KR920005746B1 - Process for the preparation of oxazino benzothiazine 6,6-dioxide derivatives - Google Patents

Abstract

A method for preparing oxazino benzothiazine 6,6-dioxide derivs. of formula (I) comprises (a) reacting a cpd. of formula (II) with bis(trihalomethyl)carbonate of formula (Hal)3COCOOC(Hal)3 in an inert organic solvent, and (b) reacting the mixture with 2-amino pyridine in the presence of an acid bonding agent. In (II), X=OH or halogen. The inert solvent is selected from dichloromethane, chloroform, tetrahydro furane, dioxane or benzene. The acid bonding agent is selected from Na2CO3, K2CO3, NaHCO3, KHCO3, triethylamine or pyridine. The cpds. (I) are useful as a prodrug of piroxicam (nonsteroidal antiphlogistic).

Description

Method for preparing oxazinobenzothiazine 6,6-dioxide derivative

The present invention relates to 5-methyl-3- (2-pyridyl) -2H of the following structural formula (I) which is a prodrug derived from pyroxicam, which is a nonsteroidal anti-inflammatory and analgesic agent. A novel process for preparing, 5H-1,3-oxazino- [5,6-c] 1,2-benzothiazine-2,4 (3H) -dione 6,6-dioxide.

The usefulness and preparation of pyroxam with excellent anti-inflammatory analgesic effects are described in US Pat. No. 3,591,584. In particular, the usefulness and preparation method of the compound of formula (I), which is the target compound of the present invention, are described in Korean Patent Publication No. 87-627, US Patent No. 4,563,452, and European Patent No. 242289, and the structural formula (I) of the present invention. The compound is reported to exhibit reduced gastrointestinal upset compared to the enolic acid, pyroxicam.

Known methods for preparing the compound of formula (I) are described in US Pat. No. 4,563,452, Korean Patent Publication No. 87-627, European Patent No. 242289, and the like. These preparation methods can be summarized as follows.

1.Method of obtaining the compound of the formula (I) by melt-reacting the following compound of the general formula (III) and the compound of the urethane derivative under high temperature and reduced pressure (US Pat. No. 4,563,452)

Wherein R is a linear or chained lower C ₁ -C ₄ alkyl group.

2. A method for preparing the compound of formula (I) by reacting phosgene or ethyl chloroformate represented by the following formula (II). (Korean Patent Publication No. 87-627, European Patent No. 242289) )

Wherein R ₁ is C ₁ -C ₄ alkoxy, phenoxy, benzyloxy, trichloromethoxy (particularly chlorine). However, the method described in U.S. Patent No. 4,563,452 not only has to melt at high temperature in a stream of nitrogen but also yields an uncomfortable yield of 68% when the phenol produced during the reaction is distilled under reduced pressure at 25 mmHg. In addition, the method described in Korean Patent Publication No. 87-627 (56% yield) and European Patent No. 242289 has a phosgene that is difficult to handle because it is not only economical but also toxic because the starting material is expensive pyroxycam. There is a hassle to use.

Unlike the above methods, the present invention is characterized in that the compound of formula (VI) is reacted with bis (trihalomethyl) carbonate of formula (VII), wherein the halogenated and haloformylated structures generated in the reaction are produced. An intermediate, such as (iii), is a novel process which can be produced in high yield by the reaction of 2-amino pyridine of formula (V) without separation.

When the present invention is represented by the reaction scheme as follows.

Wherein X is OH or halogen and Hal is a halogen atom.

In addition, the intermediate represented by Structural Formula (VIII) reacts a bis (trihalomethyl) carbonate of Structural Formula (VIII) after reacting a halogenating reagent such as thionyl chloride to the following Structural Formula (VI) wherein X is OH. By reacting, the compound of formula (VII) may be produced and used without separation in the next reaction.

Wherein X and Hal are as described above.

Bis (trichloromethyl) carbonate, one of the compounds of formula (III) used in the above reaction, is a white crystal (melting point 81-83 ° C), which is not only easy to handle as a safe reagent, but also transported and stored. This is easy. It is also a convenient reagent that can be used in chemical reactions by easily weighing the correct amount.

Structural formula (VI), wherein X is OH in the process of the invention, is described in detail in the invention of the same application.

