JP2581186B2 - Method for producing 4-substituted-2-cyclopentenone ester derivative - Google Patents

Description

The present invention relates to a method for producing a 4-substituted-2-cyclopentenone ester derivative which is extremely important as a medical or agricultural chemical intermediate, particularly as a prostaglandin intermediate. .

<Prior art> 4-substitution useful as a prostaglandin intermediate
As a method for producing a 2-cyclopentenone ester derivative, for example, a compound represented by the general formula (V) described in U.S. Pat. No. 4,159,998: (Wherein, n is an integer of 5 to 7). A method of acylating a 4-hydroxy-2-cyclopentenone derivative represented by the following formula with an acid halide or an acid anhydride can be considered. It is a process for obtaining a compound of the following general formula (III) as shown in the formula, which is long in steps, requires complicated operations, and the yield of the acylation reaction or the like is not always sufficient. Was never satisfactory.

<Problems to be Solved by the Invention> That is, the present invention overcomes such disadvantages and provides a method for producing a 4-substituted-2-cyclopentenone ester derivative in an industrially advantageous manner.

<Means for Solving the Problems> The present invention provides a compound represented by the general formula (IV): (Wherein, n represents an integer of 4 to 8), wherein the furancarbinol compound is rearranged in a solvent mainly containing water in the presence or absence of a catalyst to obtain a general formula Wherein n has the same meaning as described above. A mixture of hydroxycyclopentenones represented by the formula: is produced, and the mixture is treated with an aliphatic carboxylic acid having 5 or less carbon atoms, an acid anhydride thereof and a metal thereof. General formula (I) characterized by reacting in the presence of a salt (Wherein, n has the same meaning as described above, and R ₁ represents a C ₁ -C ₄ alkyl group.) A method for producing a single 4-substituted-2-cyclopentenone ester derivative represented by the formula: is there.

 Hereinafter, the present invention will be described in detail.

In the first step of the present invention, the furancarbinol compound represented by the general formula (IV) is rearranged in a solvent mainly composed of water in the presence or absence of a catalyst to form the general formulas (II) and (II).
The mixture of I) is produced.

The solvent used in this rearrangement reaction is one containing water as a main solvent, and is water alone or a mixed solvent containing water as a main component in which a small amount of another organic solvent is mixed with water. Here, the other organic solvent is, 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 the like. Examples of organic quaternary ammonium salts include: Tetrabutylammonium bromide, benzyltrimethylammonium chloride,
Tricaprylmethylammonium chloride, dodecyltrimethylammonium chloride, caprylpenyldimethylammonium chloride, and the like.Examples of surfactants include higher fatty acid salts, polyoxyethylene alkylphenol ethers, higher aliphatic alcohols, and the like. Methanol, ethanol, ethylene glycol and the like exemplified as the solvent are also used as the catalyst, and these are used alone or as a mixture.

When a catalyst is used, the amount thereof is usually 1/200 to 5 with respect to the furan carbinol compound represented by the general formula (IV).
Although it is in the range of double weight, it is applicable even outside this range.

After the completion of the reaction, the catalyst used here can be recovered and reused.

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

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 prepared by the above-mentioned acid-base combination may be used. For example, potassium monohydrogen phosphate, sodium acetate-acetic acid, sodium acetate-phosphate, phthalic acid-potassium carbonate, potassium hydrogen phosphate may be used. Examples include hydrochloric acid, potassium dihydrogen phosphate-potassium bicarbonate, succinic acid-sodium bicarbonate, 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.

From the reaction mixture thus obtained, a mixture of hydroxycyclopentenones represented by the general formulas (II) and (III) is obtained in good yield by operations such as extraction, liquid separation, concentration, and distillation. This mixture can be directly used in the reaction of the second step. In the reaction of the first step, the furan carbinol compound represented by the general formula (IV) used as a raw material is prepared by, for example, using furan as a raw material and performing a Friedel-Crafts reaction or a reduction reaction. Can be manufactured.

In the second step of the present invention, the general formula (I
By reacting the mixture of I) and (III) in the presence of an aliphatic carboxylic acid having 5 or less carbon atoms, an acid anhydride thereof and a metal salt thereof, an acylation reaction and a transfer reaction are simultaneously carried out. , A single 4 represented by the general formula (1)
-Substituted-2-cyclopentenone ester derivatives.

The aliphatic carboxylic acids used in the present invention are lower aliphatic carboxylic acids having 5 or less carbon atoms, such as acetic acid, propionic acid, butyric acid, and valeric acid, and the metal salts thereof include lithium salts of these aliphatic carboxylic acids. , Sodium, potassium, calcium, copper, zinc, palladium, lead, tin, manganese, and cobalt salts.

In the present invention, the amount of the aliphatic carboxylic acid used is usually at least 1 equivalent times, and the amount of the metal salt used is usually 0.01 to 5 equivalent times, preferably 0.01 to 0.5 equivalent times, relative to the mixture of the raw material hydroxycyclopentenones. The amount of the acid anhydride of the aliphatic carboxylic acid used is 1 equivalent or more times the amount of the 4-hydroxy-2-cyclopentenone derivative represented by the general formula (III) in the mixture of the raw material hydroxycyclopentenones. It is.

In the present invention, it is very important to use the above-mentioned three components of the aliphatic carboxylic acid, its metal salt and its acid anhydride, and elimination of any of these components can be an effective method. Absent. For example, when an acid anhydride is not used, the reaction products are a 4-substituted-2-cyclopentenone ester derivative represented by the general formula (I) and a 4-hydroxy-2-cyclopentene represented by the general formula (III) It becomes a mixture with a tenone derivative, and the yield is low.

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, dimethylsulfoxide, hexane and the like. Or a mixture of solvents inert to the reaction of aliphatic or aromatic hydrocarbons, ethers, halogenated hydrocarbons, and the like, and the amount of the solvent is not particularly limited. In addition, an aliphatic carboxylic acid can be used as a solvent.

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

The reaction time is not particularly limited, but is usually 0.5 to 10 hours. When the reaction time is prolonged, the resulting 4-substituted-2-cyclopennone ester derivative represented by the general formula (I) is partially decomposed, and therefore, unnecessary time extension is not preferable.

As a reaction method, for example, a mixture of hydroxycyclopentenones represented by the general formulas (II) and (III), an aliphatic carboxylic acid, an acid anhydride thereof and a metal salt thereof are simultaneously charged into a reaction vessel,
Reaction Method A mixture of hydroxycyclopentenones represented by the general formulas (II) and (III) is reacted by adding an aliphatic carboxylic acid and an acid anhydride thereof to the mixture for a certain period of time (usually 0.1 to 0.1).
After 5 hours, the method is not particularly limited), a method of adding a metal salt of an aliphatic carboxylic acid and further reacting the mixture is exemplified.

By such a method, the general formulas (II) and (III)
From a mixture of hydroxycyclopentenones represented by the formula (I),
Cyclopentenone ester derivatives can be obtained easily and in good yield.

<Effect of the Invention> Thus, according to the method of the present invention, the desired 4-substituted-2-cyclopentenone ester derivative represented by the general formula (I) can be produced industrially advantageously.

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

Example 1 α was placed in a four-necked flask equipped with a stirrer and a thermometer.
-(Ω-hydroxyheptyl) furfuryl alcohol 4
2.5 g (0.2 mol) of a buffer aqueous solution adjusted to pH 4.2 with 40 parts by weight (1700 g) of water and 1/30 parts by weight (1.4 g) of potassium monohydrogen phosphate and phosphoric acid And heating and stirring are continued under a nitrogen atmosphere at 100 ° C. until the raw materials are exhausted.

After completion of the reaction, the reaction mixture was cooled, extracted twice with 300 g of methyl isobutyl ketone and separated, and methyl isobutyl ketone was distilled off from the obtained organic layer to give 3-hydroxy-2.
A mixture 3 of-(ω-hydroxyheptyl) -4-cyclopentenone (II-1) and 4-hydroxy-2- (ω-hydroxyheptyl) -2-cyclopentenone (III-1)
1.4 g (74% yield) were obtained.

The production ratio of (II-1) to (III-1) was 3: 1.

17.0 g of acetic acid, 7 g of acetic anhydride and 0.4 g of anhydrous sodium acetate are added to 10.6 g of the above mixture, and heated at 120 ° C. for 4 hours. Check the reaction solution by gas chromatography,
The reaction was terminated after confirming that (II-1) and (III-1) were not detected in the reaction solution. The reaction solution was concentrated under reduced pressure, and 200 ml of toluene and 100 ml of water were added to the concentrated residue.
Separate to obtain an organic layer. The organic layer is washed with 3% aqueous sodium bicarbonate and then further washed with water. The obtained organic layer was dried over anhydrous magnesium sulfate, concentrated and concentrated to 4-acetoxy-2- (7
-Acetoxyheptyl) -2-cyclopentenone 13.8 g
(93.5% yield).

bp. 175-185 ° C./0.2 mmHg Example 2 1700 g of water and 1.4 g of potassium monohydrogen phosphate were charged into a flask similar to that used in Example 1, and pH 4.2 with phosphoric acid.
Adjust to Under a nitrogen atmosphere, 42.5 g (0.2 mol) of α- (ω-hydroxyheptyl) furfuryl alcohol is added dropwise at 100 ° C. over 10 hours. After dropping, 5 more
Keep reacting for hours.

After completion of the reaction, post-treatment and purification were performed according to Example 1 to give 3-
Hydroxy-2- (ω-hydroxyheptyl) -4-cyclopentenone (II-2) and 4-hydroxy-2- (ω
-Hydroxyheptyl) -2-cyclopentenone (III
35.1 g (yield 82.5%) of the mixture of -2) was obtained.

 The ratio of (II-2) to (III-2) was 2.5: 1.

20 g of propionic acid, 10 g of propionic anhydride and 0.5 g of sodium propionate were added to 10.6 g of the above mixture, and 120 ° C.
For 5 hours. The reaction is checked by gas chromatography in the same manner as in Example 1, and the time when the raw materials are no longer detected is defined as the reaction end point. After completion of the reaction, post-treatment and purification were performed according to Example 1, and 4-propionyloxy-2- (7-
Propionyloxyheptyl) -2-cyclopentenone
14.6 g (90% yield) was obtained.

Example 3 The same procedure as in Example 1 was carried out except that 42.5 g (0.23 mol) of α- (ω-hydroxypentyl) furfuryl alcohol was used instead of α- (ω-hydroxyheptyl) furfuryl alcohol. Purify 3-hydroxy-2
A mixture 3 of-(ω-hydroxypentyl) -4-cyclopentenone (II-3) and 4-hydroxy-2- (ω-hydroxypentyl) -2-cyclopentenone (III-3)
4.4 g (81% yield) were obtained.

 The ratio of (II-3) to (III-3) was 3.3: 1.

20 g of acetic acid, 8 g of acetic anhydride and 0.5 g of sodium acetate are added to 9.2 g of the above mixture, and the mixture is heated at 120 to 125 ° C. for 5 hours.
After completion of the reaction, the reaction solution is concentrated under reduced pressure, and toluene is added to the concentrated residue. Thereafter, the reaction, post-treatment and purification were conducted in the same manner as in Example 1 to obtain 12.1 g (yield 91%) of 4-acetoxy-2- (5-acetoxypentyl) -2-cyclopentenone.

Example 4 Mixture of (II-1) and (III-1) obtained in Example 1 10.
20 g of acetic acid and 6 g of acetic anhydride are added to 6 g, and the mixture is heated at 100 to 110 ° C. for 1 hour. Then add 0.5 g of sodium acetate and add 120 g
Heat at 0 ° C for 5 hours. After completion of the reaction, post-treatment and purification are performed according to Example 1. 13.6 g of 4-acetoxy-2- (7-acetoxyheptyl) -2-cyclopentenone (yield 92
%).

Example 5 A mixture of (II-1) and (III-1) obtained in Example 1 5.3
9 g of acetic acid, 4 g of acetic anhydride and 1 g of copper acetate are added to g, and the mixture is heated at 120 ° C. for 8 hours. After completion of the reaction, post-treatment and purification are performed according to Example 1.

4-acetoxy-2- (7-acetoxyheptyl)-
11.9 g (80% yield) of 2-cyclopentenone was obtained.

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Claims (2)

(57) [Claims] (1) General formula (Wherein, n represents an integer of 4 to 8), a mixture of hydroxycyclopentenones represented by the following formula:
A general formula characterized by reacting in the presence of an aliphatic carboxylic acid having 5 or less carbon atoms, an acid anhydride thereof and a metal salt thereof. (Wherein, n has the same meaning as described above, and R ₁ represents a C ₁ -C ₄ alkyl group.) A method for producing a single 4-substituted-2-cyclopentenone ester derivative represented by the formula: 2. The general formula (Wherein, n represents an integer of 4 to 8), wherein the furancarbinol compound is rearranged in a solvent mainly containing water in the presence or absence of a catalyst to obtain a general formula (Wherein n has the same meaning as described above). 4. A single 4-substituted-according to claim 1, comprising preparing a mixture of hydroxycyclopentenones.
A method for producing a 2-cyclopentenone ester derivative.