DE3740165A1 - Process for the preparation of hydroxycyclopentenones - Google Patents

Abstract

There is described a process for the preparation of optically active hydroxycyclopentenones of the formula (I) <IMAGE> in which R denotes a hydrogen atom or a hydroxyl protective group, n is an integer with a value of 4 to 8, and the asterisk (*) denotes an asymmetric carbon atom, which are useful intermediates in the synthesis of prostaglandins. In this process, a D,L-cyclopentenone ester of the formula II <IMAGE> in which the group R1CO- is an acyl radical derived from an aliphatic carboxylic acid, R' denotes a hydroxyl protective group and n has the meaning indicated above, is treated with an enzyme which has the ability selectively to hydrolyse one of the D- and L-isomers of the D,L-cyclopentenone ester II asymmetrically in an aqueous medium.

Description

The invention relates to the production of hydroxycyclopentenones. In particular, it relates to a new manufacturing process optically active hydroxycyclopentenones of the formula I.

in which R is a hydrogen atom or a hydroxyl protective group, n is an integer with a value from 4 to 8, and the asterisk (*) denotes an asymmetric carbon atom.

These are optically active hydroxycyclopentenones of the formula I. valuable intermediates e.g. B. in the synthesis of agricultural applicable chemicals, perfumes or drugs (e.g. prostaglandins). In addition, the optically active hydroxycyclopentenones of formula I in the corresponding Stereoisomers with an opposite configuration transfer, for example by reaction with p-toluenesulfonic acid or methanesulfonic acid and subsequent reaction of the sulfonates obtained with a base, or by reaction with sodium acetate, sodium dichloroacetate or sodium trichloroacetate and subsequent hydrolysis of the obtained Esters.

From the prior art are used to manufacture the optical active hydroxycyclopentenones of formula I, for example known methods:  

However, this conventional method has practical disadvantages. For example, triketones that do not have to be used are readily available as starting material. Furthermore is for converting such triketones into the optically active Hydroxycyclopentenone of formula I a lengthy series of Steps are required and the overall yield is proportional low.

To an inexpensive industrially advantageous process for Preparation of the optically active hydroxycyclopentenones of the formula I to provide with good yields and high purity, extensive research was carried out. It was now found that the optically active hydroxycyclopentenone of formula I by asymmetric hydrolysis of the corresponding D, L-cyclopentenone esters of the formula II

in which the group R₁CO- is an acyl radical derived from an aliphatic carboxylic acid, for example an alkanoyl, alkenyl, halogenated alkanoyl or a halogenated alkenoyl radical, R 'is a hydroxyl protective group and n has the meaning given above, with one Esterase produced from microorganisms or obtained from animals or plants. The terms "alkanoyl radical" and "alkenoyl radical" used here mean radicals with usually not more than 20 carbon atoms. Those with not more than 8 carbon atoms are particularly preferred.

The asymmetric hydrolysis can be achieved by using the D, L-cyclopentenone ester as the starting compound of the formula II treated with an enzyme to make one of the optically active isomers, d. H. the D or L form of the D, L-cyclopentenone ester of formula II to hydrolyze. Any enzyme can be used Use esterase that is selectively one of the optically active ones Isomers, i. H. the D or L form of the D, L-cyclopentenone ester of formula II can hydrolyze. Such esterases are or are usually produced by microorganisms available from animals or plants. Thereby, according to the invention with the term "esterase" also referred to as "lipases".

The microorganism capable of producing the esterases can be of the genus Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida, Saccharomyces, Rhodocillula, Toro Penocillus, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula, Cryptocula Aspergillus, Rhizopus, Mucor, Aureovacidium, Actynomucor, Nocardia, Streptomyces, Hansenula or Achromobacter belong. The following microorganisms can be used particularly well:
Rhodotorula minuta, Rhodotorula rubra, Rhodotolura minuta var texensis, Trichoderma longibrachiatum, Candida kursei, Candida cylindracea, Candida tripicalis, Candida utilus, Pseudomonas fragi, Pseudomonas putida, Pseudomonas fluorescens, Pseudomonas aeruginosa, Bacillus subistilis, Bacillus suberetilis, Bacillus suberetilis niger, Nocardia uniformis subtsuyanarenus, Nocardia uniformis, Chromobacterium chocolatum, Chromobacterium iodinum, Flavobacterium arbonescens, Flavobacterium heparinum, Rizopus chinensis, Mucor javanicus, Aspergillusomyces, sexicaracterium, sexicaracterium, acaricum sebacterium, Toricopsnobacterium sicarium, Toricopsnobacterium septum, Saul , Brevibacterium divaricatum. Micrococcus varians, Micrococcus iuteus, Enterobacter cloacae, Corynebacterium ezui, Lacto bacillus casei, Cryptococcus albidus, Pihia pol imorpha, Penicillium grezuentans, Aureobasidium pullulans, Actinomucor elegans, Hansenula anomala varromifferi.

The esterase can be grown by cultivating the microorganisms in produce a culture medium in a manner known per se, for example the microorganism is sterilized, inoculated liquid nutrient medium, which then 1 to 3 days a temperature of 20 to 40 ° C is shaken. If the Microorganism is a fungus or a yeast, the nutrient medium can for example 5 g peptone, 10 g glucose, 3 g malt extract and contain 3 g of yeast extract per 1000 ml of water (pH 6.5); so-called malt extract-yeast extract medium. If the microorganism is a bacterium, for example, the nutrient medium 10 g glucose, 5 g peptone, 5 g meat extract and 3 g NaCl pro Contain 1000 ml of water (pH 7.2); enriched with sucrose Bouillon medium. If necessary, the breeding of Microorganisms also take place with a solid medium.

Some of the esterases which can be used according to the invention are composed of Microorganisms are commercially available, for example the lipase manufactured by Pseudomonas ("Lipase P"; Amano Pharmaceutical Co., Ltd.), the one manufactured by Aspergillus Lipase ("Lipase AP"; Amano Pharmaceutical Co., Ltd.),  the lipase manufactured by Mucor ("Lipase M-AP"; Amano Pharmaceutical Co., Ltd.), the one manufactured by Candida cylindracea Lipase ("Lipase MY"; Meito Sangyo Co., Ltd.) by Alcaligenes manufactured lipase ("Lipase PL"; Meito Sangyo Co., Ltd.), the lipase manufactured by Achromobacter ("Lipase AL"; Meito Sangyo Co., Ltd.), the lipase manufactured by Arthrobacter (Shin-Nippon Chemical Co., Ltd.), the one manufactured by Chromobacterium Lipase (Toyojozo Co., Ltd.) by Rhizopus delemar prepared lipase ("Talipase"; Tanabe Seiyaku Co., Ltd.), or the lipase manufactured by Rhizopus ("Lipase Saiken"; Osaka Saikin Kenkyuso).

Examples of esterases obtainable from animals or plants, which can be used according to the invention are steapsin, pancreatin, Pork liver esterase or wheat germ esterase.

In the process according to the invention, the esterase can be in any use the usual form, for example in a purified form, in crude form, as a mixture with any other enzyme, as a fermentation medium, as a microbiological body or as a filtrate of a fermentation medium. In addition, the separated esterase and that for the production of the esterase Use a qualified microorganism alone or in combination. In addition, the esterase or the for the production of Esterase enabled microorganism in each immobilized Form used, for example, fixed to resinous particles will.

Asymmetric hydrolysis is usually treated of the D, L-cyclopentone ester of the formula II with the esterase itself or the microorganism capable of producing the esterase performed in a buffer with vigorous stirring. As Buffers can be used with an inorganic salt or inorganic salts such as sodium phosphate or potassium phosphate and / or an organic salt or salts, such as Contain sodium acetate or sodium citrate. If an alkalophile  Microorganism or an alkaline esterase used the buffer is preferably adjusted to a pH of 8 set to 11. If the microorganism is not alkalophilic is or the esterase is not alkali resistant, the The pH of the buffer is between about 5 and 8. The concentration the buffer can usually be about 0.05 to 2 M, preferably about 0.05 to 0.5 M. The reaction temperature is usually around 10 to 60 ° C and the reaction time is generally about 3 to 70 hours.

As a result of the asymmetric hydrolysis, one of the D- and L-isomers of the D, L-cyclopentenone ester of the formula II selectively hydrolyzed, the optically active hydroxycyclopentenone Formula I is formed while the other isomer as such remains, d. H. esterified in the 4-position. The reaction mixture thus contains the optically active hydroxycyclopentenone of the formula I as hydrolyzate and the optically active Cyclopentenone ester as a non-hydrolyzed compound. Depending on the type of the 2-position at the end of the side chain Protective group located cyclopentone ring can this at asymmetric hydrolysis (especially if the Protecting group around the same acyl group as that represented by R₁ acts) are split off at the same time. In this Case contains the reaction mixture in its end position unprotected reaction product.

To obtain these optically active compounds, the Reaction mixture for example with a suitable solvent be extracted, such as methyl isobutyl ketone, ethyl acetate or diethyl ether. After removing the solvent from the The residue is extracted from a further cleavage or purification, such as subjected to column chromatography to make this optically active hydroxycyclopentenone of formula I and the optically active acyloxycyclopentenone as its enantiomer separately collect. If necessary, the optically active acyloxycyclopentenone then as an enantiomer in the corresponding optical  active hydroxycyclopentenone can be converted by hydrolysis.

Often the use of any one is over the enzymatic Hydrolysis of inert organic solvents, such as toluene, Chloroform, methyl isobutyl ketone or dichloromethane, in addition advantageous to the buffer because the asymmetric hydrolysis then is achieved very effectively.

The D, L-cyclopentenone ester of the formula II can be used as the starting compound of the method according to the invention, for example manufacture as follows:

• (a) A furfuryl alcohol of Formula VI in which n has the meaning given above, is subjected to a rearrangement in an aqueous medium at a pH of about 3.5 to 6 in order to obtain a mixture which contains the 2-hydroxyalkyl-hydroxycyclopentenones of the formula IV and Formula V in which n has the meaning given above;
• (b) the mixture is separated or isomerized to give the 2-hydroxyalkyl to obtain hydroxycyclopentenones of the formula V; and  
• c) the 2-hydroxyalkylhydroxycyclopentonone of formula V thus obtained or its derivatives provided with a protective group, ie the hydroxyalkylhydroxycyclopentenones of formula III provided with a protective group in the 2-position in which R 'and n have the meaning given above, are reacted with an aliphatic carboxylic acid or with one of its reactive derivatives.

In another embodiment, the mixture of the 2-hydroxyalkyl hydroxycyclopentenones of formula IV and V. Acylation and simultaneous isomerization, for example with a combination of an aliphatic carboxylic acid, their acid anhydride and their metal salt in good yield to the D, L-cyclopentenone ester of the formula II are implemented, in which R 'is one of the aliphatic carboxylic acid derived acyl radical.

The reactions are explained in detail below.

The furfuryl alcohol of formula VI is new and can be produced by reducing a compound of the formula

in which n has the meaning given above, with a reducing agent such as LiAlH₄.

In step (a) the rearrangement of the furfuryl alcohol is the Formula VI to a mixture of the 2-hydroxyalkyl-hydroxycyclopentenones of formulas IV and V in an aqueous medium carried out a pH of about 3.5 to 6, optionally  in the presence of a catalyst. The aqueous medium can be as Reaction medium water or its mixture with any contain inert organic solvents in a small amount. In other words, the reaction medium contains at least water as the main component. Examples of organic Solvents are hydrocarbons such as benzene or toluene, halogenated hydrocarbons, such as chloroform, Carbon tetrachloride or dichloromethane, alcohols, such as ethylene glycol, Propanediol, methanol or ethanol, ether, such as dimethyl ether, Dioxane or tetrahydrofuran, acids such as acetic acid or propionic acid, esters, such as methyl acetate or ethyl acetate, Dimethylformamide or dimethyl sulfoxide. Usually However, it is sufficient if only water is used.

The catalyst is not essential, however will he preferably used to speed up the implementation. Metal salts, such as phosphates, are suitable as catalysts. Sulfates, chlorides, bromides, oxygenated salts, carboxylates or sulfonates of sodium, potassium, magnesium, zinc, iron, Calcium, manganese, cobalt or aluminum; quaternary ammonium salts, such as tetrabutylammonium bromide, benzyltrimethylammonium chloride, Tricaprylmethylammonium chloride, dodecyltrimethylammonium chloride or caprylbenzyldimethylammonium chloride; or surfactants such as higher fatty acid salts, polyoxyethylene alkylphenol ether or alcohols of higher fats. Alcohols which can be used for the reaction medium, such as ethylene glycol, Propanediol, methanol or ethanol can also act as a catalyst be used. These can either be used alone or in Combination can be used. The amount of the catalyst is usually in the range of about 0.005 to 5 parts by weight per part by weight of the furfuryl alcohol of the formula VI as starting compound, however, this is not a critical parameter. The catalyst once used in the reaction can be out the reaction mixture can be isolated and reused.

The reaction medium advantageously has a pH of  about 3.5 to 6, preferably from about 3.5 to 5.5. To this The reaction medium can be maintained with any pH value suitable acid or base can be added. examples for the acids are organic or inorganic acids, such as hydrochloric acid, Sulfuric acid, phosphoric acid, boric acid, acetic acid, Propionic acid, toluenesulfonic acid or methanesulfonic acid. Examples the base are inorganic or organic bases, such as Sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen phosphate or organic amines. In another Embodiment can use a buffer to adjust the pH can be used, which contains an acid and a base. Examples such buffers are potassium hydrogen phosphate phosphoric acid, Sodium acetate-acetic acid, sodium acetate-phosphoric acid, Phthalic acid potassium carbonate, potassium hydrogenphosphate hydrochloric acid, Potassium dihydrogen phosphate potassium hydrogen carbonate or succinic acid Sodium bicarbonate. Usually a strong one Acid or base, such as hydrochloric acid, hydrobromic acid, sodium hydroxide or potassium hydroxide, for adjusting the pH Value can be used.

The reaction temperature can range from about 0 to 200 ° C, are preferably from about 20 to 160 ° C.

The execution of the relocation is optional. For example can put all starting compounds in one reaction vessel filled and then heated. In addition, for example the furfuryl alcohol of the formula VI in portions so slowly be given an aqueous medium that the reaction is complete expires. The latter is the latter in terms of yield advantageous.

The reaction mixture can be post-treated in the usual way for example by extraction, separation, concentration or chromatography to a mixture of the 2-hydroxyalkyl-hydroxycyclopentenone of formulas IV and V.  

In the subsequent step (b) the mixture of 2-hydroxyalkyl-hydroxycyclopentenones of the formulas IV and V or isomerized to the 2-hydroxyalkyl-hydroxycyclopentenone Obtain Formula V.

The mixture is separated in a manner known per se, for example by silica gel column chromatography. Here the 2-hydroxyalkyl-hydroxycyclopentenone of formula V receive.

For the isomerization, the mixture can be mixed with a catalyst in an inert solvent be treated to the 2-hydroxyalkyl-hydroxycyclopentenone to obtain the formula V. Water, Ether, such as tetrahydrofuran, dioxane or diethyl ether, ester, such as methyl acetate or ethyl acetate, ketones such as acetone or Methyl ethyl ketone, hydrocarbons such as benzene, toluene, heptane or cyclohexane, or halogenated hydrocarbons, such as Chlorobenzene, dichloromethane or dichloroethane can be used. Tertiary amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N'-dimethylpiperazine, Pyridiene or lutidine, metal oxides such as aluminum oxide or Silica gel, inorganic bases, such as sodium hydroxide, potassium hydroxide, Sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen phosphate, or buffers, such as carbonate buffers or phosphate buffer can be used. The amount of the catalyst is not particularly limited and is usually about 0.005 to 3 moles per mole of the mixture of the 2-hydroxyalkyl hydroxycyclopentenones of formulas IV and V. A liquid is just like the tertiary amine or the buffer usable as a catalyst, but also as a solvent and, if used for both purposes, can be large Excess can be used. It can also be chloral or a Mixture of chlorol and the tertiary amine as a catalyst usually in an amount of 0.005 to 1 mole per mole of Starting mixture can be used. In this case, everyone can the above solvents except water  be used as the reaction medium. The implementation is common carried out at a temperature of about -20 to 130 ° C. However, the temperature may vary depending on the solvent chosen and base are different.

In step (c) below, the 2-hydroxyalkyl-hydroxycyclopentenone of the formula V as such or its one Protected group derivative, i.e. H. in the 2 position with a protected hydroxyalkyl hydroxycyclopentenone of formula III with an aliphatic carboxylic acid or its reactive Derivative are implemented. The 2-hydroxyalkyl-hydroxycyclopentenone of the formula V can be in the D, L-cyclopentenone ester of the formula II in a single or two steps, d. H. about the in the 2-position with a protective group provided hydroxyalkylhydroxy-cyclopentenone of the formula III. The one-stage Conversion can only be carried out if the designated protection group is exactly the same as the group -COR₁. The two-step conversion can be applied generally without paying attention to the type of protective group. Below first the two-step conversion and then the one-step conversion explained.

The two-step conversion involves protecting those in the side chain in the 2-position of the cyclopentenone ring in the end position located hydroxyl group in the first stage and the esterification the hydroxyl group at the 4-position of the cyclopentenone ring in the second stage.

A silyl group can be used as a protective group in the first stage can be used, such as a trialkylsilyl or diphenylalkylsilyl group; an ether group, such as a tetrahydropyranyl, ethoxyethyl, Methoxyethyl, methoxymethyl or methoxyethoxymethyl group; or an acyl radical, such as an acetyl, propionyl or butyryl group. The introduction of this protection group will achieved with a silylating agent, such as trimethylsilyl chloride, tert-butyldimethylsilyl chloride or diphenylmethylsilyl chloride;  a vinyl ether such as dihydropyran or ethyl vinyl ether; an alkoxyalkyl halide, such as methoxyethyl chloride, Methoxymethyl chloride or methoxyethoxymethyl chloride; or a reactive aliphatic carboxylic acid, such as acetic anhydride, Acetyl chloride, propionic anhydride, propionyl chloride, Butyryl chloride or chloroacetyl chloride.

The type of introduction depends on the type of reagent. Provided a silylating reagent or the alkoxyalkyl halide used, the reaction is usually in the presence a basic catalyst in an inert solvent, for example an ether such as tetrahydrofuran or ethyl ether; a ketone such as acetone or methyl ethyl ketone; one Hydrocarbon such as toluene, benzene or hexane; a halogenated Hydrocarbon, such as chlorobenzene, dichloromethane, Dichloroethane, chloroform or carbon tetrachloride; Dimethylformamide or carried out dimethyl sulfoxide. The amount of Silylating agent or the alkoxyalkyl halide usually about 0.8 to 1.3 equivalents, preferably about 0.85 to 1.1 equivalents of that used as the starting compound 2-Hydroxyalkyl-hydroxycyclopentenones of formula V. As basic Catalyst can be any organic or inorganic Base can be used, such as triethylamine, ethyldiisopropylamine, tri-n-butylamine, pyridine, dimethylaminopyridine, imidazole, Picolin, sodium carbonate, calcium hydroxide or potassium hydrogen carbonate. The basic catalyst is usually in a Amount of about 0.8 to 3 equivalents of 2-hydroxyalkyl-2- hydroxycyclopentenones of formula V. Besides, can the organic amine not only the solvent, but also be the catalyst. The reaction temperature is not limited however, it is usually in the range of about -40 to 100 ° C, preferably in the range of about -30 to 90 ° C. The Response time is not particularly important.

If vinyl ether is used, the reaction will usually be in an inert solvent in the presence of an acid catalyst  carried out. The amount of vinyl ether can be about 0.8 to 1.3 equivalents, and preferably about 0.85 to 1.1 Equivalents of the 2-hydroxyalkyl-hydroxycyclopentenone of the formula V. As a solvent, one of the related can be used with the silylating agent specified. An organic or inorganic acid, such as toluenesulfonic acid, chloroacetic acid, dichloroacetic acid, Benzenesulfonic acid, methanesulfonic acid, sulfuric acid, phosphoric acid or boron trifluoride can be used. Their amount is generally about 0.002 to 0.3 equivalents of vinyl ether. The Reaction is usually carried out at a temperature of around -30 to 120 ° C, and preferably at about -20 to 110 ° C. The response time is not particularly limited.

When using an aliphatic carboxylic acid or its reactive The implementation of derivatives is known per se Way carried out according to conventional esterification procedures. The reaction is carried out in a manner as stated above inert solvents in the presence of a catalyst. Organic or inorganic bases can be used as catalysts are used, such as triethylamine, ethyldiisopropylamine, tri-n-butylamine, pyridine, dimethylaminopyridine, picoline, sodium carbonate, Calcium hydroxide or sodium bicarbonate. The organic amine that can be used as a solvent can also be used act as a catalyst. In addition, an organic or inorganic Acid such as toluenesulfonic acid, methanesulfonic acid or Sulfuric acid can be used as a catalyst. The aliphatic Carboxylic acid or its reactive derivative are commonly used in an amount of about 0.8 to 1.3 equivalents, preferably from about 0.85 to 1.1 equivalents of the 2-hydroxyalkyl hydroxycyclopentenone Formula V used. The catalyst is usually used in an amount of 1 to 5 equivalents of the 2-hydroxyalkyl-hydroxycyclopentenone of the formula V used. The reaction can be carried out at a temperature of about -20 to 150 ° C, preferably at about -10 to 120 ° C. will.  

The reaction mixture is aftertreated in the usual way, for example by extraction, separation, concentration and / or chromatography to thereby protect the 2-position protected Win hydroxyalkyl-hydroxycyclopentenone of formula III.

In the second stage, the thus obtained, protected in the 2-position Hydroxyalkyl-hydroxycyclopentenone of formula III with a reactive aliphatic carboxylic acid in the presence esterified a catalyst. It becomes the D, L-cyclopentenone ester of formula II obtained. As a reactive aliphatic Carboxylic acid can be aliphatic carboxylic acid anhydrides or aliphatic carboxylic acid halides can be used. Specific Examples are acetic anhydride, propionic anhydride, acetyl chloride, Acetyl bromide, propionyl chloride, propionyl bromide, Butyryl chloride, butyryl bromide, caproyl chloride, caproyl bromide, Capryloyl chloride, capryloyl bromide, stearoyl chloride, stearoyl bromide, Caprynoyl chloride, caprynoyl bromide, dodecanoyl chloride, Dodecanoyl bromide, palmitoyl chloride, palmitoyl bromide, chloroacetyl chloride, Chloroacetyl bromide, dichloroacetyl chloride or Dichloroacetyl bromide. These reagents can be used in an amount of more than 1 equivalent of the 2-hydroxyalkyl-hydroxycyclopentenone of formula III can be used. There is no special one upper limit, but this can range from about 4 equivalents lie. An organic or inorganic Base can be used, such as triethylamine, tri-n-butylamine, Pyridine, picoline, sodium carbonate, sodium methoxide or Potassium hydrogen carbonate. Acids, such as toluenesulfonic acid, Methanesulfonic acid or sulfuric acid can be used as the catalyst will. In general, the catalyst is in a Amount of about 1 to 5 equivalents of the 2-hydroxyalkyl hydroxycyclopentenone Formula III used, however, this range not limited.

The use of any inert solvent is for that Esterification is not essential. However, if used one then it may be an aliphatic or  act aromatic hydrocarbon, such as benzene, toluene or hexane to halogenated hydrocarbons such as chlorobenzene, Dichloromethane, dichloroethane, chloroform or carbon tetrachloride; Ethers such as tetrahydrofuran or diethyl ether; Ketones such as acetone or methyl ethyl ketone; Chlorobenzene; Dichloromethane; Dichloroethane; Chloroform; Carbon tetrachloride; or to dimethylformamide. Any liquid organic amine can too can be used as a solvent and as a catalyst.

The reaction is usually carried out at a temperature of about -20 to 150 ° C, and preferably about -10 to 120 ° C.

The reaction mixture is subjected to a customary aftertreatment, for example an extraction, separation, concentration and chromatography so that the D, L-cyclopentenone ester Formula II is available in high yield.

In the one-step conversion, the 2-hydroxyalkyl-hydroxycyclopentenone of formula V with an aliphatic carboxylic acid or its reactive derivative in the presence of a catalyst, if appropriate in an inert solvent, treated to give the D, L To obtain cyclopentenone esters of the formula II in which R 'is one Alkanoylrest means. As an aliphatic carboxylic acid, catalyst and inert solvent can the above in the Esterification as part of the second stage of the two-stage conversion used. The amount of aliphatic Carboxylic acid is usually not less than 2 equivalents, preferably 3 to 8 equivalents of the 2- Hydroxyalkyl-hydroxycyclopentenones of formula V. The amount of catalyst is usually about 2 to 10 equivalents. The reaction can be carried out at a temperature of about -20 to 150 ° C, preferably about -10 to 120 ° C.

Also in a mixture of the 2-hydroxyalkyl obtained in step (a) hydroxycyclopentenones of formulas IV and V can be acylated and isomerized to the D, L-cyclopentenone ester of the formula II,  in the R 'one derived from an aliphatic carboxylic acid Acyl residue means to produce in a single step. This simultaneous acylation and isomerization can be achieved by Reaction of the mixture with an aliphatic carboxylic acid, their acid anhydride and their alkali metal salt. The use of the combination of these three reagents is essential for a smooth and efficient process of Implementation and to achieve good yields.

The aliphatic carboxylic acids that can be used in this reaction are acetic acid, propionic acid, butyric acid, valeric acid, Chloroacetic acid or dichloroacetic acid. Examples of aliphatic Carboxylic anhydrides are acetic anhydride, propionic anhydride, Valeric anhydride or chloroacetic anhydride. Examples of the metal salts of aliphatic carboxylic acids are Lithium, sodium, potassium, calcium, copper, zinc, palladium, Lead, tin, manganese or cobalt salts of the above listed aliphatic carboxylic acids. Generally is the amount of the aliphatic carboxylic acid and its anhydride not less than about 1 to 2 moles of the mixture of 2-Hy droxyalkyl-hydroxycyclopentenones of the formulas IV and V. Die The amount of the metal salt is usually about 0.01 to 5 Equivalents or more, preferably about 0.01 to 0.5 equivalents.

The use of any inert solvent is not essential. If one is used, it can act in hydrocarbons, such as benzene, toluene or Hexane; halogenated hydrocarbons such as chlorobenzene, Dichloromethane, dichloroethane, chloroform or carbon tetrachloride; Ethers such as tetrahydrofuran or diethyl ether; Ketones, such as acetone or methyl ethyl ketone; Dimethylformamide or around Dimethyl sulfoxide. These can be used alone or in combination will.

The reaction will usually take about 0.5 to 10 hours  a temperature of about 0 to 150 ° C, preferably at about 80 to 140 ° C.

All reactants, e.g. H. the 2-hydroxyalkyl-hydroxycyclopentenones of the formulas IV and V, the aliphatic carboxylic acid, its acid anhydride and its metal salt, be filled into a reaction vessel. Then the implementation carried out. In another embodiment the 2-hydroxyalkyl-hydroxycyclopentenones of the formulas IV and V as well as the aliphatic carboxylic acid and its acid anhydride in one Reaction vessel filled and then the reaction for one certain period of time, for example about 0.1 to 5 hours, and then the metal salt of the aliphatic Carboxylic acid added. The implementation will then be continued.

The examples illustrate the invention.

example 1 Preparation of D-4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone

1000 ml of water and 0.2 g of potassium dihydrogen phosphate are placed in a flask and the mixture is adjusted to pH 4.2 with 5 percent phosphoric acid. This mixture is mixed with 21.2 g of α - ( ω- hydroxyheptyl) furfuryl alcohol and stirred for 12 hours with heating at 100 ° C. After completion of the reaction, the reaction mixture is extracted twice with 200 ml of toluene. The organic phase is concentrated under reduced pressure. 20.5 g of residue remain.

The residue is dissolved in 100 ml dichloromethane. The solution 2.87 g of chloral and 0.98 g of triethylamine are added and Stirred at 25 ° C for 5 hours.

Then the reaction mixture is made in order with 1 percent dilute hydrochloric acid, with water and with 1 percent aqueous sodium bicarbonate solution and washed over anhydrous Magnesium sulfate dried. Then the solvent  removed at reduced pressure. It leaves a concentrated one Residue of 20.8 g.

The residue is dissolved in 100 ml of dichloromethane and mixed with 30 ml of pyridine. 23.5 g of acetyl chloride are then added dropwise over the course of 2 hours, the internal temperature of the flask being kept at 0 to 10 ° C. The mixture obtained is kept at the same temperature for 1 hour. The reaction is then carried out at 25 to 30 ° C. for 3 hours. The reaction mixture is then washed in sequence with water, 1 percent dilute hydrochloric acid, 1 percent aqueous sodium bicarbonate solution and with water and dried over anhydrous magnesium sulfate. The solvent is then removed under reduced pressure. 28.6 g of residue remain. This is purified in a column chromatography on silica gel. A mixture of toluene and ethyl acetate (5: 1) is used as the eluent. 16.6 g of 4-acetoxy-2- (7-acetoxyheptyl) -2-cyclopentenone are obtained; n = 1.4767.

4 g of the compound obtained above are mixed with 2 ml of dichloromethane, 330 mg of lipase from a microorganism belonging to the genus Pseudomonas ("Amano Lipase P", manufactured by Amano Pharmaceutical Co., Ltd.) and with 100 ml of 0.3 M phosphate buffer , pH 7.5, added and stirred vigorously at 30 ° C. for 15 hours. After the reaction is complete, the reaction mixture is extracted with twice 40 ml of methyl isobutyl ketone. The extract is concentrated under reduced pressure. The residue is purified in a column chromatography on silica gel. A mixture of toluene and ethyl acetate (5: 3) is used as the eluent. 0.97 g of the title compound of melting point 58 to 59 ° C. are obtained; [ α ] = + 16.2 ° (c = 1, methanol).

Example 2 Preparation of D-4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone

As described in Example 1, but using 280 mg of lipase from a microorganism of the genus Arthrobacter (manufactured by Shin-Nippon Chemical Co., Ltd.) instead of the lipase of a microorganism of the genus Pseudomonas, 0.87 g of the title compound of F Obtained 59 to 60 ° C; [ α ] = + 15.3 ° (c = 1, methanol).

Example 3 Preparation of (R) - (+) - 4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone

(1) The flask described in Example 1 is charged with 4000 ml of water and 4.0 g of acetic acid and adjusted to pH 4.2 with an aqueous 1 N sodium hydroxide solution. The mixture obtained is mixed with 106.1 g (0.5 mol) of α - ( ω- hydroxyheptyl) furfuryl alcohol. The reaction mixture is then stirred at 100 ° C. under a stream of nitrogen until the starting compound is completely consumed. It is confirmed by high performance liquid chromatography (HPLC) that the reaction mixture is a mixture of 3-hydroxy-2- (7-hydroxyheptyl) -4-cyclopentenone and 4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone in the ratio 3 : 1 contains.

The reaction mixture is with 1 N aqueous sodium hydroxide solution adjusted to pH 7.6. It is under a stream of nitrogen at 100 ° C stirred until the 3-hydroxy-2- (7-hydroxyheptyl) -4-cyclopentenone disappears. When the reaction is complete, the reaction mixture cooled and extracted with twice 600 ml of methyl isobutyl ketone. The combined extracts are concentrated. It remains 76.8 g (72.4% of theory) 4-Hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone.

(2) 21.2 g (0.1 mol) of the compound obtained in step (1) are dissolved in 100 ml of dimethylformamide. The solution comes with 6.86 g (0.1 mol) of imidazole were added. While the temperature of the Solution is kept at 10 to 20 ° C, a solution of 15.1 g (0.1 mol) of tert-butyldimethylsilyl chloride and 10 ml of dimethylformamide added dropwise within 30 minutes. The received  The mixture is kept at the same temperature for 12 hours. The reaction mixture is poured into 500 ml of ice water and with Toluene extracted. The extract is washed carefully with water, dried over anhydrous magnesium sulfate and under concentrated under reduced pressure. 35.3 g of residue remain. The residue is purified by column chromatography on silica gel cleaned. A mixture is used as the eluent from toluene and ethyl acetate (5: 1). There are 17.9 g (55% of theory) 4-Hydroxy-2- (7-tert-butyldimethylsilyloxyheptyl) - Obtained 2-cyclopentenone.

The silyl compound obtained above is dissolved in 200 ml of toluene solved. The solution is mixed with 20 ml of pyridine. While the solution temperature is kept at 0 to 10 ° C 7.0 g of acetyl chloride were added in portions over the course of 10 minutes. The mixture obtained is at the same for 1 hour Maintained temperature and then the reaction is 3 hours carried out at 25 to 30 ° C. After full implementation the reaction mixture in turn with water, 1 percent dilute hydrochloric acid, 1 percent aqueous sodium bicarbonate solution and washed with water. The organic phase is over dried anhydrous magnesium sulfate and at reduced Pressure reduced. 20.5 g of residue remain. The residue is purified by column chromatography on silica gel. Toluene is used as the eluent. It becomes 19.4 g (95.7% of theory) 4-acetoxy-2- (7-tert-butyldimethylsilyloxyheptyl) - Obtained 2-cyclopentenone.

3.68 g (0.01 mol) of the compound thus obtained are mixed with 50 ml of 0.3 M phosphate buffer, pH 7.0, 2 ml of chloroform and with 180 mg of lipase of a microorganism of the genus Arthrobacter (manufactured by Shin-Nippon Chemical Co., Ltd.) filled into a flask. The reaction mixture is stirred vigorously at 35 to 40 ° C for 12 hours. When the reaction is complete, the reaction mixture is extracted twice with 40 ml of toluene. The combined extracts are concentrated under reduced pressure. 3.98 g of residue remain. This is subjected to column chromatography. A mixture of toluene and ethyl acetate (5: 1) is used as the eluent. 1.56 g of R - (+) - 4-hydroxy-2- (7- tert -butyldimethylsilyloxyheptyl) -2-cyclopentenone ([ α ] = + 10.9 ° (c = 1, methanol)) and 1 , 90 g of S - (-) - 4-acetoxy-2- (7- tert -butyldimethylsilyloxyheptyl) -2-cyclopentenone ([ α ] = -42.5 ° (c = 1, methanol).

The (R) - (+) - isomer obtained above is dissolved in 10 ml of tetrahydrofuran and 1 g of tetrabutylammonium fluoride is added. The mixture obtained is desilylated by stirring at 15 to 20.degree. The reaction product is purified by rapid chromatography on silica gel. The title compound of mp 59 to 61 ° C is obtained; [ α ] = + 16.8 ° (c = 1, methanol).

Example 4 Preparation of R - (+) - 4-hydroxy-2- (7-tert-butyldimethylsilyl oxyheptyl) -2-cyclopentenone and S - (-) - 4-acetoxy-2- (7-tert.- butyldimethylsilyloxyheptyl) -2-cyclopentenone

As described in Example 3, 3.68 g of 4-acetoxy-2- (7- tert -butyldimethylsilyloxyheptyl) -2-cyclopentenone, 50 ml of 0.3 M phosphate buffer and 180 mg of lipase from a microorganism of the genus Arthrobacter (are prepared from Shin-Nippon Chemical Co., Ltd.) into a flask. The reaction mixture is stirred vigorously at 35 to 40 ° C for 12 hours. The reaction mixture is then further treated as described in Example 3. A mixture of 1.53 g of R - (+) - 4-hydroxy-2- (7-tert-butyldimethylsilyloxyheptyl) -2-cyclopentenone ([ α ] = + 10.4 ° (c = 1, methanol )) and 1.93 g of S - (-) - 4-acetoxy-2- (7-tert-butyldimethylsilyl oxyheptyl) -2-cyclopentenone ([ α ] = -40.1 ° (c = 1, methanol)) receive.

Example 5 Preparation of D-4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone

The flask used in Example 1 is charged with 2000 ml of water and 3 g of acetic acid. The mixture is adjusted to pH 4.5 with 1 N aqueous sodium hydroxide solution. 50 g of α - ( ω - hydroxyheptyl) furfuryl alcohol are added. The mixture is then stirred for 15 hours with heating at 100 ° C. The reaction mixture is extracted with 800 ml of methyl isobutyl ketone. The extract is concentrated under reduced pressure. 48.8 g of residue remain. This contains 3-hydroxy-2- (7-hydroxyheptyl) -4-cyclopentenone and 4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone.

40 g of the residue are mixed with 40 g of acetic anhydride, 10 g of sodium acetate and with 40 g of acetic acid and heated to 120 ° C. for 5 hours. The reaction mixture is poured into 300 ml of water and extracted with 100 ml of toluene. The extract is washed with 4 percent sodium hydroxide solution and then with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 50.2 g of residue remain, which are purified by column chromatography on silica gel as described in Example 1. 37.7 g of 4-acetoxy-2- (7-acetoxyheptyl) -2-cyclopentenone are obtained; n = 1.4775.

3 g of the 4-acetoxy-2- (7-acetoxyheptyl) obtained above 2-cyclopentenones with 100 mg lipase of a microorganism of the genus Alcaligenes ("PL-266", manufactured by Meito Sangyo Co., Ltd.) and 100 ml 0.1 M phosphate buffer, pH 6.0, transferred. The mixture is then stirred vigorously at 40 ° C. for 15 hours.

The reaction mixture is extracted twice with 40 ml of methyl isobutyl ketone. The combined extracts are concentrated under reduced pressure. The residue is purified by column chromatography on silica gel as described in Example 1. 0.62 g of the title compound are obtained: [ α ] = + 14.3 ° (c = 1, methanol).

Examples 6 to 11 Preparation of 4-hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone

As described in Example 5, but using the in Enzymes mentioned in Table 1, the title compound is made up of 4- Acetoxy-2- (7-acetoxyheptyl) -2-cyclopentenone.

Table 1

Example 12 Preparation of (R) - (+) - 4-hydroxy-2- [7- (2'-tetrahydropyranyl oxy) heptyl] -2-cyclopentenone

21.2 g (0.1 mol) of the compound obtained according to Example 3 4-Hydroxy-2- (7-hydroxyheptyl) -2-cyclopentenone are dissolved in 300 ml Dissolved tetrahydrofuran and mixed with 2 g of dichloroacetic acid. Then 9.3 g of dihydropyran in portions over 5 hours added at room temperature and the same temperature is over 5 hours  adhered to. The reaction mixture obtained is in 500 ml Ice water transferred and extracted with ethyl acetate. The organic Phase is washed carefully with water, over anhydrous Magnesium sulfate dried and under reduced pressure constricted. There remain 27.2 g of residue, which by column chromatography on silica gel with toluene and ethyl acetate (5: 2) be cleaned as eluent. 12.6 g (42.5% d. Th.) 4-Hydroxy-2- [7- (2'-tetrahydropyranyloxy) heptyl] -2-cyclopentenone receive.

11.8 g of the compound thus obtained are mixed dissolved by 50 ml of toluene and 10 ml of pyridine and for 30 minutes with 3.5 g of acetyl chloride, the temperature of the Reaction mixture is kept at 0 to 10 ° C. The received The mixture is kept at the same temperature for 1 hour and then 3 hours at 25 to 30 ° C. The reaction mixture is in turn with water, 1 percent hydrochloric acid, 1 percent aqueous sodium bicarbonate solution and washed with water. The organic phase is over anhydrous magnesium sulfate dried and concentrated under reduced pressure. Leave it behind 13.8 g of residue by column chromatography on silica gel getting cleaned. Toluene is used as the eluent. 12.7 g (94.3% of theory) of 4-acetoxy-2- [7- (2'- tetrahydropyranyloxy) heptyl] -2-cyclopentenone obtained.

3.38 g (0.01 mol) of the compound obtained above are combined with 50 ml of 0.3 M phosphate buffer, pH 7.0, 1 ml of toluene and 180 mg of lipase from a microorganism of the genus Arthrobacter (manufactured by Shin Nippon-Chemical Co., Ltd.) placed in a reaction vessel and stirred vigorously at 30 to 40 ° C for 10 hours. The reaction mixture is extracted twice with 40 ml of ethyl acetate and the combined extracts obtained are concentrated under reduced pressure. 2.87 g of residue remain, which are purified by column chromatography on silica gel with toluene and ethyl acetate (5: 1) as the eluent. 1.15 g of the title compound are obtained; [ a ] = + 12.2 ° (c = 1, methanol).

Claims (24)

1. Process for the preparation of optically active hydroxycyclopentenones of the general formula I in which R is a hydrogen atom or a hydroxyl protective group, n is an integer with a value from 4 to 8, and the asterisk (*) denotes an asymmetric carbon atom in which a D, L-cyclopentenone ester of the general formula II in which the group R₁CO- is an aliphatic carboxylic acid derived acyl radical, R 'is a hydroxyl protective group and n has the meaning given above, treated with an enzyme which has the ability to selectively select one of the D and L isomers of D, L-Cyclopentenonesters II to hydrolyze asymmetrically in an aqueous medium. 2. The method of claim 1, wherein the enzyme is one of the Microorganisms Pseudomonas, Aspergillus, Mucor, Candida Alcaligenes, Achromobacter, Arthrobacter, Chromobacterium or Rhizopus is produced. 3. The method of claim 2, wherein the enzyme is an esterase is. 4. The method of claim 1, wherein the aqueous medium Contains buffer. 5. The method of claim 4, wherein the aqueous medium contains organic solvent. 6. The method of claim 1, wherein the treatment under Stirring is carried out. 7. The method of claim 6, wherein the treatment in a Temperature of about 10 to 60 ° C is carried out. 8. The method according to claim 1, wherein the D, L-cyclopentenone of the formula II is prepared as the starting compound by reacting a 2-hydroxyalkyl-hydroxycyclopentenone of the formula V. in which n is an integer with a value from 4 to 8, or a derivative thereof protected in the 2-position with the formula III in which R 'is a hydroxyl protective group and n has the meaning given above, with an optionally substituted aliphatic carboxylic acid or a reactive derivative thereof. 9. The method of claim 8, wherein the aliphatic carboxylic acid used in the form of their acid anhydride or acid halide becomes. 10. The method according to claim 8, wherein the reaction in the presence a base is carried out. 11. The method according to claim 8, wherein the implementation at a Temperature of about -10 to 120 ° C is carried out. 12. The method of claim 8, wherein the 2-hydroxyalkyl-hydroxycyclopentenone Formula V first with a reagent is implemented to protect the hydroxyl group, and then the hydroxyalkyl-hydroxycyclopentenone protected in the 2-position of formula III with a reactive aliphatic carboxylic acid is implemented. 13. The method according to claim 12, in which to protect the hydroxyl group reagent used is a silyl halide Lower alkoxy (lower) alkyl halide or an aliphatic Is carboxylic acid or its reactive derivative. 14. The method according to claim 13, wherein the implementation with the the reagent protecting the hydroxyl group in the presence of a Base is performed.   15. The method according to claim 13, wherein the implementation with the the reagent protecting the hydroxyl group at a temperature from -30 to 90 ° C is carried out. 16. The method of claim 12, wherein the to protect the hydroxyl group reagent used was a vinyl ether, lower alkoxy (lower) alkyl halide or is an aliphatic carboxylic acid. 17. The method according to claim 16, wherein the implementation with the the reagent protecting the hydroxyl group in the presence of a Acid is carried out. 18. The method of claim 16, wherein the reaction with the the reagent protecting the hydroxyl group at a temperature from -30 to 110 ° C is carried out. 19. The method of claim 8, wherein the 2-hydroxyalkyl-hydroxycyclopentenone of formula V is prepared by separating or isomerizing a mixture of the 2-hydroxyalkyl-hydroxycyclopentenones of formula IV and Formula V in which n is an integer from 4 to 8. 20. The method according to claim 19, wherein the isomerization in Presence of a catalyst in an inert solvent is carried out.   21. The method of claim 20, wherein the isomerization at a temperature of -20 to 130 ° C is carried out. 22. The method of claim 20, wherein the catalyst tertiary amine, a metal oxide, an inorganic base, a buffer, chloral or a mixture of chloral and one is tertiary amine. 23. The method according to claim 1, wherein the D, L-cyclopentenone of formula II is prepared as a starting compound by

• (a) Rearrangement of a furfuryl alcohol of the formula VI in which n is an integer with a value of 4 to 8, in an aqueous medium at a pH of about 3.5 to 6, around a mixture of the 2-hydroxyalkyl-hydroxycyclopentenones of the formula IV and Formula V in which n has the meaning given above,
• (b) separation or isomerization of the resulting mixture to obtain the 2-hydroxyalkyl-hydroxycyclopentenones of formula V; and
• (c) Reaction of the 2-hydroxyalkyl-hydroxycyclopentenones of the formula V thus obtained or their hydroxyalkyl-hydroxycyclopentenone derivatives of the formula III which are provided with a protective group in the 2-position in which R 'and n have the meaning given above, with a reactive aliphatic carboxylic acid.

24. The method according to claim 1, wherein the D, L-cyclopentenone of the formula II is prepared as a starting compound by simultaneous reaction of a mixture of the 2-hydroxyalkyl-hydroxycyclopentenones of the formula IV and Formula V in which n is an integer from 4 to 8, with an aliphatic carboxylic acid, its acid anhydride and its metal salt for simultaneous acylation and isomerization to the D, L-cyclopentenone ester of the formula II, in which R 'is a derivative of the aliphatic carboxylic acid Means acyl group.