FI72317B - PROCEDURE FOR THE FRAMEWORK OF PHARMACEUTICALS 2-ETHYL-4-HYDROXY-2H-1,2-BENZOTHIAZINE-1,1-DIOXID-3- (N-2-PYRIDYL-CARBOXAMIDE OCH I FAR - Google Patents

Description

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The present invention relates to a process for the preparation of a pharmaceutically acceptable 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3- (N-2-pyridyl) carboxamide and to an intermediate used in the process. 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3- (N-2-pyridyl) carboxamide, i.e. piroxicam, for the preparation of 10 L of JT \ 0 2 13 and a new intermediate, 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid, to carry out the reaction.

The formula of the intermediate is 20 CH3-SO2-OOH n kAS> CH3

K

23 Piroxicam has been shown to be a very useful anti-inflammatory and analgesic agent without the usual side effects of steroids. Methods for preparing piroxicam have been described in numerous Finnish and foreign patent publications, 30 of which include Finnish patent publications 51189, 59392, 62297 and 63573, as well as Finnish patent application 813003.

The best method for yield is described in Finnish Patent Publication 51189 and Patent Application 35 81 3003. The process of Patent 51189 allows 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-carboxamide-1,1-dioxide 3-carboxylic acid ester to be reacted with at least equimolar ______ - · TT ..

2 7231 7 with an amount of amine containing the desired aromatic moiety, which in the case of piroxicam is pyridyl. The yield in this method is about 70%.

5 A slightly better yield is obtained by the method according to Finnish patent application 813003, which differs from the method according to Finnish patent 31189 only with respect to the esterified group. Thus, the 3-position carboxylic acid ester used in Patent 51189 is a methyl ester and methoxyethyl ester is used instead in Application 813003.

Although the above-mentioned methods based on the aminolysis reaction of the corresponding 1,2-benzothiazine-3-carboxylic acid ester and 2-aminopyridine are suitable for industrial production due to their yield and other properties, they have the disadvantage of using high temperature, boiling xylene temperatures and quite long reaction time, which is usually more than 20 to 20 hours. Both the temperature and the long reaction time degrade the product, making it difficult to purify the product and the yield tends to decrease due to decomposition. The difficulty of purification also occurs, in particular, because these methods provide colored by-products that require numerous dissolutions and recrystallizations, as well as other measures to make the final product acceptable.

Another method for the preparation of piroxicam is disclosed in Finnish patent 63573. This publication starts from a compound of the formula

Z

where R 2 is isopropoxy and is 2-pyridyl when it is desired to prepare piroxicam. The compound is contacted with an inorganic acid to cause the isopropoxy group to be cleaved off. The overall yield by this method is very low, since the preparation involves the cleavage of the amino-pyridyl group to the benzothiazine backbone prior to the cleavage of the isopropoxy group, which is preceded by the conversion of the 3-acetyl compound to the corresponding 3-carboxylic acid. Thus, only about 2% of the total catch is obtained. The disadvantages of this method are not limited to poor yield, as the method involves a large number of steps using harmful solvents such as benzene and a strong acid such as 32? Ό bromo hydrogen acid to cleave the i sopropy y 1 i r y group. The method is not suitable for industrial production.

It is an object of the present invention to provide a process by which piroxicam can be prepared in very good yield and using reaction steps which are both easy to carry out and quick to carry out. The aim is also to obtain the purest possible end product.

For the process according to the invention, piroxicam, 2-25 methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3- (N-2-pyridyl) carboxamide, 1H-i

^ Yv ° -MV

To prepare 30 k-As 2 -CH 3 O 2, it is characterized in that 2-methyl-4-mesyloxy-2H-1,1-benzothiazine-1,1-dioxide-3-carboxylic acid or a solvate thereof is reacted with dimethylacetamide 4 7231 CH3-SO2-O / CH3 ^ X1A ^ COOHTH ^ -CON ^ tt CXJ- », x ™, i, 5 to react at a temperature of about 40-80 ° C with thionyl chloride and 2-aminopyridine of formula 10 vol 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 about twice as much. Suitable inert solvents are, for example, chlorinated hydrocarbons, such as dichloromethane, or 1,2-dichloroethane, the reaction is complete, etc. The reaction is complete within 2-3 hours. If desired, tert can also be used in the reaction. amine, such as e.g.

2,6-dimethylpyridine, although it has very little effect on the reaction.

When the process of the invention is used to prepare piroxicam, the whole reaction takes place under rather mild conditions. Thus, the reaction with 2-aminopyridine takes place at a reasonable temperature and rapidly. Likewise, the mesyl group can be removed under very mild conditions, since the cleavage takes place immediately after the acylation reaction using dilute NaOH solution.

Due to the low temperature, the short reaction time and the mild conditions, piroxicam obtained as a final product 5 7231 7 is very pure, so that several of the steps used for purification by known methods can be omitted. Similarly, due to the above, the yield is high, averaging 86%.

The method according to the invention includes another surprising feature, namely that the method does not necessarily require an acid acceptor at all. Apparently, the Ν, Ν-dimethylacetamide used to form a solvate with the starting material effectively catalyzes the acylation reaction of 2-aminopyridine as an aprotic solvent, making the acid acceptor unnecessary.

The invention also relates to an intermediate of formula 13 ch3-so2-o ^ ΛΑγ: οοΗ jj

K

20 and which is a new compound. In particular, for the process of this invention, it is preferred that said intermediate form a solvate with dimethylacetamide.

The intermediate (starting material) is best prepared by hydrogenolysis of benzyl 2-methyl-4-mesyloxy-1,2-benzothiazine-1,1-dioxide-3-carboxylate of the formula CH3-SO2-O / “λ

^ 0> ^ cooch2-h ^ J> IV

kJ-5 ^ -CH3 ° 2 35 in the presence of N, N-dimethylacetamide and a hydrogenation catalyst in 6 7231 7 in an inert solvent. The starting material, benzyl 2-methyl-4-mesyloxy-1,2-benzotazine-1,1-dioxide-3-carboxylate, in turn can be prepared in almost theoretical yield by conventional means by mesylation of the corresponding 4-hydroxy compound.

Benzyl 2-methyl-4-hydroxy-1,2-benzothiazine-1,1-dioxide-3-carboxylate is a known compound disclosed, for example, in EP Patent Application 82303978.9, Accession No. 77,603.

The following examples illustrate the invention.

Example 1 2-Methyl-3-carboxy-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-N, N-dimethylacetamide solvate 20 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 Ν, Ν- dimethylacetamide and 2 g of 10% pa 11 adium carbonate were hydrogenated for 3 hours at 23 normal pressure and room temperature. The catalyst was filtered off and the solvent was distilled off under reduced pressure to give 41.8 g (99.3 S of theory) of the desired product (m.p. 102-104 ° C).

30

Example 2 2-Methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3- (N-2-pyridyl) carboxamide (piroxicam) 35

To a solution of 16.8 g (0.040 mol) of the intermediate prepared in Example 1 and 4.0 g (0.043 mol) of 7 7231 7 2-aminopyridine in 200 ml of boiling 1,2-dichloroethane and optionally 4.3 g (0 .04 moles) of 2,6-dimethylpyridine, 9.3 g (0.08 moles) of thionyl chloride were added with stirring over 0.3 hours. The mixture was refluxed for 2 hours, after which the mixture was cooled to about 40 ° C and about 500 ml of 0.5N NaOH solution was gradually added with stirring. Stirring was continued for another 0.5 hours at 40 ° C. The aqueous layer was then separated and washed with methylene chloride, filtered, and slightly acidified with acetic acid to crystallize the desired product. The product was filtered off and dried, yielding 11.4 g (86% of theory) of the desired product, m.p. 198-200 ° C (purity> 98 ° C).

Claims (6)

A process for the preparation of pharmaceutically useful 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3- (N-2-pyridyl) carboxamide of formula I OH ° 2 characterized in that 2-methyl-4-mesyloxy-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylic acid of formula II o-so2-ch3a ^ COOH S Ln3 20 0 2 is reacted with 2-aminopyridine in the presence of thionyl chloride in an inert solvent, and the mesyloxy protecting group is cleaved. 25 2. A process according to claim 1, characterized in that a tertiary amine such as 2,6-dimethylpyridine is also used in the reaction. 3. An intermediate for use in the preparation of pharmaceutically useful 2-methyl-4-hydroxy-2H-1,2-benzothiazine-1,1-dioxide-3- (N-2-pyridyl) carboxamide of the formula OH - 35 ° 2 tl