The compound of formula (VI) prepared as above was prepared in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, and acid such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine and pyridine. Carbonylation reagents such as phosgene, diphosgene, bis (trichloromethyl) carbonate, preferably bis (trichloromethyl) carbonate, in the presence of 1 to 4 molar equivalents of the binder are The reaction was carried out for 1 to 5 hours to form an intermediate of the structural formula (VII), and then without separation, 2-amino pyridine was added in a so-called one-foot reaction, followed by reaction for 5 to 20 hours at 0 ° C to 80 ° C. Can be obtained in high yield. In addition, the intermediate represented by the formula (VIII) is a compound of formula (VI) in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine And halogenating reagents such as thionyl chloride, pivaloyl chloride and oxalyl chloride in the presence of 1 to 4 molar equivalents of an acid binder such as pyridine, followed by carbonylation such as bis (trichloromethyl) carbonate. By reacting the reagent, a structural formula compound can be produced, and 2-aminopyridine and the desired structural formula (I) compound can be obtained without separating the structural formula compound thus obtained.

Hereinafter, the present invention will be described in more detail with reference to the following examples.

Reference Example 1

Preparation of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide

4 g of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide are mixed in 60 ml of ethanol and stirred for 30 minutes. 8.8 g of barium hydroxide octahydrate was added thereto, and the temperature was gradually raised to reflux for 20 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, 100 ml of cold water was added thereto, cooled to 0-5 ° C., and acidified with 5% hydrochloric acid (PH 2) to form a crystal. The resulting crystals were stirred for an additional hour at 0-5 ° C., filtered, washed three times with a small amount of cooling water and dried under reduced pressure using phosphorus pentoxide as a drying agent to yield 3.71 g (98%) of the title compound as white crystals. .

Melting Point: 140-143 ℃

IR (KBr, cm ^-1 ): 3535, 3000-2200, 1660, 1340, 1170

¹ H-NMR (DMSO / CDCl ₃ / TMS, δ): 2.90 (s, 3H), 7.60-8.18 (m, 4H), 9.0 (br.s, 2H)

Elemental Analysis: C ₁₀ H ₉ NO ₅ S

Theoretical (%): C; 46.96, H; 3.55, N; 5.48

Found (%): C; 46.85, H; 3.58, N; 5.35

Example 1

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

Bis (trichloromethyl) carbo to 2.56 g of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide (VI) obtained in Reference Example 1 above. 2.18 g of Nate were added and mixed, cooled to -15--10 ° C., and 30 ml of dried dichloromethane was added and stirred for 10 minutes. 1.5 ml of pyridine was slowly added to the reaction mixture, and the mixture was slowly stirred for 4 hours until the temperature reached room temperature, and then cooled to 0-5 ° C. 0.94 g of 2-aminopyridine is added in small portions, and the temperature is gradually increased, followed by stirring at room temperature for 18 hours. The reaction solvent was distilled under reduced pressure, 30 ml of a mixed solvent of methanol and water (1: 1) was added to the residue, followed by stirring at 0-5 ° C for 30 minutes. The resulting crystals were filtered and washed with a small amount of 1N-HCl, water, isopropanol and ether to give 3.15 g (88%) of the title compound (I) as white crystals.

Melting Point: 258-261 ℃

IR (KBr, cm ^-1 ): 1785, 1708, 1635, 1406, 1355, 1175

¹ H-NMR (DMSO / CDCl ₃ / TMS, δ): 3.10 (s, 3H), 7.58 (m, 2H), 8.03 (m, 5H), 8.63 (m, 1H)

Elemental analysis: C ₁₆ H ₁₁ N ₃ O ₅ S

Theoretical (%): C; 53.77, H; 3.08, N; 11.76

Found (%): C; 53.95, H; 3.15, N; 11.72

Example 2

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

To 2.56 g of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide (VI) obtained in Reference Example 1, 30 ml of dried dichloromethane was added and continued. 1.5 ml of pyridine is added and mixed. The reaction mixture was cooled to 0-5 ° C., 1 ml of thionyl chloride was added through a syringe, and slowly added thereto, followed by stirring at acid temperature for 3 hours. When the reaction solution becomes clear, 1.10 g of bis (trichloromethyl) carbonate is added, followed by further stirring for 3 hours. After cooling to 0-5 ° C., 0.94 g of 2-amino pyridine was added in small portions, followed by stirring at room temperature for 18 hours. When the reaction was completed, the mixture was treated as in Example 2 to obtain 3.04 g (85%) of the title compound (I) as white crystals.

Melting Point: 259-261 ℃

IR (KBr, cm ^-1 ): 1788, 1710, 1637, 1408, 1355, 1178

¹ H-NMR (DMSO / CDCl ₃ / TMS, δ): 3.12 (s, 3H), 7.60 (m, 2H), 8.05 (m, 5H), 8.68 (m, 1H)

Elemental analysis: C ₁₆ H ₁₁ N ₃ O ₅ S

Theoretical (%): C; 53.77, H; 3.08, N; 11.76

Found (%): C; 53.70, H; 3.18, N; 11.80

Example 3

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

Bis (trichloromethyl) carbo to 2.56 g of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide (VI) obtained in Reference Example 1 Nate 2.18 is added and mixed, cooled to -1--10 ° C., and 50 ml of dried tetrahydrofuran is added and stirred for 10 minutes. 1.5 ml of pyridine was slowly added to the reaction mixture, stirred for 4 hours until the temperature reached room temperature, and cooled to 0-5 ° C. 0.94 g of 2-aminopyridine is added in small portions, and the temperature is gradually increased, followed by stirring at room temperature for 18 hours. The reaction solvent was distilled off under reduced pressure, 30 ml of a mixed solvent of methanol and water (1: 1) was added to the residue, and the mixture was stirred at 0-5 ° C for 30 minutes. The resulting crystals were filtered off and washed with a small amount of 1H-HCl, water, isopropanol, and ether in order to obtain 3.11 g (87%) of the title compound (I) as white crystals.

Melting Point: 258-261 ℃

IR (KBr, cm ^-1 ): 1785, 1705, 1635, 1405, 1350, 1170

¹ H-NMR (DMSO / CDCl ₃ / TMS, δ): 3.12 (s, 3H), 7.58 (m, 2H), 8.02 (m, 5H), 8.63 (m, 1H)

Elemental analysis: C ₁₆ H ₁₁ N ₃ O ₅ S

Theoretical (%): C; 53.77, H; 3.08, N; 11.76

Found (%): C; 53.90, H; 3.14, N; 11.79

Example 4

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

Bis (trichloromethyl) carbo to 2.56 g of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide (VI) obtained in Reference Example 1 above. 2.18 g of Nate were added and mixed, cooled to -15--10 ° C., and 30 ml of dried dichloromethane was added and stirred for 10 minutes. After slowly adding 2.8 g of calcium carbonate to the reaction solution, the mixture was stirred slowly for 6 hours until the temperature reached room temperature and cooled to 0-5 ° C. 0.94 g of 2-amino pyridine is added in small portions, and the temperature is gradually raised and stirred at room temperature for 20 hours. After filtration, the reaction mixture was distilled under reduced pressure, and 30 ml of a mixed solvent of methanol and water (1: 1) was added to the residue, followed by stirring at 0-5 ° C for 1 hour. The resulting crystals were filtered and washed with a small amount of 1N-HCl, water, isopropanol and ether in order to obtain 3.97 g (83%) of the title compound (I) as white crystals.

Melting Point: 258-261 ℃

IR (KBr, cm ^-1 ): 1785, 1708, 1636, 1406, 1357, 1177

¹ H-NMR (DMSO / CDCl ₃ / TMS, δ): 3.12 (s, 3H), 7.60 (m, 2H), 8.05 (m, 5H), 8.65 (m, 1H)

Elemental analysis: C ₁₆ H ₁₁ N ₃ O ₅ S

Theoretical (%): C; 53.77, H; 3.08, N; 11.76

Found (%): C; 53.69, H; 3.05, N; 11.58

Claims (4)

The compound of formula (VI) is reacted with bis (trihalomethyl) carbonate of formula (VII) in an inert organic solvent, followed by reaction of 2-amino pyridine of formula (V) in the presence of an acid binder. A process for preparing the target compound of formula (I).

Wherein X is OH or halogen and Hal is halogen. The compound of formula (VI) wherein X is OH is reacted with a halogenating reagent such as thionyl chloride, pivaloyl chloride, oxalyl chloride, and then bis (trihalomethyl) carbonate of formula (VII). And subsequently reacting 2-aminopyridine of formula (V) to produce the target compound of formula (I). The method of claim 1, wherein as an inert solvent, dichloromethane, chloroform, tetrahydrofuran, dioxane, benzene, and acid binders include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, and pyridine. How to. The method of claim 1, wherein the reaction is carried out at a temperature of −15 ° to 80 ° C. for 1 to 24 hours.