KR870001044B1 - Process for preparing dihydro-1,4-oxathiins - Google Patents

Abstract

Dihydro-1,4-oxathiin derivs. (I; R1=H or Me; R2=amino gp. C-N(R3)(R4) or alkoxyl gp. (OR5) ; R3=H; R4=ph, chlorophenyl, bromophenyl, or methoxyphenyl; R5=H or C 6 alkyl are new. Thus, 16.5g 2-oxo-3- chlorobutyric acid ethylester is reacted with the mixture of 5.9g KOH and 7.0ml mercaptoethanol to give the neaction mixture, which is treated with 0.95g paratoluenesulfonic acid anhydride and saturated sodium bicarbonate to give 14.8g ethyl 5,6-dihydro-3-methyl-1,4-oxi thiin-2-carboxylate (I; R1=Me, R2= ethoxy) (yield 79%).

Description

Method for preparing a dihydro-1, 4-oxatiin derivative

The present invention relates to a method for producing a new compound 5, 6-dihydro-1, 4-oxathiine derivative represented by the following general formula (I).

로 표시되며 R₃와 R₄는 서로 같거나 다를 수 있는데 수소, 탄소수 6이하의 알킬기, 페닐, 클로로페닐, 브로모페닐 메틸페닐, 에틸페닐, 프로필페닐, 디메틸페닐, 디에틸페닐, 메톡시페닐, 디메톡시페닐, 에톡시페닐, 디에톡시페닐, 니트로페닐, 시아노페닐, 히드록시페닐, 페닐페닐, 아세틸페닐, 벤조일페닐 등으로 표시되는 방향족기 ,모르포린 등의 6각 고리화합물이며, 알콕시기는 -OR₅로 표시되는데 R₅는 수소, 메틸, 에틸, 프로필, 부틸, 펜틸 또는 헥실 등으로 표시되는 탄소수 6이하의 지방족 알킬기이다.Wherein R ₁ is hydrogen or methyl group, R ₂ is amino group or alkoxy group, amino group

R ₃ and R ₄ may be the same or different from each other, hydrogen, an alkyl group having 6 or less carbon atoms, phenyl, chlorophenyl, bromophenyl methylphenyl, ethylphenyl, propylphenyl, dimethylphenyl, diethylphenyl, methoxyphenyl, Hexacyclic cyclic compounds, such as aromatic groups represented by dimethoxyphenyl, ethoxyphenyl, diethoxyphenyl, nitrophenyl, cyanophenyl, hydroxyphenyl, phenylphenyl, acetylphenyl, benzoylphenyl, and morpholine, and an alkoxy group It is represented by -OR ₅ and R ₅ is an aliphatic alkyl group having 6 or less carbon atoms represented by hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl.

The new compounds (I) of the present invention can be useful intermediates for the synthesis of other compounds, as well as can be utilized for fungicides and other uses by themselves.

Oxatiin derivative, 5, 6-dihydro-2-methyl-1, 4-oxatiin having a structure similar to compound (I) (R ₁ = CH ₃ , R ₂ = NHC ₆ H ₅ ) of the present invention -3-Carbox anilide (II) is a known chemical and is a useful disinfectant for agricultural products. U.S. Patent Nos. 3,249,499 (May 3, 1966), 3,393,202 (July 16, 1968), and Canada Patent 787,893 (June 18). , 196 8), 791, 151 (July 30, 1968), Korean Patent Publication Nos. 78-235 (1978.6.1), 75-609 (Nov. 28, 1978), and are currently used as seed treatment fungicides. have.

But over time, as with all biologically active compounds, the fungicides mentioned above have created new strains of resistance to them. In preparation for this problem, it is desirable to develop a new fungicide that can overcome resistance strains.

It is an object of the present invention to prepare derivatives of 5, 6-dihydro-1, 4-oxatiin represented by formula (I) in order to develop new systemic fungicides. This compound is a novel substance whose sulfur and oxygen positions are changed in the general formula (II), a known fungicide, and because of the structure-activity relationship, the lone electron pairs of sulfur atoms in the β-position of α, β-ballonated carbonyl ( The lone pair electrons are expected to play a greater role in improving bioactivity than the original oxygen.

The synthetic process of the present invention is represented by the following formula.

로 표시되며 R₃와 R₄는 서로 같거나 다를 수 있는데, 수소, 메틸, 에틸, 프로필, 부틸, 펜틸 또는 헥실등으로 표시되는 탄소수 6이하의 알킬기, 페닐, 클로로페닐, 브로모페닐, 메틸페닐, 에틸페닐, 프로필페닐, 디메틸페닐, 디에틸페닐, 메톡시페닐, 디메톡시페닐, 에톡시페닐, 디에톡시페닐, 니트로페닐, 시아노페닐, 히드록시페닐, 페닐페닐, 아세틸페닐, 벤조일페닐 등으로 표시되는 방향족기, 모르포린 등의 6각 고리화합물이며, 알콕시기는 -OR₅로 표시되는데, R₅는 수소, 메틸, 에틸, 프로필, 부틸, 펜틸 또는 헥실 등으로 표시되는 탄소수 6이하의 지방족 알킬기이다.In the above formulas, R ₁ is hydrogen or methyl group and R ₂ is amino group or alkoxy group and amino group

R ₃ and R ₄ may be the same as or different from each other, hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl alkyl group having 6 or less carbon atoms, phenyl, chlorophenyl, bromophenyl, methylphenyl, With ethylphenyl, propylphenyl, dimethylphenyl, diethylphenyl, methoxyphenyl, dimethoxyphenyl, ethoxyphenyl, diethoxyphenyl, nitrophenyl, cyanophenyl, hydroxyphenyl, phenylphenyl, acetylphenyl, benzoylphenyl, etc. Heterocyclic compounds such as aromatic groups, morpholines, and the like, and alkoxy groups are represented by -OR ₅ , wherein R ₅ is an aliphatic alkyl group having 6 or less carbon atoms represented by hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl, etc. to be.

The compound of formula (IV) is prepared by known methods (Org, Syn. Coll. Vol. V, 255, 635. Org. Syn. Coll. Vol. 1, 115) and the α-keto acid derivative of formula (III). Prepared by reacting with SO ₂ Cl ₂ , Br ₂ , PCl ₃ , and the like, and β-hydroxysulfide of formula (V) is prepared by reacting a compound of formula (IV) with mercaptoethanol in the presence of a base. do. In this case, inorganic bases such as potassium hydroxide, sodium hydroxide, sodium carbonate, and sodium bicarbonate, and organic bases such as triethylamine and pyridine can be used, and as a solvent, methylene chloride, chloroform, ethyl acetate, benzene, toluene And inert organic solvents such as xylenes. On the other hand, when R ₂ is a hydroxy group, 2 equivalents of base should be used, since the extra 1 equivalent reacts with the carboxylic acid of α-keto acid to form a salt. The possible reaction temperature is 0-80 ° C, but the preferred temperature is l5-30 ° C.

As described above, β-hydroxysulfide of general formula (V) exists in equilibrium with cyclic 1,4-oxatian of general formula (VI). According to the hydrogen nuclear magnetic resonance spectrum, general formula (VI) Of 1,4-oxatiane are present more. The pulmonary ring of formula (VI) is easily dehydrated under extremely mild acidic conditions to form the final material of formula (I). The acid used at this time is inorganic acids, such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, and organic acids, such as paratoluenesulfonic acid and methanesulfonic acid. Inert organic solvents such as tilmerene, chloroform, ethyl acetate, benzene, toluene and xylene are used as a solvent for this reaction. This dehydration reaction is promoted by heating reflux using the azeotropy of the solvent and the resulting water and the resulting water is removed using a Dean-Stark water separator.

