JPH0119371B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an optically active 4-hydroxycyclopentenone derivative and a method for producing the same. More specifically, the present invention relates to an optically active 4-hydroxycyclopentenone derivative useful as a synthetic intermediate for prostaglandins and a method for producing the same. Prostaglandins have attracted attention due to their unique physiological activity, and their development as pharmaceuticals has become a topic of greatest interest. However, prostaglandins contain several asymmetric carbon atoms, so
This makes it difficult to obtain optically active prostaglandins. It is also known that the essential structure at positions 11 and 15 (prostaglandin number) has a large effect on physiological activity. On the other hand, natural prostaglandins are not necessarily fully satisfactory as pharmaceuticals in terms of selectivity in physiological activity, stability, absorption and excretion properties, and formulation properties. The present inventors conducted research to develop new drugs using prostaglandin derivatives, and as a result,
We succeeded in synthesizing an optically active 4-hydroxycyclopentenone derivative useful for producing the prostaglandin derivative. According to the present invention, the following formula [] [In the formula, R is a hydrogen atom,

[Formula] or

[Formula] is represented, and * represents an asymmetric carbon atom. ] An optically active 4(R)-hydroxycyclopentenone derivative represented by the following is provided. JP-A No. 54-130556 discloses a novel ether compound containing a chiral atom in an organic residue with the formula Ether compound or formula represented by [In the formula, R″ represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or a cyano group.] However, the present invention provides ether compounds represented by the above formula []
There is no description whatsoever regarding the optically active 4(R)-hydroxycyclopentenone derivative represented by. The optically active 4(R)-hydroxycyclopentenone derivative of the present invention, unlike the above-mentioned known ether compounds, can lead to prostaglandin compounds having excellent pharmacological effects such as antiplatelet aggregation and antiulcer effects. It is extremely useful as an intermediate. Optical activity 4 represented by the above formula [] of the present invention
The (R)-hydroxycyclopentenone derivative is
Although the molecule contains asymmetric carbon atoms, the present invention includes all optical isomers based on these asymmetric carbon atoms, or optically active mixtures thereof in arbitrary proportions. Preferred examples of the optically active 4(R)-hydroxycyclopentenone derivatives of the present invention include the following. 2-Allyl-4(R)
-Hydroxycyclopent-2-enone, 2-allyl-4(R)-hydroxycyclopent-2-
Enone, 2-allyl-4(R) [4-((1R,5S)
-6,6-dimethyl-2-oxo-2-oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone, 2-allyl-4(R)-
[4-((1S,5R)-6,6-dimethyl-2-oxo-3-oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone, 2-allyl-4(S)- [4-((1R,5S)-6,6-
Dimethyl-2-oxo-3-oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone, 2-allyl-4(S)[4-
((1S,5R)-6,6-dimethyl-2-oxo-
3-Oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone. These optically active 4(R)-hydroxycyclopentenone derivatives can be derived, for example, into prostaglandin derivatives having a natural configuration, as shown in the flow sheet below. [In the above general formula, R ³ and R ⁴ represent a hydrogen atom or a hydroxyl group protecting group, R ² represents a hydrogen atom or a methyl group, and R ¹ represents a pentyl group or a cyclohexyl group. ] Thus, the optically active 4(R) obtained by the present invention
-Hydroxycyclopentenone derivatives are extremely useful compounds that can lead to prostaglandin derivatives with a definite structure at position 11. In addition, the optical activity 4 represented by the formula [] of the present invention
(R)-Hydroxycyclopentenone derivative
is a hydrogen atom, a tetrahydropyranyl group,
The hydroxyl group can be protected with a t-butyldimethylsilyl group or the like before being subjected to the reaction in the flow sheet. On the other hand, optically active 4(R)-hydroxycyclopentenone derivatives in which R in the formula [] is other than a hydrogen atom can be directly subjected to the reaction on the flow sheet to lead to prostaglandin derivatives, or By cleaving the acetal bond of the optically active 4-hydroxycyclopentenone derivative, an optically active 4-hydroxycyclopentenone derivative in which R is a hydrogen atom in the formula [] is obtained, and the hydroxyl group is protected in the same manner as above. It can also be subjected to a reaction. Therefore, the optically active 4(R)-hydroxycyclopentenone derivative of the present invention has the following formula [] 4-hydroxycyclopentenone represented by and the following formula [] Or the following formula [] In [Formula [], [], R ₁ represents a hydrogen atom or a lower alkyl group. ] In the presence of an acid agent or by a dehydration method, acetal derivatives are produced by reacting with lactones represented by the formula, followed by separating the stereoisomers of the acetal derivatives, and optionally cleaving the acetal bond. be done. The raw material compound used here, 4-hydroxycyclopentenone, can be obtained extremely easily by a method separately proposed by the present inventors. In addition, the other raw material, lactones, is
Obtained by the method described in the publication. Here, in the lactones of the above formula [] or []
R ₁ represents a hydrogen atom or a lower alkyl group such as a methyl group, ethyl group, propyl group, butyl group. Examples of acid agents used when reacting these compounds include strong acidic ion exchange resins, acidic compounds such as para-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, sulfuric acid, hydrochloric acid, boron siftide, and their pyridine salts. Can be mentioned. However, since 4-hydroxycyclopentenone represented by the formula [] has the property of being easily decomposed when left under strong acidic conditions for a long time, it is particularly important to use paratoluenesulfonic acid pyridine salt,
Weakly acidic compounds such as methanesulfonic acid pyridine salt and camphorsulfonic acid pyridine salt are preferred.
As the dehydration method, an azeotropic gradient method or a dehydrating agent is used, and preferred examples of the dehydrating agent include magnesium sulfate, molecular sieves, and activated anhydrous calcium sulfate. In the production method of the present invention, the catalyst for the reaction is particularly preferably a weakly acidic compound, and by using such a catalyst, the target 4(R)-hydroxycyclopentenone can be obtained in high yield. be able to. By using such a weakly acidic compound or by a dehydration method, the target compound can be obtained in a high yield for the first time, which is one of the characteristics of the production method of the present invention. The fact that the reaction can be carried out using a weakly acidic compound can be said to be a great advantage in industrial manufacturing processes. The amount of such a catalyst used is 0.01 equivalent to 1 equivalent, particularly preferably 0.1 equivalent to 0.3 equivalent, relative to 4-hydroxycyclopentenone. Also, the amount of lactones used in the above formula [] or [] is 4
-Equivalent to 2 equivalents, particularly preferably 1.2 equivalents to 1.3 equivalents, relative to hydroxycyclopentenone. As the solvent for the reaction, common organic solvents such as ether, tetrahydrofuran, acetone, chloroform, benzene, toluene, and xylene are used, with benzene and toluene being preferred. The reaction temperature is from 0°C to 150°C, preferably from room temperature to 90°C. The reaction time varies depending on the catalyst used and the reaction temperature, but is usually 5 minutes to 120 hours, preferably 2 hours to 4 hours. After the reaction is completed, acetal derivatives, i.e., in the above formula [], R is other than a hydrogen atom corresponds to the carbon atom to which the hydroxyl group at the 4-position of the cyclopentenone skeleton of 4(R)-hydroxycyclopentenones is bonded. Diastereomer of asymmetric carbon atom, 2-allyl-4(R)-[4-((1R,5S)
-6,6-dimethyl-2-oxo-3-oxabicyclo[3,1,0]hexyl]oxy]cyclopent-2-enone and 2-allyl-4(S)-
[4-((1R,5S)-6,6-dimethyl-2-oxo-3-oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone or 2-allyl-4(R) [ 4-((1S,5R)-6,6
-Dityl-2-oxo-3-oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone and 2-allyl-4(S)-[4-
((1S,5R)-6,6-dimethyl-2-oxo-
3-Oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone is obtained, which can be easily separated from each other. Such separation can be performed with an optical yield of 100%, which is one of the major features of the present invention. Specific examples of such separation methods include distillation, recrystallization, silica gel chromatography using an appropriate solvent, alumina column chromatography, dry column chromatography, liquid chromatography, and thin layer chromatography. is preferably column chromatography. In this way, an optically active 4(R)-hydroxycyclopentenone derivative in which R in the above formula [] is other than a hydrogen atom is obtained. Then, if desired, the acetal bond of this optically active 4(R)-hydroxycyclopentenone derivative (acetal derivative) is cleaved to obtain an optically active 4(R)-hydroxycyclopentenone derivative in which R is a hydrogen atom in the formula []. is converted to The cleavage of the acetal bond is carried out by an acid agent,
Such acid agents include para-toluenesulfonic acid,
Organic acids such as methanesulfonic acid, camphorsulfonic acid, oxalic acid, acetic acid, and formic acid, and mineral acids such as sulfuric acid and hydrochloric acid are used. The solvent used is a mixed solvent of water and an organic solvent such as methanol, ethanol, acetone, dioxane, or tetrahydrofuran. The mixing ratio of organic solvent and water is preferably 1:1 to 10:1. The amount of solvent used is 1 to 20 times that of the acetal derivative. The reaction temperature is preferably 0 to the boiling point of the solvent, and the reaction time is 30 minutes to 48 hours, more preferably 1 to 12 hours. The end point of the reaction is confirmed by thin layer chromatography. After the reaction is completed, the organic solvent used is distilled off from the reaction system, and the reaction product is dissolved in a common organic solvent such as chloroform, methine chloride, ethyl acetate, methyl acetate, benzene, ether, etc., and then a basic solution is added. Washing with an aqueous solution of a compound such as sodium hydroxide, potassium hydroxide, bilayer, etc., and subsequent treatment is carried out in a conventional manner. The product obtained in this way is purified by chromatography etc. as necessary, and the optically active 4 in which R is a hydrogen atom in the above formula []
A (R)-hydroxycyclopentenone derivative is obtained. As detailed above, the optically active 4(R)-hydroxycyclopent derivative provided by the present invention is
It is extremely useful as an intermediate for prostaglandin derivatives. The present invention will be further explained below with reference to Examples. Example 1 2.06 g of (1R,5S)-6,6-dimethyl-4-hydroxy-3-oxabicyclo[3,1,0]hexane-2-one and 2-allyl-4-hydroxycyclopent-2- 2.0 g of enone was dissolved in 30 ml of benzene, 0.73 g of PPTS (pyridinium para-toluene sulfonate) was added, and the mixture was heated to reflux. The reaction was allowed to proceed for 3 hours while removing the produced water by an azeotropic gradient method. After the reaction, the solvent was distilled off under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated sodium bicarbonate water and then water. After drying, the solvent was distilled off under reduced pressure to obtain an oily substance. Purified by silica gel column chromatography (eluted with methylene chloride) to create a less polar
1.7g of 2-allyl-4(R) [4-((1R,5S)
-6,6-dimethyl-2-oxo-2-oxabicyclo[3,1,0]hexyl]oxy]cyclopent-2-enone, [α] ²³ _D : -60.8° (C1.05MeOH) and 1.9 g 2-Allyl-4(S)-
[4-((1R,5S)-6,6-dimethyl2- [α] ²³ _D = +30.1° (C: 1.16, MeOH) nmr spectrum (CDCl ₃ ) δ: 2.25 (1H, dd,
J = 18Hz, 2Hz), 2.85 (1H, dd, J = 18Hz, 6
Hz), 2.7-3.1 (2H, m), 4.8-5.3 (2H, m), 5.5
-6.3 (1H, m), 7.20 (1H, m). Example 3 2-Allyl-4(S)-[4-((1R,5S)-
The same treatment as in Example 2 was performed using 1.5 g of 6,6-dimethyl-2-oxo-2-oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone to obtain 0.6 g of 2-oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone. -Allyl-4(S)hydroxycyclopent-2-enone was obtained. [α] ²³ _D =-28.5° (C: 0.83, MeOH) The nmr spectrum was the same as that obtained in Example 2. Example 4 Optically active 2-allyl-4- obtained in Example 2
Oxo-2-oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone, [α]
^23D : −117.3 _° (C1.28MeOH) was obtained. Example 2 2-allyl-4(R)-[4-((1R,5S)-
Add 1.22 g of 6,6-dimethyl-2-oxo-2-oxabicyclo[3,1,0]hexyl)oxy]cyclopent-2-enone to 10 ml of dioxane and water.
After heating under reflux in 20 ml for 3 hours, the mixture was concentrated under reduced pressure. 10 ml of saturated sodium bicarbonate solution was added, and the mixture was extracted three times with 30 ml of ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and then with saturated brine, and then dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (cyclohexane-
0.58
g of 2-allyl-4(R)-hydroxycyclopent-2-enone was obtained. The physical property data of this product were as follows. - In order to determine the absolute structure of hydroxycyclopent-2-enone, the compound was converted to benzoate [nmr spectrum (CDCl ₃ ) δ:
2.25-3.20 (4H), 4.85-5.30 (2H), 5.50-6.2
(1H), 5.95 (1H), 7.2-8.2 (6H)]. CD spectrum of this benzoate (0.13 mg
Dissolve the benzoate in 10ml of cyclohexane)
has a + maximum peak at 229 nm (△ε=33.8, [θ]
= 1.12×10 ⁵ ). Therefore, the absolute structure of the compound obtained in Example 2 is 2-allyl-4(R)
-Hydroxycyclopent-2-enone. (References N. Harada and K. Nakanishi,
Accounts Chem. Res, 5 , 257 (1972)).

Claims (1)

[Claims] 1. The following formula [] [In the formula, R represents a hydrogen atom, [Formula] or [Formula], and * represents an asymmetric carbon atom. ] An optically active 4(R)-hydroxycyclopentenone derivative represented by: 2 The following formula [] 4-hydroxycyclopentenone represented by and the following formula [] Or the following formula [] [In formulas [] and [], R ₁ represents a hydrogen atom or a lower alkyl group. ] It is characterized by reacting with lactones represented by in the presence of an acid agent or by a dehydration method to obtain an acetal derivative, then separating the stereoisomers of the acetal derivative, and optionally cleaving the acetal bond. The following formula [] [In the formula, R represents a hydrogen atom, [Formula] or [Formula], and * represents an asymmetric carbon atom. ] A method for producing an optically active 4(R)-hydroxycyclopentenone derivative represented by: