a), the 3-fluorobenzotrifluoride of Formula-II can be prepared by process known in the prior-art or it was available in commercial scale.
In step a), the brominating agent is selected from bromine monochloride, bromate(s), N-bromosuccinamide (NBS), dibromodimethylhydantoin (DBDMH), tribromoisocyanuric acid (TBCA), perbromide(s), dimethyl bromo sulphur (DMBS), pyridinium bromide perbromide or mixture(s) thereof.
In step a), the brominating agent is used in the molar ratio of 1: 0.33 to 1: 3; preferably the molar ratio is 1: 0.5 to 1: 2; more preferably the molar ratio is 1: 0.55 to 1: 1 with respect to 3-fluorobenzotrifluoride of Formula-II.
In step a), the reaction of 3-fluorobenzotrifluoride of Formula-II with brominating agent in presence of antimony catalyst is carried out at temperature of -20 oC to 15 oC; preferably at -10 oC to 10 oC and more preferably at -5 oC to 5 oC.
In step a), the bromination reaction is carried out for 8 to 36 hours; preferably for 10 to 30 hours and more preferably for 16 to 24 hours.
The bromination reaction step a) is carried out in absence or presence of solvent system, preferably in absence of solvent.
The solvent is selected from aprotic solvents such as dichloroethane, acetonitrile, nitrobenzene, ethylene dichloride, carbon tetrachloride, ethers such as diethyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), or mixture(s) thereof.
In step a), the antimony catalyst is selected from antimony trichloride (SbCl3), antimony pentachloride (SbCl5) or mixture(s) thereof.
In step a), the antimony catalyst is used in the molar ratio of 1:0.001 to 1:0.04 with respect to 3-fluorobenzotrifluoride of Formula-II; Preferably antimony catalyst used in the molar ratio of 1:0.01 to 1:0.02 with respect to 3-fluorobenzotrifluoride of Formula-II.
After completion of reaction step a), the reaction mixture can be quenched with suitable agents such aqueous alkali thiosulphate(s), alkali bisulphite(s), thiols, sulphur dioxide gas and alkali hydroxide(s) and reaction mixture can be stirred till decolorization. Further, resulting reaction mixture can be allowed to separate organic and aqueous layers to obtain crude 2-bromo-5-fluorobenzotrifluoride of Formula-I may have purity greater than 94% by Gas chromatography (GC).
The obtained crude 2-bromo-5-fluorobenzotrifluoride of Formula-I have yield greater than 92.5%.
In step b), the crude 2-bromo-5-fluorobenzotrifluoride of Formula-I in organic layer is purified by any purification method as a person skilled in the art like flash distillation, fractional distillation is performed, to obtain pure 2-bromo-5-fluorobenzotrifluoride of Formula-I.
In accordance with the present invention's step a), the crude 2-bromo-5-fluorobenzotrifluoride of Formula I that was obtained in the organic layer is distilled by fractional distillation under decreased pressure to get pure 2-bromo-5-fluorobenzotrifluoride of Formula I.
In step b), the obtained pure 2-bromo-5-fluorobenzotrifluoride of Formula-I have yield greater than 89%.
In step b), the purity of the purified 2-bromo-5-fluorobenzotrifluoride of Formula-I is greater than 98.5% as determined by gas chromatography (GC).
The specification disclosed, in another embodiment, that the invention provides after completion of the reaction the antimony catalyst can be recovered and recycled in quantities as low as 0.01 to 0.001 moles%.
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 skilled in the art. Unless otherwise noted, 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.
EXAMPLES:
Comparative Example 01:
Add 6.00 kg of 70% sulfuric acid to a 10L glass reactor, pass chilled brine, control the temperature below 30°C, add 0.66 kg of m-fluorotrifluorotoluene while stirring, heat the mixture to keep the temperature at 45-50°C, add 0.91 kg of aluminum bromate with crystal water in 10 batches for about 4 hours, continue to keep warm and stir for 2 hours after the addition, take samples and analyze until the reaction is completed, quench, extract with dichloromethane, wash with sodium sulfite and collect the product (0.80 kg) by fraction by distillation. The product yields 81.7% and has a purity of 99.3%.
Comparative Example 02:
To a 1000 mL round-bottom flask was with charged 3-fluorobenzotrifluoride (500 g, 3.05 mole), cooled to 0 ℃ to 5 ℃ and ferric chloride (20.2 g, 0.12 mole) was added to it. Further, temperature of the reaction mass was adjusted to -5 °C to 0 °C, bromine (274 g, 3.32 mole) was added simultaneously chlorine gas was purged for 2 hours and reaction mass was maintained at -5 °C to 0 °C for 24 hours. After completion of reaction, resulting reaction mass was quenched with 10% aqueous sodium bisulphite solution (742 g) and reaction mass was allowed to separate organic and aqueous layers. Resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride (702 g, 94.86% yield) with 88.66% GC purity was obtained. Further, resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride was distilled under reduced pressure to obtain pure 2-bromo-5-fluorobenzotrifluoride (510.6 g).
Yield: 69.0%.
GC Purity: 99.13%.
Comparative Example 03:
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 °C 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 °C to 0 °C. After addition of 285 g of FBTF, add 7.0 g aluminium chloride. Addition of FBTF continues at -5 °C to 0°C. After addition of another 285 g of FBTF, add 7.0 g aluminium chloride. Addition of FBTF continues at -5 °C to 0°C. After complete addition of FBTF, 428.6 g, add 7.0 g aluminium chloride at -5 °C to 0 °C. Stir for 2.0 h at -5 °C to 0 °C. Send sample for GC monitoring. After completion of reaction, add 20% Sodium metabisulphite solution, 2140 g, at -5 °C 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%.

Examples of present Invention:
Example 01:
To a 1000 mL round-bottom flask was charged with 3-fluorobenzotrifluoride (500 g), cooled to 0 to 5 °C and antimony trichloride (SbCl3; 6.95 g) was added to it. Further, temperature of the reaction mass was adjusted to -5 °C to 5 °C, bromine (266 g) was added and simultaneously chlorine gas was purged and reaction mass was maintained at -5 °C to 5 °C for 18 hours. After completion of reaction, resulting reaction mass was quenched with 10% aqueous sodium bisulphite solution and reaction mass was allowed to separate organic and aqueous layers. Resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride (730 g, 98.60% yield) with 96.92% GC purity was obtained. Further, resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride was distilled under reduced pressure to obtain pure 2-bromo-5-fluorobenzotrifluoride (677.7 g).
Yield: 91.53%
GC Purity: 99.03%
Example 02:
To a 2000 mL round-bottom flask was charged with 3-fluorobenzotrifluoride (1000 g), cooled to 0 ℃ to 5 ℃ and antimony trichloride (13.9 g) was added to it. Further, temperature of the reaction mass was adjusted to -5 °C to 5 °C, bromine (545g) was added and simultaneously chlorine gas was purged and reaction mass was maintained for 24 hours. After completion of reaction, resulting reaction mass was quenched with 10% aqueous sodium bisulphite solution and reaction mass was allowed to separate organic and aqueous layers. Resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride (1445 g, 97.58% yield) with 96.74% GC purity was obtained. Further, resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride was distilled under reduced pressure to obtain pure 2-bromo-5-fluorobenzotrifluoride (1390.1g).
Yield: 93.87%
GC purity: 99.19%
Example 03:
To a 500 mL round-bottom flask was charged with 3-fluorobenzotrifluoride (150 g), cooled to 0 ℃ to 5 ℃ and antimony pentachloride (SbCl5;10.9g) was added to it. Further, temperature of the reaction mass was adjusted to -5 °C to 5 °C, bromine (82 g) was added and simultaneously chlorine gas was purged and reaction mass was maintained for 18 hours. After completion of reaction, resulting reaction mass was quenched with 10% aqueous sodium bisulphite solution and reaction mass was allowed to separate organic and aqueous layers. Resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride (212.59 g) with 96.8% GC purity was obtained. Further, resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride was distilled under reduced pressure to obtain pure 2-bromo-5-fluorobenzotrifluoride (204.67 g).
Yield: 92.14%.
GC Purity: 98.6%
Example 04:
To a 1000 mL round-bottom flask was charged with 3-fluorobenzotrifluoride (500 g) and cooled to 0 °C to 5 °C. After adding antimony solution (6.95 g of antimony trichloride (SbCl3) dissolved in 7 mL of MDC) gradually, the temperature of the reaction mixture was raised to between -5 °C to 5°C. In addition, bromine (272.7 g) was injected, and the reaction mass was kept constant for 22 hours while chlorine gas was simultaneously purged. After completion of reaction, resulting reaction mass was quenched with 10% aqueous sodium bisulphite solution and reaction mass was allowed to separate organic and aqueous layers. Resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride (722 g, 97.51% yield) with 95.36% GC purity was obtained. Further, resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride was distilled under reduced pressure to obtain pure 2-bromo-5-fluorobenzotrifluoride (674.0 g).
Yield: 91.03%
GC Purity: greater than 99.11%.
Example 05:
To a 1000 mL round-bottom flask was charged with 3-fluorobenzotrifluoride (150 g), cooled to 0 °C to 5 °C and mixture of antimony trichloride (SbCl3; 2.14 g) and antimony pentachloride (SbCl5; 2.73g) was slowly added. Further, temperature of reaction mass was adjusted to -5 °C to 5 °C, bromine (82.2g) was added and simultaneously chlorine gas was purged for 2 hours and reaction mass was maintained for 20 hours. After completion of reaction, resulting reaction mass was quenched with 10% aqueous sodium bisulphite solution and reaction mass was allowed to separate organic and aqueous layers. Resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride (206 g, 92.74% yield) was obtained. Further, resulting organic layer containing crude 2-bromo-5-fluorobenzotrifluoride was subjected to purification by performing distillation under reduced pressure to obtain pure 2-bromo-5-fluorobenzotrifluoride (197.7g).
Yield: 89.01%.
GC Purity: 99.04%.
Advantages of the present invention:
 The present invention is to provide the higher crude yield (more than 96%) attained in the presence of antimony catalyst.
 The isolated yield of the method is continuously high, with 89 to 95% bromine atom efficiency.
 The antimony catalyst can be recovered and recycled in quantities as low as 0.01 to 0.001 moles%.

Various modifications of the embodiments, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.
, Claims:WE CLAIM:

1. A process for the preparation of 2-bromo-5-fluorobenzotrifluoride of Formula-I,

comprising the steps of:
a) reacting 3-fluorobenzotrifluoride of Formula-II,

with brominating agent in the presence of antimony catalyst selected from antimony trichloride (SbCl3), antimony pentachloride (SbCl5) or mixture(s) thereof, at a temperature ranging between -5 °C to 5 °C to obtain 2-bromo-5-fluoro-benzotrifluoride of formula-I; and
b) optionally, purifying the 2-bromo-5-fluoro-benzotrifluoride of formula-I.

2. The process as claimed in claim 1, wherein the brominating agent is selected from bromine monochloride, bromate(s), N-bromosuccinamide (NBS), dibromodimethylhydantoin (DBDMH), tribromoisocyanuric acid (TBCA), sodium bromate (NaBrO3), perbromide(s), dimethyl bromo sulphur (DMBS), pyridinium bromide perbromide or mixture(s) thereof.

3. The process as claimed in 1, wherein in reaction step a) antimony catalyst is used in the molar ration of 1: 0.001 to 1: 0.04 with respect to 3-fluorobenzotrifluoride of Formula-II.

4. The process as claimed in claim 1, wherein the product obtained in step a) has purity greater than 94% by Gas chromatography (GC).

5. The process as claimed in claim 1, wherein the product obtained in step a) has yield greater than 92.5%.

6. The process as claimed in claim 1, wherein pure product obtained in step b) after purification by fractional distillation.

7. The process as claimed in claim 1, wherein the purified product obtained in step b) after purification has purity greater than 98.5% GC purity.