JP2645342B2 - Preparation of optically active substituted 4-hydroxy-2-cyclopentenone - 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, R represents a hydrogen atom or a protecting group for a hydroxyl group,
n shows the integer of 4-8. The present invention relates to a process for producing an optically active substituted 4-hydroxy-2-cyclopentenone represented by the formula:

<Prior Art> The optically active substituted 4-hydroxy-2-cyclopentenone represented by the above general formula (I) is useful as an intermediate for pesticides, flavors or pharmaceuticals, and is an important intermediate for prostaglandin derivatives, for example. Can be used as a body.

Further, these optically active substances are converted into sulfonic acid esters by, for example, paratoluenesulfonic acid or methanesulfonic acid, and then reacted with a base or, alternatively, reacted with sodium acetate or the like to form an ester which reacts and then hydrolyzed. By decomposition, it is also possible to lead to and utilize a substituted-4-hydroxy-2-cyclopentenone having a configuration opposite to the original configuration.

Conventionally, as a method for producing the optically active substituted-4-hydroxy-2-cyclopentenone represented by the general formula (I), for example, the following method is known.

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

From these facts, the present inventors have short production steps, are industrially easy, and can produce the optically active substituted 4-hydroxy-2-cyclopentenone represented by the general formula (I) in good yield. As a result of investigations for the production of, the present invention was reached.

<Means for Solving the Problems> The present invention relates to the compounds represented by the general formulas (VI) and (VI ′) (Wherein, R and n have the same meanings as described above), wherein the mixture of the optically active substituted hydroxy-2-cyclopentenone isomerized while maintaining steric properties. (I) the indicated optically active substitution-4
-Hydroxy-2-cyclopentenone.

Here, a mixture of the optically active substituted hydroxycyclopentenone represented by the general formulas (VI) and (VI ') is obtained by mixing the compounds represented by the general formulas (V) and (V') (Wherein, R ₁ represents an acyloxyl group, R ′ represents a hydroxyl-protecting group, and n has the same meaning as described above). Esterase produced by a microorganism as a mixture of dl-cyclopentenone esters Alternatively, it can be obtained by asymmetric hydrolysis using an esterase derived from animals and plants.

A mixture of the dl-cyclopentenone esters represented by the general formulas (V) and (V '), which is a reaction raw material, is obtained by mixing the general formulas (III) and (III') (Wherein n represents an integer of 4 to 8) The side chain hydroxyl group of each compound of a mixture comprising an 8-hydroxy-4-cyclopentenone derivative and a 4-hydroxy-2-cyclopentenone derivative With the general formulas (IV) and (IV ') (Wherein R ′ represents a protecting group for a hydroxyl group, and n has the same meaning as described above), and a mixture of cyclopentenone derivatives represented by the following formula: can be obtained by reacting the mixture with an aliphatic carboxylic acid. .

The compounds of the general formulas (III) and (I)
The mixture of the 3-hydroxy-4-cyclopentenone derivative represented by II ′) and the 4-hydroxy-2-cyclopentenone derivative is represented by the general formula (III): (Wherein, n has the same meaning as described above) can be obtained by rearranging a furfuryl alcohol derivative represented by the following formula in a solvent containing water as the main solvent while maintaining the pH in the range of 3.5 to 6. .

If such a reaction is represented by using a furfuryl alcohol derivative as a starting material, the following formula is obtained.

(In the above formula, A is _{- (- CH 2) nCH 2} - a and, n,
R, R 'and R ₁ are as defined above) The present invention is described below in detail.

In the above method, the general formula (I
The furfuryl alcohol derivative represented by I) can be easily produced from furan, for example, by the following method.

(In the above formula, R ² is a lower alkyl group, and n has the same meaning as described above.) From the furfuryl alcohol derivative represented by the general formula (II), 3 represented by the general formulas (III) and (III ′) In the rearrangement reaction to a mixture of a -hydroxy-4-cyclopentenone derivative and a 4-hydroxy-2-cyclopentenone derivative, the pH of the reaction solution is adjusted to 3.
The treatment is carried out in the presence or absence of a catalyst while maintaining at 5 to 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, as other organic solvents, for example, ethylene glycol, 1,3-propanediol, methanol, ethanol, dioxane, tetrahydrofuran, DMF, DMSO, ethyl acetate, acetic acid, dichloromethane,
Toluene, aliphatic or aromatic hydrocarbons such as dimethyl ether, alcohols, fatty acids, ethers, esters,
Solvents that are inert to the reaction, such as 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 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, etc., and organic quaternary ammonium salts Examples include tetrabutylammonium bromide, benzyltrimethylammonium chloride, tricaprytylammonium chloride, dodecyltrimethylammonium chloride, caprylbenzyldimethylammonium chloride, and the like.As the surfactant, higher fatty acid salts, polyoxyethylene alkylphenol ether And higher aliphatic alcohols. As the alcohol, methanol, ethanol, ethylene glycol and the like exemplified above as the solvent are also used as the catalyst, and these may be used alone or as a mixture. That.

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 can be applied outside this range.

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

The reaction pH is preferably in the range of 3.5 to 6, more preferably 8.5 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 /
Examples include ordinary inorganic bases and organic bases such as potassium hydrogen and organic amines.

Alternatively, a buffer solution of the above-mentioned acid-base combination may be mentioned, for example, phosphoric acid / hydrogen-cured phosphoric acid, sodium acetate acetate, sodium acetate phosphate, phthalic acid-potassium carbonate, phosphoric acid / hydrogen potash-hydrochloric acid, phosphoric acid 2 Examples thereof include potassium hydrogen-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 method in which the reaction raw materials are collectively charged into a reaction vessel and then heated, and a furfuryl alcohol derivative is dripped very slowly into 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.

From the reaction mixture thus obtained, 3-hydroxy-4 represented by the general formulas (III) and (III ') is obtained by operations such as extraction, liquid separation, concentration, and chromatography.
A mixture consisting of -cyclopentenone derivative and 4-hydroxy-2-cyclopentenone derivative is obtained.

3- represented by such general formulas (III) and (III ')
By protecting the side chain hydroxyl group of each compound of the mixture consisting of the hydroxy-4-cyclopentenone derivative and the 4-hydroxy-2-cyclopentenone derivative,
A mixture of the cyclopentenone derivatives represented by the general formulas (IV) and (IV ') is obtained.

As the hydroxyl-protecting group used herein, those usually used as a hydroxyl-protecting group are used, and examples thereof include, for example, trialkylsilyl groups, silyl groups such as diphenylalkylsilyl groups, dihydropyranyl groups,
Examples include an ether group such as an ethoxyethyl group, a methoxyethyl group, a methoxyethyl group and a methoxyethoxymethyl group, and an acyl group such as an acetyl group, a propionyl group and a butyryl group.

Specific starting compounds providing such protecting groups include, for example, silylating agents such as trimethylsilyl chloride, t-butyldimethylsilyl chloride, diphenylmethylsilyl chloride, vinyl ethers such as dihydropyran and ethyl vinyl ether, methoxyethyl chloride, methoxymethyl chloride. And alkoxyalkyl halides such as methylethoxymethyl chloride, and aliphatic carboxylic acids such as acetic anhydride, acetic chloride, propionic anhydride, propionic chloride, butyryl chloride and chloroacetyl chloride.

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

When a silylating agent or an alkoxyalkyl halide is used as a compound that provides a protective group,
The reaction is carried out by using a base catalyst in the presence 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, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, dimethylsulfoxide, and hexane. Solvents which are inert to the reaction of aliphatic or aromatic hydrocarbons, ethers, halogenated hydrocarbons and the like can be used alone or as a mixture, and the amount thereof can be used without any particular limitation.

The amount of the silylating agent or alkoxyalkyl halide used is usually 0.8 to 1.3 equivalent times with respect to the mixture of the starting materials, the 3-hydroxy-4-cyclopentenone derivative and the 4-hydroxy-2-cyclopentenone derivative, It is preferably 0.85 to 1.1 equivalent times, and the use of an excess amount 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, picoline, sodium carbonate, calcium hydroxide, and potassium hydrogencarbonate. Although not limited, it is usually 0.8 to 3 equivalents relative to a mixture of a 3-hydroxy-4-cyclopentenone derivative and a 4-hydroxy-2-cyclopentenone derivative.

