KR850001037B1 - Process for 3,4-dihydro-2-substituted-2h-1,2-benzothiazine-carboxylic acid 1,1-dioxide derivatives - Google Patents

Abstract

Benzothiazine carboxylic acid dioxide derivatives I or II [R1 = C1-3 alkyl; R2 = H, halogen, nitro, trifluoromethyl, C1-5 alkyl or alkoxy , which are used as non-steroid antiphlogistics, are prepared. Thus, 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine1,1-dioxide (6.34 g) and magneseum methylcarbonate (2M) are mixed with N,N- dimethylformamide (150 mL) and stirred at 140-150≰C for 2 hr. to give 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-3carboxylic acid-1,1- dioxide.

Description

Method for producing 3, 4-dihydro-2H-1, 2-benzothiazine-carboxylic acid-1, 1-dioxides

The present invention relates to a novel process for preparing a compound represented by the following general formula (I) or (II), which is an intermediate of carboxamides of benzothiazine dioxide, which is valuable as a nonsteroidal anti-inflammatory agent.

In general formula (I) or (II), R <_1> is a lower alkyl group having 1-3 carbon atoms, R <_2> is hydrogen, a halogen, a nitro group, a trifluoromethyl group, an alkyl group or an alkoxy group having 1-5 carbon atoms And the like.

In particular, the present invention is to prepare a compound of formula (I) or (II) by carboxylating the compound represented by formula (III) or (IV) with magnesium alkyl carbonate as shown in Schemes 1 and 2 This acid is used to prepare a compound of the general formula (V) or (VI) which is an anti-inflammatory agent.

Scheme 1

Wherein R ₁ and R ₂ are the same as described above and R ₃ is hydrogen, an alkyl group having 1-8 carbon atoms or alkoxy, phenyl, phenylalkyl, 2-pyridyl, 2-thiazolyl, 5-methyl-3-isoxazole It represents a first heterocyclic group.

Since the compound of general formula (I) or (II) is β-keto type carboxylic acid, it is unstable, and decarboxylation occurs easily, and it is known that the yield is low at the time of manufacture. There are two ways.

That is, the β-keto-type carboxylic acid structure is avoided by substituting the β-keto position with an appropriate functional group (Korean Patent Publication No. 79-858), and 3,4-dihydro-2-methyl-4-oxo- 3,4-dihydro-2-methyl-4-oxo-2H-1, 2 by base hydrolysis from alkyl or aralkyl esters of 2H-1, 2-benzothiazine 3-carboxylic acid-1, 1-dioxides -Benzothiazine-3-carboxylic acid 1, 1-dioxide (USP 4, 100, 347).

However, the process of the present invention is simpler than the prior art of preparing a suitable acid amide and then hydrolyzing esters by bringing a substituent of β-keto on contact with a mineral acid, and the reaction is almost quantitative. There are many advantages such as going forward.

The most useful of the products of the present invention are those in which R ₁ is methyl and R ₂ is hydrogen.

According to a feature of the invention, the compound of formula (III) or (IV) and 1-10 equivalents of magnesium alkylcarbonate are suspended in a suitable inert solvent. Inert solvents should not adversely affect the reactants or products under the conditions used.

Examples of such solvents are N, N-dimethyl formamide or dimethyl sulfoxide.

Magnesium alkyl carbonates have an alkyl group of methyl, ethyl, propyl and the like, but preferably have a methyl group and an equivalent of 4-7 equivalents.

The reaction temperature is carried out at 50-150 ° C., but in consideration of the effect of the substituent of R ₂ , it is preferable to react near the melting point of the compound of formula (III) or (IV).

The process takes 1-5 hours. It is preferable to neutralize the reaction solution by contacting with a suitable organic solvent which is not mixed with water in order to prevent the metal carbonate to form the general formula (I) or (II) compound by rapid pouring into the cooled hydrochloric acid.

As the organic solvent, non-polar solvents such as hexane, eret, ethyl acetate and dichloromethane are useful. In addition, it is preferable to neutralize at low temperature by adding ice cubes in order to obtain a pure product, and the organic solvent layer can be separated and concentrated under reduced pressure to obtain almost quantitative compounds of the general formula (I) or (II).

The resulting compound of (I) or (II) is particularly advantageously obtained by obtaining a general formula (V) or (VI) by a mixed acid anhydride method carried out at low temperature in order to prevent decarbonated acid.

Structural formulas of these compounds exist as mixtures of keto and enol tautomers, but for convenience only one isomer is indicated.

Hodomers of the compounds described herein are included within the scope of the present invention. Moreover, the manufacturing method of general formula (III) or (IV) is known. (J. Org. Chem. 31, 162, 1966, J. Med. Chem. 14, 973, 1971) In the following Examples, the present invention is described in more detail, but the scope of the present invention is not limited thereto.

Example 1

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

6.34 g (0.03) of 3,4-dihydro-2-methyl-4-oxo-2H-1, 2-benzothiazine-1, 1-dioxide in a three-necked flask equipped with a reflux condenser, stirrer, thermometer, and calcium tube Mole) and magnesium methyl carbonate (2 moles) are mixed with 150 ml of N, N-dimethylformamide solution and stirred at 140-150 ° C. for 2 hours.

The reaction solution is rapidly added to a mixture of 200 ml of concentrated hydrochloric acid, 200 g of ice, and 500 ml of ethyl ether. After stirring for 10 minutes, the ether layer is separated and the ether layer is concentrated under reduced pressure.

