JPH0419214B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to 2-halo-4-hydroxy-2-cyclopentenones and a method for producing the same. More specifically, the present invention relates to 2-halo-4- which has a prostaglandin A-like structure and has excellent pharmacological effects such as anticancer, antiviral, and antibacterial effects.
The present invention relates to hydroxy-2-cyclopentenones 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 _A2 is expected to be a drug with 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 suppresses DNA synthesis, it has been reported that prostaglandin A has the potential to be an antitumor agent [Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)] Biochem. Biophys.
Res.Commun.], 87, 795, 1979;
WATurner, Prostaglandins and Related Lipids, 2, 365-8
(1982)]. Also, the following formula Prostaglandin related compounds expressed by
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. Kobayashi (M.
Kobayashi et al., Tetrahedron Lett., 23 , 5331 (1982); Masanori Fukushima, Cancer and Chemotherapy, 10, 1930 (1983)]. The synthesis of prostaglandin-related compounds has also been achieved [EJCorey et al.
Journal of the American Chemical
Society (J.Am.Chem.Soc.), 106 , 3384
(1984)]. In addition, the following formula was obtained from Telesto riisei, which grows on the bottom of a boat recently collected on Oahu. Punaglandins, which are prostaglandin related substances expressed by
(1982)) 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 related compounds, they found that 4-hydroxy-4-alkyl-2-cyclopentenones By aldol condensation of aldehydes, a new punaglandin-like compound having a prostaglandin A-like structure was industrially advantageously obtained, and when its biological activity was examined, it was found to have extremely strong cancer cell proliferation inhibiting activity. We have discovered that this product is useful as a new type of medicine, and have arrived at the present invention. Therefore, the purpose of the present invention is to have an excellent anticancer effect,
The object of the present invention is to provide 2-halo-4-hydroxy-2-cyclopentenones having antiviral effects and an industrially advantageous method for producing the same. <Structure of the invention> The present invention is based on the following formula [] [In the formula, R ¹ is −COOR ⁴ (here, R ⁴
represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or 1 equivalent of a cation. ) with carbon number 4
~6 alkyl group. R ² represents an unsubstituted alkyl group having 7 to 10 carbon atoms, and R ³ represents a trimethylsilyl group, an acetyl 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 halogen atom. ] The present invention relates to 2-halo-4-hydroxy-2-cyclopentenones represented by the following and a method for producing the same. In the above formula [], R ¹ is a substituted carbon number 4
~6 alkyl group. Examples of the alkyl group having 4 to 6 carbon atoms include:
Linear or branched ones such as n-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl can be mentioned. The substituent of the alkyl group having 4 to 6 carbon atoms is -
COOR ⁴ (R ⁴ here represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or 1 equivalent of a cation). Examples of the alkyl group having 1 to 10 carbon atoms for R ⁴ include the same alkyl groups as those mentioned above, as well as methyl, ethyl, n-propyl, isopropyl, n-heptyl, n-octyl, n-nonyl,
Examples include n-decyl. Examples of 1-equivalent cations include ammonium cations such as NH ₄ ⁺ , tetramethylammonium, monomethylammonium, and trimethylammonium;
Examples include metal cations such as Na ⁺ , K ⁺ , 1/2Ca ²⁺ , 1/2Al ³⁺ , and the like. Among these, R ⁴ is preferably a hydrogen atom or a methyl group. In the above formula [], R ² represents an unsubstituted alkyl group having 7 to 10 carbon atoms. Examples of the alkyl group having 7 to 10 carbon atoms include 2-methylhexyl,
Examples include n-heptyl, n-octyl, 3,7-dimethyloctyl, and the like. In the above formula [], R ³ is a hydrogen atom,
Examples include trimethylsilyl group and acetyl group. 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. In other words, the above formula []
2-halo-4-hydroxy-2-cyclopentenones represented by the following formula [a] according to the definitions of A and B [In the formula, R ¹ , R ² , R ³ , and X are the same as defined above. ] 2-halo-4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenones represented by the following formula [b] [In the formula, R ¹ , R ² , R ³ , and X are the same as defined above. The designation indicates that the bond is in the E or Z configuration or a mixture of these in any proportion relative to the double bond. ] represents 2-halo-4-hydroxy-4-alkyl-5-alkylidene-2-cyclopentenones. In the 2-halo-4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenones represented by the above formula [a],
The 4th position on the five-membered ring, that is, the carbon atom substituted with R ² or OR ³ , the 5th position on the five-membered ring, that is, the carbon atom substituted with the hydroxyalkyl group, and the hydroxyl group.
There are eight types of stereoisomers derived from the asymmetry of the carbon atom substituted by R ¹ , and in the present invention, it is any one of these stereoisomers or a mixture of them in any proportion. . 2-halo-4-hydroxy-4-alkyl-5-alkylidene-2 represented by the above formula [b]
- In cyclopentenones, 4 on the five-membered ring
There are four stereoisomers derived from the asymmetry of the carbon atom substituted with R ² and OR ³ and the orientation of the bond to the carbon atom to which R ¹ is attached. It is either one of the isomers or a mixture of them in any proportion. In the above formulas [], [a], and [b], X represents a halogen atom, and examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, with a chlorine atom or a bromine atom being preferred; Particularly preferred is a chlorine atom. The 2-halo-4-hydroxy-2-cyclopentenones of the present invention are particularly of the following formula [] [In the formula, R ² , R ³ , R ⁴ , X, A, and B are the same as defined above. ] Compounds represented by these are preferred. In the above formula [], R ⁴ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a cation of 1 equivalent. These specific examples are the same as those described above. Also R ² ,
R ³ , A, B, and X are also the same as those described above. 2 represented by the above formula [a] or []
-halo-4-hydroxy-4-alkyl-5-
Specific examples of (1-hydroxyalkyl)-2-cyclopentenones include the following. (1) 2-chloro-4-hydroxy-4-octyl-5-(1-hydroxy-6-carboxyhexyl)-2-cyclopentenone (2) 2-chloro-4-trimethylsilyloxy-
4-octyl-5-(1-hydroxy-6-carboxyhexyl)-2-cyclopentenone (3) 2-chloro-4-acetoxy-4-octyl-5-(1-hydroxy-6-carboxyhexyl)- 2-cyclopentenone (4) 2-chloro-4-hydroxy-4-(3,7)
-dimethyloctyl)-5-(1-hydroxy-
6-carboxyhexyl)-2-cyclopentenone (5) 2-chloro-4-trimethylsilyloxy-
4-(3,7-dimethyloctyl)-5-(1-
Hydroxy-6-carboxyhexyl)-2-
Cyclopentenone (6) 2-chloro-4-acetoxy-4-(3,7
-dimethyloctyl)-5-(1-hydroxy-
6-carboxyhexyl)-2-diclopentenone (7) Methyl ester of (1) to (6) 2-halo-4-hydroxy-4-alkyl-5 represented by the above formula [b] or []
Specific examples of -alkylidene-2-cyclopentenones include the following. (8) 2-chloro-4-hydroxy-4-octyl-5-[(E)-6-carboxyhexylidene]-2
-Cyclopentenone (9) 2-chloro-4-hydroxy-4-octyl-5-[(Z)-6-carboxyhexylidene]-
2-cyclopentenone (10) 2-chloro-4-trimethylsilyloxy-
4-octyl-5-[(E)-6-carboxyhexylidene]-2-cyclopentenone (11) 2-chloro-4-trimethylsilyloxy-4-octyl-5-[(Z)-6-carboxy hexylidene]-2-cyclopentenone (12) 2-chloro-4-acetoxy-4-octyl-5-[(E)-6-carboxyhexylidene]-
2-Cyclopentenone (13) 2-chloro-4-acetoxy-4-octyl-5-[(Z)-6-carboxyhexylidene]
-2-cyclopentenone (14) 2-chloro-4-hydroxy-4-(3,
7-dimethyloctyl)-5-[(E)-6-carboxyhexylidene]-2-cyclopentenone (15) 2-chloro-4-hydroxy-4-(3,
7-dimethyloctyl)-5-[(Z)-6-carboxyhexylidene]-2-cyclopentenone (16) 2-chloro-4-trimethylsilyloxy-4-(3,7-dimethyloctyl)-5 − [(E)
-6-carboxyhexylidene]-2-cyclopentenone (17) 2-chloro-4-trimethylsilyloxy-4-(3,7-dimethyloctyl)-5-
[(Z)-6-carboxyhexylidene]-2-cyclopentenone (18) 2-chloro-4-acetoxy-4-(3,
7-dimethyloctyl)-5-[(E)-6-carboxyhexylidene]-2-cyclopentenone (19) 2-chloro-4-acetoxy-4-(3,
Methyl ester of 7-dimethyloctyl)-5-[(Z)-6-carboxyhexylidene]-2-cyclopentenone (20) (8) to (19) 2-halo-4-hydroxy- of the present invention 2-cyclopentenones represented by the above formula [a]
-halo-4-hydroxy-4-alkyl-5-
(1-hydroxyalkyl)-2-cyclopentenones have the following formula [] [In the formula, R ² represents an unsubstituted alkyl group having 7 to 10 carbon atoms. R ³⁰ represents a hydroxyl protecting group. X
represents a halogen atom. ] 2 ^- halo-4-hydroxy-4-alkyl-2-cyclopentenones represented by ^the following formula ^[ ] in
R ⁴⁰ represents an alkyl group having 1 to 10 carbon atoms. ) represents an alkyl group having 4 to 6 carbon atoms. ] It can be obtained by subjecting aldehydes represented by the following to an aldol condensation reaction, and subjecting them to deprotection, hydrolysis, and salt-forming reactions as necessary. In the above formula [], R ² represents an unsubstituted alkyl group having 7 to 10 carbon atoms, and X represents a halogen atom. Specific examples of R ² and X include those mentioned above. R ³⁰ represents a hydroxyl group-protecting group, and specific examples of R ³⁰ include trimethylsilyl group and acetyl group. In the above formula [ ], R ¹⁰ is substituted with 4 to 4 carbon atoms
6 represents an alkyl group. Examples of the alkyl group having 4 to 6 carbon atoms include:
Linear or branched ones such as n-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl can be mentioned. The substituent of the alkyl group having 4 to 6 carbon atoms is -
COOR ⁴⁰ (R ⁴⁰ here represents an alkyl group having 1 to 10 carbon atoms). Examples of the alkyl group having 1 to 10 carbon atoms for R ⁴⁰ include the same alkyl groups as those described for R ⁴ above. Among these, a methyl group can be mentioned as preferred as R ⁴⁰ . The starting material [ ] is a compound known per se, 3-halogenated-4-hydroxy-2-cyclopentenone [W Liquors (W-
Rickards et al., Journal of the Chemical Society Chemical Communications (JCS, Chem, Commun,), 121
(1979)] by the route shown in reaction scheme A below. [R ² and R ³⁰ are 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.
