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 AND ITS INTERMEDIATE

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 its intermediate 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, mentstrual cramps. NSAIDS are perhaps most popular new group of medications on 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 leads to 2-(4-hydroxyphenyl)propionitrile of formula (b), which is 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 is recrystallized in methanol to obtain p-chloro-2-(2-phenyl-5-benzoxazolyl)propionitrile of formula (f). Finally, hydrolysis with conc. HCl, to give 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 was 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;
ii) involves the use of most hazardous reagents like cyanides.
Journal of Chromatography (1976), 129, P.No. 339-345, reported a process for the preparation of Benoxaprofen of formula (I) described in scheme-III:

Scheme-III
The disadvantage of the above reported process involve the use of hazardous reagent like sodium cyanide.

Synthetic communications, (1985), 15(12), P.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 leads to the formation of an impurity in methylation step which results an impure compound.

In view of the preparation methods available for Benoxaprofen, there is a need for simple, cost effective, environmentally friendly, commercially scalable, feasible process for the preparation of highly pure Benoxaprofen (I), and its intermediate thereof by avoiding the use of hazardous reagents.

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.

Yet another objective of the present invention is to provide a process for the preparation of formula (V) which is a useful intermediate in the preparation of Benoxaprofen of formula (I).

SUMMARY OF THE INVENTION
The main embodiment of the present invention is to provide an improved process for the preparation of formula (V), which is a useful intermediate in the preparation of Benoxaprofen of formula (I).

The process comprises:
i) methylation of formula (II);

with methyl iodide inpresence of a base comprising, an alkoxide in a solvent to obtain formula (III);

wherein R is Tertiary butyl trimethyl silyl or 2-Methoxyethoxy methyl;
ii) deprotection of formula (III) to obtain formula (IV);

iii) hydrolysis of formula (IV) to obtain formula (V).

Another embodiment of the present invention is to provide a process for the preparation of Benoxaprofen of formula (I),

which comprises:
coupling of formula (VI);

with 4-chlorobenzoyl chloride of formula (e);

inpresence of a base in a solvent to obtain formula (VII);

which further undergoes cyclisation in presence of an acid to obtain Benoxaprofen of formula (I).

Yet another embodiment of the present invention is to provide a process for the purification of Benoxaprofen in ketonic solvent to obtain pure Benoxaprofen.

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

comprising:
i) methylation of formula (II);

with methyl iodide in presence of a base comprising, an alkoxide in a solvent to obtain formula (III);

Wherein R is Tertiary butyl trimethyl silyl or 2-Methoxyethoxy methyl.
ii) deprotection of formula (III) to obtain formula (IV);

iii) hydrolysis of formula (IV) to obtain formula (V).

The base used in above methylation comprises an alkoxides comprises sodium methoxide, 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.

Deprotection is carried out in presence of an acid comprises hydrochloric acid or sulphuric acid.

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

Another embodiment of the present invention, is related to a process for the preparation of Benoxaprofen of formula (I),

comprising the steps of:
coupling of formula (VI);

with 4-chlorobenzoyl chloride of formula (e);

inpresence of a base in a solvent to obtain formula (VII);

which further undergoes cyclisation in presence of an acid to obtain Benoxaprofen of formula (I).

The base used in coupling reaction comprises isopropyl amine, diisopropyl amine, diisopropyl ethyl-amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N-methyl pyridine or triethylamine. The solvent comprises of polar aprotic solvents selected from tetrahydrofuran, dimethyl sulfoxide and dimethyl formamide or mixtures thereof.
Yet another embodiment of the present invention is related to a process for purification of Benoxaprofen of formula (I) in ketonic solvent to obtain pure Benoxaprofen.

The ketonic solvent comprises acetone or methyl isobutyl ketone or mixtures thereof.

The synthetic scheme for the preparation of Benoxaprofen (I) & its intermediate according to the present invention is represented in scheme-V & scheme VI:

Scheme-V

Scheme-VI
Wherein R is Tertiary butyl trimethyl silyl or 2-Methoxyethoxy methyl.

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

EXAMPLE 1:
METHYLATION OF PROTECTED ETHYL PROPIONATE (II):

The compound (II) (350 grams) was charged in tetrahydrofuran (1000 ml) at 20-30 °C under nitrogen atmosphere. Methyl iodide (202.6 grams) was added to the reaction mass at 20-30 °C and potassium tertiary butoxide solution was added over a period of 2 hours±15 minutes at 5-15 °C. The reaction mixture was stirred for 5 hours at this temperature. Completion of reaction was checked by HPLC. DM water (1000 ml) followed by cyclohexane (1000 ml) were added to the reaction mixture at 5-15 ? and stirring was continued for 10-15 minutes at 20-30 °C. The layers were allowed to settle at 20-30 °C for 15 ± 5 minutes and organic layer was separated, cyclohexane (500 ml) was added to the aqueous layer, at 20-30 °C and stirred for 15 ± 5 minutes at this temperature. The layers were allowed to settle at 20-30 °C for 15 ± 5 minutes and the organic layer was separated at 20-30 °C and combined it with the organic layer obtained above. DM water (500 ml) was added to the combined organic layer at 20-30 °C and stirred for 10-15 minutes at this temperature. The layers were allowed to settle for 5-10 minutes and the organic layer was separated and concentrated under reduced pressure at 25-30 °C to obtain oily mass (III).
Average Yield: 326.0 grams.
HPLC Purity: 79.03%

EXAMPLE 2:
DEPROTECTION OF COMPOUND OF FORMULA (III):

The compound (III) (320 grams) prepared in Example 1 was charged in 16% aqueous methanol at 20-30 °C and concentrated hydrochloric acid (325 grams) was added to the reaction mass at 10-20 °C over a period of 45 minutes (slightly exothermic). The reaction mass was stirred for 4 hours at 10-20 °C and ethyl acetate (1900 ml) followed by DM water (950 ml) were added to the reaction mass at 10-20 °C. Stirring was continued for 15-20 minutes and the organic layer was separated. The aqueous layer was diluted with DM water (1000 ml), ethyl acetate (1000 ml) was added at 20-30 °C and stirring was continued for 15 ± 5 minutes at this temperature. The layers were allowed to settle for 15 ± 5 minutes at 20-30 °C and the organic layer was separated and combined it with the organic layer obtained above. The combined organic layers were washed with DM water (2 x 750 ml) at 10-20 ? and the organic layer was concentrated under reduced pressure at 30-40 °C till no more distillate was collected. Finally, dried the product under high vacuum at 40-45°C for 45 minutes to obtain oily crude (IV).
Average Yield: 276 grams
HPLC Purity: 55.73%

EXAMPLE 3:
HYDROLYSIS OF ETHYL 2-(4-HYDROXYPHENYL) PROPIONATE (IV):

The compound (IV) (270 grams) prepared in Example 2 was charged in methanol (1000 ml) at 20-30 °C and sodium hydroxide solution was added to the reaction mass at 20-60 °C in 30 minutes. The reaction mass was heated to 60-70 °C and stirred for 2 hours at 60-70 °C. Methanol was distilled completely from the reaction mass under reduced pressure at 60-65 °C and cooled to 20-25 °C. DM water (2000 ml) followed by methylene chloride (1000 ml) were added to the reaction mass and stirring was continued for 10-15 minutes at 20-30 °C. The aqueous layer was separated and adjusted the pH of the aqueous layer to 1.1±0.1 (initial pH 12.5) with concentrated hydrochloric acid (~270 ml) at 20-30 °?C a hazy solution was resulted. Ethyl acetate (2000 ml) was added to this reaction mass and stirred for 10-15 minutes. The layers were allowed to settle at 20-30 °C for 15 ± 5 minutes and organic layer was separated at 20-30 °C. Ethyl acetate (800 ml) was added to the aqueous layer and stirred for 10-15 minutes. The layers were allowed to settle at 20-30 °C for 15 ± 5 minutes and the organic layer was separated at 20-30 °C. Combined it with the organic layer obtained above and the combined organic layers were washed with DM water (800 ml) at 20-30 ?. The organic layer was separated at 20-30 °C and concentrated under reduced pressure at 40-50 °C till no more distillate was collected. Toluene (810 ml) was added to the concentrated mass at 40-50 °C and the reaction mass was heated to 70-80 ?. Stirring was continued at this temperature for 30 minutes and the reaction mass was cooled to 10-15 ?. The product was filtered at 10-15 °C and washed with pre-cooled toluene. Finally, the product was dried at 60-65 °C under reduced pressure (~20 mm Hg) to obtain formula (V).
Average Yield: 119 grams
HPLC Purity: 91.3%

EXAMPLE 4:
PREPARATION OF AMIDE INTERMEDIATE:

The compound (VI) (25 grams) was charged in mixture of tetrahydrofuran (525 ml) and DM water (47.5 ml) at 25-30 °C and the reaction mass was stirred for 10-15 minutes. 4-Chlorobenzoyl chloride of formula (e) (31.4 grams) was diluted in tetrahydrofuran (25 ml) and this solution was added to the reaction mass at 25-30 ? over a period of 1 hour±10 minutes. The reaction mass was stirred for 1hour 30±10 minutes at 25-30 ? and triethylamine (17.4 grams) was added to the reaction mass for 50±10 minutes at this temperature and stirring was continued for 2 hours. The reaction mass was concentrated under reduced pressure (100-20 mm Hg) at 30-40 °C until no more distillate was collected. Ethanol (175 ml) was added to the concentrated mass at 30-40 °C and stirring was continued for 1 hour±10 minutes at this temperature. The reaction mass was cooled to 0-5 °C and stirred for 1 hour±10 minutes at this temperature. The product was filtered and washed it with pre-cooled ethanol (25 ml, 0-5?). Finally, the product was kept under suction for 30 minutes and most of the filtrate was squeezed. The product was dried at 40-50 °C under reduced pressure (~20 mm Hg) to obtain formula (VII).
Average yield: 37.0 grams
HPLC Purity: 91.73%

EXAMPLE 5:

PREPARATION OF 2-(4-CHLOROPHENYL-a-METHYL-5-BENZOXAZOLEACETIC ACID (BENOXAPROFEN)

The compound (VII) (34 grams) prepared in Example 4 was charged in a mixture of tetrahydrofuran (340 ml) and DM water (7.5 ml) at 25-30 °C and stirred for 10-15 minutes. Triethylamine (11.8 grams) was added to the reaction mass at 20-30 ? and stirred for 30 minutes at this temperature. Toluene (180 ml) followed by the addition of methane sulfonic acid (20.45 grams) were added to the reaction mass at 20-30 ? and the reaction mass was heated to 60-65 °C. Tetrahydrofuran was distilled from reaction mass under atmospheric pressure at 60-90 °C to get a volume of distillate 340 ml and methane sulfonic acid (20.45 grams) was added to the reaction mass at 85-90 ? and the reaction mass was heated to 100-110 °C. The above reaction mass was stirred for 10 hours at this temperature and concentrated under reduced pressure (100-20 mm Hg) at 40-50 °C until no more distillate was collected. Ethyl acetate (680 ml) was added to the concentrated mass at 25-30 °C and the reaction mass was heated to 50-60 ?. Stirring was continued for 15 minutes at this temperature and DM water (340 ml) was added to the reaction mass at 55-60 ? and stirred for 30±5 minutes. The organic layer was separated and adjusted the pH of the reaction mass to 10.9±0.1 by using sodium hydroxide solution. The organic layer was separated and ethyl acetate (680 ml) was added to the aqueous layer at 50-60? and stirred for 10±5 minutes. The pH of the reaction mass was adjusted to 3.5±0.2 by using conc. hydrochloric acid (~40 ml) at 50-60?. The layers were allowed to settle for 10±5 minutes at 55-60? and the organic layer was separated at 55-60? and carbon enoanticromos (2 grams) was added to the combined organic layer at 55-60 ?. Stirring was continued for 15 minutes at this temperature and the above reaction mass was filtered through a hyflo pad and the residue was washed with ethyl acetate (34 ml) at 55-60 ?. The obtained filtrate was concentrated under reduced pressure (100-20 mm Hg) at 50-60 ? to give reaction mass volume 170 ml and the product was started precipitated out during the concentration. The reaction mass was cooled to 20-25°C and stirred for 30 minutes. The product was filtered and washed with ethyl acetate (34 ml) at 25-30 ?. Finally, the product was kept under suction for 30 minutes and most of the filtrate was squeezed. The product was dried at 50-60 °C under reduced pressure (~20 mm Hg) to give Benoxaprofen of formula (I).
Average Yield: 25.2 grams
HPLC Purity: 99.95%

EXAMPLE 6:
PURIFICATION OF BENOXAPROFEN (I):
Benoxaprofen (25 grams) prepared in Example 5 was charged in methyl isobutyl ketone (250 ml) at 25-30 ºC and the reaction mass was heated to 113-118 ºC. The reaction mass was stirred for 30±5 minutes at this temperature and cooled to 20-25 ºC over a period of 40±5 minutes. Stirring was continued for 30±5 minutes at 20-25 ºC and the product was filtered, washed with methyl isobutyl ketone (25 ml) at 20-25 ºC. Finally, the product was kept under suction for 30 minutes and most of the filtrate was squeezed. Later, the product was dried under reduced pressure (~20 mm Hg) at 50-60 °C till LOD is < 0.5% w/w to give Form II of pure Benoxaprofen (I).

Average Yield: 21.5 grams.
HPLC Purity: 100%.
,CLAIMS:We Claim:
1. A process for the preparation of an intermediate of Benoxaprofen of formula (V),

which comprises,
i) methylation of formula (II),

with methyl iodide inpresence of a base and an organic solvent to obtain formula (III).

wherein R is Tertiary butyl trimethyl silyl or 2-Methoxyethoxy methyl;
ii) deprotection of formula (III) to obtain formula (IV);

iii) hydrolysis of formula (IV) to obtain formula (V).

2. The process as claimed in claim 1, wherein the base used can be selected from inorganic base.

3. The process as claimed in claim 2, wherein the inorganic base comprises alkoxides selected from sodium methoxide, sodium tertiary butoxide, potassium methoxide, potassium i-butoxide or potassium tertiary butoxide.

4. The process as claimed in claim 1, wherein deprotection is carried out in presence of an acid comprises hydrochloric acid or sulphuric acid.

5. The process as claimed in claim 1, wherein hydrolysis is carried out inpresence of a base comprises alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide or lithium hydroxide or mixtures thereof.

6. A process for the preparation of Benoxaprofen of formula (I),

which comprises:
coupling of formula (VI);

with 4-chlorobenzoyl chloride of formula (e);

inpresence of a base in a solvent to obtain formula (VII);

which further undergoes cyclisation in presence of an acid to obtain Benoxaprofen of formula (I).

7. The process as claimed in claim 6, wherein the base comprises organic base.

8. The process as claimed in claim 7, wherein the organic base comprises isopropyl amine, diisopropyl amine, diisopropyl ethyl-amine, N-methyl morpholine, N-methyl piperidine, N-methyl piperazine, N-methyl pyridine or triethylamine.

9. The process as claimed in claim 6, wherein the cyclisation is carried out in presence of an acid, preferably methane sulfonic acid.

10. A compound of formula (V),

Wherein R is Tertiary butyl trimethyl silyl Or 2-Methoxyethoxy methyl.