The resulting pale yellow crystals are separated by filtration and recrystallized from the solution with dilute alcohol to give white crystals.

7.21 g of product, 94% yield

IR (KBr): 3583 cm ^-1 (enolated OH), 3000-2500 cm ^-1 (acid OH), 1600 cm ^-1 (C = O), 1340, 1170 cm ^-1 (SO ₂ )

Example 2

3-hydroxy-2-methyl-2H-1, 2-benzothiazine-4-carboxanilide-1, 1-dioxide reflux condenser, stirrer, thermometer, three-necked flask with calcium tube 3, 4 Dihydro-2-methyl-3-oxo-2H-1, 2-benzothiazine-1, 1.06 g (0.005 mol) of 1-dioxide and magnesium methyl carbonate (2 mol) N, 20 ml of N-dimethylformamide Mix and stir at 90-100 ° C. for 3 hours. The resulting solution was added rapidly with a mixture of 30 ml of concentrated hydrochloric acid, 70 g of ice and 200 ml of ethyl ether. The ether layer is separated and concentrated under reduced pressure to obtain 1.25 g of 3, 4-dihydro-2-methyl-3-oxo-2-1, 2-benzothiazine-4-carboxylic acid-1, 1-dioxide.

This is dissolved in 20 ml of benzene as it is, 1.8 ml of thionyl chloride, 0.4 ml of N and N-dimethylformamide are added, followed by stirring for 3 hours in a water bath. The resulting pale yellow precipitate was separated by filtration, washed with a small amount of benzene, dissolved in 10 ml of N and N-dimethylformamide as it was, 1.02 g of aniline was added thereto, and stirred at room temperature for 3 hours. Add 2 times the amount of ice water, and crystals are formed, filtered and recrystallized.

Yield 0.85 g, yield 51.2%, m.p 155-156 ° C

This compound was identified by elemental analysis, infrared and nuclear magnetic resonance spectra.

Example 3

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

15 ml benzene, 2.0 ml thionyl chloride, 0.4 ml N, N-dimethylformamide and 3, 4-dihydro-2-methyl-4-oxo- in a three-neck round bottom flask with thermometer, stirrer, reflux cooler and calcium tube 1.29 g (0.005 mol) of 2H-1, 2-benzodiazine-3-carboxylic acid-1, 1-dioxide are mixed and stirred for 3 hours on a water bath.

The resulting precipitate was filtered off, washed with a small amount of benzene, dissolved in 10 ml of N, N-dimethylformamide as it was, and 1.2 g of 2-aminopyridine was added thereto. Fever turns pale yellow. After stirring the mixture for 3 hours, 2 times the amount of ice water is added, the resulting crystals are separated by filtration, washed with excess water and dried.

Recrystallization by a known method.

0.87 g of product, 52% yield, m.p 199-200 ° C.

Example 4

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

15 ml of tetrahydrofuran in 3, 4-dihydro-2-methyl-4-oxo-2H-1, 2-benzothiazine-3-carboxylic acid-1, 1.29 g (0.005 mol) of 1-dioxide and 1 ml of triethylamine After dissolving in, it is cooled to -15 deg.

While stirring, 1.08 ml of pivaloyl chloride was slowly added thereto, followed by stirring, and then 0.61 g of 2-aminopyridine was added thereto.

After slowly reacting to room temperature for 5 hours, crystals formed by adding 2 times the amount of ice water were separated by filtration and dried. Recrystallization by a known method.

0.97 g of product, 58% yield, m.p 198-201 ℃ compounds were identified by elemental analysis, infrared and nuclear magnetic resonance spectra.

Similar results are obtained when benzenesulfonyl chloride or p-tolfuenesulfonyl chloride is used in place of pivaloyl chloride.

Example 5

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

The same procedure as in Example 4 was repeated using 0.64 g of 2-aminothiazole instead of 0.61 g of 2-aminopyridine to synthesize the title compound.

0.82 g product, 54% yield, m.p 250-252 ° C.

The product was identified by elemental analysis, infrared and nuclear magnetic resonance spectra.

Example 6

N- (5-methyl-3-isoxazolyl) hydroxy-2H-1, 2-benzothiazine-3-carboxamide-1, 1-dioxide

The same procedure as in Example 4 was repeated using 0.63 g of 3-amino-5-methyl-isoxazole instead of 2-aminopyridine to synthesize the title compound.

0.80 g of product, 48% yield, m.p 254-256 ° C.

The product was identified by elemental analysis, infrared and nuclear magnetic resonance spectra.

Claims (2)

A method for producing general formula (I) or (II) by reacting a compound of general formula (III) or (IV) with magnesium alkylcarbonate.

Wherein R ₁ is a lower alkyl group having ₁ to 3 carbon atoms R ₂ represents hydrogen, a halogen, a nitro group, a trifluoromethyl group, an alkyl group having 1 to 5 carbon atoms, an alkoxy group, or the like. General formula (I) and (II) of an amine of general formula R ₃ NH ₂ and an equivalent molar amount or more at low temperature by a mixed acid anhydride method using trimethylacetyl acid chloride, benzene sulfonic acid chloride or substituted benzene sulfonic acid chloride Process for preparing the formulas (V) and (IV).

R ₁ is a lower alkyl group having 1-3 carbon atoms, R ₂ is hydrogen, halogen, nitro group R ₃ represents a hydrogen, an alkyl group having 1 to ₃ carbon atoms, or a heterocyclic group such as alkoxy, phenyl, phenylalkyl, 2-pyridyl, 2-thiazolyl or 5-methyl-3-isoxazolyl.