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 amounts of the vinyl ethers used are the starting materials 3-hydroxy-4-cyclopentenone derivative and 4-hydroxy-2.
-0 to the mixture consisting of the cyclopentenone derivative.
It is 8 to 1.3 equivalent times, preferably 0.85 to 1.1 equivalent times, and the use of an excess amount is not preferable because it reacts with the secondary hydroxyl group of the cyclopentenone skeleton.

Examples of the catalyst include organic or inorganic acids such as toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, and boron trifluoride.
It is usually 0.002 to 0.3 equivalent times that of vinyl ethers.

The reaction temperature is usually from -20 ° C to 120 ° C, preferably from -10 ° C to 110 ° C.

 There is no particular limitation on the reaction time.

When an organic carboxylic acid is used as a compound providing a protective 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 amounts of the organic carboxylic acids used are the starting materials, 3-hydroxy-4-cyclopentenone derivative and 4-hydroxy-2.
-0 to the mixture consisting of the cyclopentenone derivative.
It is 8 to 1.3 equivalent times, preferably 0.85 to 1.1 equivalent times.

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

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. However, it is usually 1 to 5 equivalent times the mixture of the 3-hydroxy-4-cyclopentenone derivative and the 4-hydroxy-2-cyclopentenone derivative, and the secondary hydroxyl group of the cyclopentenone skeleton is also In the case of esterification, it is 2 to 10 equivalent times.

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

Further, an organic or inorganic acid such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can 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, general formulas (IV) and (IV ′)
A mixture of the cyclopentenone derivatives represented by is easily obtained, and these are separated by usual separation means such as extraction, separation,
It can be isolated from the reaction mixture by concentration, chromatography and the like.

From a mixture of cyclopentenone derivatives represented by the general formulas (IV) and (IV ') to a mixture of dl-cyclopentenone esters represented by the general formulas (V) and (V'), a general aliphatic carboxylic acid is used. The conditions for esterification with acids are applied, and the reaction is carried out using 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,
Inert in the reaction of aliphatic or aromatic hydrocarbons such as acetone, tyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, hexane, ethers, halogenated hydrocarbons, etc. Solvents alone or in mixtures can be mentioned. The amount can be used without any particular limitation.

Examples of the aliphatic carboxylic acids used herein include saturated or unsaturated aliphatic carboxylic anhydrides and aliphatic carboxylic acid halides, such as acetic anhydride, acetic chloride or bromide, propionic chloride or bromide, and propion anhydride. Acid, butyl chloride or bromide, caproyl chloride or bromide, caprylic chloride or bromide, stearic chloride or bromide caprynoyl chloride or bromide, dodecanoin chloride or bromide, palmitoyl chloride or bromide, chloroacetyl chloride or bromide, dichloroacetyl Examples thereof include chloride and bromide.

The amount of the aliphatic carboxylic acid used in the reaction is required to be at least 1 equivalent to the mixture of the cyclopentenone derivative as the raw material, and the upper limit is not particularly limited.
Is equivalent.

As the catalyst, for example, triethylamine, tri-n-
Butylamine, pyridine, picoline, sodium carbonate,
Organic or inorganic basic substances such as sodium methylate and potassium bicarbonate can be mentioned. The amount used is not particularly limited, but is usually 1 to 5 equivalents relative to the mixture of the cyclopentenone derivatives.

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

Further, acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can be used as the 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, general formulas (V) and (V ′)
A mixture of dl-cyclopentenone esters represented by is easily obtained in good yield, and these are easily isolated from the reaction mixture by usual separation means, for example, extraction, liquid separation, concentration, chromatography and the like. be able to.

Incidentally, when a compound in which the substituent R ₁ in the general formulas (V) and (V ′) is an acyloxyl group and R ′ is an acyl group is desired, the compound represented by the general formulas (III) and (III ′) The two hydroxyl groups in the respective compounds of the mixture of the 3-hydroxy-4-cyclopentenone derivative and the 4-hydroxy-2-cyclopentenone derivative may be simultaneously esterified. What is necessary is just to double the amount of carboxylic acids and catalyst used,
Thereby, 3 represented by the general formulas (III) and (III ')
A mixture of dl-cyclopentenone esters represented by the general formulas (V) and (V ') is prepared from a mixture of -hydroxy-4-cyclopentenone derivative and 4-hydroxy-2-cyclopentenone derivative in one step. It can be produced by a reaction.

