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 (S)-BENOXAPROFEN

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
GALAXY, FLOORS: 22-24,
PLOT No.1, SURVEY No.83/1,
HYDERABAD KNOWLEDGE CITY,
RAIDURG PANMAKTHA,
RANGA REDDY DISTRICT,
HYDERABAD – 500 032,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

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

FIELD OF THE INVENTION

The invention relates to a process for the preparation of (S)-Benoxaprofen or pharmaceutically acceptable salts and hydrates thereof comprising resolution of racemic Benoxaprofen by a general, efficient and cost-effective chiral reagent and solvents and it is feasible at commercial level.

BACKGROUND 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.

Formula I

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

It is known that the dextrorotatory form exerts a considerably greater anti-inflammatory activity than the levorotatory antipode, or than the corresponding racemic mixture.

The production of dextrorotatory form with sufficient optical purity is therefore of considerable interest.

GB Patent 1495488 covered optically active Benoxaprofen and a process for the preparation thereof. GB ‘488 Patent describes resolution of racemic 2-(4-hydroxy-3-nitrophenyl) propionitrile (A) with l-ephedrine, followed by reduction of nitro (B) to amine (C) and followed by condensation with p-chlorobenzoyl -chloride (D) and hydrolysis of nitrile (E) to carboxylic acid in (+)-Form i.e. (S)-Benoxaprofen as in the scheme below:

This processes involve costly raw materials and multistep synthetic process and results in poor yield.

GB ‘488 Patent states that all attempts to isolate two isomers in pure form from the racemate have been in vain.

US Patent 4,973,745 describes a process for obtaining (S)-enantiomers of 2-arylpropionic acids by reacting a racemic mixture thereof with an optically active form of threo-1-nitrophenyl-2-aminopropane-1,3-diol which process comprises converting the racemate of a 2-arylpropionic acid with D-(-)-threo-1-nitro-phenyl-2-aminopropane-1,3-diol into the diastereomeric salts of said 2-aryl propionic acids, separating said salts and isolating the (S)-enantiomer forms of the said 2-arylpropionic acid or the salts thereof from the resulting pure diastereomers.

US Patent 5,380,867 describes selective crystallization of the desired salt of a-aryl carboxylic acid from a mixture containing a-aryl carboxylic acid and a suitable amino acid such as lysine.

Biomedical Chromatography (2003), 17(5), 325-334 describes the resolution of the enantiomers of 2-arylpropionic drugs, including Ibuprofen, Ibuproxam, Ketoprofen, Pranoprofen, Benoxaprofen, Flurbiprofen and Tiaprofenic acid with L-(-)-serine and L-(-)-threonine and a mixture of L-(-)-serine and L-(-)-threonine (1:1) as chiral selectors.

These chiral amines such as ephedrine, L-(-)-serine and L-(-)-threonine and a mixture of L-(-)-serine and L-(-)-threonine (1:1), threo-1-nitrophenyl-2-amino -propane-1,3-diol are expensive and are often difficult to recover. Furthermore, because many are natural products, usually only one enantiomer is readily available.

Though, there are processes available in the literature for the preparation of (S)-Benoxaprofen, These methods, however, have a number of limitations including the following: they are not general; they require considerable volumes of solvent; some require relatively high temperature; they produce product of less than optimal chemical and enantiomer purity and accordingly require further purification steps resulting in reduction in yield. Many of these methods do not result in the formation of desired final product and they are too costly and/or complicated to scale up to commercial scale. To this date there is no known commercial process for the production of (S)-Benoxaprofen.

There is always a need for an alternative and improved preparative routes, which provide a higher yield of product with higher purity. In view of this we have developed the present invention, related to an improved, economic, reproducible and commercially viable process for the preparation of (S)-Benoxaprofen with good yield and high purity.

OBJECTIVE OF THE INVENTION

The primary object of the present invention is to provide an improved process for the preparing optically active Benoxaprofen with good quality and purity.

Another object of the present invention is to provide a general, efficient, cost effective and industrially feasible process for producing (S)-Benoxaprofen of formula (S)-I or pharmaceutically acceptable salts and hydrates thereof comprising resolution of racemic Benoxaprofen (I), wherein the process involves (1R,2S)-(+)-Cis-1-amino-2-indanol as chiral reagent and formation of compound of formula II.

SUMMARY OF THE INVENTION

The process according to the present invention for producing (S)-Benoxaprofen of formula (S)-I or pharmaceutically acceptable salts and hydrates thereof.

Formula (S)-I

which comprises:
a) Treating racemic Benoxaprofen with (1R,2S)-(+)-cis-1-amino-2-indanol in a solvent or mixture of solvents;
b) Isolating (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt of formula-II;

Formula -II

c) Optionally purifying (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt in a solvent or mixture of solvents;
d) Converting (S)-Benoxaprofen-(1R,2S)-(+)-Cis-1-amino-2-indanol salt to (S)-Benoxaprofen;
e) Optionally converting (S)-Benoxaprofen into its pharmaceutically acceptable salts and hydrates thereof.

The process according to the present invention for producing (S)-Benoxaprofen of formula (S)-I, or pharmaceutically acceptable salts and hydrates thereof.

Formula (S)-I

comprises:
a) Treating racemic Benoxaprofen with (1R,2S)-(+)-Cis-1-amino-2-indanol in ethanol and methanol;
b) Isolating (S)-Benoxaprofen-(1R,2S)-(+)-Cis-1-amino-2-indanol salt of formula-II;

Formula -II

c) Optionally purifying (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt in a solvent or mixture of solvents;
d) Converting (S)-Benoxaprofen-(1R,2S)-(+)-Cis-1-amino-2-indanol salt to (S)-Benoxaprofen using acid;
e) Optionally converting (S)-Benoxaprofen into its pharmaceutically acceptable salts and hydrates thereof.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the process according to the present invention for producing (S)-Benoxaprofen of formula (S)-I or pharmaceutically acceptable salts and hydrates thereof.

Formula (S)-I

comprises:
a) Treating racemic Benoxaprofen with (1R,2S)-(+)-Cis-1-amino-2-Indanol in a solvent or mixture of solvents;
b) Isolating (S)-Benoxaprofen-(1R,2S)-(+)-Cis-1-amino-2-Indanol salt of formula-II;

Formula -II

c) Optionally purifying (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt in a solvent or mixture of solvents;
d) Converting (S)-Benoxaprofen-(1R,2S)-(+)-Cis-1-amino-2-Indanol salt to (S)-Benoxaprofen;
e) Optionally converting (S)-Benoxaprofen into its pharmaceutically acceptable salts and hydrates thereof.

The solvent(s) used in present invention is selected from the group comprising of esters selected from ethyl acetate, and isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons selected from toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride; dialkyl formamides selected from dimethyl formamide; ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, dimethyl ether, and methyl butyl ether; cyclic ethers selected from tetrahydrofuran, and 1 ,4-dioxane; substituted cyclic ethers selected from 2-methyl tetrahydrofuran; alcohols selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, and diethylene glycol; ketones selected from acetone, methyl ethyl ketone, and methyl isobutyl ketone; dialkylsulfoxides selected from dimethyl sulfoxide; dialkylacetamides selected from N,N-dimethyl acetamide; nitriles selected from acetonitrile, and propionitrile; water and/or mixtures thereof.

The solvent(s) used in present invention is preferably selected from ethanol, methanol or mixture of ethanol and methanol.

The process according to present embodiment is carried at a temperature of 0-100ºC, preferably 30-80ºC, more preferably 55-75ºC.

The process according to present embodiment is carried for about 10 minutes to 10 hours, preferably 7-9 hours.

Racemic Benoxaprofen in a solvent or mixture of solvents is treated with (1R,2S)-(+)-Cis-1-amino-2-Indanol at a temperature of 55-75ºC, and stirred for 20-60 minutes, the mixture is cooled to 20-30ºC and stirred for 7-9 hours and isolated (S)-Benoxaprofen-(1R,2S)-(+)-Cis-1-amino-2-Indanol salt. The isolated salt is optionally purified using solvent or mixture of solvents.

In another embodiment, the process according to the present invention for producing (S)-Benoxaprofen of formula (S)-I, or pharmaceutically acceptable salts and hydrates thereof.

Formula (S)-I

comprises:
a) Treating racemic Benoxaprofen with (1R,2S)-(+)-cis-1-amino-2-indanol in ethanol and methanol;
b) Isolating (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt of formula-II;

Formula -II

c) Optionally purifying (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt in a solvent or mixture of solvents;
d) Converting (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt to (S)-Benoxaprofen using acid;
e) Optionally converting (S)-Benoxaprofen into its pharmaceutically acceptable salts and hydrates thereof.

(S)-Benoxaprofen-(1R,2S)-(+)-Cis-1-amino-2-Indanol salt is dissolved in a solvent and treated with an acid and the mixture is stirred for 1-3 hours and isolated (S)-Benoxaprofen. It is optionally converted into its pharmaceutically acceptable salts and hydrates thereof.

The solvent(s) used herein is selected from the group comprising of esters selected from ethyl acetate, and isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, and pentane; aromatic hydrocarbons selected from toluene, xylene, and naphthalene; halogenated aliphatic hydrocarbons selected from dichloromethane, chloroform, and ethylene dichloride; dialkyl formamides selected from dimethyl formamide; ethers selected from methyl tertiary butyl ether, di-isopropyl ether, di-ethyl ether, dimethyl ether, and methyl butyl ether; cyclic ethers selected from tetrahydrofuran, and 1 ,4-dioxane; substituted cyclic ethers selected from 2-methyl tetrahydrofuran; alcohols selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, ethylene glycol, and diethylene glycol; ketones selected from acetone, methyl ethyl ketone, and methyl isobutyl ketone; dialkylsulfoxides selected from dimethyl sulfoxide; dialkylacetamides selected from N,N-dimethyl acetamide; nitriles selected from acetonitrile, and propionitrile; water and/or mixtures thereof, preferably water.

The acid herein used is mineral acid or an organic acid selected from formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, trifluoroacetic acid, methane sulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid and the like, preferably hydrochloric acid.

Racemic Benoxaprofen can be prepared according to conventional methods known in the art including US Patent US RE 29,608 and Spain patent ES 8203863 etc.

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 the invention in any manner whatsoever.

EXAMPLES:

PREPARATION OF (S)-BENOXAPROFEN-(1R,2S)-(+)-CIS-1-AMINO-2-INDANOL SALT:

In a 5L RBF, 2.0L ethanol and 1.0L methanol was added at room temperature. To the above mixture, 50 g of racemic Benoxaprofen was added and stirred for about 15 minutes at 20-30ºC. 24.8 g of (1R,2S)-(+)-Cis-1-amino-2-Indanol was added at 20-30ºC to the mixture and heated to 70-75º and stirred for 20-40 minutes. The mixture was cooled to 20-30ºC and stirred for 7-9 hours, and it was cooled to 0-5°C and stirred for 2-3 hours and filtered and washed with Ethanol (2X50 ml) to get 95 g (wet) of (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol Salt.

PURIFICATION OF (S)-BENOXAPROFEN-(1R,2S)-(+)-CIS-1-AMINO-2-INDANOL SALT:

In a 5L RBF, 1850 ml 2:1 ratio ethanol and methanol was added and charged 95 g of (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt. The reaction mixture was stirred for about 15 minutes at 20-30ºC, heated to 70-75ºC and stirred for 30 minutes. The mixture was cooled to 20-30ºC and stirred for 1 hour, cooled to 0-5ºC for 1 hour and filtered, washed with ethanol (2X50 ml), suction dried and dried under reduced pressure (~20 mm Hg) at 50-55ºC to get 25 g of (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt.

PREPARATION OF (S)-BENOXAPROFEN:

In a 2L RBF, 25 g of (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt was charged and 200 ml purified water was added at 20-30ºC. Reaction mass was stirred for 15 minutes at 20-30ºC and adjusted pH to 1.8-2.2 with about 25 ml of 8%w/w aqueous hydrochloric acid and stirred for 2 hours. Filtered the product and washed with purified water (2X50 ml), suction dried and dried under reduced pressure (~20 mm Hg) at 50-55ºC to get 12 g of (S)-Benoxaprofen. ,CLAIMS:WE CLAIM:
1. A process for the preparation of (S)-Benoxaprofen of formula (S)-I or pharmaceutically acceptable salts and hydrates thereof

Formula (S)-I

comprising:
a) Treating racemic Benoxaprofen with (1R,2S)-(+)-cis-1-amino-2-indanol in a solvent or mixture of solvents;
b) Isolating (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt of formula-II;

Formula -II

c) Optionally purifying (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt in a solvent or a mixture of solvents;
d) Converting (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt to (S)-Benoxaprofen;
e) Optionally converting (S)-Benoxaprofen into its pharmaceutically acceptable salts and hydrates thereof.

2. The process, as claimed in claim 1, step (a), wherein the reaction is carried out at a temperature ranging between 30-100°C.

3. The process, as claimed in claim 1, step (a) and step (c), wherein the solvent comprises methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, n-pentanol, dichloromethane, chloroform, and ethylene dichloride, water.

4. The process as claimed in claim 1, step (d), wherein the conversion of (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt to (S)-Benoxaprofen is obtained by treating with an acid selected from formic acid, acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, trifluoroacetic acid, methane sulfonic acid, hydrochloric acid, hydrobromic acid, hydro iodic acid and sulfuric acid and the like, preferably hydrochloric acid.

5. (S)-Benoxaprofen-(1R,2S)-(+)-cis-1-amino-2-indanol salt of formula-II

Formula -II