FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVENTION "AN IMPROVED PROCESS FOR PREPARATION OF DIFLUNISAL"
Emcure Pharmaceuticals Limited,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of Diflunisal having desired purity. The invention relates to the preparation of 2-bromo-4-(2,4-difluorophenyl)phenol of formula (III) in presence of bromine/acid and the carboxylation of 2-bromo-4-(2,4-difluorophenyl) ethoxybenzene of formula (IV) with carbon dioxide in presence of magnesium to give 2-carboxyl-4-(2,4-difluorophenyl)ethoxybenzene (V)..
BACKGROUND OF THE INVENTION
Diflunisal (I), chemically known as 2,4-difluoro-4-hydroxybiphenyl-3-carboxylic acid or 2-hydroxy-5-(2,4-difluorophenyl)-benzoic acid is a non-steroidal anti-inflammatory drug (NSAID), developed by Merck in 1971 and available with brand names such as Adomal, Difludol, Dolisal, Dolobid, Dolobis, Flustar etc. The drug known to act by inhibition of prostaglandins, the hormones involved in pain and inflammation is indicated for acute or long term symptomatic treatment of mild to moderate pain, osteoarthritis and rheumatoid arthritis.

US' 3,714,226 discloses synthesis of Diflunisal comprising reaction of 2,4-difluoroaniline with anisole in presence of isoamyl nitrite, followed by column chromatographic purification of the resulting 4-(2,4-difluorophenyl) anisole Subsequent demethylation in presence of hydriodic acid and carboxylation of the corresponding phenol with carbon dioxide at high pressure yields Diflunisal (I).
The need for time-consuming operation of chromatographic purification of intermediates followed by an extremely hazardous, high pressure, high temperature reaction with carbon

dioxide at 175°C and under a high pressure of 1300 psi makes the method quite susceptible for impurity formation and reduced purity. All these shortcomings render the method unsuitable for commercial scale.
US 4,225,730 discloses another variant of the known synthetic method for Diflunisal, which comprises reaction of 2,4-difluoro aniline with benzene in presence of isoamyl nitrite to give 2,4-difluorobiphenyl, which is then subjected to Friedel-Craft's acylation with acetic anhydride in presence of aluminium chloride to provide, 4-(2,4-difluorophenyl) acetophenone. Further reaction with hydrogen peroxide in presence of maleic anhydride and glacial acetic acid gives 4-(2,4-difluorophenyl)phenyl acetate, which is hydrolyzed to 4-(2,4-difluorophenyl)phenol. The phenol derivative is subjected to carboxylation reaction using carbon dioxide at around 240°C and at a pressure of 890 psi. The utilization of the hazardous hydrogen peroxide and high pressure and temperature during reaction with carbon dioxide makes this process unviable on a commercial scale. Another approach disclosed in US 4,216,340 employs 2,4-difluorobenzene diazonium fluoroborate which is reacted with 3-chloromethyl salicylate followed by hydrogenation of the resulting 3-chloromethyl-5-(2,4-difluorophenyl) salicylate with hydrogen in presence of palladium catalyst to give methyl-5-(2,4-difluorophenyl) salicylate. Further hydrolysis with sodium hydroxide yields Diflunisal.
The method claims selectivity in getting the desired isomer by use of a hindering group such as chlorine, however, use of such a blocking group entails an additional step for its removal which incurs additional cost for the process. Further, the chlorosalicylate derivative which is used as the starting material is synthesized from a chloro phenol derivative by employing high pressure carboxylation procedure with carbon dioxide.
All the methods disclosed in the aforementioned references resort to the high pressure, high temperature reaction with carbon dioxide for introduction of carboxyl functionality in the synthetic route for Diflunisal. ES 494242 discloses an alternate method for circumventing the high pressure carboxylation reaction by employing Fries rearrangement of 4-(2,4-difluorophenyl)-phenyl acetate using aluminium chloride as a catalyst to give the rearranged compound, 2-hydroxy-5-(2,4-difluorophenyl)acetophenone which on oxidation with iodine in pyridine yields Diflunisal.