Formula (I) compound R ₂ is hydroxy in the invention of the general formula such as formula (Ⅲ) R ₂ is hydroxy may be prepared from the α- cache acid and R ₂ is methoxy or ethoxy in the ( I) It can also be manufactured by hydrolyzing a compound. In addition, R ₂ is an amino group (-NR ₃ R ₄₎ in formula (I) compounds of the general formula R ₂ is an amino group which may be prepared from α- cache acid derivative represented by the general formula (Ⅲ), R ₂ is hydroxy The compound (I) may be prepared by converting the compound into an acyl halide of the general formula ( _IV ) and then reacting with an amine derivative (HNR ₃ R ₄ ). This is represented by the formula:

Here, R ₁ is hydrogen or a methyl group, R ₅ is an aliphatic alkyl group having 6 or less carbon atoms represented by methyl, ethyl, propyl, butyl, pentyl or hexyl, and the like, and R ₃ and R ₄ may be the same or different from each other. Alkyl groups having 6 or less carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl or hexyl, phenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, propylphenyl, dimethylphenyl, diethylphenyl, methoxyphenyl, Heterocyclic compounds, such as aromatic groups represented by dimethoxyphenyl, ethoxyphenyl, diethoxyphenyl, nitrophenyl, cyanophenyl, hydroxyphenyl, phenylphenyl, acetylphenyl, benzoylphenyl, and the like, and morpholine.

The hydrolysis is carried out in an alkaline aqueous solution such as potassium hydroxide, sodium hydroxide and the reaction temperature is 0-100 ℃, preferably 25-100 ℃. Acyl chloride of the general formula (VII) is prepared by reacting 5, 6-dihydro-1, 4-oxaphosphoric acid (I, R ₂ = hydroxy) with SOCl ₂ , PCl ₃ or P Cl _5, etc. The solvent to be mentioned is methylene chloride, chloroform, ethyl acetate, benzene, toluene, xylene and the like, and the reaction temperature is 30-130 ° C, but preferably 50-80 ° C. The oxatiin amine derivative (I, R ₂ = NR ₃ R ₄ ) may be prepared by reacting acyl chloride of the general formula with two equivalents of amine (HNR ₃ R ₄ ), or one equivalent of tertiary amine. It may also be prepared by reacting with 1 equivalent of an amine (HNR ₃ R ₄ ) in the presence of (triethylamine, pyridine or the like). The solvent used at this time is methylene chloride, chloroform, ethyl acetate, benzene, toluene, xylene and the like, and the reaction temperature is -10 to 100 ° C, preferably 0 to 50 ° C.

5, 6-dihydro-3-methyl-N-phenyl-1, 4-oxathiin-2-carboxamide prepared according to the present invention (I, R ₁ = CH ₃ , R ₂ = HNC ₆ H ₅ The results of the biological activity test for phytopathogens of) are as follows.

Test strain minimum growth concentration

(MIC) μg / ml

Rhizoctonia solani 200

Pyricularia oryzae 200

Pellicularia sasakii 200

Fusarium roseum 200

Cocoliobolus miyabeanus 200

The following examples illustrate the invention in more detail, but the invention is not limited to the following examples unless departing from the scope of the claims.

Example 1

Preparation of ethyl 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxylate (I, R ₁ = methyl, R ₂ = ethoxy) 2-oxo-3-chlorobutyric acid 16.5 g (0.1 mol) of ethyl ester (IV, R1 = methyl, R ₂ = ethoxy, X = chlorine) was dissolved in 100 ml of benzene and 5.9 g of potassium hydroxide dissolved in 8.8 ml of methanol and 7.0 ml of mercaptoethane. 0.1 mole) of the mixed solution was added dropwise over 15 minutes while maintaining the temperature of the reactant at 15-20 ° C. After further stirring for 2 hours at room temperature (25 ℃), the resulting potassium chloride was filtered off and the solvent was removed by evaporation under reduced pressure. The reaction mixture was dissolved in benzene (100 mL), washed with cold water (20 mL x 2), dried over sodium sulfate (Na ₂ SO ₄ ), and added 0.95 g of paratoluenesulfonic acid monohydrate to reflux for 18 hours. Removal was carried out using a Stark water separator. The reaction mixture was cooled to room temperature, washed once with saturated sodium bicarbonate water and cold water, and then dried. The solvent was evaporated under reduced pressure to remove the colorless liquid ethyl 5, 6-dihydro-3-methyl-1, 4-oxatiin-2. -14.8 g (yield 79%) of carboxylate (I, R ₁ = methyl, R ₂ = ethoxy) were obtained.

Hydrogen Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ1.33 (t, 3H), 2.27 (s, 3H), (t, 2H), 4.33 (t, 2H), 4.34 (q, 2H)

Example 2

Preparation of Methyl 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxylate (I, R ₁ = methyl, R ₂ = methoxy) 2-oxo-3-chlorobutyric acid 3.0 g (20 mmol) of methyl ester (IV, R ₁ = methyl, R ₂ = methoxy, X = chlorine) were dissolved in 20 ml of chloroform, 1.4 ml (20 mmol) of mercaptoethanol was added, and then at room temperature (25 ° C). A solution of sodium bicarbonate (2.2 g) dissolved in water (15 mL) was added dropwise over 10 minutes. The reaction mixture was further stirred for 5 hours, and then the organic layer was separated, washed once with cold water, dried over sodium sulfate (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure.

Toluene (50 mL) was added to the resulting colorless liquid, 0.06 mL of methanesulfonic acid was added, and the resulting water was removed using a Dean-Stark water separator while refluxing for 5 hours.

The reaction mixture was cooled to room temperature, washed once with saturated sodium bicarbonate water and cold water, and dried, and then the solvent was evaporated under reduced pressure to obtain 2.89 g (yield 83%) of a pale yellow solid.

It was crystallized in methylene chloride and petroleum ether to give the white crystals of methyl 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxylate (I, R ₁ = methyl, R ₂ = meth). Methoxy) was obtained.

Melting Point 46-48 ℃, Hydrogen Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ2.28 (s, 3H), 3.08 (t, 2H), 3.85 (s, 3H), 4.33 (t, 2H), Infrared Absorption Spectrum ( KBr) 1695, 1600, 1420, 1300, 1280, 1230 cm ^-1

Example 3

Preparation of 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxylic acid (I, R ₁ = methyl, R ₂ = hydroxy)

0.273 g (2 mmol) of 2-oxo-3-chlorobutyric acid (IV, R 1 = methyl, R ₂ = hydroxy, X = chlorine) was dissolved in 2 ml of ethyl acetate, 0.1 g of sodium hydroxide, 0.5 ml of water, and mercapto. A mixed solution of 0.15 ml (2 mmol) of ethanol was added and then stirred at room temperature for 30 minutes. 0.1 g of sodium hydroxide was further added, followed by stirring at the same temperature for 30 minutes, followed by addition of concentrated hydrochloric acid to pH 2-3, and then 1 g of salt was added and stirred for 30 minutes.

The reaction mixture was extracted with methylene chloride (20 mL × 3), dried over sodium sulfate (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure to give a colorless liquid (396 mg). It was dissolved in benzene (20 mL), 1 drop of sulfuric acid was added, and the resulting water was removed using a Dean-Stark water separator while refluxing for 1 and a half hours.

The reaction mixture was cooled to room temperature, washed with cold water, dried, and the solvent was removed by evaporation under reduced pressure to obtain 247 mg (yield 70%) of a white solid. This was recrystallized in chloroform and petroleum ether to give 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxylic acid (I, R ₁ = methyl, R ₂ = hydroxy).

Melting Point 170-172 ℃, Hydrogen Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ2.33 (s, 3H), 3.13 (t, 2H), 4.33 (t, 2H), 10.17 (s, 1H), Infrared Absorption Spectrum ( KBr) 2950, 1660, 1560, 12 70cm ^-1

Example 4

Preparation of ethyl 5, 6-dihydro-1, 4-oxathiin-2-carboxylate (I, R ₁ = hydrogen, R ₂ = ethoxy)

22.32 g (0.115 mole) of 3-bromo-2-oxo-propanoic acid ethyl ester (IV, R ₁ = hydrogen, R ₂ = ethoxy, X = bromine) was dissolved in 100 ml of toluene and dissolved in 9 ml of methanol. A solution of 6.5 g of potassium and 8.03 ml of mercaptoethanol was added dropwise for 30 minutes while maintaining the temperature of the reaction to 15-20 ° C. After further stirring at room temperature (25 ° C.) for 30 minutes, the resulting solid was filtered off and the filtrate was evaporated under reduced pressure to remove the solvent.

The resulting oily liquid was dissolved in 100 ml of toluene, washed with cold water (20 ml × 2), dried over sodium sulfate (Na ₂ SO ₄ ), and added 1.09 g of paratoluenesulfonic acid monohydrate to reflux for 2 hours. Removed using a Stroke water separator. The reaction mixture was cooled to room temperature, washed with saturated sodium bicarbonate water and cold water, and dried, and then the solvent was removed by evaporation under reduced pressure to obtain a colorless liquid (16.5 g, yield 80%). Hydrogen Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ1.33 (t, J = 6.5Hz, 3H), 3.03 (t, J = 4Hz, 2H), 4.25 (q, J = 6.5Hz, 2H), 4.40 (t, J = 4 Hz, 2H), 6.77 (s, 1H), 7.43 (s, 1H).

Example 5

Preparation method of 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxanilide (I, R ₁ = methyl, R ₂ = phenylamino) 1: 2-oxo-3-bro A solution of 67 mg of potassium hydroxide dissolved in 1 ml of benzene and dissolved in 0.1 ml of methanol and 80 mg (1 mmol) of mocaptananilide (IV, R ₁ = methyl, R ₂ = phenylamino, X = bromine) ) Was added and stirred at room temperature for 30 minutes. 20 ml of benzene was further added, washed once with cold water, and 9 mg of paratoluene sulfonic acid monohydrate was added to reflux for 21 hours to remove the produced water using a Dean-Stark water separator. The reaction mixture was cooled to room temperature, washed with saturated sodium bicarbonate water and cold water, dried over sodium sulfate (Na ₂ SO ₄ ), and the solvent was evaporated under reduced pressure to obtain a pale yellow solid 235 mg (yield 99%). This was recrystallized from ethyl acetate and petroleum ether to give white crystals 5, 6-dihydro-3-methyl-1, 4-oxatiin-2-carboxanilide (I, R ₁ = methyl, R ₂ = phenylamino). Got.

Melting Point 82.5-84 ° C, Hydrogen Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ2.42 (s, 3H), 3.08 (t, 2H), 4.32 (t, 2H), 7.00-7.70 (m, 5H), 8.40 ( s, 1H), Infrared Absorption Spectrum (KBr) 3300, 1650, 1605, 1595, 1435 cm-1, Elemental Analysis C ₁₂ H ₁₃ O ₂ SN Theoretical (experimental) C, 61.25 (61.15), H, 5.57 (5.45 ), N, 5.05 (6.07), S, 13.63 (13.39).

Method 2:

Step 1: Preparation of 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxylic acid (I, R ₁ = methyl, R ₂ = hydroxy)

Ethyl 5, 6-dihydro-3-methyl prepared in the same manner as in Example 1 from 2-oxo-3-chlorobutymic acid ethyl ester (IV, R ₁ = methyl, R ₂ = ethoxy, X = chlorine) 18.8 g (0.1 mol) of -1,4-oxathiin-2-carboxylate was added to a mixed solution of 50 ml of water and 6 g of caustic soda and refluxed for 1 hour and a half. The reaction mixture was cooled in an ice bath and 3N hydrochloric acid was added until the pH was 2-3. The pale yellow solid was filtered and dried in air. The filtrate was extracted with chloroform (50 mL × 3) and dried, and the solvent was evaporated under reduced pressure. Removed by evaporation and combined with air dried solid (12.8 g, 80% yield). This was recrystallized from chloroform and petroleum ether and the same 5, 6-dihydro-3-methyl-1, 4-oxathi-2-carboxylic acid (I, R ₁ = methyl, R ₂ as prepared in Example 3). = Hydroxy).

Step 2: Preparation of 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxanilide (I, R ₁ = methyl, R ₂ = phenylamino)

1.6 g (10 mmol) of 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxylic acid (I, R ₁ = methyl, R ₂ = hydroxy) prepared in step 1 It was suspended in 15 ml of dry chloroform and 0.8 ml (11 mmol) of thionyl chloride was added to reflux for 2 hours. The reaction mixture was evaporated under reduced pressure to remove the solvent and remaining thionyl chloride, and 20 ml of dry benzene was added and cooled in an ice bath.

1.82 mL of aniline diluted in 10 mL of benzene was added dropwise to the reaction mixture over 15 minutes, and then the ice bath was removed and stirred at room temperature for 1 hour. The resulting solid was removed by filtration, washed once with filtrate diluted hydrochloric acid and cold water each time, dried and the solvent was removed by evaporation under reduced pressure to give 1.88 g (80% yield) of a yellow solid.

This was recrystallized from ethyl acetate and petroleum ether to give the same 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxanilide (I, R ₁ = methyl, R ₂ as prepared in Method 1). = Phenylamino) was obtained.

Example 6

Preparation of 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxamide (I, R ₁ = methyl, R ₂ = NH ₂ )

5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxylic acid (I, R 1 = methyl, R 2 = Hydroxy) 1.0 g (6.2 mmol) was suspended in 15 ml of dry benzene and 0.5 ml (6.8 mmol) of thionyl chloride was added to reflux for 2 hours. The solvent and the remaining thionyl chloride were removed by evaporation under reduced pressure, and 20 ml of dry benzene was added and cooled in an ice bath. The reaction mixture was stirred while passing ammonia gas for 10 minutes, washed once with dilute hydrochloric acid and cold water, and then dried, and the solvent was evaporated under reduced pressure to obtain a light brown solid 676 mg (yield 68%). This was recrystallized from benzene and petroleum ether to give the off-brown crystals 5, 6-dihydro-3-methyl-1, 4-oxatiin-2-carboxamide (I, R ₁ = methyl, R ₂ = NH ₂ )

Melting point 148-149 ° C. Hydrogen nuclear magnetic resonance spectrum (CDCl ₃ ) δ 2.37 (s, 3H), 3.08 (t, 2H), 4.28 (t, 2H), 5.83 (s, 2H).

Example 7

Preparation of 5, 6-dihydro-1, 4-oxathiin-2-carboxanilide (I, R ₁ = hydrogen, R ₂ = phenylamino)

Step 1: Preparation of 5, 6-dihydro-1, 4-oxathiin-2-carboxylic acid (I, R ₁ = hydrogen, R ₂ = hydroxy)

16.05 g (92 mmol) of ethyl 5, 6-dihydro-1, 4-oxathiin-2-carboxylate (I, R ₁ = hydrogen, R ₂ = ethoxy) prepared in Example 4 It was added to a solution of ml and 5.53 g of sodium hydroxide and refluxed for 2 hours. The reaction mixture was cooled in an ice bath, 3N hydrochloric acid was added until pH was 2-3, the resulting solid was dried in air, the filtrate was saturated with salt, extracted with chloroform (50 mL × 3), dried and solvent Was evaporated under reduced pressure and combined with a solid dried in air (10.3 g, yield 76%). This was recrystallized from methylene chloride and petroleum ether to give white crystals 5, 6-dihydro-1, 4-oxathiin-2-carboxylic acid (I, R ₁ = hydrogen, R ₂ = hydroxy).

Melting Point 144-145 ° C, Hydrogen Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ3.22 (t, 2H), 4.40 (t, 2H), 6.97 (s, 1H), 11.93 (s, 1H), Infrared Spectrum (KBr) ) 3200-2800, 1670, 1440, 1250cm ^-1

Step 2: Preparation of 5, 6-dihydro-1, 4-oxathiin-2-carboxanilide (I, R ₁ = hydrogen, R ₂ = phenylamino)

414 mg (2.8 mmol) of 5, 6-dihydro-1, 4-oxathiin-2-carboxylic acid (I, R ₁ = hydrogen, R ₂ = hydroxy) were suspended in 5 ml of dry chloroform and thionyl 0.2 ml (2.8 mmol) of chloride was added and refluxed for 2 hours. The reaction mixture was evaporated under reduced pressure to remove the solvent and the remaining thionyl chloride, and the resulting pale yellow liquid was dissolved in 20 ml of dry chloroform. 0.4 ml of triethylamine was added to the reaction mixture, which was then cooled in an ice bath. Then, 0.25 ml of aniline was added and stirred. The ice bath was removed, stirred at room temperature for 1 hour, washed once with cold water, washed again with dilute hydrochloric acid and cold water, dried and the solvent was removed by evaporation under reduced pressure to obtain a white solid 489 mg (yield 78%).

This was recrystallized in benzene to obtain 5, 6-dihydro-1, 4-oxatiin-2-carboxanilide (I, R ₁ = hydrogen, R ₂ = phenylamino) as white needle-like crystals.

Melting Point 125-127 ° C, Hydrogen Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) δ3.10 (t, 2H), 4.65 (t, 2H), 6.88 (s, 1H), 7.10-7.90 (m, 5H), 8.28 ( s, 1H), infrared absorption spectrum (KBr) 32 70, 1650, 1580, 1520, 1440, 1220 cm-1.

Tables 1, 2, and 3 below briefly illustrate several examples. The appearance or melting point shows the physical properties of the 5, 6-dihydro-1, 4-oxatiin derivatives prepared in the present invention, and the yield is not the highest, and higher yields are expected.

TABLE 1

TABLE 2

TABLE 3

A) Method of Example 1

b: Step 1 of Method 2 of Example 5

c: step 1 of Example 7

d: method 1 of Example 5

e: step 2 of method 2 of Example 5

f: step 2 of Example 7

g: 2 equivalents of amine derivative

PTSA: Paratoluenesulfonic Acid Monohydrate

MSA: methanesulfonic acid

Claims (3)

Dihydro- of Formula (I) wherein the compound of Formula (IV) is reacted with mercapto ethanol in the presence of a base to produce an intermediate of Formula (V), and then dehydrate the intermediate of Formula (V) in the presence of an acid catalyst. 1, 4-oxathiine derivative manufacturing method.

In general formula (I), (V) and (IV), R <_1> is hydrogen or a methyl group, R <_1> is an amino group or an alkoxy group, and an amino group is

R ₃ is hydrogen, R ₄ is an aromatic group of phenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenyl, alkoxy is represented by -OR _5, and R ₅ is hydrogen or an alkyl group having 6 or less carbon atoms. . In general formula (IV), X is halogen, such as bromine and chlorine. The compound of formula (IV) and mercaptoethanol according to claim 1, in which an inorganic base such as potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, or an organic base such as triethylamine or pyridine is present in an inert solvent. Reaction at 80 ° C. 30 ° to 130 to 5, 6-dihydro-1, 4-oxathiin-2-carboxylic acid or 5, 6-dihydro-3-methyl-1, 4-oxathiin-2-carboxylic acid The reaction is carried out in thionyl chloride, PCl ₃ or PCl ₅ and the like in an inert solvent to prepare a corresponding acyl chloride of general formula ( _III) , followed by reaction with a compound of formula (VII) and an amine derivative of formula (VII). Process for the preparation of dihydro-1,4-oxathiine derivatives of formula (I ').

In general formula (I °) (i), R ₁ is the same as in claim 1, R ₃ is hydrogen or methyl, R ₄ is hydrogen, methyl, phenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, propyl Phenyl, dimethylphenyl, diethylphenyl, methoxyphenyl, dimethoxyphenyl, ethoxyphenyl, nitrophenyl, cyanophenyl, hydroxyphenyl, phenylphenyl, acetylphenyl, benzoylphenyl.