JPS6244A - 2-halo-2-cyclopentenone derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I {X is halogen; R is alkyl or group shown by the formula II [R3 is alkyl, cycloalkyl or (substituted) benzyl]; R1 is H or lower alkyl; R2 is R1 or OH-protecting group; group shown by the formula III is single bond or double bond; with the proviso that when formula III is single bond, Q is OH, and when formula III is double bond, Q is H, and when R2 is acyl, group shown by the formula III is double bond} and its salts. EXAMPLE:2-Chloro-4-ethoxycarbonyl-4-hydroxy-5-(6-methoxycarbon-yl-2-he xenyli dene)2-cylopentenone. USE:A drug and an antitumor agent. PREPARATION:A 2-halo-4,4-substituted-2-cyclopentenone shown by the formula II (R2 is H or OH-protecting group) is reacted with an aldehyde derivative shown by the formula IV (R1 is lower alkyl) in a proper solvent in the presence of a base such as organic lithium, etc., at -70-20 deg.C for 10-60min to give a compound shown by the formula I where R1 is lower alkyl.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a 2-halo-2-sifurontenone derivative that is useful in the pharmaceutical field, for example, as an antitumor agent, and which has not been described in any known literature, and a method for producing the same.

More specifically, the invention below is based on the following formula (1) However, during the ceremony, X represents a halogen atom, R is an alkyl group or a group -COOR.

[Here, R8 represents a straight-chain or branched alkyl group, a cycloalkyl group, or a benzyl group which may have a substituent], R1 represents a hydrogen atom or a lower alkyl group, and R1 represents a hydrogen atom , represents a protecting group for an acyl group or a hydroxyl group, and in the formula 1. = indicates a single bond or a double bond; when a single bond is indicated, Q is OR; when a double bond is indicated, Q is a hydrogen atom; here, when R2 is an acyl group, Yes.

The present invention relates to a 2-halo-2-cyclopentenone derivative represented by the following formula, in which represents a double bond, pharmaceutically acceptable salts thereof, and a method for producing the same.

The compound of the formula (1') has an asymmetric carbon atom at the 4-position in the formula, and each of six and one optical isomers derived from the asymmetric carbon atom, a racemate (6:1 (1=1 mixture) and mixtures of these optical isomers in any other ratio; configuration, Z configuration or a mixture of these configurations in any proportion.

Therefore, for the purposes of the present invention, the 2-balor 2-cyclopentenone derivative represented by formula (I) and its pharmaceutically acceptable salts are defined to include all of these cases. .

The present inventors have been conducting research to develop pharmacologically active compounds with antitumor effects.

As a result, we succeeded in synthesizing a 2-hero-2-cyclopentenone derivative and its salts, which have a new structural feature represented by the above formula (I) and have not been previously described in any literature.

Furthermore, the nucleic acid (1) compound and its salts are, for example, L12
10 Regarding a culture experiment using cultured mouse leukemia cells, as shown in an example below, it is a compound useful in the medical field as a pharmacologically active compound, such as an antitumor agent, and is useful for preventing tumors in humans and non-human animals. It has been found that this is a new compound that is expected to have extremely important devices as a tumor treatment agent.

Therefore, the object of the present invention is to provide 2-
The present invention provides halo-2-cyclopentenone derivatives and salts thereof, as well as methods for producing them.

The above objects and many other objects and advantages of the present invention will become more apparent from the following description.

In the compound represented by the following formula (I) of the present invention, X represents a halogen atom, such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; R represents an alkyl group,
For example, a C8-C9 alkyl group or a group -COO
R, [wherein R5 is a straight chain or branched alkyl group, for example a C1 to R6 straight chain or branched alkyl group, a cycloalkyl group such as tf Ca to C, a cycloalkyl group,
RI represents a hydrogen atom or a lower alkyl group, such as a C1-C4 alkyl group; R1 represents a hydrogen atom, an acyl group, such as a C7-C, acyl group; group or a protecting group for a hydroxyl group; and in the formula 1. = indicates a single bond or a double bond; when a single bond is indicated, Q is OH; when a double bond is indicated, Q is a hydrogen atom; when R1 is an acyl group, ■ indicates a double bond.

In the above, R is a C1-C0 alkyl group, examples of which are methyl group, ethyl group, n-propyl L? Examples include alkyl groups such as L-7'' tyl group, n-pentyl group, n-hexyl group, n-hemethyl group, n-octyl group, and n-nonyl group.

In addition, in the above, examples of R3 being a C1 to C6 straight chain or branched alkyl group include a methyl group,
n-propyl group, isopropyl group, ? L-butyl group, 6
Examples include a class-butyl group, an isobutyl group, an n-pentyl group, an inpentyl group, an n-hexyl group, and an isohexyl group. Furthermore, in the above, R3 is C3
Examples of the ~C6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like. Furthermore, examples of the benzyl group which may have a substituent for R8 include, in addition to the benzyl group, lower alkyl groups such as methyl, ethyl, and tertiary-butyl, and methoxy, ethoxy, and methoxy. Examples include a lower alkoxy group, a benzyl group having a substituent such as a halogen such as bromine or iodine, a nitro group, an amino group, or a hydroxy group. Also,
In the above, examples of the alkyl group in which R1 is C1 to C6 include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, 6th-butyl group, etc. . Furthermore, in the above, R
Examples of acyl groups in which 1 is C1 to C1 include acetyl groups,
Examples of benzoyl groups that may have substituents include halogens such as fluorine, chlorine, and bromine, trifluoromethyl groups, methyl groups, and 5th-class substituents. Examples include substituents such as -butyl group, nitro group, and methoxy group. Furthermore, in the above, when R1 represents a hydroxyl protecting group, examples of the protecting group include tetrahydrobilan-2-yl group, tetrahydrofuran-2-yl group, 1-ethoxyethyl group, 5th-butyl, dimethyl Examples include a silyl group, a trimethylsilyl group, and a triethylsilyl group.

Furthermore, the compounds of formula (I) can be in the form of their salts, especially pharmaceutically acceptable salts; examples of such salts include, for example, Nα, K1 Ca.

Examples include metal salts such as MQ, ammonium salts, and quaternary ammonium salts such as amine salts.

The compound of the formula (1) of the present invention has the following formula +1-, where X and R have the same meanings as in formula (I), and R1 has the formula (
In the definition in formula (I), R,- represents a lower alkyl group, in the definition in formula (I), R,- represents a hydrogen atom or a protecting group for a hydroxyl group, and in the formula 1. = represents a single bond or a double bond; when a single bond is represented, Q is OH; when a double bond is represented, Q is a hydrogen atom. That is, the following formula (I
-1α) and the compound represented by formula (1-16).

In these formulas, X, R, R, and R2 represent the formula (1-1
) has the same meaning as described.

The above formula (I-1) compound is, for example, the following formula (III
) R2OR In the formula, X, R and R1 have the same meanings as described for formula (1'-1), and 2-halo-4,4- represented by -2-cyclopentenone and the following formula (IV) HC to N, 000 R. (IV) In the formula, R8 has the same meaning as described for formula (1-1), and can be produced by reacting an aldehyde derivative represented by the following. In formula (1-1), the compound of formula (■-1α) is subjected to a dehydration reaction to obtain
Formula (I-1) can be easily converted into the compound of formula (1-1b).

Further, the compound of formula (I) of the present invention has the following formula (I-, where X and R have the same meaning in formula (I), sb, and R1 has the same meaning as formula (I
) indicates a lower alkyl group, and in the formula 1. = indicates a single bond or a double bond; when a single bond is indicated, Q is OH; when a double bond is indicated, Q is a hydrogen atom;

The above formula (1-2) compound is, for example, the above formula (1-1
), where R1 represents a hydroxyl-protecting group (%), where X, R, R, and =2 have the same meanings as in the above formula (■-2), and R3 represents a hydroxyl-protecting group. It can be easily produced by subjecting a compound represented by , to a deprotecting group reaction.

Furthermore, the compound of formula (1) of the present invention has the following formula (!wherein, X
and R have the same meaning as in formula (1), and in the formula, 2 represents a single bond or a double bond, and when a single bond is represented, Q is OH and υ, when a double bond is represented. includes compounds represented by the following, where Q is a hydrogen atom.

The above formula (1-3) compound is, for example, the above formula (1-2
) can be easily produced by subjecting the compound to a hydrolysis reaction.

Furthermore, the compound of formula (I) of the present invention has the following formula (l-1C), where X1R and R have the same meanings as in formula (1), and R1 represents an acyl group in the definition in formula (1). This includes compounds represented by the following formulas.

The above formula (1-16) compound is, for example, the above formula (I-
i) A compound of the following formula (I-16') in which R1 is a hydrogen atom (or a compound in which Q in the formula (1-2) is a hydrogen atom), where X, R, and R are represented by the formula (1) It can be easily produced by acylating a compound represented by, which has the same meaning as in, with an acylating agent.

Several embodiments of the production of the compound of formula (1) of the present invention have been described above, but in the present invention, unit reactions known per se, such as dehydration reactions, deprotecting group reactions, hydrolysis and acylation reactions, and their appropriate A compound of formula (I) can be converted to another compound of formula (1) using combinatorial reaction techniques, and the compound of formula (1) of the present invention can be obtained by any of these techniques. Compounds of formula t1) that can be used. In the following, equation (1) stated above
Several aspects of compound production will be explained in more detail.

One aspect of the production of the above-described compound of formula (I) can be schematically shown as follows.

夷 Q ζ ○】

ζ In the embodiment of the production of the compound of formula (I) shown in the above process diagram, the raw material formula tm) compound is the raw material 2-halo-4 in Japanese Patent Application No. 60-457.35 filed by the same applicant.
, 4-substituted-2-cyclopentenone can be easily produced using or applying the method described for the production, the details of which will be described later.

In the compound of the formula (I) of the present invention, the following formula (1-1) is used, in which X represents a halogen atom, and R represents an alkyl group or a group -COOR3 [where R5
represents a straight-chain or branched alkyl group, a cycloalkyl group, or a benzyl group which may have a substituent],
R represents a lower alkyl group, R2 represents a hydrogen atom or a protecting group for a hydroxyl group, and in the formula ■: represents a single bond or a double bond, and when a single bond is represented, Q is OH; Q when indicating a double bond
is a hydrogen atom. As shown in the process diagram, the 2-halo-2-cyclopentenone derivative represented by, for example, the following formula (II
I) R,OR In the formula, X, R and R2 have the same meanings as described for the above formula (I-1), and 2-halo-4,4-substituted-2-cyclopentenone represented by the following formula (IV ) □′. 0R" (IV) HC In the formula, RI has the same meaning as described for the above formula (1-1), and can be produced by reacting an aldehyde derivative represented by the following.

The reaction can be carried out, for example, by contacting the compound of formula (III) and the compound of formula +IV) in a suitable reaction solvent. Examples of reaction solvents used at this time include tetrahydrofuran, dioxane, 1,2-dimethoxyethane,
Examples include ethyl ether, n-hexane, and mixtures of these solvents in arbitrary proportions.

There are no special restrictions on the amount used, and it can be selected as appropriate.
For example, the amount used may be about 10 to about 50 times the amount of the compound of formula (III).

In carrying out the reaction, the compound of formula (III) is preferably brought into contact with the compound of formula (IV) in the form of its lithium esoleate. For example, in a reaction solvent as exemplified above,
The compound of formula (III) is added with an organolithium compound such as lithium diisoprogylamide, lithium bis(trimethylsilinolyamide, etc.) as a base, for example, about -
By reacting under conditions such as 70' to about ÷20'C1 for about 10 to about 60 minutes, the lithium nilate of the compound of formula (III) is first formed, and the lithium nilate of the compound of formula (III) is formed. ) required for the compound! 17)! J-3
-It can be carried out in such a manner that a progeny (IV) compound which has been made to act on butyltin chloride is made to act on it. The amount of the organolithium compound used as the base to be used at this time can be appropriately selected and changed, and for example, the amount used can be about 1 to about 5 times equivalent to the compound of formula (III).

In the reaction of the compound of formula (III), preferably in the form of lithium esoleate, and the compound of formula (IV), the reaction conditions, particularly the reaction temperature, can be appropriately selected and adjusted as shown in the process diagram. , among the compounds of formula (I-1), select one of the compounds represented by the following formula (I-1α) and formula (I-IJ). In these formulas, X, R, R, and R1 are ) has the same meaning as described.

For example, at about -70℃ to about -50℃ for about 30 minutes to about 120 minutes.
By carrying out the reaction under conditions such as minutes, the formula (I-1
α) The compound can be formed selectively, and for example, after reacting at about -70°C to about -50°C, further reaction is carried out at about -50°C to about +30°C for about 30 minutes. By carrying out the reaction under conditions such as ~150 minutes, formula (1-1b)
Compounds can be formed selectively.

In the reaction of the above-mentioned compound of formula (III) and compound of formula (■), the amount of the compound of formula (IV) to be used can be changed as appropriate, but for example, the amount of the compound of formula (IV) can be changed from about 1 to about 5 with respect to the compound of formula (III).
Examples include amounts used such as double equivalents.

Incidentally, the compound of formula (IV) is J, Chem, Soc.

1266 (1961 and Tetrahedron La
It can be manufactured by using or applying the known manufacturing method described in J. Tters, 21.1129 (1980).

In the formula (1-1) that can be obtained as described above, the following formula (l-1α) is used.

[Here, R8 represents a linear or branched alkyl cycloalkyl group or a benzyl group which may have a substituent], R represents a lower alkyl group, and R1 represents a hydrogen atom or a hydroxyl group protecting group. 2-halo-4,4-substituted-5-(1-hydroxy-6-flukoxycarbonyl-2-hexenyl) represented by
-2-Cyclopentenones can be easily converted into compounds of formula ()-1b) in formula Cl-1) by subjecting them to a dehydration reaction, if desired, as shown in the process diagram. can be transformed.

This reaction can be carried out, for example, by formula (I-1) in a suitable reaction solvent.
α) This can be easily carried out by subjecting the compound to a dehydration reaction using a suitable dehydrating agent. Examples of the reaction solvent used in this case include methylene chloride, chloroform, tetrahydrochloride, dioxane, dimethylformamide, acetonitrile, nitromethane, or a mixture thereof in any proportion. There is no particular restriction on the amount used, but the amount used may be, for example, about 5 to about 50 times the amount of the compound of formula (I-1α). At this time, examples of the dehydrating agent used in the dehydration reaction include acids such as hydrochloric acid, hydrobromic acid, 61, oxalic acid, methanesulfonic acid, and radruenesulfonic acid, as well as methanesulfonyl chloride, radruene sulfonic acid, etc. Examples include sulfonyl chlorides such as en-sulfonyl chloride. The amount of the dehydrating agent to be used can be selected and changed as appropriate, and for example, it can be used in an amount of about 0.5 to about 2 times the equivalent of the compound of formula (summer-1α).

Furthermore, when carrying out the reaction of subjecting the above-mentioned formula (I-1α) compound to a dehydration reaction to convert it into the formula (I-1b) compound,
When using sulfonyl chlorides as exemplified above as a dehydrating agent, it is preferable to add amines such as triethylamine, triisopropyl amine, etc. to carry out the reaction. The amount to be used can be selected and changed as appropriate, and for example, the amount to be used can be about 1 to about 5 times the amount of the dehydrating agent.

The dehydration reaction to form the compound of formula (■-1b) from the compound of formula (I-1α) described above may be carried out at a temperature of, for example, about -10°C to about +60°C.
C. for about 60 minutes to about 5 hours.

Furthermore, in the compound represented by the formula (I-1) in the formula (1) that can be obtained as described in detail above, R3 in the nucleic acid (1-1) is a protected hydroxyl group. The following formula (I-1αb) represents a group, where X represents a halogen atom, and R represents an alkyl group or a group -000R.

[Here, R1 represents a linear or branched alkyl group, a cycloalkyl group, or a benzyl group which may have a substituent], R1 represents a lower alkyl group, and R1 represents a hydroxyl group-protecting group. , and in the formula 1. 2-halo°-2-cyclopene represented by = indicates a single bond or a double bond, Q is OH when it represents a single bond, and Q is a hydrogen atom when it represents a double bond. The f/-4 conductor can be obtained by subjecting it to a deprotecting group reaction using a method known per se to form the following formula (I-2) in formula (1-1), where X, R, R and Q have the same meanings as described above for formula (I-1αb), and can be easily converted into a 2-halo-2-cyclopentenone derivative. The deprotecting reaction is carried out, for example, by reacting the compound of formula (I-1αb) with an acid or a hydroxyl-protecting group removing agent such as tetra-n-butylammonium fluoride in a suitable reaction solvent. be able to.

Examples of the solvent used in this deprotecting group reaction include water, methanol, ethanol 1, acetone, acetonitrile, tetrahydrofuran, dioxane, 1,2-dimethoxynitane, dimethylformamide, or a mixture of these in any proportion. can do. There is no particular restriction on the amount used, but the amount used may be, for example, about 5 to about 40 times the amount of the compound of formula (I-1αb).

In addition, examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, noguradolenesulfonic acid,
It can be carried out under conditions such as about 2 to about 72 hours.

Furthermore, the formula (
In 1), the compound of formula (1-2) or the compound of formula (1-1) which can be obtained as described above, in which R1 represents a hydrogen atom, is subjected to a hydrolysis reaction. In the formula (I), in the following formula (1-3), X represents a halogen atom, and R represents an alkyl group or a group -COOR8 [where R3
represents a straight-chain or branched alkyl group, a cycloalkyl group, or a benzyl group which may have a substituent], R3 represents a lower alkyl group, and in the formula 1. = represents a single bond or a double bond, Q is OH when a single bond is shown, and Q is a hydrogen atom when a double bond is shown.

Examples of enzymes used in this preferred embodiment include enzymes such as lipase and esterase.

Such hair enzymes can be used regardless of their origin and are commercially available.

When carrying out enzymatic hydrolysis, pH is used as the reaction solvent.
It is preferable to use a buffer solution having a molecular weight of about 4 to about 9, for example, phosphate buffer, Mcllvain buffer, etc. Furthermore, an organic solvent may be added to these buffers as long as the enzyme activity is not significantly affected.Although there are no particular restrictions on the amount of buffer used, formula (1-2
) compound or the compound representing the R hydrogen atom in formula (1-1), for example, in an amount of about 50 to about 200 times the volume.

Examples include conditions such as about 20 to about 40 hours.

Among the compounds of formula (I-2) formed by the deprotecting group reaction of
-16') However, in the formula, X represents a halogen atom, represents a chloroalkyl group or a benzyl group which may have a substituent], and R1 represents a hydrogen atom or a lower alkyl group. 2-Halo-4,4-substituted-5-(6-alkoxycarbonyl-2-hexenyritene)-2-cyclopentenones can be acylated with an acylating agent to form a compound of formula (1), It can be easily converted into a compound represented by the following formula (1-1C), where X, R and R8 have the same meanings as described above, and R1 represents an acyl group.

In this case, the acylating agent to be used includes acylating agents having an acyl group as exemplified for the acyl group of R1, such as acetyl chloride, benzoyl chloride,
Examples include substituted benzoyl chloride and acetic anhydride. The usage amount can be selected and changed appropriately, but the formula (
For example, the amount used may be about 1' to about 5 equivalents based on the compound I-1b').

When carrying out the acylation reaction, for example, as a base,
It is preferable to add an amine such as pyridine, and the amount used is, for example, about 1 to about 40 times the amount of the acylating agent.

Examples of the solvent used in the acylation reaction include pyridine, methylene chloride, chloroform, benzene, and mixtures thereof in arbitrary proportions.

For example, the usage amount may be as follows.

I can give an example.

As described above, the present invention formula (1
) The method for producing the compound has been explained in detail, and for example, the compound of the formula (1) of the present invention which can be obtained in this way can be prepared using silica gel column chroma dog 2 fee, silica gel thin layer chroma dog 2 fee, silica gel thin layer chroma dog 2 fee, It can be separated and purified by subjecting it to a purification operation such as high performance liquid chromatography.

The compound of formula (1) of the present invention can be used in the form of a metal salt such as a free acid salt, a salt such as an ammonium salt, a quaternary ammonium salt, or an ester. The formation of such pharmaceutically acceptable salts of the compound of formula (I) or esters thereof can be carried out by means known per se.

For example, pharmaceutically acceptable salts of an alkali metal hydroxide (I) compound can be prepared in an aqueous solution of a compound of formula (1) (wherein R1 represents a hydrogen atom).

In the embodiment of the production of the compound of the formula (1) of the present invention described in detail above, as mentioned above, the compound of the starting material formula (I [ It can be manufactured by using or applying a method. The manufacturing method will be described below.

The starting compound of formula (II[) can be produced, for example, in the manner shown in the process diagram below.

(X) (IX) (■) (■)-
111) (■) (V) (Ill-1) (
Ill-2) (V-1) Above! ! ! Similarly, the known compound 4-hydroxy-2-cyclopentenone (X), which is a starting material compound of the formula (I [[-1) compound [X and R have the same meanings as described for formula (1)], is For example, the document 'I''erahedron L
It can be produced using the method described in 1976). Then, this formula (X)
For example, a compound is subjected to a reaction that protects its hydroxyl group in a reaction solvent to form a new formula (IM> compound [where R9 is a tertiary butyltmethylsilyl group, a tertiary butyldiphenylsilyl group, a tribenzylsilyl group, etc.] R represents a hydroxyl protecting group
When 5 is 3tI&butyldimethylsilyl group, it can be converted to a known compound].

As a reaction solvent, methylene chloride, chloroform, N,
N-trimethylformamide or a mixture thereof in any proportion can be exemplified. The reaction is carried out, for example, in the presence of imidazole as the base and using, for example, tertiary-butyldimethylchlorosilane, tertiary-butyldiphenylchlorosilane or tribenzylchlorosilane as the silylating agent, for example at room temperature for about 60 minutes. and nucleic acid (I
X) Compounds can be produced.

A novel compound of formula (■) [E represents an alkyl group] can be produced by reacting, for example, an alkyl metal compound with the compound of formula (IM) that can be obtained as described above in a reaction solvent. can. Examples of the reaction solvent to be used include ethyl ether, tetrahydrofuran, n-hexane, and mixtures thereof in arbitrary proportions. Further, examples of alkyl metal compounds include methyllithium, ethyllithium, n-propyllithium, n-
Examples include organic lithium compounds such as -butyllithium, n-pentyllithium, n-hexyllithium, n-heptyllithium, and n-octyllithium.

The reaction is carried out, for example, at about -70° to about 0°C for about 20 minutes to about 6
It can be carried out under the condition of 0 min tJr:J, and the formula (■
) compound (R represents an alkyl group).

The compound of formula (■・) which can be obtained as described above is subjected to a reaction to protect its hydroxyl group in a reaction solvent to form a new compound of formula (■) [R and R9 are as defined above, R2
represents a hydroxyl-protecting group]. Examples of the reaction solvent include methylene chloride, chloroform, tetrahydrofuran, and mixtures thereof in arbitrary proportions. Examples of reagents used for introducing the protecting group include 2,3-dihydropyran, 2,3-dihydrofuran, vinyl ethyl ether, and vinyl n-butyl ether.

The above reaction can be carried out, for example, under conditions such as about 90 minutes at room temperature in the presence of WIM as the acid, such as hydrochloric acid, para-toluenesulfonic acid or camphusulfonic acid.

The thus obtained compound of formula (■) is subjected to a reaction in which a protecting group such as a tertiary butyldimethylsilyl group, a 3a butyldiphenylsilyl group, or a tribesylsilyl group is removed in a reaction solvent to form a new compound of formula (Vl ) compound [R and R2 have the same meanings as above]. This deprotection reaction is carried out by adding tetrabutylammonium fluoride to the compound of formula (■) in a solvent such as tetrahydrofuran at a temperature of about θ°C to room temperature for about 60 minutes to about 150 minutes. This can be done by using a coagulant.

Next, a novel formula (V) compound [R is a furkyl group and R2 is a hydroxyl group-protecting group] is prepared by reacting an oxidizing agent with the formula (VI) compound obtained as described above in a reaction solvent. Obtainable.

Examples of the reaction solvent to be used include methylene chloride, chloroform, nochloroethane, and mixtures thereof in arbitrary proportions. Examples of the oxidizing agent include pyridinium dichromate and pyridinium chlorochromate. This reaction can be carried out, for example, at room temperature for about 2 to about 4 hours.

The thus obtained compound of formula (V) is prepared by, for example, reacting with a halogen in a reaction solvent and then reacting with a base to form a compound of formula (lit-1) in a compound of formula (Ill) as a raw material.
Compound (X is a halogen atom, R; is a hydrogen atom)
can be softened to Examples of the reaction solvent to be used include methylene chloride, chloroform, and mixtures thereof in arbitrary proportions. Further, examples of the halogen include heptadium, chlorine, bromine, and iodine. The amount used is equimolar to the compound of formula (V), but in actual reaction, for example, approximately 1
This concludes by illustrating the use of ~10 times the molar amount.

Furthermore, examples of the base used in the reaction include aliphatic amines such as triethylamine and triisopropylamine.

The reaction can be carried out, for example, at about -20°C to room temperature for about 1 to about 4 hours.

Furthermore, in the compound of formula (1-1) above, R is a group -COOR3
In the case of a compound [R, has the same meaning as described for the case where R represents 100OR in formula (+)], the starting material compound is a compound of formula (V-1) (R3 is as described above). It can be produced by using the same a) and subjecting it to the same reaction as described above. The compound of formula (V-1) can be produced by using or applying the production method described in Proceedings of the Chemical Society of Japan, 3JS, 1982, p. 1152.

Then, the formula (II[
-1) A novel compound of formula (1-2) can be produced by subjecting the compound to a protecting group introduction reaction to protect its hydroxyl group in a reaction solvent if necessary.

Examples of reaction solvents used at this time include methylene chloride,
Examples include chloroform, tetrahydro 7% NlN-trimethylformamide, and mixtures thereof in arbitrary proportions. Reagents for protecting hydroxyl groups include, for example, 2,3-dihydropyran, 2f3-dihydro7rane, vinyl ethyl ether, vinyl n-butyl ether, and furyl silanes such as trimethylchlorosilane, triethylchlorosilane, and 3a-butyldimethylchlorosilane. An example of this is chlorosilanes.

The above-mentioned protecting group introduction reaction is carried out, for example, at room temperature for about 10 to about 1
It can be carried out under conditions such as 80 minutes in the presence of acids such as hydrochloric acid, para-toluenesulfonic acid, and camphusulfonic acid.

Furthermore, when using an alkylchlorosilane-based reagent, it can be carried out by adding a base such as imidazole.

Regarding some representative examples of the compounds of formula (I) of the present invention, L121
Culture using cultured mouse leukemia cells! We conducted an experiment. The results are shown in Table 1 below. As shown in the results of Table 1, the compound of the present invention can be used at extremely low concentrations in L1210
It can be seen that the compound of formula (1) of the present invention exhibits a growth-inhibiting effect on murine leukemia cells, and is therefore a compound useful as an antitumor agent for the prevention and treatment of human tumors.

Mouse leukemia cell growth inhibition test: □ Leukemia cell E 1011 L Bboratori
L1210 mouse leukemia cultured cells maintained by es were used. Cultured cells in logarithmic growth phase at 10% F.
I x 105 cells in C8-added RPM11640 medium
s/■l in the presence of 0.01 to 1 μg 7 ml of alkylidenecyclobetenone derivative represented by formula (I).
The cells were statically cultured at 7°C and 5% CO2 for 4 days.

After culturing, Trivan blue staining solution was added and unstained cells were counted. IC after 4 days of treatment. (μg/l) is shown below.

Reference example 14-tertiary butyl-2-
Cyclopentenone (IX).

32.96 g of 4-hydroxy-2-cyclopentenone.

69.63g of tertiary butyldimethylchlorosilane, 300sj of methylene chloride! 33.70 g of imidazole in a solution of
.

A solution of 500mj+ of methylene chloride was added dropwise at room temperature over a period of 20 minutes.After the dropwise addition was completed, the mixture was further stirred at the same temperature for 30 minutes.The reaction solution was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. did. The resulting residue was separated and purified by column chromatography (silica gel, n-hexane: ethyl acetate). ! ! ! 70.8 g of the title compound was obtained as an oil.

bp 75-77℃(15Torr)IRy””am
-' 3350, 2920°aX 2850, Reference Example 21-n-butyl-4-tertiary butyldimethylsilyl quine-2-cyclopenten-1-ol (■).

n-Butyllithium n-hexane solution (1,6M solution) 64.7 theory! , a mixture of ethyl ether 30a+1 -
Cool to 55°C, add 19.50 g of 4-tertiary butyltmethylsilyloxy-2-cyclopentene, 3 ethyl ether.
0 cranes! A solution of was added dropwise at the same temperature. An aqueous ammonium chloride solution was added to separate the layers. The obtained organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 25.89 g of the title compound as an oil.

NMR (CDC/!, -TMS) δ: 0.10 (68%s) 0.90 (9H, s) 0.80-0.85 (9H, m) 2.15-2.50 (3H, ) 4.50-4.80 (IH, m) 5.65-5.90 (2Hll) i RI/""cII-': 3 3 5 0,
2900, ma to 1460.1360. 1250.1090. 1050.1010. 900.840.780 Reference Example 33-1-Butyl-5-tertiary butyldimethylsilyloxy-3-direct tetraphhydrobilan-2-yloxy)cyclopentene (■).

25.89 g of 1-n-butyl-4-tertiary butyldimethylsilyloxy-2-cyclopenten-1-ol, 100 mm of methylene chloride! , 2y3-dihydropyraf 11,
61 was stirred at room temperature for 30 minutes. After stirring, the mixture was washed successively with an aqueous sodium bicarbonate solution and a saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to separation and purification by column chromatography (silica gel, n-hexane: ethyl acetate) to obtain the title compound 26. as an oil.
6 Yield 80% NMR (CDC1.-TM
S) δ: 0, 10 ( 6 H, s) 0, 90 ( 9 t (%s) 1, to-2.00 (158, m) 2, 10-2.40 ( 2 H, s+) 3, 30-4
．． 20 (2 H, m) 4, 50-5.00 (2 H, m) 5, 50-6
．． 00(2H, ■)I R v""cts-'
: 2 9 0 0, 14601W+aX 1 3 60, 1250.

1100, 10201 900, 8 40, 780 Reference example 4 4-n-butyl-4 (tetrahuman a-pyran-
2-yl)-2-cyclopenten-1-ol (■).

28.04 g of 3-n-butyl-5-3Ik butyldimethylsilyloxy-3-(tetrahydro-pyran-2-yloxy)cyclopentene, 80 mol of tetrahydropyran
Tetrabutylammonifum fluoride (1M
Tetrahydro7 run solution) 1 3 0sj! was added and stirred at room temperature for 60 minutes.

After the completion of distillation, the solvent was distilled off and the resulting residue was subjected to separation and purification by column chromatography (silica gel, n-hexane: ethyl acetate) to obtain 15.65 g of the title compound as an oil.
I got it. Yield 89%.

NMR (CDCz, -TMS) δ: (C70-3-00(17H + 謔)3
, 20-5.10 (5 H1a+) 5, 60-6.40 ( 2 H, +*)IRl"
"am-": 3300, 2900, ax 1 430, 1 350, 1240, 1100, 1 060, 1 020, 860, 830,760 Reference example 5 4-n-butyl-4-(nato-2hydropyran-2-yloxy)- 2-cyclopenten-1-one (
■).

1.55 g of 4-n-butyl-4-(tetrahydropyran-2-yloxy)-2-cyclopenten-1-ol
, 3.61 g of biridium dichromate (viridium dichromate) was added to a solution of 30 vol of methylene chloride, and stirred at room temperature for 4 M. The reaction solution was filtered, and the filtrate obtained was concentrated. The obtained residue was separated by column chromatography (silica gel, n-hexane: ethyl acetate) to obtain 1.27 g of the title compound as an oil. 6 Yield: 82.6% NMR (CDC/
! 3-TMS) δ: 0, 30-3.00 (17H% import) 3.00-4
．． 90 (3H, m) 6.00-6.30 (I H, m) 7.30-7.70 (I HSm) Reference example 64-n-butyl-2-chloro-4-hydroxy-2-cyclopentene- 1-one (I[l-1).

3.27 g of 4-n-butyl-4-(tetrahydropyran-2-yloxy)-2-cyclopenten-1-one,
jM methylene 65-! Add 2.9 g of chlorine to the solution of
Blowing was carried out for 90 minutes at 0° to 0°C.

Next, 2.83 g of triethylamine was added and the mixture was heated at 0°C for 15 minutes.
The mixture was stirred for a minute.

The residue obtained by concentrating the reaction solution was subjected to column chromatography (
The mixture was subjected to separation and purification using silica gel and (1-hexane:ethyl acetate) to obtain 1.48 g of the title compound as an oil. Yield 56.9% NMR(CDCl3TMS)δ:0
．． 30-2.50 (9H, ff1) 2.67 (2h, S) 3.20 (I H, s) 7.43 (I H, s) Reference example 74-n-butyl-2-chloro-4- (tetrahydropyran-2-yloxy)-2-cyclopentene-
1-one (lII-2).

7.10 g of 4-n-butyl-2-chloro-4-hydroxy-2-cyclopenten-1-one, m/4-
Ren 100+++11213-dihydropyran 4.75
A mixture of 30-g of p-toluenesulfonic acid monohydrate was stirred at room temperature for 15 minutes.

The reaction solution was washed successively with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off.

The obtained residue was subjected to column chromatography (silica sol,
The mixture was subjected to separation and purification using n-hexane:ethyl acetate) to obtain 6.15 g of the title compound as an oil. Yield 59.9% NMR (CDCZ, -TMS) δ: 0.70-3.00 (17H, m) 3.00-5.50 (3H, Ken) 7.30-7.60 (IH, m) Reference Example 82-chloro-4-hydroxy-4-methoxycarbonyl- (III-1).

Chlorine was bubbled into a solution of 5.00 g of 4-hydroxy-4-methoxy[eta]carbonyl-2-cyclobentenone and 10,011 g of chloroform at about 0.degree. C. for 2 hours.

Then triethylamine 8, On j! was added and stirred at room temperature for 1 hour. The residue obtained by distilling off the solvent was subjected to separation and purification by column chromatography (silica gel, n-hexane:ethyl acetate) to obtain 3.34 g of the title compound as an oil. Yield 54.8% NMR (CDC1.
-TMS) δ: 2, 88 (2 H, dd J = 18.3, 18.4
Hz) 3, 85 (3 H, s) 4, 12 (I H, bs) 7, 29 (I H% s) Example 1 2-chloro-4-ethoxycarbonyl-4
-Hydroxy-5-(1-hydroxy-6-medquincarbonyl-2-hexenyl)-2-cyclopentenone.

A solution of 1.40 g of hexamethylnosilazane and 15 ml of tetrahydro7rane was cooled to -70°C, and under a stream of argon, n-butyllithium hexane solution (1.6M solution) 5
．． 30 mA was added and stirred for 30 minutes at -70° to -40"C. Next, 2-chloro-4-ethoxycarbonyl-4-
Add a solution of 0.9711 hydroxy-2-cyclopentenone and 5 parts of tetrahydrochloride at -70° to -20°C.
The mixture was stirred for 30 minutes.

Next, 2.97g of Trilobe Chiltin Chloride, 5mj of Tetrahydro 7ran! The solution was added and stirred at -55°C for 30 minutes. Next, a solution of 1.1 g of methyl 7-oxo-5-heptenoate and 7 l of tetrahydro7ran was added and stirred at -60° to -55°C for 60 minutes.

Next, add 2.50a of 20% ammonium chloride aqueous solution to the reaction solution.
1 was added and the liquid was separated.

The aqueous layer was extracted with ethyl acetate. The extract was combined with the organic layer, washed with brine, dried with anhydrous sulfuric acid mug,
The residue obtained by distilling off the solvent was subjected to separation and purification by column chromatography (silica gel Merck 7734, n-hexane-ethyl acetate) to obtain 0.75 tr of the title compound as an oil.

Yield 43.8%.

NMR (CDCI, -'rMS) δ: 0.60 6.35 (17H, m) 3.70 (3H, s) 7.40 (I H, bs) film-+- IRν cm, 3300.2900°a+aX 1700.1600. 1420.1220゜Example 2 2-chloro-4-ethoxycarbonyl-4-
Hydroxy-5-(6-medoxycarponyl-2-hexenylidene)-2-cyclopentenone.

2-chloro-4-ethoxycarbonyl-4-hydroxy-5-(1-hydroxy-6-medoxycarbonyl-2
-hexenyl)-2-cyclopentenone 0.520 g,
) 0.580 g of ethylamine, 6 m of methylene chloride
0.166 g of 7-tanesulfonyl chloride was added to this solution and stirred at about 15°C for 60 minutes. The reaction solution was separated and purified by column chromatography (silica sol, methylene chloride-ethyl acetate), and then further separated and purified by thin layer chromatography (silica sol plate, Merck 5717, methylene chloride-ethyl acetate) to obtain the title compound. A viscous oil of 0.110 ir was obtained.

Yield 22.3. .

NMR (CDC1, -TM'S) δ: 1.10-2.60 (9H, a+) 3.70 (3H, s) 4.00-4.50 (3H, So) 6.00-7.80 (4H% 1) IRν""cm-': 3350, 2900, 118X 1700, 1620. 1440, 1360. 1240, 1090° 860, 780 Example 3 4-n-phthoxycarbonyl-2-chloro-4-hydroxy-5-(1-hydroxy-6-medoxycarzanyl-2-hexenyl)-2-cyclopentenone.

Hexamethylsosilazane 2.16 m under argon flow
1. Cool the solution of 20°C in tetrahydrofuran to -50°C, and add 104n-butyllithium n-hexane solution &66
Then, 4-n-butoxycarbonyl-2-chloro-4-hydroxy-2-
Cyclopentenone 1,210F, Tetrahydrofuran 5
A solution of - was added dropwise at -60°C, and the mixture was stirred at the same temperature for 60 minutes.

Then methyl 7-oxo-5-heptanoate 1181
1f was added dropwise at the same temperature, and then stirred for 60 minutes at -50°C to -60°C. To the first reaction mixture was added 150r11t of an aqueous solution of 20% ammonium chloride, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a residue Lot. This was subjected to separation and purification by column chromatography (silica gel, n-hexane-ethyl acetate) to obtain the title compound cL2401 as a viscous oil. Yield 11.9%.

NMR (CDC1, -TMS) δ: (17-2,6(15Hem) 2.7-14 (2H*m) 567 (5H,m) 4.24 (2H*t*J==6Hz)4
．． 5-4.8 (2H, m, 0H) 5.6-5.86 (2H9m) 751 (IH, s) Example 4 4-n-butoxycarvinyl-2-chloro-4-hydro;-C5 -(6-Medoxycargonyl-2-hexenylidene)-2-cyclopentenone.

HOC00nC4H@ 4-n-butoxycarbonyl-2-chloro-4-hydroxy-5-(1-hydroxy-6-medoxycarbonyl-2-hexenyl)-2-cyclopentenone α240
f1 Triethylamine α54 in a solution of methylene chloride 5d
9W1tN methanesulfonyl chloride CLO4Bm was added under water cooling. After stirring at 20°C for 60 minutes, the solvent was distilled off and the resulting residue was separated and purified by thin layer chromatography (silica gel grade, Merck 5717, n-hexane-ethyl acetate, then methylene chloride-acetone). etc. to give the title compound, a viscous oil α0527f
I got it. Yield 22.9%.

MNR (CDCI, -TMS) δ: 17-2.7 (1sa, m) A67 (5H, s) 4.0-4. ．． 40C5H, m, OH included) &O~7.
7 (4H, m) 1620.1450,1200s 1080, 760 Example 5 2-chloro-4-methoxycargenyl-4-hydroxy-5-(1-hydroxy-6-medoxycarzanyl-2
-hexenyl)-2-cyclopentenone.

HOC00CR.

Under a nitrogen stream, 5.0 mm of n-butyllithium hexane solution (1.6 M solution) was added dropwise to a solution of 1.68 m of hexamethyldisilazane and 20 Wlt of tetrahydrofuran while cooling. Next, 2-chloro-4-hydroxy-4-methoxycarbonyl-2-cyclopentenone r: L624t,
A solution of tetrahydrofuran 5- was added dropwise at 60°C, and the mixture was further stirred at the same temperature for 20 minutes, followed by addition of 2.16 adt of methyl n-butyl chloride and brought to 20°C. Heptanoate α957 F
, a solution of 5d of tetrahydrofuran was added at -60°C.
Stir for 0 minutes, then add 20% ammonium chloride aqueous solution, 3
Add 2 d of N-hydrochloric acid and 10 ml of water to separate the layers, extract the aqueous layer with ethyl acetate, combine the organic layers, wash with brine, dry over anhydrous magnesium sulfate, and evaporate the solvent. Next, the obtained residue5. Of was subjected to separation and purification operations using chromatography (silica gel, n-hexane-ethyl acetate), etc. to obtain 1.064 f of the title compound as a viscous oil. Yield 76%.

NMR (CDCIs-TMS) δ: 1.55-2.45 (6H*m) 2.95-&25 (2H, m) 165 (5H*s) 5-82 (5H*a) 4-68 (2HsbssOHX2) 5, 65
~a 80 (2H*m)7.55
(IH,a) Example 6 2-chloro-4-hydroxy-4-methoxycarbonyl-5-(6-medoxycarmenyl-2-hexenylidene)-2-cyclopentenone.

HOC00CR.

2-ClCl-4-hydroxy-4-methoxycarmenyl-5-(1-hydroxy-6-medoxycarmenyl-2-hexenyl)-2-cyclopentenone a200F
, a solution of methylene chloride 5- was cooled on ice, and then 415 g of triethylamine α and further methanesulfonyl chloride [
1045- was added and stirred at about 20°C for 60 minutes. The residue obtained by concentrating the reaction solution was filtered through thin layer chroma dog 2 fie (
Silica Gluplate, Merck 5717, Methylene Chloride-
Separation and purification using acetone and then n-hexane-ethyl acetate gave the title compound as a viscous oil, 4a5η. Yield 25.6%.

NMR (CDCIA-TMS) δ: 1, s ~ 2.8 (6H, m) 567 (3H, a) 579 (5H, a) a, 1s (1u * b s e o u
)6,0~Z7 (4I(em) JR,ft1m,,,-1; 5550,5920,
1700°ax 1610.1450, 1200°1080.1000. 950°860, 820. 770 Example 7 2-Chloro-5-(6-medoxycarbonyl-2-hexenylidene)-4-n-octyl-4-(natho2hydrobilan-2-yl)oxy-2-cyclopentenone.

Hexamethylsosilazane [1490fs tetrahydro7
Cool the solution of 8 strands to -60°C and add n-butyllithium hexane solution (1,6M solution) 1 under an argon stream.
．． 90- was added and stirred for 45 minutes at 40t' to -20°C, followed by 2-chloro-4-n-octyl-4-(nato-2hydrobin-2-yl)oxy-2-cyclopentenone, A solution of 10-tetrahydrofuran was added dropwise at 150°C for 5 minutes, and the mixture was further stirred for 40 minutes at 40°C.Then, a solution of methyl 7-okine-5-hegtenoate as7op1 tetrahydrofuran 8- was added dropwise to 60°C.
Add liquid for 10 minutes at -60℃~15℃
The mixture was stirred for a minute. After the reaction was completed, 1N hydrochloric acid 7- was added at about 0° C. to separate the layers.

The aqueous layer was extracted with ethyl acetate. The extract was combined with the organic layer, washed with brine, dried over anhydrous magnesium sulfate,
The solvent was distilled off. The obtained residue 1 was subjected to separation and purification by bbtt column chromatography (silica glu, n-hexane-ethyl acetate) to obtain the title compound α400f as a viscous oil. Yield 2a2%.

NMR (CDC1, -TMS) δ: 150~5o(2quem)AOO~
4.80 (3H, m) 570 (5H, s) & 00~a OO (4Hm m) ft1m IR'crR-': 2 B
5 (l e 1 7 G (1* 1
6 2 0 -ax 1440.1110, 1010°860, 810. 720 Example 8 2-chloro-4-hydroxy-5-(6-medoxycarmenyl-2-hexenylidene)-4-n-octyl-2
-Cyclopenteno/.

2-riao-5-(6-medoxycarbonyl-2-hexenylidene)-4-n-octyl-4-(tetrahydrobilan-2-yl)oxy-2-cyclopentenone 40
A solution of ON9, 50 ml of acetone, and 5N hydrochloric acid α2- was stirred at about 20° C. for 5 hours. Next, the reaction solution was concentrated, 50 g of ethyl acetate was added, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to thin layer chromatography (silica gel plate, Merck 5717, n-hexane-ethyl acetate). ) to obtain 215.7 ml of the title compound in the form of a viscous oil.

Yield 65.8%.

NMR (CDCI, -TMS) δ2 α70~2.80 (24H, m) 565 (5[(,a) 6.00~7.50 (4H, m) i1m IRν G-": 3350, 2850° 1
700゜&X 1620.1450, 1200゜1170.1010. 820° Example 9 2-chloro-4-hydroxy-5-(6-carboxy-
2-hexenylidene)-4-n-octyl-2-cyclopentenone.

O 2-chloro-4-hydroxy-5-(6-medoxycarbonyl-2-hexenylidene)-4-n-octyl-2
-Cyclopentenone 2051Ni1 Acetone 1.50
d, pH 8 phosphate buffer 12.9 m, pig liver esterase α62mtC994 units, Sigma 10 WIy/s
The mixture of d) was stirred at 25° C. for 40 hours, and the reaction solution was extracted with ethyl acetate. The ether acetate solution was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to thin layer chromatography (silica gel plate, Merck 5517, methylene chloride-methanol).
The title compound 52 in the form of a viscous oil was subjected to separation and purification operations by
I got 1f9.

NMR (CDCI, -TMS) δ: 0.70-2.80 (25H, m) to ~zs
o (4H*m) 7.70 (2Hobg-OH-(OOH)
Example 10 4-n-Butyl-2-chloro-5-(6-medoxycarbonyl-2-hexenylidene)-4-(tetrahydrobilan-2-yl)oxy-2-cyclopentenone.

Hexamethyldisilazane 1.180f under argon stream
, 4.58- of n-butyllithium hexane solution (1,6M solution) was added to a solution of 20- of tetrahydrofuran at -50°C.
Then, 4-n-butyl-2-chloro-4-(nato-2hydropyran-2-yl)oxy-
A solution of 2.000 t of 2-cyclopentenone and 12 rnt of tetrahydrofuran was added at about -40°C over 5 minutes, and then stirred for an additional 30 minutes at -30°C to -10°C. 5-hepetenoe) 1.58Of
.

A solution of Tetrahydrone La/20-30°C to -20°C
The mixture was added dropwise over a period of 20 minutes, and further stirred at about -25°C for 40 minutes. After the completion of the reaction, 50 ml of a 20% ammonium chloride aqueous solution was added to separate the layers. The aqueous layer was extracted with ethyl acetate. The extract was combined with Organic 1, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Obtained residue A32
f was subjected to separation and purification by column chromatography (silica gel, n-hexane-ethyl acetate) to obtain the title compound α220t as a viscous oil.

NMR (CDCI, -TMS) δ: 150~! L10 (21H, m) 510~5.00 (3H, m) s7o (3H, s) 5.90~a00 (4H*m) l1m IRW cm-': 2900, 2850, 170
0°ax 1620.1450s 1100* 1010, 860. 810 Example 11 4-n-butyl-2-chloro-4-hydroxy-5-(
6-Medoxycarbonyl-2-hexenylidene)-2-
cyclopentenone.

4-n-Butyl-2-chloro-5-(6-methoxy, cargenyl-2-hexenyritene)-4-(tetrahydropyran-2-yl)oxy-2-cyclopentenone 220■, acetone 30- and 3N A solution of -hydrochloric acid 0.2- was stirred at about 20°C for 80 minutes.Anhydrous magnesium sulfate was added to the reaction mixture, and the residue α201 obtained by distilling off the solvent was subjected to thin layer chromatography (silica gel grade , Merck 5717, n-hexane-ethyl acetate) to give the title compound 81 as a viscous oil.
I got ■. Yield 46.5%, NMR (CDC1,-TMS) δ: 0.70-150 (including 16H* m t OH)
A65 (5H, II) &00~7.60 <4H, m) i1m IRν 6R-': 5550, 2900° 1700
゜ax 1620゜1450, 11809 1010, 870. 810°760, 720 Example 12 4-n-butyl-2-chloro-4-hydroxy-5-(
6-Cal? xy-2-hexenylidene)-2-cyclopentenone.

4-n-p-2-chloro-4-hydroxy-5-(
6-Medoxycargenyl-2-hexenylidene)-2-
Cyclopentenone 38■, acetone CL24m, pH 8
phosphate buffer z4-, pig liver esterase 0111
m (184 units, sigma 10~/-) at 25°C.
One reaction solution was stirred for 40 hours and extracted with ethyl monoacetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to separation and purification operations such as thin layer chromatography (silica gel plate, Merck 5717, methylene chloride-methanol) to obtain the title compound 811Ig as a viscous oil.

NMR (CDCI, -TMS) δ: 170 ~ A50 (15H*m) 6,0 ~ z60 (4II em) 7.70
' (2H, bs, OH, C00H) Example 15 4-benzyloxycarbonyl-2-chloro-4-hydroxy-5-(1-hydroxy-6-methoxycarbonyl-2-hexenyl)-2-cyclopentenone .

Hexamethylsosilazane 1.25d under argon stream
, 20m/tetrahydrofuran solution was cooled to about -50°C, and 10% n-butyllithium hexane solution 180-
was added and stirred at about 0°C for 60 minutes. Then 4-pentyloxycarl is converted into nyl-2-chloro-4-hydroxy-2-
A solution of cyclopentenone α80f1 tetrahydrofuran 5- was added at about -60°C, and the same peat was stirred for 50 minutes.

Next, a solution of 1.65 ml of tri-n-butyltin chloride and 5 ml of tetrahydropran was added at the same temperature and stirred for 50 minutes.Next, a solution of methyl 7-oxo-5-hebutenoate α469 F and tetrahydrofuran 5-5 was added at the same temperature.
The mixture was added at 5°C and further stirred for 85 minutes at -50°C to -65°C. To the reaction mixture was added 50 mj of a 20% ammonium chloride aqueous solution, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to separation and purification operations such as column chromatography (silica gel, n-hexane-ethyl acetate) to obtain the title compound as a viscous oil (122F).

Yield 17.6%.

NMR (C1) CI, -TMS) δ: (L7~2.7 (6H*m) 2.8~56 (2H*m) 57 (3H-→ 4.76 (2H, bs, 0H) ao ~5.5
(2H, m) 5.5-5.9 (2H, m) 7.2-7.7 (6H, m) Example 14 4-benzyloxycal is nyl-2-chloro-4-hydroxy-5- (6-Medoxycaryl-2-hexenylidene)-2-cyclopentenone.

4-pe/tyloxycarbyl-2-chloro-4-hydroxy-5-(1-hydroxy-6-methoxycarb-2-hexenyl)-2-cyclopentenone α220
A solution of 5 methylene chloride was cooled on ice, and 292 tst of triethylamine α and then 1040 sf of methanesulfonyl chloride were added.

The residue obtained by concentrating the reaction solution after stirring for 40 minutes under water cooling was subjected to thin layer chromatography (silica gel plate) Merck 5717, n-hexane-ethyl acetate, then methylene chloride-acetone). The title compound, α054f, was obtained as a viscous oil.

NMR (CDCI, -TMS) δ: ts ~ z, s (6asm) 566 (5H, m) 4.21 (tI (, b, 0H) 5.0 ~ 5.
4 (2H*m) 5.9-7.7 (9H9m) Example 15 4-7c)xy-4-n-butyl-2-chloro-5-(
6-Medoxycarbonyl-2-hexenylidene)-2-
cyclopentenone.

CH,CO 4-n-7'thyl-2-chloro-4-hydroxy-5-
(6-Medoxycarpnyl-2-hexenylidene)-2
- A solution of 40 μl of cyclopentenone, 154 ql of acetic anhydride, and 55!19 pyridine was left at room temperature for 5 days, then diluted hydrochloric acid and ethyl acetate were added to separate the layers, and the organic layer obtained was washed with brine. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to separation and purification operations using a thin layer Chromadog 2F (silica gel plate, Merck 5717, n-hexane-ethyl acetate) to obtain 161 Mg of the title compound as a viscous oil.

NMR (CDCI, -TMS) δ: 170~S, SQ (15H, m) 105 (5Hes) 565 (5H, a) 40 ~ 7.60 (4H*m) Example 16 2-chloro-4-methyl-4-(f)7hydro.

pyran-2-yl)oxy-5-(1-hydroxy-6
-Medoxycarponyl-2-hexenyl)-2-cyclopentenone.

A solution of 1.56 vrl of hexamethelodisilane and 20 wt of tetrahydrofuran was cooled to -70°C, and under a nitrogen gas flow, 4.06-n-butyllithium hexane solution (1,6M solution) was added and stirred at about -70°C for 10 minutes. Did 0
Then 2-chloro-4-methyl-4-tetrahydropyran-2-yl)oxy-2-cyclopentenone 1.497
A solution of fstet2hydrofuran 6- was added at the same temperature,
Further, 1.75 m of 1.75 m of primary trin-butyritine chloride (N-Ptyritine chloride), which had been stirred at the same temperature for 10 minutes, was added at -55°C, and then -2
Then, a solution of methyl 7-okine-5-hebuteno-)t520y and tetrahydrofuran 6- was heated to 0°C.
The mixture was added at 0°C, stirred at the same temperature for 10 minutes, and then brought to 0°C.

Next, 10+d of a 20% ammonium chloride aqueous solution was added to the reaction solution, and further 5N hydrochloric acid 6- was added to separate the layers. The aqueous layer was extracted with ethyl acetate.

The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was subjected to separation and purification using column Chromadog 2F (silica gel, n-hexane-ethyl acetate). to give the title compound 1 as a viscous oil.
．． 575F was obtained. Yield 54.8%.

NMR (CDC1s-TMS) δ: 180-2.50 (15H, m) AO9-405 (5Hsm) 565 (3H, 5) 440-5.0O (2H, m, including OH) 5, ro-
aas (2H*m) 7.48 (1/2H*a) 7,55
(1/2 H@m) Example 17 2-chloro-4-methyl-4-(tetrahydropyran-
2-yl)oxy-5-(6-medoxycardenyl-2
-hexenylidene)-2-cyclopentenone.

2-chloro-4-methyl-4-(tetrahydropyran-
5-yl)oxy-5-(6-methoxycarl-2)
-hexenyl)-2-cyclopentenone 1.575fz
Triethylamine 5-964 in a solution of methylene chloride 5-
, methanesulfonyl chloride α95W1t was added to the reaction solution, which was stirred at room temperature for 30 minutes.
0- was added and the mixture was separated. The aqueous layer was extracted with methylene chloride. The organic layers were combined, washed in this order with brine, sodium bicarbonate solution, and brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography (silica gel, n-
Hexane-ethyl acetate) to give the title compound [L652f] as a viscous oil. Yield 49.9
%.

NMR (CDCI, -TMS) δ: CL80~2.80 (15H*m)420~4
．． 75 (AH@m) 570 (5H*s) 5.95-7.80 (4H, m) Example 18 2-Chlo I: l-4-: l'l Kilo 4-Mef-5
-(6-Medoxycarl-2-hexenylidene)-
2-cyclopentenone.

HOCR.

2-/o-4-methyl-4-(tet?hydrobion-2-yl)oxy-5-(6-methoxycarl-2-hexenylidene)-2-cyclopentenone α65
A solution of 25-1 IN of acetone and 10 IN in hydrochloric acid was stirred at room temperature for 3 hours. After completion of the reaction, acetone was distilled off, the resulting aqueous layer was saturated with common salt, and extracted with methylene chloride.

The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off.

The resulting residue was subjected to separation by column chromatography (silica gel, n-hexane-ethyl acetate), etc. to obtain the title compound α532f in the form of a viscous oil.

Yield 66%.

NMR (CDCIs-TMS) δ: 150-2.50 (including 1oH, m, oH) 56B
(5H*i) &04~7.75 (4H, m) 1 other person

Claims (1)

[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) However, in the formula, X represents a halogen atom, and R is an alkyl group or a group -COOR_3 [Here, R_3 represents a straight-chain or branched alkyl group, a cycloalkyl group, or a benzyl group that may contain a substituent], R_1 represents a hydrogen atom or a lower alkyl group, and R_2 represents a hydrogen atom, an alkyl group, or a hydroxyl group. represents a protecting group, and in the formula, ■ represents a single bond or a double bond; when a single bond is represented, Q is OH; when a double bond is represented, Q is a hydrogen atom; 2-2 halo-2-cyclopentenone derivatives and pharmaceutically acceptable salts thereof, represented by the following formula: where R_2 is an acyl group, (2) represents a double bond. 2. In the formula (I), X represents a halogen atom, and R represents an alkyl group of C_1 to C_9 or a group -COOR
_3 [Here, R_3 represents a C_1 to C_6 linear or branched alkyl group, a C_3 to C_6 alkyl group, or a benzyl group which may have a substituent], and R_1 is a hydrogen atom or a lower alkyl group , R_2 represents a hydrogen atom, a C_2 to C_7 acyl group or a protecting group for a hydroxyl group, and in the formula, ■ represents a single bond or a double bond, and when it represents a single bond, Q is OH and double 2. The compound according to claim 1, wherein Q is a hydrogen atom when it represents a bond; and when R_2 is an acyl group, ■ represents a double bond. 3.Formula (III) below ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) However, in the formula, represents an alkyl group, a cycloalkyl group, or a benzyl group which may have a substituent], and R_2 represents a hydrogen atom or a protecting group for a hydroxyl group, 2-halo-4,4-substituted-2 represented by -Cyclopentenone and the following formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) However, in the formula, R_1 represents a lower alkyl group, and the following formula ( I-1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( I-1) In the formula, X, R, R_1 and R_2 have the same meanings as above, and in the formula, ■ is a single bond or a double bond. 2-halo-2-cyclopentenone derivatives and their pharmaceutically useful compounds represented by Acceptable methods of making salts. 4. In the formula (I-1), the following formula (I-1a) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-1a) However, in the formula, X represents a halogen atom, and R represents an alkyl group or a group - COOR_3 [Here, R_3 represents a straight-chain or branched alkyl group, a cycloalkyl group, or a benzyl group which may have substitution], R_1 represents a lower alkyl group, and R_2 represents a hydrogen atom or a hydroxyl group. 2-halo-4,4-substituted-5-(1-hydroxy-6-alkoxycarbonyl-2-hexenyl), which represents a protecting group and is represented by
Among the formulas (I-1) characterized by subjecting -2-cyclopentenones to a dehydration reaction, the following formulas (I-1b) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( I-1b) However, the formula 2-halo-4,4-substituted-5-(6-alkoxycarbonyl-2-hexenylidene)-2-cyclopentenones and their pharmaceutical method of manufacturing acceptable salts. 5. In formula (I-1), the following formula (I-1ab)▲mathematical formula,
There are chemical formulas, tables, etc. ▼ (I-1ab) However, in the formula, [represents a benzyl group which may have a group], R_1 represents a lower alkyl group, R_2 represents a hydroxyl group protecting group, and in the formula, ■ represents a single bond or a double bond, and a single bond When it represents a double bond, Q is OH, and when it represents a double bond, Q is a hydrogen atom. In the formula (1-1), the following formula ( I -2) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I -2) However, in the formula, X, R, R_1 and Q have the same meaning as above, and A process for producing the 2-halo-2-cyclopentenone derivatives and pharmaceutically acceptable salts thereof. 6. In the formula (I-1), the following formula (I-2) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-2) However, in the formula, X represents a halogen atom, and R represents an alkyl group or a group - COOR_3 [Here, R_3 represents a straight-chain or branched alkyl group, a cycloalkyl group, or a benzyl group which may have a substituent], R_1 represents a lower alkyl group, and in the formula, ■ is A 2-halo-2-cyclopentenone derivative represented by a single bond or a double bond, where Q is OH when a single bond is shown, and Q is a hydrogen atom when a double bond is shown. Formula (I-1) characterized by adding to the hydrolysis reaction
The following formula (I-3) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( I-3) However, in the formula, X, R and Q have the same meanings as above, Process for producing Tenone derivatives and pharmaceutically acceptable salts thereof. 7. In formula (I -1), the following formula (I -1b')▲mathematical formula,
Chemical formulas, tables, etc. are available▼(I-1b') However, in the formula, 2-halo-4,4-substituted-5-(6-alkoxycarbonyl-2 -hexenylidene)-2-cyclopentenone is acylated with an acylating agent (I), the following formula (I-1c) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-1c) ) In the formula, X, R and R_1 are as defined above, and R_2 represents an acyl group, 2-halo-4,4-substituted-5-(6-alkoxycarbonyl-2-hexenylidene) represented by - A method for producing 2-cyclopentenones and pharmaceutically acceptable salts thereof.