Claims:
1. A process for preparation of Diflunisal of formula (A) comprising the step of:
a) oxidation of an intermediate compound of formula (I) with a predefined oxidizing agent in presence of a predefined solvent to yield a compound of formula (II) at a predefined temperature;
b) demethylation of compound of formula (II) using a predefined acid at a predefined temperature to form a crude form of compound of formula (A); and
c) purifying the crude form of compound of formula (A) to obtain a pure form of compound of formula (A).

2. The process as claimed in claim 1, wherein the oxidizing agent in oxidation reaction is selected from hydroxylamine hydrochloride in presence of iodine, magnesium nitrate, cobalt nitrate, sodium hypochlorite, lithium hypochlorite, sodium nitrite, manganese nitrate or hydrogen peroxide.

3. The process as claimed in claim 1, wherein oxidation reaction is carried out in an alcoholic solvent selected from methanol, ethanol, n-propanol, isopropanol or butanol.

4. The process as claimed in claim 1, wherein the oxidation reaction of the intermediate compound of formula (I) in presence of alcoholic solvent is carried out by heating at a temperature from 15°C to 60°C.
5. The process as claimed in claim 1, wherein the oxidation reaction of the intermediate compound of formula (I) in presence of alcoholic solvent is carried out by heating at a temperature of 45°C.

6. The process as claimed in claim 1, wherein the acid for demethylation is selected from hydrobromic acid, aluminium trichloride, boron tribromide, piperazine or sodium iodide.

7. The process as claimed in claim 1, wherein the demethylation of compound of formula (II) is carried out by heating at a temperature from 90°C to 110°C.

8. The process as claimed in claim 1, wherein the demethylation of compound of formula (II) is carried out by cooling at a temperature from 20°C to 30°C, preferably at 28°C.

9. The process as claimed in claim 1, wherein the purification process of crude form of compound of formula (A) in presence of solvent is carried out by refluxing at a temperature from 50°C to 60°C.

10. The process as claimed in claim 1, wherein the purification process of crude form of compound of formula (A) in presence of solvent is carried out by cooling at a temperature from 20°C to 30°C.

11. The process as claimed in claim 1, wherein the pure form of compound of formula (A) is with 99.0% to 99.9% HPLC purity and with a yield of 80% to 95%.

12. The process as claimed in claim 1, wherein process for preparation of intermediate compound of formula (I) comprising steps of:
x) fries rearrangement of a starting compound of formula (III) in presence of predefined catalyst at a predefined temperature to form a compound of formula (IV); and
y) methylation by reacting the compound of formula (IV) with a predefined methylating agent in presence of a predefined base at a predefined temperature to form a intermediate compound of formula (I).

13. The process as claimed in claim 12, wherein fries rearrangement reaction is carried out in presence of catalyst selected from aluminium chloride, zinc chloride, sodium bisulfate, zinc powder, titanium tetrachloride, p-toluene sulfonic acid, methane sulfonic acid, phosphoric acid, sulfuric acid, phosphorous pentoxide or silicon dioxide.

14. The process as claimed in claim 12, wherein fries rearrangement of starting compound of formula (III) in presence of predefined catalyst is carried out by quenching at temperature from 0°C to 5°C.

15. The process as claimed in claim 12, wherein the methylating agent used in methylation reaction is selected from methyl iodide or dimethyl sulfate.

16. The process as claimed in claim 12, wherein the base used in methylation reaction is selected from alkali hydroxides or alkali metal carbonates.

17. The process as claimed in claim 16, wherein the alkali hydroxide is selected from sodium hydroxide, potassium hydroxide, or calcium hydroxide and alkali metal carbonate is selected from sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate.

18. The process as claimed in claim 12, wherein the intermediate compound of formula (I) is having 98.0% to 99.0% HPLC purity.
, Description:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)

&

THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See section 10, Rule 13]

IMPROVED PROCESS FOR THE PREPARATION OF DIFLUNISAL USING NOVEL INTERMEDIATES THEREOF

AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ADDRESS, 71, UDYOG KSHETRA, 2ND FLOOR, MULUND GOREGAON LINK ROAD, MULUND (W), MUMBAI - 400080, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

Field of the invention
The present invention relates to 1-[5-(2,4-difluorophenyl)-2-alkoxy-phenyl]ethanone. More particularly the invention relates to an process for preparation of 1-[5-(2,4-difluorophenyl)-2-alkoxy-phenyl]ethanone and its use in the preparation of Diflunisal.

