JPH0220616B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to novel 4-hydroxy-2-cyclopentenones and a method for producing the same. More specifically, the present invention relates to novel hydroxy-2-cyclopentenones having a prostaglandin A-like structure that have excellent pharmacological effects such as anticancer, antiviral, and antibacterial effects, and a method for producing the same. <Prior art> Prostaglandins have an inhibitory effect on platelet aggregation,
It is a compound that has unique biological activities such as blood pressure lowering effects, and is a useful natural product that has recently been used in the medical field as a treatment for peripheral circulatory system diseases. Among prostaglandins, prostaglandin A is known to have a double bond in its cyclopentane ring. For example, prostaglandin A ₂ is expected to be a drug having a blood pressure lowering effect. (E. J. Corey (E.
J.Corey et al., Journal of the American Chemical Society (J.Amer.Chem.
Soc.), 95, 6831 (1973)). On the other hand, since prostaglandin A strongly inhibits DNA synthesis, it has been reported that prostaglandin A has a potential as an antitumor agent. (Biochemical and Biophysical Research Communication (Biochem.Biophys.
Res.Commun.), 87, 798 (1979);
A. WATurner et al., Prostaglandins and Related Lipids, 2365-8.
(1982)). Also, the following formula 10-haloprostaglandin A, expressed as 10-haloprostaglandin A, has been reported, and its uses are suggested to have bronchodilatory and hypotensive effects (US Patent No.
3755426). On the other hand, in recent years, the following formula Prostaglandin A expressed by Okinawa soft coral (clavularia)
viridis) and is known to have anti-inflammatory and anticancer effects as physiological effects (H. Kikuchi et al., Tetrahedron Lett., 23, 5171).
(1982); M. M.Kobayashe et al.
Tetrahedron Letters
Lett.), 23, 5331 (1982); see Masanori Fukushima, Cancer and Chemotherapy, 10, 1930 (1983)). In addition, the following formula was obtained from Telesto riisei, which grows on the bottom of a boat recently collected on Oahu. A prostaglandin related substance (punagrandein) expressed as
(1982) Reference: It is known to have an anticancer effect as a physiological effect (see Masanori Fukushima et al., Proceedings of the 43rd Japanese Cancer Society 905 (1984)). <Purpose of the Invention> The present inventors focused on this point and, as a result of intensive research aimed at obtaining new prostaglandin analogue compounds, discovered that aldol condensation of aldehydes with hydroxy-2-cyclopentenones was achieved. As a result, a new punaglandin analog substance having a prostaglandin A-like structure was industrially advantageously obtained, and its biological activity was investigated.
The present invention was achieved based on the discovery that this product exhibits extremely strong cancer cell proliferation inhibitory activity and is useful as a new type of pharmaceutical. Therefore, the purpose of the present invention is to have an excellent anticancer effect,
Novel hydroxy-2- with antiviral activity
An object of the present invention is to provide cyclopentenones and an industrially advantageous manufacturing method thereof. <Structure of the invention> The present invention is based on the following formula [I] In the formula, R ¹ is -COOR ⁴ as a substituent (here, R ⁴ is a hydrogen atom, with a carbon number of 1 to 10
represents an alkyl group or one equivalent of a cation. )
represents an alkyl group having 2 to 8 carbon atoms which may have . R ² represents an unsubstituted alkyl group having 1 to 10 carbon atoms. R ³ represents a trimethylsilyl group or a hydrogen atom. A and B are a hydrogen atom and B is a hydroxyl group, or A and B are bonded to each other and represent one bond. X represents a hydrogen atom. The present invention relates to novel 4-hydroxy-2-cyclopentenones represented by and a method for producing the same. In the above formula [I], R ¹ represents a substituted or unsubstituted alkyl group having 2 to 8 carbon atoms. Examples of the alkyl group having 2 to 8 carbon atoms include ethyl, n-propyl, isopropyl, n-butyl,
n-pentyl, n-hexyl, n-heptyl, n
- Alkyl groups such as octyl can be mentioned. Examples of substituents for such alkyl groups having 2 to 8 carbon atoms include -COOR ⁴ (where R ⁴ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or 1 equivalent of a cation). . In addition to the above, examples of the alkyl group having 1 to 10 carbon atoms for R ⁴ include methyl, n-nonyl, and n-nonyl.
Examples include alkyl groups such as demyl. 1
Equivalent cations include, for example, NH ₄ ⁺ , tetramethylammonium, monomethylammonium,
Examples include ammonium cations such as trimethylammonium; metal cations such as Na ⁺ , K ⁺ , 1/2Ca ²⁺ , and 1/3 Al ³⁺ . Among these, R ⁴ is preferably a hydrogen atom or a methyl group. In the above formula [I], R ² represents an unsubstituted alkyl group having 1 to 10 carbon atoms. Examples of the alkyl group having 1 to 10 carbon atoms include methyl, ethyl, n-
Propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, 2-methyl-
Examples include 1-hexyl, n-heptyl, n-octyl, and the like. In the above formula [I], R ³ represents a hydrogen atom or a protected hydroxyl group. Examples of the protecting group for the protected hydroxyl group include a tri(C ₁ -C ₇ ) hydrocarbon-silyl group. As a tri(C ₁ - C ₇ ) hydrocarbon silyl group,
For example, trimethylsilyl, triethylsilyl, t
-tri(C ₁ -C ₇ ) such as butyldimethylsilyl group
Alkylsilyl; diphenyl(C ₁ -C ₄ )alkylsilyl such as t-butyldiphenylsilyl, tribenzylsilyl, and the like are preferred. A and B are a hydrogen atom and B is a hydroxyl group, or A and B are bonded to each other and represent one bond. That is, the above formula [I]
The novel hydroxy-2-cyclopentenones represented by the following formula [Ia] In the formula, R ¹ , R ² , R ³ and X are as defined above. 4-hydroxy-4-substituted-5-
(1-hydroxyalkyl)-2-cyclopentenones and the following formula [Ib] In the formula, R ¹ , R ² , R ³ and X are as defined above. The designation indicates that the bond is in the E or Z configuration or a mixture thereof in any proportion with respect to the double bond. 4-hydroxy-4-substituted-5-alkylidene-2-cyclopentenones represented by In the above formulas [I], [Ia] and [Ib], X represents a hydrogen atom. In particular, the novel 4-hydroxy-2-cyclopentenones of the present invention have the following formula [Ic] In the formula, R ² , R ³ , R ⁴ , X, A, and B are as defined above. Compounds represented by are preferred. In the above formula [Ic], R ⁴ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or 1 equivalent of a cation. These specific examples are the same as those described above. Further, R ² , R ³ , A, B, and X are also the same as those described above. In the above formula [I], [Ia], [Ib], [Ic], 5
Carbon atom at position 4 on membered ring, i.e. R ² , OR ³
The carbon atom substituted by is an asymmetric carbon, and when A is a hydrogen atom in [I] and [Ic],
In [Ia], the carbon at position 5 on the 5-membered ring, ie, the carbon substituted by A, is also an asymmetric carbon. In the present invention, the steric configuration of the substituents at the 4-position and 5-position is R-configuration, S-configuration, or a mixture thereof in arbitrary proportions. 4- represented by the above formula [Ia] or [Ic]
Specific examples of hydroxy-4-substituted-5-(1-hydroxyalkyl)-2-cyclopentenones include the following. (1) 4-Butyl-4-hydroxy-5-(1-hydroxy-6-carboxyhexyl)-2-cyclopentenone (2) 4-hydroxy-4-octyl-5-(1-
Hydroxy-6-carboxyhexyl)-2-
Cyclopentenone (3) 4-hydroxy-4-nonyl-5-(1-hydroxy-6-carboxyhexyl)-2-cyclopentenone (4) 4-hydroxy-4-decyl-5-(1-hydroxy- 6-carboxyhexyl)-2-cyclopentenone (5) 4-butyl-4-hydroxy-5-(1-hydroxybutyl)-2-cyclopentenone (6) 2-chloro of (1) to (5) Form (7) Methyl ester of (1) to (6) (8) 4( R ) form of (1) to (7) (9) 4( S ) form of (1) to (7) Above formula [Ib ] or 4- represented by [Ic]
Hydroxy-4-substituted-5-alkylidene-2-
Specific examples of cyclopentenones include the following. (10) 4-Butyl-4-hydroxy-5-(( 1E )
-6-carboxyhexylidene)-2-cyclopentenone (11) 4-butyl-4-hydroxy-5-(1 Z )-
6-carboxyhexylidene)-2-cyclopentenone (12) 4-hydroxy-4-octyl-5-((1
E)-6-carboxyhexylidene)-2-cyclopentenone (13) 4-hydroxy-4-octyl-5-
((1 Z )-6-carboxyhexylidene)-2-
Cyclopentenone (14) 4-hydroxy-4-decyl-5-((1
E) Roxy-6-carboxyhexylidene)-
2-cyclopentenone (15) 4-hydroxy-4-heptyl-5-
((1 Z )-6-carboxyhexylidene)-2-
Cyclopentenone (16) 4-hydroxy-4-nonyl-5-((1
E)-6-carboxyhexylidene)-2-cyclopentenone (17) 4-hydroxy-4-hexyl-5-
((1 Z )-6-carboxyhexylidene)-2-
Cyclopentenone (18) 4-Butyl-4-hydroxy-5-((1
E)-Butylidene)-2-cyclopentenone (19) 4-Butyl-4-hydroxy-5-((1
Z)-butylidene)-2-cyclopentenone (20) 2-chloro form of (10) to (19) (21) Methyl ester of (10) to (20) (22) (10) to (21) 4( R ) form (23) 4( S ) form of (10) to (21) The novel 4-hydroxy-2-cyclopentenones of the present invention represented by the above formula [Ia] are represented by the following formula: [] In the formula, R ² represents an unsubstituted alkyl group having 1 to 10 carbon atoms, and R ³¹ represents a trimethylsilyl group or a hydrogen atom. X represents a hydrogen atom. ₄ ^- Hydroxy-2-cyclopentenones represented by the following ^formula [ ^] 1-10
represents an alkyl group or one equivalent of a cation. )
represents an alkyl group having 2 to 8 carbon atoms which may have . It can be obtained by subjecting aldehydes represented by the above to an aldol condensation reaction, and subjecting them to deprotection, hydrolysis, and salt-forming reactions as necessary. R ¹ , R ² in the above formula [] or [],
Specific examples of X include those mentioned above. Specific examples of R ³¹ in the above formula [] include those similar to those exemplified above as the protecting group for the hydroxyl group of R ³ . The starting material [] is 4-hydroxy-2-cyclopentenone, a compound known per se (E. Winterfeldt et al.,
Angewante Chemi International Edition in English (Angew.
Chem.Int.Ed.Engl.), 21, 480 (1982)) or 3
-Halogenated-4-hydroxy-2-cyclopentenone (W.Rikards)
Journal of the Chemical Society Chemical Communication (JCS)
Chem-Comm) 121 (1979)) by a route as shown in reaction scheme A below. Reaction scheme A [R ² is the same as defined above. ] The compound of the above formula [] and the aldehyde of the above formula [] are subjected to an aldol condensation reaction. The reaction is carried out in a solvent in the presence of a basic compound. Examples of basic compounds and reaction solvents include literature: A. Tee. Nielsen (AT
Nielsen), DoubleU. J.A. WJ Houlihan, Organ React., 16, 1 (1968); H. Oh. HOHouse, “Modern Synthetio
Reactions) ”Second Edition (2nd
Ed.), Benjamin (1972), 629:
Those listed in New Experimental Chemistry Course 14, 736, 851, etc. will be selected. Preferably, the basic compound used is lithium diisopropylamide, lithium diethylamide, lithium bistrimethylsilylamide, or the like. The amount used is 0.1 to 0.1 to the raw material.
30 equivalents are used, preferably 0.2 to 2.0 equivalents.
As for the amount used, as the reaction solvent, ethers such as ether and tetrahydrofuran; hydrocarbons such as petroleum, ether, hexane, and pentane are used. The reaction temperature is preferably -100°C to 50°C,
Particularly preferred is a range of -78°C to 0°C. Aldehydes [ ] are 0.5 equivalent to 10 equivalent to the raw material
Equivalents are used, preferably from 0.8 equivalents to 2 equivalents. The reaction time varies depending on the raw material compounds, reagents, reaction solvents, etc. used, but is usually carried out in the range of 5 minutes to 3 days, preferably in the range of 10 minutes to 1 day. After completion of the reaction, the product can be purified and separated by conventional means such as extraction, washing with water, drying, chromatography, etc. The product is subjected to deprotection, hydrolysis, and salt-forming reactions as necessary. Deprotection of the hydroxyl protecting group can be carried out as follows. When the protecting group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin is used as a catalyst, and for example, water, tetrahydrofuran, ethyl ether, dioxane, This reaction is preferably carried out using acetone, acetonitrile, or the like as a reaction solvent. The reaction is usually carried out at a temperature range of -78°C + 30°C for about 10 minutes to 3 days. Also,
When the protecting group is a tri(C ₁ -C ₇ )hydrocarbon-silyl group, it is treated in the reaction solvent as described above at the same temperature in the presence of, for example, acetic acid, tetrabutylammonium fluoride, cesium fluoride, etc. It will be carried out for a similar amount of time. In addition, when the protecting group is an acyl group, for example, in an aqueous solution or water-alcohol mixed solvent of caustic soda, potassium hydroxide, or calcium hydroxide, or in a methanol or ethanol solution containing sodium methoxide, potassium methoxide, or sodium ethoxide, hydration can be performed. This can be carried out by decomposition. If the target compound has an ester group, it can be subjected to hydrolysis, for example, using an enzyme such as lipase in water or a solvent containing water at -10°C to
It is carried out at a temperature range of +60℃ for about 10 minutes to 24 hours. When the target compound has a carboxyl group in its molecule, it can then be further subjected to a salt-forming reaction if necessary to obtain the corresponding carboxylate. The salt-forming reaction is known per se, and is carried out in a conventional manner using a basic compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, etc., or ammonia, trimethylamine, monoethanolamine, morpholine, etc., in an approximately equal amount to a carboxylic acid. This is done by causing a sum reaction. Thus, the following formula [Ia] In the formula, R ¹ , R ² , R ³ and X are as defined above. 4-hydroxy-2-cyclopentenones represented by are obtained. Among the 4-hydroxy-2-cyclopentenones of the present invention, the compound represented by the above formula [Ib] can be obtained by subjecting the 4-hydroxy-2-cyclopentenone of the above formula [Ia] to a dehydration reaction, Deprotection according to
It can be obtained by subjecting it to hydrolysis and salt-forming reactions. The dehydration reaction is carried out using 4-hydroxy- of the above formula [Ia].
2-cyclopentenones and a reactive derivative of an organic sulfonic acid are reacted in the presence of a basic compound to form a corresponding organic sulfonyloxy derivative,
This is then carried out by treatment with a basic compound. As the basic compound used when reacting the compound of the above formula [Ia] with the reactive derivative of organic sulfonic acid, amines are preferable, and examples of such amines include pyridine, 4-dimethylaminopyridine, Triethylamine, diisopropylcyclohexylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (hereinafter abbreviated as DBN), 1,8-diazabicyclo[5.4.0]unzak-7-ene (hereinafter abbreviated as DBU) , quinuclidine, triethylenediamine, ipropyldimethylamine, diisopropylethylamine, etc., among which 4-dimethylaminopyridine, DBU, and DBN are particularly preferred. Examples of reactive derivatives of organic sulfonic acids include methanesulfonyl chloride, ethanesulfonyl chloride, n-butanesulfonyl chloride, t-
Organic sulfonic acid halides such as butanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride; methanesulfonic anhydride, ethanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride, p- Examples include anhydrous organic sulfonic acids such as toluenesulfonic acid. The basic compound itself may be used as the solvent; for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and dichloroethane; ethers such as ether and tetrahydrofuran; benzene, toluene, pentane, hexane, Hydrocarbons such as cyclohexyl are used, preferably dichloromethane and dichloroethane. The reaction is a reaction between the hydroxyl group on the 5-position alkyl group of the 4-hydroxy-2-cyclopentenone represented by the general formula [Ia] and a reactive derivative of an organic sulfonic acid, and stoichiometrically, both The compounds react in equimolar amounts. To actually carry out a reaction, usually
The reactive derivative of organic sulfonic acid is used in a ratio of 1 to 10 moles per mole of the 4-hydroxy-2-cyclopentenone of general formula [Ia]. The basic compound is used in an amount of 1 mol or more, preferably 2 mol or more, per 1 mol of the reactive derivative of the organic sulfonic acid used. The amount of solvent used is usually 1 to 1000 times the volume, preferably 5 to 100 times the volume of the raw material compound represented by the above formula [Ia]. The reaction temperature varies depending on the raw material compound, basic compound, solvent, etc. used, but is usually in the range of -100°C to 50°C, preferably in the range of 0°C to 30°C. The reaction time varies depending on the conditions, but is 0.1 to 10
It takes about an hour. The progress of the reaction is monitored by methods such as thin layer chromatography. Thus, according to the above reaction (hereinafter referred to as the first reaction), the hydroxyl group on the 5-position alkyl group of the 4-hydroxy-2-cyclopentenone represented by the above formula [Ia] is converted to an organic sulfonyloxy group. An organic sulfonyloxy derivative is produced.
The compound is then treated with a basic compound (hereinafter referred to as the second reaction) to eliminate the corresponding organic sulfonic acid and form the following formula [Ib] In the formula, R ¹ , R ² , R ³ and X are as defined above. The designation indicates that the bond is in the E or Z configuration or a mixture thereof in any proportion with respect to the double bond. It is converted into 4-hydroxy-4-substituted-5-alkylidene-2-cyclopentenones represented by: This second reaction can be carried out using the same basic compound as the first reaction and at approximately the same temperature. Furthermore, the organic sulfonyloxy derivative produced in the first reaction may be subjected to the second reaction after being isolated, or the first reaction and the second reaction may be performed in the same reaction system. . After the reaction is complete,
The target compound can be purified and fractionated by conventional means. The 4-hydroxy-2-cyclopentenones thus obtained are further subjected to the same deprotection, hydrolysis, and salt-forming reactions as described above, if necessary. In this way, novel 4-hydroxy-2-cyclopentenones of the above formula [Ib] are produced. <Effects of the Invention> The novel 4-hydroxy-2-cyclopentenones of the present invention are particularly effective against L1210 leukemia cells at an extremely low concentration of 0.1 μg/ml [(4 R )-5-(1 E )-
6-Methoxycarbonylhexylidene)-4-hydroxy-4-octyl-2-cyclopentenone], which exhibits a strong cancer cell proliferation inhibiting effect and is expected to be an anticancer agent. Further, the production method of the present invention is an industrially advantageous production method and can efficiently produce the target 4-hydroxy-2-cyclopentenones. <Examples> Hereinafter, the present invention will be explained in more detail with reference to Examples. Reference example 1 Add 30ml of THF to the reaction tube and cool to -78°C.
Here, n-butyllithium (1.6M hexane solution,
13.8ml, 22.08mmol). Next, 4-hydroxy-2-cyclopentenones (987 mg,
10.0 mmol) in 20 ml of THF was added dropwise over about 20 minutes and washed with 8 ml of THF. After 60 minutes, add 40 ml of saturated ammonium chloride aqueous solution and shake vigorously. Separate the organic layer and extract the aqueous layer with ethyl acetate (20 ml x 6). After drying over anhydrous sodium sulfate, it is filtered, concentrated, and subjected to column chromatography. (Merck silica gel 30g, hexane: ethyl acetate = 4:1) Yield 1.55 (yield approximately 90%); TLC, Rf 0.3 (1:6 = hexane: ethyl acetate); ¹ HNMR (δppm in CDCl ₃ ); 0.7 ~1.0 (t, 3H, _CH3 ) 1.1~1.8 (m, 8H, _CH2 , and _CH2 , OH), 2.0~2.1 (brs, 1H, OH) 2.2~2.5 (dd, 1H, _CH2 ), 4.5-4.8 (brs, 1H, CHOH), 5.7-5.9 (m, 2H, vinyl), Reference example 2 Weigh the diol (1.33 g, 8.48 mmol) into a flask, add about 20 ml of acetone, and cool to 0°C. Slowly drop Jonesl oxidizing agent (prepared from 2.0 g of chromium trioxide, 1.8 ml of concentrated sulfuric acid, and 5 ml of water) into this. After about 10 minutes, a saturated aqueous sodium bicarbonate solution was added dropwise. After separating the organic layer, the aqueous layer is extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (Merck silica gel, hexane:ethyl acetate = 3:1). This is concentrated and then bulb distilled. 145-150℃/2mmHg. _Yield 640 mg (yield approximately 50%); TLC Rf = 0.58 (1:6 = hexane: ethyl acetate); ^1HNMR (δppm in CDCl3); 0.7-1.1 (t, 3H, _CH3 ), 1.1-2.0 ( m, 6H, CH ₂ ), 2.5 (d, 2H, CH ₂ ), 2.6-3.1 (br, 1H, OH), 6.1 (d, 1H, vinyl), 7.4 (d, 2H, vinyl), Reference example 3 4-n-butyl-4-hydroxy- in the flask
Weigh out 2-cyclopentenone (73 mg, 0.47 mmol), add 3 ml of diisopropylethylamine, and cool to 0°C. Trimethylsilyltrifluoromethanesulfonic acid (0.25°M methylene chloride solution, 3.9ml, 0.96mmol) was then added dropwise over about 10 minutes. After about 10 minutes, pour the reaction mixture into a separating funnel, add water, and extract with pentane. Dry over anhydrous sodium sulfate, filter and concentrate. Subject to column chromatography (Merck silica gel 7g, hexane:ethyl acetate = 30:1). Yield 84 mg (yield about 78%); TLC Rf = 0.60 (3:1 = hexane: ethyl acetate); ¹ HNMR (δppm in CDCl ₃ ); 0.07 (s, 7, 9H, Si(CH ₃ ) ₃ ), 0.7-1.1 (t, 3H, CH ₃ ), 1.1-1.9 (m, 9E, CH ₂ ), 2.5 (s, 2H, CH ₂ ), 6.1 (d, 1H, vinyl), 7.4 (d, 1H, vinyl) ), Example 1 0.13 diisopropylamine in a nitrogen stream to the reaction tube
ml (0.92 mmol) and 0.58 ml (0.92 mmol) of n -butyllithium (1.6 M, hexane) to prepare an 8 ml THF solution of lithium diisopropylethylamine (hereinafter abbreviated as LDA). 4 at -78℃
- n -butyl-4-trimethylsilyloxy-2
- 12 ml of cyclopentenone 161 mg (0.71 mmol)
Add THF solution for 20 minutes, then add 7 ml THF solution of butyraldehyde 0.08 ml (0.92 mmol).
Stir for an hour. Add 20 ml of saturated NH ₄ Cl and extract with ether. Dry with anhydrous magnesium sulfate,
Filter and concentrate. Subject to column chromatography (Merck silica gel 8g, hexane:ethyl acetate = 40:1). Yield 193 mg (yield approximately 91%); ¹ H-NMR (δppm in _CDCl3 ); 0.15 (7, 9H), 0.8-1.1 (m, 6H), 1.1-2.0 (m, 10H), 2.3 (m, 1H), 3.95 (1, 1H), 6.1 (d, 1H, 6Hz), 7.4 (d, 1H, 6Hz), Example 2 4-Butyl-5-(1-hydroxybutyl)-4
40 mg (0.13 mmol) of -trimethylsilyloxy-2-cyclopentenone is dissolved in 2 ml of pyridine, 0.1 ml (1.3 mmol) of mesyl chloride is added at room temperature, and the mixture is stirred for 8 hours. After the reaction, water is added and extracted with methylene chloride. After drying, concentrate and add 2 ml of benzene.
Add 0.2 ml (1.3 mmol) of DBU and stir at room temperature for 2 hours. Add water, extract with benzene, dry, concentrate and perform silica gel chromatography (Merck silica gel 4g, hexane:ethyl acetate = 20:1)
4-Butyl-5-( 1E )-butylidene)-
4-trimethylsilyloxy-2-cyclopentenone 18 mg (48%, Rf = 0.7, hexane:ethyl acetate = 3:1) and Z- isomer 5 mg (14 g, Rf = 0.75,
Hexane: ethyl acetate = 3:1) ¹ H-NMR (δppm in CDCl ₃ ); < E form> 0.1 (9H, s), 0.7-1.0 (6H, m), 1.0-2.0 (8H, m), 2.2 ~2.5 (2H, m) 6.3 (1H, d, J = 6Hz), 6.5 (1H, d, t, J = 1Hz, 7Hz), 7.3 (1H, dd, J = 1Hz, 6Hz), < Z body> 0.1 (9H, s), 0.7~1.0 (6H, m), 1.0~1.9 (8H, m), 2.6~2.9 (2H, m), 6.0~6.2 (2H, m), 7.2 (1H, d, J =6Hz). Example 3 4-Butyl-5-(( 1E )-butylidene)-4-
Trimethylsilyloxy-2-cyclopentenone
10 mg (0.035 mmol) dissolved in 3 ml of THF and 0.14 ml of tributylammonium fluoride at 0°C.
(0.14 mmol) and stir for 40 minutes. Add saturated brine and extract with ethyl acetate. After drying, concentrate
Subject to column chromatography. (Merck silica gel 4g, hexane: ethyl acetate = 4:1) Yield 5 mg (yield 70%) ¹ H-NMR (δppm, CDCl ₃ ); 0.7-1.0 (6H, m), 1.0-2.1 (8H, m) , 2.2-2.5 (2H, m), 6.3 (1H, d, J = 6Hz), 6.6 (1H, t, J = 7Hz), 7.3 (1H, d, J = 6Hz), Example 4 5.3 mg (0.019 mmol) of 4-butyl-5-(1 Z )-butylidene)-4-trimethylsilyloxy-2-cyclopentenone and 0.07 ml (0.07 mmol) of tetrabutylammonium fluoride as in Example 3. 2.7 mg (68
%) was obtained. ^1H -NMR (δppm, _CDCl3 ); 0.7-1.0 (6H, m), 1.0-2.0 (8H, m), 2.6-2.9 (2H, m), 6.1-6.3 (1H, m), 7.2 (1H , d, J=6Hz), Example 5 iPr ₂ NH93mg (0.92mmol) and nBuLi590μ
THF of LDA adjusted from (10W/V%Hexane)
(3 ml) solution of (4 R )-4-trimethylsilyloxy-4-octyl-2-cyclopentenone 200
mg (0.71 mmol) in 2 ml of THF under _N2-78
It was added at ℃ and stirred for 1 hour. Next, 2 ml of 146 mg (0.92 mmol) of methyl 6-formylhexanoate
A THF solution was added, and the mixture was stirred at -78°C for 2 hours. The reaction was terminated with an aqueous NH ₄ Cl solution, extracted with ether, dried over anhydrous magnesium sulfate, and overconcentrated. Subjected to TLC (n-Hexane/Acoεt=3/1),
Recovery: 21mg (Rf=0.75) and low polarity (FrA)
(Rf=0.68), medium polar part (FrB) (Rf=0.6), low polar part (FrC) (Rf=0.5).
Obtained 221 mg (71%). FrA, FrB, and FrC (mixture of two types) are each corresponds to <FrA> ¹ H-NMR (CDCl ₃ ) δ; 0.05 (9H, s), 0.7-1.1 (3H, m), 1.1-2.1 (22H, m), 2.1-2.4 (3H, m), 3.6 (3H , s), 4.3 (1H, m), 6.0 (1H, d, J = 6Hz), 7.4 (1H, d, J = 6Hz), <FrB> ¹ H-NMR (CDCl ₃ ) δ; 1.0 (9H, s), 0.7-1.1 (3H, m), 1.1-2.0 (22H, m), 2.1-2.5 (3H, m), 3.6 (3H, s), 4.1 (1H, m), 6.0 (1H, d, J=6Hz), 7.35 (1H, d, J=6Hz) <FrC> ^1H -NMR ( _CDCl3 ) δ; 2.0 (9H, s), 0.7~1.1 (3H, m), 1.1~2.0 (22H, m), 2.0 to 2.5 (3H, m), 3.6 (3H, s), 3.2 to 4.0 (2H, m), 6.05 (1H, d, J = 6Hz), 7.25 (1H, d, J = 6Hz), IR (cm ^-1 , neat); 3500, 2950, 2870, 1740, 1710, 1460, 1440,
1350, 1255 Example 6 ( 4R )-5-(1-hydroxy-6-methoxycarbonyl-1-yl)-4-trimethylsilyloxy-4-octyl-2-cyclopentenone
Dissolve 188 mg (0.43 mmol) in 3 ml of pyridine,
Add 160μ (2.15mmol) of mesyl chloride at 0℃, stir at room temperature for 2 hours, add 0.5ml of DBU,
The mixture was further stirred at room temperature for 2 hours. The reaction was terminated by adding water, and extraction was performed with ether. The organic layer was washed with an aqueous solution of KHSO ₄ , NaHCO ₃ , and common salt;
After overconcentration, the product was subjected to TLC (nHexane/Acoεt=3.5/1) to obtain 27 mg (15%) of a low polar product (Z form) and 113 mg (63%) of a high polar product (E form). <E body> Rf = 0.55 (nHexane: Acoεt = 3:1) ¹ H-NMR (CDCl ₃ ) δ; 0.05 (9H, s), 0.7 to 1.0 (3H, m), 1.0 to 1.4 (12H, m) , 1.4-2.1 (8H, m), 2.1-2.6 (4H, m), 3.6 (3H, s), 6.2 (1H, d, J = 6Hz), 6.45 (1H, t, J = 7.5Hz), 7.20 (1H, d, J=6Hz) IR (cm ^-1 , neat); 2950, 2870, 1740, 1710, 1660, 1460, 1440,
1360, 1250 <Z-body> Rf = 0.6 (nHexane: Acoεt = 3:1) ¹ H-NMR (CDCl ₃ ) δ; 0.05 (9H, s), 0.7-1.0 (3H, m), 1.0-1.9 (20H , m), 2.0-2.45 (2H, m), 2.45-2.9 (2H, m), 3.55 (3H, s), 6.0 (1H, t, J = 75Hz), 6.1 (1H, d, J = 6Hz) , 7.1 (1H, d, J=6Hz) IR (cm ^-1 , neat); 2950, 2870, 1740, 1700, 1650, 1460, 1440,
1360, 1340, 1250, 1200. Example 7 ( 4R )-5-(( 1E )-6-methoxycarboxylhexylidene)-4-octenyl-4-trimethylsilyloxy-2-cyclopentenone 113
Dissolve mg (0.27 mmol) in THF (20 ml) and 0℃
1 ml (1 mmol) of nBu ₄ NF (1M in THF) was added thereto, and the mixture was stirred for 15 minutes. Ether and saturated brine were added, and the aqueous layer was extracted with ethyl acetate.
After overconcentration, the residue was subjected to TLC (nHexane:Acoεt=1/1) to obtain 31 mg (33%) of alcohol. Rf=(nHexane:Acoεt=1:1) ¹ H-NMR ( _CDCl3 ) δ; 0.65-1.00 (3H, m), 1.00-1.3 (12H, m), 1.3-2.7 (12H, m), 3.55 ( 3H, s), 6.15 (1H, d, J = 6Hz), 6.35 (1H, t, J = 8Hz), 7.20 (1H, d, J = 6Hz) IR (cm ^-1 , neat); 3450, 2950, 2880, 1740, 1710, 1640, 1360,
1340, Example 8 (4 R )-5-(1 Z -6-methoxycarbonylhexylidene)-1-octyl-4-trimethylsilyloxy-2-cyclopentenone 55 mg
(0.13 mmol) in 10 ml of THF and at -10℃
0.26 ml (0.26 mmol) of nB ₄ NF (1M in THF) was added and stirred for 10 minutes. After the reaction, ether and saturated brine were added, and the aqueous layer was extracted with ethyl acetate. Dry over anhydrous magnesium sulfate and TLC after overconcentration.
(nHexane/Acoεt=1/1) to obtain 37 mg (81%) of alcohol. Rf=0.55 (nHexane:Acoεt=1:1) ¹ H-NMR ( _CDCl3 ); δ; 0.7-1.0 (3H, m), 1.0-2.0 (20H, m), 2.0-2.9 (5H, m), 3.55 (3H, s), 6.1 (1H, t, J = 7Hz), 6.1 (1H, d, J = 6Hz), 7.1 (1H, d, J = 6Hz) IR (cm ^-1 , neat); 3450, 2950, 2870, 1740, 1700, 1650, 1460,
1440, 1360, 1260, 1200 Example 9 54 mg of 4-butyl-4-tert-butyldimethylsilyloxy-2-chloro-2-cyclopentenone was dissolved in 2 ml of dry tetrahydrofuran, cooled to -78 DEG C., and lithium diisopropylamide solution was added while stirring. Stir at -78℃ for 30 minutes, 7-
A solution of 50 ml of methyl oxoheptanoate in 1 ml of dry tetrahydrofuran was added, and the mixture was stirred at -78°C to -50°C for 1 hour. Add saturated ammonium chloride aqueous solution,
Extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After overconcentration, silica gel column chromatography (30 g of silica gel; hexane: ethyl acetate = 50:1 → 10:
1) to give 4-butyl-2-chloro-5-(1
29 mg (yield: 33%) of the low polar isomer and 17 mg (yield: 20%) of the high polar isomer of -hydroxy-6-methoxycarbonylhexyl)-4-trimethylsilyloxy-2-cyclopentenone were obtained. <Low polar isomer> Thin layer chromatography; Rf0.39 (developing solvent, hexane: ethyl acetate =
5:1) IR; (liquid film) 3460, 1729, 1602, 1256, 842 cm ^-1 NMR; δCDCl ₃ 0.04 (9H, s), 0.87 (3H, t, J = 4.6Hz), 1.0 to 2.1 (14H, m), 2.1-2.5 (3H, m), 3.59 (3H, s), 4.30 (1H, brt, J=7.0Hz), 4.80 (1H, brs), 7.39 (1H, s) <Highly polar isomer> Thin layer chromatography; Rf0.32 (developing solvent, hexane: ethyl acetate =
5:1) IR; (liquid film) 3480, 1730, 1604, 1253, 838 cm ^-1 NMR; δCDCl ₃ 0.13 (9H, s), 0.87 (3H, t, J = 4.5Hz), 1.0 to 2.0 (14H, m), 2.1~2.5 (2H, m), 2.51 (1H, d, J=4.0Hz) 3.57 (3H, s), 3.87 (1H, s), 3.8~4.4 (1H, m), 7.39 (1H, s)

Claims (1)

[Claims] 1. The following formula [I] In the formula, R ¹ is -COOR ⁴ as a substituent (here, R ⁴ is a hydrogen atom, with a carbon number of 1 to 10
represents an alkyl group or one equivalent of a cation. )
represents an alkyl group having 2 to 8 carbon atoms which may have . R ² represents an unsubstituted alkyl group having 1 to 10 carbon atoms. R ³ represents a trimethylsilyl group or a hydrogen atom. A and B are a hydrogen atom and B is a hydroxyl group, or A and B are bonded to each other and represent one bond. X represents a hydrogen atom. Novel 4-hydroxy-2-cyclopentenones represented by: 2. The novel 4-hydroxy-2 according to claim 1, wherein R ² in the above formula [I] is a propyl, pentyl, hexyl, or octyl group.
- Cyclopentenones. 3. Novel 4-hydroxy-2-cyclopentenones according to any one of claims 1 to 2, wherein R ³ in the above formula [I] is a hydrogen atom. 4. A novel 4-hydroxy compound according to any one of claims 1 to 3, wherein in the above formula [I], R ¹ is [Formula] (R ⁴ is the same as defined above) -2-cyclopentenones. 5. Novel ⁴ -hydroxy-2-cyclopentenones according to claim 1 or 4, wherein R 4 is a hydrogen atom or a methyl group. 6 The following formula [] In the formula, R ² represents an unsubstituted alkyl group having 1 to 10 carbon atoms. R ³ represents a trimethylsilyl group or a hydrogen atom. X represents a hydrogen atom. ₄ ^- Hydroxy-2-cyclopentenones represented by the following ^formula [ ^] 1-10
represents an alkyl group or one equivalent of a cation. )
represents an alkyl group having 2 to 8 carbon atoms which may have . The following formula [Ia] is characterized in that an aldehyde represented by is subjected to an aldol condensation reaction in the presence of a basic compound, and optionally subjected to deprotection, hydrolysis, and salt formation reaction. In the formula, R ¹ is -COOR ⁴ as a substituent (here, R ⁴ is a hydrogen atom, with a carbon number of 1 to 10
represents an alkyl group or one equivalent of a cation. )
represents an alkyl group having 2 to 8 carbon atoms which may have . R ² represents an unsubstituted alkyl group having 1 to 10 carbon atoms. R ³ represents a trimethylsilyl group or a hydrogen atom. X represents a hydrogen atom. A method for producing a novel 4-hydroxy-2-cyclopentenone represented by 7. The novel method for producing 4-hydroxy-2-cyclopentenones according to claim 6, wherein the basic compound used in the aldol condensation reaction is lithium diisopropylamide, lithium diethylamide, or lithium bistrimethylsilylamide. 8 The following formula [Ia] In the formula, R ¹ is -COOR ₄ as a substituent (here, R ⁴ is a hydrogen atom, with a carbon number of 1 to 10
represents an alkyl group or one equivalent of a cation. )
represents an alkyl group having 2 to 8 carbon atoms which may have . R ² represents an unsubstituted alkyl group having 1 to 10 carbon atoms. R ³ represents a trimethylsilyl group or a hydrogen atom. X represents a hydrogen atom. The following formula [Ib] is characterized by subjecting a novel 4-hydroxy-2-cyclopentenone represented by to a dehydration reaction and, if necessary, deprotection, hydrolysis, and salt formation reaction. In the formula, R ¹ , R ² , R ³ and X are as defined above. The designation indicates that the bond is in the E or Z configuration or a mixture thereof in any proportion with respect to the double bond. A method for producing 4-hydroxy-2-cyclopentenones represented by 9. Claim 8, wherein the dehydration reaction is carried out by reacting with a reactive derivative of an organic sulfonic acid in the presence of a basic compound to form the corresponding organic sulfonyloxy derivative, followed by treatment with a basic compound. A method for producing 4-hydroxy-2-cyclopentenones as described in 2.