The mixture of the optically active substituted hydroxy-2-cyclopentenone represented by the general formulas (VI) and (VI ') is a mixture of the dl-cyclopentenone esters represented by the general formulas (V) and (V') Is carried out by hydrolyzing the optically active form of the esters using a microbial esterase or an animal or plant esterase having the ability to hydrolyze.

The microorganism that produces an esterase used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze a mixture of dl-cyclopentenone esters, and is not particularly limited (this example). Esterase in the invention 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, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula, Achromobacter, As microorganisms belonging to each of these genera, for example, There are things.

Rhodotorula minuta, Rhodotorula rubra, Rhodotolura
miunta var sexensis, Trichoderma Iongibrachiatum, C
andida krusei, Candidacylindracea, Canida tropicali
s, Candidautilus, Pseudomonas fragi, Pseudomnasputid
a, Pseudomonas fluoresons, Pseudomonas aeruginosa ae
ruginosa, Bacillus cereus, Bacillus subtilit, Bacillu
s pulmilus, Bacillus subtilis var niger, Nocardia un
iformis subtsuyanarenus, Nocardia uniformis, Chromob
acterium chocolatum Chromobacterium iodinum, Flavob
acterinm arbo-nesons, Flavobacterium heparinum, Riz
opuschinensis, Mucor javanicus, Aspergillus niger, Al
caligenes faecalis, Torulopsis candida, Corynebacter
ium sepedonicum, Saccaromyces rouxii, Arthrobacter s
implex, Streptomyces grisens, Brevibacterium ammonia
genes, Brevibacterium divaricatum, Micrococcus varia
ns, Micrococcus Iuteus, Enterobacter cloacae, Conyneb
acterum ezui, Lacto bacillus casei, Cryptococcusalbi
dus, Pihia polimorpha, penicillium frezuentans, Aureo
basidium pullulans, Actinomucor elegana, Hansenula a
nomalavar ciferrii out, Hansenula anomala, Achromoba
Cter parvulus, Achromobactersinplxx., For culturing the above-mentioned microorganisms, a solvent is usually obtained by performing a liquid solvent 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, malt extract 3 g in water 1;
Dissolve 8 g of yeast extract to pH 6.5. For bacteria, use a sweetened broth medium (10 g of glucose, 5 g of peptone, 5 g of peptone,
5 g of meat extract and 3 g of Nacl are dissolved and adjusted to pH 7.2)], and the microorganism is inoculated. If necessary, solid culture may be performed.

Some of these microbial esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include, for example, the following. Pseudomonas lipase (Amano Pharmaceutical Co., Ltd.) Aspergillus lipase [Lipase AP
(Manufactured by Amano Pharmaceutical Co., Ltd.)), lipase M-Ap of Mucor genus (manufactured by Amano Pharmaceutical Co., Ltd.), lipase of Candida cylindrasse [lipase MY (manufactured by Meito Sangyo Co., Ltd.)], lipase of genus Alcaligenes [lipase PL (meansu Industrial Company)), Achromobacter lipase [Lipase AL (Meito Sangyo)],
A lipase of the genus Arthrobacter (Shin Nippon Chemical), a lipase of the genus Chromobacterium (manufactured by Toyo Brewery Co., Ltd.), a lipase of Rhizopus delemar [Talipase (manufactured by Tanabe Seiyaku Co., Ltd.)] Animal and plant esterases can also be used.
Specific examples of these esterases include the following.

Steapsin, bank creatine, pig liver esterase, Wheat Germ esterase.

Esterase (hydrolase) used in this reaction, enzymes obtained from animals, plants, and microorganisms may be used in the form of a purified enzyme, a crude enzyme, an enzyme-containing substance, a microorganism culture solution, a culture place, a cell, a culture port. It can be used as needed in various forms such as liquids and processed products thereof, and enzymes and microorganisms can be used in combination. Alternatively, it can be used as an immobilized enzyme immobilized on a resin or the like, or an immobilized cell.

This hydrolysis reaction is carried out by vigorously stirring the dl-cyclopentenone ester and the above enzyme or microorganism in a normal buffer.

As the buffer, 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 or sodium citrate or the like is used, and its pH is pH 8 to 11 in a culture solution of an alkaliphilic bacterium or an alkaline esterase. The pH is preferably 5 to 8 for a culture solution of a non-alkaliphilic microorganism or an esterase having no alkali resistance.

The concentration is usually in the range of 0.05-2M, preferably 0.05-0.5M.

The reaction temperature is usually 10 to 60 ° C, and the reaction time is generally 4 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 the completion of the hydrolysis reaction, in order to separate the hydrolysis product and the hydrolysis residue from the reaction solution, a hydrolysis reaction solution such as methyl isobutyl ketone, ethyl acetate,
Extraction treatment with a solvent such as ethyl ether is performed, and the solvent is distilled off from the organic layer, and then the concentrated residue is subjected to column chromatography.
The mixture of the optically active substituted hydroxy-2-cyclopentenone represented by I ′) and the optically active substituted acylaxyl-2-cyclopentenone remaining after hydrolysis can be separated.

The recovered optically active substituted acyloxy-2-
Cyclopentenone can be further hydrolyzed and used as a raw material for producing a symmetric body.

In the case of using a lipase belonging to the genus Pseudomonas or the genus Arthrobacter in this asymmetric hydrolysis reaction, a mixture of optically active substituted hydroxy-2-cyclopentenone with relatively high optical purity can be obtained. .

In addition, in this asymmetric hydrolysis reaction, 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. It can be performed advantageously.

The substituted 4-hydroxy-2-cyclopentenone represented by the general formula (1) can be obtained by converting the optically active substituted hydroxy-2-cyclopentenone represented by the general formulas (VI) and (VI ') into the presence of a base or a catalyst. It is produced by isomerizing while keeping the stereo below.

The optically active substituted hydroxy-2-cyclopentenone represented by the general formula (VI), which is a raw material for this reaction step, has not been known at all, and is a novel compound synthesized for the first time by the present inventors. The possibility of the optically active substance and its separation, etc., is not known, and the optically active substance is obtained by isomerization while maintaining the steric or the possibility of isomerizing while maintaining the steric. No configuration is known about the substituted-4-hydroxy-2-cyclonthenone.

In order to isomerize such a mixture of optically active substituted hydroxy-2-cyclopentenone while maintaining its steric shape, it is necessary to keep the optical purity as high as possible, that is, to minimize the racemization as much as possible. For this purpose, it is preferable to carry out the reaction under appropriate conditions for the base or catalyst used, the temperature, and the like.

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

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

The amount of the base or catalyst used is not particularly limited, but is usually an optically active substituted hydroxy-2- raw material.
It is 0.005 to 60 times the molar amount of the mixture of cyclopentenone, and an organic tertiary amine or a basic buffer can be used also as a solvent.

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

For example, when the reaction is carried out in the absence of water as a solvent, since the racemization hardly occurs, the reaction can be carried out in the range of -10 to 90C. In the case of an organic tertiary amine-water mixed system, the temperature is preferably in the range of -10 to 50 ° C.
Is preferable.

In this isomerization reaction, chloral can be used as a catalyst, and when a solvent is used in this reaction,
As the solvent, a salt exemplified solvent except water is used in the same manner.

The amount of chloral used is usually based on the mixture of the optically active substituted hydroxy-2-cyclopentenone as the raw material.
The molar ratio is 0.005 to 1 times, but in order to make the isomerization reaction more efficient with a high steric retention, the range is 0.005 to 0.5 times.

A base can be used as a cocatalyst, and its type and amount are the same as those described above.

Reaction temperatures range from -10 to 100 ° C, preferably from 0 to 90 ° C.

 The reaction time is not particularly limited.

From the reaction mixture thus obtained, the desired optically active substituted 4-hydroxy-2-cyclopente represented by the general formula (I) is obtained by general operations such as extraction, liquid separation, concentration, and distillation. Tenone can be obtained with high optical purity and high yield.

<Effect of the Invention> Thus, according to the method of the present invention, the optically active substituted 4-hydroxy-2-cyclopentenone represented by the general formula (I) can be easily obtained in a high yield. These are extremely useful as intermediates of prostaglandin derivatives that are pharmaceuticals.

<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 is concentrated under reduced pressure to obtain 20.3 g of a concentrated residue.

