JPH078819B2 - Method for producing 2-cyclopentenone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention provides a compound represented by the general formula (I): (Wherein, R .n represents a hydrogen atom or an alkyl group of C ₁ -C ₆ is an integer of 4 to 8.) Relates to a process for preparing 2-cyclopentenone derivative represented by the.

<Prior Art> The 2-cyclopentenone derivative represented by the general formula (I) is extremely important as an intermediate for medicines, agricultural chemicals, especially as a prostaglandin intermediate.

Conventionally, various methods have been known as a method for producing such a 2-cyclopentenone derivative, and examples thereof include the methods shown below.

JOC 45 , 4702 (1980) Synthesis 199-200 (1981) JOC 43 , 4247 (1978) <Problems to be Solved by the Invention> However, all of these methods have problems such that the starting materials are expensive, expensive reagents are required, the reaction process is long, etc. It is not always satisfactory.

From these things, the present inventors have made the present invention as a result of studying to solve such a problem and industrially advantageously produce the 2-cyclopentenone derivative represented by the general formula (I).

<Means for Solving Problems> The present invention includes general formulas (II) and (III) (In the formula, R and n have the same meanings as described above.) A mixture of hydroxycyclopentenones represented by the following formula is reacted with an aliphatic carboxylic acid having 1 to 5 carbon atoms to give a compound represented by the general formula (IV) or (III ) (In the formula, R ₁ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, and R and n have the same meanings as described above.) And 4-hydroxy-2- After obtaining a mixture of cyclopentenones (III) and reacting the mixture with an acylating agent to form a single cyclopentenone ester represented by the general formula (IV),
2 represented by the general formula (I) consisting of reducing this
-Provides a method for producing a cyclopentenone derivative.

In the present invention, a mixture of hydroxycyclopentenones represented by the general formulas (II) and (III) to a cyclopentenone ester represented by the general formulas (IV) and (III) and 4-hydroxy-2-cyclopentenone The reaction for obtaining the mixture of is carried out by heating the compound of formula (II) and formula (III) and the aliphatic carboxylic acid in the presence or absence of a solvent.

Here, the aliphatic carboxylic acid is a lower aliphatic carboxylic acid having 1 to 5 carbon atoms such as formic acid, acetic acid, propionic acid, butyric acid, and valeric acid, and these are used alone or together with their metal salts or organic amine salts. .

Here, examples of the metal salts include lithium salts, sodium salts, potassium salts, calcium salts, copper salts, zinc salts, palladium salts, lead salts, tin salts, manganese salts, and cobalt salts, and organic amine salts include triethylamine salts. , Pyridine salt, picoline salt, trimethylamine salt and the like.

When a solvent is used in this reaction, examples of the solvent include tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, dimethyl sulfoxide, hexane, and the like. Solvents such as aliphatic or aromatic hydrocarbons, ethers, halogenated hydrocarbons and the like which are inert to the reaction may be used alone or as a mixture. The amount used can be used without particular limitation. Also,
Aliphatic carboxylic acids can also be used as solvent.

The amount of the aliphatic carboxylic acid used in the reaction is represented by the general formula (I
It is necessary to have 1 equivalent or more, and preferably 2 equivalents or more, with respect to the hydroxycyclopentenones represented by I).

The reaction temperature is 0 to 150 ° C, preferably 30 to 140 ° C.

The reaction time is not particularly limited.

By such a reaction, the cyclopentenone ester represented by the general formula (IV) can be easily and obtained in good yield from the hydroxycyclopentenones represented by the general formula (II). A mixture of compounds represented by the general formula (III) can be easily obtained in good yield.

By reacting such a mixture with an acylating agent, a single cyclopentenone ester represented by the general formula (IV) can be obtained.

In this reaction, an aliphatic carboxylic acid having 1 to 5 carbon atoms, an aliphatic carboxylic acid halide, an aliphatic carboxylic acid anhydride or the like is used as an acylating agent.

As such an acylating agent, specifically, formic acid, acetic acid,
Aliphatic carboxylic acids such as propionic acid, butyric acid, valeric acid,
These acid halides (for example, acid chlorides) and their acid anhydrides can be mentioned.

When an aliphatic carboxylic acid is used as an acylating agent in this reaction, a mineral acid such as hydrochloric acid or sulfuric acid, an organic acid such as an aromatic sulfonic acid (for example, p-toluenesulfonic acid),
Alternatively, it is carried out in the presence of a catalytic amount of Lewis acid such as boron fluoride etherate, and when an aliphatic carboxylic acid halide is used as an acylating agent, a base such as an inorganic base such as sodium hydroxide, triethylamine, dimethylaniline, etc. The organic base is coexisted with the aliphatic carboxylic acid halide in an equivalent amount, and when an aliphatic carboxylic acid anhydride is used as the acylating agent, sulfuric acid,
It is carried out in the presence of a catalytic amount of a catalyst such as P-toluenesulfonic acid, zinc chloride, pyridine, dimethylaminopyridine or an aliphatic carboxylic acid metal salt.

The amount of the acylating agent used in such a reaction is 1 to 8 equivalent times that of the raw material mixture in this reaction.

When a solvent is used in these reactions, for example, tetrahydrofuran, ethyl ether,
Acetone, methyl ethyl ketone, toluene, benzene,
Solvents such as chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, dimethylsulfoxide and hexane, which are inert to the reaction, such as aliphatic or aromatic hydrocarbons, ethers, halogenated hydrocarbons and the like, or a mixture thereof. The amount used is not particularly limited.

The reaction temperature is usually in the range of 0 to 150 ° C, preferably 10 to 100 ° C, and the reaction time is not particularly limited.

By such a reaction, 4-hydroxy-2-cyclopentenones represented by the general formula (III) in the raw material mixture are easily converted into a cyclopentenone ester represented by the general formula (IV) in good yield, As a result, a single cyclopentenone ester represented by the general formula (IV) can be easily obtained in good yield.

The reaction from the cyclopentenone ester represented by the general formula (IV) to the desired 2-cyclopentenone derivative represented by the general formula (I) is carried out by adding a metal to the above cyclopentenone ester and reducing it. Done by.

An acid is required in this reaction, and in many cases, the excess amount of the aliphatic carboxylic acid used in the previous step is used as it is, but if necessary, it may be added or another acid may be added. Good.

Examples of the acid used here include aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, lactic acid, and valeric acid, acid anhydrides such as acetic anhydride, propionic anhydride, dilute hydrochloric acid, dilute sulfuric acid, phosphoric acid, and chlorine. An inorganic acid such as an acid is exemplified.

The amount of the acid used is not particularly limited, but is usually the same weight to 30 times the weight of the raw material.

Examples of the metal used in this reaction include zinc, zinc amalgam, iron, tin, and other metals used in general reduction reactions, and the amount used is usually 0.5 to 50 times the molar amount of the raw materials.

The reaction temperature is in the range of 0 to 160 ° C, preferably 30 to 150 ° C.

The reaction time is not limited, but is usually 0.5 to 10 hours. If the reaction time becomes long, the cyclopentenone derivative represented by the general formula (I) formed is further reduced to form a cyclopentanone compound, and therefore unnecessary extension of time is not preferable.

Filtration from the reaction mixture obtained by such a reaction,
The desired 2-cyclopentenone derivative represented by the general formula (I) can be obtained in good yield by general operations such as concentration, extraction, liquid separation, and distillation.

The mixture of hydroxycyclopentenones represented by the general formulas (II) and (III), which are the raw material compounds in the present invention, has the general formula (V) (In the formula, R and n have the same meanings as described above.) A furancarbinol compound represented by the following formula was used in the presence of a catalyst while maintaining the pH of the reaction solution at 3.5 to 6 in a solvent mainly composed of water. It can be easily produced by rearrangement in the absence.

In this reaction, the general formula (V) used as a raw material
The furan carbinol compound shown by is, for example, a method of synthesizing furan as a raw material by Friedel-Crafts reaction and reduction reaction. (JP-A-53-127462) Method for reacting furan with aldehydes in the presence of a basic catalyst (Tetrahedron Lett., No. 13, 1181-4 (1977)) and the like.

In the reaction for obtaining a mixture of hydroxyclopentenones represented by the general formulas (II) and (III) from the furancarbinol compound represented by the general formula (V), the presence of a catalyst in a solvent containing water as a main solvent or Performed in the absence.

The solvent used in this reaction has water as a main solvent, and is either water alone or a mixed solvent containing water as a main component in which a small amount of another organic solvent is mixed. Examples of the other organic solvent include ethylene glycol and 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,
Examples include solvents inert to the reaction such as ethers, esters, and halogenated hydrocarbons. However, generally, the advantage of coexisting these organic solvents in water is not particularly observed.

