DESC: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
“PROCESS FOR PREPARATION OF FLURBIPROFEN”

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 an improved process for the preparation of flurbiprofen having desired purity. The invention relates to the reaction of sodium 2-bromopropionate (3) with the magnesium complex of 4-bromo-2-fluorobiphenyl (4) in presence of a transition metal salt to give flurbiprofen.

BACKGROUND OF THE INVENTION
Flurbiprofen (1), chemically known as 2-(2-fluorobiphenyl-4-yl) propanoic acid belongs to phenylalkanoic acid family of non-steroidal anti-inflammatory drugs (NSAIDs). It is primarily indicated as a pre-operative anti-miotic in the form of an ophthalmic solution, as well as orally for arthritis or dental pain.
Flurbiprofen was first disclosed by Boots Co. Ltd., and its formulation, developed by Pharmacia & Upjohn Company was approved by USFDA on Oct 31, 1988. The formulation was later marketed under the brand name Ansaid, which is indicated for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.
Flurbiprofen is available under various brand names such as Acustop, Cataplasma, Ansaid, Biprotec, Ocufen etc. including the solutions for ophthalmic use and tablets for oral consumption, both in various strengths. The ophthalmic solutions are used before certain types of eye surgeries and after the surgery to treat pain, swelling and redness of the eyes.

Flurbiprofen (1)
US 3,755,427 discloses a method comprising reaction of 4-acetyl-2-fluorobiphenyl in presence of sulfur and morpholine, wherein the reaction mixture was refluxed for sixteen hours, followed by treatment with mixture of acetic acid, sulfuric acid and water to give 2-fluoro 4-biphenyl acetic acid. The acetic acid derivative was converted to ethyl ester, which was treated with diethyl carbonate, sodium ethoxide and dimethyl sulfate to give the corresponding ethyl 2-(2-fiuoro-4-biphenylyl)-a-methylmalonate. Hydrolysis of the malonate ester, decarboxylation, followed by recrystallization from benzene / petroleum ether provided flurbiprofen (1).

US 4,398,035 discloses two methods for preparation of flurbiprofen. The first method involves reaction of 2,4-difluoronitrobenzene with diethyl-methyl-malonate in presence of sodium hydroxide using dimethylformamide as solvent afforded the intermediate, diethyl 2-(3-fluoro-4-nitrophenyl)-2-methylmalonate. Reduction of the nitro group, followed by diazotization of the obtained amino derivative using sodium nitrite and reaction of the diazonium compound with benzene yields the biphenyl–diethyl malonate intermediate. Base-hydrolysis of the ester derivative with sodium hydroxide to give the corresponding malonic acid intermediate, which, after refluxing for seventeen hours in excess of glacial acetic acid yielded the desired compound, flurbiprofen. The second method comprises preparation of diethyl 2-(3-fluoro-4-nitrophenyl)-2-methylmalonate which was then converted to the monoester by refluxing at 130-180°C in dimethyl sulfoxide in presence of sodium chloride, followed by reduction of nitro group to amino derivative, diazotization, further reaction with excess of benzene and hydrolysis of the ester group gave flurbiprofen.

The synthetic strategy disclosed in US 3,959,364 comprised reaction of 4-bromo-2’-fluorobiphenyl with magnesium, and further reaction of the Grignard reagent with sodium 2-bromopropionate in anhydrous tetrahydrofuran as solvent to give flurbiprofen.

US 4,144,397 discloses the reaction of Grignard reagent prepared from 4-bromo-2’-fluorobiphenyl and magnesium with a mixed magnesium halide complex of a-bromopropionic acid; represented by the formula CH3CH(Br)COOMgX wherein X is chlorine or bromine. After completion of the reaction, treatment with mineral acid provided the desired compound, flurbiprofen.

The study of prior art for synthesis of aryl propionic acids, as carried out by the present inventors revealed that some of the methods disclosed in prior art resorted to lengthy reaction sequences which involved multiple synthetic steps inclusive of high temperature reactions in the range of 140 to 180°C. This not only adversely affected the overall yield, but also contributed significantly to the formation of impurities, which were required to be separated in order to obtain flurbiprofen having desired purity. The synthetic routes comprising Grignard reactions, such as those disclosed in US 3,959,364 depicted a comparatively shorter reaction sequence. However, the desired compound, flurbiprofen was obtained with a modest yield of around 30-40%. Similar preparation methods, as disclosed in US 4,144,397 were very expensive and time-consuming due to the requirement of two Grignard reactions and complexes in the synthesis of desired aryl propionic acid. Further, laboratory experiments based on the said processes showed significant impurity formation and afforded flurbiprofen in low yields. These shortcomings render the prior art methods inconvenient and unacceptable for commercial scale production.

Thus, there is a need for an industrially feasible, convenient process for the synthesis of flurbiprofen, which avoids lengthy, circuitous synthetic routes and is yet capable of providing flurbiprofen in high yield with purity conforming to regulatory specifications.

The present inventors have developed a convenient and economical process for synthesis of 2-(2-fluorobiphenyl-4-yl)propanoic acid overcoming the problems faced in the prior art, wherein the synthetic sequence comprised reaction between sodium 2-bromopropionate and the Grignard reagent of 4-bromo-2-fluorobiphenyl in presence of transition metal salts like cobalt (II) chloride. Further treatment of the resultant sodium 2-(2-fluoro biphenyl 4-yl) propionate with acid afforded the final compound, 2-(2-fluorobiphenyl-4-yl) propanoic acid (1) conforming to regulatory specifications.

OBJECT OF THE INVENTION
An objective of the present invention is to provide an industrially applicable, convenient process for synthesis of flurbiprofen which avoids use of lengthy reaction sequences and elaborate purification methods.

Another object of the invention is to provide a convenient method for synthesis of flurbiprofen (1) comprising reaction of magnesium complex of 4-bromo-2-fluorobiphenyl (4) with sodium 2-bromopropionate (3) in presence of transition metal catalyst to give the desired compound having purity conforming to regulatory specifications.

SUMMARY OF THE INVENTION
An aspect of the invention relates to an improved process for the preparation of flurbiprofen (1) comprising reaction of 4-bromo-2-fluorobiphenyl (4) with magnesium and treatment of the resultant magnesium complex with sodium 2-bromopropionate (3) in presence of cobalt (II) chloride and solvent tetrahydrofuran, followed by treatment with acid to give (1) 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
While carrying out extensive experimentation aimed at designing a convenient, industrially applicable synthetic strategy for flurbiprofen, the present inventors surprisingly found that the reaction between the Grignard reagent of 4-bromo-2-fluorobiphenyl and sodium 2-bromopropionate was very facile when it was carried out in presence of transition metal salts such as halides of Iron, Cobalt, Nickel.
These salts were required in catalytic amounts and did not interfere in the process of isolation of flurbiprofen from the reaction mixture.
Various aryl alkanoic acids such as ibuprofen, fenoprofen, naproxen, diclofenac, lumiracoxib, indomethacin, 2-(4-methylphenyl)propionic acid, 2-(4-isobutylphenyl) propionic acid, 2-(4'-fluoro-4-biphenyl)propionic acid were synthesized following the afore-mentioned strategy.
The reactions were also carried out using a phase transfer reagent.
It was observed by the inventors that in the absence of said catalysts, the reactions were associated with significant formation of various impurities. In case of flurbiprofen, the major impurity, labeled as impurity-A (structure given below), was formed to the extent of 30 to 40% when the reaction was carried out without using the above-mentioned catalysts. This necessitated a series of purification processes and resulted in a very modest yield of 30-35% for flurbiprofen as against the yield of 67 % in presence of catalyst.

Impurity-A
Some of the advantages of the present strategy are summarized below.
a) It was experimentally observed that with the use of catalysts, the desired reaction could be carried out with high chemoselectivity and employing milder reaction conditions; thus imparting significant control on impurity formation.
b) An almost two fold yield enhancement was observed with the use of catalyst like Cobalt (II) chloride.
c) Due to high solubility in water, the catalysts could be separated easily from the reaction mass after completion of the reaction.
d) Non-hazardous, inexpensive nature of the catalysts, along with their ready availability added to the convenience and cost-effectiveness of the synthetic sequence.
e) As against the disclosure in US 3,959,364 wherein it is mentioned that method of preparation of 2-bromopropionate salt could affect the yield of aryl propionic acids, the yields in the present sequence were independent of preparation methods of the said bromopropionate salt.

The above-mentioned advantages made the process described in present invention a convenient, cost-effective synthetic method which could be easily scaled up to industrial scales of operation.

Scheme 1: Method embodied in the present invention for the preparation of flurbiprofen (1)

In an embodiment, reaction of 2-bromo propionic acid (2) with sodium methoxide in methanol gave sodium 2-bromo propionate (3). Simultaneously, 4-bromo 2-fluorobiphenyl (4) was treated with magnesium to give the corresponding Grignard reagent. Reaction of (3) with the Grignard reagent of (4) in presence of a catalyst, in an organic solvent yielded sodium 2-(2-fluoro biphenyl 4-yl) propionate (5).
The reaction was carried out in the temperature range of 20 to 500C.
The catalyst was selected from a group of transition metal catalysts comprising the halides of Iron (Fe), Cobalt (Co) and Nickel (Ni), such as Iron (II) chloride, Cobalt (II) chloride, Nickel (II) chloride, preferably Cobalt (II) chloride or mixtures thereof.
The solvent was selected from a group of polar aprotic solvents comprising N-methyl pyrrolidone (NMP) and ethers like tetrahydrofuran, tert-butyl methyl ether, diphenyl ether diethyl ether, dimethyl ether etc. or mixtures thereof.
After completion of the reaction, as monitored by HPLC, the reaction mixture was acidified using acids like sulfuric acid, hydrochloric acid etc. and was partially concentrated. An organic solvent like toluene was added to the reaction mixture and the layers were separated.

An aqueous solution of a base such as sodium hydroxide was added to the organic layer and the mass was heated in the temperature range of 60-85°C. After completion of the reaction, as monitored by HPLC, the layers were separated, and aqueous layer was cooled, filtered to give sodium 2-(2-fluorobiphenyl-4-yl) propionate, compound (5).

Aqueous solution of (5) was further treated with an acid such as sulfuric acid, hydrochloric acid etc. After completion of the reaction as monitored by HPLC, the reaction mixture was filtered. The solid was optionally treated with an organic solvent like acetone to provide the desired compound 2-(2-fluorobiphenyl-4-yl) propanoic acid (1).

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 sodium 2-bromopropionate (3)
Sodium methoxide (36.4 g) was added to methanol (132 ml), the mixture was cooled to 25-30°C and added to the stirred solution of 2-bromopropionic acid (2, 100.4 g) in methanol (40 ml). The resulting mixture was stirred at 25-30°C till completion of the reaction. After completion, as monitored by HPLC, the reaction mixture was concentrated and toluene was added to the residue. The mass was heated to 50-60°C with stirring, cooled, filtered to give sodium 2-bromopropionate (3).
Yield: 97.6 g (86%)

Example 2: Synthesis of sodium 2-(2-fluorobiphenyl-4-yl) propionate (5)
Magnesium turnings (50.8 g) were added to tetrahydrofuran (1000 ml) placed in a flask followed by addition of iodine (0.05g) and the mixture was heated to 60-65°C. Solution of 4-bromo-2-fluorobiphenyl (4, 500.1 g in 500 ml tetrahydrofuran) was gradually added to the mixture and stirring was continued at 60-70°C, till completion of the reaction, as monitored by HPLC. After completion, the reaction mixture was cooled to around 0-5°C and solution of Cobalt (II) chloride hexahydrate (18.5 mg in 10 ml tetrahydrofuran) was added to it, followed by addition of sodium 2-bromopropionate (3, 352.3 g). The resultant mass was stirred at 25-30°C while completion of the reaction was monitored by HPLC. After completion, sulfuric acid solution (200 ml acid in 1500 ml water) was gradually added to the reaction mass, stirred and the reaction mixture was partially concentrated. Toluene was added with stirring to the reaction mixture and the layers were separated.
Aqueous sodium hydroxide solution (160.0 g in 2500 ml water) was added to the organic layer and the mass was heated to 70-90°C. After completion of the reaction, as monitored by HPLC, the layers were separated, and aqueous layer was cooled to around 5°C, along with stirring. The mass was filtered and the wet solid was dried to give sodium 2-(2-fluorobiphenyl-4-yl) propionate (5).
Yield: 416.1 g (78.4%)

Example 3: Preparation of 2-(2-fluorobiphenyl-4-yl) propanoic acid (1)
Concentrated hydrochloric acid was gradually added to the aqueous solution of sodium 2-(2-fluorobiphenyl-4-yl) propionate (5) (410.2 g in 2870 ml water) until the solution attained pH 2. The reaction mass was stirred at room temperature till completion of the reaction as monitored by HPLC and filtered. The obtained solid was treated with aqueous acetic acid at 40-500C and the mass was cooled to around 250C, filtered and dried to give 2-(2-fluorobiphenyl-4-yl) propionic acid, which was optionally treated with acetone-water at 40-500C, followed by cooling, filtration and drying.
Yield: 327.0 g (87%).
,CLAIMS:Claims
1. A process for preparation of flurbiprofen (1) comprising reaction of 4-bromo-2-fluorobiphenyl of formula (4) with magnesium and treating the resultant magnesium complex with sodium 2-bromopropionate (3) in presence of a catalyst, in an organic solvent to give sodium 2-(2-fluoro biphenyl 4-yl) propionate of formula (5), and further treatment with acid to give flurbiprofen (1).
2. A process as claimed in claim 1, wherein the catalyst is a transition metal halide selected from the group comprising the halides of Iron, Cobalt, Nickel and mixtures thereof.
3. A process as claimed in claim 1, wherein the catalyst is selected from the group comprising Iron (II) chloride, Cobalt (II) chloride, Nickel (II) chloride and mixtures thereof.

4. A process as claimed in claim 1, wherein the organic solvent is selected from a group of polar aprotic solvents.

5. A process as claimed in claim 4, wherein the solvent is selected from a group comprising tetrahydrofuran, N-methyl pyrrolidone, tert-butyl methyl ether, diphenyl ether, diethyl ether, dimethyl ether and mixtures thereof.

6. A process as claimed in claim 1, wherein the reaction with sodium 2-bromopropionate (3) is carried out in the temperature range of 20°C to 50°C.

Dated this Seventeenth day of November 2016

(Signed) _____________________
B.Dinesh Kumar (Dr.)
Senior Vice-President, Global IP
Emcure Pharmaceuticals Ltd.

To,
The Controller of Patents
The Patent Office Branch, Mumbai