DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF BENOXAPROFEN

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the nature of this invention and the manner in which is to be performed:

FILED OF THE INVENTION
The present invention relates to an improved process for the preparation of Benoxaprofen having formula (I) and intermediates thereof.
BACK GROUND OF THE INVENTION
Benoxaprofen (I) is chemically known as 2-(4-chlorophenyl)-a-methyl-5-benzoxazoleacetic acid. Benoxaprofen (I) is a non-steroidal anti-inflammatory drug (NSAID). Non-steroidal anti-inflammatory drugs are a class of medications that possess analgesic and anti-pyretic activities. They are used for reducing body pains, cold, fever and inflammation in a large variety of musculoskeletal disorders, menstrual cramps. NSAIDS are perhaps most popular new group of medications in the market today. Generally, these drugs are used to treat all kinds of pain including rheumatoid arthritis, pain caused by autoimmune disease and physical trauma.

The US Patent US RE 29,608 covered Benoxaprofen (I) as a product and process for the preparation thereof.

The US Patent RE ‘608 described a process for the preparation of Benoxaprofen of formula (I) comprising: a Sandmeyer reaction, by diazotization of 2-(4-aminophenyl)propanenitrile of formula (a) with sodium nitrite followed by acid hydrolysis to give 2-(4-hydroxyphenyl)propionitrile of formula (b), which further undergoes nitration with nitric acid in presence of acetic acid to give 2-(3-nitro-4-hydroxyphenyl)propionitrile of formula (c) followed by reduction with stannous chloride dihydrate or with 10% palladium carbon to give 2-(3-amino-4-hydroxyphenyl)propionitrile of formula (d). The obtained propionitrile reacts with p-chlorobenzoyl chloride of formula (e) in presence of pyridine to give p-chloro-2-(3-benzamido-4-hydroxyphenyl)propionitrile as an oil which was recrystallized in methanol to obtain p-chloro-2-(2-phenyl-5-benzoxazolyl)propionitrile of formula (f). Finally, hydrolysis with conc. HCl gave Benoxaprofen of formula (I). The process is schematically represented in scheme-I:

Scheme-I

ES 8203863 A1 of Medichem, described a process for the preparation of Benoxaprofen of formula (I), by diazotisation of formula (a) to give formula (b) which further undergoes nitration to give nitro compound of formula (c), the obtained nitro compound was reduced to give amine compound of formula (d). The obtained formula (d) was further condensed with compound of formula (g) to give formula (f). Finally, hydrolysis of formula (f) gives Benoxaprofen of formula (I). The process is schematically represented in scheme-II:
Scheme-II

The processes described in the above literature references are having the following disadvantages:
i) starting material (a) is not available easily; and
ii) involves the use of most hazardous reagents like cyanides.

ES 8302676 A1 of Ferrer International S.A described a process for the preparation of Benoxaprofen of formula (I), by acylation of compound of formula (k) with p-chlorobenzoyl chloride of formula (e) which is further heated to dehydration to give corresponding 2-phenyl benzoxazole (l) which further undergoes Grignard reaction to give Benoxaprofen (I). The process is schematically represented in Scheme-III.

Scheme-III
The process described in above literature reference involves highly exothermic Grignard reaction and therefore becomes very critical during large scale production.
Synthetic communications, (1985), 15(12), Pg. No. 1075-1080 reported a process for the preparation of Benoxaprofen of formula (I) which is represented in scheme-IV:

Scheme-IV

Where in R’ is CH3.

The disadvantage of the above said process is that it leads to the formation of a dimethyl impurity in methylation step which is difficult to eliminate in purification. Further, it is very difficult to remove unreacted intermediate (q) in the purification and also involves low temperature reaction (-78°C) in final stage.
In view of the preparation methods available for Benoxaprofen, there is a need for simple, cost effective, environmental friendly, commercially scalable, feasible process for the preparation of highly pure Benoxaprofen (I).
OBJECTIVE OF THE INVENTION
The primary objective of the present invention is to provide an improved process for the preparation of Benoxaprofen of formula (I).

Another objective of the present invention is to provide a simple, cost effective & industrially viable process for the preparation of Benoxaprofen of formula (I) having good yield and purity.

SUMMARY OF THE INVENTION
The main embodiment of the present invention is to provide an improved and cost effective process for the preparation of Benoxaprofen of formula (I).

The process comprises:
i) Reaction of N-(5-acetyl-2-hydroxyphenyl)-4-chlorobenzamide of formula (VI):

with a base and in the presence of a catalyst to give 1-(2-(4-chlorophenyl)benzo[d] oxazol-5-yl) ethanone of formula (V):

ii) Reaction of compound of formula (V) with isopropyl chloroacetate in the presence of metal alkoxides to give epoxy ester intermediate of formula (IV);

iii) Hydrolysis of compound of formula (IV) to give salt of epoxy acid compound of formula (III);

followed by acidification to give aldehyde compound of formula (II);

iv) Oxidation of aldehyde compound of formula (II) to give Benoxaprofen of formula (I).

DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to an improved process for the preparation of Benoxaprofen of formula (I);

Comprising:
i) reaction of N-(5-acetyl-2-hydroxyphenyl)-4-chlorobenzamide of formula (VI);

with a base and in the presence of a catalyst to give 1-(2-(4-chlorophenyl)benzo[d] oxazol-5-yl)ethanone of formula (V);

which may be optionally isolated or carried forward as such to the next step without isolation.
ii) Reaction of compound of formula (V) with isopropyl chloroacetate in the presence of metal alkoxide to give epoxy ester intermediate of formula (IV);

which may be optionally isolated or carried forward as such to the next step without isolation.
iii) Hydrolysis of compound of formula (IV) using alkali hydroxide to give corresponding salt of epoxy acid compound of formula (III);

followed by acidification using inorganic acid to give an aldehyde compound of formula (II);

iv) Oxidation of aldehyde compound of formula (II) using a suitable oxidising agent to give Benoxaprofen crude compound of formula (I) which is optionally purified to give pure Benoxaprofen.
The process for preparation of Benoxaprofen as described in the present invention is schematically represented as shown below.

The base used in the intramolecular cyclisation of compound of formula VI comprises triethylamine, pyridine or DIPEA (N,N-Diisopropylethylamine). The catalyst comprises methanesulfonic acid, para toluene sulfonic acid or pyridinium para-toluene sulfonate. The solvent comprises aprotic solvents toluene, hexane, dichloromethane, acetone, tetrahydrofuran, dimethyl sulfoxide and dimethyl formamide or mixture thereof.

The base used in the epoxidation step comprises alkali alkoxides selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tertiary butoxide, potassium methoxide, potassium i-butoxide or potassium tertiary butoxide. The solvent comprises polar aprotic solvents selected from tetrahydrofuran, dimethyl sulfoxide and dimethyl formamide or mixture thereof.

Hydrolysis is carried out in presence of alkali metal hydroxide comprises sodium, potassium or lithium hydroxides or mixtures thereof, preferably sodium hydroxide.

Acidification of salt of acid is carried out in presence of mineral acids comprises hydrochloric acid, sulphuric acid or nitric acid.

Oxidation of aldehyde intermediate is carried out in the presence of oxidising agents comprising Potassium permanganate, peroxy acids, Hydrogen peroxide, Sodium chlorite, Oxone, Jones reagent or a mixture thereof to provide the desired acid compound.

Purification of crude Benoxaprofen is further carried out in solvents comprises water, methanol, ethanol, propanol, isopropanol, butanol ethylacetate, acetone, methyl ethyl ketone, methyl isobutyl ketone or mixture thereof.

The invention is illustrated with the following example, which is provided by way of illustration only and should not be construed to limit the scope of invention in any manner whatsoever.

EXAMPLE:

PREPARATION OF BENOXAPROFEN:

Step-I: N-(5-Acetyl-2-hydroxyphenyl)-4-chlorobenzamide of formula (VI) (185 g) was suspended in toluene (2000 ml) at 20-30ºC. Triethylamine (74.16 g) was added to the reaction mixture. Methane sulfonic acid (104.2g) was added to the reaction mass at 20-45ºC over a period of 55 to 65 min. The reaction was heated to 110-115ºC with removal of water azeotropically. The reaction was monitored by HPLC, after completion of reaction, reaction mixture was concentrated under reduced pressure at 60-65ºC. Isopropyl alcohol was added to the concentrated mass at 40-50ºC. The reaction mixture was heated to 65-70ºC with continuous stirring and cooled to 10-15ºC, stirred at this temperature for 40 to 50 minutes. Filtered the product and washed with precooled isopropyl alcohol, dried the product under reduced pressure at 60-65ºC to get title compound of formula V.
Average Yield: 157.5 grams
HPLC Purity: 98.5%.

Step-II: 1-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)ethanone compound of formula (V) (25.0g) was suspended in tetrahydrofuran (250.0 mL) under nitrogen atmosphere. Isopropyl chloroacetate (25.0g) was added to this mixture at 20-30°C and the reaction mass was cooled to 10-15°C. Sodium ethoxide solution (58.4g) was added over a period of 30 min and continued stirring at this temperature for 2 hours ±15 min. The reaction was monitored by HPLC, after completion of reaction, DM water (25 mL) was added to the reaction mass at 10-20°C. The reaction mass was proceeded to the next step without isolation of epoxy ester intermediate.

Step-III: Sodium hydroxide (50% w/w, 7.35g) solution was added to the reaction mass obtained in step-II and stirred at 10-15°C. The reaction was monitored by HPLC. After completion of reaction, DM water (10mL) was added to the reaction mass at 20-30°C. The reaction mass was concentrated under reduced pressure at 10-50°C till the reaction mass volume was reduced to ~ 75mL. The ±reaction mass was cooled to 20-30°C and DM water was added (75mL). This reaction mass was proceeded to next step without isolation.

Step-IV: The pH of the reaction mass obtained from step –III was adjusted to 4.0 - 4.2 with conc. Hydrochloric acid (~10mL) at 20-30°C. The reaction mass was heated to reflux (65- 75°C) and maintained at this temperature for completion of epoxy acid intermediate. The reaction was monitored by HPLC. After completion of epoxy acid intermediate, the reaction mass was cooled to 50-60°C and toluene (150mL) and DM water (125mL) were added at 50-60°C. It was allowed to stir at 50-60°C for 20-25 min. The organic layer was separated and washed with water, the organic layer was further concentrated under reduced pressure at 10-50°C till reaction mass volume was about ~130mL.

Step-V: Acetonitrile (25mL) was charged into a solution of benzoxazole aldehyde solution obtained in previous stage at 20-30°C and cooled to 5-15°C. Hydrogen peroxide (12.5g) was added to the reaction mass at 5-15°C and later the pH was adjusted to 3.2 ± 0.5 with aqueous sodium dihydrogen phosphate solution (100mL) at 5-15°C followed by addition of Potassium bromide (0.25g). 80% (w/w) Sodium chlorite solution (~95mL) was added to this reaction mixture at 5-15°C for a period of 1 hour ± 5 min. The reaction mixture was stirred at 5-15°C until the completion of reaction which was monitored by HPLC.

