KR900003501B1 - Process for the preparation of oxazino benzothiazine 6,6-dioxide derivatives - Google Patents

Abstract

A 5-methyl-3-heteroaryl-2H, 5H-1,3-oxazino [5,6-C [1,2 benzothiazine-2,4-(3H)-dion 6,6-dioxide of formula (I) is prepd. by reacting amide of formula (II) with a cpd. of formula Cl-(C=O) -O-R2 in an org. solvent i.e. 4-dimethylaminopyridine, 4-(pyrrolidin-1-yl) pyridine and 2,6-ditertiary-butyl-4-methylpyridine for 3-48 hr at -5- 50 deg. C. (I) is useful as an antiphlogistic and an anodyne, that is known for droxicam.

Description

Method for preparing oxazinobenzothiazine 6,8-dioxide derivative

The present invention relates to a method for preparing an oxazinobenzothiazine 6,6-dioxide derivative, in particular 5-methyl-3-heteroaryl-2H, 5H-1,3-oxazino [5,6-c] [1 , 2] benzothiazine-2,4- (3H) -dione 6,6-dioxide derivative.

5-Methyl-3-heteroaryl-2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2 represented by the following general formula (I) according to the present invention , 4- (3H) -dione 6,6-dioxide derivative is obtained in a high purity and very pure form,

The oxazinobenzothiazine 6,6-dioxide represented by the general formula (I) corresponding to the case where R is a heteroaryl group, preferably substituted or unsubstituted pyrimidinyl or pyridyl group, is an anti-inflammatory agent and an analgesic agent. , Especially droxicam, and Chem. Abst. (1984, 100, 191893j).

In the prior art, oxazinobenzothiazine 6,6-dioxide was prepared from an ester represented by the following general formula (II),

R ¹ represents an alkoxy group such as methoxy or ethoxy group.

Further, French Patent A-2 566 408 discloses a compound represented by the above general formula (II) wherein R ¹ represents a pyridin-2-ylamino group in the presence of an organic solvent which is inert under the reaction conditions and in the presence of an acid acceptor. Reacted with phosgene to react with 5-methyl-3- (pyridin-2-yl) -2H, 5H-1,3oxazino [5,6-c] -1,2-benzothiazine-2,4- (3H) A method for producing di-ion 6,6-dioxide is described, where methylene chloride is used as the organic solvent and triethylamine is preferred as the acid acceptor in order to obtain the best economics and yield of the process. Although described, this type of method has serious problems, including the disadvantages of using phosgene, which is a fairly toxic agent, especially when carried out on an industrial scale, and its yield is very low, such as 56%.

Therefore, the present invention is a novel form of the oxazinobenzothiazine 6,6-dioxide derivative represented by the above general formula (I) to be a pure form and high yield through a simple process to solve the problems of the prior art as described above. It is an object to provide a manufacturing method.

Hereinafter, the present invention will be described in detail.

The present invention reacts the amide represented by the general formula (II) with the compound represented by the following general formula (III) to prepare an oxazinobenzothiazine 6,6-dioxide derivative represented by the general formula (I). It is a way.

In this formula (II), R ¹ represents a heteroaryl amino group, a substituted or unsubstituted pyrimidinyl amino group or a pyridyl amino group is preferable, in the general formula (III) R ² is a C ₁ -such as methyl or ethyl group Or a C ₄ lower alkyl group or an aryl group such as a phenyl group, or an alkylaryl group such as a benzyl group.

In the present invention, the compounds of the general formula (II) and (III) is allowed to react for about 3 to 48 hours at a temperature between about -5 ℃ to 50 ℃.

In addition, one important thing in the present invention is substituted pyridines such as 4-dimethylaminopyridine, 4- (pyrrolidin-1-yl) pyridine and 2,6-di-butyl-4-methylpyridine. And pyridine and an organic solvent selected from a mixture thereof. When the solvent used is a mixture of pyridine and substituted pyridine, substituted pyridine is used in a small amount in a weight ratio of about 1 to 10%.

According to the present invention as described above, not only can be obtained a derivative of the compound represented by the general formula (I) of a very high purity, but also the process is very simple enough to be carried out on an industrial scale can yield 90% or more. The process yields these derivatives.

Hereinafter, a method of preparing some derivatives of the compound represented by Formula (I) according to the present invention will be described in detail in Examples 1 to 4 below, but the present invention is not necessarily limited to the following examples.

Example 1

5-Methyl-3- (pyridin-2-yl) -2H, 5H-1,3-oxazino- [5,6-c] [1,2] benzothiazine-2,4- (3H) -dione Method for preparing 6,6-dioxide

11.9 kg (36 moles) of N- (pyridin-2-yl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1- in 301 anhydrous pyridine 13.8 L (144 mol) of methyl chloroformate was added dropwise to the partial solution by dissolving the dioxide, while cooling in an ice bath while maintaining the temperature below 18 ° C. The mixture is then stirred for 24 hours at room temperature and the whole is poured into 175 L of water / ice mixture. After filtration, the residue was washed sequentially with a large amount of distilled water, 0.5N hydrochloric acid and distilled water, and the obtained residue was dissolved in acetone to give 5-methyl-3- (pyridine-2- having a melting point of 264-266 ° C. 11.62 kg (90.5%) of 2-H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4- (3H) -dione 6,6-dioxide crystals; )

Spectral Data

IR (KBr); 1185; 1355; l410; 1640; 1710; 1790 cm ^-1

¹ H NMR, δ, [DMSO-d ₆ ]: 3.02 (s, 3H); 7.52 (m, 2 H); 7.29 (m, 5 H); 8.52 (d, H)

Example 2

5-methyl-3- (pyrimidin-2-yl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4- (3H) -dione Preparation of 6,6-Dioxide

3.32 kg (0.01 mole) N- (pyrimidin-2-yl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1 in 25 ml anhydrous pyridine, 13.6 g (0.04 mole) of benzylchloroformate was dissolved in toluene as a 50% solution in a partially dissolved solution of 1-dioxide, and the resulting solution was added dropwise while stirring while keeping the temperature below 10 ° C. Cool in an ice bath. The mixture was stirred for 8 hours at a temperature of 30 ° C. and then the whole amount was poured into 100 ml of water / ice mixture, filtered and the residue was washed with a large amount of distilled water and immediately stirred in acetone heated to boiling. The mixture is then filtered.

This gives 5-methyl-3- (pyrimidin-2-yl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine with a melting point of 282-284 ° C. 3.3 g (92%) of -2,4- (3H) -dione 6,6-dioxide compound are obtained.

Spectral Data

IR (KBr); 1180; 1355; 1400; 1632; 1710; 1787 cm ^-1

¹ H NMR, δ, [DMSO-d ₆ ]: 3.05 (s, 3H); 7.93 (m, 5 H); 8.95 (d, H)

Example 3

5-methyl-3- (4-methylpyridin-2-yl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4- (3H) Preparation of -dione 6,6-dioxide

3.45 g (0.01 mol) of N- (4-methylpyridin-2-yl) -4-hydroxy-2-methyl-2H-1,2- in a mixture of 2 g 4-dimethylaminopyridine and 25 ml anhydrous pyridine 5 mL (0.04 mole) of phenylchloroformate is added to the partial solution obtained by dissolving benzothiazine-3-carboxamide 1,1-dioxide while stirring at room temperature. The mixture is stirred at a temperature of 40 ° C. for 3 hours, cooled to room temperature, poured into 100 ml of water / ice mixture and filtered, and the residue is washed sequentially with a large amount of distilled water, 0.5N hydrochloric acid and distilled water. The residue thus obtained was dissolved in acetone to give 5-methyl-3- (4-methylpyridin-2-yl) -2H, 5H-1,3-oxazino [5,6] having a melting point of 259-261 ° C. -c] [1,2] benzothiazine-2,4- (3H) -dione 6,6-dioxide crystals yield 3.45 g (93%).

Spectral data

IR (KBr); 1195; 1360; 1415; 1640; 1720; 1795 cm ^-1

^{l H NMR, δ, [DMSO} -d 6]: 2.42 (s, 3H); 3.10 (m, 3 H); 7.40; (m, 2H); 7.98 (m, 4 H); 8.40 (d, lH)

Example 4

5-methyl-3- (6-methylpyridin-2yl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4- (3H)- Preparation of Dione 6,6-Dioxide

3.45 g (0.01 mole) N- (6-methylpyridin-2-yl) -4-hydroxy-2-methyl-2H-1,2 in a mixture of 2 g 4-dimethylaminopyridine and 25 ml anhydrous pyridine To a partial solution of benzothiazine-3-carboxamide 1,1-dioxide, add 3 ml (0.04 mole) of methyl chloroformate with stirring, keeping the temperature below 10 ° C in an ice bath. Cool. The mixture was stirred at room temperature for 30 hours, the whole amount was poured into 100 ml of water / ice mixture and filtered, and the residue was washed sequentially with a large amount of midstream, 0.5N hydrochloric acid and distilled water, and then the residue obtained When water is dissolved in acetone, 5-methyl-3- (6-methylpyridin-2yl) -2H, 5H-1,3-oxazino [5,6-c] [1,2 having a melting point of 248-250 ° C. ] 3.6 g (97%) of benzothiazine-2,4- (3H) -dione 6,6-dioxide crystals are obtained.

Spectral data

IR (KBr); 1190; 1360; 1410; 1640; 1715; 1790 cm ^-1

^{l H NMR, δ, [DMSO} -d 6]: 2.43 (s, 3H); 3.00 (m, 3 H); 7.40 (m, 2 H); 7.97 (m, 5H)

Claims (7)

5-Methyl-3-heteroaryl-2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4- (represented by the following general formula (I) In preparing 3H) -dione 6,6-dioxide, the amide represented by the following general formula (II) and the compound represented by the following general formula (III) are 4-dimethylaminopyridine and 4- (pyrrolidine- Preparation of oxazinobenzothiazine 6,6-dioxide derivative, characterized in that the reaction is carried out in an organic solvent selected from 1-yl) pyridine and 2,6-di-butyl-4-methylpyridine, pyridine and mixtures thereof. Way.

In the formulas (I), (II) and (III), R represents a heteroaryl group, preferably a substituted or unsubstituted pyrimidinyl or pyrityl group, and R ¹ represents a heteroarylamino group, preferably substituted or unsubstituted Ring pyridinylamino or pyridylamino group, R ² represents a C ₁ -C ₄ lower alkyl group such as methyl or methyl, an alkyl group such as phenyl or an alkylaryl group such as benzyl. The method of claim 1 wherein the reaction is carried out in a pyridine mixture containing 1 to 10% of at least one substituted pyridine. The method of claim 1 wherein the reaction is performed for about 3 to 48 hours at a temperature of about -5 ℃ to 50 ℃. The amide according to any one of claims 1, 2 or 3, wherein R ¹ in general formula (II) is pyridin-2-ylamino and R ² in general formula (III) is an ethyl group. The phosphorus compound was reacted for 3 to 48 hours in a pyridine solvent at a temperature ranging from -5 ° C to 40 ° C to give 5-methyl-3- (pyridin-2-yl) -2H, 5H-1,3-oxazino [5 , 6-c] [1,2] benzothiazine-2,4- (3H) -dione 6,6-dioxide. The amide according to any one of claims 1, 2 or 3, wherein R ¹ in general formula (II) is pyrimidin-2-ylamino and R ² in general formula (III) is A compound which is a benzyl group is reacted for 3 to 48 hours in a pyridine solvent within a temperature range of -5 ° C to 40 ° C to give 5-methyl-3- (pyrimidin-2-yl) -2H, 5H-1,3-oxazino [5,6-c] [1,2] benzothiazine-2,4- (3H) -dione 6,6-dioxide. The amide according to any one of claims 1, 2 or 3, wherein R ¹ in General Formula (II) is 4-methylpyridin-2-ylamino, and R in General Formula (III). 5-methyl-3- (4-methylpyridin-2yl) -2H by reacting a compound which is a ^divalent phenyl group in 4-dimethylaminopyridine and a pyridine solvent for 3 to 48 hours in a temperature range of -5 ° C to 40 ° C. , 5H-1,3-oxazino- [5,6-c] [1,2] benzothiazine-2,4- (3H) -dione 6,6-dioxide. The amide according to any one of claims 1, 2 or 3, wherein R ¹ in general formula (II) is 6-methylpyridin-2-ylamino, and R in general formula (III). 5-methyl-3- (6-methylpyridin-2yl) -2H by reacting a compound having a ^divalent methyl group for 3 to 48 hours in a temperature range of -5 ° C to 40 ° C in 4-dimethylaminopyridine and a pyridine solvent. , 5H-1,3-oxazino- [5,6-c] [1,2] benzothiazine-2,4- (3H) -dione 6,6-dioxide.