JP2570796B2 - Method for producing 4-hydroxy-2-cyclopentenone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a compound represented by the general formula (I): (Wherein, X represents CH ₂ OH or COOR, R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and n is an integer of 4 to 8). The present invention relates to a method for producing a pentenone derivative.

<Prior Art> The 4-hydroxy-2-cyclopentenone derivative represented by the above general formula (I) is an important compound as an intermediate of a medicine, a pesticide and the like, and is sometimes extremely important as an intermediate of prostaglandin. .

Conventionally, methods for producing such 4-hydroxy-2-cyclopentenone derivatives include, for example, 3-hydroxy-4
A method of treating a cyclopentenone compound in a mixture of water and an inert non-hydroxyl organic solvent miscible with water in the presence of a strong acid such as sulfuric acid or perchloric acid (JP-A-53-127462) Gazette) Method of treatment with basic alumina [Tetrahedron Letter
s, 13 1131~1134 (1977)] and the like are known.

<Problems to be Solved by the Invention> However, all of these known methods require a large amount of a reaction reagent with respect to a reaction substrate, and are not necessarily industrially advantageous from the viewpoint of reaction treatment. .

From these facts, the present inventors have studied to produce the 4-hydroxy-2-cyclopentenone derivative represented by the general formula (I) industrially easily and advantageously in good yield, and as a result, 3 The present inventors have found that the above-mentioned object can be achieved by isomerizing a -hydroxy-4-cyclopentenone derivative in the presence of a specific catalyst, leading to the present invention.

<Means for Solving the Problems> The present invention provides a compound represented by the general formula (II): (Wherein X and n have the same meaning as described above), wherein the 3-hydroxy-4-cyclopentenone derivative represented by the formula is isomerized in the presence of chloral and an organic amine. 4 shown by (I)
-Hydroxy-2-cyclopentenone derivatives.

In the present invention, the starting material, 3-hydroxy-4-cyclopentenone derivative, is not necessarily required to be alone, and may contain other compounds that do not adversely affect the reaction. The target compound of the present invention may be contained in the raw material.

Such a 3-hydroxy-4-cyclopentenone derivative has, for example, the general formula (III): (Wherein X and n have the same meanings as above) in a solvent containing water as a main solvent, while maintaining the pH in the range of 3.5 to 6 with or without a catalyst. By rearrangement below, a 4-hydroxy-2-cyclopentenone derivative generally represented by the general formula (I) can be obtained with a part thereof.

In the present invention, the furfuryl alcohol derivative represented by the above general formula (III) used as a raw material can be easily produced from furan, for example, by the following method.

The solvent used in the rearrangement reaction of the furfuryl alcohol derivative represented by the general formula (III) has water as a main solvent, and is composed mainly of water alone or water in which a small amount of another organic solvent is mixed with water. Is a mixed solvent. Here, as other organic solvents, for example, ethylene glycol,
1,3-propanediol, methanol, ethanol, dioxane, tetrahydrofuran, DMF, DMSO, ethyl acetate, acetic acid, dichloromethane, toluene, dimethyl ether, and other aliphatic or aromatic hydrocarbons, alcohols, fatty acids, ethers, esters, halogenated carbons Solvents that are inert to the reaction such as hydrogen. However, generally, there is no particular advantage in coexisting these organic solvents with water.

This reaction does not necessarily require a catalyst, but its use is effective because the addition of a catalyst increases the reaction rate and increases the reaction rate.

When a catalyst is used in this reaction, examples of the catalyst include various metal salts, organic quaternary ammonium salts, surfactants, and alcohols.

