JPS6366143A - Production of optically active cyclopenetenone alcohols - Google Patents

Abstract

PURPOSE:To easily produce the titled compound useful as an intermediate for pharmaceuticals, etc., by using a mixture of 3-hydroxy-4-cyclopentenone and 4-hydroxy-2-cyclopentenone as a raw material without separating into each component and subjecting the material e.g. to asymmetric hydrolysis, etc. CONSTITUTION:A mixture of the compound of formula I (R is 1-7C straightchain alkyl, alkenyl or alkynyl) and the compound of formula II is made to react with >=1 equivalent, especially 1-4 equivalent of an aliphatic carboxylic acid (based on the mixture of the compounds of formula I and formula II) in the presence of a catalyst at -10-+120 deg.C to obtain a mixture of cyclopentenone esters of formula III and formula IV (R'' is alkyl or alkenyl). The ester mixture is subjected to asymmetric hydrolysis with enzyme or microorganism. The resultant mixture of the compounds of formula V and formula VI (* represents asymmetric carbon) is isomerized while keeping the steric specificity to obtain the objective compound of formula VI.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention is directed to the general formula (1) (wherein, R represents a straight-chain alkyl group, alkenyl group, or alkynyl group having 1 to 7 carbon atoms). The optically active 4 shown
-Relating to a method for producing hydroxy-2-cyclobentenones.

<Prior Art> Optically active 4-hydroxy-2-cyclobentenones represented by the above general formula (1) are useful as lIl[, W materials, or intermediates for pharmaceuticals, etc., but are particularly useful for prostaglandin derivatives. 4-hydroxy-2-, in which the substituent R is an allyl group, is extremely important as an intermediate for
Allyl-2-cyclobentenone is JP-A-58-4188
As described in Publication No. 6, it is an extremely important compound as an intermediate to thiaprostaglandins, which have excellent pharmacological effects such as antiplatelet aggregation effects.

Furthermore, 4-hydroxy-2-propargyl-2-cyclobentenone in which R represents a propargyl group can also be converted into a prostaglandin derivative by introducing the propargyl group into another derivative.

For this reason, it is necessary to obtain the compound with high optical purity and industrially advantageously.

Conventionally, 4-hydroxy-2 represented by the general formula (1)
- The following method is known as an asymmetric hydrolysis method using microbial enzymes to obtain cyclobentenones.

(1) JP-A-60-64948 GI) (V) (/I)
CI) (2) JP-A-61-92578 (1!I) (W) (1)
Problems to be Solved by the Invention> In these methods, racemic alcohol, which is a raw material, is usually synthesized by the following method.

(1) (1) (■) However, in the rearrangement reaction from (I) to (1), in addition to 8-hydroxy-4-cyclobentenone (1), 4-hydroxy -2-Cyclobentenone (IT) is produced as a by-product, so it is not always easy to obtain (1) alone, and one more step is required to obtain the next ([V). , A method using each of these (I) and (IV) alone as a starting material is not necessarily satisfactory from an industrial point of view.

For this reason, the present inventors have developed a method for producing the optically active 4-hydroxy-2-cyclobentenones represented by the general formula (1) and the general formula (II) and (
If the racemic alcohol [V) can be used as a mixture, it would be extremely advantageous for industrial implementation, and as a result of research on the production method, the present invention was achieved.

<Means for solving the problems> That is, the present invention provides 8-hydroxy-4-cyclobentenone represented by the general formula (1 and (ff) (wherein R has the same meaning as above). A mixture of (I) and 4-hydroxy-2-cyclobentenone (IV) is reacted with aliphatic carboxylic acids to form the general formula (V) and (ν■) (wherein R' is substituted with halogen). is an optional alkyl group or alkenyl group, and R has the same meaning as above.) A mixture of cyclobentenone esters (V)
and (VI), and then subjected to asymmetric hydrolysis using enzymes or microorganisms to obtain general formulas (vI) and (1) (wherein, R has the same meaning as above, and * indicates an asymmetric carbon (in the formula, R
has the same meaning as above, and the * mark indicates an asymmetric carbon. ) Provides a method for producing optically active 4-hydroxy-2-cyclobentenones shown in the following.

The present invention will be explained in detail below.

The above general formula (1) used as a raw material in the present invention
8-hydroxy-4-cyclobentenone (1) and 4-hydroxy-2-cyclobentenone (ff) represented by can be synthesized into

Such racemic 8-hydroxy-4-cyclobentenone (I[) and 4-hydroxy-2-cyclobentenone (
For the esterification reaction between the mixture of ff) and aliphatic carboxylic acids, a conventional method for producing esters is applied, and racemic (1
The reaction is carried out by reacting a mixture of ) and (ff) with an aliphatic carboxylic acid, its acid hydrate, or its acid halide in the presence or absence of a solvent using a catalyst.

For example, the following compounds are exemplified.

Acetic acid, acetic acid chloride, acetate bromide, acetic anhydride, propionic acid, propionic acid chloride or pro(d), propionic anhydride, butyryl chloride or pro(d), caproyl chloride or bromide, caprylic acid chloride or bromide, cabrinoyl chloride or Promide, dodecatuin chloride or promide, pal [toyl chloride or pro [d], chloracetyl chloride or promide, dichloroacetyl chloride or pro [d].

The aliphatic carboxylic acids used in the reaction are required in an amount of 1 equivalent or more based on the mixture of racemic cyclobentenone (1) and CN') as raw materials, and the upper limit is not particularly limited, but is preferably 1 to 4 equivalents. be.

In this reaction, when a solvent is used, examples of the solvent include aliphatic or Examples include solvents that are inert to the reaction, such as aromatic hydrocarbons, ethers, and halogenated hydrocarbons, either alone or as a mixture. 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 methylate, and potassium bicarbonate. The amount used is not particularly limited, but cyclobentenone (Ill.
and (■) in an amount of 1 to 6 equivalents.

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

Furthermore, acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can also be used as catalysts.

The reaction temperature is usually -20°C to 150°C, preferably in the range of -10°C to 120°C.

There is no particular restriction on the reaction time.

By such a reaction, general formulas (V) and (Vl)
A mixture of racemic cyclobentenone esters, represented by However, the reaction mixture can proceed to the next step as it is.

Optically active 8- represented by general formulas (vI) and (1)
Hydroxy-4-cyclobentenone (1) 4-Hydroxy-2-cyclobentenone (1) has the general formula (V)
The microorganism that produces the esterase used in this reaction is a microbial esterase or an animal or plant esterase that has the ability to hydrolyze the optically active form of either one of the mixtures of racemic cyclobentenone esters represented by (vI). Any microorganism that produces an esterase capable of asymmetrically hydrolyzing a mixture of racemic cyclobentenone esters may be used, 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 genus, Arthrobacter genus, Brevibacterium genus, Pseudomonas genus, alkaline earth metals, mainly Crococcus genus, Chromobacterium genus, Microbacterium genus, Corynebacterium genus, Bacillus genus, Lactobacillus metal, Trichoderma genus, Candida, Satucharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces Examples include microorganisms belonging to the genus Hansenula and Achromobacter.

For culturing the above-mentioned microorganisms, a culture solution is usually obtained by carrying out liquid culture according to a conventional method. For example, a sterilized liquid medium [for molds and yeasts, malt extract/yeast extract medium (11 parts of water, 5 g of peptone, 1 oy of glucose, 8 f of malt extract).

Dissolve yeast extract 8f to pH 6.5), and for bacteria, add microorganisms to sweetened bouillon medium (dissolve glucose 10g 1 peptone 5f in water 11, meat extract 511, and Nac18y to make 1)H7.2)]. Usually 20
Culture may be carried out with reciprocating shaking at -40°C for 1 to 8 days, and solid culture may be carried out if necessary.

Furthermore, some of these microbial-derived esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include the following.

Pseudomonas lipase (Amano Pharmaceutical), Aspergillus lipase (Lipase AP (Amano Pharmaceutical)), Mucor lipase M-Ap (Amano Pharmaceutical), Candida cylindrasse lipase (Lipase MY (8))
(manufactured by Sugar Sangyo)) Alkaline earth metal lipase (Lipase P
L (Meito Sangyo)), Achromobacter lipase (
Lipase AL (Meito Sangyo)), Arthrobacter lipase (Lipase Joint BSL (Joint Sake Refining)), Chromobacterium lipase (Toyo Jojo), Rhizopus delemer lipase (Talipase (Tanabe Seiyaku)) ),
Rhizopus lipase (Lipase Saiken (Osaka Bacteria Research Institute)).

Further, animal/plant esterases can also be used, and specific examples of these esterases include the following.

Steapsin, pancreatin, pig liver esterase, Wheat Germ x 5-5-ase.

Esterase (hydrolase) used in this reaction,
Enzymes obtained from animals, plants, and microorganisms can be used in various forms such as purified enzymes, crude enzymes, enzyme-containing products, microbial culture fluids, cultures, bacterial cells, cultured limbs, and processed products. Enzymes and microorganisms can also be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterial cells immobilized on a resin or the like.

This hydrolysis reaction is usually carried out by vigorously stirring a mixture of 2-cyclopentinone esters and the above-mentioned enzyme or microorganism in a buffer solution.

As v1 buffer solution, commonly used sodium phosphate,
Buffers of inorganic acid salts such as potassium phosphate, buffers of organic acid salts such as sodium acetate and sodium citrate, etc. are used, and their pH ranges from 8 to 11. For culture solutions of microorganisms that are not alkaliphilic or for esterases that are not alkali tolerant, pH 5 to 8 is preferred.

The concentration is usually 0.605 to 2M, preferably 0.06 to 0.0M.
The range is 5M.

The reaction temperature is generally 10 to 60C, and the reaction time is generally 4 to 70 hours, but is not limited thereto.

Through such a reaction, optically active 8, which is a hydrolyzate, is produced.
A mixture of -hydroxy-4-cyclobentenone (Vl) and 4-hydroxy-2-cyclobentenone (1) and optically active cyclobentenone esters which are the hydrolysis residue can be obtained.

After the reaction is complete, in order to separate the hydrolysis product and hydrolysis residue from the reaction solution, the hydrolysis solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, or ethyl ether, and the solvent is distilled from the organic layer. Then, the concentrated residue is further distilled or treated with column chromatography to produce a mixture of optically active hydroxycyclobentenones, which are hydrolysis products, and optically active cyclopenteno, which is a hydrolysis residue.

The esters can be separated separately.

The optically active cyclopentyone esters recovered here can be further hydrolyzed and used as raw materials for the production of symmetrical bodies.

Next, from the mixture of optically active 8-hydroxy-4-cyclobentenone (V![) and 4-hydroxy-2-cyclobentenone (I) obtained here, optically active 4-hydroxy-2- The isomerization reaction to cyclobentenone (I) will be explained.

Optically active rx a-hydroxy-4-cyclobentenone (■) and 4-hydroxy-2-cyclobentenone (
Isomerization of the mixture of I) to optically active 4-hydroxy-2-cyclobentenone (I) is usually carried out by rearrangement while maintaining the steric structure in the presence of a base or a catalyst. In this reaction, it is necessary to carry out the rearrangement while keeping the optical purity as high as possible, that is, with as little racemization as possible, and for this purpose, it is necessary to carry out the reaction under appropriate conditions regarding the base or catalyst used, temperature, etc.

Examples of solvents used in this reaction include water, tetrahydrofuran, dioxane, acetone, benzene,
A single or mixture of solvents inert to the reaction, such as aliphatic or aromatic hydrocarbons such as toluene, ethyl acetate, chlorobenzene, heptane, dichloromethane, dichloroethane, diethyl ether, cyclohexane, nityl, ketones, esters, halogenated hydrocarbons, etc. is used.

Bases or catalysts used in this reaction include, for example, organic 8th class amines such as triethylane, N-methylmorpholine, N-methylpiperidine, N1N'-dimethylpiperazine, pyridine, and lutidine, and metals such as alumina and silica gel. oxide, iU-based soda, caustic potash,
Soda carbonate, potassium carbonate, sodium bicarbonate, phosphoric acid 1
Basic buffers such as potassium hydrogen are suitable, and these may be used alone or in combination of two or more.

The amount of such a base or catalyst used is not particularly limited, but is usually 0.05 to 60 times the mole of optically active 8-hydroxy-4-cyclobentenone (1) as a raw material, and is An amine or a basic buffer can also be used as a solvent.

The reaction temperature ranges from -20°C to 180°C and is appropriately selected depending on the solvent, base or medium used.

For example, when the reaction is carried out in the presence of water as a solvent (racemization is less likely to occur in this case, the reaction can be carried out in the range of -10 to 1800). In some cases, the temperature is preferably in the range of -10 to 90°C, and in the case of rearrangement reactions using only water or in the case of strong basicization, the range is preferably in the range of -20 to 50°C.

There is no particular restriction on the reaction time.

From the reaction mixture thus obtained, extraction, separation,
The desired optically active 4-hydroxy-2-cyclobentenone of general formula (1) can be obtained with good optical purity and high yield by common operations such as concentration and distillation. The optically active 4-hydroxy-2-cyclobentenones, which are the target compounds of the present application thus obtained, are R(
The following compounds with → configuration are exemplified.

4-hydroxy-8-methyl-2-cyclobentenone,
2-ethyl-4-hydroxy-2-cyclobentenone,
4-Hydroxy-2-n-benzene-2-cyclobentenone, 2-isopropyl-4-hydroxy-2-cyclobentenone, 4-hydroxy-2-n-butyl-2-cyclobentenone, 2-inbutyl- 4-hydroxy-2
-cyclobentenone, 4-hydroxy-Q-n-pentyl-2-cyclobentenone, 2-isopentyl-4-hydroxy-2-cyclobentenone, 4-hydroxy-2
-n-hexyl-4-cyclobentenone, 4-hydroxy-2-n-heptyl-2-cyclobentenone, 2-allyl-4-hydroxy-2-cyclobentenone, 2-(
2-cis-butenyl)-4-hydroxy-2-cyclobentenone, 4-hydroxy-2-(ω-butynyl)-2
-cyclobentenone, 2-(2-cis-pentenyl)-
4=hydroxy-2-cyclobentenone, 4-hydroxy-(2-trans-pentenyl)-2-cyclobentenone, 2-(8-cis-hexenyl)-4-hydroxy-2-cyclobentenone, 4-hydroxy -2-propargyl-2-cyclobentenone, 4-hydroxy-2-
(2-pentynyl)-4-cyclobentenone, 4-hydroxy-2-(2-methylallyl)-2-cyclopentynon-2-(8-cis-hexenyl)-4-hydroxy-2-cyclobentenone, 4-hydroxy-2-propargyl-2-cyclobentenone, 4-hydroxy-2-
(2-pentynyl)-4-cyclobentenone, 4-hydroxy-2-(2-methylallyl)-2-cyclobentenone.

<Effect of the invention> Thus, according to the method of the present invention, general formulas (1) and (
From the mixture of 8-hydroxy-4-cyclobentenone and 4-hydroxy-2-cyclobentenone represented by Active 4-hydroxy-2-cyclobentenones can be produced industrially advantageously and have extremely high practical value.

<Example> The present invention will be explained below with reference to Examples.

Example 1 dl-8-hydroxy-2-n-pentyl-4-cyclobentenone (1
-1) and dl-4-hydroxy-2-n-pentyl-2
-Mixture of cyclobentenone (ff-1) (1-1/f
f-1-85/15) Charge 16.8F, 1 g of sulfuric acid, and 85 g of acetic anhydride, and continue stirring at 70''C for 4 hours.

After the reaction is completed, acetic anhydride is distilled off under reduced pressure, and the residue is extracted with toluene. The toluene layer was washed with 1% heavy water,
Wash further with water.

Toluene was distilled off from the organic layer, and the concentrated residue was purified by column chromatography using a mixture of toluene:ethyl acetate=10:1. dl-8-acetoxy-2-n-pentyl-4-cyclope 19.91 (95%) 'tP4ri.

('1-1)/(VI-1>= 88/17(b, I)
, 106-116°C10,2-0.5x)IN) Next, the mixture obtained above and 800η of Pseudomonas lipase (Amano "p" manufactured by Amano Pharmaceutical) were mixed in 8M phosphate buffer (pH 7,0). 80-86 in 200sl
Stir vigorously at 10°C. After the reaction is completed, the reaction solution is extracted four times with 50 ml of methyl isobutyl ketone. The solution was distilled off from the obtained organic layer, and the concentrated residue was purified by column chromatography using a mixed solution of ethyl acetate:toluene-8:5 to obtain 1-8-hydroxy-2-n-pentyl-4-
Cyclobentenone (Vl-1) and d-4-hydroxy-2-n-pentyl-2-cyclobentenone (I-1
) mixture 8.4 yC((Vll-1)/(I)=s
O/20), optical rotation -42.1° (c=l, chloroform)] and [d-8-acetoxy-2-n-pentyl-4-cyclobentenone and β-4-acetoxy-
Mixture of 2-n-penwal-2-cyclobentenone 6
．． 8g1e luminosity + 87.5'(C"Is chloroform)].

Next, the 1-8-hydroxy-2-n-pentyl-4-cyclobentenone (■-1) and d-4-hydroxy-2-n-pentyl-2-cyclobentenone (I
-1) mixture 111 alumina 20f and benzene 5
0 g/ is stirred at 60°C for 7 hours. After the reaction is completed, the alkaline solution is separated from each other and washed twice with 10w1 methanol. The filtrates were combined and concentrated, and the residue was purified by column chromatography using a mixture of toluene and ethyl acetate = 5:8.
0.941 of (t)-4-hydroxy-2-n-pentyl-2-cyclobentenone was obtained.

Optical rotation +12.7° (C = 1.chloroform) Example 2 dl-2-allyl-8-hydroxy-4-cyclobentenone (If-2) and dl-2-allyl-4-
Mixture C of hydroxy-2-cyclobentenone (■-2) (l [-2) / ([V-2) = 82/18) 1B, 8
0.5f of fonic acid and 27% of acetic anhydride
．． 61 and heat at 90'C for 4 hours. Hereinafter, post-treatment and purification were carried out according to Example 1, and dl-8-acetoxy-2-allyl-4-cyclobentenone (V-2) and dl-4-acetoxy-2-allyl-2-Schif0
Beni, 'te, /:/ (vI 2) 16.1fI (96%
Yield) was obtained. ((V-2)/(W-2)-81/19
), b, p, 82-90℃10.7-1.2xxH'f
Mixture 1 of dt-8-acetoxy-2-allyl-4-cyclobentenone (V-2) and dl-4-acetoxy-2-allyl-2-cyclobentenone (Vll-2)
．． Of and Pseudomonas lipase 800Wg,
Stir vigorously in 250 ml of 0.8M phosphoric acid buffer (pH 7,0) at 20-25°C for 7 hours. After completion of the reaction, post-treatment and purification were performed according to Example 1 to obtain 1-2-allyl-8-hydroxy-4-cyclobentenone ([-2)
and 8.07 f (([-2
)/CI-2)=7'l/2B), optical rotation [α), -
18,5° (c=l, chloroform)) and d-8-acetoxy-2-allyl-4-cyclobentenone and 1-
4-acetoxy-2-aryl JL/- 5 Kuzu mixture of clobentenone 6.9 [optical rotation +6
0°4° (c=l, chloroform) was obtained.

Next, the 1-2-allyl-8-hydroxy-4- obtained here
Cyclobentenone (Vl-2) and d-2-allyl-
A mixture of 2f of 4-hydroxy-2-cyclobentenone (1-2), 0.5 g of pyridine, 80 f of Al and 150 ysl of chloroform are stirred at 40 to 60°C for 10 hours.

After the reaction is complete, the alkaline solution is separated from the furnace, and methanol 1 (1
Wash twice with +l. It was concentrated together with P solution, and the residue was purified by column chromatography using a mixture of toluene and ethyl acetate = 628 to give R(t)-2-allyl-4-hydroxy-
1.84f of 2-cyclobentenone (1-2) was added.

+18.1° after optical rotation (c=l, chloroform) Example 8 A flask is charged with 15 g of acetic anhydride, 18.2 f of methyl isobutyl ketone and 0.91 g of sulfuric acid. Next di-8
-Mixture of hydroxy-2-propargyl-4-cyclobentenone (ll-8) and dl-4-hydroxy-2-propargyl-2-cyclobentenone (ff-8) ((
ll-8)/(ff-8) =70/80)18.6
A solution of 50f of methyl isobutyl ketone from 9 is added over a period of 2 hours at 40°C. After incubating at the same temperature for 2 hours, 100% water and 50f of methyl isobutyl ketone were added. After separating the aqueous layer, the organic layer is washed with 1% NaOH water. After washing with water, it is concentrated and further distilled under reduced pressure. dl-8-acetoxy-2-propargyl-4-cyclobentenone (V-8') and dl-4-acetoxy-2-propargyl-2-cyclobentenone (vI-8
) 16.2 g (yield 91%) was obtained. ((V-8>/(
W-8)=72/28 >, b, p, 118-180
°C10,1-0.2ggHf) dl-8-acetoxy-2-propargyl-4-cyclobentenone (V-8) and dl-4-7setoxy2
- 10f of a mixture of propargyl-2-cyclobentenone (%T-8) and 100IIg of Arthrobacter lipase (Shin Nippon Kagaku 'A) at 0.8M IJ:/
Stir vigorously for 8 hours at 80°C in acid buffer (pH 7,0) 100°C.

Bentenone (■-8) and d-4-hydroxy-2-
Propargyl-2-cyclobentenone (I-8) (Da
Compound 8.24 f ((VI-8)/Cl-8) = 66
/! 94, optical rotation [α), -25.8° and l
-4.acetoxy-2-propargyl-2-cyclobentenone mixture 5.5 f [optical rotation [α] D +58.
1° (C=1.chloroform)].

Next, the 1-8-hydroxy-2-propargyl-4-cyclobentenone (Vl-8) and d-4-hydroxy-2-propargyl V 77-2-cyclobentenone (1-8>) obtained here were Mixture 2f was dissolved in 10 gt of a mixed solution of pyridine and water (1/10 volume ratio), basic alumina 6f was added, and the mixture was heated at 80°C for 20 g.
Stir for an hour.

After the reaction is completed, the alumina is separated from the furnace, and the P solution is neutralized with IN hydrochloric acid water, and then extracted four times with 20-methyl isobutyl ketone. Collect and concentrate the organic layers. The residue was purified by column chromatography using a mixture of toluene and ethyl acetate = 1:1.
R(t)-4-hydroxy-2-propargyl-2-cyclobentenone (1-8N, 61F) was obtained.

(80 complete)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. A mixture of 8-hydroxy-4-cyclopentenone and 4-hydroxy-2-cyclopentenone shown in , chemical formulas, tables, etc. ▼ (In the formula, R^9 represents an alkyl group or alkenyl group that may be substituted with halogen, and R has the same meaning as above.) Cyclopentenone esters represented by to obtain a mixture of
Next, asymmetric hydrolysis is performed using enzymes or microorganisms, resulting in the general formulas ▲Mathematical formulas, chemical formulas, tables, etc.▼ and ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formulas, R has the same meaning as above. , * indicates an asymmetric carbon.) A mixture of optically active 8-hydroxy-4-cyclopentenone and 4-hydroxy-2-cyclopentenone was obtained. There are general formulas, ▲mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R has the same meaning as above, and the * mark indicates an asymmetric carbon.) Method for producing hydroxy-2-cyclopentenones