KR900004908B1 - Alpha-(hydroxy) -1,3-oxathiolune derivatives and their preparation - Google Patents

Abstract

A method for preparing alpha-(hydroxy)-1,3-oxathiolane derivs. of formual (I) comprises, (a) reacting alphahaloacetic acid with metal salts of acetic acid or tetraalkylammonium acetate in organic solvent to form alpha-acetoxyacetoacetic acid derivs. (III); (b) reacting (III) with 2-mercaptoethanol in the presence of acid catalyst to form a cpd. of formula (II); (c) hydrolyzing the cpd. of formula (II). In the formulas, R= methoxy or phenylamino gp.. (I) are useful as intermediates in the prodn. of agricultural chemicals and medicines.

Description

Alpha- (hydroxy) -1,3-oxathiolane derivatives and preparation method thereof

The present invention relates to novel compounds alpha- (hydroxy) -1, 3-oxathiolane derivatives represented by general formula (I) and to their preparation.

In general formula (I), R represents a methoxy or phenylamino group.

Alpha- (hydroxy) -1 and 3-oxathiolane derivatives of general formula (I) are useful intermediates that can be used in the manufacture of pesticides or pharmaceuticals. -The alpha-acetoxyacetoacetic acid derivative of the general formula (III) is prepared by reacting a haloacetoacetic acid derivative with a metal acetate or a tetraalkylammonium acetate in an organic solution, and then a compound of the general formula (III) and 2-mercaptoethanol Dehydration in an organic solution in the presence of an acid catalyst to prepare alpha- (acetoxy) -1,3-oxathiolane of formula (IV), followed by hydrolysis of the compound of formula (IV) in the presence of a catalyst Alpha- (acetoxy) -1,3-oxathiolane was prepared, followed by hydrolysis of the compound of formula (IV) in the presence of a catalyst to produce alpha- (hydroxy) -1, 3-oxa of formula (I). It is to prepare a thiolane derivative. The manufacturing process thereof is expressed as follows.

In General Formulas (II), (III) and (IV), R represents a methoxy or phenylamino group.

Alpha-acetoxyacetoacetic acid derivatives of general formula (III) and alpha- (acetoxy) -1, 3-oxa of general formula (IV) excluding alpha-haloacetoacetic acid derivatives of general formula (II) in the present invention Thiolanes and alpha- (hydroxy) -1, 3-oxathiolane derivatives of general formula (I) are novel compounds. However, alpha-acetoxyacetoacetic acid ethyl ester, a known compound similar to the alpha-acetoxyacetoacetic acid derivative of general formula (III), may be used as in the magazine (J. Am. Chem. Soc., 70 2812 (1948)). Ethyl acetoacetate and lead acetate was reacted to produce a low yield (34%).

The present inventors have come to produce a simple and high yield of the desired compound beyond the expected expectations, which has been studied to prepare new and useful compounds based on the production principle of alpha-acetoxyacetoacetic acid ethyl ester which is a known compound.

In more detail, the alpha-acetoxyacetoacetic acid derivative of the general formula (III) is an alpha-haloacetoacetic acid derivative such as alpha-chloroacetoacetic acid and alpha-bromoacetoacetic acid of the general formula (II) It is prepared in a simple, economical and high yield by reacting with a metal acetate salt (CH ₃ COOM) such as salt, sodium acetate salt or tetraalkylammonium acetate (R ₁ ) ₄ NOAc such as tetramethylammonium acetate, tetraethylammonium acetate. In this case, an inert organic solvent such as methylene chloride, acetone, chloroform, ethyl acetate, benzene, acetonitrile, toluene, and xylene may be used, and a possible reaction temperature is 20-150 ° C., but a preferable temperature is 50-100 ° C.

The alpha- (acetoxy) -1 and 3-oxathiolane derivatives of general formula (IV) dehydrate the alpha-acetoxyacetoacetic acid derivatives of general formula (III) and 2-mercaptoethanol in an inert organic solution in the presence of an acid catalyst. Can be prepared. At this time, examples of the acid catalyst include inorganic acids such as sulfuric acid, hydrochloric acid and nitric acid, organic acids such as benzene sulfonic acid, paratoluene sulfonic acid and methanesulfonic acid, or aluminum chloride, boron trifluoride, tin tetrachloride, boron trifluoride diethyl ether and titanium tetrachloride. Lewis acids are possible, but benzenesulfonic acid, paratoluenesulfonic acid, tin tetrachloride, boron trifluoride, diethyl ether, and titanium tetrachloride are preferred to minimize the formation of by-products. As a solvent, an inert organic solvent such as ethyl ether, methylene chloride, chloroform, ethyl acetate, benzene, toluene, xylene and the like can be used. Possible reaction temperatures are 0-150 ° C. but preferably 25-130 ° C.

Finally, the alpha- (hydroxy) -1,3-oxathiolane derivatives of general formula (I) can be used to convert the alpha- (acetoxy) -1,3-oxathiolan derivatives of general formula (IV) in the presence of an acid or base catalyst. It can be prepared by hydrolysis. The acid catalyst may be inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, organic acids such as benzenesulfonic acid, paratoluenesulfonic acid, and metalsulfonic acid. The base catalyst may be a weak base such as sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, or a strong base such as potassium hydroxide, sodium hydroxide, barium hydroxide or calcium hydroxide. However, using a base catalyst rather than an acid catalyst is economical because there are few by-products, it is simple and the yield is high. As the solvent, a single solvent of an inert organic solvent such as water, methanol, ethanol, propanol, acetone, dioxane, acetonitrile, ethyl acetate, methylene chloride, chloroform, benzene, toluene, or a mixed solvent thereof may be used. The reaction temperature may be 0-100 ° C, but preferably 0-50 ° C.

The oxathiolane derivatives of general formula (I) and general formula (IV) of the present invention each have two asymmetric carbons, and thus may be composed of four stereoisomers and two diastereomers, respectively. Isomers are separable. The oxathiolane derivatives of formula IV prepared in the present invention are produced as a mixture of diastereomers and are separable by thin layer chromatography, tube chromatography or fractional crystallization. Asymmetric centers in the hydrolysis of alpha- (acetoxy) -1, 3-oxathiolane derivatives of general formula (IV) to alpha- (hydroxy) -1, 3-oxathiolan derivatives of general formula (I) The stereochemistry of the asymmetric centre remains unchanged. Therefore, alpha- of general formula (I) generated by hydrolyzing stereoisomers having a specific stereochemistry to two absent carbon atoms of alpha- (acetoxy) -1 and 3-oxathiolane derivatives of general formula (IV) The stereochemistry of the two absent carbon atoms of the (hydroxy) -1,3-oxathiolane derivatives is the same as the stereochemistry of the alpha- (acetoxy) -1,3-oxathiolane derivatives of the general formula (IV) as starting materials.

If necessary, diastereomers of the 1,3-oxathiolane derivatives of the general formulas I and IV may be separated.

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

Example 1

[Production of alpha-acetoxyacetoacetanilide (III, R = phenylamino)]

Suspend potassium acetate (59 g, 0.6 mol) in acetone (500 ml) and add alpha-chloroacetoacetanilide (II, X = Cl, R = phenylamino) (64 g, 0.3 mol) little by little over 30 minutes while heating under reflux. It was. After further heating at reflux for 1 hour, the reaction mixture was cooled to room temperature, the resulting white solid was filtered off, and the solvent was removed by evaporation under reduced pressure. The resulting pale yellow oily liquid was dissolved in methylene chloride, washed with cold water, dried (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure to obtain a pale yellow oily liquid (68 g). This was crystallized in benzene and petroleum ether to obtain alpha-acetoxyacetoacetanilide (III, R = phenylamino) (65 g, 91% yield) as white crystals.

Melting Point: 78-80 ℃

Elemental Analysis: for C ₁₂ H ₁₃ O ₄ N

Theoretical value (experimental value): C; 61.3 (61.3), H; 5.57 (5.54), N; 5.95 (6.01)

Example 2

Alpha-chloroacetoacetanilide (II, X = Cl, R = phenylamino) (21.2 g, 0.1 mol) and tetraethylammonium acetate and tetrahydrate (31.4 g, 0.12 mol) were added to chloroform (200 ml) for 1 hour and a half. The reaction mixture was cooled to room temperature, cooled to room temperature, washed with cold water, dried (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure.

The resulting pale yellow oily liquid (22 g) was crystallized in benzene and petroleum ether to obtain alpha-acetoxyacetoacetanilide (III, R = phenylamino) as a white crystal (17.9 g, yield 76%). This was the same in melting point, hydrogen nuclear magnetic resonance spectrum, infrared absorption spectrum as prepared in Example 1.

Example 3

Alpha-bromoacetoacetanilide (II, X = Br, R = phenylamino) (2.56 g, 10 mmol) and sodium acetate (1.23 g, 15 mmol) were added to ethyl acetate (30 ml) and heated to reflux for 5 hours. . The reaction mixture was cooled to room temperature, the resulting pale yellow solid was filtered off, washed with cold water, dried (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure to obtain a pale yellow oily liquid (2.23 g). This was crystallized in benzene and petroleum ether to obtain alpha-acetoxyacetoacetanilide (III, R = phenylamino) (2.04 g, 87% yield) as white crystals. This was the same in melting point, hydrogen nuclear magnetic resonance spectrum, infrared absorption spectrum as prepared in Example 1.

Example 4

[Production of alpha-acetoxyacetoacetic acid methyl ester (III, R = methoxy)]

To a solution of ethyl acetate (200 ml) of alpha-chloroacetoacetic acid methyl ester (II, X = Cl, R = methoxy) (45.2 g, 0.03 mol) was added sodium acetate (3.7 g, 0.045 mol) and heated for 3 and a half hours. After refluxing, the reaction mixture was cooled to room temperature and the resulting white solid was removed by filtration. The reaction mixture was washed twice with cold water and dried (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure. Alpha-acetoxyacetoacetic acid methyl ester (III, R = methoxy) (5.01 g, Yield 96%).

Example 5

[Production of alpha-acetoxyacetoacetic acid methyl ester (III, R = methoxy)]

Tetramethyl ammonium acetate (1.33 g, 10 mmol) and water (10 ml) in an acetone (50 m) solution of alpha-bromoacetoacetic acid methyl ester (II, X = Br, R = methoxy) (1.95 g, 10 mmol) Was added and heated to reflux for 5 and a half hours. The reaction mixture was evaporated under reduced pressure to remove the solvent, which was dissolved in benzene, washed with cold water and dried (Na ₂ SO ₄ ). The solvent was removed by evaporation under reduced pressure to obtain alpha-acetoxyacetoacetic acid methyl ester (III, R-methoxy) (132 g, yield 76%) as a pale yellow oily liquid. This was the same in melting point and hydrogen nuclear magnetic resonance spectrum as prepared in Example 4.

Example 6

[Production of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R = phenylamino)]

Alpha-acetoxyacetoacetanilide (III, R = phenylamino) (30 g, 0.13 mol), 2-mercaptoethanol (9.8 ml, 0.14 mol), benzene (150 ml) of paratoluenesulfonic acid monohydrate (0.25 g) The resulting water was removed using a Dean-Stark water separator while the solution was heated to reflux for 19 hours.

The reaction mixture was cooled to room temperature, washed with 0.5 N caustic soda water and cold water, dried (Na ₂ SO ₄ ), and the solvent was removed by evaporation under reduced pressure to give a pale yellow oily liquid, alpha- (acetoxy) -2-methyl-1, 3 -Oxathiolane-2-acetanilide (IV, R = phenylamino) (23.4 g, yield 62%) was obtained. According to thin layer chromatography and hydrogen nuclear magnetic resonance spectra, this was a mixture of diastereomers. The two diastereomers were separated by column chromatography using silica gel (Kiesel gel 60, 70-230mesh) and benzene-ethyl acetate as eluent.

First band, R _f = 0.8 (eluent; benzene: ethyl acetate = 7: 3)

Melting Point: 107-108 ℃

Elemental Analysis: for C ₁₄ H ₁₇ O ₄ NS

Theoretical (experimental): C; 56.9 (57.0), H; 5.80 (5.81), N; 4.74 (4.73).

Second band, R _f = 0.7 (eluent; benzene: ethyl acetate = 7: 3)

Melting Point: 108-109 ℃

Elemental Analysis: for C ₁₄ H ₁₇ O ₄ NS

Theoretical (experimental): C; 56.9 (56.8), H; 5.80 (5.79), N; 4.74 (4.81).

Example 7

[Production of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R = phenylamino)]

2-mercaptoethanol (8.4 ml, 0.12 mol) and boron trifluoride diethyl ether in an ether (400 ml) solution of alpha-acetoxyacetoacetanilide (III, R = phenylamino) (18.8 g, 0.08 mol) (9.84 ml) was added and heated to reflux for 20 hours. The reaction mixture is cooled to room temperature, the solvent is removed by evaporation under reduced pressure, the resulting oily liquid is dissolved in benzene (400 ml), washed with 1N caustic soda water and cold water, dried (Na ₂ SO ₄ ) and the solvent is removed by evaporation under reduced pressure. Alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R ₁ = phenylamino) (19.3 g, yield 82%) was obtained as an oily liquid. According to thin layer chromatography and hydrogen nuclear magnetic resonance spectra, this was a mixture of diastereomers. Each diastereomer was separated in the same manner as in Example 6, and they were identical to those prepared in Example 6 at melting point, hydrogen nuclear magnetic resonance spectrum, and infrared spectrum.

Example 8

[Production of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetic acid methyl ester (IV, R = methoxy)]

In a solution of alpha-acetoxyacetoacetic acid methyl ester (III, R = methoxy) (70 g, 0.4 mol) and 2-mercaptoethanol (42.5 ml, 0.6 mol) in an ether (350 ml) boron trifluoride diethyl ether ( 50 ml) was added and heated to reflux for 19 hours. The reaction mixture was evaporated under reduced pressure, and the oily liquid was dissolved in methylene chloride, washed twice with 1N caustic soda water (30 ml), washed with water, dried (sodium sulfate anhydride), and the solvent was removed by evaporation under reduced pressure. Fractional distillation (bp 128-134 ° C./1 mmHg) of the resulting oily liquid (65 g) gave pure alpha- (acetoxy) -2-methyl-1,3-oxathiolane-2-acetic acid methyl ester (IV, R = Methoxy) (40.5 g, yield 43%) was obtained.

bp: 128-134 ℃ / 1mmHg

Example 9

[Production of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetic acid methyl ester (IV, R = methoxy)]

Titanium tetrachloride (11 ml) was added to a dry methylene chloride (200 ml) solution of alpha-acetoxyacetoacetic acid methyl ester (III, R = methoxy) (35 g, 0.2 mol) and 2-mercaptoethanol (14 ml, 0.2 mol). Stirred at room temperature (20-25 ° C.) for 48 hours. The reaction mixture was washed three times with cold water, dried (sodium sulfate anhydride) and the solvent was removed by evaporation under reduced pressure. Fractional distillation (bp 130-135 ° C./1 mmHg) of the resulting oily liquid (29.5 g) gave pure alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetic acid methyl ester (IV, R = methoxy) (16.8 g, yield 34%). This was the same in boiling point, hydrogen nuclear magnetic resonance spectrum as prepared in Example 8.

Example 10

[Production of alpha- (hydroxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (I, R = phenylamino)]

Hydroxide in a methanol (20 ml) solution of a mixture of diastereomers of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R = phenylamino) (1 g, 3.4 mmol) An aqueous solution of potassium (0.1 g) (20 ml) was added and stirred for 30 minutes.

The reaction mixture was poured into cold water (200 ml), extracted with methylene chloride, the organic layer was washed with water and dried (sodium sulfate), and the solvent was removed by evaporation under reduced pressure. The white solid alpha- (hydroxy) -2-methyl-1, 3 -Oxathiolane-2-acetanilide (I, R = phenylamino) (0.85 g, yield 99%) was obtained. According to the hydrogen nuclear magnetic resonance spectrum, this was a mixture of diastereomers.

Melting Point: 102-118 ℃

Example 11

[Production of alpha- (hydroxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (I, R = phenylamino)]

Diastereomer (benzene-ethylacetate (7: 3) of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R = phenylamino) (0.5 g, 1.7 mmol) ) To a thin layer chromatography using a developing solution and silica gel, an aqueous solution of potassium carbonate (0.2 g) was added to a methanol (10 ml) solution of R _f = 0.8) and stirred at room temperature for 10 minutes. The solvent was removed by evaporation under reduced pressure, the resulting white solid was extracted with chloroform, the organic layer was washed with water, and the solvent was removed by evaporation under reduced pressure to give the white solid alpha- (hydroxy) -2-methyl-1, 3-oxathiolane- 2-Acetanilide (I, R = phenylamino) (0.43 g, 100% yield) was obtained.

Melting Point: 122-123 ℃

Example 12

[Production of alpha- (hydroxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (I, R = phenylamino)]

Diastereomer (benzene-ethylacetate (7: 3) of alpha- (acetoxy) -2-methyl-1, 3-oxathiolane-2-acetanilide (IV, R = phenylamino) (0.5 g, 1.7 mmol) ) In a thin layer chromatography using a developing solution and silica gel, an aqueous 1 N sodium hydroxide solution (10 ml) and acyl acetate (20 ml) were added to an ethanol (10 ml) solution of R _f = 0.7), followed by stirring at room temperature for 30 minutes. Ethyl acetate (50 ml) was added to the reaction mixture, the organic layer was separated, washed twice with cold water, dried (sodium sulfate anhydrous), and the solvent was removed by evaporation under reduced pressure to give a white solid alpha- (hydroxy) -2-methyl-1. , 3-oxathiolane-2-acetanilide (I, R = phenylamino) (0.40 g, yield 92%) was obtained.

Melting Point: 133-135 ℃

Elemental Analysis: for C ₁₂ H ₁₅ O ₃ NS

Theoretical value (experimental value): C; 56.9 (57.1), H; 5.97 (6.02), N; 5.53 (5.58)

Example 13

[Production of alpha- (hydroxy) -2-methyl-1, 3-oxathiolane-2-acetic acid methyl ester (I, R = methoxy)]

Acetonitrile (20 ml) of a mixture of diastereomers of alpha- (acetoxy) -2-methyl-1,3-oxathiolane-2-acetic acid methylester (IV, R = methoxy) (13.54 g, 0.58 mol) An aqueous solution of anhydrous potassium carbonate (8 g) (20 ml) was added to a solution of chloroform (80 ml) and stirred at room temperature for 2 hours. The reaction mixture was added to cold water (200 ml), the organic layer was separated, washed with cold water, dried (sodium sulfate anhydride), and the solvent was removed by evaporation under reduced pressure. Alpha- (hydroxy) -1, 3-oxathiolane- 2-Acetic acid methyl ester (I, R = methoxy) (9.22 g, yield 83%) was obtained. According to the hydrogen nuclear magnetic resonance spectrum, this was a mixture of diastereomers.

Claims (12)

Novel alpha- (hydroxy) -1,3-oxathiolane derivatives represented by formula (I)

In general formula (I), R represents a methoxy or phenylamino group. A first step of preparing alpha-acetoxyacetoacetic acid derivative of general formula (III) by reacting alpha-haloacetoacetic acid derivative of general formula (II) with a metal acetate or tetraalkylammonium acetate in an organic solution, general formula (III) A second process and a general formula for preparing alpha-acetoxy-1 and 3-oxathiolane of the general formula (IV) by reacting alpha-acetoxyacetoacetic acid derivatives of N 2) and 2-mercaptoethanol in an organic solvent in the presence of an acid catalyst. A third step of preparing alpha- (hydroxy) -1,3-oxathiolane derivative of general formula (I) by reacting alpha-acetoxy-1 and 3-oxathiolane of (IV) in an organic solution in the presence of a catalyst Method for producing alpha- (hydroxy) -1,3-oxathiolane derivative of formula (I), characterized in that consisting of.

In general formula (I), R represents a methoxy or phenylamino group. In formula (II), R represents a methoxy or phenylamino group and X represents chlorine or bromine. In general formula (III), R represents a methoxy or phenylamino group. In general formula (IV), R represents a methoxy or phenylamino group. 3. The alpha- (hydroxy) -1 and 3-oxathiolane derivatives of general formula (I) according to claim 2, wherein the metal acetate of the first step is reacted by selecting from potassium acetate or sodium acetate salt. Manufacturing method. The alpha- (hydroxy) -1 and 3- of general formula (I) according to claim 2, wherein the tetraalkylammonium acetate of the first step is selected from tetramethylammonium acetate or tetraethylammonium acetate. Method for preparing an oxathiolane derivative. 3. The alpha- (hydride of formula (I) according to claim 2, wherein the organic solvent of the first step is selected from methylene chloride, acetone, chloroform, ethyl acetate, benzene, acetonitrile, toluene, and xylene for reaction. Roxy) -1, 3-oxathiolane derivative. The method for producing alpha- (hydroxy) -1,3-oxathiolane derivatives of general formula (I) according to claim 2, wherein the reaction is carried out at 50-100 ° C at the reaction temperature of the first step. The alpha of the general formula (I) according to claim 2, wherein the acid catalyst of the second step is selected from benzenesulfonic acid, para-toluenesulfonic acid, tin tetrachloride, boron trifluoride diethyl ether, and titanium tetrachloride. Process for the preparation of-(hydroxy) -1,3-oxathiolane derivatives. The alpha- (hydroxy)-of the general formula (I) according to claim 2, wherein the organic solvent of the second step is selected from ethyl ether, methylene chloride, chloroform, ethyl acetate benzene, toluene, and xylene. 1, 3-oxathiolane derivatives manufacturing method. The method for preparing alpha- (hydroxy) -1,3-oxathiolane derivatives of the general formula (I) according to claim 2, wherein the reaction is carried out at 25-130 ° C. at the reaction temperature of the second step. The catalyst of claim 3, wherein the catalyst of step 3 is sulfuric acid, hydrochloric acid, nitric acid, benzenesulfonic acid, para-toluenesulfonic acid, methanesulfonic acid or sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, barium hydroxide, A method for producing alpha- (hydroxy) -1,3-oxathiolane derivatives of formula (I), characterized by reacting by selecting from a base catalyst composed of calcium hydroxide. The solvent of claim 2, wherein the solvent used in the third step is water, methanol, ethanol, propanol, acetone, dioxane, acetonitrile, ethyl acetate, methylene chloride, chloroform, benzene, toluene, or a mixture of two or more thereof. A process for producing alpha- (hydroxy) -1,3-oxathiolane derivatives of the general formula (I). The method for producing alpha- (hydroxy) -1,3-oxathiolane derivatives of the general formula (I) according to claim 2, wherein the reaction is carried out at 0-50 ° C at the reaction temperature of the third step.