FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10) IMPROVED PROCESS FOR THE PREPARATION OF LORNOXICAM
UNICHEM LABORATORIES LIMITED
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V, ROAD, JOGESHWARI (WEST), MUMBAI -
400102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

IMPROVED PROCESS FOR THE PREPARATION OF LORNOXICAM
TECHNICAL FIELD
The present invention describes an improved and economic process for the synthesis of 6-chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl) 2H-thieno [2, 3-e]-l, 2-thiazine-l, 1-dioxide, 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, (Pfister et al, 1979), discloses Lornoxicam and the process its 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 chlorosulphonatioi
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. Xylene is also used for precipitation of Lornoxicam. The process described in '662 patent is lengthy, time-consuming, involves hazardous agents and also use of large amounts of solvents.
According to the abstract of Chinese patent, CN1699372 (Wu, Weizhong et al, 2005), a process for the synthesis of Me 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-l,2-thiazine-3-formate 1,1-dioxide, an intermediate used in the synthesis of Lornoxicam is described. The synthesis describes the reaction of Me 5-chloro-3-(chlorosulfonyl)thiophene-2-carboxylate with methyl glycinate hydrochloride in water and methanol in the presence of sodium carbonate at 10-60 °C for 6-26 h to generate Me 5-chloro-3-((methyloxycarbonylmethyl)aminosulfonyl)thiophene-2-carboxylate. The inventors observed that in the cyclization step, wherein sodium methoxide in methanol solution is used, the yields obtained are very less and the time to complete the reaction is also longer.
In view of the above drawbacks, it was decided to develop an efficient, cost effective, industrial process which eliminates the hazards and draw backs of prior art.
OBJECT OF THE INVENTION
The object of the present invention is to provide good quality and yield Lornoxicam product
Another object of the present invention is to provide a process which increase the throughput in industrial scale of Lornoxicam, by reducing time and volume involved in the process.


SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of 6-chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)2H-thieno[2,3-e]-l,2-thiazine-l,l-dioxide, Lornoxicam of formula
(i)

comprising
a) cyclization of methyl-5-chloro-3-(methoxycarbonylmethyl)aminosulphonylthiophene-2-carboxylate of formula (II)

in an organic solvent by using a base;
b) methylation of the obtained 6-chloro-4-hydroxy-3-methoxycarbonyl-2H-thieno [2, 3-e]-l, 2-thiazine-1, 1-dioxide (III) in step a)


using methylating reagent and base in an organic solvent;
c) condensation of 2-aminopyridine and 6-chloro-4-hydroxy-2-memyl-3-methoxycarbonyl-2H-
thieno [2, 3-e]-l, 2-thiazine-l, 1-dioxide of formula (IV) obtained in step b)

using a high boiling solvent to give Lornoxicam of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of 6-chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl) 2H-thieno [2, 3-e]-l, 2-thiazine-l, 1-dioxide, known as Lornoxicam of the formula (I).
The present invention also relates to an improved and economical process for the synthesis of Lornoxicam (represented in Scheme-I) with high yield.
The present invention relates to a improved process for the preparation of 6-chIoro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)2H-thieno[2,3-e]-l,2-thiazine-l,1-dioxide, Lornoxicam of formula (I)


comprising a. cyclization of methyl-5-chloro-3-(methoxycarbonylmethyl)aminosulphonylthiophene-2-carboxylate of formula (II)

in an organic solvent by using a base;
b. methylation of the obtained 6-chloro-4-hydroxy-3-methoxycarbonyl-2H-thieno [2, 3-e]-l, 2-thiazine-1, 1-dioxide (III) in step a)

using methylating agent and base in an organic solvent;
c. condensation of 2-aminopyridine and 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-
using high boiling solvent, monochlorobenzene.
thieno [2, 3-e]-l, 2-thiazine-l, 1-dioxide of formula (IV)


The suitable organic solvent, used in the cyclization step of the reaction include N, N-dimethyl formamide, tetrahydrofuran preferably in mixture of N, N-dimethylformamide and tetrahydrofuran. Sodium hydride can be used in dispersion in mineral oil or in free form. The reaction is carried out at a temperature range of 0 to 50 °C, preferably 10 to 30 °C and more preferably at 15-20 °C. The reaction completed in 15 to 45 mints , preferably in 30 mints . The progress of the reaction can be monitored by any separation technique. After the reaction, the reaction mass is quenched in ice-water mixture and the pH of the reaction mixture can be acidified with suitable acids such as sulphuric acid, hydrochloric acid, preferably hydrochloric acid. The pH of the reaction mixture is adjusted at 6.0 to 2.0, preferably 5.0 to 3.0, more preferably at 4.0. The product thus obtained is collected by filtration or extraction, preferably by filtration and can be used as such for the next step.
According to the present invention, methylation of 6-chloro-4-hydroxy-3-methoxycarbony]-2H-thieno [2, 3-e]-l, 2-thiazine-l, 1-dioxide (III) is done in acetone using dimethyl sulphate or methyl iodide as methylating reagents, preferably dimethyl sulphate. The base used for the reaction is selected from potassium carbonate, sodium carbonate, cesium carbonate, preferably potassium carbonate. The reaction is done at 10 °C to refluxing temperature of the solvent, preferably at 25-30 °C. The progress of the reaction is monitored by TLC. After the reaction, the solvent can be removed from the reaction mass or water is added to the reaction mass without removing the solvent. The reaction mass is acidified with concentrated hydrochloric acid to pH 6.0 to 2.0., preferably 5.0 to 3.0, more preferably at pH 4.0. The product precipitated out is obtained by filtration or extraction, preferably by filtration.

According to the present invention, condensation is carried out by mixing 2-aminopyridine and 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2-H-thieno [2, 3-e]-l, 2-thiazine-l, 1-dioxide (IV) in monochlorobenzene and heated. The temperature at which the condensation reaction is done is from 80 °C to 130 °C, preferably at the refluxing temperature of the solvent used. Reaction completed in 10-20 hrs, preferably 14 hrs. The methanol formed in the reaction is distilled out simultaneously and the progress of the reaction is monitored by HPLC. After the required conversion is achieved, the reaction mass is cooled, the product precipitated out is collected by filtration, dried and if required purified by suitable solvent. The present invention is illustrated in the scheme given below:

Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the said invention, will become apparent to

persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as defined herein above and as exemplified and claimed herein below.
EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims
Examples
Example-I: Preparation of 6-chloro-4-hydroxy-3-methoxycarbony 1-2H-thieno [2, 3-eJ-l, 2-
thiazine-1,1-dioxide
In a clean, dry 4 neck round bottom flask having overhead stirrer charged 60 ml of Dimethylformamide and 20 ml of Tetrahydrofuran at room temperature under nitrogen atmosphere and cooled to 15-20°C. Charged 3.66 gmof sodium hydride (3 eq. 0.09 moles), in a single lot to it, under stirring. To the reaction mass, charged 10 gm of Methyl-5-chloro-3-[(methoxy carbonylmethyl)aminosulphonyl]thiophene-2-carboxylate in lots maintaining temperature 15-20 °C. After complete addition, it was stirred at 15- 20 °C for 15 -30 min. and monitored by HPLC. After the completion of the reaction, the reaction mass was poured over ice-water mixture slowly and then acidified using 2N HC1 to pH 4. The precipitated solid was kept under stirring for next 0.5 hr, filtered and washed with 20 ml water. It was unloaded, dried in oven to get 5.1 gm of the product (yield 56.67%), having purity of 98.26% by HPLC.
Example II: Preparation of 6-chloro-4-hydroxy -2-methyl-3-methoxycarbonyl-2H-thieno [2, 3-e]-l, 2-thiazine-l, 1-dioxide

In a clean, dry four neck round bottom flask having overhead stirrer, charged 45 ml of acetone and cool to 15-20 °C. Charged 3.0 gm of 6-chloro-4-hydroxy-3-methoxycarbonyl-2H-thieno[2,3-e]-I,2-thiazine-l,I -dioxide at 15- 20 °C, followed by addition of 2.79 gm of potassium carbonate (2.0 eq., 0.02 mole). Charged 1.92 ml of dimethyl sulphate (2 eq., 0.02 mole) in one lot at 25-30 °C, stirred at 25-30 °C for 2 hrs and the progress of the reaction was monitored by HPLC. After completion of the reaction, charged 20 ml of water and it was acidified using 2N HC1 to pH 4. The precipitated solid was kept under stirring for next 0.5 hrs, filtered and washed with 20 ml water. It was unloaded and dried in oven to give 2.1 gm (66.14%) of the product, having purity 99.06% by HPLC.
Example III: Preparation of Lornoxicam.
In a clean, dry four neck round bottom flask having overhead stirrer, charged 4200 ml of monochlorobenzene and 70 gm of 6-chloro-4-hydroxy -2-methyl-3-methoxycarbonyl-2H-thieno [2,3-e]-l,2-thiazine-l,l-dioxide at room temperature. Charged 24.45 gm of 2-aminopyridine and heated to 130 °C with continuous drop wise distillation for 14 hrs. The progress of the reactions was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 10-15 °C and maintained for 1 hour. The precipitated solid was filtered and washed with 70 ml of monochlorobenzene, followed by addition of 70 ml of chilled methanol. The product obtained was dried to get 45.1 gm (yield 53.69%) of Lornoxicam, having 98.80% purity by HPLC.

We Claim:
1. An improved process for the preparation of 6-chloro-4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl) 2H-thieno [2, 3-eJ-l, 2-thiazine-l, 1-dioxide, Lornoxicam, of formula (I),

comprising
a) cyclization of methyl-5-chloro-3-(methoxycarbonylmethyl)aminosulphonylthiophene-2-carboxylate of formula (II)

in an organic solvent by using a base;

using methylating reagent and base in an organic solvent;
b) methylation of the obtained 6-chloro-4-hydroxy-3-methoxycarbonyl-2H-thieno [2, 3-e]-l, 2-thiazine-1, 1-dioxide (III) in step a)

c) condensation of 2-aminopyridine and 6-chloro-4-hydroxy-2-methy]-3-methoxycarbonyl-2H-thieno [2, 3-e]-l, 2-thiazine-l, 1-dioxide of formula (IV) obtained in step b)

using a high boiling solvent to give Lornoxicam of formula (I).
2. An improved process according to claim la, wherein the organic solvent used for cyclization is N, N-dimethyl formamide, tetrahydrofuran and mixture thereof, preferably mixture of solvent, and base used is sodium hydride.
3. An improved process according to la , wherein the reaction temperature is at 0 to 50 °C, preferably 10 to 30 °C and more preferably at 15-20 °C.
4. An improved process according to claim la, wherein the product is obtained after quenching the reaction mass in ice water and acidification of the resulting reaction mass.
5. An improved process according to claim 4, wherein the reaction mass is acidified with concentrated hydrochloric acid to pH 6.0 to 2.O., preferably at pH 5.0 to 3.0, more preferably at pH 4.0.
6. An improved process according to claim lb), wherein the methylating agent used is dimethyl sulphate or methyl iodide, preferably dimethyl sulphate, and the organic solvent used is acetone
7. A process according to claim lb), wherein the base used for the reaction is sodium carbonate, potassium carbonate, cesium carbonate, preferably potassium carbonate.
8. An improved process according to claim lb), wherein the reaction is done at temperature 10 °C to reflux, preferably at 25-30 °C.

9. An improved process according to claim lc, wherein the high boiling solvent used for
condensation is monochlorobenzene.
10. An improved process according to claim lc, wherein the reaction temperature is 80 °C to 130 °C, preferably at refluxing temperature.
11. An improved process according to any of the preceding claims substantially as herein described with reference to the examples.