JP3015813B2 - Method for producing optically active 4-hydroxy-2-cyclopentenone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing an optically active 4-hydroxy-2-cyclopentenone derivative [1], a precursor thereof, and a method for producing the precursor.

[0002]

BACKGROUND OF THE INVENTION Optically active 4-hydroxy-2-cyclopentenone derivatives [1] are compounds useful as intermediates for medicinal and agricultural chemicals, especially prostaglandins. Optically active 4-hydroxy-2-
As a method for producing cyclopentenone, 2-propargyl-4-hydroxy-2-cyclopentenone is esterified, and the ester is hydrolyzed using an enzyme (JP-A-63-000292). -Hydroxy-2-cyclopentenone is esterified, and the esters are reacted with an optically active 1,6-diphenyl-4,4-hexadiyne-1,6-diol derivative to form a complex, separated, and further separated. Optically active 4-hydroxy-
2-cyclopentenone esters are obtained and hydrolyzed (JP-A-63-179848), by reacting 2-allyl-4-hydroxy-2-cyclopentenone with optically active lactones. A method is known in which an ether compound is obtained by subjecting the compound to an isomer separation, followed by hydrolysis after isomer separation (Japanese Patent Application Laid-Open No. 58-41836). However, both methods have drawbacks in that it is necessary to once protect the hydroxy group by esterification, etherification or the like of 4-hydroxy-2-cyclopentenone, and the separation operation is complicated. However, it is not industrially satisfactory. Recently, attempts have been made to obtain a corresponding optically active substance without protecting the hydroxy group of 4-hydroxy-2-cyclopentenone (JP-A-4-66550), but satisfactory results have been obtained. Not.

[0003] From the above, the present inventors have conducted intensive studies on a method for producing optically active 4-hydroxy-2-cyclopentenones, and as a result, have found that racemic 4-hydroxy-2
When the cyclopentenone derivative [4] is reacted with the optically active propargyl alcohol derivative [2], an optical system comprising the optically active 4-hydroxy-2-cyclopentenone derivative [1] and the optically active propargyl alcohol derivative [2] is obtained. The active complex [3] is found to be obtained as a crystal, and the optically active complex is decomposed to introduce a protective group into the hydroxy group of the racemic 4-hydroxy-2-cyclopentenone derivative [4]. Even without this, the present inventors have found that the optically active 4-hydroxy-2-cyclopentenone derivative [1] can be produced with a high optical yield and can be advantageously produced industrially.

[0004]

That is, the present invention provides a compound represented by the general formula [4]: (Wherein R is an alkyl group having 1 to 6 carbon atoms, 2 to 6 carbon atoms)
Or an alkynyl group having 2 to 6 carbon atoms. ) And a 4-hydroxy-2-cyclopentenone derivative represented by the general formula [2]: (Wherein, R ₁ and R ₂ each independently represent a halogenated phenyl group, an alkylphenyl group, or an alkyl group optionally substituted with a halogen atom, and the # mark represents an asymmetric carbon atom.) With an optically active propargyl alcohol derivative to obtain a compound of the general formula [1] (In the formula, * represents an asymmetric carbon atom, and R represents the same meaning as described above.)
Obtaining an optically active complex [3] comprising a 2-cyclopentenone derivative and an optically active propargyl alcohol derivative [2], and decomposing the optically active complex [3]. The present invention relates to a method for producing a pentenone derivative [1], the optically active complex [3], and a method for producing the optically active complex [3].

Hereinafter, the present invention will be described in detail. The optically active complex [3] comprising the optically active 4-hydroxy-2-cyclopentenone derivative [1] and the optically active propargyl alcohol derivative [2] is optically active with the 4-hydroxy-2-cyclopentenone derivative [4]. It can be produced by reacting with propargyl alcohol derivative [2]. 4-hydroxy- used in the reaction
Examples of the substituent R of the 2-cyclopentenone derivative [4] include an alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group, a vinyl group, a methylvinyl group, a propenyl group, Methylpropenyl group, dimethylpropenyl group, ethylpropenyl group, methylethylpropenyl group, trimethylpropenyl group, butenyl group, methylbutenyl group, dimethylbutenyl group, ethylbutenyl group, butadienyl group, methylbutadienyl group, dimethylbutadienyl group, Ethyl butadienyl group,
Alkenyl group such as pentenyl group, methylpentenyl group, pentadienyl group, methylpentadienyl group, hexenyl group, hexadienyl group, hexatrienyl group, ethynyl group, propynyl group, methylpropynyl group, dimethylpropynyl group, ethylpropynyl group, methyl Alkynyl groups such as an ethylpropynyl group, a butynyl group, a methylbutynyl group, a dimethylbutynyl group, an ethylbutynyl group, a pentynyl group, a methylpentynyl group, and a hexynyl group can be exemplified. The 4-hydroxy-2-cyclopentenone derivative [4] can be produced, for example, by the method described in JP-A-57-99546. The 4-hydroxy-2-cyclopentenone derivative [4] is usually used in a racemic form, but may be an optically active mixture containing a large amount of one of the optically active substances. The amount of the 4-hydroxy-2-cyclopentenone derivative [4] is usually 1 equivalent or more, preferably 2 to 5 equivalent, to the optically active propargyl alcohol derivative [2].

The substituents R ₁ and R _{2 of the} optically active propargyl alcohol derivative may be the same or different, but preferably the same is used. Substituent R ₁ ,
Examples of R ₂ include an alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, a propyl group, a butyl group, a chloromethyl group, a chloroethyl group, a bromopropyl group, a fluorobutyl group, a chlorophenyl group, Examples include a halogenated phenyl group such as a fluorophenyl group and a bromophenyl group, and an alkylphenyl group such as a methylphenyl group, an ethylphenyl group, and a propylphenyl group. Preferably, a chlorophenyl group, a fluorophenyl group, and a bromophenyl group can be mentioned, and more preferably, a chlorophenyl group can be mentioned. Such specific compounds include, for example, (+) or (-)
-1,4-bis [1-phenyl-1- (o-chlorophenyl) -1-hydroxypropynyl] benzene, (+)
Or (-)-1,4-bis [1-phenyl-1- (o
-Bromophenyl) -1-hydroxypropynyl] benzene, (+) or (-)-1,4-bis [1-phenyl-1- (o-fluorophenyl) -1-hydroxypropynyl] benzene, (+) or (-)-1,4-bis [1-phenyl-1- (p-chlorophenyl) -1-
[Hydroxypropynyl] benzene, (+) or (-)
-1,4-bis [1-phenyl-1- (o-methylphenyl) -1-hydroxypropynyl] benzene, (+)
Or (-)-1,4-bis [1-phenyl-1- (o
-Ethylphenyl) -1-hydroxypropynyl] benzene, (+) or (-)-1,4-bis [1-phenyl-1- (p-methylphenyl) -1-hydroxypropynyl] benzene, (+) or (-)-1,4-bis [1-phenyl-1- (p-propylphenyl) -1-
[Hydroxypropynyl] benzene, (+) or (-)
-1,4-bis [1-phenyl-1- (2-chloroethyl) -1-hydroxypropynyl] benzene, (+) or (-)-1,4-bis [1-phenyl-1- (4-
(Chlorobutyl) -1-hydroxypropynyl] benzene, (+) or (−)-1,4-bis [1-phenyl-1-propyl-1-hydroxypropynyl] benzene, (+) or (−)-1,4 -Bis [1-phenyl-1-methyl-1-hydroxypropynyl] benzene,
(+) Or (-)-1- [1-phenyl-1- (o-
Chlorophenyl) -1-hydroxypropynyl] -4-
[1-Phenyl-1- (o-bromophenyl) -1-hydroxypropynyl] benzene, (+) or (-)-
1- [1-phenyl-1- (o-chlorophenyl) -1
-Hydroxypropynyl] -4- [1-phenyl-1-
(O-methylphenyl) -1-hydroxypropynyl]
Benzene, (+) or (-)-1- [1-phenyl-
1- (o-bromophenyl) -1-hydroxypropynyl] -4- [1-phenyl-1- (o-ethylphenyl) -1-hydroxypropynyl] benzene and the like.

The reaction is usually carried out in the presence of a solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and ethylbenzene, hexane, and the like.
Aliphatic hydrocarbons such as heptane, octane, ligroin and petroleum ether, hydrocarbon solvents such as cyclopentane, cyclohexane and cycloheptane, and aliphatic halogenated carbons such as carbon tetrachloride, chloroform and dichloroethane Halogenated hydrocarbon solvents such as aromatic halogenated hydrocarbons such as hydrogen, chlorobenzene and dichlorobenzene; alcohol solvents such as methanol, ethanol, propanol, butanol and cyclopentanol; ether solvents such as ethyl ether; and ethyl acetate And polar solvents such as acetonitrile, etc., and these can be used alone or in combination. Preferably, an aromatic hydrocarbon or a mixture of an aromatic hydrocarbon and an aliphatic hydrocarbon can be used.

[0008] The reaction temperature is optional in the range of -20 ° C to the boiling point of the solvent used, but is usually in the range of 0 to 80 ° C. If necessary, crystallization of the optically active complex [3] is performed by, for example, adding a seed crystal, cooling the reaction solution during crystallization, or adding a solvent, particularly an aliphatic hydrocarbon such as hexane or heptane, to the reaction solution. Can be promoted. After completion of the reaction, for example, by filtration and washing, the optically active complex [3] is obtained as crystals, and can be purified if necessary. The filtrate after crystallization of the optically active complex [3] is
For example, it can be recycled after racemization.

The optically active propargyl alcohol derivative [2] obtained above and the optically active 4-hydroxy-2
-Optically active 4-hydroxy- is obtained by decomposing the optically active complex [3] comprising the cyclopentenone derivative [1].
The 2-cyclopentenone derivative [1] is obtained.

The decomposition can be easily performed by melting, dissolving in a solvent or the like, and decomposing the optically active complex [3] and forming the optically active 4-hydroxy-2-cyclopentenone derivative [1]. Separation can be performed, for example, by the following method. The industrial method is preferred. Distillation method Chromatography method Method of acting guest molecules First, the method will be described. The optically active complex [3] is melted and distilled under normal pressure or reduced pressure to obtain an optically active complex [3].
-Hydroxy-2-cyclopentenone derivative [1] can be distilled off. Usually, the distillation is performed under reduced pressure, and the pressure is usually 0.1 to 30 mmHg. The optically active propargyl alcohol derivative [2] can be recovered and recycled. The following is described. The optically active 4-hydroxy-2-cyclopentenone derivative [1] can be obtained by dissolving the optically active complex [3] in a solvent or the like and performing chromatography, for example, column chromatography. As the developing solvent, for example, solvents such as toluene, ethyl acetate, and chloroform can be used alone or as a mixture. The optically active propargyl alcohol derivative [2] can be recovered and recycled.

The following will be described. By causing a guest molecule to act on the optically active complex [3], an optically active 4-hydroxy-2-cyclopentenone derivative [1] can be obtained. The method comprises mixing an optically active complex [3] with a guest molecule, removing a complex comprising the optically active propargyl alcohol derivative [2] and the guest molecule as crystals, and removing the complex from the optically active 4-hydroxy-2-cyclopentenone. This is a method for obtaining the derivative [1], and various methods can be applied. For example, the following method can be mentioned. (1) After mixing the optically active complex [3] and the guest molecule to form a homogeneous solution, a solvent is added to precipitate a complex comprising the guest molecule and the optically active propargyl alcohol derivative [2]. (2) After mixing the optically active complex [3] and the guest molecule in a solvent to form a homogeneous solution with or without heating, the guest molecule and the optically active propargyl alcohol derivative [2] are cooled or not cooled. Is deposited. (3) An optically active complex [3] and an excess amount of guest molecules are mixed and heated to form a homogeneous solution, and then cooled to precipitate a complex composed of the guest molecules and the optically active propargyl alcohol derivative [2]. Here, the solvent refers to the same solvent as used in the production of the above-mentioned optically active complex [3], and the same solvent as the solvent can be used in this method.

In the reaction, the guest molecules include, for example, methyl ethyl ketone, diethyl ketone, acetone,
Cyclopentanone, ketones such as cyclohexanone, cyclic ethers such as tetrahydrofuran, dioxane and tetrahydropyran, dimethylamine, diethylamine,
Aliphatic amines such as triethylamine; aromatic amines such as aniline, toluidine, xylidine and anisidine; aromatic aldehydes such as benzaldehyde, salicylaldehyde and anisaldehyde; aliphatic sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide;
Formamides such as dimethylformamide and the like can be mentioned, and the amount of use is usually 1 equivalent or more, preferably 2 to 10 equivalent, to the optically active complex [3].
The reaction temperature is optional within the range of -20 ° C to the boiling point of the solvent or guest molecule used, and is usually -10 to 100 ° C.
Range.

After completion of the reaction, the complex consisting of the precipitated guest molecule and the optically active propargyl alcohol derivative [2] is removed by filtration. For example, the filtrate is concentrated to obtain an optically active 4-hydroxy-2-cyclopentene. The tenone derivative [1] is obtained, and if necessary, purification such as chromatography and distillation may be performed. Further, the complex comprising the guest molecule and the optically active propargyl alcohol derivative [2] collected by filtration is recovered and recycled as an optically active propargyl alcohol derivative [2] by, for example, heating under reduced pressure or treatment such as column chromatography. can do.

The optically active propargyl alcohol derivative [2] can be produced, for example, by the following route.

[0015]

According to the present invention, the optically active 4-hydroxy-2-cyclopentenone derivative [1] can be obtained with high optical purity. Further, according to the present invention, in the production of the target compound [1], it is not necessary to introduce a protecting group into the hydroxy group of the 4-hydroxy-2-cyclopentenone derivative [4], and the compound [4] can be directly used. It is industrially advantageous because it can be used, and the operation is simpler and more efficient than the conventional method, and the target compound [1] can be efficiently produced.

[0016]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples. Example 1 A four-necked flask equipped with a stirrer, a thermometer and a condenser was charged with (-)-1,4-bis [1-phenyl-1- (o-).
[Chlorophenyl) -1-hydroxypropynyl] benzene (3.0 g), 2-allyl-4-hydroxy-2-cyclopentenone (1.48 g), and a toluene-hexane mixed solution (20 ml) are charged, dissolved, and allowed to stand at room temperature for 12 hours. The precipitated crystals are filtered to give (-)-1,4-bis [1-phenyl-1-
(O-chlorophenyl) -1-hydroxypropynyl]
Benzene: (+)-2-allyl-4-hydroxy-2-
1.83 g of an optically active complex of cyclopentenone = 1: 1 is obtained. mp 118-120 ° C, optical purity 99.5% ee (measured by HPLC)

Example 2 By performing the same treatment as in Example 1 except that (+)-1,4-bis [1-phenyl-1- (o-chlorophenyl) -1-hydroxypropynyl] benzene is used, +)-
1,4-bis [1-phenyl-1- (o-chlorophenyl) -1-hydroxypropynyl] benzene: (-)-
2-allyl-4-hydroxy-2-cyclopentenone =
A 1: 1 optically active complex is obtained.

Example 3 (-)-1,4-bis [1-phenyl-1- (o-chlorophenyl) -1-hydroxypropynyl] benzene obtained in Example 1: (+)-2-allyl-4 -Hydroxy-2-cyclopentenone = 1: 1 optically active complex 1.83
g was distilled under heating under reduced pressure to give (+)-2-allyl-4-
0.35 g of hydroxy-2-cyclopentenone is obtained. bp 200 ° C / 1mmHg, [α] _D + 35.3 ° (c = 0.6, MeOH),
Optical purity 100% ee (measured by HPLC)

Example 4 (+)-1,4-bis [1-phenyl-1- (o-chlorophenyl) -1-hydroxypropynyl] benzene obtained in Example 2: (-)-4-hydroxy-2 When the optically active complex of -cyclopentenone = 1: 1 is treated in the same manner as in Example 3, (-)-2-allyl-4-hydroxy-
2-cyclopentenone is obtained.

Example 5 A four-necked flask equipped with a stirrer, a thermometer and a condenser was charged with (-)-1,4-bis [1-phenyl-1- (o-
[Chlorophenyl) -1-hydroxypropynyl] benzene (5.58 g), 2-propargyl-4-hydroxy-2-cyclopentenone (2.72 g) and toluene (20 ml) were charged, dissolved, and allowed to stand at room temperature for 12 hours. The precipitated crystals are filtered to give (-)-1,4-bis [1-phenyl-1- (o-
Chlorophenyl) -1-hydroxypropynyl] benzene: (-)-2-propargyl-4-hydroxy-2-
3.5 g of an optically active complex of cyclopentenone = 1: 1 is obtained. mp 110-115 ° C, optical purity 90% ee (measured by HPLC) ¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm) 2.4-2.5 (m, 1H) (-
(S), 2.6-2.8 (m, 2H) (-S), 3.3 (s, 2H) (-P), 3.5 (s, 1H)
(-S), 3.8-3.9 (m, 1H) (-S), 5.75-5.85 (m, 2H) (-S), 7.
2-7.9 (m, 22H) (-P) (where -S is (-)-2-propargyl-4-hydroxy-2-cyclopentenone and -P is (-)-1,4-
Bis [1-phenyl-1- (o-chlorophenyl) -1
-Hydroxypropynyl] benzene. )

Example 6 By performing the same treatment as in Example 5 except that (+)-1,4-bis [1-phenyl-1- (o-chlorophenyl) -1-hydroxypropynyl] benzene is used, +)-
1,4-bis [1-phenyl-1- (o-chlorophenyl) -1-hydroxypropynyl] benzene: (+)-
An optically active complex of 2-propargyl-4-hydroxy-2-cyclopentenone = 1: 1 is obtained.

Example 7 (-)-1,4-bis [1-phenyl-1- (o-chlorophenyl) -1-hydroxypropynyl] benzene obtained in Example 5: (-)-2-propargyl-4
3.5 g of an optically active complex of 1-hydroxy-2-cyclopentenone = 1: 1 and acetone are mixed, kept under reflux for 3 hours, added with 40 to 50 ml of n-hexane, and cooled to 0 to 10 ° C. After maintaining at the same temperature for 1 hour, the precipitated crystals were filtered and (-)-1,4-bis [1-phenyl-1- (o-
Chlorophenyl) -1-hydroxypropynyl] benzene: acetone = 1: 2 complex (3.0 g) and a filtrate are obtained. This complex is treated at 5 to 10 mmHg and 70 to 80 ° C. to give (−)-1,
4-bis [1-phenyl-1- (o-chlorophenyl)
2.8 g of [-1-hydroxypropynyl] benzene are obtained. mp 122 ° -125 ° C., [α] _D ²⁰ -60.0 ° (c = 1.0, MeOH) On the other hand, the filtrate obtained is concentrated under reduced pressure, and the concentrated residue is purified by column chromatography II to give (−) −
0.67 g of 2-propargyl-4-hydroxy-2-cyclopentenone is obtained. (Α) _D ²⁰ -8.4 ° (c = 1, CHCl ₃ ), optical purity 92% ee (HPLC
(Measured by)

Production Example 1 (-)-1-phenyl-1-in a 1000 ml eggplant flask
After mixing 53.5 g of (o-chlorophenyl) -2-propyn-1-ol ([α] _D = -138 °), 26.0 g of p-dibromobenzene and 280 ml of triethylamine, Pd was added.
Cl ₂ (PPh ₃ ) ₂ -0.10 g, CuI-0.10 g, PPh ₃ -0.52 g were added,
Reflux for about 4 hours after connecting the Dimroth condenser. After cooling, 300 ml of ether was added to dilute the mixture, and the salt between hydrogen bromide and triethylamine was removed by filtration, and the salt was washed with ether. The filtrate and washings are washed with water and dilute hydrochloric acid, and further washed with aqueous sodium bicarbonate and saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated, acetone was added to the concentrated residue, and the mixture was allowed to stand as a crystal as (-)-1,4-bis [1-
A complex of phenyl-1- (o-chlorophenyl) -1-hydroxypropynyl] benzene and acetone is obtained. After recrystallizing this from acetone several times, the crystal was dried in a glass tube oven to obtain (-)-1,4.
-Bis [1-phenyl-1- (o-chlorophenyl)-
49.3 g of [1-hydroxypropynyl] benzene are obtained. mp 72-83 ° C, [α] _D -62.6 ° (c = 1.13, MeOH)

Production Example 2 (+)-1-phenyl-1- (o-chlorophenyl)-
By conducting the reaction and post-treatment in the same manner as in Production Example 1 except for using 2-propyn-1-ol, (+)-1,4-bis [1-phenyl-1- (o-chlorophenyl) -1-hydroxy [Propynyl] benzene is obtained.

────────────────────────────────────────────────── (5) References JP-A-5-255170 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 49/707 C07C 45/85 CA (STN ) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. The general formula [4] (Wherein R is an alkyl group having 1 to 6 carbon atoms, 2 to 6 carbon atoms)
Or an alkynyl group having 2 to 6 carbon atoms. ) And a 4-hydroxy-2-cyclopentenone derivative represented by the general formula [2]: (Wherein, R ₁ and R ₂ each independently represent a halogenated phenyl group, an alkylphenyl group, or an alkyl group optionally substituted with a halogen atom, and the # mark represents an asymmetric carbon atom.) With an optically active propargyl alcohol derivative to obtain a compound of the general formula [1] (In the formula, * represents an asymmetric carbon atom, and R represents the same meaning as described above.)
Obtaining an optically active complex [3] comprising a 2-cyclopentenone derivative and an optically active propargyl alcohol derivative [2], and decomposing the optically active complex [3]. A method for producing the pentenone derivative [1]. 2. An optically active complex [3] comprising an optically active 4-hydroxy-2-cyclopentenone derivative [1] and an optically active propargyl alcohol derivative [2]. 3. An optically active 4-hydroxy-2-cyclopentenone derivative [1] characterized by reacting a 4-hydroxy-2-cyclopentenone derivative [4] with an optically active propargyl alcohol derivative [3]. ] And an optically active propargyl alcohol derivative [2].