JPH0244458B2 - 22HAROO22SHIKUROPENTENONRUINOSEIZOHO - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to a method for producing 2-halo-2-cyclopentenones. More specifically, the present invention relates to a method for producing novel 2-halo-2-cyclopentenones having a prostaglandin A-like structure and having excellent pharmacological effects such as anticancer, antiviral, and antibacterial effects. . <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 circulation disorders.
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 that has a blood pressure lowering effect (EJCorey et al., J.Amer.Chem.,
95.6831 (1973)). On the other hand, since prostaglandin A strongly suppresses DNA synthesis, the possibility of prostaglandin A as an antitumor agent has been reported (Biochem.Biophys.Res.Commun.87.795, 1979;
WATurner et al., Prostaglandins Relat. Lipids,
2, 365-8 (1982)). The present inventors previously wrote in Japanese Patent Application No. 58-121518,
As a prostaglandin A compound, the following formula [In the formula, X represents a halogen atom. ] 7 in prostaglandin nomenclature, expressed as
Synthesize 7,8-dehydro-10-haloprostaglandin A or its various derivatives, which have a double bond between the 8- and 8-positions and a halogen atom at the 10-position, and study their pharmacological effects. We have found that these compounds have excellent pharmacological effects such as anticancer, antiviral, and antibacterial effects, and have relatively low prostaglandin-like physiological activity, and are therefore useful as a new type of drug. Also, conventionally, the following formula [In the formula, X represents a chlorine atom or a bromine atom, and 〓 represents a single bond or a double bond. ] 10 in the prostaglandin nomenclature, expressed as
10-haloprostaglandin A having a halogen atom at the position is known (USP 3755426), and its uses are suggested to have bronchodilation and hypotensive effects. However, nothing is known about the potential of 10-haloprostaglandin A as an antitumor agent. Such 10-haloprostaglandin A is produced by the method shown in the following reaction formula. <Purpose of the Invention> The present inventors have discovered a novel compound 2 with a prostaglandin A-like structure that has excellent anticancer and antiviral effects and has low prostaglandin-like physiological activity.
-When we intensively investigated a new method for producing halo-2-cyclopentenones, we surprisingly found that two double conjugates to the carbonyl group of 2-cyclopentenones, as shown in the following reaction formula. The epoxidation reaction occurs selectively on only one of the bonds, yielding 2,3-epoxycyclopentanones as reaction intermediates, which are further subjected to halogenation and dehydration reactions to form the desired 2-halo- 2-
The present invention was achieved by discovering that cyclopentenones can be obtained. [Table] [Table] Therefore, the purpose of the present invention is to develop a novel 2-2-2-2-2-2-2 with a prostaglandin A-like structure that has excellent anticancer and antiviral effects and has a relatively low prostaglandin-like physiological activity. An object of the present invention is to provide a novel method for producing halo-2-cyclopentenones. <Structure and effects of the invention> The present invention is based on the following formula [] [In the formula, R ² represents an alkyl group having 1 to 5 carbon atoms, and R ³ represents a hydrogen atom or a hydroxyl group. The symbol 〓 indicates that the bond is bonded to a double bond in the E or Z configuration, and the symbol 〓 indicates a single bond or a double bond. ] 2-cyclopentenones represented by the following formula [] are subjected to an epoxidation reaction. [wherein 〓, 〓, R ² and R ³ are the same as defined above. ] 2,3-epoxycyclopentanones represented by the following formula [] [In the formula, X represents a halogen atom,
Indication 〓, R ² and R ³ are the same as defined above. ] This is a method for producing 2-halo-2-cyclopentenones represented by: In the above [], formula [] and formula [],
R ² represents an alkyl group having 1 to 5 carbon atoms, and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t
-butyl, n-pentyl and the like. R ₃ represents a hydrogen atom or a hydroxyl group. The symbol 〓 indicates that the bond is bonded to the double bond in the E or Z configuration. That is, the 2-cyclopentenones represented by the above formula [] are represented by the following formulas [-E] and [-Z] [wherein, R ² and R ³ are the same as defined above]. ] It represents either one of the two isomers represented by or any mixture of both isomers. The symbol 〓 represents a single bond or a double bond. When the symbol 〓 represents a double bond, it means that the double bond has either the E or Z configuration, or a mixture of both isomers in any proportion. The 2-cyclopentenones of the above formula [] can be produced, for example, by the method shown in the following reaction formula described in JP-A-55-153725. As a reagent for the epoxidation reaction of 2-cyclopentenone represented by the above formula [], an alkyl hydroperoxide such as t-butyl hydroperoxide or hydrogen peroxide is used, and hydrogen peroxide is preferred. Although anhydrous hydrogen peroxide can be used, 90 to 5% hydrogen peroxide is usually used, preferably 50 to 10% hydrogen peroxide. The amount of hydrogen peroxide used is 1 to 50 equivalents, preferably 3 to 20 equivalents, relative to 2-cyclopentenone represented by the above formula []. The epoxidation reaction is preferably carried out in the presence of a basic compound, such as quaternary ammonium hydroxides such as tetramethylammonium hydroxide and benzyltrimethylammonium hydroxide; lithium hydroxide, water Hydroxides such as sodium oxide and potassium hydroxide; carbonates such as sodium carbonate and potassium carbonate; preferably alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium carbonate and carbonate. Alkali metal carbonates such as potassium are used, particularly preferably sodium hydroxide. The basic compound is used in an amount of 0.01 to 5 equivalents, preferably 0.05 to 2 equivalents, relative to 2-cyclopentenone represented by the above formula []. As a reaction solvent, methanol, ethanol, t
-Alcohols such as butyl alcohol; acetone. Ketones such as methyl ethyl ketone; dioxane. Examples include solvents that are inert to hydrogen peroxide and miscible with water, such as ethers such as dimethoxyethane, preferably methanol. ethanol. Alcohols such as t-butyl alcohol are used, particularly preferably methanol. Ethanol is used. The reaction temperature of the epoxidation reaction is preferably −20 to
The temperature is 50°C, particularly preferably in the range of -5 to 30°C. The reaction time of the epoxidation reaction varies depending on the raw material compounds, reagents, reaction solvent, and reaction temperature used, but is usually carried out in a range of 5 minutes to 5 hours, preferably in a range of 10 minutes to 1 hour. After the completion of the epoxidation reaction, the 2,3-epoxycyclopentanone represented by the above formula [] can be extracted by conventional means such as extraction, washing with water, drying, concentration, etc.
Although the 2,3-epoxycyclopentanones can be purified and fractionated by chromatography or the like, the unpurified reaction mixture can also be directly subjected to the following reaction without isolating the 2,3-epoxycyclopentanones. The method for producing 2-halo-2-cyclopentenones represented by the above formula [] by halogenation reaction and dehydration reaction of the 2,3-epoxycyclopentanones represented by the above formula [] obtained by the above reaction is , as an intermediate as shown in the following reaction formula,
Via 2-halo-3-hydroxycyclopentanones. [Table] [In the formula, X represents a halogen atom. Display〓,
Indication 〓, R ² and R ³ are the same as defined above. ] As a reagent for the halogenation reaction, hydrogen iodide,
Hydrogen halides such as hydrogen bromide, hydrogen chloride, etc.;
or metal halides such as titanium tetrachloride, tin tetrachloride, aluminum trichloride, iron trichloride, zinc chloride, titanium tetrabromide, aluminum tribromide, etc., preferably hydroiodic acid, bromide, etc. Hydrohalic acids such as hydrogen acid and hydrochloric acid; or metal chlorides such as titanium tetrachloride, tin tetrachloride, and aluminum trichloride are used, and hydrobromic acid, hydrochloric acid, and titanium tetrachloride are particularly preferably used. When the reagent for the halogenation reaction is a hydrogen halide, the amount of the hydrogen halide used is 1 to 100 equivalents, preferably 5 equivalents, based on the 2,3-epoxycyclopentanone represented by the above formula []. ~
50 equivalents are used. Examples of the reaction solvent include alcohols such as methanol, ethanol, t-butyl alcohol, etc.; ketones such as acetone, methyl ethyl ketone; and ethers such as dioxane, tetrahydrofuran, dimethoxyethane, etc., which are miscible with water, and are preferred. Ketones such as acetone and methyl ethyl ketone, alcohols such as methanol, ethanol and t-butyl alcohol are used, and acetone and methanol are particularly preferably used. When the reagent for the halogenation reaction is a metal halide, the amount of metal halide used is 1 to 200 equivalents, based on the 2,3-epoxycyclopentanone whose halogen ion is represented by the above formula [];
Preferably 2 to 50 equivalents are used. As a reaction solvent, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, tetrachloroethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; saturated hydrocarbons such as hexane, cyclohexane, etc., methanol, ethanol. Solvents such as alcohols such as cyclomethane, chloroform, carbon tetrachloride, tetrachloroethane and the like are preferably used. The halogenation reaction temperature is preferably -40 to 50
℃, particularly preferably in the range of -5 to 30℃. The reaction time of the halogenation reaction varies depending on the raw material compound, reagent, reaction solvent, and reaction temperature used, but is usually carried out in a range of 5 minutes to 5 hours, preferably in a range of 10 minutes to 1 hour. After the completion of the halogenation reaction, the intermediate 2-halo-3-hydroxycyclopentanones can be purified and fractionated by conventional means such as extraction, water washing, drying, chromatography, etc. The reaction mixture can also be directly subjected to the following dehydration reaction without isolating the -halo-3-hydroxycyclopentanones. Examples of dehydrating agents used in the dehydration reaction of the 2-halo-3-hydroxycyclopentanones obtained in the above reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, and phosphoric acid; acetic acid; , propionic acid, oxalic acid, citric acid, maleic acid, and other organic carboxylic acids; methanesulfonic acid, ethanesulfonic acid,
It is preferably carried out in the presence of organic sulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid, among others, inorganic acids and organic carboxylic acids. In the above halogenation reaction, when hydrogen halides such as hydrogen iodide, hydrogen chloride, and hydrogen bromide are used, following the halogenation reaction,
Dehydration reactions can be carried out within the same system. The amount of dehydrating agent used is preferably 0.5 to 100 per mole of 2-halo-3-hydroxycyclopentanone.
The proportion is particularly preferably 1 to 50 mol. As reaction solvents for the dehydration reaction, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, etc.; alcohols such as methanol, ethanol, t-butyl alcohol, etc.; ketones such as acetone, methyl ethyl ketone, etc.; dimethyl sulfoxide, dimethyl formamide, hexane, etc. Methylphosphoric triamide, acetonitrile, water, etc. can be used alone or in any combination thereof. The reaction temperature of the dehydration reaction is preferably 0 to 100°C,
Particularly preferably, the temperature is in the range of 10 to 80°C. The reaction time for the dehydration reaction varies depending on the raw material compound, dehydrating agent, and reaction solvent used, but is usually carried out in the range of 10 minutes to 10 days, preferably in the range of 20 minutes to 5 days. After the dehydration reaction is completed, the 2-halo-2-cyclopentenone represented by the above formula [] can be purified and fractionated by conventional means such as extraction, washing with water, drying, chromatography, etc. As detailed above, according to the present invention, 2-halo- 2-cyclopentenones are produced by a halogenation reaction and a dehydration reaction of 2,3-epoxycyclopentanones obtained by a selective epoxidation reaction with respect to 2-cyclopentenones. Hereinafter, the present invention will be explained in more detail with reference to Examples. Example 1 Synthesis of 2-chloro-4-butyl-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone (i) 4-butyl-5-(6-methoxycarbonylhexylidene)-2-cyclopene Tenon 660mg
Dissolve (2.37 mmol) in 10 ml of methanol, add 1.2 ml of 30% hydrogen peroxide while stirring on ice,
Next, add 0.23 ml of 1N sodium hydroxide and
The mixture was stirred for 20 minutes. Saturated ammonium chloride water was added, and the mixture was extracted with hexane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering and concentrating, it was subjected to silica gel column chromatography (silica gel, 30 g; elution solvent, hexane:ethyl acetate = 10:1) to obtain 2,3-epoxy-4-butyl-5-(6-methoxycarbonylhexyl). 500 mg (yield 72%) of cyclopentanone was obtained. Spectral data 2,3-epoxy-4-butyl-5-(6-
methoxycarbonylhexylidene) cyclopentanone Thin layer chromatography; Rf0.40 (developing solvent,
Hexane: ethyl acetate = 3:1) IR (liquid film); 1735, 1651, 839 cm ^-1 NMR (CDCl ₃ ); δ0.85 (3H, brt, J = 5.0Hz),
1.0~1.8 (12H, m), 1.8~2.5 (4H, m), 2.8
~3.3 (1H, m), 3.34 (1H, d, J=2.8Hz),
3.54 (3H.s), 3.64 (1H, d, J=2.8Hz), 6.44
(1H, td, J=7.2, 2.0Hz) (ii) 2,3-epoxy-4-butyl-5 obtained in (i)
300 mg (1.02 mmol) of -(6-methoxycarbonylhexylidene)cyclopentanone was dissolved in 3 ml of acetone, 0.5 ml of concentrated hydrochloric acid was added, and the mixture was stirred for 50 minutes. Saturated sodium bicarbonate water was added, and the mixture was extracted with hexane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, overconcentrated, and subjected to silica gel column chromatography (silica gel, 20 g; elution solvent, cyclohexane:ethyl acetate = 10:1) to obtain 2-chloro- 4-Butyl-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone less polar isomer (Z form) 28 mg (yield 9%) and more polar isomer (E form) 183 mg (yield 57%). Spectral data 2-chloro-4-butyl-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone Low polar isomer (Z form) Thin layer chromatography; Rf0.53 (developing solvent;
Benzene: Ethyl acetate = 10:1) IR (liquid film); 1738, 1698, 1645, 1588 cm ^-1 NMR (CDCl ₃ ); δ0.87 (3H, brt, J = 4.7Hz),
1.1~2.0 (12H, m), 2.0~2.5 (2H, m), 2.5
~3.1 (2H, m), 3.1 ~ 3.5 (1H, m), 3.63
(3H, s), 6.13 (1H, brt, J=7.8Hz), 7.33
(1H, d, J = 3.5Hz) Highly polar isomer (E form) Thin layer chromatography; Rf0.47 (developing solvent;
Benzene: Ethyl acetate = 10:1) IR (liquid film); 1738, 1710, 1658, 1588 cm ^-1 NMR (CDCL ₃ ); δ0.87 (3H, brt, J = 4.8Hz),
1.1~1.95 (12H, m), 1.95~2.5 (4H, m),
3.3-3.8 (1H, m), 3.63 (3H, s), 6.64
(1H, brt, J=7.7Hz), 7.41 (1H, d, J=
2.6Hz) Example 2 Synthesis of 2-bromo-4-butyl-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone 2,3-epoxy-4-butyl-5-( obtained in (i) of Example 1) 6-methoxycarbonylhexylidene) cyclopentanone 100 mg (0.34 mmol) in 1 ml
Dissolve in acetone, add 0.2 ml of hydrobromic acid,
Stirred for 1 hour. Saturated sodium bicarbonate water was added, and the mixture was extracted with hexane. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate,
After overconcentration, the 2-bromo-
3.5 mg (yield 3%) of the less polar isomer (Z form) and 43 mg (yield) of the more polar isomer (E form) of 4-butyl-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone. 35%). Spectral data 2-bromo-4-butyl-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone low polar isomer (Z form) Thin layer chromatography; Rf0.51 (developing solvent;
Benzene: Ethyl acetate = 10:1) IR (liquid film); 1736, 1698, 1642, 1580 cm ^-1 NMR (CDCL ₃ ); δ0.88 (3H, brt, J = 4.7Hz),
1.1~2.0 (12H, m), 2.1~3.1 (4H, m), 3.4
~3.9 (1H, m), 3.66 (3H, s), 6.14 (1H,
t), 7.45-7.7 (1H, m) Highly polar isomer (E form) Thin layer chromatography; Rf0.45 (developing solvent;
Benzene: Ethyl acetate = 10:1) IR (liquid film); 1736, 1708, 1655, 1577 cm ^-1 NMR (CDCl ₃ ); δ0.87 (3H, brt, J = 4.7Hz),
1.1~2.0 (12H, m), 2.0~2.6 (4H, m), 3.3
~3.8 (1H, m), 3.66 (3H, s), 6.69 (1H,
brt, J = 7.1Hz), 7.65 (1H, brd, J = 3.2
Hz) Example 3 2-chloro-4-(1-octenyl)-5-(6
Synthesis of -methoxycarbonylhexylidene)cyclopentanone (i) 4-(1-octel)-5-(6-methoxycarbonylhexylidene)cyclopentanone 600
Dissolve mg (1.8 mmol) in 6 ml of methanol,
0.92 ml of 30% hydrogen peroxide solution while stirring on ice.
After adding (9.0 mmol), 1N sodium hydroxide
60 μl (60 μmol) was added and stirred at 0° C. for 45 minutes. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with hexane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, overconcentrated, and subjected to silica gel column chromatography (silica gel, 40 g; elution solvent, hexane:ethyl acetate = 10:1 → 5:1)2. 3-Epoxy-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone
491 mg (yield 78%) was obtained. Spectral data 2,3-epoxy-4-(1-octenyl)-
5-(6-methoxycarbonylhexylidene)
Cyclopentanone Thin layer chromatography; Rf0.50 (developing solvent;
Hexane: ethyl acetate = 2:1) IR (liquid film); 1732, 1648, 840 cm ^-1 NMR (CDCl ₃ ); δ0.84 (3H, brt, J = 4.6Hz),
1.0~1.8 (14H, m), 1.7~2.5 (6H, m), 3.3
~3.5 (1H, m), 3.57 (3H, s), 3.5~3.8
(2H, m), 5.15 (1H, dd, J = 14.4, 7.0
Hz), 5.47 (1H, dt, J = 14.4, 5.8Hz), 6.57
(1H, td, J=7.2, 2.0Hz) (ii) 450 mg of 2,3-epoxy-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone obtained in (i) (1.29mmol)
was dissolved in 12 ml of acetone, 2 ml of concentrated hydrochloric acid was added, and the mixture was stirred for 2 hours. Saturated sodium hydrogen carbonate water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After overconcentration, it was subjected to silica gel column chromatography (silica gel, 40 g; elution solvent, hexane:ethyl acetate = 10:1 → 5:1),
-chloro-4-(1-octenyl)-5-(6-
Low polar isomer (Z form) of methoxycarbonylhexylidene) cyclopentanone 19 mg (yield 4
%) and highly polar isomer (E form) 177 mg (yield
37%). Spectral data Low polar isomer (Z form) Thin layer chromatography; Rf0.57 (developing solvent;
Hexane: ethyl acetate = 2:1) IR (liquid film); 1738, 1699, 1647, 1587 cm ^-1 NMR (CDCl ₃ ); δ0.84 (3H, brt, J = 4.8Hz),
1.0~2.5 (18H, m), 2.5~3.1 (2H, m),
3.58 (3H, s), 3.5-3.9 (1H, m), 5.08
(1H, dd, J = 14.8, 7.8Hz), 5.52 (1H, dt,
J = 14.8, 6.1Hz), 5.98 (1H, brt, J = 7.6
Hz), 7.07 (1H, d, 2.4Hz) Highly polar isomer (E form) Thin layer chromatography; Rf0.51 (developing solvent;
Hexane: ethyl acetate = 2:1) IR (liquid film); 1738, 1710, 1657, 1586 cm ^-1 NMR (CDCl ₃ ); δ0.84 (3H, brt, J = 4.5Hz),
1.0~2.5 (20H, m), 3.58 (3H, s), 3.7~
4.1 (1H, m), 5.11 (1H, dd, J = 15.2, 8.0
Hz), 5.56 (1H, dt, J=15.2, 6.2Hz), 6.62
(1H, brt, J=7.0Hz), 7.11 (1H, d, J=
2.8Hz) Example 4 2-chloro-4-(1-octenyl)-5-(6
-Methoxycarbonylhexylidene)-2-cyclopentenone synthesis (i) 2,3-epoxy-4- obtained in Example 3 (i)
(1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone 100mg
(0.3 mmol) was dissolved in 2 ml of dichloromethane,
8% titanium tetrachloride-dichloromethane solution 0.5ml
was added and stirred for 30 minutes. After washing three times with saturated brine, it was dried over anhydrous sodium sulfate. Filter and concentrate to give 2-chloro-3-hydroxy-4-
An oil containing mainly (1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone was obtained. 2-chloro-3-hydroxy-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone Thin layer chromatography; Rf 0.45 and 0.38
(Developing solvent; hexane: ethyl acetate = 2:1) IR (liquid film); 3470, 1736, 1644 cm ^-1 NMR (CDCl ₃ ); δ0.84 (3H, brt, J = 4.5Hz),
1.0~1.8 (14H, m), 1.8~2.6 (7H, m), 3.0
~3.5 (1H, m), 3.58 (3H, s), 3.7~4.6
(m, 2H), 5.1~5.8 (2H, m), 6.5~7.0 (m,
1H) (ii) 2-chloro-3-hydroxy-4- obtained in (i)
An oil containing (1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone was added to 1 ml of acetic acid and 0.5 ml of tetrahydrofuran.
Dissolve in a mixed solvent of 0.5 ml of water and 4 ml at 80°C.
Stir for hours. Add saturated brine, extract with ethyl acetate, and extract the organic layer with saturated sodium bicarbonate water,
Subsequently, it was washed with saturated saline. After drying with anhydrous magnesium sulfate and overconcentration, silica gel column chromatography (silica gel, 10 g; elution solvent, cyclohexane: ethyl acetate = 15:
1) and the 2-chloro-4- obtained in Example 3.
(1-octenyl)-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone, 8 mg (yield 8%) of the less polar isomer (Z form) and 56 mg of the more polar isomer (E form) ( A yield of 53% was obtained. Example 5 2-Bromo-4-(1-octenyl)-5-(6
-Methoxycarbonylhexylidene)-2-cyclopentenone synthesis (i) 2,3-epoxy-4- obtained in Example 3 (i)
(1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone 100mg
Dissolve (0.29 mmol) in 2 ml of acetone, add 0.4 ml of 47% hydrobromic acid while stirring on ice, and add 0.4 ml of 47% hydrobromic acid.
Stirred at °C for 10 minutes. A saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying with anhydrous magnesium sulfate, filtering, and concentrating, 2-bromo-3
-Hydroxy-4-(1-octenyl)-5-
122 mg of an oil containing mainly (6-methoxycarbonylhexylidene)cyclopentanone was obtained. Spectral data 2-bromo-3-hydroxy-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone Thin layer chromatography; Rf 0.35 and 0.25
(Developing solvent; hexane: ethyl acetate = 3:1) IR (liquid film); 3460, 1726, 1640 cm ^-1 NMR (CDCl ₃ ); δ0.84 (3H, brt, J = 4.3Hz),
1.0~1.8 (14H, m), 1.8~2.5 (6H, m), 2.5
~3.4 (2H, m), 3.54 (3H, s), 3.8 ~ 4.4
(2H, m), 5.0-5.8 (2H, m), 6.71 (1H,
td, J = 7.5, 3.2Hz) (ii) 2-bromo-3-hydroxy-4- obtained in (i)
Dissolve 30 mg of an oil mainly containing (1-octenyl)-5-(6-methoxycarbonylhexylidene)cyclopentanone in a mixed solvent of 1 ml of acetic acid, 0.5 ml of tetrahydrofuran, and 0.5 ml of water.
The mixture was stirred at 70°C for 3 hours. The reaction solution was poured onto a saturated aqueous sodium hydrogen carbonate solution and extracted with hexane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After overconcentration, silica gel column chromatography (silica gel, 15 g;
Elution solvent, cyclohexane: ethyl acetate = 20:
1→10:1) to give 13 mg of 2-bromo-4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone (yield
44%). Spectral data 2-bromo-4-(1-octenyl)-5-
(6-methoxycarbonylhexylidene)-2-
Cyclopentenone Thin layer chromatography; Rf0.52 (developing solvent;
Hexane: ethyl acetate = 3:1) IR (liquid film); 1738, 1713, 1658, 1578 cm ^-1 NMR (CDCl ₃ ); δ0.83 (3H, brt, J = 4.7Hz),
1.0~2.5 (20H, m), 3.55 (3H, s), 3.6~
4.0 (1H, m), 5.04 (1H, dd, J = 15.2, 7.8
Hz), 5.51 (1H, dt, J=15.2, 6.2Hz), 6.56
(1H, brt, J=7.2Hz), 7.23 (1H, d, J=
3.0Hz) Example 6 Synthesis of 10-chloro-7,8-dehydroPGA ₁ methyl ester (i) 7,8-dehydro PGA ₁ methyl ester 420
Dissolve mg (1.21 mmol) in 10 ml of methanol,
0.61ml of 30% hydrogen peroxide solution while stirring on ice.
(6 mmol) was added, and then 0.12 ml (0.12 mmol) of 1N sodium hydroxide solution was added. After stirring at 0° C. for 50 minutes, saturated ammonium chloride water was added and extracted with ether. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate.
After overconcentration, silica gel column chromatography (silica gel, 15 g; elution solvent, hexane:
Ethyl acetate = 5:1 → 2:1), 10,11
-Epoxy-7,8-dehydroPGA ₁ methyl ester 300 mg (yield 68%) was obtained. Spectral data 10,11-epoxy-7,8-dehydroPGA ₁
Methyl ester Thin layer chromatography; Rf0.41 (developing solvent;
Hexane: ethyl acetate = 1:1) IR (liquid film); 3460, 1727, 1646, 839 cm ^-1 NMR (CDCl ₃ ); δ0.84 (3H, brt, J = 4.4Hz),
1.0~1.8 (14H, m), 1.8~2.5 (5H, m),
3.39 (1H, d, J = 2.4Hz), 3.55 (3H, s),
3.64 (1H, d, J = 2.4Hz), 3.5-3.8 (1H,
m), 3.8-4.2 (1H, m), 5.3-5.7 (2H, m),
6.56 (1H, brt, J=7.0Hz) (ii) Add 300 mg of 10,11-epoxy-7,8-dehydroPGA ₁ methyl ester obtained in (i) to 3 ml of acetone.
0.6 ml of concentrated hydrochloric acid was added, and the mixture was stirred for 45 minutes. Saturated sodium hydrogen carbonate water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After overconcentration, the 10-chloro-
7,8-dehydroPGA ₁ methyl ester 143mg
(yield 45%). Spectral data 10-chloro-7,8-dehydroPGA ₁ methyl ester Thin layer chromatography; Rf0.20 (developing solvent;
Hexane; ethyl acetate = 3:1) IR (liquid film); 3450, 1735, 1709, 1655, 1584cm
^-1 NMR (CDCl ₃ ); δ0.86 (3H, brt, J=5.6Hz),
1.0~2.0 (14H, m), 2.0~2.6 (5H, m),
3.66 (3H, s), 3.8~4.3 (2H, m), 5.1~6.1
(2H, m), 6.78 (1H, t, J=7.9Hz), 7.1
~7.4 (1H, m)

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ² represents an alkyl group having 1 to 5 carbon atoms, and R ³ represents a hydrogen atom or a hydroxyl group. The symbol 〓 represents that the bond is bonded to a double bond in the E or Z configuration, and the symbol 〓 represents a single bond or a double bond. ] The following formula [] is characterized by subjecting 2,3-epoxycyclopentanones represented by the following to a halogenation reaction and then a dehydration reaction under acidic conditions. [In the formula, X represents a halogen atom,
Indication 〓, R ² and R ³ are the same as defined above. ] A method for producing 2-halo-2-cyclopentenones represented by: 2. The method for producing 2-halo-2-cyclopentenones according to claim 1, wherein the halogenation reaction is carried out using hydrogen halides or metal halides. 3. A method for producing 2-halo-2-cyclopentenones according to claim 1 or 2, wherein the halogenation reaction is carried out using hydrogen chloride or hydrogen bromide. 4. 2-halo-2- according to claim 1 or 2, wherein the halogenation reaction is carried out with titanium tetrachloride, tin tetrachloride, or aluminum trichloride.
Method for producing cyclopentenones. 5 The following formula [] [In the formula, R ² represents an alkyl group having 1 to 5 carbon atoms, and R ³ represents a hydrogen atom or a hydroxyl group. The symbol 〓 indicates that the bond is bonded to a double bond in the E or Z configuration, and the symbol 〓 indicates a single bond or a double bond. ] 2-cyclopentenones represented by the following formula [] are subjected to an epoxidation reaction. [wherein 〓, 〓, R ² and R ³ are the same as defined above. ] The following formula [] is characterized in that the 2,3-epoxycyclopentanones represented by the following are obtained, and then the 2,3-epoxycyclopentanones are subjected to a halogenation reaction and then a dehydration reaction under acidic conditions. [In the formula, X represents a halogen atom,
Indication 〓, R ² and R ³ are the same as defined above. ] A method for producing 2-halo-2-cyclopentenones represented by: 6. The method for producing 2-halo-2-cyclopentenones according to claim 5, wherein the epoxidation reaction is carried out using hydrogen peroxide in the presence of a basic compound. 7 Claim 5 or 6, wherein the basic compound is an alkali metal hydroxide or carbonate
2. Method for producing 2-halo-2-cyclopentenones as described in 2. 8. 2-halo- according to any one of claims 5 to 7, wherein the halogenation reaction is carried out using hydrogen halides or metal halides.
Method for producing 2-cyclopentenones. 9. The method for producing 2-halo-2-cyclopentenones according to any one of claims 5 to 8, wherein the halogenation reaction is carried out using hydrogen chloride or hydrogen bromide. 10 2- according to any one of claims 5 to 8, wherein the halogenation reaction is carried out with titanium tetrachloride, tin tetrachloride, or aluminum trichloride.
Method for producing halo-2-cyclopentenones.