As various metal salts, for example, sodium, potassium,
Magnesium, zinc, iron, calcium, manganese, cobalt, aluminum and other phosphates, sulfates, chlorides, bromides, oxides, organic fatty acids, organic sulfonates, and organic quaternary ammonium Examples of salts include tetrabutylammonium bromide, benzyltrimethylammonium chloride, tricaprylmethylammonium chloride, dodecyltrimethylammonium chloride,
Caprylbenzyldimethylammonium chloride and the like, and surfactants include higher fatty acid salts, polyoxyethylene alkylphenol ethers, higher aliphatic alcohols, and the like. Examples of the alcohol include methanol, ethanol, and ethylene glycol exemplified above as the solvent. And the like are also used as catalysts, and these are used alone or as a mixture.

When a catalyst is used, the amount of the catalyst used is usually the general formula (III)
1/200 with respect to the furfuryl alcohol derivative represented by
It is in the range of up to 5 times the weight, but application outside this range is also possible.

The catalyst used here can be recovered and reused after the completion of the reaction.

The reaction pH is preferably in the range of 3.5 to 6, more preferably in the range of 3.5 to 5.

Examples of the acid used to maintain the pH include, for example, common inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, boric acid, acetic acid, propionic acid, toluenesulfonic acid, and methanesulfonic acid, and organic acids. Examples of the alkali include caustic soda, potassium carbonate, sodium hydrogen carbonate, phosphoric acid 1
Examples include ordinary inorganic bases and organic bases such as potassium hydrogen and organic amines.

Alternatively, a buffer solution of the above acid-base combination may be mentioned, for example, monohydrogen phosphate potassium phosphate, sodium acetate-acetic acid, sodium acetate-phosphate, phthalic acid-potassium carbonate, monohydrogen phosphate potassium-hydrochloride, phosphorus phosphate Examples thereof include potassium dihydrogen acid-potassium hydrogen carbonate, succinic acid-sodium hydrogen carbonate, and the like.

Generally, it is more preferable to avoid strong acids such as hydrochloric acid and hydrobromic acid and strong alkalis such as caustic soda and caustic potash as acids or alkalis used for pH adjustment.

The reaction temperature is optional at 0 to 200 ° C., preferably 20 to 200 ° C.
~ 160 ° C.

As a reaction method of this rearrangement reaction, a reaction vessel is charged in a lump in a reaction vessel and then heated, and a furfuryl alcohol derivative is dripped extremely slowly in a solvent containing water as a main solvent over a time required for the reaction. Although any method such as a method can be adopted, the latter method is advantageous in terms of yield.

The reaction mixture thus obtained is subjected to operations such as extraction, liquid separation, concentration, and chromatography to obtain a compound of the general formula (I) containing a part of the 4-hydroxy-2-cyclopentenone derivative represented by the general formula (I). A 3-hydroxy-4-cyclopentenone derivative represented by II) is obtained,
This mixture can be used as it is in the next isomerization treatment without separating the mixture.

The isomerization treatment of the 3-hydroxy-4-cyclopentenone derivative is usually performed in a solvent in the presence of chloral and an organic amine.

The amount of chloral used is based on the starting material 3-hydroxy-
It is usually 0.005 to 1-fold mol, preferably 0.01 to 0.3-fold mol, based on 4-cyclopentenone.

As organic amines, for example, triethylamine,
N-methylmorpholine, N-methylpiperidine, N, N '
Organic tertiary amines such as dimethylpiperazine, pyridine, lutidine and the like, which are used alone or
Used in more than species.

The use amount of such organic amines is not particularly limited,
Usually, it is in the range of 0.005 to 0.5 mole per mol of the 3-hydroxy-4-cyclopentenone derivative.

Solvents used in this isomerization reaction include, for example, aliphatic or aromatic hydrocarbons such as tetrahydrofuran, dioxane, acetone, benzene, toluene, ethyl acetate, chlorobenzene, heptane, dichloromethane, dichloroethane, diethyl ether, and cyclohexane; , Ketones, esters, halogenated hydrocarbons and the like, and solvents inert to the reaction are exemplified, and these are used alone or as a mixture.

The reaction temperature ranges from -10 to 100 ° C, preferably from 0 to 90 ° C.

