The present invention provides a method for a-bromination of ketone to obtain a compound of formula I,

Formula I
wherein R1 and R2 independently represent fluorine, chlorine, or bromine; R3 represents hydrogen, fluorine, chlorine, bromine, aryl, or heteroaryl ring. R4 represents hydrogen, fluorine, chlorine, or bromine.

BACKGROUND OF THE INVENTION
Bromoketones are useful as intermediates in pharmaceuticals and agricultural industry.
In J. Am. Soc. 74, 3902 (1952) discloses a batch process for preparation of bromotrifluoroacetone by bromination of 1,1,1-trifluoroacetone in presence of concentrated sulfuric acid. It leads to the formation of multibrominated compounds and lower yield of desired monobrominated product.
US3444150 discloses bromination of 1,1,1-trifluoroacetone in sulfuric acid using 0.5 equivalent of bromine with respect to 1,1,1-trifluoroacetone to give 64% monobrominated compound.
CN106632009A and Journal of Medicinal Chemistry, 60(13), 5613-5637; 2017 disclose a-bromination carried out in an organic solvent such as dichloromethane, trichloromethane, and tetrachloromethane. However, process requires one equivalent of bromine and longer reaction time.
All the known processes are either limited by lower selectivity for monobrominated product, longer reaction time or use of one equivalent of bromine making the process less economical.
Therefore, there is a need in the art to evolve a selective, high yielding and time saving method for a-bromination of ketones.
The inventors of the present invention have come up with a facile, timesaving, energy efficient and environment friendly process for a-bromination of ketones.

OBJECT OF THE INVENTION
In an object, the present invention provides a method for a-bromination of ketone to obtain a compound of formula I

Formula I
wherein R1 and R2 independently represent fluorine, chlorine or bromine; R3 represents hydrogen, fluorine, chlorine, bromine, aryl or heteroaryl ring. R4 represents hydrogen, fluorine, chlorine or bromine.

SUMMARY OF THE INVENTION
The present invention provides a process for preparation of a compound of formula I,

Formula I
wherein R1 and R2 independently represent fluorine, chlorine or bromine; R3 represents hydrogen, fluorine, chlorine, bromine, aryl or heteroaryl ring. R4 represents hydrogen, fluorine, chlorine or bromine,
comprising a step of brominating a compound of Formula II using bromine,

Formula II
wherein R1, R2, R3 and R4 are as represented above,
wherein the bromination is either carried out in a continuous flow reactor or in a batch reactor in a biphasic solvent.

DETAILED DESCRIPTION OF DRAWING
Figure 1: The continuous flow reactor system consists of five zones, namely, mixing zone, reaction zone, extraction zone, layer separation zone and distillation zone. There are three inlets for reactant, bromine and acid, equipped with pumps A, B and C respectively. The reactants and the acid enter the Mixing zone, which is connected to the Reaction zone, whereas inlet for bromine (or its solution in a solvent) directly enters the Reaction Zone. The Reaction Zone further consists of two Residence Time Zones namely Residence Time Zone-1 and Residence Time Zone-2. Two residence time zones are equipped with temperature regulator to enable optimization and manipulation of temperature. After completion of reaction, the reaction mixture (biphasic in nature) enters the gravity-based layer separation zone where upper organic layer and bottom acid layer get separated. Upper organic layer is introduced to distillation chamber. Bottom acid layer enters extraction zone, where it is extracted with dichloromethane (from pump D). From extraction zone, upper organic layer is transferred to the distillation chamber and bottom acid layer is treated as spent acid. At distillation chamber, product is isolated by fractional distillation.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, aryl and heteroaryl ring includes, benzene, pyridine, pyran, furan, thiophene, pyrrole and imidazole.
As used herein, aryl, heteroaryl ring may be further substituted with a group selected from C1-C6 alkyl, C1-C6 alkoxy, nitro, fluoro, chloro, bromo, -CX3 (where X = F, Cl), and cyano group.
As used herein, “biphasic solvent system” refers to a mixture of two solvents which are mutually immiscible or partially miscible. One of this solvent is an acid or mixture of acids and other one is an organic solvent.
As used herein, “acid” refers to inorganic acid such as sulfuric acid, nitric acid, oleum, or a mixture thereof.
As used herein, “organic solvent” refers to any organic solvent stable under the reaction condition and not prone to bromination under conditions of the present reaction.
As used herein, “substantially free of multi brominated/dibromo impurity” refers to the product having 0.01 to 1.0% of multi brominated/dibromo impurity, preferably 0.01 to 0.1% of multi brominated /dibromo impurity.
The organic solvent is selected from a group consisting of dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, diethyl ether, hexane, cyclohexane, toluene and 1,4-dioxane.
In an embodiment, the present invention provides a process for preparation of 3-bromo-1,1,1-trifluoro acetone, comprising a step of brominating 1,1,1-trifluoroacetone, wherein the bromination is either carried out in a continuous flow reactor or in a batch reactor in a biphasic solvent.
In an embodiment, the bromination is carried out in continuous flow reactor in a single solvent.
In an embodiment, the present invention is carried out in continuous flow reactor in a biphasic solvent.
In an embodiment, the present invention is carried out in batch reactor in a biphasic solvent.
In an embodiment, the present invention is carried out in batch reactor in the presence of acid in a biphasic solvent.
In another embodiment, the present invention is carried out in a biphasic solvent wherein one phase is acid itself and other one is organic phase.
In an embodiment, the bromination is carried out at a temperature of 0°C to 50°C.
In another embodiment, the compound of formula II and biphasic solvent are added slowly using dosing pump in the reactor.
In another specific embodiment, the process is carried out in a continuous flow reactor.
In yet another specific embodiment, the process is carried out in a batch reactor in a biphasic solvent.
In another embodiment of the present invention, the process provides 3-bromo-1,1,1-trifluoroacetone, substantially free of multi brominated impurities.
In another embodiment of the present invention, the process provides 3-bromo-1,1,1-trifluoroacetone, substantially free of dibromo-impurity,