This reaction does not necessarily require a catalyst, but its use is effective because the addition of the catalyst improves 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,
Examples include alcohol.

Examples of various metal salts include phosphates such as sodium, potassium, magnesium, zinc, iron, calcium, manganese, cobalt, and aluminum, sulfates, chlorides, bromides, oxides, organic fatty acid salts, organic sulfonates, etc. Examples of the organic quaternary ammonium salt include tetrabutylammonium bromide, benzyltrimethylammonium chloride, tricaprylmethylammonium chloride, dodecyltrimethylammonium chloride, caprylbenzyldimethylammonium chloride, and the like. Are higher fatty acid salts, polyoxyethylene alkylphenol ethers, higher aliphatic alcohols, and the like, and as the alcohol, methanol, ethanol, ethylene glycol, etc., which are exemplified as the above-mentioned solvents, are used as catalysts. Also used, it is used alone or as a mixture.

When a catalyst is used, the amount used is usually in the range of 1/200 to 5 times the weight of the furancarbinol compound represented by the general formula (V), but it is also applicable outside this range.

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

The reaction pH is preferably in the range of 3.5-6, more preferably
It is in the range of 3.5 to 5.5.

Examples of the acid used to maintain the pH include hydrochloric acid, sulfuric acid, phosphoric acid, boric acid, acetic acid, propionic acid, toluenesulfonic acid, normal inorganic acids such as methanesulfonic acid, and organic acids. Examples of the alkali include caustic soda, potassium carbonate, sodium hydrogen carbonate, phosphoric acid /
Ordinary inorganic bases and organic bases such as potassium hydrogen and organic amines can be used.

Alternatively, there may be mentioned buffer solutions of the above acid-base combinations, such as phosphoric acid / potassium hydrogen-phosphoric acid, sodium acetate-acetic acid, sodium acetate-phosphoric acid, phthalic acid-potassium carbonate, phosphoric acid / potassium hydrogen-hydrochloride. , Potassium dihydrogen phosphate-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 potassium hydroxide as the acid or alkali used for pH adjustment.

The reaction temperature is 0 to 200 ° C., but it is preferably 20 to 1
60 ° C.

From the reaction mixture thus obtained, extraction, liquid separation,
By operations such as concentration and distillation, general formulas (II) and (II
A mixture of hydroxycyclopentenones represented by I) is obtained in good yield, and this mixture can be directly used for the reaction with the above-mentioned aliphatic carboxylic acid.

<Effects of the Invention> Thus, according to the method of the present invention, the compounds represented by the general formulas (II) and (II
The desired 2-cyclopentenone derivative represented by the general formula (I) can be industrially advantageously produced from the mixture of the hydroxycyclopentenones represented by the general formula (I), and the compound represented by the general formula (V) can be produced. From the furancarbinol compound to obtain a mixture of hydroxycyclopentenones represented by the general formulas (II) and (III), and the 2-cyclopentenone derivative represented by the general formula (I) from the mixture. By combining the resulting reaction steps, a 2-cyclopentenone derivative can be industrially advantageously produced from a furancarbinol compound.

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

Example 1 In a four-necked flask equipped with a stirrer and a thermometer, 2- (1-
Hydroxy-7-methoxycarbonylheptyl) furan
114 g and 4560 g of water, 3.8 g of phosphoric acid / potassium hydrogen and a buffered aqueous solution adjusted to pH 4.2 with phosphoric acid are charged, and stirring is continued at 100 ° C. under a nitrogen stream until the raw materials run out.

After completion of the reaction, the reaction mixture was cooled, extracted twice with 600 ml of methyl isobutyl ketone and separated, and the methyl isobutyl ketone was distilled off from the obtained organic layer to give 3-hydroxy-
2- (6-methoxycarbonylhexyl) -4-cyclopentenone (II-1) and 4-hydroxy-2- (6-
96 g of a mixture of methoxycarbonylhexyl) -2-cyclopentenone (III-1) was obtained. (Yield 84.2%).

To 24 g of the above mixture, 3.6 g of sodium acetate and 96 g of acetic acid are added, and the mixture is heated at 110 to 120 ° C for 4 hours.

The reaction solution is checked by gas chromatography, and it is confirmed that (II-1) is not detected in the reaction solution, and the reaction is terminated.

Next, the reaction solution was cooled to room temperature, 10.2 g of acetic anhydride was added,
Stir at room temperature for 3 hours.

Then, 200 g of zinc dust is added and the mixture is heated at 90 to 100 ° C for 4 hours. After completion of the reaction, insoluble materials are removed by filtration, and the reaction solution is concentrated under reduced pressure. 200 ml of hexane and 100 ml of water are added to the concentrated residue and the layers are separated to obtain an organic layer. 3 organic layers
% After washing with heavy water, further wash with water. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated to give 2- (6-
Methoxycarbonylhexyl) -2-cyclopentenone
21.3 g were obtained [yield based on the sum of (II-1) and (III-1): 95%] 2- (6-methoxycarbonylhexyl)
The by-product amount of cyclopentanone was 0.5%.

bp 125-130 ° C./0.2-0.3 mmHg Example 2 3-hydroxy-2- (6 obtained in the same manner as in Example 1
-Methoxycarbonylhexyl) -4-cyclopentenone (II-2) and 4-hydroxy-2- (6-methoxycarbonylhexyl) -2-cyclopentenone (III-
To 24 g of the mixture of 2), 3.6 g of sodium acetate and 96 g of acetic acid are added, and the mixture is heated at 110 to 120 ° C for 4 hours.

The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was mixed with toluene.
100 ml and 100 ml of water are added, and the layers are separated to obtain an organic layer A. The aqueous layer is further extracted twice with 50 ml of toluene, the extracted organic layer B and the above organic layer A are combined, washed successively with a 5% aqueous sodium carbonate solution and water, and then dried over anhydrous magnesium sulfate. The dried organic layer is concentrated, the residue is dissolved in 150 ml of chloroform and 7.9 g of acetyl chloride are added.

To this, 10.1 g of triethylamine is added dropwise with stirring at 0 to 10 ° C. After completion of dropping, the mixture is stirred at 25 ° C for 3 hours.
After completion of the reaction, the reaction solution was washed with water and dried over anhydrous magnesium sulfate, and then chloroform was distilled off to give 4-acetoxy-2.
27.6 g of-(6-methoxycarbonylhexyl-2-cyclopentenone was obtained (yield 98%).

80g of acetic acid and 200g of zinc dust are added to this, and 90 ~ 100 ℃
Heat for 4 hours. After completion of the reaction, post-treatment was carried out according to Example 1 to give 2- (6-methoxycarbonylhexyl) -2.
21.5 g of cyclopentenone [(II-2) and (III
-Yield to the total of 96): 96%] The amount of 2- (6-merxycarbonylhexyl) cyclopentanone by-product was 0.5%.

b.p.125-130 ℃ / 0.2-0.3mmHg

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07C 59/90

Claims (2)

[Claims] 1. A general formula (In the formula, R represents a hydrogen atom or a C _{1 to} C ₆ alkyl group. N is an integer of 4 to 8.) A mixture of hydroxycyclopentenones represented by the formula: Reacts with carboxylic acids to give the general formula (In the formula, R ₁ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, and R and n have the same meanings as described above.) And 4-hydroxy-2-cyclopentenone To obtain a mixture of the general formulas and reacting the mixture with an acylating agent. (Wherein R, R ₁ and n have the same meanings as described above), and a single cyclopentenone ester represented by the following formula is obtained, which is then reduced in the presence of an acid. (In the formula, R and n have the same meanings as described above.) A method for producing a 2-cyclopentenone derivative represented by: 2. (Wherein, R represents a hydrogen atom or a C ₁ to 6 alkyl radical, n represents. An integer of 4-8) furan carbinol compound represented by the solvent consisting mainly of water, 3.5 to pH By rearranging in the presence or absence of a catalyst while maintaining at ~ 6, (In the formula, R and n have the same meaning as described above.) A mixture of hydroxycyclopentenones represented by the following formula is obtained, which is reacted with an aliphatic carboxylic acid having 1 to 5 carbon atoms to give a compound represented by the general formula (In the formula, R ₁ represents a hydrogen atom or a C ₁ -C ₄ alkyl group, and R and n have the same meanings as described above.) And 4-hydroxy-2-cyclopentenone To obtain a mixture of the general formulas and reacting the mixture with an acylating agent. (Wherein R, R ₁ and n have the same meanings as described above), and a single cyclopentenone ester represented by the following formula is obtained, which is then reduced in the presence of an acid. (In the formula, R and n have the same meanings as described above.) A method for producing a 2-cyclopentenone derivative represented by: