Description:FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(See Section 10 & Rule 13)

TITLE OF THE INVENTION:
A METHOD FOR PRODUCING 2-BROMO-5 FLUOROBENZOTRIFLUORIDE

APPLICANT(S):
DEEPAK NITRITE LIMITED
An Indian entity having address at:
Register & Corporate Office, 2nd Floor, Fermenter House, Alembic City, Alembic Avenue Road, Vadodara – 390 003, Gujarat, India

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

CROSS-REFERENCE TO RELATED APPLICATIONS AND PRIORITY
[0001] The present application does not claim priority from any of the patent applications(s).
TECHNICAL FIELD
[0002] The present disclosure relates to the field of bromination of halogenated aromatic compounds and, in particular, relates to a method for producing 2-bromo-5-fluorobenzotrifluoride by bromination of 3-fluorobenzotrifluoride.
BACKGROUND
[0003] Bromination is a chemical reaction in which a bromine atom is introduced into a molecule. This process can occur through different mechanisms depending on the type of compound involved. In electrophilic bromination, bromine reacts with aromatic compounds like benzene, in the presence of a catalyst, resulting in brominated aromatic compounds. Radical bromination is common in alkanes and occurs through a free radical mechanism initiated by heat or ultraviolet (UV) light, making it useful for selective substitution at specific carbon positions.

[0004] The bromination of 3-Fluorobenzotrifluoride (3-FBTF) is an electrophilic aromatic substitution reaction in which a bromine atom is introduced into the benzene ring. Since both the fluorine (-F) and trifluoromethyl (-CF₃) groups are electron-withdrawing, they deactivate the ring but also influence regioselectivity. Here, due to the directing effects of the substituents, bromination predominantly occurs at the ortho (2-position) or para (4-position) relative to the fluorine atom.

[0005] The synthesis of 2-Bromo-5-fluorobenzotrifluoride generally involves electrophilic bromination of 3-fluorobenzotrifluoride using bromine or brominating agents in the presence of catalysts. Different synthetic routes have been explored, including oxidative bromination, diazotization-bromination, and direct bromination methods, each with varying degrees of efficiency, selectivity, and environmental impact.

[0006] The bromination reaction of halogenated aromatic compounds is typically carried out using bromine (Br₂) in the presence of a Lewis acid catalyst with solvents to dissolve the reactants. However, the method has several drawbacks, such as the use of molecular bromine with Lewis’s acid catalysts, which generates corrosive byproducts and poses significant environmental and safety hazards. Additionally, these catalysts are often difficult to remove from the reaction mixture, leading to contamination and waste disposal challenges.

[0007] In the realm of catalysis, composite catalysts are mostly used in the bromination of 3-Fluorobenzotrifluoride (3-FBTF). However, the preparation of such catalysts is often characterized by complexity and high costs. Furthermore, there is a possibility of leaching at the active sites in certain composite catalysts, which can diminish their long-term efficacy across multiple reaction cycles. Additionally, some composite catalysts may exhibit sensitivity to moisture or by-products of the reaction, resulting in a decline in catalytic activity or unintended side reactions. Moreover, the prior art discloses the use of specific catalysts and reagents, such as palladium compounds and potassium tetrafluorocobaltate (KCoF₄), which present challenges regarding cost, accessibility, and scalability, particularly when considering large-scale industrial applications.

[0008] In the state of the art, bromination using bromine monochloride and AlCl₃ as a catalyst is conducted within a narrow temperature range of -5 to 0 °C. However, the bromination reaction faces challenges, such as while below the temperature range, the reaction rate decreases significantly, while above it, catalyst deactivation occurs due to halogen exchange between the trifluoromethyl group of 3-fluorobenzotrifluoride and AlCl₃. Additionally, bromine monochloride is unstable above its boiling point. The key drawbacks of such a process are catalyst deactivation, formation of unstable halogen-exchanged impurities, and the limited operational temperature window, rendering the process commercially unviable.

[0009] Several alternative bromination methods using bromine or other brominating agents such as metal bromates (e.g., MBrO₃) under anhydrous or hydrous conditions have been reported. However, these approaches offer low conversion and selectivity due to the relatively low reactivity of the substrate. Additional limitations include high effluent load and increased bromine consumption. While agents like 1,3-Dibromo-5,5-Dimethylhydantoin (DBDMH), and N-Bromosuccinimide (NBS) show increased reaction rates under anhydrous conditions, they often lead to over-bromination and poor selectivity. Moreover, these methods require large quantities of sulfuric acid and acetic acid, contributing to significant effluent disposal challenges. The higher cost of such brominating agents further reduces process viability.

[0010] Therefore, it can be concluded that the reactants, reaction conditions, catalysts, and the sequence of addition play a crucial role in determining the selectivity, purity, and yield of the final product. Consequently, each of these factors must be carefully considered, as a change in even a single parameter can significantly influence the outcome of the reaction.

[0011] In light of the foregoing discussion, there exists a need for an improved, cost-effective bromination process that offers high yield and environmental sustainability for synthesizing 2-Bromo-5-fluorobenzotrifluoride (2-Br-5-FBTF).
SUMMARY
[0012] Before the present method and its steps are summarized, it is to be understood that this disclosure is not limited to the method and its sequence as described, as there can be multiple possible embodiments which are not expressly illustrated in the present disclosure. The present disclosure overcomes one or more shortcomings of the prior art and provides additional advantages discussed throughout the present disclosure. Additional features and advantages are realized through the techniques of the present disclosure. It is also to be understood that the terminology used in the description is for the purpose of describing the versions or embodiments only and is not intended to limit the scope of the present disclosure. This summary is not intended to identify essential features of the claimed subject matter, nor is it intended for use in detecting or limiting the scope of the claimed subject matter.

[0013] In an embodiment, the present disclosure provides a method for producing 2-bromo-5-fluorobenzotrifluoride. The method may include a step of charging anhydrous iron powder and a solvent into a reaction vessel, followed by the addition of bromine at a temperature range of 30 to 60°C to obtain an anhydrous suspension comprising an in-situ generated catalyst FeBr3. The method may include a step of adding 3-fluorobenzotrifluoride to the anhydrous suspension comprising in-situ generated catalyst FeBr3 to obtain a reaction mass.

[0014] In another embodiment, the method may include a step of purging chlorine gas in the reaction mass for converting the in-situ generated catalyst FeBr3 to an in-situ generated catalyst A. Herein, the in-situ generated catalyst A is a catalyst comprising two or more compounds having formula of (FeXmYn), wherein m and n are integers varying from 0 to 3, and m+n=3, wherein X and Y are selected from chloro and bromo. The method may include a step of subjecting the reaction mass with the in-situ generated catalyst A in the reaction vessel to obtain a reaction mixture.

[0015] In yet another embodiment, the method may include a step of quenching the reaction mixture in water, followed by layer separation to obtain an organic layer comprising brominated 3-fluorobenzotrifluoride. The method may include a step of washing the organic layer comprising brominated 3-fluorobenzotrifluoride, followed by a solvent recovery to obtain a crude 2-bromo-5-fluorobenzotrifluoride (2-Br-5-FBTF). The method may include a step of distilling the crude 2-bromo-5-fluorobenzotrifluoride to obtain the 2-bromo-5-fluorobenzotrifluoride having a purity of more than 99.5%.
DETAILED DESCRIPTION
[0016] Reference will now be made in more detail to embodiments, and examples. In this regard, the present embodiments may have different forms and should not be construed as being limited to the descriptions set forth herein. Accordingly, the embodiments are merely described below, by referring to the figures, to explain aspects of embodiments of the present description. As used herein, the term "and/or" includes any and all combinations of two or more of the associated listed items. Throughout the present disclosure, the expression "at least one of a, b and c" indicates only a, only b, only c, both a and b, both a and c, both b and c, all of a, b, and c, or variations thereof.

[0017] The subject matter of the present disclosure may include various modifications and various embodiments, and example embodiments will be described in more detail in the detailed description. Effects and features of the subject matter of the present disclosure, and implementation methods therefor will become clear with reference to the embodiments described herein below. The subject matter of the present disclosure may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

[0018] It will be understood that although the terms "first," "second," etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another.

[0019] An expression used in the singular may also encompass the expression of the plural, unless it has a clearly different meaning in the context.

[0020] In the following embodiments, it is to be understood that the terms such as "including," "includes," "having," "comprises," and "comprising," are intended to indicate the existence of the features or elements disclosed in the specification and are not intended to preclude the possibility that one or more other features or elements may exist or may be added.

[0021] The present disclosure provides an efficient method for the industrial-scale production of 2-bromo-5-fluorobenzotrifluoride (2-Br-5-FBTF) with high yield and selectivity, while also achieving improved utilization of the brominating agent and catalyst compared to reported bromination methods.

[0022] More particularly, the disclosure provides an in situ catalyst generation, which plays a critical role in enhancing the efficiency and selectivity of the bromination reaction to obtain 2-bromo-5-fluorobenzotrifluoride. By generating the catalyst directly within the reaction environment, the method minimizes handling steps, reduces potential contamination, and ensures optimal catalyst activity during the reaction. Furthermore, in situ generation can lead to improved reproducibility and scalability of the reaction, making it highly suitable for industrial applications.

[0023] The present disclosure also provides a one-pot synthesis of 2-bromo-5-fluorobenzotrifluoride. By integrating multiple reaction steps into a single reaction vessel, the need for intermediate purification is minimized, thereby reducing overall reaction times and minimizing product loss. In addition, the streamlined method reduces equipment and labor costs while lowering the risk of contamination, ultimately leading to higher yields and improved product purity, and thus enhances scalability, making it particularly beneficial for both research and industrial applications.

[0024] Herein, the bromination reaction may be carried out in batch mode or continuous mode, preferably batch mode.

[0025] In an embodiment of the present disclosure, the method may include a step of charging anhydrous iron powder and a solvent into a reaction vessel. Herein, the iron powder and solvent undergo reflux to remove the moisture content from the reaction vessel and to obtain anhydrous iron powder. Herein, the solvent and iron powder are anhydrous in nature. Prior to the chlorination step, it is essential to remove moisture from the reaction vessel and iron powder through azeotropic distillation, as the presence of moisture can lead to the deactivation of the catalyst within the reaction mixture, which in turn will reduce the reaction rate.

[0026] Subsequently, after charging the anhydrous iron powder (Fe) and solvent into a reaction vessel, the reaction vessel is cooled down to a temperature range of 30 to 60°C. Thereafter, the addition of bromine is carried out at a temperature range of 30 to 60°C to obtain an anhydrous suspension. Preferably, the temperature of the reaction vessel is cooled and maintained at a temperature of 55 to 58°C. Herein, the anhydrous suspension comprises an in-situ generated catalyst, FeBr3.

[0027] Here, the particle size of iron powder plays a key role in the rate of reaction. Thus, the iron powder has a particle size in the range of about 50 to 700 mesh, preferably more than 100 mesh, and more preferably more than 300 mesh. The particle size of iron powder ensures that a fine powder of Fe results in better conversion to FeBr₃ due to the larger surface area of the iron. Otherwise, more time would be required for the transformation of Fe to FeBr₃. This primarily impacts the batch cycle time, with minimal adverse effect on the quality of the output.

[0028] Herein, the solvent is selected from a group of chlorine-containing solvents comprising dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethane, pentachloroethane, and a combination thereof. Herein, chlorine-containing solvents such as dichloroethane (EDC) are preferred. Herein, EDC may react with HBr through an SN2 mechanism to form 1,2-dibromoethane. This intermediate can then be reconverted back into EDC via halogen exchange when chlorine is purged in the presence of the in situ generated catalyst, especially under conditions where HBr is already present. This cycle effectively traps HBr in the solvent, enabling its reuse and allowing continuous in situ bromine regeneration with minimal loss of material.

[0029] Preferably, 3 volumes of EDC are employed due to EDC’s moderate solubility for HBr, ensuring efficient retention of HBr within the reaction medium, preventing its escape, and contributing to better control over the reaction environment. Moreover, mass analysis prior to chlorine addition shows about 2% conversion of EDC to halogen-exchanged impurities in the reaction process. This balance of chemical reactivity, stability, and solvent properties makes EDC an ideal choice for the bromination reaction.

[0030] In another embodiment of the present disclosure, the method may include adding 3-fluorobenzotrifluoride (3-FBTF) to the anhydrous suspension comprising an in-situ generated catalyst FeBr3, to obtain a reaction mass. Herein, 3-fluorobenzotrifluoride is preferably is anhydrous 3-fluorobenzotrifluoride.

[0031] In yet another embodiment of the present disclosure, the method may include a step of purging chlorine gas (Cl2) in the reaction mass to convert the in-situ generated catalyst FeBr3 to an in-situ generated catalyst A. The purging of the chlorine gas is carried out over a time period of 13 to 16 hours. Improper feeding of chlorine in the method may lead to the formation of nucleic chlorination impurities.

[0032] Herein, the chlorine enhances the activity of the in situ generated catalysts and regenerates bromine from its side product (Hydrobromic acid). However, chlorine is added in limited quantity, as an uncontrolled addition rate of chlorine can lead to the formation of nucleic chlorination-based impurities.

[0033] Herein, the addition of chlorine results in the in situ generation of the catalyst A. The in-situ generated catalyst A is a catalyst comprising two or more compounds having a formula FeXmYn, wherein m and n are integers varying from 0 to 3, and m+n=3, wherein X and Y are selected from chloro and bromo.

[0034] In an exemplary embodiment, the in-situ generated catalyst A may comprise a mixed catalyst having two or more compounds of formula FeXmYn, wherein X is chloro and Y is bromo, wherein m and n are integers varying from 0 to 3, and m+n=3. Preferably, the two or more compounds may be selected from a group comprising FeBr3, FeCl3, FeCl2Br, and FeClBr2. Preferably, the in situ generated catalyst A may be selected from a group comprising FeBr3, FeCl3, FeCl2Br, FeClBr2, and any combination thereof.

[0035] Below is provided the flow of catalyst activation that may be taking place in the reaction vessel.
Activation of Iron for reaction initiation
2Fe + 3Br2  2FeBr3
Chemical transformation of the catalyst during the reaction to enhance its activity
2FeBr3 + 3Cl2 2FeCl3 + 3Br2
and 2FeBr3 + 6HCl  2FeCl3 + 6HBr
and 2FeCl3 + excessive Br2  FeXmYn + corresponding qty. of chlorine.
Herein, m and n are integers varying from 0 to 3, and m+n=3, wherein X and Y are selected from chloro and bromo.

[0036] Herein, Cl2 is being added in the reaction mass at the temperature range of 30 to 60°C, preferably 50 to 60°C, more preferably 55 to 58°C for in-situ regeneration of bromine from its side product (HBr) and to enhance the catalyst activity during the reaction progress. Herein, the temperature range enables conversion of in-situ generated FeBr3 into in-situ generated catalyst A. Herein, in-situ generated FeBr3 is predominantly converted into in-situ generated catalyst A. However, depending on the reaction conditions and stage, there exists the possibility of either complete conversion or the simultaneous presence of both catalysts in the reaction vessel. Preferably, in-situ generated FeBr3 is converted to FeCl3 as FeCl3 is considerably more stable and active compared to FeBr3, and it is helpful to improve reaction rate and consumption norms of bromine.

[0037] No catalyst deactivation was found in the case of FeXmYn, wherein m and n are integers varying from 0 to 3, and m+n=3, wherein X and Y are selected from chloro and bromo due to fluorination. The generation of fluorine containing metal halides leads to formation of halogen exchange-based impurities. Moreover, the excessive brominated compounds may be effectively mitigated, which in turn prevents the formation of impurities, whereas no such impurities are formed while using in situ generated catalyst of the present disclosure.

[0038] Approximately 97% to 100% conversion is observed in the case of chlorine being used. Moreover, only traces of excessive bromination have been noted even after complete consumption of 3-FBTF at 50 to 60°C, indicating that the reaction is kinetically controlled due to the catalyst being moderately activated as it is prepared in situ. Enhanced conversion and selectivity are achieved at temperatures between 50 and 60°C, preferably 55°C and 58°C.

[0039] In yet another embodiment of the present disclosure, the method may include a step of subjecting the reaction mass with the in-situ generated catalyst A in the reaction vessel to obtain a reaction mixture. Herein, the reaction mixture is blended at 250 to 300 rpm for proper mixing of raw materials with the catalyst to maintain the reaction rate.

[0040] Here, proper agitation is required for proper distribution of chlorine to get rid of nucleic chlorination and for maximum utilization of the catalyst. In case of slow stirring, chlorine, bromine, and HBr may be lost. In case the catalyst is of poor quality, it will generate water during chlorination. The resulting water will adversely impact conversion and selectivity during bromination.

[0041] Herein, iron, bromine, chlorine, and 3-FBTF have a molar ratio in a range from 0.01 :0.55 :0.5 :1.0 to 0.35 :0.70 :0.70 :1.0, preferably 0.05 :0.55 :0.5 :1.0 to 0.1 :0.6 :0.55 :1.0 is maintained. The proper molar ratio ensures that the method has regioselectivity of more than 95%, no excessive bromine impurities, and no halogen-exchanged impurities with reduced effluent load. The molar proportion of bromine in the bromination mass must be in excess compared to chlorine to suppress the nucleic chlorination impurities. Due to the use of chlorine, the eluent primarily contains HCl, which is less corrosive than HBr. Furthermore, the lower concentration of HBr in the effluent indicates its effective utilization, contributing to cost efficiency.

[0042] In yet another embodiment of the present disclosure, the method may include a step of quenching the reaction mixture in water, followed by layer separation to obtain an organic layer comprising brominated 3-fluorobenzotrifluoride. Herein, the reaction mixture on adding removes the aqueous layer, which mainly comprises trapped acidity and metal halides.

[0043] In yet another embodiment of the present disclosure, the method may include a step of washing the organic layer comprising brominated 3-fluorobenzotrifluoride, followed by a solvent recovery to obtain a crude 2-bromo-5-fluorobenzotrifluoride (2-Br-5-FBTF). Herein, the organic layer is washed with a sulphite-based reducing agent to remove excessive brominating agent.

[0044] Herein, the sulphite-based reducing agent is selected from sodium sulfite (Na₂SO₃), sodium bisulfite (NaHSO₃), sodium metabisulfite (Na₂S₂O₅), and a combination thereof. After washing with the sulphite-based reducing agent, the organic layer is washed with an alkaline solution such as sodium bicarbonate to remove excessive acidity, HBr and trapped SO2( sulfur dioxide).

[0045] In an alternative embodiment of the present disclosure, direct recovery and recycling of solvent and unconverted 3-FBTF may be carried out by atmospheric distillation or under mild vacuum distillation after reaction completion. Herein, the bromine or chlorine content is completely removed after washing. Moreover, bromide as bromine or HBr and chloride as Cl2 or HCl will be completely removed after washing of the organic layer.

[0046] In yet another embodiment of the present disclosure, the method may include a step of distilling the crude 2-bromo-5-fluorobenzotrifluoride at a reducing pressure ranging from about 50 to 100 mbar to obtain the 2-bromo-5-fluorobenzotrifluoride having a purity of more than 99%, preferably more than 99.5%. Herein, the method has a product yield in a range of about 85 to 90%, a conversion rate in a range of about 97 to 100%, an overall selectivity in a range of about 90 to 95%, and a regioselectivity is more than 95%.

[0047] Herein, the method for producing 2-bromo-5-fluorobenzotrifluoride results in the production of 2-bromo-5-fluorobenzotrifluoride: 3-bromo-5-fluorobenzotrifluoride: 4-bromo-5-fluorobenzotrifluoride: 6-bromo-5-fluorobenzotrifluoride isomers in the ratio of 96:0.1:2.0:1.9. Herein, the step sequence plays a significant role in better selectivity, minimum solvent impurities and nucleic chlorination impurities.

[0048] Herein, the method for producing 2-Br-5-FBTF has demonstrated 97-100% conversion with 90 to 95% overall purity & ~95-96% regio selectivity (The isomeric ratio of 2-bromo-5-fluorobenzotrifluoride: 3-bromo-5-fluorobenzotrifluoride: 4-bromo-5-fluorobenzotrifluoride: 6-bromo-5-fluorobenzotrifluoride obtained was 96:0.1:2.0:1.9), and no halogen exchange and excessive bromination impurities were found.

[0049] Further, for a better understanding of the present disclosure and associated method, the following examples are discussed.

EXAMPLE 1: Preparation of 2-Bromo-5-fluorobenzotrifluoride (2-Br-5-FBTF)
750g of EDC (3 volume based on 3-FBTF) under nitrogen blanketing and 6.8g of anhydrous iron powder (100-400 mesh) are charged in a reaction vessel. Further, the reaction vessel undergoes reflux to remove water. The anhydrous suspension in the reaction is then cooled to 55 to 58°C in the vessel, followed by the addition of 118g of bromine over 30 minutes to obtain an anhydrous suspension comprising in situ generated catalyst FeBr3. Further, 200g of 3-FBTF is charged at 55 to 58°C and stirred for 60 minutes to obtain a reaction mass. Further, 60 to 62g of chlorine is slowly purged over the period of 13 to 14 hours in the reaction mass.
Thereafter, the reaction mixture is quenched in water, which further undergoes layer separation to obtain an organic layer. In the subsequent step, the organic layer is washed with an appropriate quantity of SMBS, which is added to kill excessive bromine and neutralized with an appropriate quantity of NaHCO3 solution. Further, the organic layer is subjected to solvent recovery under reduced pressure to obtain a crude 2-bromo-5-fluorobenzotrifluoride having a purity of 91.29%. The crude 2-bromo-5-fluorobenzotrifluoride is then distilled to obtain 86.4 % yield of pure product (2-bromo-5-fluorobenzotrifluoride) having a purity of 99.7%.

EXAMPLE 2: Comparison with conventional brominating processes
Several trials were carried out based on subjecting 3-FBTF with various brominating agents such as Br2/ DBDMH/ NBS/ NaBrO3; different catalysts such as Al/ AlCl3/ Fe/ FeCl3, and co-catalysts to study the impact of the reagents on the yield and purity of the 2-Br-5-FBTF. A comprehensive overview of the process is provided in Table 1.
TABLE 1: Trials based on brominating agents such as Br2 and different catalysts
Batch No. 3-FBTF (g)
Reagents
Qty. g (Eq.) Catalyst
Qty. g (Eq.) Solvent
(V) Temp. and Time Molar Yield (%) Purity (%) of product in mass
#1 20 Br2: 11.8 (0.61)
AcOH: 7.38 (1.0) - H2SO4 (3) T1:17-20°C (2h)
T2: 40-45°C (6h) 0% No Initiation
#2 40 Br2: 48 (1.23)
Iron: 0.33 (0.02) No Solvent T1: 40-45°C (3.5h) T2: 40-45°C (10h) 8% 16.64% and 80.91% (SM)
#3 25 Br2: 29.5 (1.21)
Iron: 1.29 (0.14) EDC (4) T1: 50-55°C (3h) T2: 50-55°C (20h) 85% on conversion 69.56% and 16.52% SM
#4 50 Br2: 55 (1.13)
FeCl3: 15.5 (0.3) EDC (4) T1:50-55°C (8h)
T2:50-55°C (2h) 83% on conversion 66.57% and 25.31% SM
#5 200 Br2: 120 (0.62)
Cl2: 66 (0.76)
Al: 1.34 (0.04) No Solvent Br2 and Cl2 addn
T1: -5 to 0°C (2h) 0% No conversion
#6 200 Br2: 120 (0.62)
Cl2: 66 (0.76)
Al: 1.34 (0.04)
AlCl3: 4.96 (0.03) No Solvent Br2 and Cl2 addn
T1:-5 to 0°C (10h)
T2: -5 to 0°C (18h) 76.0% 85.16%
#7 200 Br2: 120 (0.62)
Cl2: 66 (0.76) Al: 1.34 (0.04) FeCl3: 2.0 (0.01) No Solvent Br2 and Cl2 addn:
T1: -5 to 0°C (4h) 0.0 % No Initiation after Al and then Anhyd. FeCl3
#8 200 Br2: 120 (0.62)
Cl2: 66 (0.76)
Al: 1.34 (0.04)
FeCl3: 2.0 (0.01)
AlCl3: 1.65 (0.01) No Solvent Br2 and Cl2 addn:
T1: -5 to 0°C(10h)
T2: -5 to 0°C (18h) 42.7% 65.12%
#9 40 Br2: 47.20 (1.21)
AlCl3: 1.0 (0.03) EDC (1.8)
Br2 Addn:
T1:40-45(2 h 45 min)
T2: 40-45°C (1h 30 min) 14.0% 22.00%
#10 200 Br2: 120.0 (0.62)
Cl2: 66.0 (0.76)
AlCl3: 4.88 (0.03) No Solvent
Br2 and Cl2 addn:
T1: -5 to 0°C (6h)
T2: -5 to 0°C (4h) 79.55% 85.42%
#11 20
AcOH: 7.9 (1.08)
NBS: 28 (1.25) - H2SO4: (3.0) T1: 12-17°C (45m)
T2: 35-40°C (7h)
45-50°C (34h) 44.33% 76.95%
#12 50 98% H2SO4: 91.27(3)
AcOH: 18.44 (0.99)
DBDMH: 44.4 (0.5) - No Solvent T1: 15-20°C (5h)
T2: 15-20°C (8h) 45.28% 68.77%
#13 25 NaBrO3: 30 - 70% H2SO4 (5) T1: 40°C (4h)
T2: 40°C (10h) 30% 36% and 51% SM
#14 200 Br2:120 (0.62)

Cl2: 66 (0.76)
TEA -HCl: 1.9g (0.01)
AlCl3: 4.96 (0.03) No Solvent T1: -5 to 0°C (6.5h)
T2: 5°C to 0 (6h) (4.94%) 12.74% and 81.6% SM
#15 100 Br2: 60.97 (0.63)
Cl2:32.83 (0.76)
TEA: 2.0 (0.03)
AlCl3: 2.40 (0.03) No Solvent T1: -4 to 0°C (4h)
T2: -4 to 0°C (4h) (2.0%) (2.4% and 94.15%SM
Example 1 200g Bromine: 118.04 (0.61)
Chlorine: 62 (0.72) Fe powder: 6.87 (0.1)
EDC (3) Cl2 addition Temp: 55-58°C
Cl2 addition Time
13.0 h 86.4 % 91.29%
**T1: Addition temperature **T2: Maintaining temperature **SM is starting material

The reaction progress was evaluated across a range of catalytic conditions, including the use of anhydrous ferric chloride (#4) and aluminium (#5), both individually and in combination (#7, #8), under a consistent temperature range. However, the use of bromine (Br₂) as the brominating agent did not result in a product with high purity under these conditions.

Further experiments were carried out using Br₂ in the presence of either iron (#3) or FeCl₃ (#4) as catalysts, with reactions conducted in a solvent medium at 50–55°C. These conditions led to a slower reaction rate, producing a similar yield of 85%, but with lower product purity, below 70%. Notably, when the solvent was excluded from the reaction (#2), the yield dropped sharply to below 10%, indicating the solvent’s critical role in enabling conversion.

In contrast, the combination of an aluminium-based catalyst with bromine as the brominating agent (#6 and #10) in the absence of solvent resulted in a crude yield ranging from 76% to 80%, with product purity of approximately 85%. Whereas when the aluminium-based catalyst with bromine is used in the presence of a solvent, a lower yield with lower purity is observed.

Alternative brominating agents were also evaluated: reaction #11, using N-Bromosuccinimide (NBS) in the presence of H₂SO₄ and acetic acid, achieved a yield of 44.33% with 76.95% purity; while #12, using 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) under similar acidic conditions, yielded 45.28% with 68.77% purity and while #13, using NaBrO3, yielded 30% with 36% purity.

In batch reactions #14 and #15, slower conversions were observed at lower temperatures, leading to products with less purity.

Whereas Example 1 demonstrated that a controlled and slower chlorine purging rate in the presence of solvent enhanced both yield and selectivity while reducing the formation of nucleophilic chloro-impurities.

Overall, the combination of iron, bromine, and chlorine in an EDC medium (Example 1), operated at 55–58°C, delivered the best performance in terms of yield and selectivity among all the conditions evaluated. Thus, the method involving Fe, Br₂, and Cl₂ presents a promising alternative to the AlCl₃–BrCl route, particularly when assessed on the basis of yield, impurity profile, and product quality.

EXAMPLE 3: Impact of temperature and solvent on the bromination reaction
Several trials were carried out based on using 3-FBTF, Fe, Br2, and Cl2 to study the impact of temperature range and the presence of solvent on the conversion and selectivity of the 2-Br-5-FBTF. The output is provided in Table 2.

Table 2: Impact of varying temperature range and solvent presence
Trials 3-FBTF (g) Reagents
Qty. g (Eq.) Catalyst
Qty. g (Eq.) Solvent (V) Temp. (°C)
Time (h) Purity (%) of product in mass
#16 100g Br2: 60 (0.62)
Cl2: 31 (0.72) Iron: 3.44g (0.1)
No solvent *T1: 55-58°C (14h)
**T2: 55-58°C (1h) (74.41% and 18.28% SM)
Conversion: 81.72%
#17 100g Br2: 60 (0.62)
Cl2: 31 (0.72) Iron: 3.44g (0.1) EDC (3) T1: 50-55°C (14h)
T2: 50-55°C (1h) (88.12% and 4.17% SM)
Conversion 95.83%
Example 1
(Lab-scale production) 200g Br2: 118.04 (0.61)
Cl2: 62 (0.72) Iron: 6.87g (0.1) EDC (3) T1: 55-58°C (14h)
T2: 55-58°C (1h) (91.29% and 2.86% SM)
Conversion: 97.50%
#21
(Scale-up production) 1200g Br2: 718 (0.61)
Cl2: 286 (0.55) Iron: 43g
(0.1) EDC (3) T1: 55-58°C(14h)
T2: 55-58°C(1h) (93.30 and 0.0% SM)
Conversion: 100.00%
*T1: Chlorine Addition temperature; **T2: Maintaining temperature

It is noted from #17 that temperatures below 55°C result in less conversion and reduced purity of the product. Additionally, the absence of a solvent (#16) further diminishes the purity. Therefore, to obtain a product with enhanced purity and conversion as achieved in Example 1 and #21, it is essential to maintain the temperature within the range of 55 to 58°C and to carry out the bromination in the presence of solvent.

EXAMPLE 4: Chlorine addition
Several trials were carried out based on using 3-FBTF, Fe, and Br2 to study the impact of chlorine addition on the conversion and selectivity of the 2-Br-5-FBTF. The output is provided in Table 3.

TABLE 3: Impact of chlorine addition
Batch No Bromine (M. Eq) Iron Powder (M. Eq) Chlorine (M. Eq) Conversion Selectivity Yield
#18 1.5 0.35 0 83.48 83.33 70
#19 1.5 0.18 0 75 87 65
#20 1.5 0.05 0 22.04 90.61 20
Example 1 0.61 0.1 0.72 97.5 93.76 86.4

It can be observed from the above-mentioned example that the yield of the bromination reaction is significantly lower in the absence of chlorine addition (#18, #19, #20). Chlorine plays a crucial role in enhancing the reaction efficiency, likely by facilitating the formation of the active species of the catalyst. Without purging chlorine gas, the reaction proceeds at a slower rate, leading to reduced conversion and overall yield.
[0053] Thus, a person skilled in the art should recognize that the reaction parameters, such as temperature, pressure, presence of solvent, and each component, such as bromine, chlorine, and 3-FBTF, involved in the reaction must be considered to achieve an effective bromination reaction. Variations in components and their concentrations, temperature, and the timing of additions can significantly impact the reaction selectivity, conversion rate, regioselectivity, yield, and purity of product. Therefore, optimizing each parameter is essential for the successful execution and scalability of the process.
[0054] The process disclosed in the present invention offers several advantages:
• Achieves an overall purity of 93–95% for the isomeric mixture, with >96% regioselectivity toward 2-bromo-5-fluorobenzotrifluoride (2-Br-5-FBTF).
• Provides a crude yield of approximately 90% with 97–100% conversion, an isolated yield of ~86.4%, and purity of 99.7% after fractional distillation.
• Delivers >90% overall selectivity for 2-Br-5-FBTF.
• Effectively eliminates bromo-chloroethane by-products.
• Minimizes nucleophilic chlorination impurities through the controlled addition of chlorine gas.
• Facilitates in situ conversion of HBr to bromine through the gradual, stoichiometric addition of chlorine gas based on reaction progress, ensuring effective bromine utilization.
• Enables 85 to 90% recovery of solvent and excessive bromine.
• In case of chlorine addition, the bromine loss is reduced by solvent regeneration from the corresponding halogen exchange byproducts.
• Prevents excessive bromination, as the reaction is kinetically controlled.
• Utilizes a moderately activated catalyst or catalyst mixture that does not displace fluoride from the trifluoromethyl group of the reactant or product, demonstrating catalyst durability and eliminating safety concerns related to free fluoride ions or decomposition of the activated –CX₃ group, wherein X may be a halogen selected from Cl, Br, and F.
• Enhances commercial viability due to an operable temperature range, allowing for large-scale implementation without significant losses of bromine or HBr.

[0055] It should be understood that the embodiments described herein should be considered in a descriptive sense only and not for purposes of limitation. Descriptions of features or aspects within each embodiment should typically be considered as available for other similar features or aspects in other embodiments. While one or more embodiments have been described, it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the scope of the present disclosure as defined by the following claims, and equivalents thereof.
, C , C , C , Claims:WE CLAIM:
1. A method for producing 2-bromo-5-fluorobenzotrifluoride, wherein the method comprises:
charging anhydrous iron powder and a solvent into a reaction vessel, followed by the addition of bromine at a temperature range of 30 to 60°C to obtain an anhydrous suspension comprising an in-situ generated catalyst FeBr3;
adding 3-fluorobenzotrifluoride to the anhydrous suspension comprising in-situ generated catalyst FeBr3 to obtain a reaction mass;
purging chlorine gas in the reaction mass for converting the in-situ generated catalyst FeBr3 to an in-situ generated catalyst A, wherein the in-situ generated catalyst A is a catalyst comprising two or more compounds having a formula of FeXmYn, wherein m and n are integers varying from 0 to 3, and m+n=3, wherein X and Y are selected from chloro and bromo;
subjecting the reaction mass with the in-situ generated catalyst A in the reaction vessel to obtain a reaction mixture;
quenching the reaction mixture in water, followed by layer separation to obtain an organic layer comprising brominated 3-fluorobenzotrifluoride;
washing the organic layer comprising brominated 3-fluorobenzotrifluoride, followed by a solvent recovery to obtain a crude 2-bromo-5-fluorobenzotrifluoride (2-Br-5-FBTF); and
distilling the crude 2-bromo-5-fluorobenzotrifluoride to obtain the 2-bromo-5-fluorobenzotrifluoride having a purity of more than 99.5%.

2. The method as claimed in claim 1, wherein the 3-fluorobenzotrifluoride has a moisture content of less than 100 ppm.

3. The method as claimed in claim 1, wherein the iron powder has a particle size in a range of about 50 to 700 mesh.

4. The method as claimed in claim 1, wherein the organic layer is washed with a sulphite-based reducing agent and an alkaline solution.

5. The method as claimed in claim 4, wherein the sulphite-based reducing agent is selected from sodium sulfite (Na₂SO₃), sodium bisulfite (NaHSO₃), sodium metabisulfite (Na₂S₂O₅), and a combination thereof.

6. The method as claimed in claim 1, wherein the solvent is selected from a group of chlorine-containing solvents comprising dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethane, pentachloroethane, and a combination thereof.

7. The method as claimed in claim 1, wherein the iron, bromine, chlorine, and 3-FBTF have a molar ratio in a range from 0.01:0.55:0.5:1.0 to 0.35:0.70:0.70:1.0.

8. The method as claimed in claim 1, wherein the bromine and chlorine have a molar ratio in a range from 0.55: 0.5 to 0.70: 0.70.

9. The method as claimed in claim 1 has
a yield in a range of at least 86%;
a purity in a range of at least 99.5% after distillation;
a conversion rate in a range of at least 97%;
an overall selectivity in a range of about 90 to 95%; and
a regioselectivity is more than 95% with respect to the overall selectivity.
Dated this 22nd day of May 2025

ABHIJEET GIDDE
IN/PA-4407
AGENT FOR THE APPLICANT