KR900008812B1 - A process for the preparation of 4-hydroxy-2-methyl-2h-1,2-benzothiazine-3-carboxamide-1,1-dioxides - Google Patents

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Description

Method for preparing 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

The present invention provides a method for preparing 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of the following general formula (I) having analgesic and anti-inflammatory action It is about.

Wherein R is phenyl; Aryl substituted with halogen (C1, Br or I) or C ₁ -C ₆ alkyl group; Unsubstituted or substituted with halogen (Cl, Br or I) or C ₁ -C ₆ alkyl group or 2,3 or 4-pyridyl; 5-methyl-isoxazolyl or 2-thiazolyl.

Among these products, particularly compounds having excellent therapeutic effects are 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of the following general formula (II).

General formula (I) compound of this invention is alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide of following general formula (III) Prepared by reaction with a magnesium derivative of formula (IV).

R-NH-Mg-X (IV)

Wherein R 1 is a C ₁ -C ₆ alkyl group, X is halogen, preferably Br, and R is as defined in formula (I).

This reaction is carried out until the reaction is almost complete at a temperature of 0 to 130 ° C. in a solvent inert to the reaction. The obtained intermediate is hydrolyzed in an acid medium to obtain a compound of formula (I), which is then recrystallized.

일 경우)와 반응에 불활성인 용매중에서 반응시키고, 다음에 얻어진 중간체를 산 매체중에서 가수분해하여 일반식(II)의 화합물을 제조하는데, 이는 다음 반응식으로 나타낼 수 있다.According to the invention, 4-hydroxy-2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of general formula (II) Is 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide of formula (V) wherein R ₁ in formula (III) is -CH _2- CH ₃ ) is 2-aminopyridyl-magnesium bromide of formula (VI) (R in formula (IV)

In a solvent inert to the reaction, and then the obtained intermediate is hydrolyzed in an acid medium to produce a compound of formula (II), which can be represented by the following scheme.

This reaction is preferably carried out by stirring in an inert atmosphere for 1 to 8 hours in a mixture of product (V) and (VI) xylene-tetrahydrofuran (THF) at 0 ° to 130 ° C. The reaction can be carried out, for example, at reflux temperature.

The starting product (V) can be prepared by the process described in J. Org. Chem. 2241 (1965) and US Pat. No. 3,501,466, and product (VI) is not yet described in the literature. , A process analogous to that described in the VOGEL "Text-book of practicla organic chemistry", page 1124, 4 th Edition, which can be prepared as indicated in the table below.

Example 1

a) 1 g (0.04 mol) Mg, 3.5 ml (0.04 mol) ethyl bromide and 25 ml THF are added to a three necked flask equipped with a nitrogen inlet, reflux cooler and panel and stirred at room temperature. Since this reaction is exothermic, the reaction itself is heated for 10 minutes even after reflux. The reaction solution is then cooled and 4.0 g (0.043 mol) of 2-aminopyridine dissolved in 25 ml of THF is added dropwise over 15 minutes, followed by stirring for 30 minutes.

b) To a three-necked flask equipped with an N ₂ inlet, reflux condenser and funnel, add 5.7 g of the starting product of formula (V) dissolved in 100 ml of xylene and heat until boiling.

Thereafter, the solution of the general formula (VI) product prepared in the above example was added dropwise over 30 minutes while continuing reflux, at which point it was refluxed and stirred for 2 hours at the end of the dropwise addition.

Yellow rubbery material is produced in the migration. After 2 1/2 hours, the reaction solution is cooled and decanted. Hydrolysis of the residue with 1N hydrochloric acid gives the yellow gummy material a crude solid which is filtered off, dried and then suspended in water and stirred for 30 minutes. Filtration gave a yellow precipitate, which gave 3.3 g (yield = 50%) of the compound of formula (II) having a melting point of 198 to 200 캜. Recrystallized with isopropanol to obtain a sample for analysis.

The moisture content according to Karl Fischer method is 0.1% and the infrared spectrum approximate absorption bands in KBr tablets are 3340, 1635, 1580, 1530, 1440, 1355, 1305, 1185 cm-1.

Example 2

a) Add 1 g (0.04 mol) of Mg to a 3-necked flask equipped with an N ₂ inlet, reflux condenser and funnel, add funnel with 3.5 ml (0.04 mol) of ethyl bromide dissolved in 20 ml of tetrahydrofuran and 25 minutes. After dropwise addition to Mg over a portion, the mixture is stirred at room temperature for 10 minutes and heated at 50 ° C. for 30 minutes. Next, the reaction mixture was cooled, 4 g (0.043 mol) of 2-aminopyridine dissolved in 20 ml of tetrahydrofuran was added, followed by stirring for 15 minutes.

b) 5.42 g of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3 dissolved in 50 ml of xylene in a 250 ml three necked flask equipped with N ₂ inlet, reflux cooler and panel The carboxylate is dissolved at 100 ° C. The magnesium solution prepared above is added dropwise to the solution prepared subsequently over 30 minutes while heating for 1 1/2 hours while refluxing in an oil bath. The mixture is then cooled and the solvent is decanted off. The resulting intermediate is a rubbery substance, to which 100 ml of 1N hydrochloric acid is added, stirred for 45 minutes, and filtered. The crude product obtained is suspended with stirring in 80 ml of water to give a yellow solid precipitate which is collected by filtration.

The yellow solid in dichloromethane-methanol is recrystallized to give 4 g of product having a melting point of 198 to 200 ° C. This solid is 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.

Infrared spectrum approximate absorption bands in KBr tablets are 3340, 1635, 1580, 1530, 1440, 1355, 1305, 1185 cm ⁻¹ .

Example 3

a) 1 g (0.04 mole) Mg was added to a 100 ml three-necked flask equipped with an N ₂ inlet, reflux condenser and panel, and 3.5 g (0.04 mole) ethyl bromide dissolved in 20 ml of tetrahydrofuran was added to the funnel. After dropwise addition to Mg over 25 minutes, after the dropwise addition, the mixture was stirred at room temperature and then heated at 50 ° C for 30 minutes. After cooling the mixture, 4 g (0.043 mol) of aniline dissolved in 20 ml of tetrahydrofuran are added dropwise over 20 minutes. After the addition, the mixture is stirred for 15 minutes.

b) 5.7 g of ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate at 100 ° C. in a 250 ml three necked flask equipped with N ₂ inlet, reflux condenser and panel. Dissolve in 50 ml of xylene. The Grignard's reagent prepared above is added dropwise to the solution prepared over 30 minutes, and heated for 1 1/2 hours while refluxing in an oil bath. This liquid is cooled and the solvent is decanted to remove.

The resulting intermediate was rubbery, to which 100 ml of 1N hydrochloric acid was added, stirred for 45 minutes and filtered to give crude 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxycyanide-1, Obtain 1-dioxide. This was recrystallized from dichloromethane-methanol to obtain 2.1 g (yield 30%) of pure product having a melting point of 210 ° to 213 ° C. Recrystallized with isopropanol to obtain a sample for analysis.

Example 4

a) 1 g of Mg (0.04 mol) is placed in a 100 ml three-necked flask equipped with an N ₂ inlet, reflux cooler and funnel, and 3.5 ml (0.04 mol) of ethyl bromide dissolved in 20 ml of tetrahydrofuran is added to the funnel. . The solution is added dropwise to Mg over about 25 minutes, and after the addition, the solution is stirred at room temperature for 10 minutes and then heated at 50 ° C. for 30 minutes. After the mixture was cooled, 4.2 g (0.043 mol) of 3-amino-5-methyl-isoxazole dissolved in 20 ml of tetrahydrofuran were added and stirred for 15 minutes.

b) 50 ml of 5.7 g of ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate at 100 ° C. in a three necked flask equipped with an N ₂ inlet, reflux cooler and funnel. Dissolve in xylene. The magnesium solution prepared above is added drop wise to the prepared solution above over 30 minutes and heated for 1 1/2 hours under reflux on an oil bath. The solution is cooled and the solvent is decanted to remove it. The resulting intermediate is rubbery, to which 100 ml of 1N hydrochloric acid is added. After stirring for 15 minutes, it was filtered to obtain gray 4-hydroxy-2-methyl-N- (5-methyl-isoxazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1 Obtain dioxide. Recrystallization from dichloromethane-methanol gives the pure product at melting point 250-252 ° C.

Claims (4)

The alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide of the following general formula (III) is reacted with the magnesium derivative of the following general formula (IV) Reaction was carried out at 0 to 130 DEG C in the presence of an inert solvent and the resulting intermediate was hydrolyzed in an acid medium to recrystallize the product to yield 4-hydroxy-2-methyl-2H-1,2-. Process for the preparation of benzothiazine-3-carboxamide-1,1-dioxide.

R-NH-Mg-X (IV) Wherein R ₁ is C ₁ -C ₆ alkyl, X is halogen, R is aryl substituted with phenyl halogen (Cl, Br or I) or an alkyl group of C ₁ -C ₆ ; 2,3 or 4 pyridyl unsubstituted or substituted with halogen (C1, Br or I) or an alkyl group of C ₁ -C ₆ ; Or 5-methyl-isoxazolyl or thiazolyl. A compound according to claim 1, wherein ethyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide of formula (V) is substituted with 2 of formula (VI). 4-hydroxy-2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide by reaction with -amino-pyridyl-magnesium bromide How to prepare. The process according to claim 1 or 2, wherein the inert solvent consists of a mixture of xylene-terrahydrofuran. The method according to claim 1 or 2, wherein hydrolysis is performed using N hydrochloric acid.