SE464411B - The intermediate 2-methyl-4-mesyloxy-2H-1,2-benzothiazine- 1,1-dioxide-3-carboxylic acid, or a solvate thereof with dimethylacetamide, for use in preparing a pharmaceutically utilizable benzothiazine dioxide - Google Patents

Abstract

The present invention relates to an intermediate for preparing a pharmaceutically utilizable 2-methyl-4- hydroxy-2H-1,2-benzothiazine-1,1-dioxin of the formula I <IMAGE> The intermediate consists of 2-methyl-4-mesyloxy-2H-1,2- benzothiazine-1,1-dioxide-3-carboxylic acid of the formula II <IMAGE>

Description

464 411 methyl ester was used as the ester of the carboxylic acid in the 3-position, and in 813003 methoxyethyl ester was used instead.

The above methods based on an aminolysis reaction of the respective esters of 1,2-benzothiazine-3-carboxylic acid and 2-amino- in pyridine are admittedly suitable for industrial production due to the yield and also due to other properties, but disadvantages thereof. involves the use of a high temperature, including the temperature of boiling xylene, and a very long reaction time which usually exceeds 20 hours. Both the temperature and the long reaction time tend to have a degrading effect on the product, whereby the purification of the product becomes difficult and the yield tends to decrease due to decomposition. The purification is further complicated in particular by the fact that the methods in question give colored by-products which require a number of solutions and recrystallizations, and also other steps, in order to give an acceptable end product.

Another method for the preparation of piroxicam which is worth mentioning is described in the Finnish patent specification 63573. In this description the starting material is a compound of the formula z - \ CUNHR2 s, -cuB I ° 2 wherein Z is isopropoxy and R2 is 2 -pyridyl as the desired product is piroxicam. The compound is contacted with an inorganic acid, whereby the isopropoxy group is cleaved. The total yield obtained according to this method is very small, because before the cleavage of the isopropoxy group the preparation also comprises binding of an aminopyridyl group to the benzothiazine, which is preceded by a conversion of the 3-acetyl compound to the respective 3-carboxylic acid. The total yield achieved is thus only about 2%. The disadvantages of this method are not limited to poor yield, as the method comprises several steps in which harmful solvents such as benzene and strong acid such as 32% hydrobromic acid are used, by means of which the isopropyl group is cleaved. The method is not suitable for industrial production. With the new intermediate according to the invention, the compound píroxicam can be prepared in a very good yield and using reaction steps which are both easy to carry out and which can be completed quickly.

The compound piroxicam is prepared by reacting the new intermediate 2-methyl-4-mesyloxy-2H-1,1-benzothiazine-1,1-dioxide-3-carboxylic acid or a solvate thereof with dimethyl acetamide. . CH CH, SO 2. at a temperature of about 40-80 ° C with thionyl chloride and 2-aminopyridine of formula FM) in an inert solvent.

The starting material II and 2-aminopyridine are used in approximately equimolar amounts, while thionyl chloride can be used in excess, for example in the double amount. Inert solvents suitable for use include chlorinated hydrogen chlorides such as dichloromethane, or 1,2-dichloroethane, acetonitrile, etc.

The reaction is complete within 2-3 hours. When desired, it is also possible to use a tertiary amine such as β-dimethylpyridine in the reaction, although it has a very small effect on the reaction. 10 15 _2o 25 30 35 464 411 4 The production of piroxicam takes place under rather mild conditions. The reaction with 2-aminopyridine thus takes place at a moderate temperature and rapidly. Likewise, the mesyl group can be removed under very mild conditions, as the cleavage takes place immediately after the acylation reaction, by using a dilute NaOH solution.

Due to the low temperature, the short reaction time and the mild conditions, the piroxicane obtained as a final product is very pure, so that several of the purification steps used in known methods can be eliminated. For the reasons stated above, the yield is also high, averaging 86%. The above procedure further includes a surprising feature, namely that an acid acceptor is not necessarily required at all in the process. Obviously, the N, N-dimethyl acetamide used, which forms a solvate with the starting material, which is an aprotic solvent, effectively catalyzes the acylation reaction of 2-aminopyridine, after which the acid acceptor no longer becomes necessary.

The novel intermediate of the invention is best prepared by hydrogenating benzyl 2-methyl-4-mesyloxy-1,2-benzothiazine-1,1-dioxin-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-methyl-4-mesyloxy-1,2-benzothiazine-1,1-dioxide-3-carboxylate, can in turn be prepared in an almost theoretical yield by mesylation according to conventional procedures of the respective 4-hydroxy compound.

Benzyl 2-methyl-4-hydroxy-1,2-benzothiazine-1,1-dioxide-3-carboxylate is a known compound described in, for example, EP patent application 82303978.9, publication number 77 603.. The invention is further illustrated by the following examples which are not to be construed as limiting thereof.

Example 1 2-Methyl-3-carboxy-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-N, N-dimethylacetamide solvate A solution containing 42.3 g (0.1 mol) of benzyl-2 -methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate (m.p. 110-112 ° C), 8.7 g (0.1 mol) of N, N-dimethylacetamide and 2 g of 10% palladium-charcoal catalyst were hydrogenated for 3 hours at normal pressure and room temperature. The catalyst was filtered off and the solvent was distilled off under reduced pressure, whereby 41.8 g (99.5% of theory) of the desired product (melting point 102 DEG-104 DEG C.) were obtained.

Example 2 2-Methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3- (N-2-pyridyl) -carboxamide (piroxicam) To a solution containing 16.8 g (0.040 mol ) of the intermediate prepared in Example 1 and 4.0 g (0.043 mol) of 2-aminopyridine in 200 ml of boiling 1,2-dichloroethane and optionally 4.3 g (0.40 mol) of 2,6-dimethylpyridine, 9.5 g (0.08 mol) of thionyl chloride were added with stirring over 0.5 hours. The mixture was refluxed for two hours, after which the mixture was cooled to about 40 ° C and gradually with stirring was added about 500 ml of 0.5 N NaOH solution. Stirring was continued for another 0.5 hours at a temperature of 40 ° C. Then the aqueous layer was separated and washed with methylene chloride, filtered and slightly acidified with acetic acid, after which the desired product was crystallized. The product was filtered and dried to give 11.4 g (86% of theory) of the desired product, mp 198-200 ° C (purity> 98%).

Claims (1)

1. 5 10 15 20 25 30 464 411 EATENT REQUIREMENTS Intermediate for use in the preparation of pharmaceutically usable 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3- (N-2- pyridyl) -carboxamide of the formula OH Û-NH I -CH3 I 02 is characterized in that it consists of 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid of the formula CH 2 SO 2 -D 2 CODH Al-CH; n O-u-p or a solvate thereof with dimethylacetamide.