Background of the invention
Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity.
It acts by inhibiting the production of hormone prostaglandin, involved in inflammation and pain. It also has some antipyratic and anti-bacterial activity.

In the prior art cited patent application US3,714,226 synthesis of Diflunisal is first disclosed. In this cited patent application the process involves reaction of 2,4-difluroaniline with anisol and isoamyl nitrite. In this process mixture was heated for 3 hours and excess anisol is removed and residue was chromatographed on silica gel to yield 4-(2’,4’-difluorophenyl)anisol. 4-(2’,4’-difluorophenyl)anisol is hydrolyzed to 4-(2’,4’-difluorophenyl)phenol by reaction with glacial acetic acid and hydroiodic acid. Finally, this compound is carbonated with potassium carbonate and carbon dioxide at 175°C and at a pressure of 1300 p.s.i. to yield Diflunisal.
Another cited prior no-patent literature document Med. Chem. 21, 1093 (1978) describes of a five step synthesis of Dilflunisal. The process route as disclosed in the reference follows sequence of Gomberg-Bachmann-Hey reaction (GBH), Friedel-Crafts acylation, Bayer-Villiger oxidation, saponification and finally carbonation of phenol through a Kolbe-Schmitt reaction achieving Diflunisal. The yield obtained is low about 35.78%.

Both the processes as reported in the prior art references have yield in the lower range and requires high pressure for the reaction. Hence the process is not feasible on higher scale.

Thus there exist a need for alternative process for the preparation of Diflunisal using novel intermediate 1-[5-(2,4-difluorophenyl)-2-alkoxy-phenyl]ethanone which is cost effective and provides better yield and higher purity.

Objects of the invention
An object of present invention is to provide a process for synthesis of Diflunisal using novel intermediate, which is feasible on plant scale.

An object of present invention is to provide a process for synthesis of Diflunisal, which is
cost effective and provides higher yield with better quality of the product.

Summary of the invention
In an embodiment, a process for preparation of Diflunisal of formula (A) comprising the step of: (a) oxidation of an intermediate compound of formula (I) with a predefined oxidizing agent in presence of a predefined solvent to yield a compound of formula (II) at a predefined temperature; (b) demethylation of compound of formula (II) using a predefined acid at a predefined temperature to form a crude form of compound of formula (A); and (c) purifying the crude form of compound of formula (A) to obtain a pure form of compound of formula (A).

The oxidizing agent in oxidation reaction is selected from hydroxylamine hydrochloride in presence of iodine, magnesium nitrate, cobalt nitrate, sodium hypochlorite, lithium hypochlorite, sodium nitrite, manganese nitrate or hydrogen peroxide. The oxidation reaction is carried out in an alcoholic solvent selected from methanol, ethanol, n-propanol, isopropanol or butanol. The oxidation reaction of the intermediate compound of formula (I) in presence of alcoholic solvent is carried out by heating at a temperature from 15°C to 60°C. The oxidation reaction of the intermediate compound of formula (I) in presence of alcoholic solvent is carried out by heating at a temperature of 45°C.
The acid for demethylation reaction is selected from hydrobromic acid, aluminium trichloride, boron tribromide, piperazine or sodium iodide. The demethylation of compound of formula (II) is carried out by heating at a temperature from 90°C to 110°C for 10-15 hours. Further cooling of the mass after heating is carried out from 20°C to 30°C. The purification process of crude form of compound of formula (A) in presence of solvent is carried out by refluxing at a temperature from 50°C to 60°C. Further the purification process of crude form of compound of formula (A) in presence of solvent is carried out by cooling at a temperature from 25°C to 30°C. The pure form of compound of formula (A) is from 99.0% to 99.9% HPLC purity and with a yield of 80% to 95%.

In another embodiment, the process for preparation of intermediate compound of formula (I) comprising steps of: x) fries rearrangement of a starting compound of formula (III) in presence of predefined catalyst at a predefined temperature to form a compound of formula (IV); and y) methylation by reacting the compound of formula (IV) with a predefined methylating agent in presence of a predefined base at a predefined temperature to form a intermediate compound of formula (I).

Fries rearrangement reaction is carried out in presence of catalyst selected from aluminium chloride, zinc chloride, sodium bisulfate, zinc powder, titanium tetrachloride, p-toluene sulfonic acid, methane sulfonic acid, phosphoric acid, sulfuric acid, phosphorous pentoxide or silicon dioxide. Further the fries rearrangement reaction of starting compound of formula (III) in presence of predefined catalyst is carried out by quenching at temperature from 0°C to 5°C. The methylating agent used in methylation reaction is selected from methyl iodide or dimethyl sulfate. The base used in methylation reaction is selected from alkali hydroxides or alkali metal carbonates. The alkali hydroxide is selected from sodium hydroxide, potassium hydroxide, or calcium hydroxide and alkali metal carbonate is selected from sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate. The intermediate compound of formula (I) is having 98.0% to 99.0% HPLC purity.
Detailed description of the invention
The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.
All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.

Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.

References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.

In general aspect, the present invention relates to a process for the preparation of Diflunisal of formula (A).

In another aspect, the present invention relates to a process for the preparation of a novel intermediate compound of formula (I) used for preparation of Diflunisal of formula (A).

In a preferred embodiment, an improved process for the preparation of Diflunisal of formula (A) is disclosed. The process comprises:
a) oxidation of intermediate compound of formula (I) with predefined oxidizing agents in presence of predefined alcohol solvent to yield compound of formula (II) at predefined temperature;
b) demethylation of compound of formula (II) using predefined acid at a predefined temperature to form crude form of compound of formula (A); and
c) purification of crude form of compound of formula (A) to pure form of compound of formula (A).

In this preferred embodiment, oxidation step (a) of intermediate compound of formula (I) to form crude form of compound of formula (II) is disclosed. The process comprises:
a1) addition of alcoholic solvent to intermediate compound of formula (I) at predefined temperature,
a2) heating of the reaction mixture containing intermediate compound of formula (I) and predefined alcoholic solvent at a predefined temperature;
a3) stirring and heating continuously of the reaction mixture till at above said predefined temperature till all mixture dissolves to obtain faint orange clear solution;
a4) drop wise addition of predefined quantity of predefined oxidizing agent to above solution at a predefined temperature for a predefined time;
a5) cooling of the reaction mass is at a predefined temperature to obtain orange yellow solution;
a6) adding predefined quantity of acid to above solution and stirring until white slurry is obtained; and
a7) filtering the reaction mixture under vacuum to obtain solid and washing the obtained said solid with predefined quantity of water to obtain crude compound of formula (II).
In accordance with this preferred embodiment, the oxidizing reagent used in step (a4) is selected from magnesium nitrate, Cobalt nitrate, Sodium hypochlorite, Lithium hypochlorite, Sodium Nitrite, Manganese nitrate, hydrogen peroxide and hydroxylamine hydrochloride in presence of iodine. Further the reaction of step (a1) is carried out in predefined alcoholic solvent selected from methanol, ethanol, n-propanol, isopropanol, butanol, preferably methanol. The addition of alcoholic solvent to intermediate compound of formula (I) at step (a1) is done at room temperature. Further heating of the reaction mixture containing intermediate compound of formula (I) and predefined alcoholic solvent at step (a3) is done at a predefined temperature from 15°C to 60°C, preferably at temperature from 20°C to 50°C, particularly at temperature of 45°C. The drop wise addition of oxidizing agent preferably sodium hypochlorite at step (a4) is done at a temperature of 45°C for a predefined time of 1 hour. The cooling of the reaction mass at step (a5) is done at a temperature from 15°C to 25°C.

In this preferred embodiment, purification of crude form of compound of formula (II) is disclosed. The process comprises:
i. adding predefined quantity of water to crude compound of formula (II) at a predefined temperature and stirring the reaction mixture for predefined time;
ii. adding predefined base drop wise to above reaction mixture for predefined time;
iii. stirring the reaction mass at a predefined temperature to obtain clear solution;
iv. adding predefined solvent to above solution and further stirring for a predefined time;
v. separating the layers and adding predefined acid solution drop wise to the aqueous layer;
vi. stirring the reaction mixture for predefined time at predefined temperature;
vii. cooling the reaction mass obtained at a predefined temperature to a predefined time;
viii. filtering the reaction mass under vacuum and washing the solid obtained with water; and
ix. drying the solid obtained at a predefined temperature vacuum to yield pure form of compound (II).