Dibromo-impurity
In another embodiment, the continuous flow reactor system used in this study is shown in Figure-1. The reactor system has four reagent inputs. At first, reactant or solution of reactant in a suitable solvent (from pump C) and acid (from pump A) are pumped into a mixing zone at ambient temperature (20-45°C). At the exit of the mixing zone, the said fluid encounters liquid bromine or solution of liquid bromine in a suitable solvent. The mixed fluid now enters the residence time zone. The reactor system has two residence time zone in a row where reaction temperature can be manipulated independently. Having two residence time zone helps to achieve different programming reaction time and temperature as required. After completion of reaction the said reaction mixture (biphasic in nature) enters into the gravity-based layer separation zone where upper organic layer and bottom acid layer get separated. Upper organic layer is introduced to distillation chamber as such. Bottom acid layer enters extraction zone, where it further extracted with dichloromethane (from pump D). From extraction zone, upper organic layer is transferred to the distillation chamber and bottom acid layer is treated as spent acid. At distillation chamber, the product is isolated by fractional distillation.
The present invention for preparation of compound of formula I has following advantages over the known methods:
1. The use of low temperature range prevents degradation of product and improves yield significantly.
2. The mode of addition of reactant and reagent used in the reaction positively affects the product selectivity. The present inventors observed an improvement in the selectivity with slow and continuous addition of bromine to the reaction mixture.
3. The biphasic solvent system facilitates the consumption of only 0.5 equivalent of bromine in the reaction to get 100% conversion, minimizes the impurity and thereby increases the selectivity towards the desired monobrominated product significantly.
4. The biphasic solvent system of the present invention provides higher output, lesser impurity production thereby making it cost effective industrial process.
5. The process of present invention provides efficient recycling and recovery of solvents.
In an embodiment, solvent for extraction of compound of formula I is selected from a group consisting of dichloromethane, ethyl acetate, pentane, hexane, heptane, xylene, chlorobenzene, ethylbenzene, chloroform and toluene or like.
In another embodiment of the present invention, the yield of isolated compound of formula I is greater than 90%.
The raw material used in the present invention may be prepared by any method known in the literature or can be obtained commercially.
The product is isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, or a mixture thereof.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike.
The reagents used in the present invention may be prepared or obtained commercially.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES
Example-1: Preparation of 3-bromo-1,1,1-trifluoroacetone in continuous mode.
In a flow reactor (figure-1), sulfuric acid (270 ml) and 1,1,1-trifluoroacetone (112g, 1mol) were premixed in a mixing zone at a flow rate of 1.82 ml/min and 1.1 ml/min respectively at 25°C to 30°C to form a reaction mixture. Thereafter bromine with a flow rate of 0.38 ml/min was added to reaction mixture at 0°C-5°C. The resulting mixture was passed through the residence time zone with residence time of 1 hour at 0°C-5°C. The exit material of residence time zone was taken for layer separation followed by extraction of sulfuric acid layer with dichloromethane at flow rate of 1 ml/min. Thereafter the reactor was run for 12 hours to isolate 1534 g of 3-bromo-1,1,1-trifluoroacetone after distillation of organic layer (isolated yield 90%).
Example-2: Preparation of 3-bromo-1,1,1-trifluoro acetone in continuous mode in biphasic solvent system.
1,1,1-Trifluoroacetone mixed with an equal volume of dichloromethane was pumped (from pump C) into a mixing zone at a flow rate of 2.25 ml/min. Concentrated sulfuric acid was also pumped (from pump A) into the mixing zone at a flow rate of 2 ml/minutes. At the mixing zone, mixing of above said fluid was carried out at 25°C to 30°C. At the exit of the mixing zone the fluid contacted bromine solution in dichloromethane (from pump B, at a flow rate of 1.42 ml/min). Bromine solution was prepared by mixing one volume of liquid bromine with 3.5 volume of dichloromethane. The combined fluid entered the residence time zone-1 where reaction takes place at 25oC with residence time of 30 minutes. The reaction mass was then entered into the residence time zone-2 where reaction was carried out at 45oC with residence time of 30 minutes. Exit of the residence time zone-2 entered into the gravity-based layer separation zone where layer separation occurred at ambient temperature. From layer separation zone, upper organic layer containing product was transferred to distillation chamber. Bottom acid layer from layer separation zone was further extracted with dichloromethane (from pump D) at a flow rate of 1 ml/min at extraction zone. The upper organic layer from extraction zone was also introduced to distillation chamber. At distillation chamber the combined organic was subjected to the fractional distillation to get unreacted 1,1,1-trifluoroacetone and recovered dichloromethane and 3-bromo-1,1,1-trifluoroacetone. Conversion of 1,1,1-trifluoroacetone was 88% and isolated yield of 3-bromo-1,1,1-trifluoroacetone was 97%.
Example-3: Preparation of 3-bromo-1,1,1-trifluoroacetone in batch mode in biphasic solvent system
To a 2 L vessel containing (780 g) of concentrated sulfuric acid and (600 g) of dichloromethane at 25°C to 30 °C were slowly added to 1,1,1-trifluoroacetone (302 g, 2.69 mole) with continuous stirring. The reaction mixture was cooled to a temperature of 15 to 20oC and then bromine (215 g, 1.34 mole) was added slowly, over 4 hours. The reaction mixture was then slowly heated to a temperature of 45oC and stirred for another 2 hours to obtain 3-bromo-1,1,1-trifluoroacetone (yield of 95%), which was isolated after fractional distillation under atmospheric pressure.

COMPARATIVE EXAMPLE
Preparation of 3-bromo-1,1,1-trifluoroacetone in batch mode without employing biphasic solvent system
To a 2 L vessel containing (610 g) of conc. sulfuric acid at ambient temperature was slowly added to 1,1,1-trifluoroacetone (250 g, 2.23 mole) with continuous stirring. The reaction mixture was cooled to a temperature of 5 to 10oC and then bromine (179 g, 1.11 mole) was added slowly over 4 hours. The reaction mixture was then slowly heated to a temperature of 45oC and stirred for another two hours.
After completion of reaction, more than 8% 3,3-dibromo-1,1,1-trifluoro-2-propanone and 65% of 3-bromo-1,1,1-trifluoroacetone were obtained.

WE CLAIM:

1. A process for preparation of a compound of formula I

Formula I
wherein R1 and R2 independently represent fluorine, chlorine or bromine; R3 represents hydrogen, fluorine, chlorine, bromine, aryl or heteroaryl ring; R4 represents hydrogen, fluorine, chlorine or bromine,
comprising a step of brominating a compound of Formula II using bromine,

Formula II
wherein R1, R2 R3 and R4 as defined above,
wherein the bromination is either carried out in a continuous flow reactor or in a batch reactor in a biphasic solvent.
2. The process as claimed in claim 1, wherein the reaction is carried out in the continuous flow reactor in a single solvent.
3. The process as claimed in claim 1, wherein the biphasic solvent system refers to a mixture of two solvents which are mutually immiscible or partially miscible with each other.
4. The process as claimed in claim 3, wherein the one solvent is an acid, or a mixture of acids and the other solvent is an organic solvent.
5. The process as claimed in claim 4, wherein the acid is selected from a group consisting of sulfuric acid, nitric acid, oleum, or a mixture thereof and the organic solvent is selected from a group consisting of dichloromethane, chloroform, 1,1-dichloroethane, 1,2-dichloroethane, diethyl ether, hexane, cyclohexane, toluene and 1,4-dioxane.
6. The process as claimed in claim 1, wherein the bromination is carried out at a temperature of 0°C to 50°C.
7. The process as claimed in claim 1, wherein the compound of formula I is substantially free of dibromo impurity,

Dibromo-impurity
8. The process as claimed in claim 1, wherein the continuous flow reactor consists of five zones, namely, mixing zone, reaction zone, extraction zone, layer separation zone and distillation zone, as shown in Figure 1.