"AN IMPROVED PROCESS FOR THE PREPARATION OF LORNOXICAM"

FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Lornoxicam. The present invention is also provides a process for the purification of Lornoxicam.

BACKGROUND OF THE INVENTION:

Lornoxicam, chemically known as 6-chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)2H-thieno[2,3-e]-l,2-thiazine-l,l-dioxide of formula (I), is a thienothiazine derivative useful as an anti-inflammatory, analgesic and anti-rheumatic agent.

Lornoxicam is a non steroidal anti-inflammatory drug (NSAID) of the oxicam class. It is often used to treat individuals who suffer from rheumatoid arthritis and other rheumatic diseases, U.S. patent, 4,180,662, discloses Lornoxicam and the process it's for preparation. In the process described in '662 patent, Lornoxicam is synthesized in seven chemical steps by using 2, 5-dichlorothiophene as the starting raw material. The process involves chlorosulphonation using chlorosulphonic acid; carboxylation using n-butyl lithium and dry carbondioxide under cryogenic conditions. The preparation of Lornoxicam as described in the last step, involves the condensation of 2-aminopyridine and 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2-H-thieno [2, 3-e]-l, 2-thiazine-l, 1-dioxide using large amount of xylene, wherein the xylene is also used for precipitation of Lornoxicam. The synthetic process is illustrated as per the following Scheme-I.

Scheme-I

Chinese patent, CN1699372 discloses a process for the synthesis of methyl 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-l,2-thiazine-3-carboxylate 1,1 -dioxide, an intermediate used in the synthesis of Lornoxicam. The synthesis describes CN'372 is illustrated as per the following Scheme-Il

The process described in aforesaid patents are lengthy, time-consuming, involves hazardous agents and also use of large amounts of solvents. The resultant yields obtained are very less and it takes more time consumption for a complete reaction.

None of the aforementioned prior arts discloses a process for Lornoxicam with increased yield and purity in a simple, easy and cost-effective manner, without the use of toxic and hazardous materials. Hence, there is a need to develop a simple, cost effective and industrially viable process which is more efficient and environment friendly.

Therefore, the present inventors developed a commercial process by using Grignard reagent in the preparation of Lornoxicam by following advantages.

a) reaction temperature has been reduced to 70-80°C instead of 140-145°C. Hence the decomposition of reaction product reduced drastically; with increased yield and purity.

b) reaction time decreased to 4 hrs instead of 8-10 hrs.

c) the usage of solvent has been reduced to 20-25 volumes instead of 80 volumes.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide an improved process for the preparation of Lornoxicam of formula (I) comprising the steps of;

a) cyclization of methyl-5-chloro-3-(methoxycarbonylmethyl) aminosulphonyl thiophene-2-carboxylate of formula (IV) in presence of alkali metal alkoxide,

b) methylation of the obtained product step a) using dimethylsulphate in an organic solvent,

c) condensation of the obtained product step b) with 2-aminopyridine in presence of Grignard reagent and aromatic hydrocarbon solvent, and

d) isolating the Lornoxicam of formula(I)

Scheme-Ill

In another aspect of the present invention is to provide a process for purification of Lornoxicam comprises the steps of;

a) adding crude Lornoxicam to alcohol solvent and cooled to 5-10°C,

b) resulting suspension of step a) is basified with aqueous alkali metal hydroxide solution,

c) adding a mixture of hydrochloric acid and water(l:l) to the step b) at 5-10° C, till the reaction mass pH at 4.0-5.0,

d) stirring the obtained slurry of step c), and

e) isolating the purified Lornoxicam.

Detailed Description of the Invention

The present invention relates to an improved process for the preparation of Lornoxicam. The present invention is also provides a process for the purification of Lornoxicam.

One embodiment of the present invention is to provide an improved process for the preparation of Lornoxicam of formula (I) comprising the steps of;

a) cyclization of methyl-5-chloro-3-(methoxycarbonylmethyl) aminosulphonyl thiophene-2-carboxylate of formula (IV) in presence of alkali metal alkoxide,

b) methylation of the obtained product step a) using dimethylsulphate in an organic solvent,

c) condensation of the obtained product step b) with 2-aminopyridine in presence of Grignard reagent and aromatic hydrocarbon solvent, and

d) isolating the Lornoxicam of formula(I)

According to the present invention, the cyclization of methyl-5-chloro-3-(methoxycarbonylmethyl) aminosulphonylthiophene-2-carboxylate of formula (IV) in alcohol solvent, added alkali metal alkoxide at 30°C over a period of 30-45 min. The resulting mixture is stirred for 60 min at same temperature and heated to 65-75°C. After completion of reaction, the alcohol solvent is distilled out under reduced pressure to obtained residual product, followed by addition of distilled mineral water and 6-chloro-4-hydroxy-l,l-dioxo-l,2-dihydro-lX,6-thieno [2,3-e][l,2] thiazine-3-carboxylic acid methyl ester and cooled to 10-15° C.

The dimethyl sulphate is slowly added to the mixture at 10-15°C in 30 min., temperature of the reaction mixture is raised to 25-30°C and maintained reaction mixture for 2-3 hrs at same temperature. After completion of reaction, mixture was cooled 10-15°C, followed by addition of chlorinated solvent, and mixture was acidified to pH 1.0 - 2.0 with hydrochloric acid at 10-15°C under stirring condition, separated organic layer and aqueous layers. The organic layer isdistilled out completely, followed by addition of alcohol solvent to the residue and distilled out completely under vacuum at below 50°C to get a residue, further it is recrystallized with alcohol solvent to get compound of formula (II).

Accordingly, the compound of formula (II) is suspended in aromatic hydrocarbon solvent and heated to 70-75°C to get clear solution, followed by slow addition of THF solution of 2-Amino pyridine and Grignard reagent at 70-75°C, maintained the same temperature for 3-4 hrs. After completion of reaction, the mass is allowed to cool at room temperature, further it is treated with dilute hydrochloric acid at 10-15°C. The resultant solid is filtered and washed with water to get crude Lornoxicam.

According to the embodiment, alcohol solvent is selected from methanol, ethanol and isopropyl alcohol; alkali metal alkoxides is selected from sodium methoxide or sodium ethoxide; aromatic hydrocarbon solvent is selected from xylene, toluene or mesitylene; Grignard reagent is selected from isopropyl magnesium bromide, ethyl magnesium bromide or ethyl magnesium chloride; chlorinated solvent is selected from dichloromethane, ethylene dichloride or chloroform.

In a preferred embodiment, the present invention provides advantages by using Grignard reagent in the preparation of Lornoxicam:

a) reaction temperature has been reduced to 70-80°C instead of 140-145°C. Hence the decomposition of reaction product reduced drastically; with increased yield and purity.

b) reaction time decreased to 4 hrs instead of 8-10 hrs.

c) the usage of solvent has been reduced to 20-25 volumes instead of 80 volumes.

In yet another embodiment of the present invention is to provide a process for purification of Lornoxicam comprises the steps of;

a) adding crude Lornoxicam to alcohol solvent and cooled to 5-10°C,

b) resulting suspension of step a) is basified with aqueous alkali metal hydroxide solution,

c) adding a mixture of hydrochloric acid and water(l:l) to the step b) at 5-10° C, till the reaction mass pH at 4.0-5.0,

d) stirring the obtained slurry of step c), and

e) isolating the purified Lornoxicam.

Accordingly, the present invention provides a process for purification of Lornoxicam with increased yield and purity in a simple, easy and cost-effective manner, without use of toxic and hazardous materials.

In a preferred embodiment, the crude Lornoxicam was added to the solvent mixture of water and alcohol under stirring, subsequently alkali metal hydroxide was added to form a clear solution at 5-10°C .The reaction mass was stirred at 5-10°C and filtered through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 5-10°C till the reaction mass reached pH at 4.0 to 5.0, and then stirred for 30 to 60 minutes. The resultant solid was filtered, washed with 1:1 mixture of alcohol and water and dried at 50-55°C to obtained pure Lornoxicam.

According to the embodiment, the solvent mixture comprises water and alcohol in the ratio of 1:1, wherein alcohol is selected from methanol, ethanol or isopropyl alcohol; Alkali metal hydroxide used in the present invention is selected from but not limited to sodium hydroxide or potassium hydroxide.

According to the present invention, the compound of formula (I) or Lornoxicam having HPLC purity is greater than 99.5%.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Experimental procedure:

Example: 1

Preparation of 6-chloro-4-hydroxy-l,l-dioxo-l,2-dihydro-lX6-thieno [2,3-e][l,2] thiazine-3-carboxylic acid methyl ester To the mixture of methanol ( 1000 ml) and 5-chloro-3-(methoxy carbonyl methyl sulfamoyl)-thiophene-2-carboxylicacid methyl ester ( 100 g ,0.305 moles), added sodium methoxide solution (200 ml ) at 25-30°C over a period of 30-45 min. The resulting mixture was stirred for 60 min at same temperature; allowed to heat at 65-75°C and stirred for 10-12 hrs. After completion of reaction, methanol was distilled out under reduced pressure to obtained titled residual product which is directly used to next step (Example-2).

Example: - 2:

Preparation of 6-chloro-4-hydroxy-2-methyl-l,l-dioxo-l,2-dihydro-U6- thieno[2,3-e][l,2] thiazine-3-carboxylic acid methyl ester 6-chloro-4-hydroxy-1,1 -dioxo-1,2-dihydro-1 X,6-thieno [2,3-e][ 1,2] thiazine-3-carboxylic acid methyl ester was suspended in DM water (500 ml) and cooled to 10-15° C, dimethyl sulphate ( 70 g) was slowly added to the mixture at 10-15°C in 30 min. The reaction mixture was raised to 25-30°C and maintained for 2-3 hours at same temperature. After completion of reaction, mixture was cooled to 10-15°C, methylene dichloride (1600 ml) was added, reaction mixture pH was adjust to 1.0 -2.0 with hydrochloric acid at 10-15° C, stir reaction mixture to separate the layers. The methylene dichloride layer was distilled out completely at below 30°C to get an residue, followed by addition of methanol (60 ml) and distilled out methanol completely under vacuum at below 50°C to get an residue; further it was crystallized by addition of methanol 190 ml and stirred for 30 min at 50-55°C; cooled the reaction mixture at 25-30°C and stirred for 60 min at same temperature. The resultant solid was filtered, washed with methanol (40 ml) and dried at 50-55°C for 4 - 6 hrs to obtain the titled product.

Example: 3

Preparation of 6-Chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazine-3-carboxamide 1,1-dioxide (Lornoxicam) 6-chloro-4-hydroxy-2-methyl-l, 1 -dioxo-1,2-dihydro-l X.6-thieno[2,3-e][l ,2] thiazine-3-carboxylic acid methyl ester ( 50 g 0.161 moles) was suspended in O-xylene (500 ml) and allow to stirred at 70-75°C to obtained clear solution. To this clear solution slowly added the mixture of THF ( 50 ml) solution of 2-Amino pyridine ( 14 g ) and ethyl magnesium bromide 2 molar solution (100 ml) at 70-75°C and allow to stirred for 3-4 hrs at same temperature. After completion of reaction, the dilute hydrochloric acid was added to the mixture at 10-15°C and stirred for 60 min. The resultant solid was filtered, washed with water (100 ml) to obtain crude Lornoxicam.

Example: 4

Preparation of 6-Chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e)-l,2-thiazine-3-carboxamide 1,1-dioxide (Lornoxicam) 6-chloro-4-hydroxy-2-methyl-l,l-dioxo-l,2-dihydro-R6-thieno[2,3-e][l,2] thiazine-3-carboxylic acid methyl ester ( 50 g 0.161 moles) was suspended in O-xylene (500 ml) and allow to stirred at 70-75°C to obtained clear solution. To this clear solution slowly added the mixture of THF ( 50 ml) solution of 2-Amino pyridine ( 14 g ) and isopropyl magnesium bromide 2 molar solution (100 ml) at 70-75°C and allow to stirred for 3-4 hrs at same temperature. After completion of reaction, the dilute hydrochloric acid was added to the mixture at 10-15°C and stirred for 60 min. The resultant solid was filtered, washed with water (100 ml) to obtain crude Lornoxicam.

Example: 5

Purification of Lornoxicam.

The crude Lornoxicam was suspended in methanol (500 ml) and cooled to 5-10°C, resulting suspension was basified to pH 11-13 by using sodium hydroxide solution to get clear solution; followed by filtration through hyflo bed; the obtain filtrate was acidified to pH 4.5 - 5.0 with dil. HC1 (1:1) at 5-10°C; stirred the slurry for 30 min. at 5-10°C. The resultant solid was filtered, washed with DM water (100 ml) and dried at 50-55°C to obtained pure Lornoxicam.

WE CLAIM:

1. An improved process for the preparation of Lomoxicam of formula (I) comprising the steps of;

a. cyclization of methyl-5-chloro-3-(methoxycarbonylmethyl) aminosulphonylthiophene-2-carboxyIate of formula (IV) in presence of alkali metal alkoxide,

b. methylation of the obtained product step a) using dimethylsulphate in an organic solvent,

c. condensation of the obtained product step b) with 2-aminopyridine in presence of Grignard reagent and aromatic hydrocarbon solvent, and

d. isolating the Lornoxicam of formula(I).

2. The process according to claim 1, wherein the alkali metal alkoxides is selected from sodium methoxide or sodium ethoxide

3. The process according to claim 1, wherein the Grignard reagent is selected from ethyl magnesium bromide, isopropyl magnesium bromide or ethyl magnesium chloride.

4. The process according to claim 1, wherein the cyclization of methyl-5-chloro-3-(methoxycarbonylmethyl aminosulphonylthiophene-2-carboxylate of formula (IV) is carried out in an alcohol solvent.

5. A process for purification of Lornoxicam comprises the steps of;

a) adding crude Lornoxicam to alcohol solvent and cooled to 5-10°C,

b) resulting suspension of step a) is basified with aqueous alkali metal hydroxide solution,

c) adding a mixture of hydrochloric acid and water(l:l) to the step b) at 5-10° C,till the reaction mass pH at 4.0-5.0,

d) stirring the obtained slurry of step c), and

e) isolating the purified Lornoxicam.

6. The process according to claim 5, wherein the alkali metal hydroxide is selected from sodium hydroxide or potassium hydroxide.

7. The process according to claim 5, wherein the mixture of hydrochloric acid and water is in the ratio of 1:1.

8. The process according to preceding claims, wherein the aromatic hydrocarbon solvent is selected from xylene, toluene or mesitylene; alcohol solvent is selected from methanol, ethanol or isopropyl alcohol.