DESC:FIELD OF THE INVENTION
The present invention relates generally to the preparation of bromo methyl biphenyl derivatives. More specifically, the present invention relates to an improved process for the preparation of a 4’-bromomethyl-2-cyanobiphenyl (Br-OTBN) by photochemical bromination of the 4'-methyl-2-cyanobiphenyl (OTBN).
BACKGROUND OF THE INVENTION
Br-OTBN is known by the chemical name 4’-bromomethyl-2-cyanobiphenyl of Formula (I), bromo methyl biphenyl derivatives have long proven to be valuable intermediates for the production of active ingredients, such as pharmaceuticals.

Formula-I
EP 0324377 and US 5, 312,958 A discloses the preparation of 4'-bromomethyl biphenyl derivatives that are particularly useful in the synthesis of many active principles of medicinal products acting in particular against hypertension by a mechanism of inhibition of angiotensin II. Various methods have been reported for the synthesis of 4'-bromomethyl-2-cyanobiphenyl, these methods being based on a chemically-initiated radical reaction.
Patent applications US 5,138,069, JP 2859791 , JPH 06298683, EP 0553879, EP 0595150 and EP 0709369 describes the bromination of O-tolyl benzonitrile (OTBN) by means of brominating agents such as N-bromosuccinimide (NBS), dibromodimethylhydantoin (DBDMH), N-bromophthalimide or bromine, in the presence of a chemical initiator, generally benzoyl peroxide, t-butyl peroxide, t-butyl per benzoate or 2,2'-azobis(isobutyronitrile) (AIBN) in the presence of solvents such as C5-C7 alkane, a halogenated C1-C4 aliphatic hydrocarbon such as dichloromethane or carbon tetrachloride, a C1-C4 alkyl ester of acetic acid such as ethyl acetate, or a halogenated aromatic hydrocarbon such as chlorobenzene.
A radical-mediated reaction for the preparation of 4’-bromomethyl-2-cyanobiphenyl (Br-OTBN) which involves a photochemical initiation has been described in patent applications JPH 06298683 and EP 0709369.
EP 0709369 discloses a process for brominating OTBN, wherein, 4'-methyl-2-cyanobiphenyl is reacted with bromine at a temperature of from 0 to 100° C., preferably 20 to 80° C. and in the presence of a chemical initiator, i.e. an azobis derivative or benzoyl peroxide and in a halogenated hydrocarbon or a C5-C7 alkane as solvent.
These methods comprises both drawbacks and disadvantages, which are occasionally sufficient to exclude them from any industrial-scale use. Use of peroxides possibly leads to explosions at larger scales and azobis derivatives are non-benign to cost and may leads to unexpected by product formation.
WO2008078340A1 discloses the prior art bromination of 4'-methyl-2-cyanobiphenyl always yields a mixture of 4’-bromomethyl-2-cyanobiphenyl of formula (I) and 4`-di-bromomethyl-2-cyanobiphenyl (di bromo impurity). The presence of dibromo impurity possess drawbacks like 1. Unwanted parallel reactions at subsequent stages; 2. Lowering the yield of final product; 3. Lowering the purity of final product; 4. Consumption of expensive reagents in large quantity; 5. Difficulty in purifying the final product; 6. Difficulty in handling the process at large scale; 7. Overall process expensive, thus uneconomical, and hence WO ‘340 publication provides a separation process for 4’-bromomethyl-2-cyanobiphenyl of formula (I) and 4`-di-bromomethyl-2-cyanobiphenyl (di bromo impurity).
Considering the importance of Formula (I) as a valuable intermediate in the preparation of there remains a need to prepare compound of Formula (I) with high quality and yield in manufacturing point of view.
SUMMARY OF THE INVENTION
In one aspect, the present invention encompasses a process for the preparation of 4’-bromomethyl-2-cyanobiphenyl of formula (I):

comprising brominating 4'-methyl-2-cyanobiphenyl (OTBN) using a bromine source by photochemical means using a UV light source in a photochemical reactor, wherein the improvement comprises interposing between said light source and the compound to be brominated, with an aqueous solution of copper sulfate as wavelength filter.
In another aspect, the present invention encompasses a process wherein reaction is carried out using 10% copper sulphate solution as a wavelength filtration media which filters lower wavelength and only allows to pass selective wavelength for UV light in the range of 350 to 400 nm that enhance selective bromination of 4'-methyl-2-cyanobiphenyl (OTBN) by reducing formation of 2'-cyano-4-(di bromo methyl) biphenyl (di bromo impurity).
BRIEF DESCRIPTION OF DRAWING
FIG. 1: Schematic view of continuous photo-bromination device.
Fig.1 comprises reaction vessel (round bottom flask) which contains 4'-methyl-2-cyanobiphenyl (OTBN), dichloromethane (water immiscible) and water mixture under stirring. Side neck contains a pressure equalizing funnel which contains liquid bromine and dichloromethane mixture. On the other hand the photo reactor contain a medium pressure mercury vapor lamp [UV light] and a quartz based cylindrical container having corrugated tubing with static mixture elements - that provides effective phase mixing due to internal turbulence in reaction mass to facile photochemical bromination. There is a space between corrugated tubes and mercury vapor lamp, where certain concentration of aqueous copper sulphate solution is circulated - that increase reaction selectivity by filtration of unwanted light wavelengths to pass through.
Fig.2: Continuous photochemical bromination reactor
A suitable device which allows, for example, the introduction, at controlled flow rate and into a two-phase medium, of a solution or suspension of substrate 4'-methyl-2-cyanobiphenyl (OTBN) and of brominating agent optionally in the organic solvent chosen, may advantageously be used, the flow rate being adjusted by means of an assembly composed of a metering pump and a flow regulator coupled to a balance. This device is also completed by a reactor comprising an inlet, for the introduction of the various constituents of the reaction medium, and an outlet for collecting the products derived from the reaction. This reactor, which is intended to receive the two-phase medium, consists of a tube made, for example, of PFA or FEP preferably in the spiral coil form.
Fig.3: Corrugated PFA tube with internal static mixture.
The reactor offers the possibility of arranging the lamp coaxially, for example a reactor is in the form of a circular tube structure.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention, the bromination of 4'-methyl-2-cyanobiphenyl (OTBN) is carried in a photochemical reactor. The said reactor can be designed in the form of a simple bent U tube or a helical tube such that the lighting system can be positioned in the immediate vicinity of this reactor. The reactor designed such a way which offers the possibility of arranging the lamp coaxially, for example a reactor in the form of a coil or of a circular tube structure. The lamps are preferably placed in the center of the reactor. The lamp and circular tube structure is separated by a means to pass through a copper sulphate solution. The system thus allows passing of UV light to reaction medium through a copper sulphate filter. The design may also accomplished by inserting the lamps into double-walled immersion wells through which a copper sulphate can be circulated.
In another embodiment of the present invention, a suitable UV light source such as medium-pressure mercury vapor lamp is used as a photochemical light source.
In still another embodiment of the present invention, the photochemical reaction can be carried out a photochemical reactor the reactor which offers the possibility of arranging the lamp coaxially, for example a reactor in the form of a circular tube Structure. The circular tube structure can be made with any material that allows UV light source such a but not limited and made with corrugated tubes made from Fluorinated Ethylene Propylene (FEP) grade material. FEB grade material allow to pass UV light. For organic photosynthesis FEP is an ideal material due to its good transmission properties, excellent physical properties and superb chemical resistance to organic solvents. Moreover, FEP is commercially available in a wide range of diameters; thus, its use in photo-reactors is cost-efficient. To make the system capable of producing efficient turbulence to biphasic (Immiscible phase) reaction medium corrugated tubing with static mixture is being preferred. The photo-bromination device for carrying out the process of the invention having corrugated Fluorinated ethylene propylene (FEP) tubing with static mixture element and means to have light source as described in Fig 2. The corrugated FEP tubes are further facilitated by inserting a set of static mixtures to create an additional turbulence in fluid flowing in reaction tubes ( i.e. corrugation slots and space between static elements) which ultimately avoid phase separation between organic and aqueous layer.

In yet another embodiment of the present invention, the reaction in photochemical reactor can be carried out in batch mode or by continuous mode of operation. Preferably the reaction can be carried out by continuous mode.
In one more embodiment of the present invention, passing of UV light source through aqueous copper sulphate solution provides several advantages such as 1) selectivity towards 4'-bromomethyl-2-cyanobiphenyl (mono bromo-OTBN) is increased 2) it filters unwanted UV wavelengths which can more energize the said bromination due to which more formation of dibromo impurity; and 3) minimize an unwanted 4’-di-bromomethyl-2-cyanobiphenyl (di bromo impurity). Thus interposing between said light source and the compound to be brominated, with an aqueous solution of copper sulfate. An aqueous solution of copper sulfate is capable to filter unwanted wave lengths of light. The reaction according to the invention is usually carried out using an aqueous copper sulphate solution having concentrations between 0 to 15%, preferably between 9 to 12%, more preferably 10 %.
The reaction according to the invention is usually carried out under a medium pressure mercury vapor lamp capable of emitting radiation with a wave length in the range of 350- 400 nm, more preferably 365 to 385 nm. The mercury vapor lamp as used herein is energized by using a step-up transformer device, which regulates electrical current and phase voltages to enforce UV emission.
In yet another embodiment, brominating source is selected from liquid bromine or an organic compound containing bromine, chosen from N-bromoacetamide, N-bromophthalimide, N-bromomaleimide, N-bromosulphonamide, N-bromosuccinimide (NBS) and 1, 3-dibromo-5, 5-dimethylhydantoin (DBDMH), more preferably, liquid bromine. Since liquid bromine maintains homogeneity during bromination, while NBS and DBDMH as being solid in nature doesn’t maintain uniform flow through flow reactor. Further, increase in an amount of bromine source more than 1.1 molar equivalents leads to formation of 4’-di-bromomethyl-2-cyanobiphenyl [di bromo impurity] in higher extent. Alternatively, the brominating source can also consist of a hydrobromic acid/alkali metal bromate such as sodium bromate or sodium hypobromide.
In yet another embodiment of the present invention, the bromination reaction is carried out in a solvent system that does not affect the course of the reaction such as but not limited to water, water-immiscible organic solvents selected from halogenated C-C, aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or tetrachloroethane, or halogenated C-C aromatic hydro carbons such as chlorobenzene or dichlorobenzene, More preferably, the reaction is carried out a biphasic (two-phase) medium comprises water and dichloromethane. The two-phase medium has a ratio of from 0.33 to 0.5 volume of water per volume of dichloromethane. Further, two-phase medium is used in a proportion of from 8-10 volume by weight of OTBN.
In yet another embodiment of invention, reaction is usually carried out at a temperature of between 0°C to 45°C, more preferably between 30 to 40°C.The process of the invention takes place over a period of about 0.5 to 1.5 hours according to the reaction temperature applied and the duration of the reagent introduction phase, in most cases over a period of about 0.75 to 1 hour. Thus, at temperature of about 30 to 35°C, the reaction is completed in 1 hour, on the other hand, at temperature ranging from about 0 to 15°C, the reaction remains incomplete in about 2 to 3 hours if the reagent-introduction time is also about 0.75 to 1 hour.
4'-bromomethyl-2-cyanobiphenyl (Br-OTBN) as obtained according to the process of the invention can be subsequently separated from the reaction medium according to conventional methods, for example by separating out the organic phase followed by 5% aq. sodium sulfite or sodium bisulfite wash after settling of the phases and removal of the solvent by vacuum evaporation.
4'-bromomethyl-2-cyanobiphenyl (Br-OTBN) as obtained is having purity greater than 92% and the content of 4’-di-bromomethyl-2-cyanobiphenyl(di bromo impurity) is less than 5% by HPLC analysis.
In yet another embodiment 4'-bromomethyl-2-cyanobiphenyl (Br-OTBN) as obtained by the above process is further recrystallized using isopropanol, which is having purity greater than 99.0 % and content4’-di-bromomethyl-2-cyanobiphenyl(di bromo impurity) is less than 0.5 % by HPLC analysis.
In the foregoing section, embodiments are described by way of an example to illustrate the process of the invention. However, this is not intended in any way to limit the scope of the present invention. Several variants of the example would be evident to persons ordinarily skilled in the art which are within the scope of the present invention.

Examples:
General procedure
Experimental device preparation: Prepare the photochemical bromination device, peristaltic pump and line up all connections to ensure no any leakages. The corrugated pipe containing static mixture is a transparent Fluorinated ethylene propylene (FEP) material quality, the light source uses a 450 W medium mercury vapor pressure lamp. Certain concentration containing aq. copper sulphate is used as a filter media of unwanted UV lights. The volume of the UV illuminated portion is about 200 ml.
In a round bottom four neck flask prepare 4'-methyl-2-cyanobiphenyl (OTBN), dichloromethane and water mixture. Circulate aq. copper sulphate solution as a wavelength filtration media for unwanted UV lights. Start UV lamp followed by circulation of 4'-methyl-2-cyanobiphenyl (OTBN) biphasic mixture through corrugated tubes having static mixture. Meanwhile charge bromine and dichloromethane mixture in a pressure equalizing funnel. After achieving certain temperature of reaction mass start drop wise bromine addition in to reaction mass over a period of 30 to 45 mins. Maintain for 10-15 mins. at same temperature. TLC is performed to monitor formation of 4'-bromomethyl-2- cyanobiphenyl (Br-OTBN), 4'-methyl-2-cyanobiphenyl (OTBN) and 4’-di-bromomethyl-2-cyanobiphenyl (di bromo impurity). Stop UV lamp and peristaltic pump circulation. Collect reaction mass and separate organic layer. Wash organic layer by aq. sodium sulfite and water. Recover dichloromethane under vacuum to obtain crude 4’-bromomethyl-2- cyanobiphenyl (Br-OTBN). Purify crude material using respective solvent and isolate pure 4'-bromomethyl-2-cyanobiphenyl.
Example-I:
Preparation of 4'-bromomethyl-2-cyanobiphenyl (Br-OTBN) by using Thermal Method
4'-methyl-2-cyanobiphenyl (OTBN) (50g, 0.256 mol), dichloromethane( 300 ml ) and water (100 ml) were added into a round bottom flask equipped with a thermo pocket, condenser and a dip pipe on overhead stirrer with stirring rate of 300 RPM. Solution of liquid bromine (41.33 gms, 0.258 mol) and MDC (200 ml) was added dropwise to the reaction mixture at 20 deg C in 35 mins. The reaction mixture was heated at 40 C for 3 hrs. The reaction mixture was allowed to cool at 20-25 C. The cooled reaction mixture was then allowed to settle for organic phase and aqueous phase separation. Organic phase was washed twice with sodium sulfite to remove excess of bromine and the solvent was removed by vacuum distillation to obtain 4'-bromomethyl-2-cyanobiphenyl.
Example-II:
Preparation of 4'-bromomethyl-2-cyanobiphenyl (Br-OTBN) without using aq. copper sulphate solution
4'-methyl-2-cyanobiphenyl (OTBN) (100g, 0.517 mol), dichloromethane(460 ml) and water (200 ml) were added into a round bottom flask equipped with thermo pocket, condenser and a dip pipe on overhead stirrer with stirring rate 300 RPM. A medium pressure mercury vapor lamp (Power: 450 W) is located in a vertical plane without aq. copper sulphate solution was switched on and circulation of biphasic 4'-methyl-2-cyanobiphenyl (OTBN) mixture through corrugated FEP pipes containing static mixture with flow rate of 20 ml/min using peristaltic pump to achieve reaction mass temperature above 30°C was started. A solution of bromine (91g, 0.569 mol) in dichloromethane (140 ml) was added over 30-45 mins. at temperature of 30-35°C and then for a further 10-15 mins. UV lamp was stopped, the reaction mixture was cooled to 20 and 25°C and the phases were allowed to separate by settling for 5 min. The upper aqueous phase was removed, organic phase was washed twice with sodium sulfite followed by water and DCM was completely distilled to obtain crude 4'-bromomethyl-2-cyanobiphenyl. To a crude 4'-bromomethyl-2-cyanobiphenyl, isopropyl alcohol was added and refluxed to obtain clear solution. The reaction mixture was cooled 0 to 5°C, filtered, washed with isopropyl alcohol and dried at 55 to 60°c for 3 to 4 hrs. under vacuum to obtain pure 4'-bromomethyl-2-cyanobiphenyl 95 g (68-70%). HPLC purity analysis is as given below in table:
Bromine (eq.) Bromine addition time (mins.) Feeding rate
(ml/min.) Reaction
Temperature (°C) Maintaining
(mins.) Unreacted OTBN OTBN Dibromo
Impurity
1.1 35 20 30-35 15 1.24% 81.76% 16.63%

Example-III: Preparation of 4'-bromomethyl-2-cyanobiphenyl by photochemical bromination
4'-methyl-2-cyanobiphenyl (OTBN) (100g, 0.517 mol), dichloromethane(460 ml) and 200 ml of water were added into a round bottom flask equipped with thermo pocket, condenser and a dip pipe on overhead stirrer with stirring rate of 300 RPM. A medium pressure mercury vapor lamp (Power: 450 W) located in a vertical plane surrounded by circulation of aq. copper sulphate solution jacket as a filtration media was switched on and circulation of biphasic 4'-methyl-2-cyanobiphenyl (OTBN) mixture through corrugated FEP pipes containing static mixture with flow rate of 20 ml/min using peristaltic pump to achieve reaction mass temperature above 30°C was started. A solution of bromine (91g, 0.569 mol) in dichloromethane (140 ml) was added over 30-45 mins. at temperature of 30-35°C and then for a further 10-15 mins. UV lamp was stopped, the reaction mixture was cooled to 20 and 25°C and the phases were allowed to separate by settling for 5 min. The upper aqueous phase was removed, organic phase was washed twice with sodium sulfite followed by water and DCM was completely distilled to obtain crude 4'-bromomethyl-2-cyanobiphenyl.(Final % of Dichloromethane < 2% on GC) [Crude yield: 141-146 gm/100-104 %]. HPLC purity analysis is as given below in table:

Crude
Br-OTBN Bromine (eq.) Bromine addition time (mins.) Feeding rate
(ml/min.) Maintaining
(mins.) Reaction
Temperature (°C) Unreacted OTBN Bromo
-OTBN Dibromo
Impurity
1.1 35 20 15 30-35 2% >92% <5%

To a crude 4'-bromomethyl-2-cyanobiphenyl, isopropyl alcohol was added and refluxed to obtain clear solution. The reaction mixture was cooled 0 to 5°C, filtered, washed with isopropyl alcohol and dried at 55 to 60°c for 3 to 4 hrs. Under vacuum to obtain pure 4'-bromomethyl-2-cyanobiphenyl 110-115 g (Molar yield: 78.12-81.67%).

Pure
Br-OTBN Isopropyl
alcohol
(Vol.) Temperature
(°C) Filtration
Temperature
(°C) Unreacted OTBN Bromo
-OTBN Dibromo
Impurity
11 80-85 0-5 0.01% 99.95% 0.02%

Following tables provides the results of the bromination of OTBN carried out with different mole equivalent of bromine in two phase medium (dichloromethane and water) according to the process of example- I and example III to form 4'-bromomethyl-2- cyanobiphenyl of formula-I
a) Bromination under Thermal method according to Example –I :
Bromine (eq.) Bromine addition time (mins.) Maintaining
(mins.) Unreacted OTBN (%) Br-OTBN (%) Dibromo
Impurity (%)
0.9 35 180 20% 75% 5%
1.0 35 180 9% 80% 10%
1.1 35 180 5% 85% 9%
1.2 35 180 2% 78% 19%

b) Bromination under photochemical method according to Example III:
Bromine (eq.) Bromine addition time (mins.) Maintaining
(mins.) Unreacted OTBN (%) Br-OTBN (%) Dibromo
Impurity (%)
0.9 35 15 15% 80% 5%
1.0 35 15 7% 84% 8%
1.1 35 15 2% 92% 5%
1.2 35 15 1% 82% 17%

The results above were obtained, expressed as % of 4'-methyl-2-cyanobiphenyl (OTBN), of Br-OTBN (4'-bromomethyl-2- cyano biphenyl) and of 4’-di-bromomethyl-2-cyanobiphenyl (di bromo impurity). ,CLAIMS:We claim:
1. A process for the preparation of 4'-bromomethyl-2-cyanobiphenyl (Br-OTBN) of formula (I):

Formula (I)
comprising brominating 4'-methyl-2-cyanobiphenyl (OTBN) using a bromine source by photochemical means using a UV light source in a photochemical reactor, wherein the improvement comprises interposing between said light source and the compound to be brominated, with an aqueous solution of copper sulfate as wavelength filter.
2. The process as claimed in claim 1, wherein the photochemical reactor is having corrugated Fluorinated ethylene propylene (FEP) tubing with static mixture elements and means to have light source as described in Fig 2.

3. The process as claimed in claim 1, wherein the bromination of 4’-methyl-2-cyanobiphenyl (OTBN) using a bromine source in photochemical reactor is carried out in continuous mode of operation.

4. The process as claimed in claim 1, wherein the bromine source is liquid bromine.

5. The process as claimed in claim 1, wherein the bromination is carried out in presence of water and water immiscible solvent at a temperature in the range of 30- 35°C.

6. The process as claimed in claim 1, wherein the water immiscible solvent is selected from dichloromethane, dichloroethane, chloroform and carbon tetrachloride.

7. The process as claimed 6, wherein the bromination reaction is carried out in a solvent mixture comprising water and dichloromethane.

8. The process as claimed in claim 1, wherein the bromine source as used is 1.1 molar equivalents per molar equivalent of OTBN.

9. The process as claimed in claim 1, wherein 4'-bromomethyl-2-cyanobiphenyl (Br-OTBN) obtained according to claim 1 having purity greater than 92% and the content of 4’-di-bromomethyl-2-cyanobiphenyl in Formula (I) is less than 5% by HPLC.

10. A process as claimed in claim 1, wherein 4'-bromomethyl-2-cyanobiphenyl is purified using isopropyl alcohol.

Dated this 13thday of Sep. 2024