JPH0811077B2 - Process for producing optically active hydroxycyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a compound represented by the general formula (I): (In the formula, R represents a hydrogen atom or a protective group for a hydroxyl group, n represents an integer of 4 to 8, and * represents an asymmetric carbon.) The present invention relates to a process for producing an optically active hydroxycyclopentenone.

<Prior Art> The optically active hydroxycyclopentenones represented by the above general formula (I) are useful as intermediates for agricultural chemicals, fragrances or pharmaceuticals, and can be used, for example, as important intermediates for prostaglandin derivatives. .

Furthermore, these optically active compounds are converted into sulfonic acid esters with, for example, paratoluenesulfonic acid or methanesulfonic acid, and then reacted with a base, or with sodium acetate, sodium dichloroacetate, sodium trichloroacetate, or the like. The corresponding ester can be hydrolyzed and then converted to a hydroxycyclopentenone having a configuration that is opposite to the original configuration and used.

Conventionally, as a method for producing the optically active hydroxycyclopentenones represented by the general formula (I), for example, the following method is known.

<Problems to be Solved by the Invention> However, in this method, it is not easy to synthesize the triketone body as a raw material, the number of subsequent steps is large, and the yield is low, which is industrially advantageous. It was not a manufacturing method.

Therefore, the present inventors have studied to produce the optically active hydroxycyclopentenones represented by the general formula (I) in a good yield with a short number of production steps and industrially easily. As a result, the present invention has been achieved.

<Means for Solving the Problems> The present invention has the general formula (II) (Wherein R ₁ represents an alkyl group, R ′ represents a protective group for a hydroxyl group, and n represents an integer of 4 to 8), and dl-cyclopentenone ester represented by Of the general formula (I) characterized by asymmetric hydrolysis using the esterase of (Wherein R represents a hydrogen atom or a hydroxyl-protecting group, n has the same meaning as described above, and * represents an asymmetric carbon), and a method for producing an optically active hydroxycyclopentenone compound is provided. To do.

Here, the dl-cyclopentenone ester represented by the general formula (II) as a raw material is represented by the general formula (V) (In the formula, n represents an integer of 4 to 8) Protecting the hydroxyl group of the side chain of the 4-hydroxy-2-cyclopentenone derivative represented by the general formula (III) (In the formula, R'represents a protective group for a hydroxyl group, and n has the same meaning as described above), and the cyclopentenone derivative can be obtained by reacting it with an aliphatic carboxylic acid.

Further, the 4-hydroxy-2-cyclopentenone derivative represented by the general formula (V) used in this reaction is
General formulas (IV) and (V) (In the formula, n represents an integer of 4 to 8) It can be obtained by isomerizing a mixture of hydroxycyclopentenone derivatives or by separating only compound (V) from the mixture.

Furthermore, the mixture of the hydroxycyclopentenone derivatives represented by the above general formulas (IV) and (V), which is the starting material for this reaction, has the general formula (VI) (In the formula, n represents an integer of 4 to 8) A furfuryl alcohol derivative can be obtained by rearrangement in a solvent containing water as a main solvent while maintaining pH in the range of 3.5 to 6. it can.

The furfuryl alcohol derivative represented by the general formula (VI) is a novel compound synthesized for the first time by the present inventors, and can be produced, for example, by the reaction shown below.

In addition, among the dl-cyclopentenone esters represented by the general formula [II], for the compounds in which R ′ represents an alkylcarbonyl group, 4-hydroxy-2-cyclopentenone derivatives represented by the general formula (V) can be used. Can be produced by reacting with an aliphatic carboxylic acid. Furthermore, a mixture of hydroxycyclopentenone derivatives represented by the general formulas (IV) and (V) is reacted in the presence of a lower aliphatic carboxylic acid, an acid anhydride thereof and a metal salt thereof to carry out an acylation reaction. It can also be produced by allowing the isomerization reaction to occur simultaneously.

 Hereinafter, these reactions will be described by following the reaction steps.

The rearrangement reaction for obtaining a mixture of the hydroxycyclopentenone derivatives represented by the general formulas (IV) and (V) from the furfuryl alcohol derivative represented by the general formula (VI) is carried out in a solvent containing water as a main solvent. It is carried out in the presence or absence of a catalyst while maintaining the pH in the range of 3.5-6.

The solvent used in this reaction is a solvent 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, other organic solvents include, for example, ethylene glycol, 1,3
-Propanediol, methanol, ethanol, dioxane, tetrahydrofuran, DMF, DMSO, ethyl acetate,
Acetic acid, dichloromethane, toluene, chlorobenzene, 1,
2-dichloroethane, aliphatic or aromatic hydrocarbons such as dimethyl ether, alcohols, fatty acids, ethers,
Examples include solvents inert to the reaction such as esters and halogenated hydrocarbons. 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 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, alcohols and the like.

Examples of various metal salts include sodium, potassium,
Examples include phosphates, sulfates, chlorides, bromides, oxides, organic fatty acid salts, organic sulfonates of magnesium, zinc, iron, calcium, manganese, cobalt, aluminum and the like, and organic quaternary ammonium salts. Examples 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 used is usually 0.005 to the furfuryl alcohol derivative represented by the general formula (VI).
Although it is in the range of 5 times the weight, it can be applied outside this range.

