KR810000291B1 - Process for preparing of 3,4-dihydro-2-methyl-4-oxo-2h-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide - Google Patents

Abstract

Title compd. (I; R2 = 2-pyridyl or 2-thiazolyl), useful as antiinflammatory agent, was prepd. by coupling R2NH2 and compd. II(Z = Cl, Br or OX; X = H, C1-4 alkoxycarbonyloxy or benzyloxycarbonyloxy). Thus, 5.0 g methyl-4,3-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide was added in aq. soln. of sodium hydroxide at 70≰C, and obtained slurry was heated at 90-95≰C for 45 min to give I.

Description

Method for preparing 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide

The present invention relates to a process for preparing 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide, which is a valuable intermediate as a nonsteroidal anti-inflammatory agent. It is about.

More particularly, the present invention can be obtained by base hydrolysis with alkyl or aralkyl esters of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide. Preparation of the carboxylic acid compound and N- (2-pyridyl) -3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide which dissolves diacids -1,1-dioxide and N- (2-thiazolyl) -3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1 It relates to the use to prepare dioxide.

The instability of β-ketocarboxylic acids is evidenced by their ease of decarboxylation, and is known to those skilled in the art.

3,4-Dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxanes are prepared by hydrolysis of the corresponding esters but are rapidly dehydrated once they have been produced It is known to be carboxylated.

It was observed that this instability is due to their β-keto structure.

The production of N-substituted-3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxides useful as anti-inflammatory agents is known. Two synthetic routes of N-substituted-benzothiazine-carboxamide-1,1-dioxides; That is, (a) a route for reacting a suitable 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-1,1-dioxide with an organic isocyanate and (b) 3,4-dihydro- Routes for ammonolysis of esters of 4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide with ammonia or suitable amines are known. Also known are methods for producing compounds wherein the N-substituent is a heterocyclic component by amino group transfer reactions. 3,4-dihydro-4-alkoxy-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide with coupling promoter (dicyclohexyl carbodimide, pocl ₃ , N-ethoxycarbonyl-2-esci-1,2-dihydro quinoline), followed by contacting the resulting carboxamide with a photoacid to convert the 4-alkoxy group to 4-oxo to prepare a carboxamide derivative. How to do is reported.

In each case, 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1, even as a temporary intermediate, was used to prevent the instability of the β-keto photosensitivity of these acids so far reported. Special synthetic routes should be applied to avoid the formation of dioxide.

This acid instability is consistent with β-keto acid being prone to decarboxylation.

The ester of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide (formula I) is present in the presence of a source of hydroxide ions. It has been surprisingly found that it can be prepared as a stable crystalline material under atmospheric pressure by decomposing and then acidifying the reaction mixture to pH 6.0 or below, and can be otherwise.

By acylation of the appropriate amines thus produced are valuable intermediates for the preparation of non-steroidal anti-inflammatory agents such as formula II.

Z in formula II is selected from the group consisting of 2-pyridyl and 2-thiazolyl.

The process of the present invention for preparing 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide (I) is a compound of formula Is hydrolyzed in the presence of a source of hydroxyl ions and then acidified to give a compound of formula I.

Compounds of structures I, II and III exist as a mixture of keto and enol tautomers.

Formulas I, II, and III represent keto tautomers. Both tautomers of the compounds described herein are included within the scope of the present invention.

Conveniently, only keto forms are illustrated.

Methods for preparing 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide ester are known.

Alkyl esters of C ₁ -C ₄ , in particular methyl and ethyl esters, are easy to prepare and are therefore advantageous as reactants in hydrolysis processes.

Hydrolysis of the structural formula III esters is carried out in the presence of hydroxide ions using, for example, alkali metal hydroxides and alkaline earth metal hydroxides as source of hydroxyl ions. Hydrolysis can be carried out in an aqueous or non-aqueous solvent system. When performed in the aqueous medium, the hydrolysis is carried out between 20 ° C. and the reflux temperature of the reaction medium. Among metal hydroxides, alkali metal hydroxides are more preferred and advantageous because they are more water soluble than alkaline earth metal hydroxides. Preferred alkali metal hydroxides are It is preferred because of their utility as sodium and potassium hydroxides and when they are more economically advantageous than other alkali metal hydroxides in large scale production.

Preferred alkaline earth metal hydroxides are calcium and magnesium hydroxides because they are more advantageous in price than their alkaline earth metal hydroxides.

In addition to metal hydroxides, quaternary ammonium hydroxides such as, for example, tetraalkyl ammonium hydroxide, trialkyl benzyl ammonium hydroxide and dialkyl dibenzyl ammonium hydroxide, where the alkyl group is C ₁ -C _12, are also sources of hydroxide ion. Can be used. Representative of such bases are tetramethyl ammonium hydroxide, dimethyl dibenzyl ammonium hydroxide and trimethylbenzyl ammonium hydroxide.

The molar ratio of metal hydroxide to ester reactant is not critical.

About 1: 1-10: 1. In practice, it has been found that about 1: 1-5: 1 molar ratios are effective in obtaining satisfactory rates and yields of hydrolysis.

When performed in a non-aqueous solvent system, the same metal hydroxides as listed above can be used as the source of hydroxide ions.

In order to carry out the reaction efficiently, the dissolution effect obtained in the metal hydroxide in a hydrocarbon solvent such as benzene or toluene is used, for example, by the presence of a crown ether such as macrocyclic ether.

Representative crown ethers useful in the process include 18-crown-6, dibenzo-18-crown-6, cyclohexyl-18-crown-6, dicyclohexyl-15-crown-6, and cyclohexyl-15-crown -5.

Useful sources of hydroxyl ions in non-aqueous solvent systems are alkali metal hydroxides, since crown ethers have a relatively strong tendency to form complexes with alkali metal cations, because they dissolve well and increase their reactivity in the presence of crown ethers.

Preferred alkali metal hydroxides are potassium hydroxide and sodium.

Hydrolysis in a non-aqueous system with crown ether assistance results in the desired 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide. Since it is obtained in substantial yield, it is a preferable hydrolysis method.

In general, when crown ethers are used, the molar ratio of alkali metal or alkaline earth metal hydroxides to crown ethers and ester reactants varies from 1: 0.1-100: 1: 10. In practice, excess metal hydroxide is used because it minimizes the reaction time and hydrolyzes the ester more completely than when using a small volume. Of course, higher proportions of crown ethers may be used. The reaction is usually carried out at the reflux temperature of the solvent used. Generally, the temperature is in the range of about 80-150 ° C. and of course depends on the solvent used (eg benzene, toluene, xylene).

Crown ether-alkalimetal complex compounds may be produced in advance or in situ. To simplify the operation it is advantageous to produce the complex in situ and to use an excess of alkali metal hydroxide to accelerate the reaction.

Complexes are prepared by reacting a suitable base such as, for example, potassium hydroxide with a suitable crown ether in methanol or benzene. Methanol or benzene is removed and toluene or benzene is added to the residue. The hydrolysis product is recovered by adjusting the aqueous solution of the hydrolysis product to pH 0-6.0. Mines and especially hydrochloric acid are commonly used for economic reasons. Of course, if the hydrolysis is carried out in a non-aqueous solvent system, the solid hydrolysis product is separated from the solvent system using a suitable method (filtration, centrifugation), then dissolved in water and the pH adjusted. Advantageous pH ranges are about 1-4; The preferred range is pH 2-3.

As mentioned above, 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide is an effective anti-inflammatory agent N- (2-pyridine). Di)) and N- (2-thiazolyl) -3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide It is a valuable intermediate for manufacturing.

These compounds may be selected from suitable amines (R ₂ NH ₂ ) such as 2-aminopyridine or 2-aminothiazole with 3,4-diside-2-methyl-4-oxo-2H-1,2-benzothiazine- Prepared by acylating with a reactive functional derivative of the carboxy group of 3-carboxylic acid-1,1-dioxide. Suitable reactive functional derivatives of acid reactants are acid chlorides, acid bromide, acid azide and active esters or thioesters with N-hydroxy succinimide, N-hydroxyphthalimide, phenol or thiophenol such as N, N ' Dicyclohexylcarbodimid, N, N'-carbonyldiimidazole, N, N'-carbonyl-ditriazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline Reactive intermediates with various such dehydrating coupling agents and alkoxy carboxylic acids (particularly alkoxy groups having C ₁ -C ₄ ) or mixed anhydrides with benzyloxy carboxylic acids.

Preferred acylating agents are mixed anhydrides with acid chlorides because of their ease of preparation.

Acylation is performed in an aqueous or non-aqueous solvent system. In an aqueous system, the reaction is generally carried out at pH 6-9, at a temperature of about 0 ° -50 ° C. When using acid chlorides, the reaction can be carried out at pH 2-4 in an unstable emulsion of water miscible organic solvents such as methyl isobutyl ketone and lower alkyl acetates and water. When using carbodimid in an aqueous system it is advantageous to adjust the pH to about 5-8, preferably at pH 6-7.

In a typical manner, acid reactants and carbodimids are mixed in the same proportions in a suitable solvent (tetrahydrofuran, dioxane), and a water-water miscible organic solvent solution containing amine (water and dioxane or tetrahydrofuran) After addition at room temperature the mixture is stirred for several hours until the reaction is complete. Generally a temperature of -5 ° -30 ° C is used. In most instances an excess of about 10% condensation agent is used. Acylation products are recovered by known methods.

In the case of using an acid chloride as the acylating agent, the oxygen solution is preferably an organic base such as triethylamine, pyridine, N-methylaniline, or an excess amine reactant (R ₂ NH ₂ ), or sodium carbonate or sodium bicarbonate. Use the same inorganic base.

Example 1

3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide (hydrolysis in aqueous medium)

Methyl 4,3-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (5.0 g) in sodium hydroxide (160 g) (500 ml) ) Is added to the solution at 70 ℃. The resulting pale yellow slurry is heated at 90 ° -95 ° C. for 45 minutes and then cooled to room temperature in an ice water bath. The pH of the reaction mixture is adjusted to 1-1,5 by slowly adding concentrated hydrochloric acid (350ml).

If necessary, add ice cubes to keep the temperature below 35 ° C. The acid product is precipitated and granulated by stirring at 10 ° -15 ° C. for 15 minutes. The resultant was collected by suction filtration, washed with water (100 ml) and then reslurried in water (250 ml) for 30 minutes to remove excess hydrochloric acid.

After suction suction filtration again and washed with water (100ml). 25 g of wet filter cake (total wet filtrate is 25.5 g) are dissolved in warm methanol, the solution is filtered and water (50 ml) is added to the filtrate. The addition of seed crystals immediately precipitates the product. The slurry is granulated by stirring at about 10 ° C. for 30 minutes. The white crystalline product is isolated by filtration, washed with water and air dried. Yield = 13.2 g, Melting point 144 ° -146 ° C

The filtrate is evaporated to 1/2 volume to yield more product (3.2 g). This process is repeated to recover the tertiary crystals (2.6 g). Total yield = 16.4 g (34.6%) MS (molecular ion) = 255

IR (KBr): 3535cm ^-1 (Enol OH), 2900-2000cm ^-1

(Acid OH), 1660 cm ⁻¹ (C═O), 1340, 1170 cm ⁻¹ (SO ₂ ).

Similar results are obtained by repeating the above method using potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide or barium hydroxide as the base.

Example 2

Hydrolysis in 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide nonaqueous medium (crown ether method)

Sodium hydroxide (2.8 g), methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide (6.73 g) and benzene ( 100 ml) is stirred and to this is added a solution of benzene (10 ml) of dicyclohexyl-18-crown-6-ether (0.93 g) over 1 minute. The reaction mixture is heated at reflux for 2 hours. Add potassium hydroxide (2.8 g) and continue refluxing for a total of 50 hours. The tan slurry is filtered when hot and the filter cake is washed with benzene (50 ml) and dried. After dissolving this in water (100 ml), the pH of the solution was adjusted to 1.0 with hydrochloric acid while maintaining the temperature at about 15 ° C. The resulting precipitate is granulated for 30 minutes, filtered, washed with water and dried (4.4 g of crude product). The crude product is dissolved in warm methanol (49 ml), the solution is filtered and diluted by the slow addition of water (63 ml). The resulting precipitate is granulated at 10-15 ° C. for 30 minutes, then filtered, washed with water (2 × 10 ml) and air dried. Yield = 3.5g 61.9% Melting Point 134-141 ° C

18-crown-6, dibenzo-18-crown-6, cyclohexyl-18-crown-6, cyclohexyl-15-crown-5- and sodium hydroxide or potassium, lithium hydroxide and dibenzo-14-crown 4: Barium hydroxide or strontum and Minaphthal-20-crown-6

Or using potassium hydroxide and dibenzo-30-crown-10 and repeating the above procedure to obtain the acid.

Example 3

According to the method of Example 1 or 2, the esters in the following table are synthesized with 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide. Decompose

Example 4

N- (2-pyridyl) -3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

25 ml three-ply round-bottomed flask with magnetic stirrer, reflux condenser and choker stopper, thionyl chloride (1.82 ml), isopropyl ether (12.8 ml) and 3,4-dihydro-2-methyl-4-oxo-2H -1,2-benzothiazine-3-carboxylic acid-1,1-dioxide (1.28 g) is added. The mixture is heated to reflux, stirred for 5 hours and then evaporated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (10 ml) and the resulting solution was used directly in the next step.

To the resulting acid chloride N, N-dimethylformamide solution was added 2-aminopyridine (1.03 g) while stirring. An exothermic reaction occurs and red develops to orange in about 5 minutes. The reaction mixture is stirred overnight and then diluted by the slow addition of water (40 ml). The resulting precipitate is granulated for 30 minutes, filtered, washed with water and air dried (1.3 g., 79%). Melting point 160-175 ° C.

It is dissolved in N, N-dimethylacetamide (1 ml per 0.1 g) at 50 ° -60 ° C. and purified by adding 5 times the volume of methanol to the resulting precipitate. Yield of pure product = 30% Melting point 198-200 ° C

Compounds are identified by infrared and mass spectrometry.

Similar results are obtained when thionyl bromide is used in place of thionylchloride.

Example 5

N- (2-thiazolyl) -3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

510 mg of 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide, 1.45 ml of thionyl chloride, 10.0 ml of isopropyl ether, and N The procedure of Example 4 was repeated except that 2.0 ml of N-dimethylformamide was used. 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1 Prepare acid chlorides of 1, dioxide.

The acid chloride was reacted with 2-aminothiazole (400 mg) according to the acylation method of Example 4 to give 532 mg (79%, crude) of the title product.

It is dissolved in N, N-dimethylacetamide at 60 ° C., the solution is filtered and the filtrate is purified by dilution with methanol (15 ml). Yield = 208 mg (33%) Melting Point 234-240 ° C

This treatment is repeated to obtain pure product.

The product is confirmed by infrared and mass spectrometry.

Example 6

N- (2-pyridyl) -3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3-carboxylic acid-1,1-dioxide (127 mg) and 2-aminopyridine (52 mg) were treated with tetrahydrofuran ( 5 ml) is added to a solution of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (148 mg) in tetrahydrofuran (1 ml) while stirring. The mixture is stirred at room temperature (23-25 ° C.) for 4 hours and then concentrated under reduced pressure to an oil.

The title product was present when thin layer chromatography on silica gel in benzene: acetic acid (95: 5) solvent system and the plates were compared to the real samples under a 366 μm lamp.

N, N'-dicyclohexylcarbodimid, N, N'-carbonyl-S-triazine, N as coupling reagent instead of N-ethoxycarbonyl-2-ethoxy-1,2-dihydro quinoline Using N-carbonyl, di-imidazole, ethoxyacetylene, diphenylketene P-tolylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or N-hydroxypiperidine Similar results are obtained by repeating the method.

Claims (1)

A method for producing a compound of formula (I), comprising coupling an amine of the general formula R ₂ NH ₂ or more with an equivalent molar amount to a compound of formula (II).

In the common sense R ₂ is a 2-pyridyl or 2-thiazolyl group Z is the active receiving derivative of the corresponding reactant, preferably chlorine, bromine or OX (X is selected from alkoxycarbonyloxy and benzyloxycarbonyloxy groups having 1 to 4 carbon atoms).