KR820000411B1 - Process for preparing thiazine derivatives - Google Patents

Abstract

Thienothiazines(I; A = II, III, IV; R1 = lower alkyl;R2=lower alkyl-substituted heterocyclic or halogen, hydroxy, lower alky, alkoxy, trifluoromethyl-substituted phenyl), useful as antiinflammatory, analgesic, antithrombic and antirheumatic agent, were prepd. Thus, 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno[3,2-e -1,2-thiazin-1,1-dioxide and 2-aminopyridine were refluxed in 45 ml xylene for 16 hr followed by recrystallization with dioxane to give 6-chloro-4-hydroxy-2-methyl-3-(2-pyridyl carbamoyl)-2H-thieno[3,2-e -1,2-thiazine-1,1-dioxide.

Description

Method for preparing thiazine derivative

The present invention relates to a thienothiazine derivative of the following formula (I) and a method for preparing the salt thereof.

In the above structural formula,

R ¹ is lower alkyl, R ² is optionally substituted with 1-4 aromatic heterocyclic groups substituted by one or two lower alkyl groups, or optionally substituted with halogen, hydroxy, lower alkyl, trifluoromethyl or lower alkoxy Is a phenyl group, and R ³ is halogen.

As used herein, the term "lower alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl and tert-butyl. “Lower alkoxy” refers to a hydrocarbonoxy group having up to 4 carbon atoms and “halogen” refers to four halogen atoms, chlorine, bromine, fluorine and iodine.

이 Heteroatoms 1-4 aromatic heterocyclic groups optionally substituted with one or two lower alkyl groups ˝ the term nitrogen and / or oxygen and / or sulfur atoms optionally substituted with one or two lower alkyl groups. Four five or six-ring aromatic heterocyclic groups such as 2-thiazolyl, 4-methyl-2-thiazolyl, 4,5-dimethyl-2-thiazolyl, 5-methyl-1,3,4- Thiadiazolyl, 2-pyrazinyl, 2-pyrimidinyl, 1,2,4-triazin-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-2-pyri Dyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-isoxazolyl, 5-methyl- 3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 2,6-dimethyl-4-pyrimidinyl and 1,2,3,4-tetrazol-5-yl.

가 그룹(i) 또는 (iii)인 것이 바람직하다.Among the compounds of the above formula (I), R ³ is preferably chlorine or bromine (particularly preferably chlorine), R ¹ is a methyl group and R ² is 2-thiazolyl, 5-isoxazolyl or 2-pyri Deal

Is preferably a group (i) or (iii).

Particularly preferred compounds are 6-chloro-4-hydroxy-2-methyl-3- (2-pyridyl carbamoyl) -2-H-thieno [2,3-e] -1,2-thiazine-1 , 1-dioxide and 6-chloro-4-hydroxy-2-methyl-3- (2-pyridyl-carbamoyl-2H-thieno [3,2-e] -1,2-thiazine-1, 1-dioxide.

Thienothiazine derivatives of formula (I) are according to the invention,

a) reacting a compound of formula (II) with an amine of formula (III), or

b) closing the reactive functional derivative of the acid of formula (V), or

c) lower alkylating the compound of formula (V), or

d) reacting a compound of formula (VI) with an isocyanate of formula (VII) in the presence of a strong base, or

e) hydrolyzing the enamine of formula (VIII)

f) If necessary, the compound of formula (I) obtained is prepared by converting it into a salt.

, R¹및 R²는 상기된 바와 같고, R⁵및 R⁶는 각각 저급알킬기를 나타내거나, 또는 이들과 결합된 질소원자와 함께 피롤린, 피롤리딘, 피페리딘, 모르폴린 또는 N-(저급알킬)-피페라진 기를 형성한다.R in the above formula is lower alkyl,

, R ¹ and R ² are as described above, and R ⁵ and R ⁶ each represent a lower alkyl group, or together with the nitrogen atom to which they are attached, pyrroline, pyrrolidine, piperidine, morpholine or N- To form a (lower alkyl) -piperazine group.

The reaction according to reaction step a) can be carried out in the presence or absence of an inert solvent. Suitable solvents are alcohols such as ethanol, hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, chlorobenzene, methylene chloride and carbon tetrachloride, dimethylformamide and dioxane. This reaction is preferably carried out by heating, in particular the melting point temperature or reflux temperature of the reaction mixture.

In the reaction step b) according to the present invention, the reactive functional derivative of the compound of formula IV is closed. This ring closure is carried out in the presence of a base and preferably in the presence of a solvent between 0 ° C. and the reflux temperature of the reaction mixture (preferably between room temperature and 60 ° C.). Suitable bases are in particular hydrides, amides and alcoholates of alkali metals. Suitable solvents are aprotic and protic compounds such as alcohols such as methanol and ethanol, ethers such as dioxane and acid amides such as dimethylformamide. The starting compound of formula (IV) is dissolved in a solvent and a base is added and the reaction mixture is conveniently closed for 1 to 4 hours at room temperature or by heating until it reaches 60 ° C. Particularly suitable reactive functional derivatives of compounds of formula (IV) are their lower alkyl esters, for example their methyl esters.

According to reaction step c), the compound of formula (V) is lower alkylated. This alkylation reaction dissolves the starting compound of formula (V) in an aprotic solvent such as acetonitrile, dioxane or dimethylformamide, converts it to an alkali metal salt with an alkali metal amide or hydride and then lower alkylating agent, especially lower alkyl halide or It is conveniently carried out by treatment with sulfate and conversion to the corresponding compound of formula (I). The temperature and pressure of this process are not critical and are conveniently performed at room temperature and atmospheric pressure.

According to reaction step d), the compound of formula (VI) is reacted with isocyanate of formula (VII) in the presence of a strong base. Suitable strong bases include alkali metal amides, alkali metals or alkaline earth metal hydrides in addition to metal alkalis or alkaline earths. The reaction is carried out at temperatures between 0 ° C. and 50 ° C. (preferably room temperature) under an inert gas (eg nitrogen), toluene, dioxane, dimethylformamide, dimethylsulfoxide or hexamethyl phosphoric acid triamide (HMPT). Preference is given to performing in the presence of the same inert, polar solvent.

The isocyanate of formula (VII) as starting material can be synthesized in a known or analogous manner to the preparation of known compounds.

According to reaction step e), the enamine of structural formula (VIII) is hydrolyzed. The hydrolysis is preferably carried out with an aqueous inorganic acid or trifluoro acetic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid, at a temperature between 50 ° C. and the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture. In this hydrolysis, the acid acts simultaneously as a solvent.

Starting materials of reaction step a) are prepared by known methods starting from known products.

In particular, they can be synthesized according to the description in the following schemes and examples.

가 (i)그룹인 화합물들이고, 반응도표 (II)는

가 (ii) 그룹인 화합물들이며, 반응도표 (III)는

가 (iii)그룹인 화합물들이다.Scheme (I) is

Are compounds of group (i), and Scheme (II)

Are compounds of which (ii) is a group, and Scheme (III)

Are (iii) groups.

[Schematic Diagram I]

[Schematic Diagram II]

[Schematic Diagram III]

Lower alkyl esters of acids of formula (IV) which can be used as starting compounds in reaction process b) are obtained by reacting the product of formula (XIV) obtained by, for example, reacting amine of formula (III) with chloroacetyl chloride. Obtained by reaction with

R ₂ in the above formula is as described above.

Other reactive functional derivatives of the acid of formula (IV) can be prepared from known esters by known methods.

The starting compound of formula (V) used in reaction step c) can be obtained, for example, by reacting a compound of formula (XXI), (XXVIII) or (XXXII) with an amine of formula (III).

The starting material of formula (IV) used in reaction step d) can be prepared by a known method.

Starting materials of the reaction process e) can be prepared according to the following Reaction Scheme (IV).

[Reaction Chart IV]

Compounds of formula (I) may also form pharmaceutically harmless salts with the corresponding bases. Suitable bases include alkali metals (e.g. lithium, sodium, potassium), alkaline earth metals (e.g. magnesium and calcium) and amines (e.g. triethanol aminediethylaminoethanol, triethylamine, triethylamine, diethylamine, etc.). There is). The compounds of formula (I) containing R ₂ as a basic heterocyclic group may also form pharmaceutically harmless acid addition salts with strong acids, in particular inorganic acids (eg hydrochloric acid).

Compounds of formula (I) and salts thereof have anti-inflammatory, analgesic and antirheumatic effects. Such pharmacologically useful properties can be measured, for example, by standard methods, such as testing for paw edema with known mice kaolin.

In this test, 0.1 ml of a 10% kaolin suspension (bols alba) is injected subcutaneously into the rat's right foot, causing acute local inflammation. The test substance is administered orally and the following parameters are measured:

1. Diameter of foot (mm) (indicates the degree of inflammation)

2. Pressure in feet (g) (determining the threshold of pain)

The test substance is administered 1/2 hour before and 3 1/2 hours after kaolin injection and the above parameters are measured 6 hours after kaolin injection. The edema suppression effect is expressed in% based on the difference in the degree of edema between the animal treated with the test substance and the untreated animal, and the noxious inhibitory effect is expressed as an increase in the threshold of pain.

In this test, 6-chloro-4-hydroxy-2-methyl-3- (2-pyridyl-carbamoyl) -2H-thieno [2,3-e] -1,2-thiazine-1, Oral administration of 1-dioxide at a dose of 0.mg/kg increases the threshold of 20% edema inhibition and 97% pain, and oral administration of 1-mg / kg at 33 mg / kg edema and 129% Increase the threshold of pain;

Compounds of formula (I) are qualitatively similar to the effects of phenylbutazone, for which therapeutic uses and properties are well known.

It also inhibits platelet aggregation (as can be seen by appropriate standard tests) and therefore has anticoagulant properties.

The compounds of formula (I) can be used as pharmaceuticals, for example in the intestinal tract such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols and petrolatum or It is used in the form of a pharmaceutical preparation containing the compound in admixture with a pharmaceutical organic or inorganic inert carrier suitable for parenteral administration. The pharmaceutical preparations can be molded into solids such as tablets, dragees, suppositories or capsules, semisolids such as ointments, or liquids such as liquids, suspensions or emulsions.

If necessary, sterilization and / or auxiliary agents such as preservatives, stabilizers or emulsifiers, salts or buffers that change the osmotic pressure, and the like are included. It may also contain other therapeutically effective substances.

The daily oral dose for adults of the compound of formula (I) is 1-100 mg, with 2-10 mg being preferred.

The following examples illustrate the invention and all temperatures are in degrees Celsius.

Example 1

0.4 g (1.29 mmol) 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno [3,2-e] -1,2-thiazine-1,1- Dioxide and 0.18 g (1.94 mmol) of 2-amino pyridine are refluxed for 16 hours while passing through a stream of nitrogen in 45 ml of anhydrous xylene. The reaction mixture is cooled to room temperature and the product is scraped off to crystallize. The reaction mixture is left under cooling overnight to precipitate filtered crystals by suction and recrystallize from dioxane. 6-chloro-4-hydroxy-2-methyl-3- (2-pyridyl carbamoyl) -2H-thieno [3,2-e] -1,2- with a melting point of 239 to 241 ° C. (decomposition) Thiazine-1,1-dioxide is obtained.

The starting material of this example is obtained as follows.

59 g (1.48 moles) of sodium hydroxide are dissolved in 637 ml of water and the solution is heated to 90 °, 290.7 g (1.48 moles) of 2,5-dichlorothiophene-3-carboxylic acid is added and stirred to dissolve. 156 g (1.50 mol) of sodium hydrogen sulfite dissolved in 430 ml of water are added to the solution, and about 167 ml of 30% aqueous sodium hydroxide solution is added to adjust the pH of the solution to 7.5 to 7.7. 12 g (0.12 mol) of copper chloride fine powder are added to a clear solution and then boiled under reflux for 24 hours. The solution is filtered off from copper oxide while hot and the filtrate is acidified with 400 ml of concentrated hydrochloric acid and cooled to 5 °. The sediment to be separated is suction filtered without rewashing and dried under vacuum at 110 ° until the mass is reached.

The precipitate is boiled with 3 x 500 ml of methylene chloride. The residue is dried under 70 ° and vacuum to give sodium 5-chloro-2-sulfothiophene-3-carboxylate.

129 g (0.488 mole) of sodium 5-chloro-2-sulfothiophene-3-carboxylate was dissolved in a solution made by dissolving 84.7 g (1.523 mole) of potassium hydroxide in 430 ml of water, and the resulting solution was 130 Acidify with ml of concentrated hydrochloric acid to pH 1 and slowly cool to 5 °. The separated precipitate is suction filtered without rewashing. The filtrate is concentrated to evaporation to 220 ml and cooled to 5 ° again.

The precipitate separated out was suction filtered and combined with the dust obtained product and dried under vacuum at 110 °. Mothium-5-chloro-2-sulfothiophene-3-carboxylate is obtained.

25 g (0.089 moles) of potassium 5-chloro-2-sulfothiophene-3-carboxylate are suspended in 100 ml of phosphorus oxy chloride with stirring. 39 g (0.187 mole) of phosphorus pentachloride is added to the suspension and the mixture is stirred at 95 ° for 3 hours. The mixture is cooled to 10 ° and separated by suction filtration from the precipitated inorganic salts. The filtrate is concentrated as much as possible under vacuum and taken up in 200 ml of anhydrous chloroform to remove the inorganic salt still remaining and finally filtered. The solvent is distilled off to remove the amorphous oil. 5-Chloro-2-chlorosulfonyl-thiophene-3-carboxylic acid chloride is obtained.

21 g (0.075 moles) of 5-chloro-2-chlorosulfonyl-thiophene-3-carboxylic acid chloride are dissolved in 210 ml of anhydrous chloroform, 3.6 g (0.113 moles) of anhydrous methanol are added and the mixture is further refluxed. Boil until no more HCl is generated (approximately 4 hours). The solvent is distilled off and the remaining oil is cooled to precipitate crystals which can be used in subsequent operations without further purification. Methyl 5-chloro-2-chloro sulfothylthiophene-3-carboxylate is obtained.

18.6 g (0.068 mol) of methyl 5-chloro-2-chlorosulfonylthiophene-3-carboxylate and 17 g (0.135 mol) of glycine methyl ester hydrochloride are stirred in 190 ml of anhydrous pyridine for 6 hours at room temperature. The solvent is distilled off under vacuum. The residue is partitioned between 150 ml 2N HCl and 400 ml ether. The organic phase is separated and the aqueous phase is extracted by shaking with 3 x 100 ml of ether. The combined organic phases are dried over sodium sulfate, stirred with activated charcoal, filtered and distilled to concentration. The oily residue is crystallized with ether, suction filtered and immersed in a small amount of ice-cold ether. Methyl 5-chloro-2- (N-methoxycarbonylmethyl) -sulfamoylthiophene-3-carboxylate having a melting point of 95 to 97 ° is obtained.

10.6 g (0.0693 g paper) of sodium is dissolved in 100 ml of anhydrous methanol. The solution is concentrated by evaporation under vacuum and then heated at 100 ° and under vacuum for 1 hour.

Dissolve 10.6 g (0.033 mole) of methyl 5-chloro-2- (N-methoxycarbonylmethyl (-sulfamoylthiophene-3-carboxylate) in 75 ml of anhydrous benzene, which was prepared above and made anhydrous benzene 33 Sodium methylate suspended in ml is added to the solution and stirred for 6 hours at 60 ° The mixture is extracted by shaking with 150 ml of 2N HCl and 100 g of ice with 3 × 200 ml of methylene chloride. Shake the organic phase with 3 × 100 ml of 10% sodium acetate solution and shake the aqueous phase again with a small amount of methylene chloride each time Extract the organic phase with 5 × 150 ml of 10% sodium carbonate solution with a small amount of aqueous phase each time Shake again with methylene chloride of the combined aqueous phase is denatured with concentrated HCl to pH 1 and the precipitated product is extracted with 3 x 200 ml of methylene chloride. Dried over, stirred with activated carbon, filtered and concentrated by evaporation to precipitate the product as crystals 6-chloro-4hydroxy-3-methoxycarbonyl-2H-thieno [3,2] having a melting point of 178-179 °. -e] -1,2-thiazin-1,1-dioxide is obtained.

19 ml of 1.9 g (6.43 mmol) of 6-chloro-4-hydroxy-3-methoxycarbonyl-2H-thieno [3,2-e] -1,2-thiazine-1,1-dioxide In anhydrous dimethylformamide and cooled to 0 °. 0.56 g (13.5 mmol) sodium hydride suspension in 58% oil, which was washed with 2x10 mL of anhydrous benzene and freed from oil, was added and the mixture was stirred at 0 ° for 2 hours. 1.0 g (7.07 mmol) methyl iodide is added while the temperature does not exceed 10 ° and stirred at room temperature for 2 hours. The solvent is distilled off under vacuum and the residue is partitioned between 100 mL 2N HCl and 200 mL methylene chloride. The phases are separated and the aqueous phase is extracted by shaking with 50 ml of methylene chloride. The combined organic phases are dried over sodium sulfate, stirred with activated carbon, filtered and evaporated to concentrate. The remaining oil is crystallized from methanol. The product is suction filtered and immersed in a small amount of methanol. 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno [3,2-e] -1,2-thiazine-1,1- having a melting point of 173 to 174 ° Dioxide is obtained.

Example 2

0.4 g (1.29 mmol) 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-dieno [3,2-e] -1,2-thiazine-1,1- The dioxide is heated under reflux for 16 hours under nitrogen stream with 0.19 g (1.94 mmol) of 2-amino thiazole in 45 mL of anhydrous xylene. The reaction mixture is cooled to room temperature and the product is scraped off to crystallize and left overnight under cooling. The precipitated crystals are suction filtered and recrystallized from ethanol. 6-chloro-4-hydroxy-2-methyl-3- (2-thiazolylcarbamoyl) -2H-thieno [3,2-e] -1,2- with a melting point of 136 to 138 ° (decomposition) Thiazine-1,1-dioxide is obtained.

Example 3

2.59 g of 6-chloro-3,4-dihydro-2-methyl-4-oxo-2H-thieno [3,2-e] -1,2-thiazine-1,1-dioxide with 1.8 ml Pyrrolidine is dissolved in 20 ml of benzene. 3 mg of p-toluenesulfonic acid monohydrate is added and the mixture is heated to reflux until 0.2 ml of water is collected on a water separator. The mixture is evaporated to dryness and dried in high vacuum, then the residue is taken up in a small amount of benzene and diluted with dimethyl ether and hexane.

6-chloro-2-methyl-4- (1-pyrrolidino) -2H-thieno [3,2-e] -1,2-thiazine-1,1-dioxide with a melting point of 150 to 151.5 ° Precipitates red-brown cubes at -25 °.

1.34 g of 6-chloro-2-methyl-4- (1-pyrrolidino) -2H-thieno [3,2-e] -1,2-thiazine-1,1-dioxide and 0.8 ml of tree A solution made by dissolving ethylamine in 25 ml of a mixture of tetrahydrofuran and benzene in 4: 1 was added to a stirred mixture (cooled to -10 ° C) of 0.5 g of phosgene, 6 ml of benzene, and 3 ml of tetrahydrofuran. Add dropwise for 1 hour. The reaction mixture was left at -25 ° for 15 hours, heated to 20 °, and then a solution made by dissolving 0.64 g of 2-aminopyridine and 0.8 ml of triethylamine in 5 ml of tetrahydrofuran was stirred for 30 minutes. Add it down. The reaction mixture is further heated under reflux for 2 hours, poured into ice water, extracted with methylene chloride and the organic phase is evaporated to dryness and the residue is chromatographed on silica gel. The column was eluted with methylene chloride-ethylacetate (9: 1), evaporated to concentration and then from diethyl ether, 6-chloro-2-methyl-3- (2-pyridyl carbomoyl) with a melting point of 167.5 to 168 °. 4- (1-pyrrolidino) -2H-thieno [3,2-e] -1,2-thiazine-1,1-dioxide precipitates in the form of a yellow hexagonal crystal.

0.5 g of 6-chloro-2-methyl-3- (2-pyridylcarbamoyl) -4- (1-pyrrolidino) -2H-thieno [3,2-e] -1,2-thiazine -1,1-dioxide is heated to reflux for 15 minutes in 15 ml of 2N hydrochloric acid. Most of the hydrochloric acid is removed in vacuo and the residue is taken up in pH 6 phosphate buffer and extracted several times with methylene chloride. The solvent is removed in vacuo and the yellow solid residue is recrystallized from dioxane. 6-chloro-4-hydroxy-2-methyl-3- (2-pyridyl-carbamoyl) -2H-thieno [3,2-e] -1,2-thiazine with a melting point of 238 to 239 ° -1,1-dioxide is obtained as a yellow crystalline powder.

Example 4

A mixture of 1230 g (10.6 moles) of chlorosulfonic acid and 1000 g (8.45 moles) of thionyl chloride is placed in a 4 L flask and cooled to 5 ° on an ice bath. 647 g (5.23 mol) of 2,5-dichloro thiophene are slowly and carefully added so that the temperature of the reaction mixture does not exceed 7 °. Gas is badly generated. After the addition, the reaction solution is further stirred at 15 ° for 1 1/2 hours. The resulting scarlet solution is carefully obtained on ice. The mixture thus obtained is stirred for a few more minutes to break up a larger mass of crystalline sulfochloride. After the excess ice is removed, the precipitate is suction filtered, washed with distilled water and then compressed to dryness.

The red impure sulfochloride thus obtained is taken up in 4000 ml of methylene chloride and the solution is dried over anhydrous magnesium sulfate. After decomposition with ice, sulfochloride precipitates into oil, the aqueous phase is extracted with methylene chloride and the same process as described above is carried out.

The clear methylene chloride phase is evaporated to concentration and the resulting red oil is liberated from the residual solvent with a water pump and placed in an icebox (-20 °). 2,5-dichlorothiophene-3-sulfonic acid chloride is obtained in intimate crystal form, which is used as a next step without further purification. When recrystallized from petroleum ether, the product has a melting point of 25 to 27 degrees.

3500 ml of anhydrous chloroform are placed in a 4 L flask and 533 g (2.12 mol) of 2,5-dichlorothiophene-3-sulfonic acid chloride are dissolved therein.

The anhydrous methylamine is passed through with stirring at 20 ° until the test paper moistened with water shows a basic reaction.

The solution is further stirred for 1 to 1 1/2 hours at room temperature, then extracted several times with 0.5 N HCl on a separatory funnel, dried over anhydrous sodium sulfate and then concentrated in vacuo. Extremely cooling the oil obtained will crystallize. The product thus obtained is recrystallized from 1500 ml of carbon tetrachloride and dried at 40 ° and vacuum. 2,5-dichlorothiophene-3-sulfonic acid methyl amide having a melting point of 59 to 61 ° is obtained.

250 g (1.016 mole) of 2,5-dichlorothiophene-3-sulfonic acid methyl amide are dissolved in 1500 ml of anhydrous ether in a 4 L volumetric flask, the apparatus is washed with dry nitrogen, then washed with dry nitrogen and stirred 2200 mL ether solution with 2.54 mole of n-butyllithium was slowly added dropwise within 1 hour. Heating until the solution boils precipitates a white precipitate, which gradually becomes grey. After all the butyllithium is added, the solution is boiled under reflux for 5 hours.

Cool to about 25 ° and continue to stir dry carbon dioxide for 1/2 hour with continued stirring. The suspension is then poured into 2000 ml of water and concentrated hydrochloric acid is added until the aqueous phase gives a strong reaction. The ether phase containing the starting material and the final product is separated in a separatory funnel to further extract the aqueous phase with ether. The combined ether phases are extracted three times with 300 ml of 5% sodium bicarbonate solution each time. The combined sodium bicarbonate phases are acidified with concentrated hydrochloric acid (pH 1-2) and extracted with 4000 ml of ether. The ether phase is dried over anhydrous magnesium sulfate and concentrated by evaporation. Light yellow impure carboxylic acid is crystallized immediately. The obtained product is purified by recrystallization from glacial acetic acid.

5-Chloro-3-methylsulfamoylthiophene-2-carboxylic acid is obtained.

1500 ml of anhydrous chloroform are placed in a 4 L flask and 90 g (0.352 mol) of 5-chloro-3-methylsulfamoyl thiophene-2-carboxylic acid micropowder is suspended in the flask with stirring. Add 85.17 g (0.14 mole) of phosphorus pentachloride and heat the solution to 35 °. After about 15 minutes, a clear solution is obtained. (Avoid more than 35 ° because the starting material is closed at high temperatures). Stir for a total of 20 to 30 minutes and stop heating. The titration funnel is connected and 250 ml of anhydrous methanol is added dropwise to the solution. After adding all the methanol, the solution is boiled under reflux for 10 minutes and cooled.

The chloroform phase is extracted several times with a small amount of sodium bicarbonate solution (5%) in a separatory funnel, washed with water, dried over anhydrous sodium sulfate and concentrated by evaporation under vacuum. The oil obtained is polished to crystallize.

The crude product obtained is purified by recrystallization from methanol. Methyl 5-chloro-3-methylsulfamoylthiophene-2-carboxylate having a melting point of 103 to 104 ° is obtained.

The oil with 9.7 g (0.2224 moles) of 55% sodium hydride suspension is washed with anhydrous benzene in a glass suction filter and suspended in 70 ml of anhydrous dimethyl formamide under a stream of nitrogen in a 1 L volumetric flask.

60 g (0.2224 mol of methyl-5-chloro-3-methylsulfamoylthiophene-2-carboxylate) dissolved in 525 ml of anhydrous dimethylformamide was added dropwise within 1 hour with stirring at 0 °. Stir and add 65 mL of anhydrous dimethylformamide solution containing 44.5 g (0.2224 mol) of methyliodo acetate dropwise in 2 hours with cooling at 0-5 ° C. Solution until the test paper soaked in water shows a neutral reaction. The dimethyl formamide is distilled under vacuum (about 1 mm) and the residue is partitioned between 400 ml of 0.5 N hydrochloric acid and 400 ml of methylene chloride.

The methylene chloride phase is separated in a separatory funnel and the aqueous phase is extracted with a small amount of methylene chloride. The combined organic phases are extracted twice by shaking with 150 ml of 5% sodium bicarbonate solution. The methylene chloride phase is dried over anhydrous sodium sulfate and concentrated by evaporation in vacuo. The crystalline residue thus obtained is purified by recrystallization from methanol. Methyl 5-chloro-3- (N-methoxycarbonyl-N-methyl) -sulfamoyl thiophene-2-carboxylate having a melting point of 103 to 104 ° is obtained.

170 ml of dry methanol was placed in a 0.5 L flask and the dried nitrogen was washed. 3.53 g of sodium (0.146 mol) is added in several portions with stirring. Cool the mixture to about 30 ° when the sodium is completely dissolved and 50 g of methyl 5-chloro-3- (N-methoxycarbonyl-N-methyl) -sulfamoyl thiophene-2-carboxylate (0.146 mol) Is added while stirring. The suspension is stirred at 30 ° for 15 minutes and carefully heated until boiling. A clear orange solution is formed. Continue boiling by thin layer chromatography until all the starting material has finished (about 25-35 minutes).

The solution is cooled to about 45 ° and then poured into 200 g ice / 300 ml 2N hydrochloric acid to precipitate the desired product. The resulting aqueous suspension is extracted several times by shaking with 2 x 400 ml of methylene chloride in a separatory funnel. The combined methylene chloride phases are extracted with 2 x 150 ml of 10% sodium acetate solution and then shaken together with sodium carbonate solution. The combined sodium carbonate phases are washed with a small amount of methylene chloride and acidified with concentrated hydrochloric acid with vigorous stirring to pH 1 to 2. The aqueous phase containing the precipitated final product is concentrated by drying 2x500 ml of methylene chloride phase with sodium sulfate and evaporating under vacuum. 6-Chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno [2,3-e] -1,2-thiazine-1,1-dioxide as a yellow overgrape crystal It is absorbed in a small amount of cold methanol, suction filtered and dried at 70 ° under vacuum, which is pure enough for the next reaction. A small amount is recrystallized from benzene for elemental analysis, which has a melting point of 200 to 203 ° (decomposition).

1200 ml of anhydrous xylene was placed in a 2 l volumetric flask and 11 g of 6-chloro-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno [2,3 e] -1,2-thiazine -1,1 dioside (0.0355 mol) is added while stirring. 4.42 g of 2-aminopyridine (0.0469 mol) is added and the solution is boiled under reflux until thin film chromatography completes the reaction of all starting products (about 4 hours). While boiling under reflux, a moderated stream of nitrogen is passed through the mixture to remove the methanol formed. After the reaction is completed, the solution is cooled to about 120 ° and activated carbon is added and the solution is boiled a little more. Fill a glycerol in a funnel with hot water, preheat it to 120 ° and filter the hot reaction solution at 120 ° through this funnel. When the temperature of the solution drops to 70 °, scraping the solution begins to separate small orange crystals. When cooled, the solution is left in an ice box (-5 °) for 12 hours to filter off the precipitate which is separated off and washed with xylene. The product is dried under vacuum (1 mm, 120 °, 2 hours). The orange to yellow crystals obtained in this way have 6-chloro-4-hydroxy-2-methyl-3- (2-pyridyl-carbamoyl) -2H-thieno [1] having a melting point of 225 to 230 ° (decomposition). 2,3-e] -1,2-thiazine-1,1-dioxide.

Example 5

268.5 g of sodium 2,5-dibromothiophene-3-sulfonate fine powder (0.78 mol) is suspended in 400 ml of phosphorus oxychloride and 171 g of phosphorus pentachloride (0.82 mol) is added. The reaction solution is heated at 90 ° for 21/2 hours. The solution is evaporated under vacuum to deeply concentrate and the residue is poured into 600 g of ice and the product is extracted with 3 x 250 ml of chloroform. The organic phase is washed with 2 x 100 mL of water, dried and concentrated by evaporation. A dark oil containing 2,5-dibromothiophene-3-sulfonic acid chloride is left behind which is pure enough to be used for the next reaction.

150 g (0.44 mole) of 2,5-dibromothiophene-3-sulfonic acid chloride is dissolved in 500 ml of anhydrous chloroform. Pass the anhydrous methylamine at 20-25 ° until the pH paper soaked in water gives a basic reaction. After stirring for another hour the reaction mixture is extracted several times with 0.5N hydrochloric acid, washed with water and then the organic phase is dried over sodium sulfate. The organic phase is concentrated by evaporation under vacuum and the remaining crystalline residue is immersed in a small amount of diisopropyl ether. N-butyl-1,5-dibromothiophene-3-sulfonamide having a melting point of 100 to 104 ° is obtained.

An n-butyl lithium solution prepared from 223 ml of ether 24.3 g n-butyl bromide and 4.4 g lithium was charged with 33.5 g N-methyl-2,5-dibromothiophene-3-sulfonamide (0.1 mol). To 520 ml of anhydrous ether solution was added dropwise at room temperature. The solution is stirred for another 2 hours at room temperature and dry carbon dioxide is passed through the solution. The reaction mixture is poured into water, the ether phase is separated and the aqueous phase is acidified with hydrochloric acid and the product is extracted with ether. The dehydrated ether phase is concentrated by evaporation and the remaining crystalline product is taken up in benzene. 5-Bromo-3-N-methyl-sulfamoyl thiophene-2-carboxylic acid having a melting point of 165 to 185 ° is obtained.

30.0 g (0.1 mole) of 5-bromo-3-N-methyl sulfamoyl thiophene-2-carboxylic acid is suspended in 400 ml of anhydrous chloroform and cooled to 24.2 g of phosphorus pentachloride (0.11 mole) of 5 to 10 Add at ° As soon as a clear solution is formed, it is further stirred at 10 ° for 20 minutes and 100 ml of anhydrous methanol is added dropwise. The solution is boiled under reflux for 10 minutes, extracted with sodium bicarbonate solution, dried and concentrated by evaporation. The remaining oil is triturated with methanol to give methyl-5-bromo-3-N-methyl-sulfamoyl-thiophene-2-carboxylate with a melting point of 114 to 117 °.

160 ml of anhydrous dimethylformamide solution containing 31.4 g (0.1 mol) of methyl 5-bromo-3-N-methyl-sulfamoyl-thiophene-2-carboxylate were dissolved in 2.52 g of sodium hydride (0.105 mol). ) Is added dropwise at 0 ° to a suspension suspended in 12 ml of anhydrous dimethyl formamide. The reaction solution is further stirred for 1 hour at 0 to 2 °, and a solution prepared by dissolving 16.1 g (0.10 mol) of methyl bromo acetate in 20 ml of anhydrous dimethyl formamide is added dropwise at 0 to 5 °. The reaction solution is further stirred at room temperature for 3 hours, the reaction solution is concentrated by evaporation in vacuo and the residue is partitioned between methylene chloride and 2N hydrochloric acid. The organic phase is separated, washed with sodium bicarbonate solution and water, dried and concentrated by evaporation. The crystalline residue is taken up in a small amount of carbon tetrachloride. Methyl 5-bromo-3- (N-methoxycarbonylmethyl-N-methyl) sulfamoylthiophene-2-carboxylate having a melting point of 98 to 101 ° is obtained.

3.86 g (0.01 mole) of methyl 5-bromo-3- (N-methoxycarbonyl methyl-N-methyl) -sulfamoylthiophene-2-carboxylate is divided into several parts to give 0.01 mole of sodium methylate. It is added to 15 ml of methanol solution with stirring. The resulting solution is stirred at room temperature for 515 minutes and heated at reflux for 20 minutes. The solution is poured into ice and 2N hydrochloric acid and the product is extracted with methylene chloride. The organic phase is washed with 10% sodium acetate solution and extracted with 10% sodium carbonate solution. The sodium carbonate solution is acidified with hydrochloric acid and the precipitated product is extracted by shaking with methylene chloride. The dehydrated organic phase is concentrated by evaporation and the resulting crystalline product is taken up in a small amount of methanol. 6-Bromo-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno [2,3-e] -1,2-thiazine-1,1 with a melting point of 196 to 201 ° -Dioxide is obtained.

3.54 g (0.01 mol) of 6-bromo-4-hydroxy-2-methyl-3-methoxycarbonyl-2H-thieno- [2,3-e] -1,2-thiazine-1, Boil 1-dioxide with 1.42 g (0.015 mol) of 2-aminopyridine in 150 ml of anhydrous xylene under reflux for 6 hours. The reaction mixture is cooled at room temperature and the precipitated crude product is recrystallized from dioxane. 6-Bromo-4-hydroxy-2-methyl-3- (2-2pyridyl-carbamoyl) -2H-thieno [2,3-e] -1,2- with a melting point of 232 to 235 ° Thiazine-1,2-dioxide is obtained.

Example 6

Dissolve 40 g (0.2 mole) of methyl 4-acetylamino-3-thiophenecarboxylate in 1 L of anhydrous chloroform and dissolve 27 g (0.2 mole) of sulfuryl chloride in 100 mL of anhydrous chloroform in 20 minutes. Drop by. The reaction solution is boiled under reflux for 1 hour. Cool the resulting brown solution and add 1 liter of ice water when the solution temperature reaches 0 °. The organic solution is washed with 200 ml of 5% sodium bicarbonate solution, dried over sodium sulphate and evaporated to dryness in vacuo. The oily residue was ground with 100 ml of ether to form crystals. The product is suction filtered and recrystallized from ethyl acetate. Methyl 4acetylamino-5-chloro-3-thiophene carboxylate having a melting point of 119 to 121 ° is obtained. The ethereal filtrate and the mother liquor recrystallized from ethyl acetate are combined and evaporated to dryness and the remaining oil is chromatographed on 300 g silica gel with methylene chloride / ethyl acetate (4: 1) as the eluent. Further methyl 4-acetylamino-5-chloro-2-thiophene carboxylate having a melting point of 119 to 121 ° is obtained.

35 g of methyl 4-acetylamino-5chloro-3-thiophene-carboxylate are boiled for 30 minutes under reflux with 350 ml of 5N hydrochloric acid solution in anhydrous methanol. The dark solution is treated with activated carbon in a conventional manner, filtered and evaporated to dryness in vacuo. The crystalline residue is dissolved in 180 ml of anhydrous methanol at room temperature and 1400 ml of anhydrous ether is added while stirring the resulting solution. After cooling for 30 minutes in an ice bath, the almost colorless product which precipitates as crystals is suction filtered, washed with ether and dried in air for 1 hour. Methyl 4-amino-5-chloro-3-thiophene carboxylate hydrochloride is obtained that decomposes between 120 ° and 140 °. This hydrochloride can be used for the next step without further purification.

22.8 g (0.1 mole) of methyl 4-amino-5-chloro-3-thiophene-carboxylate hydrochloride are suspended in 100 ml of 36% hydrochloric acid. A solution prepared by dissolving 7.25 g (0.105 mole) of sodium nitrite in 20 ml of water is added dropwise at -10 ° below the surface of the reaction mixture for 10 minutes. The reaction mixture was further reacted at -10 ° for 30 minutes and a mixture just prepared from a solution made by dissolving 7.5 g of copper chloride in 150 ml of 30% sulfur dioxide solution in glacial acetic acid and 10 ml of water was added. The mixture is further stirred for 1 hour at 0-5 °, stirred for another 3 hours at room temperature and then poured into 2 l of ice water. The product precipitated as crystals was suction filtered and dissolved in 800 ml of toluene. The toluene solution is washed with water, then with sodium bicarbonate solution and finally with water again. Dry over sodium sulphate and evaporate under reduced pressure, then residual oil is triturated with a small amount of hexane and left overnight in an ice box. 3-Carbomethoxy-5-chlorothiophen-4-sulfochloride having a melting point of 65 to 67 ° is obtained in almost colorless crystal form. Recrystallization from hexane raises the melting point from 67 to 68 °.

7.5 g (0.06 mole) glycine methyl ester hydrochloride in a solution of 16.5 g (0.06 mole) 3-carbomethoxy-5-chlorothiophene-4-sulfochloride in 300 ml anhydrous pyridine Within 5 minutes. The reaction mixture is stirred for 4 h at 25 ° and evaporated to dryness in vacuo. The residue is dissolved in methylene chloride and the solution is extracted by shaking with ice cold 2N hydrochloric acid.

The organic phase is dried over sodium sulphate, evaporated in vacuo and the remaining oil is chromatographed on 350 g silica gel with methylene chloride / ethylacetate (4: 1) as eluent. The homogeneous fractions are combined, concentrated by evaporation and the residue is recrystallized from methylene chloride / hexane. N- (3-carbomethoxy-5-chlorothiophen-4-sulfonyl) -glycinemethyl ester having a melting point of 68 to 70 ° is obtained.

A solution made by dissolving 1.15 g (0.05 mol) of sodium in 24 ml of ethanol is evaporated to dryness in vacuo, then evaporated to dryness under high vacuum and 240 ml of anhydrous toluene is poured into the residue. 8.2 g (0.025 mol) of N- (3-carbomethoxy-5-chlorothiophen-4-sulfonyl) -glycine methylester are added and the reaction mixture is stirred at 60 ° for 4 hours.

The reaction mixture is cooled to 0 ° and poured into 240 ml of 2N hydrochloric acid cooled with ice while stirring. The precipitate formed is suction filtered, washed with water until neutral and dried under 60 ° and vacuum. The resulting product is taken up in 30 ml of methanol, suction filtered again and dried. 3-carbomethoxy-7-chloro-4-hydroxy-2H-thieno [3,4-e] -1,2-thiazine-1,1-dioxide is obtained that decomposes and melts around 230 °. .

75 ml of 2.93 g (0.01 mol) of 3-carbomethoxy-7-chloro-4-hydroxy-2H-thieno [3,4-e] -1,2-thiazine-1,1-dioxide The solution dissolved in dimethyl formamide is mixed with 0.022 molar sodium hydride (1.0 g of 55% mineral oil dispersion) under 10 ° and argon and the resulting solution is further stirred at 25 ° for 4 hours.

2.5 mL (0.04 mole) of methyl iodide is added dropwise at 10-15 °. The reaction mixture is stirred for 16 hours at room temperature and poured into 750 ml of ice water and the resulting mixture is acidified with concentrated hydrochloric acid. The precipitate that precipitates is suction filtered, dissolved in chloroform and dried over sodium sulfate.

The residue was concentrated by evaporation in vacuo and then chromatographed on 150 g silica gel with chloroform as eluent. 3-carbomethoxy-7-chloro-4-hydroxy-2-methyl-2H-thieno [3,4-e] -1,2-thiazine having a melting point of 188 to 191 ° after recrystallization from acetonitrile -1,1-dioxide is obtained.

2.2 g (0.07 mol) 3-carbomethoxy-7-chloro-4-hydroxy-2-methyl-2H-thieno- [3,4-e] -1,2-thiazine-1,1- A mixture of dioxide, 0.9 g (0.09 mol) of 2-aminopyridine and 240 ml of dry 0-xylene is boiled for 7 hours with stirring under reflux. About 80 mL of 0-xylene is slowly distilled during the first 2 hours. The reaction mixture is cooled to room temperature and then concentrated by evaporation in vacuo to about 60 mL and cooled in an ice bath. The product which precipitates out as crystals is suction filtered, washed with ether, dried and recrystallized from acetonitrile.

7-chloro-4-hydroxy-2-methyl-3- (2-pyridylcarbamoyl) -2H-thieno- [3,4-e] -1,2 with a melting point of 218 to 220 ° (decomposition) -Thiazine-1,1-dioxide is obtained.

Example A

Suppositories with the following composition are prepared by conventional methods:

6-chloro-4-hydroxy-2-methyl-3- (2-pyridyl-carbamoyl (-2H-thieno- [2,3-e] -1,2-thiazine-1,1-dioxide 0.005g

Hydrogenated Coconut Oil 1.250g

Carnauba Wax 0.045g

Example B

Tablets having the following composition are prepared by conventional methods:

Per tablet

6-chloro-4-hydroxy-2-methyl-3- (2-pyridyl-carbamoyl) -2H-thieno- [2,3-e] -1,2-thiazine-1,1-dioxide 5.00mg

Lactose 84.50mg

Corn Starch 10.00mg

Magnesium Stearate 0.50mg

EXAMPLE

A capsule having the following composition is prepared by a conventional method:

Per capsule

6-chloro-4-hydroxy-2-methyl-3- (2-pyridyl-carbamoyl-2H-thieno- [2,3-e] -1,2-thiazine 1,1-dioxide 10 mg

Lactose 165mg

Corn starch 30mg

Talc 5mg

Total weight 210mg

Claims (1)

Reacting a compound of formula (II) with an amine of formula (III), or closing a reactive functional derivative of an acid of formula (IV), or lower alkylating a compound of formula (V), or The thienothiazine derivatives of the following formula (I) and salts thereof are reacted with an isocyanate of the following formula (VII) in the presence of a strong base or by hydrolyzing the amine of the following formula (VIII) How to prepare.

In the above structural formula

R and R ¹ are lower alkyl, and R ² is heteroatoms 1 to 4 aromatic heterocyclic groups optionally substituted with one or two lower alkyl groups or with halogen, hydroxy, lower alkyl, trifluoro methyl or lower alkoxy Is an optionally substituted phenyl group, R ³ is halogen, R ⁵ and R ⁶ each represent a lower alkyl group or together with the nitrogen atom bonded to them pyrroline, pyrrolidine, pepperidine, morpholine or N- (lower) An alkyl) -piperazine group is formed.