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 5.5.

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 containing the above-mentioned acid-base combination may be mentioned, and examples thereof include potassium monohydrogen phosphate-phosphoric acid, sodium acetate acetate-acetic acid, sodium acetate phosphoric acid, phthalic acid, potassium carbonate, potassium hydrogen phosphate monohydrogen-hydrochloric acid. , 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 caustic potash as acids or alkalis used for pH adjustment.

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

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

From the reaction mixture thus obtained, a mixture of hydroxycyclopentenone derivatives represented by the general formulas (IV) and (V) can be obtained by operations such as extraction, liquid separation, concentration and chromatography.

With respect to the 4-hydroxy-2-cyclopentenone derivative represented by the general formula (V), only (V) can be separated from the mixture of the hydroxycyclopentenone derivatives by a separating means such as silica gel column chromatography. . Furthermore, it can be obtained by isomerizing the above hydroxycyclopentenone derivative as it is in a solvent in the presence of a catalyst.

Examples of the solvent used in this isomerization reaction include water, tetrahydrofuran, dioxane, acetone,
Solvent alone such as benzene, toluene, ethyl acetate, chlorobenzene, heptane, dichloromethane, dichloroethane, diethyl ether, cyclohexane and other aliphatic or aromatic hydrocarbons, ethers, ketones, esters, halogenated hydrocarbons and other inert solvents. Or a mixture is used.

Examples of the catalyst used in this reaction include organic tertiary amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N'-dimethylpiperazine, pyridine and lutidine, metal oxides such as alumina and silica gel. Inorganic bases such as sodium hydroxide, caustic soda, caustic potash, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium monohydrogen phosphate, and buffers such as carbonates are suitable, and these may be used alone or in combination of two or more.

The amount of such a catalyst to be used is not particularly limited, but it is usually 0.005 to 3 times by mole with respect to the mixture of the hydroxycyclopentenone derivative which is a raw material, and the organic tertiary amine or the buffer may also serve as a solvent. it can.

When used also as a solvent, the amount used may be larger, regardless of the above.

The reaction temperature is in the range of -20 to 130 ° C and is appropriately selected depending on the solvent and catalyst used.

In this isomerization reaction, chloral can be used as a catalyst, and when a solvent is used in this reaction,
As the solvent, the above exemplified solvents are similarly used.

The amount of chloral used is usually 0.005 to 1 times the molar amount of the mixture of the hydroxycyclopentenone derivative as the raw material.

4-hydroxy-2-represented by the general formula (V)
By protecting the side chain hydroxyl group of the cyclopentenone derivative, the cyclopentenone derivative represented by the general formula (III) can be obtained.

As the hydroxyl-protecting group used here, those usually used as a hydroxyl-protecting group are used, and examples thereof include a silyl group such as a trialkylsilyl group and a diphenylalkylsilyl group, a tetrahydropyranyl group, and ethoxy. Examples thereof include ether groups such as ethyl group, methoxyethyl group, methoxymethyl group and methoxyethoxymethyl group, and acyl groups such as acetyl group, propionyl group and butyryl group.

Specific raw material compounds for providing such a protecting group include, for example, trimethylating agents such as trimethylsilyl chloride, t-butyldimethylsilyl chloride, diphenylmethylsilyl chloride, dihydropyran, vinyl ethers such as ethyl vinyl ether, methoxyethyl chloride, methoxymethyl chloride. Examples thereof include alkoxyalkyl halides such as methoxyethoxymethyl chloride, acetic anhydride, acetic acid chloride, propionic anhydride, propionic acid chloride, butyryl chloride, and lower aliphatic carboxylic acids such as chloroacetyl chloride.

The method of introducing the protecting group differs depending on the protecting group to be introduced, and a general method for introducing the protecting group will be described below for each protecting group.

When a silylating agent or an alkoxyalkyl halide is used as a compound that provides a protecting group, it is usually
It is carried out by reacting with a base catalyst in the presence of a solvent.

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

The amount of the silylating agent or the alkoxyalkyl halide used is usually 0.8 to 1.3 equivalent times, preferably 0.85 to 1.1 equivalent times, with respect to the 4-hydroxy-2-cyclopentenone derivative (V) as a raw material, and an excess amount. The use of is not preferred because it reacts with the secondary hydroxyl group of the cyclopentenone skeleton.

Examples of the catalyst include organic or inorganic base catalysts such as triethylamine, ethyldiisopropylamine, tri-n-butylamine, pyridine, dimethylaminopyridine, imidazole, picoline, sodium carbonate, calcium hydroxide, potassium hydrogencarbonate, and the amount thereof used. Is not particularly limited, but usually 4-hydroxy-2-
The amount is 0.8 to 3 equivalent times that of the cyclopentenone derivative (V).

When an organic amine is used as a solvent, the amine also acts as a catalyst.

The reaction temperature is usually from -40C to 100C, preferably from -30C to 90C.

 There is no particular limitation on the reaction time.

When a vinyl ether is used as a compound providing a protective group, the reaction is usually carried out using an acid catalyst in the presence of a solvent.

As the solvent, those similar to the silylating agent described above are used alone or as a mixture, and the amount of the solvent is not particularly limited.

