JPS6366148A - Production of optically active 2-substituted-4-hydroxy-2-cyclopentenones - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for agricultural chemicals, perfumes or pharmaceuticals, in high yield and optical purity on an industrial scale at a low cost, by rearranging a mixture of optically active substituted-hydroxy-2-cyclopentenone while keeping the steric configuration. CONSTITUTION:The objective compound of formula VII useful as an intermediate for pharmaceuticals such as prostaglandin derivatives, etc., can be produced by (1) reacting a mixture of dl-cyclopentenone alcohols of formula I [R is group of formula II (X-Y is CH2-CH2 or cis CH=CH; R' is H or alkyl)] or formula III with aliphatic carboxylic acids to produce a mixture of dl- cyclopentenone esters of formula IV (R1 is acyloxy) or formula V, (2) subjecting the components to asymmetric hydrolysis with esterase produced by microorganism or esterase originated from animal or vegetable and (3) rearranging the resultant mixture of optically active substituted hydroxy-2-cyclopentenoic acids of formula VI or formula VII while keeping the steric configuration.

Description

[Detailed description of the invention] <Industrial application field> The present invention is based on the general formula (1) The substituent represented by y is CH, -CH.

Or V7. CH-CM is an optically active 2-substituted-4-hydroxy-v-2-
◎ <Prior art> Regarding the production method of cyclobentenones Optically active 2-substituted 14- represented by the above general formula (I)
HydroxoS/2-cyclobentenones are useful as intermediates for agricultural chemicals, fragrances, or pharmaceuticals, and can be used, for example, as important intermediates for Glostagrandein derivatives. After leading to a disulfonic acid ester with toluenesulfonic acid or methanesulfone W1, react with a base, or
Alternatively, by reacting with sodium acetate, dichloroμ sodium acetate, sodium trichloroacetate, etc. to form the corresponding ester, and then hydrolyzing it, the 2-substituted-4- It can also be used by leading to hydroxy-2-cyclobentenones. Conventionally, optically active 2-M represented by the general formula (1)
For example, the following methods for producing hydroxy-4-hydroxy-2-cyclobentenones are known: ◇ 1) Tetrahedron L@tterm, I
&L49*4959 (1978) <Problems to be solved by the invention> However, the method 1) is not necessarily satisfactory in terms of yield and optical purity, and there is a problem that some by-products are produced. Additionally, method 2) has problems such as it is not easy to produce the triketone as a raw material, and the number of subsequent steps is large, so it cannot be declared as an industrially advantageous method. All of these methods are unsatisfactory as industrial production methods, and an industrially advantageous production method has been desired. As a result of studies to industrially advantageously produce -substituted-4-hydroxy\-2-cyclobentenones, we have arrived at the present invention. and ■ (0 in the formula, R has the same meaning as above) and M (in the formula, R has the same meaning as above, and R1 represents an AV〃oxyμ group) Mutocyclobentenone esters P are obtained, and then asymmetric hydrolysis is performed using esterases produced by microorganisms or esterases derived from animals and plants to obtain general formulas (1) and (1) (where B has the same meaning as above). A mixture of optically active substituted hydroxy-2-cyclobentenones I represented by A method for producing 2-substituted-4-hydroxy-2-cyclobentenones is provided.

The present invention will be described in detail below.0 In the present invention, a mixture of dj-cyclobentenone alcohols represented by general formulas (b) and 0 can be easily synthesized by rearranging the
■ The reaction of the mixture of dl-cyclobentenone alcohol, /L/(b) and (5) with aliphatic carboxylic acids is carried out by the conventional method for producing ester/L', and the racemic The reaction is carried out by reacting a mixture of (8) and (5) with an aliphatic carboxylic acid, its acid anhydride or its acid hafide using a catalyst in the presence or absence of a solvent.

Here, examples of the aliphatic carbons used as raw materials include the following compounds.

Acetic acid, acetic acid chloride, acetate bromide, acetic anhydride, propionic acid, propionic acid chloride or bromide, propionic anhydride, butyryl chloride or bromide, caproyl chloride or bromide, caprylic acid chloride or bromide, cabrinoyl chloride or bromide, dodecatuin Chloride or bromide, chloride or bromide, chloracetyl chloride or bromide, dichloroacetyl chloride or bromide〇 The aliphatic carboxylic acids used in the reaction are raw materials. It is necessary to use 1 equivalent or more with respect to the mixture of (1) and (2), and the upper limit is not particularly limited, but is preferably in the range of 1 to 4 equivalents.