 The reaction time is not particularly limited.

Obtaining the desired 4-hydroxy-2-cyclopentenone derivative represented by the general formula (I) from the reaction mixture thus obtained by general operations such as extraction, liquid separation, concentration, and distillation. Can be.

<Effect of the Invention> Thus, according to the method of the present invention, the 4-hydroxy-2-cyclopentenone derivative represented by the general formula (I) can be easily obtained in a high yield, and its industrial value is Very high.

<Example> Hereinafter, the present invention will be described with reference to examples.

Example 1 A flask was charged with 1,000 ml of water and 0.2 ml of potassium dihydrogen phosphate.
g, and adjust the pH to 4.4 with 5% phosphoric acid.

To this is added 21.2 g of α- (ω-hydroxyheptyl) furfuryl alcohol, and the mixture is heated and stirred for 12 hours.

After completion of the reaction, extraction is performed twice with 200 ml of toluene.
The organic layer was concentrated under reduced pressure to give 3-hydroxy-2- (7
-Vidroxyheptyl) -4-cyclopentenone and 4-
20.3 g of a mixture of hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone (weight ratio: 4: 1) was obtained.

4.8 g of this mixture was added to 0.5 g of chloral and triethylamine
Stir for 5 hours at 30-40 ° C. with 0.4 g and 100 ml of dichloromethane.

After completion of the reaction, the reaction solution is washed successively with water, 1% aqueous hydrochloric acid, 1% aqueous sodium bicarbonate, and water. The organic layer was concentrated to obtain 4.3 g of 4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone.

Example 2 The same treatment as in Example 1 was carried out except that 21.2 g of α- (ω-methoxycarbonylhexyl) furfuryl alcohol was used in place of α- (ω-hydroxyheptyl) furfuryl alcohol, and 3-hydroxy-2- (6-methoxycarbonylhexyl) -4-cyclopentenone and 4-hydroxy-2- (6-methoxycarbonylhexyl) -2-
19.1 g of a mixture of cyclopentenone (weight mixing ratio: 3: 1) was obtained.

5.0 g of this mixture is stirred with 0.46 g of chloral, 0.29 g of pyridine and 20 ml of toluene at 30-40 ° C. for 6 hours.

After completion of the reaction, the reaction solution is washed successively with water, 1% aqueous hydrochloric acid, 1% aqueous sodium bicarbonate, and water.

The organic layer was concentrated to obtain 4.9 g of 4-hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone.

Example 3 A four-necked flask was charged with 50.0 g of α- (5-hydroxypentyl) furfuryl alcohol, 2,500 g of water and 2.5 g of acetic acid and a buffer aqueous solution adjusted to pH 4.3 with a 1N aqueous sodium hydroxide solution, Stirring is continued at 100 ° C. under a nitrogen atmosphere until the raw materials disappear.

After the completion of the reaction, the reaction mixture was cooled, extracted twice with 200 g of toluene, and subjected to liquid separation to conduct 3-hydroxy-2- (5-methoxypentyl) -4-cyclopentenone and 4-hydroxy-2- (5 A solution of toluene containing 40 g of a mixture with (-methoxypentyl) -2-cyclopentenone was obtained.

0.64 g of chloral and 0.34 g of triethylamine are added to this toluene solution, and the mixture is stirred at 30 ° C. for 6 hours.

After completion of the reaction, the reaction solution is washed successively with water, 1% aqueous hydrochloric acid, 1% aqueous sodium bicarbonate, and water.

The organic layer was concentrated, and 36.8 g of 4-hydroxy-2- (5-hydroxypentyl) -2-cyclopentenone (yield 73.
6%).