Although this route avoids high pressure carboxylation but incorporation of a low yielding rearrangement reaction, clubbed with use of a hazardous and toxic reagent such as iodine for oxidation makes this route industrially unviable.
Thus, there is an urgent need for a convenient and industrially feasible process for the synthesis of Diflunisal, which does not involve use of hazardous, high pressure and high temperature carboxylation reaction and is yet capable of providing Diflunisal in higher yields with purity conforming to regulatory specifications.
The present inventors, while designing a synthetic strategy for Diflunisal were able to overcome the problems faced in the prior art to develop a novel process.
The novel process involves bromination of 4-(2,4-difluorophenyl)phenol of formula (II) in presence of an acid to give 2-bromo-4-(2,4-difluorophenyl)phenol (III), which on reaction with ethyl bromide gave 2-bromo-4-(2,4-difluorophenyl)ethoxybenzene (IV), subsequent treatment with magnesium and carbon dioxide gave 2-ethoxy-5-(2,4-difluorophenyl)benzoic acid of formula (V) which on further treatment with hydrobromic and acetic acid gave Diflunisal (I) having desired purity.
OBJECT OF THE INVENTION
An objective of the present invention is to provide a safe, industrially applicable process for synthesis of Diflunisal, which avoids use of hazardous, high pressure reaction for introduction of carboxyl group in the desired molecule.
Another object of the invention is to provide a convenient method for synthesis of Diflunisal which involves a facile carboxylation of 2-bromo-4-(2,4-difluorophenyl)ethoxybenzene (IV) by utilizing magnesium and carbon dioxide, followed by dealkylation of the ethoxy group to yield Diflunisal having purity conforming to regulatory specifications.

A further object of the invention involves bromination of 4-(2,4-difluorophenyl)phenol of formula (II) in presence of an acid to give the desired 2-bromo-4-(2,4-difluorophenyl)phenol (III).
SUMMARY OF THE INVENTION
An aspect of the invention relates to an improved process for the preparation of 2-hydroxy-5-(2,4-difluorophenyl)-benzoic acid (I) comprising reaction of 4-(2,4-difluorophenyl)phenol of formula (II) with bromine in presence of an acid to give 2-bromo-4-(2,4-difluorophenyl)phenol of formula (III), which on reaction with ethyl bromide in presence of a phase transfer reagent gave 2-bromo-4-(2,4-difluorophenyl)ethoxybenzene (IV), which on further treatment with carbon dioxide in presence of magnesium gave 2-ethoxy-5-(2,4-difluorophenyl)benzoic acid (V), which on dealkylation gave Diflunisal (I) having purity conforming to regulatory specifications.
The objectives of the present invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
During the investigation on the development of an industrially scalable, convenient process for Diflunisal, the present inventors took up rigorous experimentation focused on finding out an alternative for the high pressure, high temperature carboxylation reaction. It was surprisingly observed that the aforementioned hazardous reaction could be circumvented by using 2-bromo-4-(2,4-difluorophenyl)ethoxybenzene of formula (IV). A highly facile carboxylation reaction could be carried out by treating compound (IV) with magnesium and carbon dioxide and further dealkylation of the resulting carboxylated derivative (V) yielded Diflunisal having desired purity.
With the use of this strategy, the need of hazardous high temperature, high pressure carboxylation was eliminated. Not only, that the reaction with carbon dioxide could be carried out at modest temperature and pressure, but the formation of side products was also reduced substantially. This resulted in an industrially scalable, convenient process for the preparation of Diflunisal.


Scheme 1: Method embodied in the present invention for the preparation of Diflunisal (I)
In an embodiment, 4-(2,4-difluorophenyl)phenol of formula (II) was treated with bromine solution in a solvent like a chlorinated solvent such as dichloromethane, an alcoholic solvent such as methanol, a dipolar aprotic solvent like dimethyl sulfoxide and mixtures thereof. The reaction was carried out in presence of an acid such as a carboxylic acid like acetic acid, a sulfonic acid like para-toluenesultonic acid or a Lewis acid like aluminium chloride to give 2-bromo-4-(2,4-difluorophenyl)phenol of formula (III). The reaction was carried out in the temperature range of 5-35°C and was monitored by TLC. After completion of the reaction, 2-bromo-4-(2,4-difluorophenyl) phenol, having desired purity was obtained by concentrating the reaction mixture under reduced pressure, followed by treatment of the residue with aqueous methanol.
The bromo derivative, 2-bromo-4-(2,4-difluorophenyl) phenol of formula (III) was further treated with an alkyl halide in a solvent such as aqueous dimethylforrnamide or aqueous

acetonitrile or aqueous dimethyl sulfoxide or aqueous acetone to yield the ethoxy derivative. The alkyl halide was selected from ethyl chloride, ethyl bromide etc.
The reaction was carried out at 25-35°C, optionally in presence of a phase transfer catalyst
such as tetrabutyl ammonium bromide and potassium carbonate. After reaction completion,
as monitored by TLC, the mixture was quenched with toluene and water, followed by
concentration of the organic layer to give 2-bromo-4-(2,4-difluorophenyl)ethoxybenzene of
formula (IV) which was then isolated in good yield by adding water to the residue and
concentrating the mixture.
The compound (IV) thus isolated was treated with magnesium metal and 1,2-
dibromoethane in an organic solvent.
The organic solvent is preferably ether and is selected from the group comprising of
tetrahydrofuran, tert-butyl methyl ether, diphenyl ether etc.
The mixture was heated at a temperature of 60-65°C and after completion of the reaction as monitored by TLC, the reaction mass was cooled to around 45-55°C and treated with carbon dioxide gas applying pressure of 1 -2 Kg/cm2 .
When the reaction was complete, as monitored by TLC, the reaction mass was acidified using hydrochloric acid and extracted with water immiscible solvents like ethyl acetate. Separation and concentration of the organic layer yielded 2-ethoxy-5-(2,4-difluorophenyl)benzoic acid of formula (V).
The compound of formula (V) was then treated with hydrobromic acid and acetic acid at 90-120°C till completion of the reaction after which the reaction mixture was cooled and extracted with ethyl acetate
Concentration of the organic layer, followed by optional treatment with toluene yielded Diflunisal (I) having desired purity.
4-(2,4-difluorophenyl)phenol employed for preparing Diflunisal was obtained by prior art method.

The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.
EXAMPLES
Example 1: Synthesis of 2-bromo-4-(2,4-difluorophenyl)phenol (HI)
A solution of bromine (73.6 g in 200 ml dichloromethane) was slowly added to a stirred mixture of 4-(2,4-difluorophenyl)phenol (100.3g) and acetic acid (1000 ml) at 15-20°C. After completion of the reaction, as monitored by TLC, acetic acid was distilled from reaction mass. The obtained residue was mixed with aqueous methanol (1000ml) to give 2-bromo-4-(2,4-difluorophenyl) phenol. Yield: 120.7 g M.P: 82 - 83.4°C
Example 2: Synthesis of 2-bromo-4-(2,4-difluorophenyl)phenol (III)
A solution of bromine (73.6 g in 200 ml dichloromethane) was slowly added to the stirred mixture of 4-(2,4-difluorophenyl)phenol (100.3g) and p-toluenesulfonic acid (l.leq) at 0-5°C in methanol (400ml). After completion of the reaction, as monitored by TLC, the reaction mass was concentrated and quenched with water (1000ml) to give 2-bromo-4-(2,4-difluorophenyl) phenol. Yield: 124.2 g M.P: 82 - 83.4°C HPLC purity: 99.78%
Example 3: Synthesis of 2-bromo-4-(2,4-difluorophenyl)ethoxybenzene (IV)
2-Bromo-4-(2,4-difluorophenyl) phenol (120.2gms) was added to a stirred mixture of dimethylformamide (120ml) and water (120ml), followed by addition of potassium carbonate (200.8 gms), ethyl bromide (300.6ml) and tetrabutylammonium bromide (4.2 g) at 25-35 C till completion of reaction as monitored by TLC.
The reaction mixture was quenched with water (600 ml) and toluene (1200 ml) and the organic layer was then separated and concentrated and the desired compound was then

isolated by adding water to the residue. The mixture was then heated at 45-65°C and partially concentrated to give 2-bromo-4-(2,4-difluorophenyl)ethoxybenzene on cooling. Yield: 140.5 g M.P: 87- 89.5°C HPLC purity: 98.40%
Example 4: Synthesis of 2-ethoxy-5-(2,4-difluorophenyl)benzoic acid (V)
Magnesium (l0.lgms) and 1,2 dibromoethane (1.4gms) were added to a stirred solution of 2-bromo-4-(2,4-difluorophenyl)ethoxybenzene (140.2gms) in tetrahydrofuran (1400ml) under nitrogen atmosphere at 25-30°C. The reaction mixture was heated to reflux and stirred at the same temperature till completion of the reaction.
When the reaction was complete, as monitored by TLC, the reaction mass was cooled to 50-55°C and reacted with carbon dioxide gas under a pressure of 1-2 Kg/cm2. After completion of the reaction, as monitored by TLC, dilute hydrochloric acid was added to the reaction mixture, followed by extraction withethyl acetate. Separation and concentration of the organic layer yielded 2-ethoxy-5-(2,4-difluorophenyl)benzoic acid. Yield: 130.6 g M.P.:109-110.5°C HPLC purity: 98.09%
Example 5: Synthesis of Diflunisal (I)
A stirred mixture of 2-ethoxy-5-(2,4-difluorophenyl)benzoic acid (130.1g), hydrobromic
acid (48%, 2600 ml) and acetic acid (1300 ml) were heated to 100-110°C till completion of
reaction as monitored by TLC.
The reaction mass was then cooled and extracted with ethyl acetate, the organic layer was
separated and concentrated. If required, toluene (2500 ml) was added to the residue and the
mixture was heated to reflux, and concentrated partially, which on cooling yielded
Diflunisal with desired purity.
Yield: 120.5gms
M.P:210-213°C
HPLC Purity: 99.93%.

We claim, 1 A process for preparation of Diflunisal of formula (I) comprising
a) reaction of 4-(2,4-difluorophenyl)phenol of formula (II) with bromine in presence of an acid and isolating 2-bromo-4-(2,4-difluorophenyl)phenol of formula (III),
b) treating compound of formula (III) with ethyl halide in presence of an inorganic base and a phase transfer catalyst to give 2-bromo-4-(2,4-difluorophenyl)ethoxybenzene of formula (IV),
c) reaction of compound of formula (IV) with magnesium and carbon dioxide in an organic solvent to give 2-ethoxy-5-(2,4-difluorophenyI)benzoic acid of formula (V),
d) deprotection of compound of formula (V) with a mixture of hydrobromic acid and acetic acid and isolation of Diflunisal (I) of desired purity.

2. A process as claimed in step a) of claim 1, wherein the acid is either a protic acid or a sulphonic acid or a Lewis acid.
3. A process as claimed in claims la) and 2, wherein the acid is preferably para toluenesulfonic acid or acetic acid or a Lewis acid.
4. A process as claimed in step a) of claim 1, wherein 2-bromo-4-(2,4-difluorophenyl)phenol of formula (III) is isolated by adding either aqueous methanol or water.
5. A process as claimed in claims lb), wherein the ethyl halide is ethyl bromide or ethyl chloride
6. A process as claimed in step c) of claim 1, wherein the organic solvent is selected from tetrahydrofuran, diethyl ether and diphenyl ether.

7. A process as claimed in claim 1, wherein Diflunisal is isolated from the reaction mixture by concentrating the ethyl acetate extract, adding toluene to the residue, and partially concentrating the mixture to give Diflunisal (I) of desired purity.
8. The intermediate, 2-bromo-4-(2,4-difluorophenyl)ethoxybenzene of formula (IV) and a process for its preparation.