CLIAMS:We claim,

1. A process for obtaining Flurbiprofen with high purity comprises,
i. converting diethyl ester of flurbiprofen into flurbiprofen methyl ester, which is purified via high vacuum distillation;
ii. converting the vacuum-distilled flurbiprofen methyl ester to sodium salt of flurbiprofen via hydrolysis and
iii. acidifying the sodium salt of flurbiprofen to obtain pure flurbiprofen.

2. The process as claimed in claim1, wherein step (i) of conversion of diethyl ester of flurbiprofen to flurbiprofen methyl ester is carried in one pot which involves reaction of diethyl ester of flurbiprofen with sodium hydroxide and acetic acid to form flurbiprofen and insitu reaction of flurbiprofen with methanol and sulfuric acid to obtain Flurbiprofen methyl ester.

3. The process according to claim 1, wherein in step (i) the flurbiprofen methyl ester is purified under a vacuum of 1-5 mm of Hg at 60°C – 115 °C.

4. The process as claimed in claim 1, wherein step (ii) is carried out in presence of sodium hydroxide.

5. The process as claimed in claim 1, wherein step (iii) is carried out in presence of hydrochloric acid.

Dated this the 29th day of July, 2014

Dr. P. Aruna Sree
(Regn.No.: IN/PA 998)
Agent for the Applicant
Gopakumar Nair Associates ,TagSPECI:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)

1. TITLE OF THE INVENTION:

“A PROCESS FOR OBTAINING FLURBIPROFEN WITH HIGH PURITY”

2. APPLICANT:

(a) NAME: FDC LIMITED

(b)NATIONALITY: Indian Company incorporated under the
Companies Act, 1956

(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102,
Maharashtra, India.

3.PREAMBLE TO THE DESCRIPTION:

The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field:
The present invention provides an improved process for obtaining Flurbiprofen with high purity.

Background and prior art:
Flurbiprofen is a non-steroidal anti-inflammatory and analgesic agent well known for use in anti-inflammatory and pain management medicaments. The chemical name of flurbiprofen is (2-(2-fluoro-4-biphenylyl) propionic acid and is structurally represented as below:

Flurbiprofen

Flurbiprofen is generally prepared by reacting ethyl ester of 2-fluoro-4-biphenylyl acetic acid with diethylcarbonate to give sodium derivative of biphenyl diester, methylating the sodium derivative of the biphenyldiester, followed by hydrolysis of the biphenyl diester and decarboxylating the resulting acid to give Flurbiprofen. The said process is depicted as follows in Scheme A.

Scheme A

Several processes for the preparation of Flurbiprofen involves use of diethyl ester of Flurbiprofen, which is an important intermediate in the synthesis of flurbiprofen and which is structurally represented as below.

Diethyl ester of Flurbiprofen

US 3755427 and US 4266069 disclosemulti-step synthesis of flurbiprofen involving the diethyl ester of Flurbiprofen of formula (A) as an intermediate which gets converted to flurbiprofen via hydrolysis & decarboxylation.

IN 234415 discloses a process for preparation of flurbiprofen involving vacuum distillation, wherein the intermediate, diethyl ester of Flurbiprofen is subjected toshort path distillation for purification, followed by hydrolysis and decarboxylation to isolate the sodium salt of flurbiprofen, which is then acidified with HCl to re-precipitate flurbiprofen. However, the above process has disadvantages of the diethyl ester of Flurbiprofen being distilled out at high temperature, leading to thermal impurities that may be formed during distillation at higher temperatures, and moreover the process involves use of toxic chlorinated solvents for washing off the acidic impurities from the sodium salt of flurbiprofen obtained during the process.

Hence, there is a need for an improved process for obtaining Fluribiprofen, with minimum impurity content, while avoiding the use of toxic solvents.

Therefore, it is an object of present invention to provide an improved process for obtaining Fluribiprofen with reduced impurities in an environmental friendly and convenient manner.

The present invention achieves the above objective by employing vacuum distillation of methyl ester of Flurbiprofen at low temperature, while avoiding distillation of diethyl ester of Flurbiprofen at higher temperatures so as to eliminate the formation of thermal impurities that occurs during the distillation of diethyl ester of Flurbiprofen at higher temperatures.

Description of Drawings:

Figure 1 shows HPLC chromatogram of Flurbiprofen w.r.t Comparative Example

Figure 2 shows HPLC chromatogram of Flurbiprofen w.r.t Example 1

Figure 3 shows HPLC chromatogram of Flurbiprofen w.r.t Example 2

From the Figures 1,2 & 3, it is evident that the present invention process provides Flurbiprofen with reduced impurities.

Summary of the invention

In accordance with the above objective, the present invention describes a process for obtaining Flurbiprofen with high purity, which involves:

i) converting diethyl ester of flurbiprofen to flurbiprofen methyl ester, which is purified via high vacuum distillation;
ii) converting the vacuum-distilled flurbiprofen methyl ester to sodium salt of flurbiprofen via hydrolysis, and
iii) acidifying the sodium salt of flurbiprofen to obtain pure flurbiprofen.
The present process provides highly pure flurbiprofen, as the purification of flurbiprofen methyl ester is achieved through vacuum distillation at reduced temperature, while avoiding distillation of flurbiprofen diethyl ester at higher temperatures to eliminate the formation of various thermal impurities. Moreover, the present invention provides an environmental friendly and convenient process for obtaining pure Flurbiprofen.

The present invention provides flurbiprofen with reduced number of impurities, and moreover the content of the individual impurities are also found to be reduced, thus yielding Flurbiprofen with high purity.

Detailed description of the invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention describes an improved process for obtaining Flurbiprofen with high purity, which involves:
i) converting diethyl ester of flurbiprofen to flurbiprofen methyl ester, which is purified via high vacuum distillation;
ii) converting the vacuum-distilled flurbiprofen methyl ester to sodium salt of flurbiprofen via hydrolysis, and
iii) acidifying the sodium salt of flurbiprofen to obtain pure flurbiprofen.

The process of the present invention is outlined in Scheme 1:

Scheme 1

The conversion of diethyl ester of flurbiprofen to flurbiprofen methyl ester is a one pot process, involving reaction of diethyl ester of flurbiprofen with sodium hydroxide and acetic acid to form flurbiprofen which is insitu reacted with methanol and sulfuric acid to obtain Flurbiprofen methyl ester.The flurbiprofen methyl ester is purified under a vacuum of 1-5 mm of Hg at 60°C – 115 °C. Purified Flurbiprofen methyl ester is treated with sodium hydroxide to form sodium salt of Flurbiprofen, which is then treated with hydrochloric acid to obtain flurbiprofen.

The prior art process requires vacuum distillation of diethyl ester of Flurbiprofen at higher temperature leading to various thermal impurities. The inventiveness of the present invention lies in vacuum distillation of methyl ester of flurbiprofen at reduced temperatures, in order to obtain flurbiprofen with high purity. Further, the present invention avoids the use of chlorinated solvents during preparation of sodium salt of flurbiprofen which makes the process environmental friendly.

The present invention provides flurbiprofen with reduced number of impurities including Impurity A, Impurity C and Impurity D, which are structurally represented as below:
Impurity A Impurity C Impurity D

2-(biphenyl-4-yl) propanoic acid 2-(2-fluorobiphenyl-4-yl)-2-
hydroxypropanoic acid, 1-(2-fluorobiphenyl-4-yl) ethanone

Moreover, the content of these individual impurities are also found to be reduced in the end-product Flurbiprofen obtained by the present invention process, thus yielding Flurbiprofen with high purity.

The present invention is exemplified by the following examples which are provided for illustration only and should not be construed to limit the scope of the invention.
Examples:

Comparative Example:

i) Preparation of pure diethyl ester of Flurbiprofen
In a round bottom flask fitted with a high vacuum distillation set up, was added crude diethyl ester of Flurbiprofen (430 gms) obtained by a known process, followed by addition of magnesium carbonate (1.2 gms). The oil was subjected to fractional distillation under vacuum(1-5 mm of Hg) at 170°- 225°C. The distillate was collected in a four-necked round bottom flask, and to that was charged toluene (300 ml) to get a clearsolution. The toluene layer was washed with 2% alkali solution followed by washing with water. The toluene layer was then concentrated to obtain pure diethyl ester of Flurbiprofen as an oil. (Weight 191 gms; Gas chromatography (GC) purity 60-70 %).

ii) Preparation of sodium salt of Flurbiprofen:
In a four-necked round bottom flask fitted with a condenser for downward distillation, was added sodium hydroxide (133 gms) and water (277 ml), followed by drop-wise addition of diethyl ester of Flurbiprofen oil (185 gms) at 80°-85°C over a period of 1.5 hours. Ethanol was distilled out simultaneously, and removed completely under vacuum at 80°-85°C once the dropwise addition of diethyl ester was complete. Water (950 ml) was added to the residue and the reaction mass was stirred at 80°-85°C to get a clear solution. Thereafter, hydrose (9.9 gmsof Sodium Hydro Sulphite) was charged and stirred for 30 minutes. The resulting reaction mass was washed with trichloroethylene (TCE) at 85°-90°C. Thereafter, acetic acid (185 ml) was added dropwise at 80°-85°C and the reaction mixture was digested at 80°-85°C for a further period of 4 hours. Sodium hydroxide (59.8 gms) was added slowly to the reaction mixture, keeping the temperature between 85°-90°C, and stirred at 85°-90°C for 30 minutes, and then the temperature was brought to 10°C. The resulting solid was filtered and washed with water to yield wet sodium salt of flurbiprofen (Wet weight = 120 gms containing about 12-15% moisture w/w).

iii) Preparation of Flurbiprofen:
In a round bottom flask was charged, wet sodium salt of Flurbiprofen (120 gms) and water (630 ml). The reaction mass was heated to 60°-65°C followed by the addition of activated carbon (9 gms). The reaction mass was maintained at 60°-65°C for 60 minutes and then filtered through a bed of celite, and the bed was then washed with hot water. The resulting filtrate was collected in a flask to which was added concentrated HCl drop wise to bring the pH in the range of 1-2. Thereafter, the reaction mixture was maintained at 50°-55°C for 2 hours and then cooled to 25°-30°C. The resulting solid was filtered and washed with water and further dried at 70°-80°C for 12 hours to yield Flurbiprofen (Dry weight = 73 gms, HPLC purity 99.78 %)
The HPLC chromatogram of Flurbiprofen obtained using this example is shown in figure 1 and Flurbiprofen along with various known and unknown thermal impurities obtained are listed in table 1.
Table 1
Peak No. Peak name Retention Time (min) Area
(AU*sec) % Area
1. unknown impurity 3.020 1812.569 0.00
2. unknown impurity 5.420 33826.010 0.05
3. unknown impurity 8.543 15422.443 0.02
4. Impurity A 12.337 6414.054 0.01
5. Flurbiprofen 13.877 74602185.344 99.78
6. Impurity D 20.887 55014.832 0.07
7. unknown impurity 21.867 14519.425 0.02
8. unknown impurity 24.397 17619.744 0.02
9. unknown impurity 25.770 21748.367 0.03
Sum 74768562.788 100

Example 1:
i) Preparation of Flurbiprofen Methyl Ester:
In a four- necked round bottom flask fitted with a condenser for downward distillation, was added sodium hydroxide (310 gms) and water (645 ml), followed by slow addition of diethyl ester of Flurbiprofen (430 gms) at 80°-85°C over a period of 1.5 hours. Ethanol was distilled out simultaneously, and removed completely under vacuum at 80°-85°C once the dropwise addition of diethyl ester was complete. Water (3.01 liters) was added to the residue and the reaction mass was stirred at 80°-85°C to get a clear solution. Thereafter, hydrose (23 gms of Sodium Hydro Sulphite) was charged and stirred for 30 minutes. Thereafter, acetic acid (430 ml) was added drop wise at 80°-85°C and the reaction mixture was digested at 80°-85°C for a further period of 4 hours. The resulting reaction mass was then extracted with toluene, and the toluene extracts were combined and distilled out completely under vacuum at 80°-85°C to obtain a neat oil of crude flubiprofen. To this oil, methanol (360 ml) was added along with conc sulfuric acid (9 ml). The reaction mixture was refluxed for a period of 2 hours and methanol was distilled out, to obtain crude oil of Flurbiprofen methyl ester. The crude oil was subjected to distillation under high vacuum (1-5 mm of Hg) at 60°-115°C to obtain pure Flurbiprofen methyl ester as an oil. (Weight: 116 gms; HPLC Purity: 80-95%).

ii) Preparation of sodium salt of Flurbiprofen:
In a round bottom flask fitted with a condenser, was charged sodium hydroxide (58.4 gms) , water (690 ml) and Flurbiprofen methyl ester oil (115 gms). The reaction mass was heated to 80°-85°C and maintained at 80°-85° for 3 hours. Hydrose (3 gms ) was added to the reaction mass and stirred at 80°-85°C for 30 minutes. The reaction mass temperature was brought to room temperature and the resulting solid was filtered and then washed with water to yield wet sodium salt of flurbiprofen (Wet weight = 131 gms containing about 12-15% moisture w/w).

iii) Preparation of Flurbiprofen:
In a round bottom flask was charged, wet sodium salt of Flurbiprofen (130 gms) and water (700 ml). The reaction mass was heated to 75°-80°C followed by addition of activated carbon (5 gms). The reaction mass was maintained at 75°-80°C for 30 minutes, and then filtered through a celite bed, and the bed was then washed with hot water. The resulting filtrate was collected in a flask and heated to 55°-60°C, and to it was added concentrated HCl drop wise at 55°C , to adjust the pH in the range of 1-2. The reaction mixture was maintained at 50°-55°C for 1 hour and then cooled to 25°-30°C. The resulting solid was filtered and washed with water and further dried at 70°-80°C for 12 hours to yield Flurbiprofen (Dry weight = 76.22 gms, HPLC purity 99.93%).
The HPLC chromatogram of Flurbiprofen obtained using this example is shown in figure 2 and Flurbiprofen along with known impurities obtained are listed in Table 2.

Table 2
Peak No. Peak name Retention Time (min) Area
(AU*sec) % Area
1. Impurity C 4.09
2. Impurity A 8.06
3. Flurbiprofen 8.92 46246890 99.93
4. Impurity D 12.69 32479 0.07
Sum 46279369 100

Example 2:
i) Preparation of Flurbiprofen Methyl Ester:
In a four-necked round bottom flask fitted with a condenser for downward distillation, was added sodium hydroxide (144 gms) and water (430 ml), followed by slow addition of diethyl ester of Flurbiprofen (430 gms) at 80°-85°C over a period of 1 hour. Ethanol was distilled out simultaneously, and removed completely under vacuum at 80°-85°C once the dropwise addition of diethyl ester was complete. Water (2.58 liters) was added to the residue and the reaction mass was stirred at 80°-85°C to get a clear solution. Thereafter, acetic acid (200 mL) was added drop wise at 80°-85°C and the reaction mixture was digested at 80°-85°C for a further period of 4 hours. The resulting reaction mass was then extracted with toluene, and the toluene extracts were combined and distilled out completely under vacuum at 80°-85°C to obtain neat oil of crude Furbiprofen. To this oil, methanol (500 ml) was added along with conc. sulfuric acid (10 ml). The reaction mixture was refluxed for a period of 2 hours and methanol was distilled out completely. Thereafter, toluene was added to the reaction mixture and stirred till the solution was clear. The toluene layer was washed with water and 1% sodium bicarbonate solution and then again with water . Thereafter, the toluene layer was distilled out to obtain crude oil of Flurbiprofen methyl ester. The crude oil was subjected to distillation under high vacuum (1-5 mm of Hg) at 60°-115°C to obtain pure Flurbiprofen methyl ester as an oil. (Oil weight: 120 gms; HPLC Purity 70-75%).

ii) Preparation of Flurbiprofen Sodium:
In a round bottom flask fitted with a dropping funnel and a condenser for downward distillation, was charged sodium hydroxide (37.7 gms) and water (120 ml). The reaction mass was heated to 80°-85°C followed by drop wise addition of Flurbiprofen methyl ester oil (120 gms) as a neat oil at 80°-85°C in 1 hour. Methanol was distilled out during the course of the addition. Once the addition was complete, the reaction mass was stirred at 80°-85° for 30 minutes. Traces of methanol were distilled out under vacuum at 80°-85°C. Water (714 ml) was added to the reaction mass and maintained at 80°-85° for 1 hour. Hydrose(6 gm) was added to the reaction mass and stirred at 80°-85°C for 30 minutes. Thereafter, the reaction mass temperature was brought to room temperature and the resulting solid was filtered and then washed with brine solution to yield wet sodium salt of flurbiprofen. (Wet weight = 140 gms containing about 12-15% moisture w/w).

iii) Preparation of Flurbiprofen:
In a round bottom flask, was charged wet sodium salt of Flurbiprofen (140 gms) and water (720 ml). The reaction mass was heated to 80°-85°C followed by the addition of activated carbon (6 gms). The reaction mass was maintained at 80°-85°C for 30 minutes, and then filtered through a celite bed, and the bed was then washed with hot water (300 ml). The resulting filtrate was collected in a flask and heated to 55°-60°C, and to it was added concentrated HCl drop wise at 55°C to adjust the pH in the range of 1-2. The reaction mixture was maintained at 50°-55°C for 2 hours, and then cooled to 25°-30°C. The resulting solid was filtered and washed with water and further dried at 55°-60°C for 12 hours to yield Flurbiprofen (Dry weight = 85 gms, HPLC purity 99.94%).

The HPLC chromatogram of Flurbiprofen obtained using this example is shown in figure 3 and Flurbiprofen along with known impurities obtained are listed in table 3.

Table 3
Peak No. Peak name Retention Time (min) Area
(AU*sec) % Area
1. Impurity C 5.19
2. Impurity A 11.13 -
3. Flurbiprofen 12.58 67602151 99.94
4. Impurity D 18.64 40322 0.06
Sum 67642473 100