The amount of vinyl ether used is 0.8-based on the starting 4-hydroxy-2-cyclopentenone derivative (V).
It is 1.3 equivalent times, preferably 0.85 to 1.1 equivalent times, and use of an excessive amount is not preferable because it reacts with the secondary hydroxyl group of the cyclopentenone skeleton.

As the catalyst, toluenesulfonic acid, chloroacetic acid, dichloroacetic acid, benzenesulfonic acid, methanesulfonic acid,
Organic or inorganic acids such as sulfuric acid, phosphoric acid and boron trifluoride can be used, and the amount thereof is usually 0.002 to 0.3 equivalent times the vinyl ethers.

The reaction temperature is usually -30 ° C to 120 ° C, preferably -20 ° C to 110 ° C.

 There is no particular limitation on the reaction time.

When an aliphatic carboxylic acid is used as a compound which gives a protecting group, ordinary esterification conditions are applied, and the reaction is carried out by using a catalyst in the presence of a solvent.

When a solvent is used, the same solvent as above is used alone or as a mixture, and the amount of the solvent is not particularly limited.

The amount of the aliphatic carboxylic acids used is 0.8 with respect to the starting 4-hydroxy-2-cyclopentenone derivative (V).
˜1.3 equivalent times, preferably 0.85 to 1.1 equivalent times.

When organic carboxylic acids are used, the reaction of esterifying the secondary hydroxyl group of the cyclopentenone skeleton in the next step can be carried out at the same time. In this case, the amount of the organic carboxylic acids used is 2 equivalents or more. It is necessary and preferably 2 to 8 equivalent times.

Examples of the catalyst include organic or inorganic bases such as triethylamine, ethyldiisopropylamine, tri-n-butylamine, pyridine, dimethylaminopyridine, picoline, sodium carbonate, calcium hydroxide and potassium hydrogencarbonate, and the amount thereof is not particularly limited. However, it is usually 1 to 5 equivalent times with respect to the 4-hydroxy-2-cyclopentenone derivative (V), and is 2 when the secondary hydroxyl group of the cyclopentenone skeleton is also esterified.
~ 10 equivalents.

When an organic amine is used as a solvent, the amine may act as a catalyst.

Further, an organic or inorganic acid such as toluene sulfonic acid, methane sulfonic acid or sulfuric acid can be used as a catalyst.

The reaction temperature is usually −20 ° C. to 150 ° C., preferably -10 ° C. to 120 ° C.

The reaction time is not particularly limited. By such a reaction, the cyclopentenone derivative represented by the general formula (III) can be easily obtained, and these can be isolated from the reaction mixture by a conventional separation means such as extraction, separation, concentration and chromatography. You can

From such a cyclopentenone derivative (III), the general formula (I
General conditions for esterification with an aliphatic carboxylic acid are applied to the dl-cyclopentenone ester represented by I), which is carried out by reacting with a catalyst in the presence or absence of a solvent.

When a solvent is used in this reaction, examples of the solvent include tetrahydrofuran, ethyl ether,
Acetone, methyl ethyl ketone, toluene, benzene,
Solvents such as chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, hexane and other 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.

Examples of the aliphatic carboxylic acids used here include saturated or unsaturated aliphatic carboxylic acid anhydrides and aliphatic carboxylic acid halides, such as acetic anhydride, acetic acid chloride or bromide, propionic acid chloride or bromide, and propionic anhydride. Acid, butyryl chloride or bromide, caproyl chloride or bromide, caprylic acid chloride or bromide, stearic acid chloride or bromide, caprynoyl chloride or bromide, dodecanoyl chloride or bromide, palmitoyl chloride or bromide, chloroacetyl chloride or bromide, di Examples include chloroacetyl chloride or bromide.

The amount of the aliphatic carboxylic acid used in the reaction is 1 equivalent or more with respect to the starting material cyclopentenone derivative (III), and the upper limit is not particularly limited, but preferably 4
It is equivalent.

As the catalyst, for example, triethylamine, tri-n-
Butylamine, pyridine, picoline, sodium carbonate,
Examples thereof include organic or inorganic basic substances such as sodium methylate and potassium hydrogen carbonate. The amount used is not particularly limited, but is usually 1 to 1 relative to the cyclopentenone derivative.
~ 5 equivalents.

When an organic amine is used as a solvent, the amine may act as a catalyst.

Further, acids such as toluene sulfonic acid, methane sulfonic acid and sulfuric acid can also be used as a catalyst.

The reaction temperature is usually −20 ° C. to 150 ° C., preferably -10 ° C. to 120 ° C.

 There is no particular limitation on the reaction time.

By such a reaction, dl- represented by the general formula (II)
Cyclopentenone esters are easily obtained in good yield, and can be easily isolated from the reaction mixture by usual separation means such as extraction, liquid separation, concentration, chromatography and the like.

When a compound in which the substituent R ′ in the general formula (II) is an alkylcarbonyl group is desired, the general formula (V)
The two hydroxyl groups of the 4-hydroxy-2-cyclopentenone derivative represented by are simultaneously esterified, and in this case, the amounts of the above-mentioned aliphatic carboxylic acids and the catalyst may be doubled. A dl-cyclopentenone ester represented by the general formula (II) can be produced from a 4-hydroxy-2-cyclopentenone derivative represented by the general formula (V) by a one-step reaction. Furthermore, the compound in which the substituent R ′ is an alkylcarbonyl group is obtained by reacting a mixture of the general formulas (IV) and (V) in the presence of a lower aliphatic carboxylic acid, its acid anhydride and its metal salt. Alternatively, the acylation reaction and the isomerization reaction can be carried out at the same time to produce the compound without passing through the cyclopentenone derivative (III).

Examples of the lower aliphatic carboxylic acid used in this reaction include acetic acid, propionic acid, butyric acid, valeric acid, chloroacetic acid, dichloroacetic acid, and the like, and the metal salt thereof is a lithium salt or sodium salt of these lower aliphatic carboxylic acids. Examples thereof include potassium salt, calcium salt, copper salt, zinc salt, palladium salt, lead salt, tin salt, manganese salt, and cobalt salt.

In this reaction, the amount of the lower aliphatic carboxylic acid used is usually 2 equivalents or more and the amount of the metal salt used is usually 0.01 to 5 equivalents or more, preferably 0.01 to 0.5 equivalents, based on the mixture of the starting hydroxycyclopentenone derivatives. is there. Also,
The amount of the acid anhydride of the aliphatic carboxylic acid used is 2 equivalents or more with respect to the mixture of the starting hydroxycyclopentenone derivative.

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.

By such a reaction, only the acylation of the 4-hydroxy-2-cyclopentenone derivative (V) and the acylation and isomerization of the 3-hydroxy-4-cyclopentenone derivative (IV) proceed at the same time, and dl -Cyclopentenone esters (II) are obtained in a one-step reaction.

When a solvent is used in this reaction, the solvent is, for example, tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, dimethyl sulfoxide, hexane or the like. Solvents such as aromatic or aromatic hydrocarbons, ethers, halogenated hydrocarbons and the like which are inert to the reaction can be used alone or as a mixture, and the amount used 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 becomes long, the dl-cyclopentenone ester represented by the general formula (II) thus formed is partially decomposed, so that unnecessary time extension is not preferable.

As a reaction method, for example, a mixture of hydroxycyclopentenone derivatives represented by the general formulas (IV) and (V), an aliphatic carboxylic acid, an acid anhydride thereof and a metal salt thereof are simultaneously charged into a reaction vessel,
Method of reacting Aliphatic carboxylic acid and its acid anhydride are added to a mixture of hydroxycyclopentenone derivatives represented by the general formulas (IV) and (V), and the mixture is reacted for a certain time (usually 0.1 to
After 5 hours, although not particularly limited), a method such as a method of adding a metal salt of an aliphatic carboxylic acid and further reacting is exemplified.

By such a method, a desired dl-cyclopentenone ester represented by the general formula (II) can be easily obtained from a mixture of hydroxycyclopentenone derivatives represented by the general formulas (IV) and (V), and Obtained in good yield.

The optically active hydroxycyclopentenone represented by the general formula (I) is prepared by using a microbial esterase or an animal or plant esterase having the ability to hydrolyze the dl-cyclopentenone ester represented by the general formula (II). It is carried out by hydrolyzing one of the optically active esters.

The microorganism that produces an esterase used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze dl-cyclopentenone esters, and is not particularly limited (in the present invention). Esterase means esterase in a broad sense including lipase.) Specific examples of such a microorganism include, for example, microorganisms belonging to the following genera.

Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, Alcaligenes,
Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida, Saccharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Microorganisms belonging to the genera Aspergillus, Rhizopus, Mucor, Aureopasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, and Achromobacter.

Examples of microorganisms belonging to each of these genera include the following.

Rhodotorula minuta, rubra, minuta, bartexensis, Trichoderma genus Gibrachiatum, Candida crusei, Cyrindrasse, Tropalis, Utilus, Pseudomonas fragilis, Putida, Fluorescens, Arginosa, Bacillus cereus, subtilis, purmyrus, subtilis baru Niger, Nocardia spp. , E. saccharomyces Roxy, Arthrobacter simplex, Streptomyces Lisens, Brevibacterium ammoniagenes, Zibarichatum, Micrococcus variance, Iutells, Enterobacter cloacae, Lactobacillus casei, Cryptococcus albizus, Pichia polymorpha, Penicillium flesentan, Aureobasidium pullulans, Actinomcor elegans , Hansenula anomala, Balsiferuri out, Hansenula anomala, Achromobacter parvulus, simplex.

For the culture of the above-mentioned microorganisms, a liquid culture is usually obtained by performing liquid culture according to a conventional method. For example, a sterilized liquid medium [malt extract / yeast extract medium for molds and yeasts (peptone 5 g, glucose 10 g, water malt extract 3
g, yeast extract 3 g, pH 6.5), for bacteria, sweetened bouillon medium (10 g glucose, peptone 5 in water 1)
g, meat extract 5 g, and NaCl 3 g are dissolved to adjust the pH to 7.2)], and a reciprocal shaking culture is usually performed at 20 to 40 ° C. for 1 to 3 days. If necessary, solid culture may be performed.

Some of these esterases originating from microorganisms are commercially available and can be easily obtained. Specific examples of commercially available esterases include the followings. Pseudomonas lipase [Lipase P (manufactured by Amano Pharmaceuticals)], Aspergillus lipase [Lipase AP (manufactured by Amano Pharmaceuticals]], Mucor lipase [Lipase M-AP (manufactured by Amano Pharmaceuticals), Candida syrindrasse] Lipase [Lipase MY (manufactured by Meito Sangyo)], lipase of Alcaligenes genus [Lipase PL (manufactured by Meito Sangyo)], lipase of Achromobacter genus [Lipase AL (manufactured by Meito Sangyo]], genus of Arthrobacter Lipase (Nippon Kagaku), Chromobacterium lipase (Toyo Brewing Co.), Rhizopus Derema lipase [Talipase (Tanabe Seiyaku Co.)], Rhizopus lipase [Lipase Saiken (Osaka Bacteria Research Institute) )].

Also, animal / plant esterase can be used,
Specific examples of these esterases include the following.

Steapsin, buncreatin, pig liver esterase, Wheat Germ esterase.

Esterases (hydrolases) used in this reaction, enzymes obtained from animals, plants, and microorganisms may be used in the form of purified enzymes, crude enzymes, enzyme-containing substances, microbial culture solutions, cultures, cells, culture ports It can be used as needed in various forms such as a liquid and a product obtained by treating them, and a combination of an enzyme and a microorganism can also be used. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterium immobilized on a resin or the like.

This hydrolysis reaction is carried out by vigorously stirring the dl-cyclopentenone esters (II) and the enzyme or microorganism in a buffer solution.

As the buffer solution, sodium phosphate which is usually used,
A buffer solution of an inorganic acid salt such as potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate and sodium citrate, etc. is used, and the pH thereof is 8 to 11 in a culture solution of an alkaliphilic bacterium or alkaline esterase, A pH of 5 to 8 is preferable for a culture solution of a non-alkaline microorganism or an esterase having no alkali resistance.

The concentration is usually 0.05 to 2M, preferably 0.05 to 0.5M.

The reaction temperature is usually 10 to 60 ° C., and the reaction time is generally 8 to 70 hours, but is not limited thereto.

In addition, at the time of hydrolysis, in addition to a buffer solution, an organic solvent which is inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, and dichloromethane can be used, and by using these, an asymmetric hydrolysis is advantageously performed. be able to.

After completion of such a hydrolysis reaction, in order to separate the hydrolysis product and the hydrolysis residue from the reaction solution, the hydrolysis reaction solution is subjected to extraction treatment with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, The solvent is distilled off from the organic layer, and then the concentrated residue is treated by column chromatography. The optically active hydroxycyclopentenones represented by the general formula (I) and the optically active acyloxycyclopentene remaining as a hydrolysis residue are obtained. The tenones can be separated from each other.

The optically active acyloxycyclopentenone recovered here can be further hydrolyzed and used as a raw material for the production of antipodes.

<Effect of the Invention> Thus, according to the method of the present invention, the optically active 4-hydroxy-2-cyclopentenones represented by the general formula (I) can be easily obtained in good yield. Is extremely useful as an intermediate for a prostaglandin derivative which is a drug.

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

Example 1 1000 ml of water and 0.2 g of potassium dihydrogen phosphate in a flask
And adjust the pH to 4.2 with 5% phosphoric acid.

To this, 21.2 g of α- (ω-hydroxyheptyl) -furfuryl alcohol was added, and the mixture was heated with stirring at 100 ° C for 12 hours.

After completion of the reaction, extraction is performed twice with 200 ml of toluene.
The organic layer is concentrated under reduced pressure to obtain 20.5 g of a concentrated residue.

The concentrated residue is dissolved in 100 ml of dichloromethane, 2.87 g of chloral and 0.98 g of triethylamine are added, and the mixture is stirred at 25 ° C. for 5 hours.

After completion of the reaction, the reaction mixture is washed with 1% dilute hydrochloric acid, water and 1% aqueous sodium hydrogen carbonate in this order, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.

20.8 g of the concentrated residue are dissolved in 100 ml of dichloromethane and 30 ml of pyridine are added. While maintaining the internal temperature at 0 to 10 ° C, 23.5 g of acetyl chloride is added over 2 hours. After keeping at the same temperature for 1 hour, the reaction is carried out at 25-30 ° C for 3 hours.

After the completion of the reaction, the mixture was washed sequentially with water, 1% diluted hydrochloric acid, 1% aqueous sodium bicarbonate and water, and the organic layer was dried over anhydrous magnesium sulfate.
Concentration under reduced pressure gives 28.6 g of concentrated residue.

This was purified by silica gel column chromatography using a mixed solution of toluene: ethyl acetate (5: 1), 4-
16.6 g of acetoxy-2- (7-acetoxyheptyl) -2-cyclopentenone was obtained.

▲ n ²⁰ _D ▼ = 1.4767 Next, 4.0 g of 4-acetoxy-2- (7-acetoxyheptyl) -2-cyclopentenone was added to 2 m of dichloromethane.
l, Pseudomonas lipase (amanolipase "P") 330 mg and 0.3 M concentration phosphate buffer (pH 7.
5) Mix with 100 ml and stir vigorously at 30 ° C for 15 hours.

After completion of the reaction, the reaction solution is extracted twice with 40 ml of methyl isobutyl ketone. The organic layers are combined and concentrated under reduced pressure.

The concentrated residue was purified by column chromatography using toluene: ethyl acetate (5: 3) to obtain 0.94 g of d-4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone.