In accordance with this preferred embodiment, water was added at room temperature, preferably at 28°C and stirred for sufficient time. The predefined base used at step (ii) is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, or like. Stirring of the reaction mass is done at temperature of 20°C to 30°C to get clear solution. The solvent used at step (iv) is selected from methylene dichloride, chloroform, ethyl acetate, or like. The acid added to aqueous layer at step (v) is selected from hydrochloric acid and Sulfuric acid or like. Further stirring of the reaction mixture at step (vi) is done at temperature of 20°C to 30°C. Cooling of the reaction mass in step (vii) is done at a temperature from 10°C to 15°C. Drying of the solid obtained in step (ix) is done at temperature 40°C to 45°C under vacuum to yield pure form of compound of formula (II) having about 98.5% to 99.5 % HPLC purity with Yield 90% to 98%.
In accordance with this preferred embodiment, compound of formula (I) is 1-5-(2,4-difluorophenyl)-2-methoxy-phenyl]ethanone and compound of formula (II) is 1-5-(2,4-difluorophenyl)-2-methoxy-benzoic acid.

In this preferred embodiment, demethylation of compound of formula (II) at step (b) to form crude form of compound of formula (A) is disclosed. The process comprises:
b1) adding predefined solvent to pure form of compound of formula (II) at predefined temperature and stirring for predefined time;
b2) adding acid solution to obtained mixture until off white slurry is obtained;
b3) heating the reaction mass to a predefined temperature and continue stirring for a predefined time;
b4) cooling the mixture to a predefined temperature;
b5) washing with the solid obtained with water and drying under vacuum to obtain crude form of compound of formula (A).

In accordance with this preferred embodiment, the solvent used in step (b1) is acetic acid. The addition of solvent at step (b1) is at temperature from 20°C to 25°C with stirring for 10 minutes. Further the acid used for demethylation of step (b2) is selected from hydrobromic acid, Aluminium trichloride, Boron tribromide, piperazine and sodium iodide. Heating the reaction mass at step (b3) is done at temperature from 90°C to 110°C with continue stirring for a time sufficient for completion of the reaction. Cooling of the reaction mass of step (b4) is done at temperature from 20°C to 30°C, preferably at 28°C.

In this preferred embodiment, purification step (c) of crude form of compound of formula (A) is disclosed. The process comprises:
c1) dissolving crude form of compound of formula (A) in predefined solvent and further refluxing the reaction mixture at a predefined temperature;
c2) adding activated charcoal to the reaction mass and refluxing for predefined period of time;
c3) filtering the reaction mass in predefined conditions under vacuum and washing with the predefined solvent as used in the above step;
c4) cooling the solution to a predefined temperature; and
c5) drying the solid obtained at predefined temperature under vacuum to obtain pure form of compound of formula (A).

In accordance with this preferred embodiment, the solvent used in step (c1) is acetone. At step (c2) the solution from step (c1) is refluxed from 50°C to 60°C. Refluxing of the reaction mass of step (c2) is done for a sufficient time to complete the reaction. The reaction mass as obtained in step (c3) is done in hot conditions under vacuum. Cooling of the solution in step (c4) is done at a temperature from 20°C to 30°C, preferably at 25°C. Drying of the solid obtained in step (c5) is done at temperature 45°C to 55°C under vacuum to yield pure form of compound of formula (A) with 90% to 99.9% purity and with a yield of 80 % to 95%.

In another preferred embodiment, process for the preparation of a novel intermediate compound of formula (I) used for preparation of compound of formula (A) is disclosed. The process comprises:
x) fries rearrangement of starting compound of formula (III) in presence of predefined catalyst at a predefined temperature to form compound of formula (IV); and
y) methylation by reacting compound of formula (IV) with predefined methylating agent in presence of predefined base at a predefined temperature to form novel intermediate compound of formula (I).

