FIELD OF THE INVENTION
The present invention relates to an improved industrial process for the preparation of oxicam derivatives of the Formula I
ormula I
wherein Ar represents 5-methyl-2-thiazolyl, 2-thiazolyl, 2-pyridyl, 6-methyl-2-pyridyl and 2-pyridyl-isoxazole groups and their pharmaceutically acceptable
salts.
BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of enolizable 1,1-dioxides of N-heteroaryl-4-hydroxy-2-alkyl-2H-l,2-benzothiazine-3-carboxamide derivatives which are other wise known as oxicams.
Several oxicam derivatives such as Ampiroxicam, Piroxicam, Meloxicam and Lornoxicam have been developed as non-steroidal anti-inflammatory drugs (NSAIDs). These oxicams contain 1,2-benzothiazine nucleus with aromatic heterocyclic rings in the amide side chain. For example Piroxicam contains pyridine in the side chain, Meloxicam contains 5-methyl-thiazole in the side chain.
The oxicams and their utility as anti-inflammatory agents are disclosed in US Patents 3,591,584; 3,787,324; 3,822,258; 4,180,662; 4,309,427 and 4,233,299.

The synthesis of the 1,2-benzothiazine nucleus was first reported in J.Pharm.Soc Japan 1956, 76, 1058. The key transformation consisted of a base catalyzed isomerization of saccharine derivatives to 1,2-benzothiazine nucleus.
US 3,591,584 describes the synthesis of compound of Formula I and in particular the synthesis of Piroxicam. The method consists of reacting 1,2-benzothiazine carbalkoxy ester with an appropriate aromatic amine base in an inert organic solvent to give Piroxicam. The reaction is generally conducted by mixing the two components together in the said solvent system at or near room temperature and then refluxing the resultant reaction mixture for a period of up to 48 hrs.
The synthesis of Piroxicam described in this patent is shown below :

US 3,787,324 describes the synthesis of Isoxicam wherein, the 1,2-benzothiazine is refluxed with 3-aminoisoxazole in an inert solvent like xylene for 24 hrs which is shown below :

US 4,233,299 describes the synthesis of Meloxicam wherein, the 1,2-benzothiazine dioxide is refluxed with 2-amino-5-methyl thiazole in an inert organic solvent for 24 hrs which is shown below :


It is apparent from the above procedures that a limited number of methods are available for the synthesis of oxicam derivatives. Most of the above mentioned methods are time consuming as the aminolysis reaction takes up to 48 hrs in reflux conditions. Hence, it is essential that an industrial synthesis with moderate reaction times is always preferable as it minimizes the occupancy of the plant equipment thus saving time and cost. Also it was observed that the condensation reaction at high temperatures for prolonged period of reaction time results in the formation of side products.
Another drawback of the above mentioned processes is the formation of the oxicams derivatives with intense colour which is difficult to reduce to pharmacoepial limits.
Given the importance of the oxicam derivatives, a cost effective method has been envisaged to overcome the above mentioned drawbacks.
The inventors have now developed a new industrial synthesis that requires shorter reaction times yielding the oxicam derivatives in good yield and high purity.
OBJECTIVES OF INVENTION
The objective of the present invention is to develop a simple, improved process for the preparation of oxicam derivatives while minimizing the side products formed during the condensation of the individual components at the commercial scale and at the same time reducing the reaction time.

SUMMARY OF INVENTION
Accordingly, the present invention relates to an improved process for the preparation of compound of Formula I

wherein Ar represents 5-methyl-2-thiazolyl, 2-thiazolyl, 2-pyridyl, 6-methyl-2-pyridyl and 2-pyridyl-isoxazole groups,
which comprises reacting the compound of Formula II

wherein R represents methyl, ethyl or isopropyl with an amine of Formula III
Ar-NH2 Formula III
wherein Ar represents 5-methyl-2-thiazolyl, 2-thiazolyl, 2-pyridyl, 6-methyl-2-pyridyl and 2-pyridyl-isoxazole groups in presence of an acid in an inert organic solvent and isolating the compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION
The present invention describes an improved purification process for the preparation of oxicam derivatives free of many pharmacoepial impurities.
The aim of the present invention is to eliminate the formation of N-alkyl impurity which is also an pharmacoepial impurity and also to reduce the reaction times, thereby decreasing the plant occupancy time without compromising on yield and purity.
The condensation of compound of Formula II with compound of Formula III to give compound of Formula I can be achieved in an inert organic solvent in the presence of an acid.
Preferred acids used are aliphatic and aromatic carboxylic acids like acetic acid and benzoic acid. Examples of the acids used during the condensation reaction are benzoic acid, acetic acid in quantities ranging from 0.2 to 1.2 molar equivalents to benzothiazine used.
The inventors have found that by using an acid during the condensation of the 1,2-benzothiazine dioxide with an heteroaromatic amine they could substantially reduce the formation of the N-alkyl impurity. The N-alkylated product usually occurs as a result of the alkanol which is formed as a by product during the reaction of compound of Formula II and III to yield compound of Formula I. The alkanol then replaces the hydrogen in the amide group.
Preferred products of the process of this invention are those in which Ar represents 5-methyl-2-thiazolyl and 2-pyridyl.
The above condensation reaction is effected in inert organic solvents, for example in an aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene,

o-dichlorobenzene, tetrahydronapthalene or in dimethylformamide, dimethylacetamide or dimethylsulfoxide or in hexamethylphosphoric acid triamide or in an ether such as dimethoxyethane, diethylene glycol dimethyl ether or diphenyl ether.
The reaction is carried out at temperatures between 70°C-180°C. Preferably reaction is carried out in toluene or xylene at the boiling point and the resulting by-product alkanol is removed during the reaction by azeotropic distillation.
After completion of the reaction, reaction mixture is slowly cooled to room temperature and filtered. The product thus obtained is recrystallised from xylene to get pharmacoepial grade finished product.
Although xylene was previously used for the condensation of the compounds of Formula II and III, crystallization using xylene was not reported. The inventors could establish that by recrystallizing the condensation product from the same solvent of the reaction vessel, they were able to obtain the required enol tautomer of the respective oxicam derivative. This enol tautomer is the one suitable for preparing pharmaceutical products. By the present process of the invention as the required tautomer is obtained directly, an additional step of preparing the suitable polymorph is also avoided and thus making the process more viable.
The present invention is exemplified by the following examples which are provided for illustration purposes, and does not limit the scope of the invention
Example 1
A mixture of Methyl 4-hydroxy-2-methyl-2H-l,2-benzothiazine-3-carboxylate 1,1-dioxide (20 g, 0.074 mole), 1.2 L o-xylene, acetic acid (4.46 g, 0.074 mole) and 2-amino-5-methyl thiazole (3.1 g, 0.027 mole) was heated tol40-146°C with slow and simultaneous distillation of o-xylene-methanol azetrope for -3 hrs. A second lot (3.1 g, 0.027 mole) of 2-amino-5-methyl thiazole, dissolved in 10 ml of

o-xylene was added and continued the azeotropic distillation for 3 hrs at 143-148°C. A final lot, (3.1 g, 0.027 mole) of 2-amino-5-methyl thiazole, was added at 140°C and continued the slow azeotropic distillation for additional 12-13 hrs. Cooled the reaction mass to 30-35 °C in -3 hrs while the product crystallized out. Filtered the product and washed with 2 x 100 ml o-xylene to get meloxicam 22.01 g. The technical product thus obtained was recrystallized for o-xylene. The product was finally powdered and dried under reduced pressure for 12-13 hrs at 40-50°C to remove the residual solvents (90-92 % recovery, HPLC purity >99.7%).
Example 2
A mixture of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (20 g, 0.074 mole), 1.2 L o-xylene, benzoic acid (9.07 g, 0.074 mole) and 2-amino-5-methyl thiazole (3.11 g, 0.027 mole) was heated to 140-45°C with slow and simultaneous distillation of o-xylene-methanol azeotrope for ~3hrs. Second and third lots of 2-amino-5-methyl thiazole was added at the end of 6h and 9h period of azeotropic distillation which was continued for a further period of 12-13 hrs while monitoring the reaction by HPLC. The volume of the reaction mass was maintained constant by intermittent addition of o-xylene. Cooled the reaction mass to 30-35 °C in -3 hrs while the product crystallized out. Filtered the product and successively washed with 2 x 60 ml o-xylene followed by 2 x 40 ml methanol. Dried the powdered product under reduced pressure at 40-50°C. yield = 17.2 g. (HPLC Purity > 99.8%).
Example 3
A mixture of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (100 g, 0.37 mole), 6 L o-xylene, benzoic acid (22.67 g, 0.186 mole) and 2-amino-5-methyl thiazole (15.56 g, 0.136 mole) was heated to 146-149°C in about 1 h with simultaneous slow distillation of o-xylene-methanol azeotrope (typically 1-3 ml per minute) for ~3hrs. Second and third lots of 2-amino-5-methylthiazole (15.56 g, 0.136 mole each) were added at the end of 6 h and 9 h

period of azeotropic distillation. The reaction was continued for additional period of 12-13 hrs while monitoring the progress of the reaction by HPLC. Throughout the reaction, volume of the reaction mass was maintained by addition of fresh o-xylene either continuously or at regular intervals in quantity equivalent to the distillate collected. Cooled the reaction mass to 30-35°C in 3-4 hrs, filtered the crystalline product and washed successively with o-xylene (2 x 225ml) and methanol (2 x 125ml) yield. Process for their preparation and pharmaceutical compositions containing them 84.12 g. [HPLC purity > 99.9% N-Methyl meloxicam 0.05%]. The product was recrystallized from o-xylene ( > 90 % recovery) resulting in pure meloxicam (HPLC purity > 99.95%).

WE CLAIM
1. A process for the preparation of compound of Formula I

wherein Ar represents 5-methyl-2-thiazolyl, 2-thiazolyl, 2-pyridyl, 6-methyl-2-pyridyl and 2-pyridyl-isoxazole groups,
which comprises reacting the compound of Formula II

wherein R represents methyl, ethyl or isopropyl with an amine of Formula III
Ar-NH2 Formula III
wherein Ar represents 5-methyl-2-thiazolyl, 2-thiazoloyl, 2-pyridyl, 6-methyl-2-pyridyl and 2-pyridyl-isoxazole groups in presence of an acid in an inert organic solvent and isolating the compound of Formula I.
2) The process according to claim 1, wherein the acid used is aromatic acid or aliphatic carboxylic acid.
3) The process according to claim 2, wherein the aromatic acid employed is benzoic acid.

4) The process according to claim 2, wherein the aliphatic carboxylic acid employed is acetic acid.
5) The process s according to claim 1, wherein the inert organic solvents used are aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, o-dichlorobenzene, tetrahydronapthalene or dimethylformamide, dimethylacetamide or dimethylsulfoxide or hexamethylphosphoric acid triamide or ethers such as dimethoxyethane, diethylene glycol dimethyl ether or diphenyl ether, more preferably xylene.
6) The process according to claim 1, wherein Ar represents 5-methyl-2-thiazole.
7) The process according to claim 1, wherein Ar represents 2-pyridyl.
8) The process according to claim 1, where Meloxicam is obtained as Form I.