After completion of reaction, 20% aqueous sodium sulphite solution (~55mL) was added to the reaction mass followed by dilution with ethyl acetate (250mL) and DM water (75mL) at 5-15°C. The reaction mass was warmed to 40-50°C stirred for 10-15 min. The organic layer was allowed to settle and separated. The aqueous layer was further extracted with ethyl acetate (75mL) at 40-50°C. DM water (5mL) was added to the combined organic layer and adjusted the pH to 12.3±0.2 with aqueous sodium hydroxide solution (60mL) at 40-50°C. The reaction mixture was stirred at 40-50°C for 10-15 min, the layers were allowed to settle and separated the aqueous layer. 250mL of ethyl acetate was added to the aqueous layer and adjusted the pH the reaction mass to 3.4±0.2 with conc. Hydrochloric acid (10mL) at 20-30°C. The organic layer was separated and further extracted the aqueous layer with ethyl acetate (25mL) at 20-30°C. The combined organic layers were concentrated under reduced pressure which was further slurried in ethyl acetate (250mL). It was then cooled, filtered and washed with ethyl acetate to give Benoxaprofen crude (16.8g).

Step-VI: The crude Benoxaprofen compound (16g) was suspended in methyl isobutyl ketone (MIBK) (288mL) at 25-30°C. The reaction mass was then heated to 110-115°C. To this reaction mass carbon enoanticromos (0.8g) was added and continued to stir at this temperature for 15-20 min. the reaction mass was then passed through celite bed and washed with MIBK (32mL) at 110-115°C. The filtrate was concentrated under reduced pressure at 50-60°C to obtain a reaction mass volume ~ 130mL, cooled the slurry mass to 20-25°C and stirred for 1hour ±10min. The resulting product was filtered, washed and dried to get pure Benoxaprofen.
Average Yield: 14.4 grams.
HPLC Purity: 99.94%.

1H NMR: 1.45 (d, 3H), 3.89 (q, 1H), 7.36-8.20 (m, 7H, Ar-H), 12.37 (S, 1H) ,CLAIMS:We Claim:
1. A process for the preparation of Benoxaprofen of formula (I),

which comprises,
i) Reaction of N-(5-acetyl-2-hydroxyphenyl)-4-chlorobenzamide of formula (VI);

with a base and in the presence of a catalyst to give 1-(2-(4-chlorophenyl)benzo[d] oxazol-5-yl)-ethanone of formula (V);

ii) Reaction of compound of formula (V) with isopropyl chloroacetate in the presence of metal alkoxides to give epoxy ester intermediate of formula (IV);

iii) Hydrolysis of compound of formula (IV) to give salt of epoxy acid compound of formula (III);

followed by acidification to give aldehyde compound of formula (II);

iv) Oxidation of aldehyde compound of formula (II) to give Benoxaprofen of formula (I).

2. The process as claimed in claim 1, wherein the base used in step (i) comprises organic base selected from triethylamine, pyridine or diisopropylethyl amine.
3. The process as claimed in claim 1, wherein the catalyst used in step (i) comprises methanesulfonic acid, para toluene sulfonic acid or pyridinium para-toluene sulfonate.

4. The process as claimed in claim 1, wherein the solvent used in step (i) comprises aprotic solvents selected from toluene, hexane, dichloromethane, acetone, tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide or mixture thereof.

5. The process as claimed in claim 1, wherein the metal alkoxide used in step (ii), comprises sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tertiary butoxide, potassium methoxide, potassium i-butoxide or potassium tertiary butoxide.

6. The process as claimed in claim 1, wherein the solvent used in step (ii), comprises polar aprotic solvent selected from tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide or mixture thereof.

7. The process as claimed in claim 1, wherein the base used in step (iii) comprises alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, lithium hydroxide or mixtures thereof.

8. The process as claimed in claim 1, wherein acidification of salt is carried out in presence of an acid comprises mineral acid selected from hydrochloric acid, sulphuric acid and nitric acid.

9. The process as claimed in claim 1, wherein the oxidising agent used in step (iv), comprises potassium permanganate, peroxy acids, hydrogen peroxide, sodium chlorite, oxone, Jones reagent or mixtures thereof.

10. Compounds of formula (II) & (IV),