IE44998B1 - Process for tje preparation of n-(2-pyridyl)-and n(2-thiazolyl)-3,4-dihydro-i-methyl-4-oxo-2h-1,2-benzothiazine-3-caboxamide-1,1-dioxide and novel reactive derivatives of 3,4-dihydro-2-methyl-4-oxo-2h-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide used in same - Google Patents

Description

This invention relates to a process for producing the non-steroidal antiinflammatory agents N-(2-pyridyl)3/4-dihydro-2-methyl-4-oxo-2H-l,2-benzothia2ine-3-earboxamide-I,1-dioxide and N-(2-thiazolyl)-3,4-dihydro-2-methyl5 4-ΟΧΟ-2Η-1,2-benzothiazine-3-carboxamide-1,1-dioxide and to reactive functional derivatives of 3,4-dihydro-2-methyl4-ΟΧΟ-2Η-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide which are used in the preparation of said antiinflammatory compounds.

IQ The preparation of N-substituted~3,4-dihydro-4-oxo2H-l,2-benzothiazine-3-carboxamide-l,l-dioxides useful as antiinflammatory agents is described in U.S. Patents 3,591,584; 3,891,637 and 3,892,740.

The first patent discloses two routes for the synthesis of N-substituted-benzothiazine-carbOxamide-1,1dioxidess (a) reaction of the appropriate 3,4-dihydro~4oxo-2H-l,2-benzothiazine-l,1-dioxide with an organic isocyanate; and (b) ammonolysis of an ester of 3,4-dihydrO4-OXO-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide. with ammonia or an appropriate amine. The second patent describes the preparation of such compounds wherein the N-substituent is a heterocyclic moiety by a transamidation reaction. The third, patent reports preparation of such carboxamide derivatives by contacting a 3,4-dihydro~425 alkoxy-2H-l,2-benzothiazine-3-carboxylic acid-1,1-dioxide with a coupling promoter (dicyclohexylcarbodiimide, POClg, N-ethoxycarbohyl-2-ethoxy-1,2-dihydroquinoline) followed by contacting the resulting carboxamide with a mineral acid to convert the 4-alkoxy group to 4-oxo.

In each instance, the particular synthetic route employed carefully avoids the formation oi 3,4-dihydro-4OXO-2H-1,2-benzothiasine--3-carboxylic acid-1,1-dioxide, even as a transient intermediate, in order to circumvent the instability of the β-keto function of this acid. The instability of this acid is in keeping with the well-known tendency of β-lceto acids to undergo decarboxylation.

Patent Specification No. 44997 provides a process for the preparation of 3,4-dihydro~2-methyl-4-oxo~2ii-l,2-benzo~ thiazine-3-carboxylic acid-1,1-dioxide which comprises hydrolysis, in the presence of a source of hydroxide ion, of a compound having the formula wherein R.. is alkyi having from one to twelve carbon atoms or phenylalkyl having up to three carbon atoms in the alkyl moiety, followed by acidification of the resulting product to a pH of from 0 tc 5.0, Tha present invention provides a process for preparing a compound having the formula ‘3 49 9 8 wherein R is 2-pyridyl or 2-thiazolyl which comprises coupling at least substantially equimolar proportions of an amine having the formula R2®H2 an<^ 3,4-dihydro-2-methyl-4oxo-2H-l,2-benzothiazine-3-carboxylic acid-1,1-dioxide or a reactive functional derivative thereof selected from the acid chloride, the acid bromide, the acid azide, active esters or thioesters with N-hydroxysuccinimide, N-hydroxyphthalimide, a phenol or a thiophenol, or mixed anhydrides with alkoxycarbonic acids or benzyloxycarbonic acid.

Preferably, the amine is reacted with a compound having the formula (I) wherein Z is chloro, bromo or OX wherein X is hydrogen , benzyloxycarbonyloxy or alkojrycarbonyloxy having from one to four carbon atoms.

N-(2-pyridyl)- and N-(2-thiazolyl)-3,4-dihydro-2methyl-4-oxo-2H-l,2-benzothiazine-3-oarboxamide-l,1dioxides, are both efficient antiinflammatory agents.

In the ease where OX is hydroxy, the coupling reaction is preferably carried out in the presence of at least an equivalent proportion cf a dehydrative coupling agent. Suitable dehydrative coupling agents are selected from Ν,N1-dicyclohexylcarbodiimide, Η, N'-carbonyldiimida20le, N,N'-carbonylditriazole, N,N‘-carbonyl-s-triazine, Nhydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, ι alkoxyacetylene, diphenylketene p-tolylamine, and hexahalocyclotripho sphatriazines.

The most preferred dehydrative coupling agent is Nethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.

The preferred reactive functional derivatives are the acid chloride and mixed anhydrides because of their ease of preparation. Especially useful is a compound of formula (I) wherein OX is ethoxycerbonyloxy.

The coupling reaction is conducted in an aqueous or non-aqueous solvent system. In aqueous systems, the reaction is generally carried out at a pH of from 6 to 9 and a temperature of from 0°C to 50°C. It can, when using the acid chloride, also be performed in unstable emulsions of water and a water-immiscible organic solvent such as methyl isobutyl ketone and lower alkyl acetates over the pH range of from 2 to 4. When using a carbodiimide in an aqueous system, the pH is desirably adjusted to the range of 5 to 8, and preferably to 6 to 7. In a typical procedure, the acid reactant and carbodiimide are mixed in equimolar proportions in a suitable solvent (tetrahydrofuran, dioxan) and a water-water-miscible organic solvent solution (water plus dioxan or tetrahydrofuran) containing the amine is added at room temperature and the mixture stirred for several hours until reaction is complete. Temperatures of from -5°C to 30°C are generally used. In most instances, an excess up to 10% of the condensing agent is used. The desired product is recovered by methods known to tho art.

When the acid chloride is used an acid acceptor, desirably an Organic base such as triethylamine, pyridine, N-methylaniline, or an excess of the amine reactant (R„HK„) or an inorganic base such as sodium carbonate or z z - 6 bicarbonate, is preferably present.

The present invention also provides novel intermediates which are reactive functional derivatives of 3»4-dihydro-2methyl-4-oxo-2H-l,2-benzothiazine-3-carboxylic acid-1,1dioxide selected from the acid chloride, the acid bromide, the acid azide, active esters or thio esters with N-hydroxysuccinimide, N-hydroxyphthalimide, a phenol or a thiophenol, reactive intermediates formed with Ν,N1-dicyclohexylcarbodiimide, N,N'-carbonyldiimidasole, N,N'-carbonylditriazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an alkoxyacetylene or hexahalocyclotriphosphatriazines, and mixed anhydrides with alkoxycarbonic acids or benzyloxycarbonie acid.

The invention is illustrated by the following Examples.

EXAMPLE 1 N- (2-Pyridyl)-3,4-dihydro-2-methyl-4-oxo-2H-l,2-benzothiaz ine-3-carboxamide-1,1-dioxide A 25 ml. three-neck, round-bottom flask equipped with magnetic stirrer, reflux condenser and glass stoppers is charged with thionyl chloride (1.82 ml.), isopropyl ether (12.8ml.) and 3,4-dihydro-2-methyl-4-oxo-2H-l,2-benzothiazine-3-carboxylic acid-1,1-dioxide (1.28 g.). The mixture is heated at reflux and stirred for five hours and is then evaporated under reduced pressure. The residue is taken up in Ν,Ν-dimethylformamide (10 ml.) and the resulting solution used directly in the following step.

To the Ν,Ν-dimethylformamide solution of the acid chloride formed above is added, with stirring, 2-aminopyridine (1.03 g.). An exothermic reaction occurs with development of a red color which changes to orange-yellow within about five minutes. The reaction mixture is stirred overnight and is then diluted by slow addition of water (40 ml.). The resulting precipitate is granulated for one-half hour and is then filtered, ’washed with vzater, and air-dried (1.3 g., 79%). M.p. 16O°-175°C. It is purified by dissolution in N,N-dimethylacetamide (1 ml. per 0.1 g.) at 5O°-6O°C. and precipitation therefrom by addition of a five-fold volume of methanol and chilling. Yield of pure product = 30%; 'M.p. 198°-200°C. The identity of the compound is confirmed by infrared and eass spectrometry.

A similar result is achieved by substitution of thionyl bromide for thionyl chloride.

EXAMPLE 2 N-(2-Thiazolyl)-3,4-dihydro-2-methyl-4-oxo-2H~l,2-benzothiazine-3-carboxamide-l,1-dioxide The procedure of Example 1 is repeated by using 510 mg„ of 3, A-dihydro-2-methyl-4-oxo-2B-l,1-benzothiazine-3carboxylie acid-1,1-dioxide, 1.45 ml. of thionyl chloride, 10.0 ml. of isopropyl ether and 2.0 ml. of N,K-dimathylformaraide to prepare the acid chloride of 3,4-dihydro-2-methyl4-OXO-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide.

The acid chloride is then reacted with 2-aminothiasole (400 mg.) according to the acylation procedure of Example 1 to afford Ξ32 mg. (79%, crude) of the title product.

It is purified by dissolution in M,H-diaothylaeetamide (3 mi.) at 6o°C., filtration of the solution followed by dilution of the filtrate with methanol (15 ml.) to precipitate the product. Yield ~ 208 mg. (33%), M.p. 234°240°C. Repetition of this treatment affords the pure product.

The identity of the product is confirmed by infrared and mass spectrometry. - 8 EXAMPLE 3 N-(2-Pyridyl) -3,4-dihydro-2-methyl-4-oxo-2H-l, 2-benzothiaz ine-3-carboxamide-1,1-dioxide To a solution of 3,4-dihydro-2-methyl-4-oxo-2H-1,25 benzothiazine-3-carboxylic acid-1,1-dioxide (127 mg.) and 2-aminopyridine (52 mg.) in tetrahydrofuran (5 ml.) is added, with stirring, a solution of N-ethoxycarbonyl-2ethoxy-1,2-dihydroquinoline (148 mg.) in tetrahydrofuran (1 ml.). The mixture is stirred at room temperature (23°-25°C) for four hours and'is then concentrated under reduced pressure to an oil. Thin layer chromatography on silica gel plates in the system - benzene:acetic acid (65:5) and visualization of the plate under a 366 mji lamp showed, by comparispn with an authentic sample, the title compound is present.

Repetition of this procedure but using Ν,Ν'-dicyclohexylcarbodiimide, Ν,Ν'-carbonyl-s-triazine, N,N-carbonyldiimidazole, ethoxyacetylene, diphenylketene p-tolylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or N-hydroxy20 piperidine as coupling agents in place of N-ethoxycarbonyl2-ethoxy-1,2-dihydroquinoline achieves similar results.

Claims (11)

1. CLAIMS;1. A process for preparing a compound having the formula 5 wherein R 2 i.3 2-pyridyl or 2-thiazolyl which comprises coupling at least substantially equimolar proportions of an amine having the formula an< ^ 3,4-dihydro-2-methyl4-oxo-2H--l,2~benzothiazine-3-carboxylic acid-1,1-dioxide, or a reactive functional derivative thereof selected from 10 the acid chloride, the acid bromide, the acid azide, active esters or thio esters with H-hydroxysueeinimide, N-hydroxypfcfciialiraide, a phenol or a thiophenol, or mixed anhydrides with alkoxycarbonic acids or benzyloxycarbonic acid.

2. . A process as claimed in claim 1 wherein the amine 15 is reacted with a compound having the formula (I) wherein 2 is chloro, bromo or 02 wherein X is hydrogen,· benzyloxycarbonyloxy or alkoxycarbonyloxy having from one to four carbon atoms. &

3. A process as claimed in claim 2 wherein OX is hydroxy and the coupling reaction is carried out in the presence of at least an equivalent proportion of a dehydrative coupling agent.

4. A process as claimed in claim 3 wherein the dehydrative coupling agent is selected from Ν,Ν'-dicyclohexylcarbodiimide, Ν,N 1 -carbonyldiimidazole, Ν,N'-carbonylditriazole, N,N'-carbonyl-s-triazine, N-hydroxyphthalimide, N-hydroxysuccinimide, N-hydroxypiperidine, N-ethoxycarbonyl· 2-ethoxy-l,2-dihydroquinoline, alkoscyacetylene, diphenylketene p-tolylamine, and hexahalocyclotriphosphatriazines.

5. A process as claimed in claim 4 wherein the dehydrative coupling agent is N-ethoxycarbonyl-2-ethoxy1,2-dihydroquinoline.

6. A process as claimed in claim 2 wherein OX is ethoxycarbonyloxy.

7. A process as claimed in claim 2 wherein Z is chloro and the coupling reaction is carried out in the presence of an acid acceptor.

8. A process as claimed in claim 7 wherein the acid acceptor is 2-aminopyridine.

9. A process as claimed in claim 7 wherein the acid acceptor is 2-aminqthiazole.

10. A reactive functional derivative of 3,4-dihydro2-methyl-4-oxo-2H-l,2-benzothiazine-3-carboxylic acid-1,1dioxide selected from the acid chloride, the acid bromide, the acid azide, active esters or thio esters with N-hydroxysuccinimide, N-hydroxyphthalimide, a phenol or a thiophenol, reactive intermediates formed with N,N‘-dicyclohexylcarbodiimide, N,N‘-carbonyldiimidazole, Ν,Ν'-carbonylditriazole, N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline, an alkoxyacetylene or hexahalocyclotriphosphatriazines, and mixed anhydrides with alkoxycarbonic acids or benzyloxycarbonie acid.

11. N-(2-pyridyl)- and N-(2-thiazolyl)-3,4-dihydro2-methyl-4-oxo-2H-l,2-benzothiazine-3-carboxamide-l,15 dioxide, when prepared by the process of any one of claims 1 to 9.