In this reaction, when a solvent is used, examples of the solvent include tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, Examples include solvents that are inert to the reaction, such as aliphatic or aromatic hydrogen chlorides such as hexane, ethers, and halogenated hydrogen chlorides, either alone or in mixtures.The amount used can be used without any particular restriction.

Examples of the catalyst include organic or inorganic basic substances such as triethylamine, tri-n-butylamine, pyridine, picoline, sodium carbonate, sodium methifoot, and potassium bicarbonate. The lid used is not particularly limited, but usually dl-cyclobentenoneaanico-L
/(III) and (5) in an equivalent amount of 1 to 6 times.

When using an organic amine as a solvent, the amine may act as a catalyst.Acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid may also be used as catalysts.The reaction temperature is usually -20°C. There is no particular restriction on the zero reaction time, which ranges from -10°C to 150°C, preferably from -10°C to 120°C.

Through such a reaction, a mixture of di-cyclobentenone esters represented by general formulas M and (2) can be easily prepared.
They can be easily isolated from the reaction mixture by conventional separation means such as extraction, separation, concentration, isobaric distillation, etc., but the reaction mixture can be passed on to the next step as it is. be able to.

The optically active substituted hydroxy-2-cyclobentenone m represented by the general formula M and (2) is a microbial esterase or The microorganism that produces the esterase used in this reaction may be any microorganism that produces an esterase capable of asymmetrically hydrolyzing a mixture of dj-cyclobentenone esters, and is not particularly limited. (Esterase in the present invention means esterase in a broad sense including lipase.) Specific examples of such microorganisms include microorganisms belonging to the following genera.

Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Fuctobacillus, Trichoderma, Candy Da, Satucharomyces, Rhodotorula, Cryptococcus, Torulopsis, Vichia, Penicillium, Aspergillus, Rhizopnu, Muco-μ, Aureopacidium, Actinomucor, Tucadia, Streptococcus Examples include microorganisms belonging to the genus Myces, Hansenula, and Achromobacter.

The above-mentioned microorganisms are usually cultured in a liquid culture according to a conventional method to obtain a liquid culture.
Dissolve 5f of peptone, 10f of glucoke, 8f of malt extract, and 8f of yeast extract in [1] water and adjust the pH to 6.5),
For bacteria, sweetened bouillon medium (11 parts water to 10 parts glucose)
Microorganisms are inoculated into the solution (dissolve peptone 5f, meat extract 3f, N1a18f and adjust the pH to 7.2), and usually 20
Carry out reciprocating shaking culture at ~40°C for 1 to 8 days.◎Alternatively, solid culture may be performed if necessary.

In addition, some of these esterases originating from microorganisms are commercially available. Specific examples of commercially available esterases that can be easily obtained include the following: ◎ Shademonas lipase (Ohno Pharmaceutical product) Asbegillus lipase (Lipase AP (
(manufactured by Ohno Pharmaceutical)), Mucor lipase M-Ap (manufactured by Ohno Pharmaceutical), lipase of Candida sylindfusse (manufactured by Ohno Pharmaceutical)
Lipase MY (manufactured by Meito Sangyo)) Lipase of the genus Brucalignes (Lipase PL (manufactured by Meito Sangyo)), lipase of the genus Achromobacter (Lipase AL (manufactured by Meito Sangyo)), lipase of the genus Arthrobacter (Shin Nihon Kagaku type) ), Chromobacterium lipase (manufactured by Toyo Jozo Co., Ltd.), Tzobus deremer lipase (talibase (Tanabe Seiyaku type)), Rhizopus lipase (Lipase Saiken (Osaka Bacteria Research Institute)), animal and plant esterases. Specific examples of these esterases include the following.

Steapsin, pancreatin, pig liver esterase, Wheat Germ esterase 0 Esterase (hydrolyzed U) used in this reaction, enzymes obtained from animals, plants, and microorganisms are used in the form of purified enzymes,
It can be used as needed in various forms such as crude enzymes, enzyme-containing substances, microbial culture fluids, cultures, bacterial cells, cultured limbs, and processed products, and enzymes and microorganisms can also be used in combination. can. Alternatively, an immobilized enzyme immobilized on a resin or the like can be used as an immobilized bacterial cell. This hydrolysis reaction can be carried out by vigorously mixing a mixture of dJ-cyclobentenone esters and the above enzyme or microorganism in a normal buffer solution. This is done by stirring. As the buffer, commonly used buffers of inorganic acid salts such as sodium phosphate and potassium phosphate, buffers of organic acid salts such as sodium acetate and sodium citrate, etc. are used. The pH is preferably 8 to 11 for culture solutions of alkalophilic bacteria and alkaline esterases, and 5 to 8 for culture solutions of microorganisms that are not alkalophilic and esterases that do not have alkali resistance.〇The concentration is usually 0.06 to 2M, preferably 0.05~0.
The range is 6M.