In this embodiment, fries rearrangement step (x) of starting compound of formula (III) to form compound of formula (IV) is disclosed. The process comprises:
x1) lot wise addition of starting compound of formula (III) into a predefined catalyst;
x2) heating the reaction mixture to a predefined temperature for a predefined period of time after addition of three lots of starting compound of formula (III) into above said catalyst;
x3) further heating reaction mixture to a predefined temperature for a predefined period of time after addition of the fourth lot of starting compound of formula (III) into above said catalyst;
x4) quenching the reaction mass as obtained with predefined acid solution at a predefined temperature for a predefined time;
x5) filtering and washing the solid obtained with water;
x6) further washing the wet solid obtained with predefined base and once again washing with water
x7) drying the solid at a predefined temperature under vacuum to obtain compound of formula (III).
In accordance with this preferred embodiment, addition of compound of formula (III) is done lot wise into the catalyst at step (x1). The suitable catalyst used in step (x1) is selected from aluminium chloride, zinc chloride, sodium bisulfate, Zinc powder, titanium tetrachloride, p-toluene sulfonic acid, methane sulfonic acid, phosphoric acid, sulfuric acid, phosphorous pentoxide, silicon dioxide. Further after addition of compound of formula (III) in three lots into catalyst heating is done at a temperature from 90°C to 110°C. After addition of fourth lot of compound of formula (III), heating is done at temperature from 90°C to 110°C for 1 hour. Washing the wet solid in step (x6) is done with base selected from sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate and potassium bicarbonate. Drying of the solid obtained in step (x7) under vacuum is done at a temperature from 40°C to 50°C to yield compound of formula (IV) having about 98% to 99.5% HPLC purity with 90% to 98% yield.

In this embodiment, methylation step (y) of compound of formula (IV) to form novel intermediate compound of formula (I) is disclosed. The process comprises:
y1) adding a predefined solvent to compound of formula (IV) at a predefined temperature to obtain off white slurry;
y2) adding a predefined phase transfer catalyst to above slurry at same predefined temperature as that in the above step;
y3) further adding drop wise predefined base in the reaction mass of step (b) for a predefined period of time;
y4) adding drop wise predefined base in the reaction mass for a predefined period of time;
y5) adding drop wise at predefined methylating agent methyl sulfate for a predefined period of time till light yellow slurry is obtained;
y6) maintaining the reaction mass for a predefined period of time at a predefined temperature;
y7) adding water in the mass and maintained the reaction mixture of for a predefined period of time;
y8) separating aqueous layer and extraction with predefined solvent; and
y9) concentrating the extracted solvent layer under vacuum at a predefined temperature to yield intermediate compound of formula (I).

In accordance with this preferred embodiment, the solvent used in step (y1) is toluene, and the addition of solvent is at temperature from 20°C to 30°C. Phase transfer catalyst used in step (y2) is selected from tertiary butylammonium bromide, tertiary butylammonium chloride, benzyltriethylammonium chloride, methyltributylammonium chloride or like (please confirm catalyst). The reaction of step (y3) is carried out in presence of suitable base selected from alkali hydroxides and alkali carbonates. Alkali hydroxide is selected from sodium hydroxide, potassium hydroxide, and calcium hydroxide. Further the alkali carbonate is selected from sodium carbonate, potassium carbonate, calcium carbonate and caesium carbonate. The methylating agent in step (y5) is selected from methyl iodide and dimethyl sulfate. Concentrating solvent layer under vacuum is done at a temperature from 55°C to 65°C to yield novel intermediate compound of formula (I) having 98.0% to 99.0% HPLC purity.

In accordance with this preferred embodiment, compound of formula (III) is [4-(2,4-difluorophenyl)phenyl] acetate and compound of formula (IV) is 1-[5-(2,4-difluorophenyl)-2-hydroxy-phenyl]ethanone.

The reaction scheme of preparing the compound of formula (A) is represented below:


EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.
Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1
Preparation of 1-[5-(2,4-difluorophenyl)-2-hydroxy-phenyl]ethanone
[4-(2,4-difluorophenyl)phenyl] acetate (250 gm) was charged lot wise to aluminium trichloride (400 gm) in four lots of (62.5 gm).
[4-(2,4-difluorophenyl)phenyl] acetate (62.5 gm) was added to Aluminium trichloride (400 gm) and the reaction mixture was heated to 105°C for 15 minutes. Further three lots of [4-(2,4-difluorophenyl)phenyl] acetate (62.5 gm) were charged to the reaction mass. After addition of each lot the reaction mixture was heated to 105°C for 15 minutes.
After addition of fourth lot the mixture was heated for 1 hour at 105°C. After completion of the reaction, the mass was quenched with 4.5% HCl solution at 0-5°C. After 2 hours, the the mass was filtered and solid was washed with water (2 L). Further the wet cake was washed with 1% NaHCO3 solution (500 ml). The cake was again washed with water (2 L). The solid obtained was suck dried well under vacuum. The solid obtained was dried under vacuum at 40-50°C to yield 1-[5-(2,4-difluorophenyl)-2-hydroxy-phenyl]ethanone (235 gm). (94% Yield).
HPLC Purity = 98.29%

