CS253593B2 - Method of pharmaceutically applicable 2-methyl-4-hydrox!-2h-1,2-benzothiazine-1,1-dioxide-3-(n-2-pyridyl)carboxamide production - Google Patents

Description

The invention relates to a process for the preparation of a pharmaceutically usable 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3- (N-2-pyridyl) carboxamide, i.e. piroxicam, corresponding to formula I

(AND)

Further, a novel intermediate used in the above-described process as well as a process for its preparation are described. This intermediate is 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid of formula II

CH ₃ -SO ₂ -O ^^ I ^ COOH кчД J1-CH3 | (II) ° 2

Piroxicam has proven to be a very useful anti-inflammatory and analgesic agent without the harmful effects it usually possesses for eteroids. Methods of making piroxicam are disclosed in numerous Finnish and other patents, including Finnish Patent Nos. 51,189, 59,592, 62,297 and 63,573.

The best method in terms of yield is disclosed in Finnish Patent No. 51189. In accordance with this patent, a 3-carboxylic acid ester derived from 3,4-dihydro-4-O-O-2N-1,2- benzothiazinecarboxamide-1,1-dioxide is reacted with at least an equimolar amount of an amine containing the desired aromatic moiety, which is pyridyl in the case of piroxicam. The yield obtained using this method is about 70%.

The above-described process, based on the aminolytic reaction of the corresponding 1,2-benzothiazine-3-carboxylic acid ester and 2-aminopyridine, is undoubtedly suitable for industrial production due to its yield and other properties, but its disadvantage is the need to use high temperatures, such as the boiling point of xylene, and the need to use a very long reaction time, which is usually more than 20 hours.

Both the temperature and the long reaction time result in decomposition of the product, making it difficult to purify the product and at the same time reducing the yield. The purification is further complicated in particular by the fact that the above-described process produces colored by-products whose removal requires numerous extractions and recrystallizations as well as other purification operations in order to obtain an acceptable final product.

A further noteworthy process for the production of piroxicam is disclosed in Finnish Patent No. 63,573. According to this patent, the starting material is a compound of the formula

OF

wherein Z represents isopropoxy and R ₂ in the event that the desired product as piroxicam, is 2-pyridyl.

This compound is contacted with an inorganic compound which results in cleavage of the isopropoxy group. The overall yield achieved in this process is very low since the aminoppyidyl group is also coupled to the benzothiazine core prior to the isopropoxy cleavage, which is preceded by the conversion of the 3-aceeyl derivative to the corresponding 3-carboxylic acid. Thus, the overall yield is only about 2%. The disadvantages of this method are not only low yields, but also a multi-step process using harmful solvents such as benzene, and a strong acid such as 32% hydrobromic acid to remove the isopropoxy group. The method described above is not suitable for industrial production.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process which can be prepared in a very good yield and using reactions which are both easy to carry out and quick to carry out. It is also an object of the present invention to provide the purest end product.

Accordingly, the present invention provides a process for the preparation of a polyisocyanate, i.e., S-meetl-4-hydroxy-1H-1H-benzzthiazine-1,1-ditoxide-3- (N-22pididene) carboxamide of formula I

(I) characterized by reacting a 2-methyl-1,4-oxyl-2H-1,1-benzothiazin-1,1-ditxide-13-cipyl group or a solvate of formula II

(Ii) ^p s temperature of between 40 and ⁸⁰ ° C in přítomncti! with 2-aminopyridane of III h ₂ n

(III) in an inert solvent.

The starting compound of formula (II) and 2-aminthyllidium are used in approximately equimolar amounts, while the thitnyl chloride can be used in excess, for example twice as much. Inert solvents suitable for use include: chlorinated hydrocarbons such as 1,2-dichlorotetra, aceeotitrile, etc. The reaction is complete in 2 to 3 hours. Alternatively, it is also possible to use a tertiary amine such as 2,6-diethylpiperidium in the reaction, since it has a very weak effect on the reaction.

In the process according to the invention, the complete reaction takes place under completely mild conditions. Thus, the reaction with 2-aminopyridane proceeds at moderate temperature and rapidly. Similarly, the pstartate may be a yellow group under very mild conditions, since cleavage occurs immediately in the acylation reaction with the dilute sodium hydroxide solution.

Due to the low temperature, short reaction time and mild conditions, the resulting product is very pure, whereby some of the steps used for purification in the known processes can be eliminated. Similarly, due to the above factors, the yield is high, on average 86%.

The method of the invention further includes one unexpected factor that an acid acceptor is not necessarily required in the method. Obviously, the aprotic solvent used N, N-dimethylacetamide, which forms a solvate with the starting compound, effectively catalyzes the acylation reaction of N-aminoppridine, thereby eliminating the need for an acid acceptor. The intermediate of formula II

(II) is a novel compound. It is particularly preferred for the process of the invention that said intermediate forms a solvate with dieethylacetaeidee.

The preparation of the intermediate (starting material) is preferably carried out by hydrogenation of butyl-4-methyl-4-methyroxyl-2-benziethylthio-1,1-dioxide-3-carboxylate of formula IV ^.

In the presence of N, N-dimethylacetamide and a hydrogenation catalyst in an inert solvent. The starting material, benzyl-2-ethyl-4-ethyl-hydroxy, 2-beta-quizine-1,1-dicoxide-3-carboxlate, can be prepared in almost theoretical yield from the 4-hydroxy compound by a conventional method.

Betzir-2-methyl-4-hydrocyrl, 2-benzi-thiazole-1,1-dioxide-3-carboxlate is a known compound which is disclosed, for example, in published European patent application 82 303 978.9.

The invention will be clear from the following examples without sweeping it.

Příklaa.

2-tert-3- (3-bicyclo-e) -cryloyyl-22H-1,2-benzooticin-1,1-dioxide-N, N-diethyracetamide-salt.

A solution containing 42.3 g (0.1 mc) o-azyl-2-ethyl-4-eesyloxy-2H-benzothiazole-1,1-dioxide-S-carboxylate m.p. 110-112 [deg.] C., 8.7 g (0.1% C, N-dimethylacetamide) and 2 g of 10% palladium on carbon catalyst are hydrogenated for 3 hours at normal pressure and lower temperature. The catalyst was filtered off and the solvent was removed under reduced pressure to give 41.8 g (99.5% of titanium dioxide) of the desired product (m.p.). 102-104 ° C;

Example 2

2-teryl-1-hydroxy-2-1,2-benzylthiazole, 1-dioxide-3- (N-2-pyrimidylcarbonyl) (piroxicam)

To a solution containing 16.8 g (0.040 ec) of the intermediate prepared in the example and 4.0 g (0.043 mol) of 2-aeinoppyidine in 200 ml of boiling 1,2-ficilcrttaz and optionally

4.3 g (0.40 mol) of 2,6-diethylpyrifin are added with stirring over a period of 0.5 hours 9.5 g (0.08 µl) of thiyl ylcillifif.

The mixture was heated under reflux for 2 hours, then the mixture was cooled to 40 ° C and 500 ml of 0.5 N sodium hydroxide solution was added gradually with stirring. Stir for a further 1/2 hour at 40 ° C. The aqueous layer was separated and washed with ethylene chloride, filtered and adjusted to slightly acidic pH with acetic acid, whereupon the desired product crystallized. The product was dried, and thus 11.4 g / 86% of theory mooství / ^aft aného ^P ro ^d uktu ^ll. 8 ^{and 9 2} 00 ° C> 98%.

Claims (2)

1. A process for producing 2-farmaceuuiiky pouUitenného meetl-4-hydroxy-roxyy22 ^d l ^^^ e ^ enoothiaZinl, 1УiixiУ-3- (2-Ы "РР1Гс1у1) carboxamide of the formula The OH (I) is characterized by reacting 2-methylpolyoxy-2H-β-2-reuzo-thiazol-2-yl-β-α-carbonyl acid of formula (II) in an inert solvent with 2-aminopridine in thionyl carbonate. 2. The process of claim 1, wherein the reaction is also carried out in the presence of a tertiary amine, such as 2,6-dimethylpyridine.