JP3053714B2 - Method for producing phenyl 2- (furfurylthio) acetate derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound of the formula (III)

[0002]

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(Wherein Ph is an o-nitrophenyl group, p
—Nitrophenyl group or 2,4-dinitrophenyl group. The present invention relates to a method for producing a phenyl 2- (furfurylthio) acetate derivative represented by the following formula:

[0004] The phenyl 2- (furfurylthio) acetate derivative represented by the above formula (III) is a compound useful as an intermediate for producing pharmaceuticals, agricultural chemicals or various functional materials.

[0005]

2. Description of the Related Art Phenyl 2- (furfurylthio) acetate represented by the above formula (III) is known as an intermediate for producing pharmaceuticals, especially antipeptic ulcers [Japanese Patent Application Laid-open No. Hei 1 (1994)]. No. 230576].

Conventionally, 2-
The (furfurylthio) phenyl acetate derivative is, for example, 2
-(Furfurylthio) acetic acid and nitrophenols have been produced by dehydration-condensation using a dehydration-condensation agent such as dicyclohexylcarbodiimide [JP-A-1-
No. 230576].

However, the conventional production method is economically disadvantageous because a very expensive dehydration condensing agent such as dicyclohexylcarbodiimide is used.
In addition, since a step for removing the compound derived from the dehydrating condensing agent is required, the operation is complicated, and the number of steps is increased, which is a problematic method for an industrial production method.

[0008]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of the problems of the conventional production method, and as a result, have found that 2- (furfurylthio) acetic acid and nitrophenols can be converted to a nitrophenol in the presence of a base. Can be easily condensed by reacting with thionyl chloride, and the desired phenyl 2- (furfurylthio) acetate derivative can be obtained, and the post-treatment operation after completion of the reaction is greatly simplified. They have found that they can do so and have reached the present invention.

That is, the present invention provides the following formula (I)

[0010]

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2- (furfurylthio) acetic acid represented by the general formula (II)

[0012]

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(Wherein Ph is an o-nitrophenyl group, p
—Nitrophenyl group or 2,4-dinitrophenyl group. (III) characterized by reacting a nitrophenol represented by the formula) with thionyl chloride in the presence of a base.

[0014]

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(Wherein Ph is an o-nitrophenyl group, p
—Nitrophenyl group or 2,4-dinitrophenyl group. This is a method for producing a phenyl 2- (furfurylthio) acetate derivative represented by the following formula:

The 2- (furfurylthio) acetic acid represented by the general formula (I), which is a raw material of the present invention, is, for example, 2
It can be produced by hydrolyzing 2- (furfurylthio) acetic acid ester such as methyl- (furfurylthio) acetate in a mixed solvent of alcohol and water using a base such as potassium hydroxide. The present inventors have conducted intensive studies on this production method. As a result, it has been found that 2- (furfurylthio) acetic acid ester can be hydrolyzed with an aqueous solution of an alkali metal hydroxide even when a solvent immiscible with water is used as a reaction solvent. It has been found that 2- (furfurylthio) acetic acid can be easily produced, and the 2- (furfurylthio) acetic acid represented by the general formula (I) produced by this method is particularly purified. None, it can be subjected to the reaction of the present invention.

The nitrophenols represented by the above general formula (II) used in the present invention are o-nitrophenol, p-nitrophenol and 2,4-dinitrophenol, and the amount used is a raw material. The amount may be at least 1 equivalent to 2- (furfurylthio) acetic acid, but is preferably 1 to 2 equivalents. Addition of more than 2 equivalents is not preferred because the reaction does not change much and is only economically disadvantageous, and the burden on post-treatment to remove excess nitrophenols. More preferably, it is 1 equivalent to 1.5 equivalents.

The product of the present invention has the general formula (II)
The 2- (furfurylthio) acetic acid phenyl derivative represented by I) is obtained by reacting 2- (furfurylthio) acetic acid represented by the above general formula (I) with the above-mentioned phenols with thionyl chloride in the presence of a base. Can be manufactured. The phenyl 2- (furfurylthio) acetate derivative represented by the general formula (III), which is the product of the present invention, is specifically described as 2- (furfurylthio)
They are -o-nitrophenyl acetate, 2- (furfurylthio) acetic acid-p-nitrophenyl, and 2- (furfurylthio) acetic acid-2 ', 4'-dinitrophenyl.