This concentrated residue is dissolved in 100 ml of dichloromethane, and 30 ml of pyridine is added. While maintaining the internal temperature at 0 to 10 ° C, 28.5 g of acetyl chloride is added over 2 hours. After holding at the same temperature for 1 hour, the reaction is carried out for 3 hours at 25-30 ° C.

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 28.3 g of a concentrated residue.

This was purified by silica gel column chromatography using a toluene: ethyl acetate (5: 1) mixed solution to give 3-
18.2 g of a mixture of acetoxy-2- (7-acetoxyheptyl) -4-cyclopentynone and 4-acetoxy-2- (7-acetoxyheptyl) -2-cyclopentenone was obtained.

The production ratio of the above compound in this mixture was 7: 3.

▲ n ²⁰ _D ▼ = 1.4882 The above mixture was added to 100 ml of 0.3 M phosphate buffer (pH 7.5).
0 g, 3 ml of dichloromethane, and 300 mg of Pseudomonas lipase (Amano lipase “P]) are added, and the mixture is vigorously stirred at 25 to 30 ° C. for 15 hours.

After completion of the reaction, the reaction solution is extracted twice with 40 ml of toluene.
The organic layers were combined and concentrated under reduced pressure to obtain a concentrated residue (3.45 g).

The concentrated residue was purified by column chromatography using toluene: ethyl acetate (5: 3) to give l-3-hydroxy-2- (7-ethyl acetate).
Hydroxyheptyl) -4-cyclopentenone and d-4
-Hydroxy-2- (7-hydroxyheptyl) -2-
11.3 g of a mixture of cyclopentenone was obtained.

▲ [α] ²⁰ _D ▼ -9.8 ゜ (c = 1, CHCl ₃ ) 0.5 g of the above obtained mixture is stirred with 10 g of alumina in 30 ml of toluene at 30-40 ° C. for 24 hours.

 After completion of the reaction, the alumina is separated and the liquid is concentrated.

The concentrated residue was further purified by silica gel column chromatography with toluene-ethyl acetate (5: 8) to obtain 0.45 g of d-4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone.

▲ [α] ²⁰ _D ▼ + 16.9 ゜ (c = 1, chloroform) mp 60 ° C. Separately, in the above reaction, 1-3-3-hydroxy-2-
(7-hydroxyheptyl) -4-cyclopentenone and d-4-hydroxy-2- (7-hydroxyheptyl)
0.48 g of a mixture of -2-cyclopentenone was added to chloral 0.0
5 g, triethylamine 0.04 g and dichloromethane 10 ml
And stirred at 30-40 ° C for 5 hours.

After completion of the reaction, the reaction solution is washed successively with water, 1% aqueous hydrochloric acid, 1% aqueous sodium bicarbonate, and water. After concentrating the organic layer, the residue was purified by column chromatography, and d-4-hydroxy-2- (7-
0.43 g of (hydroxyheptyl) -2-cyclopentenone was obtained.

▲ [α] ²⁰ _D ▼ + 16.7 ゜ (c = 1, methanol) mp 58-59 ° C. Example 2 In Example 1, except that the lipase was replaced with Arthrobacter lipase (manufactured by Shin Nippon Chemical Co., Ltd.) Was reacted and worked up in the same manner as in Example 1 to give l-3-hydroxy-2- (7-
Hydroxyheptyl) -4-cyclopentenone and d
-4-Hydroxy-2- (7-hydroxyheptyl)-
1.04 g of a mixture of 2-cyclopentenone ｛▲ [α] ²⁰ _D ▼-
9.1 {(c = 1, methanol)} was obtained.

0.5 g of this mixture, 0.2 g of pyridine, 10 g of alumina and 20 ml of tetrahydrofuran are stirred for 2 hours at 30-35 ° C.

After the completion of the reaction, the alumina was separated, and the concentrated residue obtained by concentrating the solution was purified by silica gel column chromatography in the same manner as in Example 1 to obtain 0.43 g of d-4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone. I got

▲ [α] ²⁰ _D ▼ + 15.3 ゜ (c = 1, methanol) mp 59-60 ° C

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location C12P 41/00 C12P 41/00 GC // B01J 31/02 102 B01J 31/02 102Z C07M 7: 00

Claims (4)

(57) [Claims] (1) General formula (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group, and n represents an integer of 4 to 8.) A mixture of an optically active substituted hydroxy-2-cyclopentanone represented by the following formula: Or, in an aromatic hydrocarbon, ether, ketone, ester, halogenated hydrocarbon solvent, an organic tertiary amine, a metal oxide, an inorganic base,
Using a basic buffer or chloral, the reaction temperature is -20 to
General formula characterized by isomerization while maintaining stericity in the range of 130 ° C (Wherein, R and n have the same meanings as described above.) A process for producing an optically active substituted 4-hydroxy-2-cyclopentenone represented by the formula: 2. The general formula (Wherein, R ¹ represents an acyloxyl group, R ′ represents a hydroxyl-protecting group, and n represents an integer of 4 to 8.) A mixture of dl-cyclopentenone esters,
Asymmetric hydrolysis using Pseudomonas lipase or Arthrobacter lipase (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group, and n represents an integer of 4 to 8.), and a mixture of optically active substituted hydroxy-2-cyclopentanones is obtained. In water, aliphatic or aromatic hydrocarbons, ethers, ketones, esters, halogenated hydrocarbon solvents, organic tertiary amines, metal oxides,
Using an inorganic base, a basic buffer or chloral, at a reaction temperature of −20 to 130 ° C., a general formula characterized by isomerization while maintaining stericity (Wherein, R and n have the same meanings as described above.) A process for producing an optically active substituted 4-hydroxy-2-cyclopentenone represented by the formula: 3. The general formula (In the formula, n represents an integer of 4 to 8.) Side chain of each compound of a mixture of a 3-hydroxy-4-cyclopentenone derivative and a 4-hydroxy-2-cyclopentenone derivative represented by General formula with protecting hydroxyl group (Wherein R ′ is a hydroxyl-protecting group, and n has the same meaning as described above.) A mixture of cyclopentenone derivatives is obtained, which is reacted with an aliphatic carboxylic acid to obtain a compound of the general formula (Wherein R ¹ represents an acyloxyl group, and R ′ and n have the same meanings as described above.) A mixture of dl-cyclopentenone esters represented by the following formula: is obtained from Pseudomonas lipase or Arthrobacter Asymmetric hydrolysis using lipase (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group, and n has the same meaning as described above). A mixture of an optically active substituted hydroxy-2-cyclopentenone represented by the formula: Organic tertiary amines, metal oxides, in aliphatic or aromatic hydrocarbons, ethers, ketones, esters, halogenated hydrocarbon solvents,
Using an inorganic base, a basic buffer or chloral, at a reaction temperature of −20 to 130 ° C., a general formula characterized by isomerization while maintaining stericity (Wherein, R and n have the same meanings as described above.) A process for producing an optically active substituted 4-hydroxy-2-cyclopentenone represented by the formula: 4. General formula (In the formula, n represents an integer of 4 to 8.) A furfuryl alcohol derivative represented by the following formula is transferred in a solvent containing water as the main solvent while maintaining the pH in the range of 3.5 to 6, and (In the formula, n has the same meaning as described above.) A mixture comprising a 3-hydroxy-4-cyclopentenone derivative and a 4-hydroxy-2-cyclopentenone derivative represented by the following formula is obtained. Protecting the side chain hydroxyl group of the compound by the general formula (Wherein R ′ represents a hydroxyl-protecting group, and n has the same meaning as described above), and a mixture of cyclopentenone derivatives represented by the following formula is reacted with an aliphatic carboxylic acid to obtain a compound represented by the general formula: (Wherein R ¹ has an acyloxyl group, and R ′ and n have the same meanings as described above.) A mixture of dl-cyclopentenone esters represented by the following formula: Asymmetric hydrolysis using genus lipase (Wherein, R represents a hydrogen atom or a protecting group for a hydroxyl group, and n has the same meaning as described above.). Organic tertiary amines, metal oxides, in aliphatic or aromatic hydrocarbons, ethers, ketones, esters, halogenated hydrocarbon solvents,
Using an inorganic base, a basic buffer or chloral, at a reaction temperature of −20 to 130 ° C., a general formula characterized by isomerization while maintaining stericity (In the formula, R and n have the same meanings as described above.) A process for producing an optically active substituted 4-hydroxy-2-cyclopentenone represented by the formula: