JPH0635422B2 - 2-halo-4-hydroxy-2-cyclopentenones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to 2-halo-4-hydroxy-2-cyclopentenones.

More specifically, the present invention relates to 2-halo-4-hydroxy-2-cyclopentenones having a prostaglandin A-like structure having excellent antitumor action, antiviral action, antibacterial action and other pharmacological actions.

<Prior Art> Prostaglandins are compounds having specific biological activities such as an inhibitory effect on platelet aggregation, an antihypertensive effect, etc., and are useful natural compounds which have recently been used as therapeutic agents for peripheral circulatory diseases in the medical field. It is a thing. Among prostaglandins, prostaglandins A are known as those having a double bond in the cyclopentane ring, and for example, prostaglandin A ₂ is expected as a drug having a hypotensive action [E・ Jee Corey
Et al., Journal. of. The. American. Chemical Society (J. Amer. Chem. Soc.), 95,6831 (1973)).

On the other hand, since prostaglandins A strongly suppress DNA synthesis, it has been reported that prostaglandins A have potential as antitumor agents [Biochemical &
Bio-Offical Research Comunication (Bio
Chem.Biophys.Res.Commun.), 87,795 (1979); WATurner et al., Prostagladins R.
Elat. Lipids), 2, 365-8 (1982)].

Also, the following formula The prostaglandin analog represented by is the Okinawa coral (Okinawan soft coral).
al): clavularia viridi
s)], and is known to have an anti-inflammatory effect and an anti-cancer effect as physiological effects [ETCHI Kikuchi (HK
ikuchi) et al., Tetrahedron Letters
ct.), 23 , 5171 (1982); M. Kobayashi
Tetrahedron Lett., 2
3 , 5331 (1982); Masanori Fukushima, Cancer and Chemotherapy, 10, 1930 (1)
983)]. In addition, the synthesis of this prostaglandin analog compound has also been carried out [EJ Cory (EJCor
Ey) et al., Journal of the American Chemical Society (J. Am. Chem. Soc.), 106 , 3384 (1984)].

Furthermore, from the telesto riisei that has recently arrived on the island of Oahu and has settled on the bottom of the boat, Prostaglandin related substance represented by Is a single bond or a double bond) has been isolated (see Monthly Pharmaceutical Affairs 24, 41 (1982)) and known to have a carcinogenic effect as a physiological action (Fukushima Masanori et al., No. 43). See The Annual Meeting of the Japanese Cancer Society 905 (1984)).

<Purpose of the Invention> The inventors of the present invention have paid attention to such a point, and have conducted diligent research for the purpose of obtaining a new prostaglandin-related compound. As a result, 4-hydroxy-4-alkyl-2-cyclopentenones have been obtained. By aldol-condensing aldehydes, a novel punaglandin-like compound having a prostaglandin A-like structure can be industrially advantageously obtained,
The present invention has been found to have extremely strong cancer cell growth inhibitory activity and has been found to be useful as a new type of drug, and thus has reached the present invention.

Therefore, an object of the present invention is to provide 2-halo-4-hydroxy-2-cyclopentenones having excellent anticancer activity, antiviral activity, etc., and an industrially advantageous production method thereof. .

<Structure of Invention> The present invention has the following formula [I]. And a 2-halo-4-hydroxy-2-cyclopentenone represented by

In the above formula [I], A is a hydrogen atom, Or Represents Here, R ¹ represents a pentyl group substituted with a methoxycarbonyl group.

When A is a hydrogen atom, the 2-halo-4-hydroxy-2-cyclopentenones of the present invention have the following formula [Ia] It is represented by.

A is 2-halo-4-hydroxy-2- of the present invention
Cyclopentenones are represented by the following formula [Ib] [In the formula, R is the same as the above definition. ] 2-halo-4-hydroxy-4-alkyl-5- (1-hydroxyalkyl) -2-cyclopentenones represented by

A is 2-halo-4-hydroxy-2- of the present invention
Cyclopentenones have the following formula [Ic] [In the formula, R, indication Is as defined above. ] 2-halo-4-hydroxy-4-alkyl-5-alkylidene-2-cyclopentenones represented by

R ^{1 in the} formulas [Ib] and [Ic] represents a pentyl group substituted with a methoxycarbonyl group, but with reference to the fact that it may be a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms other than this group. Show. Examples of the alkyl group having 1 to 10 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and n-.
Examples thereof include linear or branched ones such as pentyl, n-hexyl and n-decyl.

As the substituent of the alkyl group having 1 to 10 carbon atoms,
For example, —COOR ² (wherein R ² represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms or 1 equivalent of a cation), a hydroxyl group, a protected hydroxyl group and the like can be mentioned.

Examples of the alkyl group having 1 to 10 carbon atoms for R ² include the same alkyl groups as described above. Examples of 1 equivalent of cations include ammonium cations such as NH ₄ ⁺ , tetramethylammonium, monomethylammonium and trimethylammonium; Na ⁺ , K ⁺ , 1 / 2Ca ²⁺ , 1 / 3Al
^Examples thereof include metal cations such as ³⁺ .

Examples of the protected hydroxyl-protecting group include a C ₂ -C ₇ acyl group, a tri (C ₁ -C ₇ ) hydrocarbon-silyl group, and a group that forms an acetal bond with the oxygen atom of the hydroxyl group.

Examples of the C _{2 to} C ₇ acyl group include acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, caproyl, enanthyl, benzoyl and the like.

Of these, C ₂ -C ₆ aliphatic acyl group such as acetyl,
Preference is given to n-butyryl or isobutyryl, caproyl or benzoyl.

Examples of the tri (C ₁ -C ₇ ) hydrocarbon silyl group include tri (C ₁ -C ₄ ) alkylsilyl such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl group; diphenyl such as t-butyldiphenylsilyl group. Preferable ones are (C ₁ -C ₄ ) alkylsilyl or tribenzylsilyl groups.

Examples of the group that forms an acetal bond with the oxygen atom of the hydroxyl group include methoxymethyl, 1-ethoxyethyl,
2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy) methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2 Mention may be made of the -oxo-bicyclo [3.1.0] hex-4-yl group. Among these, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl,
A 2-methoxy-2-propyl, (2-methoxyethoxy) methyl or 6,6-dimethyl-3-oxa-2-oxo-bicyclo [3.1.0] hex-4-yl group is preferred.

Preferable substituents of the substituted alkyl group having 1 to 10 carbon atoms include -COOH, -COOCH ₃ or hydroxyl group.

2-halo-4-hydroxy-4-alkyl-of the formula [Ib]
The preferred form of 5- (1-hydroxyalkyl) -2-cyclopentenones is represented by the following formula [Ib ′] 2-halo-4-hydroxy-4-alkyl-5- (1-hydroxyalkyl) -2-cyclopentenones represented by

The preferred form of 2-halo-4-hydroxy-2-cyclopentenones of the formula [Ic] is the following formula [Ic ′] 2-halo-4-hydroxy-4-alkyl-5-alkylidene-2-cyclopentenones represented by

4-position on the 5-membered ring of 2-halo-4-hydroxy-2-cyclopentenones of formula [Ia], The carbon atom substituted by OR is an asymmetric carbon, and the present invention includes two isomers based on the asymmetric carbon, and a mixture thereof in any ratio.

In 2-halo-4-hydroxy-4-alkyl-5- (1-hydroxyalkyl) -2-cyclopentenones represented by the above formulas [Ib] and [Ib ′], 4-position on the five-membered ring , Ie Carbon atom substituted by OR, 5-position on the 5-membered ring, ie 1-
There are eight stereoisomers derived from asymmetry of a carbon atom substituted with a hydroxyalkyl group and a carbon atom bonded with a hydroxyl group. In the present invention, any one of these stereoisomers is present, It is a mixture in any proportion thereof.

In 2-halo-4-hydroxy-4-alkyl-5-alkylidene-2-cyclopentenones represented by the above formulas [Ic] and [Ic '], 4-position on the 5-membered ring, that is, Asymmetric carbon atom substituted by OR, and R ¹ or There are four types of stereoisomers derived from the orientation (E configuration, Z configuration) of the bond to the carbon atom to which is bonded. In the present invention, any one of these stereoisomers is Is a mixture in any proportion.

The above formulas [I], [Ia], [Ib], [Ib '], [Ic],
In [Ic '], R represents a hydrogen atom or a protective group for a protected hydroxyl group.

When representing the hydroxyl protecting groups R are protected, C ₂ -C ₇ acyl group as such protecting groups, tri (C ₁ ~C ₇₎ hydrocarbon silyl group or a hydroxyl group which forms an acetal bond together with an oxygen atom And the like. Specific examples thereof include the same ones as described above.

Among these protecting groups, more preferable examples of R include a hydrogen atom, a trimethylsilyl group and an acetyl group, and a hydrogen atom is particularly preferable.

(i) Specific examples of the 2-halo-4-hydroxy-4-alkyl-2-cyclopentenones represented by the above formula [Ia] include the following.