The amount of thionyl chloride used in the present invention may be at least 1 equivalent to the starting material 2- (furfurylthio) acetic acid, but is preferably 1 to 2 equivalents. The addition of more than 2 equivalents is not preferred because the reaction does not change much and is only economically disadvantageous, and furthermore, it decomposes the excess thionyl chloride and places a burden on the post-treatment step. More preferably, it is 1 equivalent to 1.5 equivalents.

As the base used in the present invention, for example, organic bases such as triethylamine and pyridine can be used. The amount of the base used may be 2 equivalents or more based on thionyl chloride used, but is preferably 2 equivalents to 3 equivalents. Even if more than 3 equivalents are added, there is no significant change in the reaction, and it is only economically disadvantageous,
In addition, it is not preferable because a load is applied to the post-treatment for removing the excess base. More preferably 2 equivalents to 2.5
Is equivalent.

In the present invention, it is preferable to use a reaction solvent, for example, halogenated hydrocarbons such as methylene chloride, carbon tetrachloride, 1,2-dichloroethane (EDC) and ethers such as diethyl ether. And aromatic hydrocarbons such as benzene and toluene.

The reaction temperature in the present invention is not particularly limited, but is preferably from -20 ° C to 80 ° C. If the temperature is lower than −20 ° C., the reaction rate is low, and the reaction time is extremely long. On the other hand, if the temperature is higher than 80 ° C., the decomposition becomes intense, which causes a decrease in yield, which is not preferable. More preferably, the temperature is from -5C to 25C.

In the reaction of the present invention, the starting material, 2- (furfurylthio) acetic acid, represented by the above general formula (I), is converted into 2- (furfurylthio) acetic acid chloride by thionyl chloride, which is the other starting material. General formula (II)
Reacts with nitrophenols represented by However, the intermediate 2- (furfurylthio) acetic chloride is a very unstable compound,
Decomposes in a short time [Dokl. chem. (Engl.
Transl. ), 142, (1962), 38]. Therefore, in order to suppress the generation of impurities such as tar and to produce the desired 2- (furfurylthio) acetic acid phenyl derivative represented by the general formula (III) in good yield,
The resulting 2- (furfurylthio) acetic acid chloride is preferably reacted with nitrophenols as quickly as possible.

The phenyl 2- (furfurylthio) acetate derivative represented by the above general formula (III) obtained as described above is recovered by a usual post-treatment, but is derived from a dehydrating condensing agent according to a conventional method. The method of the present invention is industrially very advantageous because the phenyl 2- (furfurylthio) acetate derivative represented by the above general formula (III) is unnecessary because the operation such as the removal of the compound is unnecessary and the process can be shortened. It is a manufacturing method of.

[0025]

The present invention will be described in more detail with reference to the following examples. Reference Example 1 Production of methyl 2- (furfurylthio) acetate

[0026]

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Furfuryl mercaptan 11.40 g
(0.1 mol), 10.85 g of methyl chloroacetate
(0.1 mol) and polyethylene glycol-10
00 (PEG-1000) 0.11 g in toluene.
The solution was dissolved in 2 g, and 13.82 g of anhydrous potassium carbonate was added, followed by stirring at 95 ° C. for 5 hours.

After cooling, salts were removed by suction filtration, and the solvent was distilled off to obtain a brown oily substance 19.47.
g was collected. This was distilled under reduced pressure to obtain methyl 2- (furfurylthio) acetate as a colorless oil.

Yield 16.21 g Yield 87.2% b. p. 138 ° C./17 mmHg GLC Pu. Reference Example 2 Production of methyl 2- (furfurylthio) acetate 8.55 g of furfuryl mercaptan (0.075 mol)
l), 8.14 g of methyl chloroacetate (0.075 mol
l) and 18-crown-6-ether (0.03 g) were dissolved in toluene (100 ml), and anhydrous potassium carbonate (10.l) was dissolved.
37 g was added, and the mixture was stirred at 95 ° C. for 7 hours and then cooled. Analysis of the organic composition at this time by gas chromatography revealed that methyl 2- (furfurylthio) acetate was 96.
It was 69%.

Next, 50 ml of water was added to dissolve the salt, followed by liquid separation to collect a toluene layer. The recovered toluene layer was used as it was in Reference Example 4. Reference Example 3 Production of 2- (furfurylthio) acetic acid

[0031]

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Methyl 2- (furfurylthio) acetate
0 g (0.183 mol) was dissolved in 17.0 g of toluene, and 58.7 g of a 15% -NaOH aqueous solution (0.
(220 mol) was gradually added dropwise, followed by stirring at room temperature for 2 hours. The toluene layer at this time was analyzed by gas chromatography, and it was confirmed that the peak of methyl 2- (furfurylthio) acetate had disappeared.