▲ [α] ²⁰ _D ▼ + 16.2 ° (c = 1, methanol) mp 58-5
9 ° C. Example 2 Reaction and treatment were carried out in the same manner as in Example 1 except that 280 mg of Arthrobacter lipase (manufactured by Shin Nippon Chemical Co., Ltd.) was used in place of Pseudomonas lipase, and d-4-hydroxy-
2- (7-Hydroxyheptyl) -2-cyclopentenone
0.87 g was obtained.

▲ [α] ²⁰ _D ▼ + 15.3 ° (c = 1, methanol) mp 59
-60 ° C Example 3 A four-necked flask equipped with a stirrer and a thermometer was added with α-
(Ω-Hydroxyheptyl) furfuryl alcohol 106.
Charge 1 g (0.5 mol), 4 liters of water, 4.0 g of acetic acid and a buffer aqueous solution adjusted to pH 4.2 with a 1N sodium hydroxide aqueous solution, and heat and stir under a nitrogen stream at 100 ° C. until the raw materials run out. After cooling, the reaction mixture was analyzed by high performance liquid chromatography to find that it was 3-hydroxy-2- (7-hydroxyheptyl) -4-cyclopentenone and 4-hydroxy-
2- (7-Hydroxyheptyl) -2-cyclopentenone was present in a composition ratio of about 3: 1.

The reaction mixture was adjusted to pH 7.6 with 1N aqueous sodium hydroxide solution.
After that, the mixture is heated and stirred at 100 ° C. again in a nitrogen atmosphere until the 3-hydroxy-2- (7-hydroxyheptyl) -4-cyclopentenone produced in the previous reaction disappears.

After completion of the reaction, the reaction mixture was cooled, extracted twice with 600 g of methyl isobutyl ketone and subjected to liquid separation treatment, and methyl isobutyl ketone was distilled off from the obtained organic layer to give 4-hydroxy-
76.8 g (yield 72.4%) of 2- (7-hydroxyheptyl) -2-cyclopentenone was obtained.

21.2 g (0.1 mol) of 4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone obtained above was dissolved in 100 ml of dimethylformamide, and 6.86 g of imidazole (0.
1 mol) is added. While maintaining the internal temperature at 10 to 20 ° C, t-
Butyldimethylsilyl chloride 15.1 g (0.1 mol) DMF10
Add the ml solution over 30 minutes. After keeping the temperature at the same temperature for 12 hours, the reaction mixture is poured into 500 ml of ice water and extracted with toluene. After washing the toluene layer well with water, the organic layer is dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give a concentrated residue.
35.3 g was obtained.

This was purified by silica gel column chromatography using a mixed solution of toluene: ethyl acetate (5: 1), 4-
17.9 g (yield 55%) of hydroxy-2- (7-t-butyldimethylsiloxyheptyl) -2-cyclopentenone was obtained.

Further, the silyl compound is dissolved in 200 ml of toluene, and 20 ml of pyridine is added. While maintaining the internal temperature at 0 to 10 ° C, 7.0 g of acetyl chloride is added over 10 minutes. After incubating at the same temperature for 1 hour, react at 25-30 ° C for 3 hours.

After the completion of the reaction, the mixture was washed sequentially with water, 1% diluted hydrochloric acid, 1% aqueous sodium bicarbonate and water, and the organic layer was dried over anhydrous magnesium sulfate.
Concentration under reduced pressure gave 20.5 g of concentrated residue. This was subjected to silica gel flash column chromatographic purification using toluene to obtain 19.4 g of 4-acetoxy-2- (7-t-butyldimethylsiloxyheptyl) -2-cyclopentenone (yield 95.7%).

4-acetoxy-2- (7-t-butyldimethylsiloxyheptyl) -2-cyclopentenone 3.68 g (0.01 mol), 0.3 M phosphate buffer (pH 7.0) 50 ml, chloroform 2 ml and Arthrobacter lipase (Shin-Nippon Chemical Co., Ltd.) 180 mg was charged into a flask, and 1
Stir vigorously for 2 hours. After the reaction is complete, add 4 parts of toluene to the reaction solution.
Extract twice with 0 ml. The organic layers were combined and concentrated under reduced pressure to obtain 3.47 g of a concentrated residue. This was purified by column chromatography using a toluene-ethyl acetate mixed system, and (R)-
(+)-4-Hydroxy-2- (7-t-butyldimethylsiloxyheptyl) -2-cyclopentenone 1.56 g ▲ [α] ²⁰ _D ▼ 10.9 ° (c = 1, methanol) and (S) -(-)-4-acetoxy-2- (7-t-butyldimethylsiloxyheptyl) -2-cyclopentenone 1.90 g ▲ [α] ²⁰ _D ▼ = -42.5 ° (c = 1, methanol) was obtained. .

The (R)-(+) form was dissolved in 10 ml of tetrahydrofuran, 1 g of tetrabutylammonium fluoride was added, desilylation was performed at 15 to 20 ° C., and silica gel flash chromatography purification was performed to obtain (R)- (+)-
4-hydroxy-2- (7-hydroxyheptyl) -2-
Cyclopentenone could be obtained.

▲ [α] ²⁰ _D ▼ ＝ + 16.8 ° (c = 1, methanol) Melting point 59-61 ° C. Example 4 4-acetoxy-2- (7-t-butyldimethylsiloxyheptyl) -2-cyclopentenone 3.68 g, 0.3M concentration phosphate buffer 50ml, Arthrobacter lipase 180m
Charge g into a flask and stir vigorously at 35-40 ° C for 12 hours. After completion of the reaction, by the same operation as in Example 3,
(R)-(+)-4-Hydroxy-2- (7-t-butyldimethylsiloxyheptyl) -2-cyclopentenone 1.53
g ▲ [α] ²⁰ _D ▼ ＝ + 10.4 ° (c = 1, methanol) and (S)-(−)-4-acetoxy-2- (7-t-butyldimethylsiloxyheptyl) -2-cyclopen Tenon (1.93 g) [α] ²⁰ _D ▼ = -40.1 ° (c = 1, methanol) was obtained.

Example 5 2000 ml of water and 3 g of acetic acid are charged in the same apparatus as in Example 1, and the pH is adjusted to 4.5 with a 1N sodium hydroxide aqueous solution. To this, 50 g of α- (ω-hydroxyheptyl) -furfuryl alcohol was added, and the mixture was heated and stirred for 15 hours.

After completion of the reaction, extraction was performed with 800 ml of methyl isobutyl ketone, and the organic layer was concentrated under reduced pressure to give 3-hydroxy-2- (7-hydroxyheptyl) -4-cyclopentenone and 4-hydroxy-2- ( 48.8 g of a residue of a mixture of 7-hydroxyheptyl) -2-cyclopentenone are obtained.

40 g of this concentrated residue was mixed with 40 g of acetic anhydride and 10 g of sodium acetate.
g and 40 g of acetic acid are added and reacted at 120 ° C. for 5 hours. After completion of the reaction, the reaction mixture is poured into 300 ml of water and extracted with 100 ml of toluene. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 50.2 g of a residue.

According to Example 1, this was mixed with toluene-ethyl acetate (5:
1) Purification by silica gel column chromatography using the mixed solution to obtain 37.7 g of 4-acetoxy-2- (7-acetoxyheptyl) -2-cyclopentenone.

▲ n ²⁰ _D ▼ = 1.4775 Next, 3.0 g of 4-acetoxy-2- (7-acetoxyheptyl) -2-cyclopentenone, 100 mg of alkaligenes lipase [PL-266 (manufactured by Meito Sangyo Co., Ltd.)] and 0.1
Mix with 100 ml of M concentration phosphate buffer (pH 6.0), 40 ℃
Stir vigorously for 15 hours.

After completion of the reaction, the reaction solution is extracted twice with 40 ml of methyl isobutyl ketone. The organic layers are combined and concentrated under reduced pressure.

The concentrated residue is purified by column chromatography according to Example 1. d-4-hydroxy-2- (7-hydroxyheptyl)
0.62 g of 2-cyclopentenone is obtained.

▲ [α] ²⁰ _D ▼ + 14.3 ° (c = 1, methanol) Examples 6 to 11 Reaction, post-treatment and purification in the same manner as in Example 5 except that the esterase shown in Table 1 was used in place of the Alcaligenes esterase. Then, the results shown in Table 1 were obtained.

Example 12 21.2 g (0.1 mol) of 4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone obtained in Example 3 is dissolved in 300 ml of tetrahydrofuran, and 2 g of dichloroacetic acid is added. At room temperature, 9.3 g of dihydropyran are added over 5 hours. After keeping the mixture at the same temperature for 5 hours, the mixture is poured into 500 ml of ice water and extracted with ethyl acetate. The organic layer was washed well with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 27.2 g of a concentrated residue.

This was purified by silica gel column chromatography using a mixed solution of toluene: ethyl acetate (5: 2), 4-
Hydroxy-2- [7- (2'-tetrahydropyranyloxy) heptyl] -2-cyclopentenone 12.6 g (yield 4
2.5%).

Next, 11.8 g of the above tetrahydropyranyl ether compound was dissolved in 50 ml of toluene and 10 ml of pyridine, and the internal temperature was 0 to 10 ° C.
Add 3.5 g of acetyl chloride over 30 minutes while maintaining. After incubating at the same temperature for 1 hour, react at 25-30 ° C for 3 hours.

After the completion of the reaction, the mixture was washed sequentially with water, 1% diluted hydrochloric acid, 1% aqueous sodium bicarbonate and water, and the organic layer was dried over anhydrous magnesium sulfate.
Concentrate under reduced pressure to give 13.8 g of concentrated residue. This was purified by silica gel flash column chromatography using toluene to give 4-acetoxy-2- [7- (2'-tetrahydropyranyloxy) heptyl] -2-cyclopentenone.
12.7 g (94.3% yield) are obtained.

Next, 4-acetoxy-2- [7- (2'-tetrahydropyranyloxy) heptyl] -2-cyclopentenone
3.38 g (0.01 mol) 0.3 M phosphate buffer (pH 7.0) 50 ml
Charge 1 ml of toluene and 180 mg of Arthrobacter lipase (manufactured by Shin Nippon Kagaku Co., Ltd.) into a flask and stir at 35-40 ° C for 1
Stir vigorously for 0 hours. After completion of the reaction, the reaction solution is extracted twice with 40 ml of ethyl acetate. The organic layers are combined and concentrated under reduced pressure to obtain 2.87 g of a concentrated residue. This was purified by column chromatography using a toluene-ethyl acetate mixed system, and (R)-
(+)-4-Hydroxy-2- [7- (2'-tetrahydropyranyloxy) -heptyl] -2-cyclopentenone 1.15 g ▲ [α] ²⁰ _D ▼ = + 12.2 ° (c = 1, Methanol).

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Tomomasa Kondo 3-98 Kasugadenaka, Konohana-ku, Osaka City, Osaka Prefecture Sumitomo Chemical Co., Ltd. 2-1 Sumitomo Chemical Co., Ltd. (72) Inventor Ken Mitsuda 4-2-1 Takashi Takarazuka-shi, Hyogo Sumitomo Chemical Co., Ltd.

Claims (7)

[Claims] 1. A general formula (In the formula, R ₁ is an alkyl group, R ′ is a protective group for a hydroxyl group,
n represents an integer of 4 to 8) A general formula characterized by subjecting dl-cyclopentenone esters represented by (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group,
n has the same meaning as described above, and * represents an asymmetric carbon.) A process for producing an optically active hydroxycyclopentenone. 2. General formula (Wherein R'represents a hydroxyl-protecting group, and n represents an integer of 4 to 8) and the cyclopentenone derivative represented by the general formula is reacted with an aliphatic carboxylic acid. (In the formula, R ₁ is an alkyl group, R ′ is a protective group for a hydroxyl group,
n represents an integer of 4 to 8), and dl-cyclopentenone esters represented by the following formula are obtained, and then esterase is allowed to act to perform asymmetric hydrolysis. (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group,
n has the same meaning as described above, and * represents an asymmetric carbon.) A process for producing an optically active hydroxycyclopentenone. 3. General formula (In the formula, n represents an integer of 4 to 8) The hydroxyl group of the side chain at the 2-position of the hydroxycyclopentenone derivative is represented by the general formula (Wherein R'represents a hydroxyl-protecting group, and n has the same meaning as described above), and the cyclopentenone derivative is obtained and then reacted with an aliphatic carboxylic acid to give a compound of the general formula (Wherein R ₁ represents an alkyl group and R ′ and n have the same meanings as described above), and dl-cyclopentenone esters are obtained, and esterase acts to effect asymmetric hydrolyzation. General formula (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group,
n has the same meaning as described above, and * represents an asymmetric carbon.) A process for producing an optically active hydroxycyclopentenone. 4. A general formula (Wherein n represents an integer of 4 to 8) by isomerizing a mixture of hydroxycyclopentenone derivatives represented by the general formula (Wherein n has the same meaning as described above), and a hydroxycyclopentenone derivative represented by (Wherein R'represents a hydroxyl-protecting group, and n has the same meaning as described above), and the cyclopentenone derivative is obtained and then reacted with an aliphatic carboxylic acid to give a compound of the general formula (Wherein R ₁ is an alkyl group, R ′ and n have the same meanings as described above), and dl-cyclopentenone esters are obtained, and esterase is allowed to act to effect asymmetric hydrolysis. General formula (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group,
n has the same meaning as described above, and * represents an asymmetric carbon.) A process for producing an optically active hydroxycyclopentenone. 5. A general formula (In the formula, n represents an integer of 4 to 8) The furfuryl alcohol derivative represented by the general formula is rearranged in a solvent containing water as a main solvent while maintaining pH in the range of 3.5 to 6. (Wherein n has the same meaning as defined above) to obtain a hydroxycyclopentenone derivative, and then isomerize the mixture to give a compound of the general formula (Wherein n has the same meaning as described above), a mixture of hydroxycyclopentenone derivatives represented by the formula: (Wherein R'represents a hydroxyl-protecting group, and n has the same meaning as described above), and the cyclopentenone derivative is obtained and then reacted with an aliphatic carboxylic acid to give a compound of the general formula (Wherein R ₁ is an alkyl group, R ′ and n have the same meanings as described above), and dl-cyclopentenone esters are obtained, and esterase is allowed to act to effect asymmetric hydrolysis. General formula (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group,
n has the same meaning as described above, and * represents an asymmetric carbon.) A process for producing an optically active hydroxycyclopentenone. 6. A general formula (In the formula, n represents an integer of 4 to 8) An aliphatic carboxylic acid is reacted with the hydroxycyclopentenone derivative to form a hydroxyl group at the 2-position side chain and 4
The general formula by acylating the hydroxyl groups at the same time (In the formula, R ₁ is an alkyl group, R ′ is a protective group for a hydroxyl group,
n has the same meaning as described above), and dl-cyclopentenone ester represented by (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group,
n has the same meaning as described above, and * represents an asymmetric carbon.) A process for producing an optically active hydroxycyclopentenone. 7. General formula (In the formula, n represents an integer of 4 to 8) A mixture of hydroxycyclopentenone derivatives represented by the general formula (In the formula, R ₁ is an alkyl group, R ′ is a protective group for a hydroxyl group,
n has the same meaning as described above), and dl-cyclopentenone ester represented by (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group,
n has the same meaning as described above, and * represents an asymmetric carbon.) A process for producing an optically active hydroxycyclopentenone.