Basic compounds and reaction solvents include, for example, literature:
ATNielsen, WJ Houlinan, Organ React., 16.
1 (1968); H O House (HO
House), “Modern Synthetic Reactions, 2nd Ed., Benjamin (1972), P629; New Experimental Chemistry Course 14,
Those listed in 736, 851, etc. are selected. The aldol condensation reaction is preferably carried out in the presence of metal amides such as lithium diisopropylamide, lithium diethylamide, and lithium bistrimethylsilylamide; or dialkyls such as dibutylboron trifluoromethanesulfonic acid in the presence of tertiary amines such as triethylamine, diisopropylethylamine, and tributylamine. Boron trifluoromethanesulfonic acids are used. When the aldol condensation reaction is carried out using metal amides, the amount used is 0.5 to 30 equivalents, preferably 0.5 to 30 equivalents, based on the 2-halo-4-hydroxy-4-alkyl-2-cyclopentenone of the above formula []. 0.9
~10 equivalents are 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℃
The temperature range is from -50°C, particularly preferably from -80°C to 0°C. When the aldol condensation reaction is carried out using tertiary amines and dialkylboron trifluoromethanesulfonic acids, the amount used is determined by the above formula []
2-halo-4-hydroxy-4-alkyl-2
-For cyclopentenones, each is 0.5~
50 equivalents are used, preferably 1 to 10 equivalents. The aldehyde [] is 0.5 to 10 equivalents, preferably 0.8 equivalent to the 2-halo-4-hydroxy-4-alkyl-2-cyclopentenone of the above formula []
~2 equivalents are used. The reaction time varies depending on the raw material compounds, reagents, reaction solvents, etc. used, but is usually carried out in a range of 5 minutes to 1 day, preferably in a range of 10 minutes to 12 hours. After completion of the reaction, the product can be purified and fractionated 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 between -78°C and +30°C.
It is carried out for about 10 minutes to 3 days at a temperature range of . Furthermore, when the protecting group is a tri(C ₁ -C ₇ )hydrocarbon-silyl group, the same reaction method as described above is carried out in the presence of acetic acid, tetrabutylammonium fluoride, cesium fluoride, etc. carried out for a similar period of time at temperature. In addition, when the protecting group is an acyl group, for example, in an aqueous solution or water-alcohol mixed solution 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 [a] [In the formula, R ¹ , R ² , R ³ , and X are the same as defined above. ] 2-halo-4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenones are obtained. 2-halo-4-hydroxy-2-cyclopentenones of the present invention represented by the above formula [b]
-Halo-4-hydroxy-4-alkyl-5-alkylidene-2-cyclopentenones have the following formula [a'] [In the formula, R ¹⁰ , R ² , R ³⁰ and X are the same as defined above. ] The 2-halo-4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenones represented by It can be obtained by adding In the above formula [Ia'], R ¹⁰ is - as a substituent
COOR ⁴⁰ (herein, R ⁴⁰ represents an alkyl group having 1 to 10 carbon atoms), and R ² is an unsubstituted alkyl group having 7 to 10 carbon atoms. , R ³⁰ represents a hydroxyl group, and X represents a halogen atom. Specific examples of R ¹⁰ , R ² , R ³⁰ and X include those mentioned above. The dehydration reaction of 2-halo-4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenones represented by the above formula [a'] Halo-4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)
-Carried out by reacting 2-cyclopentenones with a reactive derivative of an organic sulfonic acid in the presence of a basic compound to form the corresponding organic sulfonyloxy derivative, and then treating with a basic compound. . As the basic compound used when reacting the compound of the above formula [a'] with the reactive derivative of organic sulfonic acid, amines are preferable, and examples of such amines include pyridine, 4-dimethylaminopyridine, etc. , triethylamine, diisopropylcyclohexylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (hereinafter abbreviated as DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (hereinafter abbreviated as DBU) ), quinuclidine, triethylenediamine, isopropyldimethylamine, diisopropylethylamine, etc. Among them, pyridine, 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, Hydrocarbons such as hexane and cyclohexane may also be used. Preferably pyridine dichloromethane is used. The reaction is a 2-halo- represented by the general formula [a′]
5 of 4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenones
This is a reaction between the hydroxyl group on the alkyl group in position and a reactive derivative of an organic sulfonic acid, and stoichiometrically, the two compounds react in equimolar amounts. In order to actually carry out the reaction, 2-halo-4- of the general formula [a'] is usually used.
The reactive derivative of organic sulfonic acid is used in an amount of 1 to 10 equivalents to hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenone. The basic compound is used in an amount of 1 equivalent or more, preferably 2 equivalents or more, based on the reactive derivative of the organic sulfonic acid used. The amount of solvent used is usually 1 to 1 to 2-cyclopentenones relative to the 2-halo-4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenones represented by the above formula [a']. 1000 times the volume, preferably 5 to 100 times the volume is used. The reaction temperature varies depending on the raw material compound, basic compound, solvent, etc. used, but is usually in the range of -10°C to 50°C,
The temperature is preferably from 0°C to 30°C. The reaction time varies depending on the conditions, but is about 0.1 to 10 hours. 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), 2-halo-4-hydroxy-4-alkyl-5-(1-
An organic sulfonyloxy derivative in which the hydroxyl group on the 5-position alkyl group of the (hydroxyalkyl)-2-cyclopentenone is converted into an organic sulfonyloxy group 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 [b'] [In the formula, R ¹⁰ , R ² , R ³⁰ and X are the same as defined above. The designation indicates that the bond is in the E or Z configuration or a mixture of these in any proportion relative to the double bond. ] It is converted into 2-halo-4-hydroxy-4-alkyl-5-alkylidene-2-cyclopentenones represented by the following formula. Examples of the basic compound that can be used in this second reaction include the same basic compounds as those mentioned in the first reaction. The basic compound used in the second reaction may be different from that used in the first reaction. This second reaction can proceed over a similar temperature range. Further, the organic sulfonyloxy derivative produced in the first reaction may be isolated and then subjected to the second reaction, or the first reaction and the second reaction may be performed in the same reaction system. After the reaction is completed, 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. Thus, the following formula [b] [In the formula, R ¹ , R ² , R ³ , X and the representations are the same as defined above. ] 2-halo-4-hydroxy-4-alkyl-5-alkylidene-2-cyclopentenones are produced. <Effects of the Invention> The 2-halo-4-hydroxy-2-cyclopentenones of the present invention exhibit an inhibitory effect on the proliferation of L1210 leukemia cells and are expected to be used as anticancer agents. Furthermore, the 2-halo-4-hydroxy-2 of the present invention
- Cyclopentenones exhibit growth-inhibitory effects on herpesviruses and are expected to be used as antiviral agents. Moreover, the production method of the present invention is an industrially advantageous production method, and the target 2-halo-4-hydroxy-2-
Cyclopentenones can be efficiently produced. <Examples> The present invention will be explained in more detail below using examples. Reference example 1 2-chloro-4-octylcyclopenta-2-
Production of ene-1,4-diol 108 mg of 3-chloro-4-t-butyldimethylsilyloxy-2-cyclopentenone was dissolved in 4 ml of ether, and after cooling to -78°C, 0.79 ml of octylmagnesium bromide-tetrahydrofuran solution (0.72M) was added. After stirring for 10 minutes, water was added and extracted with ether. It was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained oil was dissolved in 6 ml of tetrahydrofuran, 1.1 ml of tetrabutylammonium fluoride-tetrahydrofuran solution (1M) was added, and the mixture was stirred for 2 days. Saturated brine was added, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After overconcentration, it was subjected to silica gel column chromatography to obtain 92 mg of 2-chloro-4-octylcyclopent-2-ene-1,4-diol.
(yield 83%). Reference example 2 2-chloro-4-hydroxy-4-octyl-
Production of 2-cyclopentenone 700 mg of 2-chloro-4-octylcyclopent-2-ene-1,4-diol obtained according to Reference Example 1 was dissolved in 8 ml of dimethylformamide.
1.68 g of pyridinium dichromate was added and stirred for 20 hours. After filtration, saturated brine was added, and the mixture was extracted with ether. The residue was dried over anhydrous magnesium sulfate, overconcentrated, and subjected to silica gel column chromatography to obtain 547 mg (yield: 75%) of 2-chloro-4-hydroxy-4-octyl-2-cyclopentenone. Spectrum data NMR ( _CDCl3 ) δ 0.7-1.0 (brt, 3H), 1.1-2.0 (m, 15H), 2.53 (d, 1H, J = 18.7Hz), 2.77 (d, 1H, J = 18.7Hz), 7.33 (s, 1H) Reference example 3 Production of 2-chloro-4-octyl-4-trimethylsilyloxy-2-cyclopentenone 2-chloro-4-hydroxy-4-octyl-2-cyclopentenone obtained according to Reference Example 2
77 mg was dissolved in 4 ml of dichloromethane, and 0.54 ml of diisopropylethylamine was added. Add 0.07ml of trimethylsilyltrifluoromethanesulfonic acid
Stir for 15 minutes. Water was added and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography to yield 96 mg of 2-chloro-4-octyl-4-trimethylsilyloxy-2-cyclopentenone. rate
97%). Spectrum data NMR (CDCl ₃ ) δ 0.08 (s, 9H), 0.7-1.0 (brt, 3H), 1.1-1.9 (m, 14H), 2.63 (s, 2H), 7.34 (s, 1H) Reference example 4 3 -t-butyldimethylsilyloxy-2-chloro-5-(3,7-dimethyloctyl)-5-
Production of hydroxycyclopentene 3.70 g of 4-t-butyldimethylsilyloxy-3-chloro-2-cyclopentenone was dissolved in ether 30
ml and cooled to -78°C. A 3,7-dimethyl-1-octylmagnesium bromide-ether solution was added, and the mixture was stirred at -78°C for 1.5 hours. The mixture was poured onto a saturated aqueous ammonium chloride solution and extracted with ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After overconcentration, it was subjected to silica gel column chromatography to obtain 3-t-butyldimethylsilyloxy-2-
Chloro-5-(3,7-dimethyloctyl)-5-
Low polar isomer of hydroxycyclopentene 3.17
g, highly polar isomers 0.60 g and mixtures thereof
1.12g was obtained (yield 84%). spectral data Low polar isomer NMR ( _CDCl3 ) δ 0.13 (6H, s), 0.7-1.0 (9H, m), 0.87 (9H, s), 1.0-1.8 (12H, m), 1.78 (1H, dd, J = 14.0, 3.0Hz), 2.15 (1H, s), 2.36 (1H, dd, J=14.0, 6.4Hz), 4.38 (1H, dd, J=6.2, 3.8Hz), 5.71 (1H, s) Highly polar isomer NMR ( _CDCl3 ) δ 0.1-0.3 (6H, m), 0.7-1.0 (9H, m), 0.87 (9H, s), 1.0-1.8 (12H, m), 1.68 (1H, s) , 1.84 (1H, dd, J = 12.4, 4.2Hz), 2.19 (1H, dd, J = 12.4, 6.4Hz), 4.6-4.9 (1H, m), 5.63 (1H, s) Reference example 5 2-chloro -4-(3,7-dimethyloctyl)
-Production of 4-hydroxy-2-cyclopentenone 3-t-Butyldimethylsilyloxy-2-chloro-5-(3,7-
Dissolve 50 mg of dimethyloctyl-5-hydroxycyclopentene in 1 ml of tetrahydrofuran and add 200 mg of tetrabutylammonium fluoride trihydrate.
mg was added and stirred for 4 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. Overconcentrate to obtain 1-chloro-3-(3,7-
30 mg of a crude product of (dimethyloctyl)-3,5-dihydroxycyclopentene was obtained. This was dissolved in 1 ml of dimethylformamide, 100 mg of pyridinium dichromate was added, and the mixture was stirred for 2 hours. Water was added and extracted with ethyl acetate, and the organic layer was washed with brine. It was dried over anhydrous magnesium sulfate, overconcentrated, and subjected to silica gel column chromatography.
-chloro-4-(3,7-dimethyloctyl)-4
-Hydroxy-2-cyclopentenone 14 mg (yield
40%). Spectrum data NMR (CDCl ₃ ) δ 0.7-1.0 (9H, m), 1.0-2.4 (12H, m), 2.56 (1H, s), 7.33 (1H, s) Reference example 6 2-chloro-4-(3 ,7-dimethyloctyl)
-Production of 4-trimethylsilyloxy-2-cyclopentenone 2-chloro-4- obtained according to Reference Example 5
(3,7-dimethyloctyl)-4-hydroxy-
147mg of 2-cyclopentenone and 700μ of N,O-bistrimethylsilyltrifluoroacetamide
(2.6 mmol) was added, and after stirring for 16 hours, it was subjected to silica gel column chromatography.
4-(3,7-dimethyloctyl)-4-trimethylsilyloxy-2-cyclopentenone 165 mg
(yield 89%). Spectrum data NMR (CDCl ₃ ) δ 0-0.3 (9H, m), 0.7-1.0 (9H, m), 1.0-2.0 (12H, m), 2.57 (2H, s), 7.30 (1H, s) Examples 1 2-chloro-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-octyl-4
-Production of trimethylsilyloxy-2-cyclopentenone 526 mg of 2-chloro-4-octyl-4-trimethylsilyloxy-2-cyclopentenone obtained according to Reference Example 3 was dissolved in 18 ml of ether.
Cool to 350 µC of diisopropylethylamine.
was added and stirred for 10 minutes. After adding 2.03 ml of dibutylboron trifluoromethanesulfonic acid-dichloromethane solution (1.0 M) and stirring for 30 minutes, a solution of 321 mg of methyl 7-oxoheptanoate in 7 ml of ether was added. After stirring at -78°C for 80 minutes, an aqueous ammonium chloride solution was added, and the mixture was extracted with ether. After drying over anhydrous magnesium sulfate and overconcentrating, it was subjected to silica gel column chromatography to obtain 2-chloro-
360 mg (yield 46%) of a mixture of isomers of 5-(1-hydroxy-6-methoxycarbonylhexyl)-4-octyl-4-trimethylsilyloxy-2-cyclopentenone was obtained. Spectral data NMR (CDCl ₃ ) δ 0.13 and 0.19 (s, 9H), 0.7-1.0 (brt, 3H), 1.0-2.0 (m, 23H), 2.32 (t, 2H, J = 7.2Hz), 2.42 (d , 1H), 3.66 (s, 3H), 3.8-4.1 (m, 1H), 7.32 and 7.47 (s, 1H) Example 2 2-chloro-5-(6-methoxycarbonylhexylidene)-4-octyl -Production of 4-trimethylsilyloxy-2-cyclopentenone 2-chloro-5- obtained according to Example 1
(171 mg of 1-hydroxy-6-methoxy-2-cyclopentenone was dissolved in 7 ml of pyridine, 50 μm of methanesulfonic acid chloride was added, and the mixture was stirred for 14 hours.
Water was added, extracted with dichloromethane, and dried over anhydrous sodium sulfate. After overconcentration, the obtained 2-
Chloro-5-(1-methanesulfonyloxy-6
-Methoxycarbonylhexyl)-4-octyl-4-trimethylsilyloxy-2-cyclopentenone was dissolved in 10 ml of benzene.
0.1 ml of 8-diazabicyclo[5.4.0]undec-7-ene was added and stirred for 55 minutes. Water was added, extracted with ether, and dried over anhydrous magnesium sulfate.
After overconcentration, it was subjected to silica gel column chromatography to obtain 73 mg of a mixture of Z and E forms of 2-chloro-5-(6-methoxycarbonylhexylidene)-4-octyl-4-trimethylsilyloxy-2-cyclopentenone. (yield 43%). Spectral data NMR ( _CDCl3 ) δ 0.03 (s, 9H), 0.7~1.0 (brt, 3H), 1.0~2.0 (m, 20H), 2.1~2.5 (m, 4H), 3.68 (s, 3H), 6.66 (t, 1H, J=7.7Hz), 7.20 (s, 1H) Example 3 2-chloro-4-hydroxy-5-(6-methoxycarbonylhexylidene)-4-octyl-2-cyclopentenone manufacturing 2-chloro-5- obtained according to Example 2
31 mg of a mixture of E and Z forms of (6-methoxycarbonylhexylidene)-4-octyl-4-trimethylsilyloxy-2-cyclopentenone was added to acetic acid.
Tetrahydrofuran-water mixed solvent (6:1:3)
3 ml was added and stirred for 2 hours. A saturated aqueous sodium bicarbonate solution was added, extracted with ether, and dried over anhydrous sodium sulfate. After overconcentration, it was subjected to silica gel column chromatography to obtain 2-chloro-4-
25 mg (yield 97%) of a mixture of Z and E forms of hydroxy-5-(6-methoxycarbonylhexylidene-4-octyl-2-cyclopentenone) was obtained. Spectral data NMR ( _CDCl3 ) δ 0.7 ~1.1 (t, 3H), 1.1 ~ 2.1 (m, 21H), 2.35 (t, 2H), 2.5 ~ 3.0 (m, 2H), 3.67 (s, 3H), 6.35 (t, 1H, J = 7.9Hz ) and 6.66 (dd, 1H, J=8.3, 7.5Hz), 7.17 (s, 1H) and 7.24 (s, 1H) Example 4 2-chloro-4-(3,7-dimethyloctyl)
-Production of 5-(1-hydroxy-6-methoxycarbonylhexyl)-4-trimethylsilyloxy-2-cyclopentenone 2-chloro-4- obtained according to Reference Example 4
(3,7-dimethyloctyl)-4-trimethylsilyloxy-2-cyclopentenone 54mg
(157 μmol) was dissolved in 2 ml of tetrahydrofuran,
Cool to -45°C and 1.5 ml (0.30
mmol) and stirred at -45°C for 20 minutes. 47 mg (0.3 mmol) of methyl 7-oxoheptanoate was dissolved in 1 ml of dry tetrahydrofuran, added after cooling to -45°C, and stirred at -45°C for 20 minutes. Acetic acid 100μ
was added, stirred for 5 minutes, and poured onto saturated ammonium chloride water. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine. It was dried over anhydrous magnesium sulfate, overconcentrated, and subjected to silica gel column chromatography to recover 24 mg of raw material.
-(3,7-dimethyloctyl)-5-(1-hydroxy-6-methoxycarbonylhexyl)-4
22 mg (yield 50%) of -trimethylsilyloxy-2-cyclopentenone was obtained. Spectrum data NMR (CDCl ₃ ) δ 0.20 (s, 9H), 0.7-1.0 (m, 9H), 1.0-2.0 (m, 20H), 2.0-2.7 (m, 3H), 2.9-3.5 (m, 1H) , 3.60 (s, 3H), 3.5-4.2 (m, 1H), 7.25-7.4 (m, 1H) Example 5 2-chloro-4-(3,7-dimethyloctyl)
-5-[(Z)-6-methoxycarbonylhexylidene]-4-trimethylsilyloxy-2-
Cyclopentenone and 2-chloro-4-(3,
Production of 7-dimethyloctyl)-5-[(E)-6-methoxycarbonylhexylidene]-4-trimethylsilyloxy-2-cyclopentenone 2-chloro-4- obtained according to Example 4
(3,7-dimethyloctyl)-5-(1-hydroxy-6-methoxycarbonyl)-4-trimethylsilyloxy-2-cyclopentenone 22mg
(44μmol) was dissolved in 500μ of pyridine, 50μ of methanesulfonyl chloride (646μmol) was added, and 1.5
Stir for hours. 1,8-diazabicyclo [5.4.0]
200μ (1.34 mmol) of undec-7-ene was added and stirred for 30 minutes. A saturated aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium bicarbonate solution, then saturated brine, and dried over anhydrous sodium sulfate.
After overconcentration, it was subjected to silica gel thin layer chromatography to obtain 2-chloro-4-(3,7-dimethyloctyl)-5-[(Z)-6-methoxycarbonylhexylidene]-4-trimethylsilyloxy-2-
6.3 mg (yield 30%) of cyclopentenone and 2-
Chloro-4-(3,7-dimethyloctyl)-5-
[(E)-6-methoxycarbonylhexylidene]-4
-Trimethylsilyloxy-2-cyclopentenone (11.0 mg, yield 52%) was obtained. spectral data NMR ( _CDCl3 ) δ 0-0.3 (m, 9H), 0.7-1.0 (m, 9H), 1.0-2.0 (m, 18H), 2.0-2.5 (m, 2H), 2.5-3.0 (m, 2H) , 3.61 (s, 3H), 6.21 (t, 1H, J=7.5Hz), 7.07 (s, 1H) NMR (CDCl ₃ ) δ 0-0.3 (m, 9H), 0.7-1.0 (m, 9H), 1.0-2.0 (m, 18H), 2.0-2.8 (m, 4H), 3.63 (s, 3H), 6.63 (t, 1H, J=7.5Hz), 7.17 (s, 1H), Example 6 2-chloro-4-(3,7-dimethyloctyl)
Production of -4-hydroxy 5-[(Z)-6-methoxycarbonylhexylidene]-4-trimethylsilyloxy-2-cyclopentenone 2-chloro-4- obtained according to Example 5
(3,7-dimethyloctyl)-5-[(Z)-6-
methoxycarbonylhexylidene]-4-trimethylsilyloxy-2-cyclopentenone 6.3mg
(13 μmol) was dissolved in 0.5 ml of acetic acid-tetrahydrofuran-water mixed solvent (3:1:1) and stirred for 2.5 hours. Saturated sodium hydrogen carbonate water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel thin layer chromatography to obtain 2-chloro-4-(3,7-dimethyloctyl)-4-hydroxy- 5-[(Z)-6-methoxycarbonylhexylidene]-4-trimethylsilyloxy-2
- 5.2 mg (yield 97%) of cyclopentenone was obtained. Spectral data NMR ( _CDCl3 ) δ 0.7-1.0 (m, 9H), 1.0-2.0 (m, 18H), 2.0-2.6 (m, 4H), 2.6-3.1 (m, 1H), 3.60 (s, 3H) , 6.33 (t, 1H, J = 7.5Hz), 7.13 (s, 1H) Example 7 2-chloro-4-(3,7-dimethyloctyl)
Production of -4-hydroxy-5-[(E)-6-methoxycarbonylhexylidene]-2-cyclopentenone 2-chloro-4- obtained according to Example 5
(3,7-dimethyloctyl)-5-[(E)-6-methoxycarbonylhexylidene]-4-trimethylsilyloxy-2-cyclopentenone 11mg
(230 μmol) was dissolved in 0.5 ml of acetic acid-tetrahydrofuran-water mixed solvent (3:1:1) and stirred for 2.5 hours. Saturated sodium bicarbonate water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration, it was subjected to silica gel thin layer chromatography, and 2-
Chloro-4-(3,7-dimethyloctyl)-4-
8.6 mg (yield 92%) of hydroxy-5-[(E)-6-methoxycarbonylhexylidene]-2-cyclopentenone was obtained. Spectral data NMR ( _CDCl3 ) δ 0.7-1.0 (m, 9H), 1.0-2.0 (m, 18H), 2.0-3.1 (m, 5H), 3.59 (s, 3H), 6.61 (dd, 1H, J= 9.0, 7.0Hz), 7.20 (s, 1H)

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ is −COOR ⁴ (here R ⁴
is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or 1
Represents equivalent cations. ) represents an alkyl group having 4 to 6 carbon atoms. R ² represents an unsubstituted alkyl group having 7 to 10 carbon atoms, and R ³ represents a trimethylsilyl group, an acetyl 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 halogen atom. ] 2-halo-4-hydroxy-2-cyclopentenones represented by these. 2 In the above formula [], R ² is octyl or 3,
2-halo-4-hydroxy-2-cyclopentenones according to claim 1, which are 7-dimethyloctyl groups. 3. 2-halo- according to claim 1 or 2, wherein in the above formula [ ], X is a chlorine atom
4-hydroxy-2-cyclopentenones. 4 The following formula [] [In the formula, R ² , R ³ , A, B, X, and R ⁴ are the same as defined above. 2-halo-4-hydroxy- according to any one of claims 1 to 3 represented by
2-cyclopentenones. 5. 2-halo-4-hydroxy-2-cyclopentenones according to claim 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 7 to 10 carbon atoms. X represents a halogen atom. R ³⁰ represents a trimethylsilyl group or an acetyl group. ] to 2-halo-4-hydroxy-4-alkyl-2-cyclopentenones represented by the following formula [] OHC-R ¹⁰ ...[] [wherein R ¹⁰ is -COOR ⁴⁰ ( here
R ⁴⁰ represents an alkyl group having 1 to 10 carbon atoms. ) represents an alkyl group having 4 to 6 carbon atoms. ] The following formula [a] is characterized in that an aldehyde represented by is subjected to an aldol condensation reaction, and optionally subjected to deprotection, hydrolysis, and salt formation reaction. [In the formula, R ¹ is −COOR ⁴ (here R ⁴
is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or 1
Represents equivalent cations. ) represents an alkyl group having 4 to 6 carbon atoms. R ² represents an unsubstituted alkyl group having 7 to 10 carbon atoms, and R ³ represents a trimethylsilyl group, an acetyl group, or a hydrogen atom. X represents a halogen atom. ] A method for producing 2-halo-4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenones. 7. 2-halo-4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenones according to claim 6, wherein the aldol condensation reaction is carried out in the presence of lithium diisopropylamide. Manufacturing method. 8 Aldol condensation reaction in the presence of a basic compound,
2-halo-4-hydroxy-4-alkyl- according to claim 6, which is carried out by using dibutylborontrifluoromethanesulfonic acid.
Method for producing 5-(1-hydroxyalkyl)-2-cyclopentenones. 9 The following formula [a′] [In the formula, R ¹⁰ is -COOR ⁴⁰ (here, R 10 is a substituent)
R ⁴⁰ represents an alkyl group having 1 to 10 carbon atoms. ) represents an alkyl group having 4 to 6 carbon atoms.
R ² represents an unsubstituted alkyl group having 7 to 10 carbon atoms. R ³⁰ represents a trimethylsilyl group or an acetyl group. ] 2-halo-4-hydroxy-4-alkyl-5-(1-hydroxyalkyl)-2-cyclopentenones are subjected to a dehydration reaction and optionally subjected to deprotection, hydrolysis, and salt formation reactions. The following formula [b] is characterized by [In the formula, R ¹ is −COOR ⁴ (here R ⁴
is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or 1
Represents equivalent cations. ) represents an alkyl group having 4 to 6 carbon atoms. R ² represents an unsubstituted alkyl group having 7 to 10 carbon atoms, and R ³ represents a trimethylsilyl group, an acetyl group, or a hydrogen atom. X represents a halogen atom. 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 2-halo-4-hydroxy-4-alkyl-5-alkylidene-2-cyclopentenones. 10 The method according to claim 9, 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 a deorganic sulfonic acid reaction. A method for producing 2-halo-4-hydroxy-4-alkyl-5-alkylidene-2-cyclopentenones.