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, during hydrolysis, in addition to the buffer, organic solvents inert to the reaction, such as toluene, chloroform, methyl isobutyl ketone, dichloromethane, etc., can be used, and by using these, asymmetric ice thawing can be carried out advantageously. be able to.

After completion of such hydrolysis reaction, in order to separate the hydrolysis product and hydrolysis residue from the reaction solution, the hydrolysis reaction solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, or ethyl acetate. After the solvent is distilled off from the organic layer, the concentrated residue is further distilled or treated with cuff chromatography to obtain optically active substituted-hydroxy-V-2-cyclobentenones (9). ) and a mixture of (1) and an optically active substitution which is a hydrolysis residue -
AV/L/oxy-2-cyclobentenone can be separated, respectively.

The optically active substituted-V/L/oxy-2-cyclobentenones recovered here can be further hydrolyzed and used as a raw material for producing a symmetrical object.

In addition, when a lipase belonging to the genus Pseudomonas or Arthrobacter is used as the lipase in this asymmetric ice-breaking reaction, optically active substituted hydroxy-2-cyclobentenones can be obtained with relatively high optical purity.

Also, during this hydrolysis, in addition to the buffer, toluene,
It is also possible to use inert organic solvents for the reaction such as chloroform, methyl isobutyl ketone, dichloromethane, etc.
, the optically active 2-substituted-4-hydroxy-V-2-\clobendeno 7 represented by the general formula (1) can be used to advantageously perform asymmetric ice-breaking using the above-mentioned method. It is produced by rearranging the optically active substituted-hydroxy-2-cyclobentenones represented by the general formula (11) while maintaining the steric structure in the presence of a base or catalyst◇ , The optically active 5-substituted-4-hydroxy-V-2-cyclobentenones represented by the general formula (■), which are the raw materials for this reaction step, have not been known at all, and only as an integral part of d. @trah@doronI, ett@r
s,, 1181-1184 (1977), but this text does not describe at all the steric coordination of the hydroxyl group at the 4-position and the substituent at the 5-position.Of course, optically active substances and There is no mention of the possibility of such separation, and there is a possibility that the separated optically active substance undergoes rearrangement while retaining its steric configuration, or that 2-M-converted-4- The steric configuration of hydroxy-2-cyclobentenones is described below.

On the other hand, as a stereoisomer of optically active 5-film-4-hydroxyV-2-cyclobentenones represented by the above general formula -, Aa
ta Ch@mI@Aaad@rnla* Sai@
ntiarum Hungarfeae, Tomum
lo 2 (1), PP91-100 (1979) K is described by the following method.
) Optically active 6-substituted-4-hydroxy V-2 represented by
-Since the steric configuration is different from that of cyclobentenones, K is the starting material for its production. O μ must be an optically active substance, and it requires many steps to reach -, which is not necessarily a satisfactory method. Thus, in the present invention, the optical activity shown by the general formula (9) 5-substituted-4-hydroxy-2-cyclobentenones are compounds that were synthesized by a previously unknown method, and the inventors of the present invention have clearly demonstrated their steric configuration for the first time. In rearranging such optically active 6-substituted-4-hydroxy-V-2-V-tetrabentenones while preserving their steric structure, it is necessary to maintain optical purity as high as possible, that is, to reduce polar cuffsemization. It is necessary to transpose T
For this reason, it is preferable to use K under appropriate conditions for the base or catalyst used, temperature, etc. The solvents used in this rearrangement reaction include, for example, water, tetrahydrofuran, dioxane, acetone, and benzene. ,
Toluene, ethyl acetate, chlorobenzene, ben9tane,
Dichloromethane, V chloroethane, diethyl ether,
Solvents inert to the reaction, such as aliphatic or aromatic hydrogens of the cyclohexane type, technical compounds, ketones, esters, halogenated hydrocarbons, are used alone or in mixtures.

Examples of bases or catalysts used in this reaction include triethyl μamine, N-methyμJ+! :/L/holin, N-methyl biberyline, N, zodimethyl bipefudin, pyridine, ruti-V-barley organic 8th class amine, a/
Metal oxides such as L/Mina and V Rikageμ, caustic soda,
Inorganic bases such as caustic potash, sodium carbonate, potassium carbonate, sodium bicarbonate, monohydrogen potassium phosphate, or basic buffers such as carbonate buffer are suitable, and these may be used alone or in combination of two or more. It will be done.

The amount of the base or catalyst to be used is not particularly limited, but it is usually 0.05 to 60 times the mole of optically active 4-cyclobentenone alcohol as a raw material, and organic 8th-class amines and basic The buffer solution can also be used as a solvent.

The reaction temperature ranges from -20 DEG to 180 DEG 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, racemization is less likely to occur, so the reaction can be carried out in the range of -10 to 90°C.
In the case of a water-mixed system, the temperature is preferably in the range of -10 to 50°C,
For rearrangement reactions in water alone or in strong basicity, -20
The reaction time is preferably in the range of ~80°C.The reaction time is not particularly limited.The reaction mixture thus obtained is subjected to general operations such as extraction, separation, concentration, and distillation to obtain the desired general formula (1). Thus, by the method of the present invention, optically active 2-substituted 4-hydroxy-2-cyclobentenones can be obtained.
4-Hydroxy-2-cyclobentenones (I) can be obtained with good optical purity and high yield, and are extremely useful as intermediates for prostaglandin derivatives, which are pharmaceuticals.

<Example> Hereinafter, the present invention will be explained using examples.

Example 1 A flask was charged with 1,000 mJ of water and 0.0 mJ of sodium acetate.
Charge 2t and adjust the pH to 4.4 with 5% acetic acid.

This [2-(ω-methoxycarbonylhexy〃)-fu μ
pretend! Add Akko/I/20f and heat and stir for 14 hours ◇ After the reaction is complete, extract twice with 200 mJ of toluene ・Concentrate the organic layer under reduced pressure to obtain a concentrated residue yk 19.6f 〇This concentrated residue 19 Dissolve .6F in 100 mJ of dichloromethane and add 80 mJ of pyridine to bring the internal temperature to 0 to 10°C.
Acetyl chloride/k18.0V was added over 2 hours while maintaining the temperature. After incubating at the same temperature for 1 hour, at 25-80℃
After the reaction is completed, the organic layer is washed with water, 1% diluted hydrochloric acid, 1% sodium bicarbonate solution, and water in sequence, and the organic layer is dried over magnesium sulfate and concentrated under reduced pressure to obtain the concentrated residue 2B, Of. , purified by silica column chromatography using a toluene:ethyl acetate/I/(5:2) mixture,
4-acetoxy-6-(ω-methoxycarbonyphexy/I/)-2-cyclobentenone (V-1) and 4-
Acetoxy-2-(ω-methoxycarbonylhexyfi
/ ) -2-cyclobentenone (Vl-1) mixture e
J 17.6 f I got it ◎ (V-1) and (Vl-1)
The production ratio is 70:80.

Refractive index n' 1.4866 Next, the 4-acetoxy-5-(ω-methoxycarbonylhexy/l/)-2-cyclobentenone (V
-1) and 4-acetoxy-2-(ω-methoxycarbonyhexyne/L/)-2-cyclobentenone (VI-
1) a Compound 4 y 5008M phosphate buffer y'
-(pH7,5) 100ml 11g' black μmethane 8mj
and Pseudomonas lipase (Amano Riverase rp
J) Charge 800 mF and stir vigorously at 25-80°C for 15 hours. After the reaction is complete, dilute the reaction solution with 40 mF of toluene.
Extract twice with mjK. The organic layers are combined and concentrated under reduced pressure to obtain a concentrated residue of 8.85F.

The concentrated residue was purified by column chromatography using toene:ethyl acetate/I/(5:2) to obtain j-4-hydroxy$'-
5-(ω-methoxyca~bonihexV/')-2-cyclobentenone (■-1) and d-4-hydroxyS'-
A mixture of 2-(ω-methoxycarbonyμhexy/I/)-2-cyclobentenone (X-1) 1.16F [optical rotation -9.7° (C-1°CHCJI), crystallization on standing 0] and d-4-acetoxyV-5-(ω-methoxycarbonylhexyl$'/Lz)-2-cyclobentenone and no-4-acetoxy-2-(ω-methoxycarbonylhexylVlv)- Mixture of 2-cyclobentenones 2.4
0f (optical rotation +7.9° (C-1, CHCjs)) was obtained. Next, the j-4-hydroxy-5-(ω-methoxycarbonylhexy/L/)-2-cyclobentenone obtained here. (
■-1) and d-4-hydroxy-2-(ω-methoxyVcarbonylhexV/I/)-2-cyclobentenone<x-
0.5 r of the ffi compound of 1> is stirred with 10F alumina in 80 mJ of toluene at 80 to 40°C for 24 hours.

After the reaction is complete, the alumina is separated, and the F solution is concentrated. methoxycarbonylhextOLt)
0.452 of -2-cyclobentenone was obtained.

(q+15.8°(C-1, methanol m, p
59℃ Separately, change to alumina, add 0.48f of the mixture of (■-1) and (I-1) to Flora/l'0.59F, ) ethylamine 0.04F and dichloromethane 10rnJ.
Stir at 80-40°C for 6 hours. After the reaction is complete, wash the reaction solution sequentially with water, 1% hydrochloric acid, 1% sodium bicarbonate, and water. After concentrating the organic layer, the residue is purified by cuff chromatography. , 4R(+)-hydroxy-2-(ω-methoxyVka~
0.4 m of Bonylhexy A/)-2-cyclobentenone.

[ffl, 1” +15.17 (c-1, fig/
-, A/) m, p, 57-8°C Example 2 Example 1 except that the lipase in Example I was replaced with Arthrobacter lipase (New Japan Chemical Industry) 200mf
4-Hydroxy-5-(ω-methoxyVcarbonylhexy/L/)-2- which is reacted, worked up and purified in the same manner as
￥ K compound of clobentenone (■-1) and d-4-hydroxy-2-(ω-methoxycarbonyμhexyl)-2-cyclobentenone (I-1) 1.02 f [optical rotation g -9, i (C-1, cHcts), crystallizes if left standing. ] and d-4-7cetoyacyi 5-(ω-methoxycarbonylhexylhexylV/L/)-2-cyclobentenone and J-4-
Acetoxy-2-(ω-methoxycarbonylhexS//
v) -2-cyclobentenone 2.64F (optical rotation yr<'
+7.4 (c=t, CHC4s), n%'
1.4879) was obtained.0 Next, J-4-hydroxy-5-(ω-methoxycarbonylhexy/L')-2-cyclobentenone (
■-1) and d-4-hydroxy5y-2-(ω-methoxycarbonyhexyl)-2-cyclobentenone (1-1
) mixture 0.48f, pyridine 0. S'', 7/ add 10f of mina and 20mj of tetrahydrofuran from 30 to 86
Stir at ℃ for 20 hours.

After the reaction is completed, the alumina is separated and Pir& is concentrated. The concentration residue method is carried out in the same manner as in Example 1, using V licagel column clot 1.
Manufactured by M ◇4R(+1-hydroxy-2-(ω-methoxycarbonyl)-2-cyclobentenone 0.4
2 F wo get fc.

Ge o + Is, 1° (C20, methanol) m, p,
59~60℃ (29 complete)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and X-Y is CH_2-CH_2
or cisCH=CH, and R' represents a hydrogen atom or an alkyl group) A general method characterized by rearranging a mixture of optically active substituted hydroxy-2-cyclopentenones while maintaining the steric configuration. Optically active 2-substituted-4-hydroxy-2- represented by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R has the same meaning as above.)
Method for producing cyclopentenones. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is a substituent represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ X-Y is CH_2-CH_2
or cisCH=CH, and R' represents a hydrogen atom or an alkyl group. R_1 represents an acyloxyl group. ) A mixture of dl-cyclopentenone esters represented by is asymmetrically hydrolyzed using esterases produced by microorganisms or esterases derived from animals and plants to obtain the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and ▲mathematical formulas, There are chemical formulas, tables, etc. ▼ (In the formula, R has the same meaning as above.) Obtain a mixture of optically active substituted hydroxy-2-cyclopentenones, and further rearrange while maintaining the steric structure. Optically active 2-substituted-4-hydroxy-2- represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R has the same meaning as above.)
Method for producing cyclopentenones. (8) General formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is a substituent represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, (X-Y represents CH_2-CH_2 or cis-CH=CH, and R' represents a hydrogen atom or an alkyl group.) By reacting the mixture with aliphatic carboxylic acids, the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ and ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R has the same meaning as above, and R_1 represents an acyloxyl group.) A mixture of dl-cyclopentenone esters represented by the formula is obtained, and then microorganisms Asymmetric hydrolysis using esterase produced by or esterase derived from animals and plants produces the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R is the same as above. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ A mixture of optically active substituted hydroxy-2-cyclopentenones represented by (In the formula, R has the same meaning as above.) Optically active 2-substituted-4-hydroxy-2-
Method for producing cyclopentenones.