Next, the aqueous layer was recovered by liquid separation, and 133.4 g of a 10% HCl aqueous solution was added dropwise to the aqueous layer under ice-cooling.
Neutralized and acidified. At this time, an oily substance was precipitated in the lower layer. After separating and collecting the oily substance, 102 g of methylene chloride was further added to the aqueous layer.
Was added for extraction, and the methylene chloride layer was recovered. The collected oil and the collected methylene chloride layer were combined, washed with saturated saline, dried, and the solvent was distilled off to obtain 2- (furfurylthio) acetic acid as a pale yellow oil.

Yield 31.0 g 95.8% GLC Pu. 97.17% Reference Example 4 Production of 2- (furfurylthio) acetic acid To a toluene solution containing methyl 2- (furfurylthio) acetate recovered in Reference Example 2, 30 g of a 20% -KOH aqueous solution was added, and the mixture was stirred at room temperature for 5 hours. The toluene layer at this time was analyzed by gas chromatography, and it was confirmed that the peak of methyl 2- (furfurylthio) acetate had disappeared.

Next, the aqueous layer was separated and the aqueous layer was recovered. Under ice-cooling, 125 g of a 10% aqueous HCl solution was added dropwise to the aqueous layer to make it neutral and acidified. It was extracted twice, washed with saturated saline, dried, and the solvent was distilled off to collect a pale yellow oil. Furthermore, 2- (furfurylthio) acetic acid was obtained by distillation under reduced pressure.

Yield 9.75 g Yield 75.6% b. p. 146-147 ° C / 3mmHg GLC Pu. 99.36% Example 1 Preparation of 2- (furfurylthio) acetic acid-p-nitrophenyl
Construction

[0037]

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31.0 g of 2- (furfurylthio) acetic acid obtained in Reference Example 3 (Pu. 97.17%, 0.175 mol)
1) and 25.4 g of p-nitrophenol (0.18
3 mol) was dissolved in 157 g of methylene chloride, and cooled under ice-cooling.
31.8 g (0.420 mol) of pyridine was gradually added dropwise. Next, 22.9 g of thionyl chloride (0.1
A solution of 78 g of (92 mol) -methylene chloride was gradually added dropwise. After the completion of the dropwise addition of the thionyl chloride solution, stirring was further continued for 1 hour.

Next, 100 ml of cold water was gradually added dropwise to decompose excess thionyl chloride and at the same time washed. Then 1
After washing with 107 g of 0% -HCl aqueous solution, 10% -K ₂ C
The mixture was washed twice with 50 g of an O ₃ aqueous solution, further washed with 100 ml of water, dried, and the solvent was distilled off to obtain a black-brown clay-like compound.

[0040] The recovered product was again treated with 200 g of methylene chloride.
And 10 g of powdered activated carbon was added. After stirring for 2 hours, the mixture was filtered and the filtrate was collected, and the solvent was distilled off to obtain 2- (furfurylthio) acetic acid-p-nitrophenyl as pale yellow crystals.

Yield 40.9 g Yield 78.1% HPLC Pu. 98.0% The recovered product was recrystallized from ethyl acetate-n-hexane (1: 1).

HPLC Pu. 99.8% m. p. 67.0-68.0 ° C

[0043]

According to the method of the present invention, the post-treatment operation which was very complicated in the conventional method for producing phenyl 2- (furfurylthio) acetate can be greatly simplified.
-A phenyl (furfurylthio) acetate derivative can be efficiently produced.

──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Yoshiyuki Kikuchi 2805 Imafukunakadai, Kawagoe-shi, Saitama Central Glass Co., Ltd. Examiner at Tokyo Research Laboratory Junko Uchida (56) References JP 1-2230576 (JP, A JP-A-1-193247 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 307/38 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) The following formula (I): 2- (furfurylthio) acetic acid represented by the general formula (I
I) (In the formula, Ph represents an o-nitrophenyl group, a p-nitrophenyl group or a 2,4-dinitrophenyl group.) A nitrophenol represented by the formula: is reacted with thionyl chloride in the presence of a base. The general formula (II
I) (Wherein Ph represents an o-nitrophenyl group, a p-nitrophenyl group or a 2,4-dinitrophenyl group). A method for producing a 2- (furfurylthio) acetic acid phenyl derivative represented by the formula: