JPH06104644B2 - Process for producing optically active cyclopentenone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention provides a compound of formula (I) (In the formula, R represents an acylating agent residue or an etherifying agent residue, and an asterisk represents an asymmetric carbon atom.) The optical activity represented by the formula relates to a method for producing a cyclopentenone derivative.

<Prior Art> The optically active cyclopenone derivative represented by the general formula (I) is useful as an intermediate for medicines, agricultural chemicals, and the like, and is particularly useful as a medicine for various antiulcer action, thrombolytic action, blood pressure lowering action and the like. It is useful as an intermediate of a prostaglandin derivative or a thiaprostaglandin derivative having a pharmacological action.

By the way, conventionally, the substituent R in the general formula (I) is
Is a hydrogen atom, for example R (+)-2-allyl-4
-Hydroxy-2-cyclopentenone is known,
Since the compound has —OH as it is, it is difficult to lead it to a prostaglandin derivative. Therefore, in the above general formula (I) having a protecting group which can be easily removed at any stage for leading to a prostaglandin derivative. The shown optically active cyclopentenone derivatives are of importance.

Conventionally, as a method for producing such an optically active cyclopentenone derivative, for example, a method of introducing a protecting group into the hydroxyl group of R (+)-2-allyl-4-hydroxy-2-cyclopentenone is known (special feature (Kaisho 57-171932 publication).

By the way, R (+)-2- which is a raw material in this method
Allyl-4-hydroxy-2-cyclopentenone is, for example, dl-2-allyl-4-hydroxy-2-cyclopentenone and an optically active formula. The compound is produced by dehydrating and condensing the lactone represented by the formula (1) and then hydrolyzing (JP-A-58-41836). However, this method involves the reaction at a high temperature in the condensation and hydrolysis with the lactone. -Allyl-4-hydroxy-2-cyclopentenone has a problem that it is easily decomposed, and this method has a problem that it involves complicated treatments such as separation and hydrolysis of diastereomers. In terms of aspects, it is not an industrially advantageous method.

<Problems to be Solved by the Invention> From the above, the present inventors show the compound represented by the general formula (I) without passing through the optically active 2-allyl-4-hydroxy-2-cyclopentenone. As a result of investigations for producing an optically active cyclopentenone derivative, the present invention has been achieved.

<Means for Solving Problems> The present invention provides a compound represented by the general formula (II): (In the formula, R represents an acylating agent residue or an etherifying agent residue, and * indicates an asymmetric carbon atom.) The optically active 2-propargyl-4-hydroxy-2-cyclopentenone derivative The present invention provides a method for producing an optically active cyclopentenone derivative represented by the above general formula (I), which comprises catalytically hydrogenating in the presence of a palladium catalyst to carry out partial reduction.

In this reaction, the optically active 2-propargyl-4-hydroxy-2-cyclopentenone derivative represented by the general formula (II) used as a raw material is, for example, an optically active 2-propargyl-4-hydroxy-2-cyclopentenone. Can be easily obtained by acylating or etherifying.

In such acylation or etherification, examples of the acylating agent include saturated or unsaturated organic carboxylic acid anhydrides and organic carboxylic acid halides.
Acetic acid chloride or bromide, propionic acid chloride or bromide, propionic anhydride, butyryl chloride or bromide, caproyl chloride or bromide, caprylic acid chloride or bromide, stearic acid chloride or bromide, caprynoyl chloride or bromide, dodecanoin chloride or bromide , Palmitoyl chloride or bromide, chloroacetyl chloride or bromide, dichloroacetyl chloride or bromide, and the like.

As the etherifying agent, trimethylsilyl chloride, dimethylisopropylsilyl chloride, t-butyldimethylsilyl chloride, benzyl chloride, benzyl bromide, dihydropyran, tetrahydropyran, vinyl ethyl ether, (1R, 5S) -6,6-dimethyl-4 -Hydroxy-3-oxabicyclo [3,1,0] hexan-2-one and the like are exemplified.

The reaction of the optically active 2-propargyl-4-hydroxy-2-cyclopentenone with the acylating agent or etherifying agent is carried out by reacting with a catalyst in the presence or absence of a solvent.

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

The amount of the acylating agent or etherifying agent used in the reaction must be 1 equivalent or more with respect to the optically active 2-propargyl-4-hydroxy-cyclopentenone, and the upper limit is not particularly limited, but preferably 4 equivalents. Is.

Examples of the catalyst include organic or inorganic basic substances such as dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine, picoline, lysine, imidazole, sodium carbonate, sodium methylate and potassium hydrogen carbonate. Further, an organic acid such as toluene sulfonic acid, methane sulfonic acid or sulfuric acid or an inorganic acid can be used as a catalyst.

In using such a catalyst, for example, pyridine is particularly preferable when an acid halide is used as an acylating agent, and dimethylaminopyridine and imidazole are tetrahydropyran when a silyl chloride is used as an etherifying agent. In this case, p-toluenesulfonic acid is particularly preferably used.

The amount of the catalyst used varies depending on the combination of the acylating agent or etherifying agent and the catalyst used, and cannot be specified.For example, when an acid halide or silyl chloride is used as the acylating agent or etherifying agent, Is used in an amount of 1 equivalent or more with respect to the acylating agent or etherifying agent. When tetrahydropyran is used as the etherifying agent and p-toluenesulfonic acid is used as the catalyst, the amount of the catalyst is 1 to 10 wt% with respect to tetrahydropyran. %.

The reaction temperature is usually −30 ° C. to 100 ° C., preferably −2
The temperature is 5 ° C to 80 ° C.

The reaction time is not particularly limited, and the time point when the optically active 2-propargyl-4-hydroxy-2-cyclopentenone as the raw material disappears can be used as the end point of the reaction.

After completion of the reaction, the desired optically active 2-propargyl-4-hydroxy-formula represented by the general formula (II) is obtained from the reaction mixture by a conventional separation means such as extraction, concentration and distillation.
The 2-cyclopentenone derivative can be isolated and, if necessary, purified by column chromatography or the like.

In addition, the optically active 2 which is a raw material compound in this reaction
-Propargyl-4-hydroxy-2-cyclopentenone has the general formula (III) (In the formula, R'represents an alkyl group or an alkenyl group which may be substituted with halogen), and it can be obtained by asymmetric hydrolysis of an esterase on dl-cyclopentenone esters. .

In this reaction, the above-mentioned dl-cyclopentenone ester as a raw material can be easily synthesized by reacting dl-2-propargyl-4-hydroxy-2-cyclopentenone with an organic carboxylic acid.

Here, as the organic carboxylic acid, a saturated or unsaturated organic carboxylic acid anhydride similar to the acylating agent described above,
Examples thereof include organic carboxylic acid halides.

Such asymmetric hydrolysis of dl-cyclopentenone esters hydrolyzes one of the optically active substances of the raw material dl-4-cyclopentenone esters by causing an esterase produced by a microorganism or an esterase derived from animals and plants to act. It is done by

The esterase-producing microorganism used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze the dl-cyclopentenone esters represented by the general formula (II), and is not particularly limited. It is not something that will be done.

The esterase in the present invention means an esterase in a broad sense including lipase.

Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candidate, Saccharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus,
Examples are microorganisms belonging to the genera Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula and Achromobacter.

For the culture of the above-mentioned microorganisms, a liquid culture is usually obtained by performing liquid culture according to a conventional method.

Some of these esterases originating from microorganisms are commercially available and can be easily obtained. Specific examples of commercially available esterases include the followings.

Pseudomonas lipase (manufactured by Amano Pharmaceuticals) Lipase of genus Aspergillus [lipase AP (manufactured by Amano Pharmaceuticals)], lipase AP of genus Mucor (manufactured by Amano Pharmaceuticals), Candida. Cylindracee lipase [Lipase MY (Meito Sangyo)], Alcaligenes lipase [Lipase PL (Meito Sangyo)], Achromobacter lipase [Lipase AL (Meito Sangyo)], Arthrobacter Lipase [lipase joint BSL (purified joint liquor)], chromobacterium lipase (manufactured by Toyo Brewery Co., Ltd.), Rhizopus. Derema lipase [Talipase (manufactured by Tanabe Seiyaku), Rhizopus lipase [Lipase Saiken (Osaka Bacteria Research Institute)].

Also, animals. Plant esterases can also be used, and specific esterases thereof include the following.

Steapsin, pancreatin, pig liver esterase, Wheat Gevm esterase.

As the esterase used in this reaction, an enzyme obtained from an animal, a plant or a microorganism is used, and its usage forms include a purified enzyme, a crude enzyme, an enzyme-containing material, a microbial culture solution, a culture, a bacterium, a culture port. It can be used in various forms such as a liquid and a product obtained by treating them as needed, and an enzyme and a microorganism can also be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterium immobilized on a resin or the like.

The asymmetric hydrolysis reaction of dl-cyclopentenone esters is usually carried out by vigorously stirring a mixture of the starting dl-cyclopentenone esters and the enzyme or microorganism in a buffer solution.

As the buffer solution, a commonly used buffer solution of an inorganic acid salt such as sodium phosphate or potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate or sodium citrate, and the like can be used. PH of 8 to 11 for the culture broth and alkaline esterase, and for the culture broth of non-alkalophilic microorganisms and the esterase not having alkali tolerance
A pH of 5-8 is preferred. The concentration is usually 0.05 to 2M, preferably
It is in the range of 0.05 to 0.5M.

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

By such a reaction, either one of the raw material dl-cyclopentenone esters is hydrolyzed to produce optically active 2-propargyl-4-hydroxy-2-cyclopentenone.

After the completion of such a hydrolysis reaction, in order to separate the hydrolysis product and the hydrolysis residue from the reaction solution, the hydrolysis reaction solution is treated with, for example, methyl isobutyl ketone, ethyl acetate,
Extraction treatment with a solvent such as ethyl ether, the solvent is distilled off from the organic layer and then the concentrated residue is further distilled, or it is carried out by a method such as column chromatography.
This gives optically active 2-propargyl-4-hydroxy-2-cyclopentenone.

The optically active cyclopentenone derivative represented by the general formula (I) is obtained by reacting the optically active 2-propargyl-4-hydroxy-2-cyclopentenone derivative represented by the general formula (II) in the presence of a palladium catalyst. It is produced by catalytic hydrogenation and partial reduction of triple bond to double bond.

The palladium-based catalyst used in this reaction can be used without particular limitation as long as it can selectively reduce the triple bond to selectively stop the double bond,
Generally, a palladium-based catalyst having calcium carbonate, barium carbonate, barium sulfate, diatomaceous earth, etc. as a support carrier is preferable.

Among such palladium-based catalysts, lead acetate,
Those partially poisoned with lead sulfate, zinc acetate, quinoline, iron, lead, copper and the like are suitable because of their excellent selectivity, and a Lindlar catalyst is particularly preferably used.

As a specific example of such a catalyst, for example, 5% palladium-
Lead-calcium carbonate, 5% palladium-lead acetate-calcium carbonate, 5% palladium-quinoline-barium sulfate, 5% palladium-calcium carbonate, 5% palladium-barium carbonate, 5% palladium-barium sulfate, 5% palladium-diamond Soil etc. are illustrated.

The amount of the palladium-based catalyst used is not particularly limited and may be appropriately set depending on the reaction conditions such as the type of the palladium-based catalyst, the solvent and the reaction temperature, and is not particularly limited. Generally, the starting optically active 2-propargyl- 4-hydroxy-2
-0.01-10% by weight, based on the cyclopentenone derivative.

The reduction reaction is usually carried out in a solvent, and any solvent that is inert to the reaction can be used without particular limitation. Specifically, water, methanol, ethanol, ether, ethyl acetate,
Tetrahydrofuran, dioxane, toluene and the like are exemplified.

The reaction temperature is usually in the range of -20 to 100 ° C.

The reaction time is not particularly limited, but it is preferable to stop the reaction when the hydrogen consumption reaches about 1 to 1.1 times the equivalent of the raw material in order to further increase the selectivity.

After completion of the reaction, a solid compound such as a catalyst is separated by an ordinary separation means such as a reaction liquid to separate solids such as a catalyst, and then the liquid is concentrated and then represented by the desired general formula (I) by a method such as distillation or column chromatography. The optically active 2-allyl-4-hydroxy-2-cyclopentenone derivative can be obtained.

<Effects of the Invention> According to the method of the present invention, an optically active 2-allyl-4-hydroxy-2-cyclopentenone derivative having high optical purity with high selection and high yield can be obtained.

Further, an optically active 2-compound produced by introducing the acylating agent residue or the etherifying agent residue thus produced as a protecting group.
The allyl-4-hydroxy-2-cyclopentenone derivative can be removed to the prostaglandin derivative by removing the protecting group at any stage.

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

Example 1 R (+)-was added to a 50 ml shaking type reaction vessel equipped with a normal pressure hydrogenation device.
2-propargy-4-acetoxy-2-cyclopentenone (▲ [α] ²⁰ _D ▼ = + 62.8 ° (C = 1, chloroform) 1
gr, 5% pd-pb ( OCOCH 3)) was charged ₂ CaCO ₃ catalyst 0.02gr and methanol 30 ml, shaken vigorously at room temperature while blowing hydrogen gas. Hydrogen absorption amount is 130 ml (about theoretical amount)
The reaction was stopped when. The reaction solution is passed through to remove the catalyst, and the solution is concentrated to obtain a residue of 1.0 gr. The residue is purified by chromatography (developing solvent, toluene: ethyl acetate = 5: 3) to give R (+)-2- 0.96 g (yield 96.0%) of allyl-4-acetoxy-2-cyclopentenone was obtained.

▲ [α] ²⁰ _D ▼ + 82.5 (C = 1, chloroform) ▲ n ²⁵ _D ▼ 1.4858 Example 2 (1R, 5S) -6,6-dimethyl-3-in the same device as that used in Example 1. Oxa-4 (R)-[1 (R) -4-oxo-3-propargyl) -2-cyclopentenyloxy]
Bicyclo [3,1,0] hexan-2-one (▲ [α] ²⁰ _D ▼
= -77.1 ° (C = 1, ethanol) 1g, 5% Pd-Pb (OCOC
H ₃₎ were charged ₂ CaCO ₃ catalyst 0.02gr and methanol 30 ml, perform the same treatment as in Example 1 (1R, 5S) -6,6-
Dimethyl-3-oxa-4 (R)-[1 (R) 4-oxo-3-allyl) -2-cyclopentenyloxy] bicyclo [3,1,0] hexan-2-one 0.94 g (yield 94.7 %)
Got

▲ [α] ²⁰ _D ▼ -55.9 ° (C = 1, ethanol) ▲ n ²⁵ _D ▼ 1.5112 Example 3 A device similar to that used in Example 1 was equipped with R (+)-4-trimethylsiloxy-2-propargyl- 2-Cyclopentenone (▲ [α] ²⁰ _D ▼ + 6.0 ° (C = 1, chloroform)) 1
g, 5% Pd-BaSO ₄ catalyst 0.02 g and methanol 30 ml were charged, and the same treatment as in Example 1 was carried out to carry out R (+)-4-.
Trimethylsiloxy-2-allyl-2-cyclopentenone 0.97 g (yield 96.1%) ▲ [α] ²⁰ _D ▼ + 16.8 ° (C = 1, chloroform) ▲ n ²⁵ _D ▼ = 1.4678 Example 4 Example 4 R (+)-4-t-butyldimethylsiloxy-2-propargyl-2-cyclopentenone (▲ [α] ²⁰ _D ▼ = 9.28 ° (C = 1, chloroform) 1 g, 0.02 g of 5% Pd-BaSO ₄ catalyst, and methanol
Charge 30 ml and perform the same treatment as in Example 1
(+)-4-t-Butyldimethylsiloxy-2-allyl-2-cyclopentenone 0.98 gr (yield 97.2%) was obtained.

▲ [α] ²⁰ _D ▼ + 21.31 ° (C = 1, chloroform) ▲ n ²⁰ _D ▼ 1.4701 Example 5 A device similar to that used in Example 1 was used, in which R (+)-4-tetrahydropyranyl-2- Propargyl-2-cyclopentenone 1 g (▲ [α] ²⁰ _D ▼ + 2.5 ° (C = 1, chloroform)), 5% Pd-BaSO ₄ catalyst 0.02 g, and methanol 30
After charging ml, the same treatment as in Example 1 was performed to obtain R (+)
0.98 g (yield 97.1%) of -4-tetrahydropyranyl-2-allyl-2-cyclopentenone was obtained.

▲ [α] ²⁰ _D ▼ + 10.52 (C = 1, chloroform) ▲ n ²⁵ _D ▼ 1.4891 Examples 6 to 10 The catalysts shown in Table 1 were used instead of the catalysts used in Example 1. Reaction and post-treatment were carried out in the same manner as in Example 1 and Table-1
The results shown in are obtained.

Example 11 4 g of dl-2-propargyl-4-acetoxy-2-cyclopentenone and 40 mg of lipase "Amano p" (manufactured by Amano Pharmaceutical Co., Ltd.) were added to 40 ml of 0.1 M phosphate buffer (pH = 7),
The mixture is reacted under vigorous stirring at room temperature under a nitrogen atmosphere for 25 hours. After completion of the reaction, Glauber's salt is added to the reaction solution, and the mixture is extracted with methyl isobutyl ketone. The extract was concentrated, and the concentrated residue was purified by column chromatography with a mixed solvent of ethyl acetate: toluene = 3: 5 to obtain R (+)-2-propargyl-4-hydroxy-2-cyclopentenone (1.2 g, optical purity). 94.6%)
Got

This R (+)-2-propargyl-4-hydroxy-2
-1.2 g of cyclopentenone, 1.2 g of pyridine and 30 ml of dichloromethane are charged into a flask, and 1.04 g of acetyl chloride is added dropwise thereto at 10 to 20 ° C over 1 to 2 hours. After the addition is complete, stir at room temperature for 24 hours, add 20 ml of water,
Decomposes excess acetyl chloride. The obtained reaction mixture is separated, and the organic layer is washed with 1% aqueous hydrochloric acid and 1% aqueous sodium hydrogen carbonate and then with water. Dichloromethane was distilled off from the obtained organic layer, and the concentrated residue was distilled to obtain R (+)-2.
- propargyl-4-acetoxy-2-cyclopentenone [▲ [α] _{^{20 D ▼ + 82.5 ° (C}} = 1, chloroform)]
1.48 g was obtained.

This R (+)-2-propargyl-4-acetoxy-2
- cyclopentenone 1.4g, 5% Pd-Pb ( OCOCH 3) 2 -CaC
0.03 g of O ₃ catalyst and 30 ml of methanol were charged in the same apparatus as used in Example 1 and treated in the same manner as in Example 1 to give R
1.36 g (yield 96.1%) of (+)-2-allyl-4-acetoxy-2-cyclopentenone was obtained.

▲ [α] ²⁰ _D ▼ + 82.3 ° (C = 1, chloroform) ▲ n ²⁵ _D ▼ 1.4858

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07F 7/18 A C12P 7/38 // B01J 23/44 X 8017-4G C07B 61/00 300

Claims (4)

[Claims] 1. A compound of the general formula obtained by acylating or etherifying optically active 2-propargyl-4-hydroxy-2-cyclopentenone with an acylating agent or an etherifying agent. (In the formula, R represents an acylating agent residue or an etherifying agent residue, and * indicates an asymmetric carbon atom.) The optically active 2-propargyl-4-hydroxy-2-cyclopentenone derivative General formula characterized by subjecting the resulting product to catalytic hydrogenation in the presence of a palladium-based catalyst to carry out partial reduction. (In the formula, R and * have the same meanings as described above.) Optically active 2-allyl-4-hydroxy-2
-Method for producing cyclopentenone derivatives. 2. General formula (In the formula, R ′ represents an alkyl group or an alkenyl group which may be substituted with halogen), the esterase is allowed to act on the dl-cyclopentenone ester to asymmetrically hydrolyze the resulting optically active compound. 2-propargyl-4-
Hydroxy-2-cyclopentenone is acylated or etherified with an acylating agent or an etherifying agent to give a compound of the general formula (In the formula, R represents an acylating agent residue or an etherifying agent residue, and * indicates an asymmetric carbon atom.) The optically active 2-propargyl-4-hydroxy-2-cyclopentenone derivative General formula characterized by subjecting the resulting product to catalytic hydrogenation in the presence of a palladium-based catalyst to carry out partial reduction. (In the formula, R and * have the same meanings as described above.) Optically active 2-allyl-4-hydroxy-2
-Method for producing cyclopentenone derivatives. 3. The palladium catalyst according to claim 1, wherein the palladium catalyst is a partially poisoned palladium catalyst.
The manufacturing method according to item. 4. The method according to claim 3, wherein the partially poisoned palladium-based catalyst is a Lindlar catalyst.