Example 2
Preparation of 1-[5-(2,4-difluorophenyl)-2-methoxy-phenyl]ethanone
Toluene (920 ml) was charged to 1-[5-(2,4-difluorophenyl)-2-hydroxy-phenyl]ethanone (230 g) obtained in example 1 at 25°C. Tertiary butylammonium bromide (4.6 gm) was added to off white slurry obtained above at 25°C. 25% sodium hydroxide solution (300 ml) was added drop wise in the reaction mass at 25°C within 20 minutes. Dimethyl sulfate (175 gm) was added drop wise at 25°C within 30 minutes till light yellow slurry is obtained. The mass was maintained for 60 minutes at 25°C. Water (460 ml) was charged in the mass and maintained 0.5 hour. The aqueous layer was separated and extracted with Toluene (230 ml) at 25°C. Water washing (230 ml) was given to combined organic layer followed by washing of 10% brine (250 ml). Separated organic layer was concentrated under vacuum below 60°C to yield 1-[5-(2,4-difluorophenyl)-2-methoxy-phenyl]ethanone (242 gm).
HPLC Purity: 98.31%

Example 3
Preparation of 5-(2,4-difluorophenyl)-2-methoxy-benzoic acid
Methanol (1.45 L) was charged to 1-[5-(2,4-difluorophenyl)-2-methoxy-phenyl]ethanone (242 gm) at room temperature. The reaction mixture was stirred and heated to 45°C till the material dissolves. Faint orange clear solution was obtained. Sodium hypochlorite (2 L) was added drop wise to the solution at 45°C within 1 hour and the mixture was maintained for 1 hour. The mass was cooled to 25°C and 15% HCl (550 ml) was added to the orange yellow solution formed. The mixture was stirred till the white slurry was obtained and was filtered under vacuum. The solid obtained was washed with water (250 ml x 2).
Crude 5-(2,4-difluorophenyl)-2-methoxy-benzoic acid obtained was charged to water (2.5 L) at 28°C and stirred well for 20 minutes. 10% sodium hydroxide (700 ml) was added drop wise to the mass within 1 hour. The mass was stirred well at 28°C to get clear solution. MDC (500 ml) was charged in the reaction mass at 28°C and the mixture was stirred for 30 minutes. The layers were separated and 3M HCl solution (600 ml) was charged drop wise to the aqueous layer within 30 minutes. The mixture was stirred for 20 minutes at 28°C. The mass was cooled at 15°C and stirred for next 2 hours at 15°C. The mass was filtered at 15°C under vacuum and wet cake was washed with water (500 ml) at 28°C. The cake was suck dried well and further dried at 40-45°C under vacuum to yield pure 5-(2,4-difluorophenyl)-2-methoxy-benzoic acid (227 gm) (Yield: 93%)
Purity: 98.98%

Example 4
Preparation of Diflunisal
Acetic acid (900 ml) was charged to 5-(2,4-difluorophenyl)-2-methoxy-benzoic acid (225 gm) at 25°C and stirred for 10 minutes. 48% HBr solution (562.5 ml) was added to the off white slurry obtained. Exotherm was observed and mass was heated to 100°C and kept under stirring for 12 hours. Heating was removed and the mass was cooled to 28°C. Water (1.8 L) was added drop wise to the reaction mass within 0.5 hours. The slurry obtained was stirred for 1 hour and filtered at 25°C. The cake obtained was washed with water (225 ml x 3) and solid was suck dried to yield crude Diflunisal.

Example 5
Purification of Diflunisal
Diflunisal obtained above was purified with acetone. Diflunisal (77 gm) was dissolved in acetone (230 ml) and mass obtained was refluxed at 55°C. Activated charcoal (7.7 gm) was charged and mass was refluxed for 1 hour. The mass was filtered in hot conditions under vacuum and washed with acetone (77 ml). The solution was cooled to 25°C and water (770 ml) was charged to the filtrate at 25°C. The mixture was stirred for 2 hours at 25°C. The slurry obtained filtered under vacuum, washed with water (300 ml) and dried at 50°C under vacuum to yield pure Diflunisal (65 gm). (Yield: 84.41%)
HPLC Purity: 99.63 %

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.