(1) 2-Chloro-4-hydroxy-4- [3- (3,4-dimethoxyphenyl) propyl] -2-cyclopentenone (2) 2-Chloro-4-trimethylsilyloxy-4-
[3- (3,4-dimethoxyphenyl) propyl] -2-
Cyclopentenone (3) 2-chloro-4-acetoxy-4- [3- (3,4-dimethoxyphenyl) propyl] -2-cyclopentenone (ii) 2-represented by the above formula [Ib '] Halo-4-hydroxy-4-alkyl-5- (1-hydroxyalkyl)
The following are specific examples of the 2-cyclopentenones.

(4) 2-Chloro-4-hydroxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5- (1-hydroxy-6-methoxycarbonylhexyl) -2-cyclopentenone (5) 2-chloro-4-trimethylsilyloxy-4-
[3- (3,4-dimethoxyphenylpropyl] -5-
(1-hydroxy-6-methoxycarbonylhexyl)
-2-Cyclopentenone (6) 2-chloro-4-acetoxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5- (1-hydroxy-6-methoxycarbonylhexyl) -2- Cyclopentenone (iii) Specific examples of the 2-halo-4-hydroxy-4-alkyl-5-alkylidene-2-cyclopentenones represented by the above formula [Ic '] include the following.

(8) 2-chloro-4-hydroxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5-[(E) -6-methoxycarbonylhexylidene] -2-cyclopentenone ( 9) 2-chloro-4-hydroxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5-[(Z) -6-methoxycarbonylhexylidene] -2-cyclopentenone (10 ) 2-Chloro-4-trimethylsilyloxy-4-
[3- (3,4-dimethoxyphenyl) propyl] -5-
[(E) -6-Methoxycarbonylhexylidene] -2
-Cyclopentenone (11) 2-chloro-4-trimethylsilyloxy-4-
[3- (3,4-dimethoxyphenyl) propyl] -5-
[(Z) -6-methoxycarbonylhexylidene] -2
-Cyclopentenone (12) 2-chloro-4-acetoxy-4- [3- (3,4-
Dimethoxyphenyl) propyl] -5-[(E) -6-
Methoxycarbonylhexylidene] -2-cyclopentenone (13) 2-chloro-4-acetoxy-4- [3- (3,4-
Dimethoxyphenyl) propyl] -5-[(Z) -6-
Methoxycarbonylhexylidene] -2-cyclopentenone The 2-halo-4-hydroxy-2-cyclopentenones [Ia], [Ib] and [Ic] of the present invention are separately filed by the present inventors ( Japanese Patent Application No. 60-28429), a known compound 3-chloro-4-hydroxy-2-cyclopentenone [W.Rickards et al., Journal of the Chemical Society] was used. -Chemical communication (JC Chem.Comm.), 121 (1979)] can be produced by a route as shown in the following reaction scheme.

Reaction scheme 2-halo-4-hydroxy-2-cyclopentenones represented by the following formula [II] It can be obtained by subjecting the cyclopentene alcohols represented by the formula 1 to an oxidation reaction and, if necessary, a hydroxyl group protection reaction.

As the oxidizing agent used in the oxidation reaction, a reagent selected from Diones reagent, manganese dioxide, pyridinium chlorochromate (PCC) and pyridinium dichromate (PDC) is preferably used. Reaction solvents include ethers such as ether and tetrahydrofuran; hydrocarbons such as petroleum ether, pentane, n-hexane and cyclohexane; halogen compounds such as dichloromethane, chloroform and carbon tetrachloride; aromatics such as benzene, toluene and xylene. A material selected from ketones such as acetone and methyl ethyl ketone is used. The reaction temperature is
It is preferably in the range of -50 ° C. The oxidizing agent used is 0.5 equivalent to 10 equivalents, preferably 0.8 equivalent to 4 equivalents, relative to the raw materials.

The reaction time varies depending on the starting material compound, reagent, reaction solvent, etc. used, but it is usually 5 minutes to 3 days, preferably 10 minutes to 1 day.

The reaction product obtained by the oxidation reaction is purified and separated by usual means such as extraction, washing with water, drying, and chromatography.

The reaction product is optionally subjected to a hydroxyl group protection reaction.

When the hydroxyl-protecting group is a tri (C ₁ -C ₇ ) hydrocarbon silyl group, the silylating agent used in the protection reaction is trialkylsilyltrifluoromethanesulfonate (hereinafter abbreviated as trialkylsilyltriflate) or trialkylsilyltriflate. Alkylsilyl chloride and the like. The protection reaction is carried out in the presence of a base, without solvent or in a suitable solvent. As solvents, hydrocarbons such as pentane and hexane; ethers,
Ethers such as tetrahydrofuran and dioxane; halogen compounds such as chloroform, dichloromethane and carbon tetrachloride; or acetone, DMF, DMSO and the like are used.
Examples of the base include pyridine, 4-dimethylaminopyridine, triethylamine, imidazole, diisopropylcyclohexylamine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.
[0] Undec-7-enequinoclidine, triethylenediamine, isopropyldimethylamine, diisopropylethylamine and the like. Specific examples of the silylating agent used include trimethylsilyl triflate, triethylsilyl triflate, t-butyldimethylsilyl triflate, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl triflate, etc. 0.5 to 1 for raw materials
It is 0 equivalent, preferably 1 to 3 equivalents. The base is
0.5 to 100 equivalents, preferably 1 to 5 equivalents to the raw materials
Used in 0 equivalents.

The reaction temperature will differ depending on the silylating agent, base, etc., but is usually in the range of −78 ° C. to 80 ° C., and preferably −50 ° C.
To 50 ° C. The reaction time is about 0.1 to 24 hours, varying depending on the conditions.

The protection reaction when the hydroxyl-protecting group is an alcyl group is a reaction known per se, and for example, a carboxylic acid such as acetic acid and propionic acid; an acid halide such as acetic acid chloride and acetic acid bromide are reacted by a usual method. It is done by things.

When the hydroxyl-protecting group is a group that forms an acetal bond together with the oxygen atom of the hydroxyl group, the protection reaction is a reaction known per se, and examples thereof include 2,3-dihydropyran, 2,3-dihydrofuran and ethyl vinyl ether. It is carried out by a conventional method in the presence of a reaction aid such as pyridine-paratoluenesulfonate (PPTS) or camphorsulfonic acid.

Thus, 2-halo-4-hydroxy-2-cyclopentenones of the formula [Ia] are obtained.

The 2-halo-4-hydroxy-4-alkyl group-5- (1-hydroxyalkyl) -2-cyclopentenones of the formula [Ib] have the following formula [Ia ′] [In the formula, R ³ represents a protective group for a protected hydroxyl group. Following formula 2-halo-4-hydroxy-2-cyclopentenone represented by] [III] OHC-R ¹ ...... (III) wherein, R ¹ is the same as defined above. ] It can be obtained by subjecting an aldehyde represented by the formula [4] to an aldol condensation reaction and, if necessary, subjecting it to deprotection, hydrolysis, and salt formation reaction.

The 2-halo-4-hydroxy-2-cyclopentenones of the formula [Ia ′] are compounds in which the hydroxyl group at the 4-position is protected among the compounds of the formula [Ia].

The aldol condensation reaction is preferably carried out in a solvent in the presence of a basic compound. Examples of basic compounds and reaction solvents include literatures: A.T. Nielsen, D.A. Nielsen (ATNielsen, WJHoulinan), Organic Reaction (Org. React.), 16, 1 (1968);
HOHouse, Modern Synthetic Reactions,
Second Edition (2nd Ed.), Benjam (Benjam)
in) (1972), p629; New Experimental Chemistry Course 14 , II736, III
851 and the like are selected. The aldol condensation reaction is preferably a metal amide such as lithium diisopropylamide, lithium diethylamide or lithium bistrimethylsilylamide; or a dialkylboron trifluoromethanesulfonic acid or the like in the presence of a tertiary amine such as triethylamine, diisopropylethylamine or tributylamine. Carried out using boron trifluoromethanesulfonic acids.

When the aldol condensation reaction is carried out using metal amides, the amount used is 0.5 to 30 equivalents relative to 2-halo-4-hydroxy-2-cyclopentenones of formula [Ia ′],
Preferably 0.9 to 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 ° C to 5
0 ° C, particularly preferably in the range of -80 ° C to 0 ° C.

When the aldol condensation reaction is carried out using a tertiary amine and a dialkylboron trifluoromethanesulfonic acid, the amount of them used is 2-halo-4-hydroxy-2-cyclopentenone of the formula [Ia ′]: 0 for each.
5 to 50 equivalents, preferably 1 to 10 equivalents are used.

The aldehydes [III] are 2-halo-4- of the formula [Ia ′].
0.5-10 for hydroxy-2-cyclopentenones
Equivalents, preferably 0.8-2 equivalents, are used.

While the reaction time varies depending on the starting compounds, reagents, reaction solvent, etc. used, it is generally 5 minutes to 1 day, preferably 10 minutes to 12 hours.

After completion of the reaction, the product is treated by conventional means such as extraction, washing with water,
It can be purified and fractionated by drying or chromatography. The product is subjected to deprotection, hydrolysis, and salt formation reaction 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 water, tetrahydrofuran, ethyl ether,
It is preferably carried out by using dioxane, acetone, acetonitrile or the like as a reaction solvent. Reaction is usually -78 ° C
The temperature is in the range of + 30 ° C for 10 minutes to 3 days. When the protecting group is a tri (C ₁ -C ₇ ) hydrocarbon-silyl group, the same temperature is applied in the reaction solvent as described above in the presence of acetic acid, tetrabutylammonium fluoride, cesium fluoride and the like. Will be implemented for the time. When the protecting group is an acyl group, it is hydrolyzed in, for example, an aqueous solution of caustic soda, caustic potash, calcium hydroxide or a water-alcohol mixed solution, or a methanol or ethanol solution containing sodium methoxide, potassium methoxide or sodium ethoxide. It can be carried out.

If the target compound has an ester group, it can be subjected to hydrolysis, for example, using an enzyme such as lipase,
It is performed in water or a solvent containing water at a temperature range of -10 ° C to + 60 ° C for about 10 minutes to 24 hours.

When the target compound has a carboxyl group in the molecule, it can be further subjected to a salt formation reaction to obtain a corresponding carboxylic acid salt, if necessary. The salt-forming reaction is known per se, and basic compounds such as sodium hydroxide, potassium hydroxide and sodium carbonate in about the same amount as the carboxylic acid, or ammonia, trimethylamine, monoethanolamine, morpholine, etc. It is carried out by causing a Japanese reaction.

Thus, 2-halo-4-hydroxy-4-alkyl-5- (1-hydroxyalkyl) -2-cyclopentenones of the formula [Ib] are obtained.

2-halo-4-hydroxy-4-alkyl-of the formula [Ic]
The 5-alkylidene-2-cyclopentenones have the formula [I
b] of 2-halo-4-hydroxy-4-alkyl-5-
It is obtained by subjecting (1-hydroxyalkyl) -2-cyclopentenones to a dehydration reaction and, if necessary, to deprotection, hydrolysis and salt formation reaction.

The dehydration reaction is performed by the 2-halo-4-hydroxy-4 of the formula [Ib].
-Alkyl-5- (1-hydroxyalkyl) -2-cinlopentenones and a reactive derivative of an organic sulfonic acid are reacted in the presence of a basic compound to give a reacting organic sulfonyloxy derivative, and then a basic compound is added. It is carried out by processing.

As the basic compound used when reacting the compound of the formula [Ib] with the reactive derivative of the organic sulfonic acid, amines are preferable, and examples of the 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] undec-7-
Examples thereof include ene (hereinafter abbreviated as DBU), quinuclidine, triethylenediamine, isopropyldimethylamine, and diisopropylethylamine. Of these, pyridine, 4-dimethylaminopyridine, DBU, and DBN are particularly preferable.

Examples of the reactive derivative of organic sulfonic acid include methanesulfonyl chloride, ethanesulfonyl chloride, n-
Organic sulfonic acid halides such as butanesulfonyl chloride, t-butanesulfonyl chloride, trifluoromethanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonyl chloride; anhydrous methanesulfonic acid, anhydrous ethanesulfonic acid, anhydrous trifluoromethanesulfonic acid, anhydrous benzene Examples thereof include anhydrous organic sulfonic acids such as sulfonic acid and anhydrous p-toluenesulfonic acid.

As the solvent to be used, the above-mentioned basic compound itself may be used, but 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 be used. Pyridine dichloromethane is preferably used.

The reaction is represented by the formula [Ib]: 2-halo-4-hydroxy-4-alkyl-5- (1-hydroxyalkyl) -2.
-A reaction of a hydroxyl group on the 5-position alkyl group of cyclopentenones with a reactive derivative of an organic sulfonic acid, and stoichiometrically both compounds react in equimolar amounts.

In order to actually carry out the reaction, the 2-halo-of the formula [Ib] is usually used.
The reactive derivative of organic sulfonic acid is used in a ratio of 1 to 10 equivalents based on 4-hydroxy-4-alkyl-5- (1-hydroxyalkyl) -2-cyclopentenones.

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 the solvent used is usually represented by the formula [Ib]
1 for halo-4-hydroxy-4-alkyl-5- (1-hydroxyalkyl) -2-cyclopentenones
˜1000 times capacity, preferably 5 to 100 times capacity is used. The reaction temperature varies depending on the raw material compound, basic compound, solvent, etc. used, but it is usually from -10 ° C to 50 ° C.
C., preferably 0.degree. C. to 30.degree. The reaction time varies depending on the conditions, but is 0.1-1
About 0 hours. The progress of the reaction is followed by a method such as thin layer chromatography.

Thus, according to the above reaction (hereinafter referred to as the first reaction), 2-halo-4-hydroxy-4 represented by the formula [Ib] is obtained.
-Alkyl-5- (1-hydroxyalkyl) -2-cyclopentenones represented by the following formula [IV] in which the hydroxyl group on the 5-position alkyl group is converted to an organic sulfonyloxy group: An organic sulfonyloxy derivative represented by is produced.

In the formula [IV], R ⁴ represents an alkyl group such as methyl, ethyl, propyl or butyl, or a substituted or unsubstituted phenyl group such as phenyl or p-methylphenyl.

The organic sulfonyloxy derivative is then treated with a basic compound (hereinafter referred to as the second reaction) to eliminate the corresponding organic sulfonic acid to give a 2-halo-formula represented by the formula [Ic].
4-hydroxy-4-alkyl-5-alkylidene-2
-Converted to cyclopentenones.

As the basic compound that can be used in this second reaction, the same basic compounds as those mentioned in the above first reaction can be mentioned.
The basic compound used in the second reaction may be different from that used in the first reaction.

This second reaction can proceed in the same temperature range. Alternatively, the organic sulfonyloxy derivative produced in the first reaction may be isolated and then subjected to the second reaction,
Further, the first reaction and the second reaction may be carried out in the same reaction system. After completion of the reaction, the target compound can be purified and fractionated by a conventional means. 4-hydroxy-2 obtained
If necessary, cyclopentenones are subjected to the same deprotection, hydrolysis and salt formation reaction as described above.

Thus, 2-halo-4-hydroxy-4 represented by the following formula [Ic]
-Alkyl-5-alkylidene-2-cyclopentenones are obtained.

<Effects of the Invention> The 2-halo-4-hydroxy-2-cyclopentenones of the present invention exhibit a growth inhibitory action on L1210 leukemia cells, and are expected to be anticancer agents.

In addition, the 2-halo-4-hydroxy-2-cyclopentenones of the present invention show a growth inhibitory action against herpes virus and are expected as antiviral agents.

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> Hereinafter, the present invention will be described in more detail with reference to Examples.

Reference Example 4-t-butyldimethylsilyloxy-3-chloro-1
Preparation of-(3,4-dimethoxyphenylpropyl) -1-hydroxy-2-cyclopentene After taking 128 mg (5.3 mmol) of magnesium and adding 4 m of dry THF, a small amount of a solution of 1-bromo-3- (3,4-dimethoxyphenyl) propane 1.37 g of dry THF 10 m was added and heated. After starting the reaction, 1-bromo-3-
The (3,4-dimethoxyphenyl) propane-THF solution was added little by little, and the mixture was refluxed for 1.5 hours. The obtained reagent is -78 ° C.
Cooled to 1,3-chloro-4-t-butyldimethylsilyloxy-2-cyclopentenone 1.305 g dry THF1.
The 0m solution was cooled and added. After stirring at −78 ° C. for 1.5 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After overconcentration, it was subjected to silica gel column chromatography, and 4-t-butyldimethylsilyloxy-3-chloro-1- (3,4-dimethoxyphenylpropyl) -1-hydroxy-2-cyclopentene 600.
mg (yield 27%) was obtained.

<Spectral data> NMR, δCDCl ₃ 0.10 (s, 6H), 0.87 (s, 9H), 1.5 to 2.8 (m, 9H), 3.81 (s, 6H), 4.
6-4.9 (m, 1H), 5.72 (s, 1H), 6.5-6.9 (m, 3H) Example 1 2-chloro-4- (3,4-dimethoxyphenylpropyl) -4-hydroxy-2- Production of cyclopentenone Dissolve 242 mg of 4-t-butyldimethylsilyloxy-3-chloro-1- (3,4-dimethoxyphenylpropyl) -1-hydroxy-2-cyclopentene obtained by the method shown in Reference Example in 3 m of dry tetrahydrofuran. ,
1.5m of 1M tetrabutylammonium fluoride-tetrahydrofuran solution was added and stirred for 7 hours. A saturated aqueous sodium chloride solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. 3 obtained after overconcentration
-Chloro-1- (3,4-dimethoxyphenylpropyl)
The crude product of -1,4-dihydroxy-2-cyclopentene was dissolved in 5 m of dimethylformamide, 500 mg of pyridinium dichromate was added, and the mixture was stirred for 5 hours. Saturated aqueous sodium chloride was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After overconcentration, the residue was subjected to silica gel column chromatography to obtain 104 mg of 2-chloro-4- (3,4-dimethoxyphenylpropyl) -4-hydroxy-2-cyclopentenone (yield 59%).

<Spectral data> NMR: δCDCl ₃ 1.5 to 2.0 (m, 4H), 2.15 to 2.35 (brs, 1H), 2.4 to 2.8 (m, 4H), 3.78 (s, 6H), 6.5 to 6.9 (m, 3H) , 7.24 (s, 1H) Example 2 2-chloro-4-trimethylsilyloxy-4- [3-
Production of (3,4-dimethoxyphenyl) propyl] -2-cyclopentenone 235 mg of 2-chloro-4-hydroxy-4- [3- (3,4-dimethoxyphenyl) propyl] -2-cyclopentenone obtained by the method described in Example 1 was added to N, O-bis (trimethylsilyl). It was dissolved in 1 m of trifluoroacetamide and stirred for 5 days. Subjected to silica gel column chromatography, 2-chloro-4-trimethylsilyloxy-4- [3- (3,4-dimethoxyphenyl) propyl]
2-229 mg (yield 59%) of 2-cyclopentenone was obtained.

<Spectral data> NMR: δCDCl ₃ 0.09 (s, 9H), 1.4 to 1.9 (m, 4H), 2.3 to 2.8 (m, 4H), 3.80 (s, 6H), 6.4 to 6.9 (m, 3H), 7.24 (s, 1H) Example 3 2-chloro-4-trimethylsilyloxy-4- [3-
(3,4-Dimethoxyphenyl) propyl] -5- (1-
Hydroxy-6-methoxycarbonylhexyl) -2-
Production of cyclopentenone 2-chloro-4-trimethylsilyloxy-4- [3- (3,4-dimethoxyphenyl) propyl] -2-cyclopentenone (159 mg) obtained by the method described in Example 2 was dissolved in 5 m of dry tetrahydrofuran to obtain -78. Cooled to ° C. A 0.2 M lithium diisopropylamine-tetrahydrofuran solution (4.15 m) was added, and the mixture was stirred at -78 ° C for 1 hr. A solution of 131 mg of methyl 7-oxoheptanoate in 3 m of dry tetrahydrofuran was cooled to -78 ° C and added,-
The mixture was stirred at 78 ° C for 2 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After overconcentration, use for silica gel column chromatography.
-Chloro-4-trimethylsilyloxy-4- [3-
(3,4-Dimethoxyphenyl) propyl] -5- (1-
Hydroxy-6-methoxycarbonylhexyl) -2-
102 mg (yield 45%) of cyclopentenone was obtained.

<Spectral data> NMR: δCDCl ₃ 0.18 (s, 9H), 1.0 to 2.1 (m, 12H), 2.1 to 2.8 (m, 6H), 3.59 (s, 3H), 3.80 (s, 6H), 3.5 to 4.1 (m, 1
H), 6.5 to 6.9 (m, 3H), 7.2 to 7.35 (brs, 1H) Example 4 2-chloro-4-hydroxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5- (1-hydroxy-
Preparation of 6-methoxycarbonylhexyl) -2-cyclopentenone 2-Chloro-4-trimethylsilyloxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5- (1-hydroxy-6-methoxycarbonylhexyl) -obtained by the method described in Example 3 2-cyclopentenone 15.2mg
(28.1 μmol) was added to acetic acid-tetrahydrohylan-water (3:
1: 1) It was dissolved in a mixed solvent and stirred for 2 hours. Saturated aqueous sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
After over-concentration, it was subjected to thin-layer chromatography and 2-chloro-4-hydroxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5- (1-hydroxy-6-methoxycarbonylhexyl). -2-Cyclopentenone 9.2m
g (yield 70%) was obtained.

<Spectral data> NMR: δCDCl ₃ 1.0 to 2.0 (m, 12H), 2.0 to 2.9 (m, 7H), 3.60 (s, 3H), 3.80 (s, 6H), 3.5 to 4.4 (m, 1H), 6.5 ~ 6.9 (m, 3
H), 7.35 and 7.37 (s, 1H) Example 5 2-chloro-4-trimethylsilyloxy-4- [3-
(3,4-Dimethoxyphenyl) propyl] -5- (1-
Methanesulfonyloxy-6-methoxycarbonylhexyl) -2-cyclopentenone and 2-chloro-4-
Preparation of trimethylsilyloxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5- (6-methoxycarbonylhexylidene-2-cyclopentenone 2-Chloro-4-trimethylsilyloxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5- (1-hydroxy-6-methoxycarbonylhexyl) -obtained by the method described in Example 3 2-Cyclopentenone (46 mg) was dissolved in pyridine (1 m), and methanesulfonyl chloride was added.
0 μ was added and stirred for 2.5 hours. 150 μ of 1,8-diazabicyclo [5.4.0] undec-7-ene was added and stirred for 6 hours. A saturated aqueous solution of potassium hydrogen sulfate was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After overconcentration, it was subjected to silica gel column chromatography, and 2-chloro-4-trimethylsilyloxy-4- [3- (3,4-dimethoxyphenyl) propyl] was used.
-5- (1-Methanesulfonyloxy-6-methoxycarbonylhexyl) -2-cyclopentenone 15 mg (yield 28%) and 2-chloro-4-trimethylsilyloxy-4- [3- (3,4-dimethoxy Phenyl) propyl] -5- (6-methoxycarbonylhexylidene-2
-Cyclopentenone 7.7 mg (17% yield) was obtained.

<Spectral data> 2-chloro-4-trimethylsilyloxy-4- [3-
(3,4-Dimethoxyphenyl) propyl] -5- (1-
Methanesulfonyloxy-6-methoxycarbonylhexyl) -2-cyclopentenone NMR: δCDCl ₃ 1.0-2.0 (m, 10H), 2.0-2.8 (m, 5H), 2.94 (s, 3H), 3.59 (s, 3H ), 3.81 (s, 6H), 4.6 to 5.1 (m, 1H), 6.5 to 6.9 (m, 3H), 7.1 to 7.3 (brs, 1H) 2-chloro-4-trimethylsilyloxy-4- [3-
(3,4-Dimethoxyphenyl) propyl] -5- (6-
Methoxycarbonylhexylidene) -2-cyclopentenone NMR: δCDCl ₃ 1.1-2.1 (m, 10H), 2.1-2.8 (m, 6H), 3.62 (s, 3H), 3.82 (s, 6H), 6.4- 6.8 (m, 3H), 7.03 and 7.10 (s, 1H) Example 6 2-chloro-4-trimethylsilyloxy-4- [3-
Production of (3,4-dimethoxyphenylpropyl] -5- (6-methoxycarbonylhexylidene) -2-cyclopentenone 2-chloro-4-trimethylsilyloxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5- (1-methanesulfonyloxy-obtained by the method shown in Example 5
15 mg (24.2 μmol) of 6-methoxycarbonylhexyl) -2-cyclopentenone was dissolved in 0.5 m of benzene,
1,8-diazabicyclo [5.4.0] undec-7-ene 50
mg (329 μmol) was added, and the mixture was stirred for 2.5 hours. Saturated saline was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline. The extract was dried over anhydrous sodium sulfate, overconcentrated, and subjected to thin-layer chromatography to give 2-chloro-4-trimethylsilyloxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5- (6-methoxy. Carbonylhexylidene) -2-cyclopentenone 8.2 mg (yield 65%)
Got

Example 7 Preparation of 2-chloro-4-hydroxy-4- [3- (3,4-dimethoxyphenyl) propyl] -5- (6-methoxycarbonylhexylidene) -2-cyclopentenone 2-obtained by the method shown in Example 5 or 6
Chloro-4-trimethylsilyloxy-4- [3- (3,
4-Dimethoxyphenyl) propyl] -5- (6-methoxycarbonylhexylidene) -2-cyclopentenone
15.9 mg (30.4 μmol) was dissolved in acetic acid-tetrahydrofuran-water (3: 1: 1) mixed solvent 0.5 m and stirred for 2 hours. Saturated aqueous sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After overconcentration, it was subjected to thin-layer chromatography, and 2-chloro-4-hydroxy-4- [3- (3,3,
4-Dimethoxyphenyl) propyl] -5- [6-methoxycarbonylhexylidene) -2-cyclopentenone
12.1 mg (88% yield) was obtained.

<Spectral Data> NMR: δCDCl ₃ 1.0 to 3.2 (m, 17H), 3.60 (s, 3H), 3.79 (s, 6H), 6.0 to 6.9 (m, 4H), 7.07 and 7.13 (s, 1H) Examples 8 Growth inhibitory effect on leukemia cell L1210 Leukemia cell L1210 contains 10% of FCS (fetal calf cerum)
In addition to RPMI medium, the cell concentration was adjusted to 1 × 10 ⁵ cells / m.

The compounds of the invention as shown in Table 1 were dissolved in 99.5% ethanol. Final concentration of ethanol solution is 0.1% before measurement
It was prepared as follows and added to the medium. Then add 3 media
It was left for 4 days at 7 ° C. After culturing, the number of surviving cells was measured by trivan blue staining. 0.1% ethanol was used as a control. A dose response curve was created from the growth inhibition rate relative to the control, and the IC50 value was calculated.

The results are as shown in Table 1.

Claims (4)

[Claims] 1. The following formula [I]: 2-halo-4-hydroxy-2-cyclopentenones represented by: 2. The following formula [Ia]: (In the formula, R is the same as defined above.) The 2-halo-4 according to claim 1.
-Hydroxy-2-cyclopentenones. 3. The following formula [Ib '] 2-halo-4 according to claim 1, represented by
-Hydroxy-2-cyclopentenones. 4. The following formula [Ic '] 2-halo-4 according to claim 1, represented by
-Hydroxy-2-cyclopentenones.