A process for the preparation of 2-bromo-5-fluoro trifluorotoluene

Abstract

The present invention discloses a cost-effective and industrially amenable process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) from 3-fluoro benzotrifluoride of formula (II).

Description

[0001] “A PROCESS FOR THE PREPARATION OF 2-BROMO-5-FLUORO TRIFLUOROTOLUENE”

[0002] FIELD OF THE INVENTION:

[0003] The present invention relates to a process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I). More particularly, the present invention relates to a process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) using 3- fluorobenzotrifluoride of formula (II).

[0004] BACKGROUND OF THE INVENTION:

[0005] 2-bromo-5-fluoro trifluorotoluene has wide applications in the area of medicines and pesticides. Specifically, Ipfentrifluconazole and Mefentrifluconazole are two well known fungicides, wherein 2-bromo-5-fluoro trifluorotoluene is used as a key intermediate.

[0006] There are several synthetic methods reported in the prior arts to prepare 2-bromo-5-fluoro trifluorotoluene.

[0007] CN101759597 discloses a process for preparing 2-bromo-5-fluoro trifluorotoluene from 3- fluoro benzotrifluoride using vitriol oil (sulfuric acid), glacial acetic acid and bromine. The drawbacks associated with this process are low yield, low purity and difficulty in handling due to the formation of residues from the reaction system. The mixed acids (glacial acetic acid and sulfuric acid) from the reaction system are difficult to separate and result in higher operational cost.

[0008] CN102951996 discloses a process for preparing 2-bromo-5-fluoro trifluorotoluene from 3- fluoro benzotrifluoride using a four step synthesis process. The process includes the nitration of 3 -fluorobenzotrifluoride using mixed acid followed by hydrogenation and Sandmeyer reaction. The drawbacks associated with this process are that it is a multistep reaction which results in the formation of large waste residues and hence cost intensive.

[0009] CN104311386 discloses a process for preparing 2-bromo-5-fluoro trifluorotoluene from 3- fluoro benzotrifluoride using sulfuric acid followed by treatment with metal bromate as brominating agent. The drawback associated with this process is that the bromate reagents are not suitable at industrial scale. Further, the processes as disclosed in CN105152853, CN107337576, CN114163294 and CN116143581 use different types of catalysts such as composite catalyst, quaternary amine salt and metal salts. Therefore, these processes are not economical for industrial scale production because of the expensive catalyst used. The above given synthetic methods have several drawbacks including multiple steps, expensive reagents, high waste and residue formation, high cost, larger energy requirements, comparatively lower yield, high catalyst cost and the like.

[0010] Therefore, there is a need to develop a process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) which at least partially obviates one problem of prior art processes, such as use of catalyst, large waste or residue formation, lower yield, purity and cost effectiveness. Accordingly, the present invention provides a simple, cost-effective and industrially feasible process for the preparation of 2-bromo-5-fluoro trifluorotoluene from 3-fluoro benzotrifluoride which obviates the use of expensive catalyst and provide higher yield, higher purity.

[0011] OBJECTIVE OF THE INVENTION:

[0012] The objects of the present invention are described herein below:

[0013] An object of the present invention is to provide a process for the preparation of 2-bromo- 5-fluoro trifluorotoluene of formula (I) from 3-fluoro benzotrifluoride of formula (II).

[0014] Another object of the present invention is to provide a cost effective process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) having improved yield and purity.

[0015] Yet another object of the present invention is to provide a process for the preparation of 2- bromo-5-fluoro trifluorotoluene of formula (I) which obviates the solid waste generation and hence is environmentally friendly.

[0016] Yet another object of the present invention is to provide an atom -efficient process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I).

[0017] Yet another object of the present invention is to provide a process for the preparation of 2- bromo-5-fluoro trifluorotoluene of formula (I) which obviates the use of expensive specialized industrial set up.

[0018] Yet another object of the present invention is to provide a simple, cost-effective and industrially viable process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) having improved yield.

[0019] Other objects and advantages of the present invention will be a more apparent description which is not intended to limit the scope of the present invention.

[0020] SUMMARY OF THE INVENTION:

[0021] Accordingly, the present invention provides a process for the preparation of 2-bromo-5- fluoro trifluorotoluene of formula (I) comprising the step of brominating 3-fluoro benzotrifluoride of formula (II) in the presence of a suitable brominating agent and a suitable acid at a temperature in the range of 10-50 °C to obtain 2-bromo-5-fluoro trifluorotoluene of formula (I).

[0022] Another aspect of the present invention is to provide a simple, cost-effective and industrially viable process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) having yield more than or equal to 90%.

[0023] DESCRIPTION OF THE INVENTION:

[0024] References in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, characteristic, or function described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment. References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function is described in detail thereby omitting known constructions and functions for clear description of the present invention.

[0025] The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed and obviously many modifications and variations are possible in light of the above teaching. The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure.

[0026] 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 disclosure to achieve one or more of the desired objects or results.

[0027] The numerical values mentioned for the various physical parameters, dimensions or quantities are only approximations and it is envisaged that the values higherdower than the numerical values assigned to the parameters, dimensions or quantities fall within the scope of the disclosure, unless there is a statement in the specification specific to the contrary.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skilled in the art. In case of conflict, the present document, including definitions will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0029] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures.

[0030] The term “ambient temperature” as used herein, is temperature in the range of 10-20 °C.

[0031] The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0032] In view of the above defined objectives, the process for the preparation of 2-bromo-5- fluoro trifluorotoluene of formula (I) provides a simple, cost-effective and industrially viable process having improved yield and purity. In an embodiment, the present invention provides a process for the preparation of 2-bromo- 5-fluoro trifluorotoluene of formula (I) comprising the step of brominating 3-fluoro benzotrifluoride of formula (II) in the presence of a suitable brominating agent and a suitable acid at a temperature in the range of 10-50 °C to afford 2-bromo-5-fluoro trifluorotoluene.

[0033] The process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) from 3-fluoro benzotrifluoride of formula (II) is depicted in scheme 1:

[0034] Non-limiting examples of the suitable brominating agent in accordance with the present invention include bromine, hydrogen bromide, -bromo- succinimide (NBS), cupric bromide, sodium bromide, potassium bromide, bromine chloride or combination thereof.

[0035] In one embodiment, the brominating agent is bromine.

[0036] Typically, the suitable acid in accordance with the present invention is selected from mineral acid or organic acid.

[0037] Non-limiting examples of the suitable mineral acid in accordance with the present invention include hydrochloric acid, oleum or combination thereof.

[0038] Non-limiting examples of the suitable organic acid in accordance with the present invention include formic acid, acetic acid, chloro sulfonic acid, methanesulfonic acid, the trifluoromethanesulfonic acid or combination thereof.

[0039] In one embodiment, the molar ratio of 3-fluoro benzotrifluoride of formula (II) and the brominating agent for the reaction in accordance with the present invention is in the range of 1:0.5 to 1:0.7. In another embodiment, the molar ratio of 3 -fluoro benzotrifluoride of formula (II) and the brominating agent for the reaction in accordance with the present invention is in the range of 1:0.5 to 1:0.6.

[0040] In one embodiment, the molar ratio of 3 -fluoro benzotrifluoride of formula (II) and the suitable acid for the reaction in accordance with the present invention is in the range of 1: 1 to 1: 10.

[0041] In another embodiment, the molar ratio of 3 -fluoro benzotrifluoride of formula (II) and the suitable acid for the reaction in accordance with the present invention is in the range of 1:2 to 1:5.

[0042] In an embodiment of the present invention, the reaction is carried out at a temperature in the range of 10-50 °C.

[0043] In one embodiment of the present invention, the reaction is carried out at a temperature in the range of 10-30 °C.

[0044] Typically, in accordance with the present invention the total conversion of 3 -fluoro benzotrifluoride of formula (II) is more than 99%.

[0045] In accordance with the process of the present invention, the compound of formula (I) is obtained in the yield more than or equal to 90%.

[0046] In another embodiment of the present invention, the compound of formula (I) is obtained in the yield ranging from 90 to 95%.

[0047] The prior art process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) using acid catalyst such as sulfuric acid gives the maximum yield of 87%. However, the inventors of the present invention repeated the prior art process refer Comparative example 3) for finding out a similar results, and surprisingly found out that almost 99.5% starting material i.e. 3 -fluoro benzotrifluoride of formula (II) remains unreacted. On the contrary, the process of the present invention for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) achieved maximum yield i.e. more than or equal to 90%, particularly 95%.

[0048] In one embodiment of the present invention, the concentration of acid is in the range of 10- 65%. In another embodiment of the present invention, the concentration of acid is in the range of 10-60%.

[0049] In another embodiment of the present invention, the concentration of acid is in the range of 10-45%.

[0050] In one embodiment of the present invention, the acid is oleum.

[0051] In accordance with the present invention, after completion of the reaction, the resulting wet cake comprising the compound of formula (I) is purified to obtain 2-bromo-5-fluoro trifluorotoluene having purity ranging from 96 to 99.9%.

[0052] In one embodiment of the invention, the purity of the compound of formula (I) is more than or equal to 99%.

[0053] In another embodiment, the process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) from 3 -fluoro benzotrifluoride of formula (II) is carried out in the absence of a catalyst.

[0054] In one embodiment of the present invention, the suitable acid is added in a continuous, controlled or lot- wise or batch-wise manner. In another embodiment, the lot-wise or batch- wise addition of acid is subjected for at least two times.

[0055] The starting compound 3-fluorobenzotrifluoride of formula (II) can be prepared from 3- aminobenzotrifluoride by using the known processes reported in the art. Alternatively, the starting compound 3-fluorobenzotrifluoride of formula (II) can be prepared by direct ring fluorination of benzotrifluoride.

[0056] The compound 3-aminobenzotrifluoride can be prepared from 3 -nitrobenzotrifluoride by using the known processes reported in the art.

[0057] The preparation processes as disclosed in the present invention are preferably carried out batch- wise. However, semi -continuous or continuous reaction passages, for instance under flow reaction conditions, are also possible.

[0058] Any person skilled in the art knows the best work-up of the reaction mixtures after the end of the respective reactions. In one embodiment, the work-up is usually carried out by isolation of the product by filtration, and optionally washing with a solvent, further optionally drying of the product if required.

[0059] Advantages of the invention:

[0060] • Reaction time of the process is reduced which in turn reduces the operational cost

[0061] • Use of inexpensive economically viable reagents

[0062] • Catalyst free process

[0063] • Involves simple filtration method and zero effluents

[0064] • Enhanced reaction rate at lower temperatures

[0065] • Improved selectivity to a specific position of the aromatic ring

[0066] • Bromine in stoichiometric quantity is fully utilized without any elemental loss thus depicting maximum atom efficient process.

[0067] Various features and embodiments of the present invention are illustrated in the following representative examples, which are intended to be illustrative and non-limiting.

[0068] EXAMPLES:

[0069] Example 1: Preparation of 2-bromo-5-fluoro trifluorotoluene

[0070] 3 -fluorobenzotrifluoride (50 g), bromine (25 g) and 23% oleum were charged into a four necked round bottomed flask and mixed. The reaction mixture was stirred for 2-3 hrs at ambient temperature. After completion of the reaction, quenched reaction mass into water and the reaction mixture was filtered and layers were separated. The organic layer was washed with sodium bicarbonate solution followed by water. The organic layer was distilled out to obtain an oily product. The obtained oily product was degassed for 1 hrs under vacuum followed by fractional distillation to obtain the compound of formula (I). (Yield: 95 % and GC Purity: 100%).

[0071] Example 2: Preparation of 2-bromo-5-fluoro trifluorotoluene

[0072] 3 -fluorobenzotrifluoride (50 g), bromine (25 g) and 15% oleum were charged into a four necked round bottomed flask and mixed. The reaction mixture was stirred for 7 hrs at ambient temperature. After completion of the reaction, quenched reaction mass into water and the reaction mixture was filtered and layers were separated. The organic layer was washed with sodium bicarbonate solution followed by water. The organic layer was distilled out to obtain an oily product. The obtained oily product was degassed for 1 hrs under vacuum followed by fractional distillation to obtain the compound of formula (I). (Yield: 90 % and GC Purity: 99%).

[0073] Example 3: Preparation of 2-bromo-5-fluoro trifluorotoluene

[0074] 3-fluorobenzotrifluoride (50 g), bromine (25 g) and 65% oleum were charged into a four necked round bottomed flask and mixed. The reaction mixture was stirred for 7 hrs at ambient temperature. After completion of the reaction, quenched reaction mass into water and the reaction mixture was filtered and layers were separated. The organic layer was washed with sodium bicarbonate solution followed by water. The organic layer was distilled out to obtain an oily product. The obtained oily product was degassed for 1 hrs under vacuum followed by fractional distillation to obtain the compound of formula (I). (Yield: 75% and GC Purity: 100%).

[0075] Comparative Example 1: Preparation of 2-bromo-5-fluoro trifluorotoluene (CN107337576)

[0076] A four necked round bottomed flask was charged with 3-fluorobenzotrifluoride (20 g) and sulfuric acid at 25°C. A-bromosuccinimide, tetrabutylammonium bromide and lithium bromide were added at room temperature. Bromine (25.03 g) was added dropwise into the above reaction mixture over 10-15 min. The reaction mass was stirred for 8 hrs at 25-30°C. The sample was analyzed which shows an unreacted 3-fluorobenzotrifluoride (98.72%).

[0077] Comparative Example 2: Preparation of 2-bromo-5-fluoro trifluorotoluene (CN107337576)

[0078] A round bottomed flask was charged with 3-fluorobenzotrifluoride (50.0 g) and acetic acid at 25°C. A-bromosuccinimide and tetrabutylammonium bromide were added at room temperature. Further, the reaction mass was cooled to 10°C and bromine (25.03 g) was added dropwise into the above reaction mixture over 10-15 min at 10-15 °C temperature. The reaction mixture was stirred for 30 mins and raised the temperature to room temperature. 50% hydrogen peroxide was added at the same temperature and after complete addition the reaction mixture was stirred at room temperature for 30 mins. The reaction mass was heated to 35-45°C and stirred for 9.5 hrs. The sample was analyzed which shows an unreacted 3-fluorobenzotrifluoride (97.20%).

[0079] Comparative Example 3: Preparation of 2-bromo-5-fluoro trifluorotoluene (CN101759597)

[0080] A round bottomed flask was charged with 3-fluorobenzotrifluoride (50 g) at 25 °C, concentrated sulfuric acid and acetic acid were charged under stirring at room temperature. The reaction mass was cooled to 15-20°C and bromine (25.03 g) was added drop wise into the above reaction mixture over 10-15 min. The reaction mixture was stirred for 7 hrs at 15-20°C temperature. The sample was analyzed which shows an unreacted 3- fluorobenzotrifluoride (99.50%).

[0081] The comparative examples 1, 2, and 3 show no formation of product and the results show an unreacted 3-fluoro benzotrifluoride (97-99.5 %).

[0082] The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

[0083] The description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and / or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein. While considerable emphasis has been placed herein on the particular features of this invention, it will be appreciated that various modifications can be made, and that many changes can be made in the preferred embodiments without departing from the principles of the invention. These and other modifications in the nature of the invention or the preferred embodiments will be apparent to those skilled in the art from the invention herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

[0084] Various features and embodiments of the present invention are illustrated in the following representative examples, which are intended to be illustrative and non-limiting.

[0085] The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

[0086] It is understood that various omissions and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the scope of the present invention.

Claims

CLAIMS:

1. A process for the preparation of 2-bromo-5-fluoro trifluorotoluene of formula (I) comprising the step of brominating 3-fluorobenzotrifluoride of formula (II) using a bromine as brominating agent and a suitable acid is selected from the group consisting of formic acid, chloro sulfonic acid, methanesulfonic acid, the trifluoromethanesulfonic acid, hydrochloric acid, oleum and combination thereof, to obtain 2-bromo-5-fluoro trifluorotoluene of formula (I).

2. The process as claimed in claim 1, wherein the molar ratio of 3- fluorobenzotrifluoride of formula (II) to bromine is in the range of 1:0.5 to 1:0.7.

3. The process as claimed in claim 1, wherein the molar ratio of 3- fluorobenzotrifluoride of formula (II) to the acid is in the range of 1: 1 to 1: 10.

4. The process as claimed in claim 1, wherein the molar ratio of 3- fluorobenzotrifluoride of formula (II) to the acid is in the range of 1:2 to 1:5.

5. The process as claimed in claim 1 , wherein said process is carried out at temperature in the range of 10-50 °C.

6. The process as claimed in claim 1, wherein the concentration of acid is in the range of 10-65%.

7. The process as claimed in claim 1, wherein the concentration of acid is in the range of 10-45%.

8. The process as claimed in claim 5 or claim 6, wherein the addition of said acid is in a continuous, controlled or lot-wise manner.

9. The process as claimed in claim 1, wherein the yield of 2-bromo-5-fluoro trifluorotoluene of formula (I) is more than or equal to 90%.

10. The process as claimed in claim 1, wherein the purity of 2-bromo-5-fluoro trifluorotoluene of formula (I) is more than or equal to 99%.

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