Example 4 A flask was charged with water 1, 0.4 g of sodium acetate and α-
20 g of (ω-hexyloxycarbonylhexyl) furfuryl alcohol is charged and adjusted to pH 4.3 with acetic acid. The reaction is stirred at 100 ° C. for 12 hours while maintaining the pH at 4.3-4.5. After completion of the reaction, extraction is performed twice with 200 ml of toluene. The organic layer was concentrated under reduced pressure to give 3-hydroxy-2-
19.3 g of a mixture of (ω-hexyloxycarbonylhexyl) -4-cyclopentenone and 4-hydroxy-2- (ω-hexyloxycarbonylhexyl) -2-cyclopentenone (weight mixture ratio: 4; 1) was obtained. .

5.0 g of this mixture is 0.5 g of chloral, triethylamine
Stir for 5 hours at 30-40 ° C. with 0.4 g and 100 ml of dichloromethane.

After completion of the reaction, the reaction solution is washed successively with water, 1% aqueous hydrochloric acid, 1% aqueous sodium bicarbonate, and water. The organic layer is concentrated and 4-hydroxy-2- (ω-hexyloxycarbonylhexyl)
4.5 g of -2-cyclopentenone was obtained.

Example 5 Water 1 and 8-hydroxy-8- (2-
The mixture is charged with 22.6 g of furyl) octanoic acid and adjusted to pH 4.3 with 5% sodium hydroxide and acetic acid. PH 4.3 ~
Stir at 100 ° C. for 12 hours while maintaining at 4.5. After completion of the reaction, the mixture is cooled to room temperature, adjusted to pH 2 with hydrochloric acid, added with 100 g of sodium chloride, and extracted three times with 200 ml of ethyl ether.
The organic layer was washed with 100 ml of saturated saline and concentrated under reduced pressure to give 7- (2-oxo-5-hydroxy-3-cyclopentenyl) heptanoic acid and 7- (5-oxo-3-
Hydroxycyclopentenyl) heptanoic acid as a mixture gave 15.1 g.

0.6 g of chloral and 3.0 g of triethylamine
Stir with 2.0 g and 100 ml of dichloromethane at 30 ° C to 40 ° C for 5 hours.

After the completion of the reaction, 50 ml of water is added to the reaction solution, and the mixture is adjusted to pH 2 with hydrochloric acid and then separated, and the organic layer is washed with 20 ml of saturated saline.
The organic layer was concentrated under reduced pressure to obtain 2.1 g of 7- (5-oxo-3-hydroxycyclopentenyl) heptanoic acid.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C07C 69/738 9546-4H C07C 69/738 A // C07B 61/00 300 C07B 61/00 300 ( 72) Inventor Shizuichi Kai 3-1-198, Kasuganaka, Konohana-ku, Osaka-shi, Japan Sumitomo Chemical Industries Co., Ltd. (72) Inventor Masayoshi Minami 3-1-198, Kasuganaka, Konohana-ku, Osaka-shi, Osaka Sumitomo Chemical Co., Ltd. (56) References JP-A-63-112533 (JP, A)

Claims (2)

(57) [Claims] 1. A compound of the general formula (II) (Wherein, X represents CH ₂ OH or COOR, R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and n represents an integer of 4 to 8). A general formula (I) wherein a 4-cyclopentenone derivative is subjected to isomerization treatment in the presence of 0.01 to 0.3 times mol of chloral and 0.005 to 0.5 times mol of organic amine with respect to the derivative. I) (Wherein X and n have the same meanings as described above.) A method for producing a 4-hydroxy-2-cyclopentenone derivative represented by the formula: 2. A compound of the general formula (III) (Wherein X and n have the same meanings as described above). In a solvent containing water as a main solvent, the furfuryl alcohol derivative is transferred while maintaining the pH in the range of 3.5 to 6, and 3-hydroxy-4- represented by the formula (II)
A general formula characterized by obtaining a cyclopentenone derivative and then subjecting it to isomerization treatment in the presence of 0.01 to 0.3 moles of chloral based on the derivative and 0.005 to 0.5 moles of an organic amine based on the derivative. A method for producing the 4-hydroxy-2-cyclopentenone derivative represented by (I).