JPH0152394B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing thiochromone-3-carboxylic acids. More specifically, the present invention consists of the following three reactions (a) to (c),
It is characterized in that it is produced without isolating the reaction product during this period. That is, (a) General formula (1) [In the formula, R ₁ and R ₂ may be the same or different,
hydrogen, halogen atom, lower alkyl, or lower alkoxy group], and in which at least one of the ortho positions of the mercapto group is hydrogen, and the general formula (2) When a dialkyl alkoxymethylene malonate represented by the formula [wherein R ₃ and R ₄ are the same or different and each represents a lower alkyl group] is heated in polyphosphoric acid, the general formula (3) is obtained. [In the formula, R ₁ , R ₂ and R ₄ have the meanings defined above] A dialkyl aryl thiomethylene malonate is produced, and (b) when the heating reaction is continued, the ring is closed to form the general formula ( Four) [In the formula, R ₁ , R ₂ and R ₄ have the meanings defined above] thiochromone-3-carboxylic acid esters are produced, and (c) when polyphosphoric acid is further heated as phosphoric acid, Hydrolysis occurs, and the general formula (3) [In the formula, R ₁ and R ₂ represent the meanings defined above]
Thiochromone-3-carboxylic acids represented by are precipitated as crystals.

Conventionally, the method for synthesizing dialkylarylthiomethylene malonates (3) involves heating arylthiols (1) and dialkylalkoxymethylene malonates (2) at high temperatures for a long period of time, for example, at 140°C for 48 hours. required reaction conditions. (Japanese Patent Publication No. 54-109995,
(page 8)).

The present inventors investigated various conditions for this condensation reaction and found that dialkyl arylthiomethylene malonate is produced at a high reaction rate in a short time when the reaction is heated in polyphosphoric acid.

On the other hand, dialkyl arylthiomethylene malonate (3) was ring-closed in polyphosphoric acid to produce thiochromone.
The reaction to produce 3-carboxylic acid esters (4) has been known for a long time. Therefore, according to the method of the present invention, the arylthiol represented by the general formula (1) and the general formula
Thiochromone-3-carboxylic acid esters (4) are produced from the dialkylalkoxymethylene malonate shown in (2) in a substantially one-step reaction. Further, by adding water to the reaction solution and heating the polyphosphoric acid as phosphoric acid, hydrolysis of the ester occurs, and the thiochromone-3-carboxylic acids represented by the general formula (3) can be easily obtained.

The synthesis of dialkyl arylthiomethylene malonate (3) by the method of the present invention, that is, the reaction (a), uses 1 to 1.5 times the mole of dialkyl alkoxy methylene malonate (2) to the aryl thiol (1). , mixed in polyphosphoric acid in an amount of 10 to 30 times that of (1) at 20°C to 100°C, preferably 40°C.
Good yields are achieved by heating at a relatively low temperature of 80° C. for 2 to 5 hours. Under relatively high temperature conditions, a partially closed ring is formed.

For the synthesis of thiochromone-3-carboxylic acid esters (4) , that is, reaction (b), the above reaction solution was continued.
At a temperature of 50℃ or higher, preferably 80℃ to 150℃
The reaction may be carried out by heating for 0.5 to 5 hours. These 2
The boundaries between the two reaction conditions may be made without distinction.

Furthermore, the synthesis of thiochromone-3-carboxylic acid (3) by hydrolysis, i.e., the reaction (c), is carried out by adding 0.5 to 3.0 times the amount of water to the polyphosphoric acid used to the above reaction solution and heating from 80°C to reflux. 2 hours at a temperature of
Cook for 10 hours. After the reaction, the product is cooled and further water is added to lower the phosphoric acid concentration, so that the product precipitates and can be easily isolated.

Thiochromone-3 obtained by the method of the present invention
- Carboxylic acids (3) may give a mixture of isomers depending on the substituents of arylthiols (1), but they can be separated by column chromatography after esterification, and It is a compound useful as a fungicide for agricultural and horticultural purposes.

An experimental example will be shown for more specific explanation.

Example 1 Synthesis of 6-methylthiochromone-3-carboxylic acid: 5 g (0.04 mol) of p-toluenethiol and 10 ml (0.05 mol) of diethyl ethoxymethylene malonate were mixed with 50 g of 116% polyphosphoric acid, and 1
The mixture was then heated and stirred at 110° C. for 40 minutes. 25 ml of water was added little by little to the reaction solution, followed by reaction at 100°C for 3 hours. After the reaction, 200 ml of water was added to remove the precipitate, washed with water, then methanol, and dried. 5.2 g of white crystals were obtained. Yield 59%, mp220−
It was 222℃.

Example 2 Synthesis of 8-methylthiochromone-3-carboxylic acid: 8-Methylthiochromone-3-carboxylic acid was synthesized in the same manner as in Example 1 using o-toluenethiol.
4.7g was obtained. Yield was 53%, mp 230-232°C.

Example 3 (a) Synthesis of 5- and 7-methylthiochromone-3-carboxylic acid: 25 g (0.2 mol) of m-toluenethiol and 50 ml (0.25 mol) of diethyl ethoxymethylene malonate.
mol) was thoroughly mixed with 500 g of 116% polyphosphoric acid. The mixture was stirred for 3 hours at an external temperature of 70°C to 80°C. After further stirring at 100°C to 110°C for 1.5 hours, 250 ml of water was carefully added and the mixture was reacted at 100°C for 3 hours. After cooling, add water to remove the precipitate, wash with methanol and ether, and remove the 5- and 7-
Mixture of methylthiochromone-3-carboxylic acids
31.2g was obtained. The yield was 70.4%.

(b) Separation of 5-methylthiochromone-3-carboxylic acid and 7-methylthiochromone-3-carboxylic acid: Suspend 43.5 g of the mixture in 150 ml of benzene,
43.5 ml of thionyl chloride was added and heated at 70°C to 80°C for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 50 ml of benzene, and 30 ml of methanol was added for esterification. Silica gel column chromatography was performed using a mixed solvent of benzene and ethyl acetate in a ratio of 10:1. 5-methylchromone-3-
Carboxylic acid methyl ester 11g, yield 24%,
mp79−81℃ and 7-methylthiochromone−
3-carboxylic acid methyl ester 20g, yield 43
%, mp128−131°C was obtained.

(c) Thiochromone-3-carboxylic acid methyl ester becomes 80% when heated with 50% sulfuric acid at 80℃ for 2.5 hours.
It was hydrolyzed with a yield above. Thus 5-methylthiochromone-3-carboxylic acid, mp220-
222°C and 7-methylthiochromone-3-carboxylic acid, mp 261-262°C were obtained.

Example 4 Production of thiochromone-3-carboxylic acid: 22 ml of thiophenol and 50 ml of diethyl ethoxymethylene malonate are added to 50.0 g of 116% polyphosphoric acid and stirred at 100°C for 1.5 hours.

Next, add 250ml of water little by little, and after the heat generation subsides, heat to 100℃ for 3 hours. After cooling, add another 250 ml of water and remove the precipitated crystals. After thoroughly washing with water, washing with 100ml of methanol, further washing with 100ml of ethyl ether and air drying, 28g
Obtained the objective. Melting point 235-237℃.

Examples 5-8 The following compound was produced in the same manner as in Example 4.

6-Chlorthiochromone-3-carboxylic acid Melting point 235-240℃ 6-methoxythiochromone-3-carboxylic acid Melting point 203-205℃ 5-Chlor-8-methoxythiochromone-3-
Carboxylic acid Melting point 262-264℃ 1-oxo-1H-naphtho[2,1-b]thiopyran-2-carboxylic acid Melting point 295-297℃ Reference example 1 Production of thiochromone-3-carboxylic acid ethyl ester: Method (a) Add 22 ml of thiophenol and 50 ml of diethyl ethoxymethylene malonate to 500 g of 116% polyphosphoric acid, and stir at 100°C for 1.5 hours.

Pour into ice water 1, extract with 200ml of ethyl acetate,
Wash with a 5% aqueous sodium hydrogen carbonate solution until the washing solution becomes alkaline. Next, the solvent was distilled off and the residue was purified by column chromatography (trade name, Wako Gel C-200, benzene:ethyl acetate = 10:1), and then recrystallized from a benzene-hexane mixed solvent. I got my destination. Melting point 67-69℃.

Method (b) 5 g of thiochromone-3-carboxylic acid obtained in Example 1 is refluxed in 5 ml of thionyl chloride for 30 minutes, and then excess thionyl chloride is distilled off.

After adding 5 ml of ethanol to the residue and stirring at room temperature for 10 minutes, it was dried under reduced pressure, and the residue was recrystallized from a mixed solvent of benzene and hexane to obtain 4.5 g of the desired product.
Melting point: 67-69°C Reference Examples 2-4 The following compounds were obtained by method (b).

5-Methylthiochromone-3-carboxylic acid methyl ester Melting point 79-81°C 7-Methylthiochromone-3-carboxylic acid methyl ester Melting point 128-131°C 1-Oxo-1H-naphtho[2,1-b]thiopyran-2- Carboxylic acid ethyl ester Melting point 103-105°C Reference example 5 Production of diethyl phenylthiomethylene malonate: Add 22 ml of thiophenol and 50 ml of diethyl ethoxy methylene malonate to 500 g of 116% polyphosphoric acid and stir at 60°C for 3 hours.

Pour into ice water 1, extract with 200ml of ethyl acetate,
After washing with a 5% aqueous sodium hydrogen carbonate solution, drying with anhydrous sodium sulfate. After the desiccant was removed and the solvent was distilled off, the residue was distilled under reduced pressure to obtain 40 g of the desired product. Boiling point 180-190℃/2×10 ^-4 mmHg.

Claims (1)

[Claims] 1 General formula (1) [In the formula, R ₁ and R ₂ may be the same or different and represent hydrogen, a halogen atom, lower alkyl, or lower alkoxy group. ], and at least one of the ortho positions of the mercapto group is hydrogen, and the general formula (2) [In the formula, R ₃ and R ₄ may be the same or different and represent a lower alkyl group] is reacted with a dialkylalkoxymethylene malonate in polyphosphoric acid, and then water is added and heated. General formula (3) consisting of A method for producing thiochromone-3-carboxylic acids represented by the formula [wherein R ₁ and R ₂ have the meanings defined above].