JPS62114933A - 2-halo-2-cyclopentenone derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A 2-halo-2-cyclopentenone derivative expressed by formula I [X is halogen; R is alkyl or COOR3 (R3 is alkyl, benzyl, etc.); R1 is H or lower alkyl; R2 is acyloxy; R4 is H or protecting group of hydroxyl group; the broken line indicates single bond or double bond; Q is OH when the broken line indicates single bond and Q is H when the broken line indicates OH or double bond] and salt thereof. EXAMPLE:2-Chloro-4-methyl-4-tetrahydropyranyloxy-5-[ (4R)-4-acetyloxy-6- methoxycarbonyl-2-hexenylidene ]-2-cyclopentenone. USE:Useful as an antitumor treating agent for preventing and treating tumors of humans and animals. PREPARATION:A 2-halo-4,4-substituted-2-cyclopentenone expressed by formula II is reacted with an aldehyde derivative expressed by formula III to afford a compound expressed by formula IV in the compound expressed by formula I.

Description

[Detailed description of the invention]

The present invention relates to a 2-no-rho-2-cyclobentenone derivative that is useful in the pharmaceutical field, for example, as an antitumor agent, and which has not been previously described in any known literature, and a method for producing the same. More specifically, the present invention relates to the following formula (11, where X represents a halogen atom, and R represents an alkyl group or a group -COOR5 [where R3
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, R1 represents an acyloxy group, and R4 represents hydrogen Indicates a protecting group for an atom or a hydroxyl group, and in the formula indicates a single bond or a double bond, Q is OH when a single bond is present, and Q is hydrogen when a double bond is present. The present invention relates to a 2-halo-2-cyclobentenone derivative represented by the following atoms, pharmaceutically acceptable salts thereof, and a method for producing the same. The compound of the following formula (II) has an asymmetric carbon atom at the 4th position in the formula, and each optical isomer of 6 bodies and 1 body derived from the asymmetric carbon atom, racemic body (6 bodies: 1 body is 1 body) = 1 mixture) and any other proportions of these optical isomers, in which the feeder configuration at the 4' position is the (I() configuration); The configurational isomerism at the 1' and 3' positions in the formula (1) can be E configuration, Z configuration, or a mixture of these configurations in any proportion. (2-halo-2-cyclobentenone derivatives represented by Tl and their pharmaceutically acceptable salts are defined as including all of these cases.) We have been conducting research and development of active compounds.As a result, we have succeeded in synthesizing a 2-halo-2-cyclobentenone derivative and its salts, which have a new structural feature represented by the above formula (1) and have not been described in the literature. Further, the compound and its salts include, for example, L1210
As shown in an example below regarding a culture experiment using cultured mouse leukemia cells, it is a compound useful in the medical field as a pharmacologically active compound, such as an antitumor agent, and is used for the prevention or treatment of tumors in humans and non-human animals. It was found that this is a new compound that is expected to have extremely important value as a tumor treatment agent. Therefore, the object of the present invention is to
The present invention provides halo-2-cyclobentenone derivatives and pharmaceutically acceptable salts thereof, as well as their formulations. 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,
For example, C,,C0 alkyl group, especially C,,C,
or a lower alkyl group such as -COOR, (where R3 is a chain or branched alkyl group such as 01-
C0 straight-chain or branched alkyl group, especially 01-C
Lower alkyl groups such as 3, cycloalkyl groups such as C
5 to C6 cycloalkyl group or a benzyl group optionally having one substituent]; R represents a hydrogen atom or a lower alkyl group, such as a C1 to C4 lower alkyl group; R7 represents an acyloxy group, for example, an acyloxy group of 02 to C7; R4 represents a hydrogen atom or a protective group for a hydroxyl group, and in the formula, □ represents a single bond or a double bond; It's OH,
When representing a double bond, Q is a hydrogen atom. In the above, examples of the alkyl group in which R is C1 to C0 include methyl group, ethyl group, n-propyl group, n-7''f group, n-pentyl L, n-hexyl group, n-hebutyl group, n- Examples include alkyl groups such as -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 methyl group, ethyl group, n-
Examples include propyl group, isopropyl group, n-butyl group, tertiary-butyl group, isobutyl Ln-pentyl group, impentyl group, n-hexyl group, and isohexyl group. Furthermore, in the above, examples of the cycloalkyl group in which R8 is C3 to C6 include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Furthermore, examples of the benzyl group which may have a substituent for J include, in addition to the benzyl group, lower alkyl groups such as methyl, ethyl, and tertiary-butyl; and lower alkyl groups such as methoxy, ethoxy, and butoxy. Examples include alkoxy groups, fluorine, chlorine, bromine, iodine, etc., and benzyl groups having substituents such as nitro groups, amino groups, and hydroxy groups. In addition, with reference to the above, examples of lower alkyl groups in which R8 is C1 to C2 include methyl group, ethyl group, n-propyl group, inpropyl group, n-butyl group, isobutyl group, tertiary-butyl group, etc. can be exemplified. Furthermore, examples of the acyloxy group in which R is C7 to C2 include an acetyloxy group, and A with a substituent.
Examples of substituents that the benzoyloxy group may have include halogens such as fluorine, chlorine, and bromine, trifluoromethyl groups,
Examples of substituents include methyl group, tertiary-butyl group, nitro group, and methoxy group. Furthermore, in the above, when R4 represents a hydroxyl group-protecting group, examples of the protecting group include tetrahydropyran-2
-yl group, tetrahydrofuran-2-yl group, 1-ethoxyethyl group, tertiary-butyldimethylsilyl group, trimethylsilyl group, triethylsilyl group, tribenzylsilyl group, and the like. Furthermore, the compound of formula (11) can be in the form of its salts, particularly pharmaceutically acceptable salts, examples of such salts include metal salts such as Na, K, Ca, Mg, ammonium salts, etc. , quaternary ammonium salts such as amine salts, etc. The above-mentioned compound of the present invention has the following formula (r-1), where X, It has the same meaning as in IIC, and R1 represents a lower alkyl group in the definition of formula H. Therefore, in the formula, chopsticks = represents a single bond or a double bond, and when a single bond is represented, Q is OH, and Q is a hydrogen atom when it represents a double bond.In other words, the following formula (T
-1a) and the compound represented by formula (1-1b). In these formulas, X, R, R1, R, and R2 have the same meanings as described for formula (r-1) above. The above formula (r-1) compound is, for example, a 2-halo-4.4-j4-substituted compound represented by the following formula (ITIα, where X, R and R6 have the same meanings as described for formula (1-1)). A can be produced by reacting -2-cyclopentenone with an aldehyde derivative represented by the following formula flll1, in which 1R, R2 and =2 have the same meanings as described for formula (T-]). In (1-1), the compound of formula (1-1a) can be easily converted into the compound of formula ([-xbM,) in formula (I-1,) by subjecting it to a dehydration reaction. In addition, the compound of the present invention has the following formula (1-2), where X, R and R7 are the same as in formula (11), R is
8 represents a lower alkyl group in the definition in formula H, 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 OH; includes compounds where Q is a hydrogen atom. The above formula (1-2) compound is, for example, the above formula (1-1
) in which It4 represents a hydroxyl group protecting group (% formula %) In the formula, X, R, R, , R, 2 and □ represent the above formula (r-2
), and R4 represents a hydroxyl group-protecting group. It can be easily produced by subjecting a compound represented by the following to a deprotecting group reaction. Furthermore, the compound of formula (I) of the present invention has the following formula (T-3), in which X1R and R are the same as in formula (1),
In the formula, ;2 represents a single bond or a double bond; when it represents a bond, Q is OH; when it represents a double bond, Q is a hydrogen atom; do. The above formula (r-3) compound is, for example, the above formula (1-2)
) can be easily produced by subjecting the compound to a hydrolysis reaction. Several embodiments of the production of the compound of formula m of the present invention have been described above, but in the present invention, reaction units known per se, such as dehydration reaction, decapturing group reaction, hydrolysis reaction, and appropriate combination reactions thereof. The compound of formula (TI) can be converted to other compounds of formula m by using the technique, and the compound of formula m of the present invention is a compound of formula m that can be obtained by these techniques. Includes h below.
Now, several aspects of the production of the above-mentioned compound of formula (■) will be explained in more detail. One aspect of the production of the above-mentioned formula m compound can be schematically shown as follows. Formula (11) shown in the above process diagram In the embodiment of compound production, the raw material formula (Ill compound production method will be described in detail later.
rahedron Letters, 25.362
1 (1984). In the compound of the formula m of the present invention, the following formula (1-1) is used, in which X represents a halogen atom; , represents a cycloalkyl group or a benzyl group which may have a substituent], R1 represents a lower alkyl group, R2 represents an acyloxy group, R4 represents a hydrogen atom or a hydroxyl group protecting group U2, In the formula, r---jd represents a single bond or a double bond, Q is OH when a single bond is represented, and Q is a hydrogen atom when a double bond is represented by 2. - Halo 2-cyclobentenone rust conductor is, as shown in the process diagram, for example, the following formula ("), where X, R and R4 have the same meaning as described for the following formula (T-]), 2-halo 4.4-T; substituted-2-cyclobentenone and an aldehyde derivative represented by the following formula (11, where Ro and 2 are the same as described for the above formula (1-1) K) By reacting I
) can be manufactured. The reaction can be carried out, for example, by bringing the compound of formula 1rl and the compound of formula fl) into contact in a suitable reaction solvent. In this case, examples of the reaction solvent to be used include tetrahydrofuran, dioxane, 1,2-dimethoxyethane, ethyl ether, n-hexane, and mixtures of these solvents in arbitrary proportions. There are no special restrictions on the messenger m-fi, and you can choose it as you see fit.
For example, about 10 to about 50 times the capacity of the compound of formula (III) may be used. In carrying out the reaction 1c, the compound of formula fU) in the form of its lithium erate may be ) is suitable for contacting with a compound. For example, in a reaction solvent as exemplified above, a compound of formula (Ill) is combined with a base and an organolithium compound such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, etc., for example, about -7
By reacting at 0' to +20° C. for about 10 to about 50 minutes, lithium erlate of the formula in) is first formed, and a compound of the formula (in) of the formula (in) is formed.
The reaction can be carried out in the same manner as above, in which the Ill compound is reacted with tri-n-butyltin chloride if necessary, and then the compound of formula fl) is reacted with the compound. At this time, the amount of the organic 1-notium compound to be used based on the base used can be changed as appropriate, but for example, the amount of the compound used is about 1 to 5 times the amount of the 2fTI) compound. The reaction of a compound of formula (TI), preferably in the form of lithium erulate, with a compound of formula (1) can be carried out.
By appropriately selecting and adjusting the reaction φ, especially the reaction temperature, the formula (r
-1) In the compound, the following formula (r-1*) and the formula (■-1b
) can form a 7E selective IC with one of the compounds represented by the formula (71R,0), where X, J R,, r (, and R4 are
It has the same meaning as described for 1-1). For example, about -70°C to about -5 low 5030 minutes to about 120
By controlling the reaction under conditions such as
a) The compound can be formed selectively and, for example, after reacting from about -70°C to about -50°C, further for example at about -30°C to about +30°C for about 30 minutes to about 150 minutes. The compound of formula (T-1b) can be selectively formed by carrying out the reaction under the following conditions. In the reaction of the above-mentioned compound of formula (IJ) and compound of formula (1), the amount of the compound of formula (ll) to be used can be changed as appropriate; In the compound of formula (T-1) that can be obtained as described above, the following formula (1-1a) is used, where X represents a halogen atom, and R represents an alkyl group. or the group -COOR,, [where R
8 represents a straight-chain or branched alkyl group, a cycloalkyl group, or a benzyl group having a substituent and which may be A], R8 represents a lower alkyl group, R1 represents an acyloxy group, R6 represents a hydrogen atom 2-halo-2-cyclobentenone derivatives, which represent a protecting group for a hydroxyl group, can be easily converted into the formula ( T-1) In the compound, formula (T-1b
) can be converted into compounds. This reaction can be carried out, for example, by formula (1-1) in an appropriate reaction solvent.
a) This can be easily carried out by subjecting the compound to a dehydration reaction using a suitable dehydrating agent. Examples of reaction solvents used at this time include methylene chloride, dichloroform, tetrahydrofuran, dioxane, dimethylformamide,
Examples include acetonitrile, nitromethane or a mixture of these in different proportions. There are no particular restrictions on the amount used, but the amount used may be, for example, about 5 to about 30 times the amount of the compound of formula (T-1a). At this time, as a dehydrating agent used in the dehydration reaction, for example, triethylamine, triinpropylamine, pyridine, and 4-dimethylamino Preferably, amines such as pyridine are used. The amount of the sulfonyl chloride to be used can be selected and changed as appropriate, and may be, for example, about 1 to about 2 times the amount of the compound of formula (1-1a). Furthermore, the use of amines (k) can be appropriately selected and used, for example, in an amount of about 1 to about 5 times the equivalent of the sulfonyl chloride. The dehydration reaction to form the compound of formula (I-1b) from the compound of formula (1-1a) described above may be carried out at a temperature of, for example, about -20°C to about +60°C.
This can be carried out at a temperature of about 30 minutes to about 5 hours. Furthermore, in the compound represented by the formula (T-1) in the formula (1) that can be obtained as described in detail above, R4 in the formula (T-1) is a protected hydroxyl group. The following formula (1-1ab) represents a group, where X represents a halogen atom, R is an alkyl group or a group -C'OOR, [where R
8 represents a straight-chain or branched alkyl group, a cycloalkyl group, or a benzyl group which may have a substituent], R1 represents a lower alkyl group, R2 represents an acyloxy group, and R4 represents 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, and when a double bond is represented, Q is a hydrogen atom; The 2-halo 2-cyclobentenone derivative represented by the following formula (1-2') in formula (r-1) can be obtained by subjecting it to a deprotecting group reaction using a method known per se. However, in the formula, X, RXR, , R, and =-1 are the formula (

[-1ab)
A 2-halo-2-cyclobentenone derivative represented by the following formula can be easily converted. The deprotecting group reaction can be carried out, for example, using the formula (1-1) in an appropriate reaction solvent.
ab) This can be carried out by reacting the compound with an acid or a hydroxyl-protecting group removing agent such as tetra-n-butylammonium fluoride. Examples of the solution W used in this disassociation G4 reaction include water, methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dimethylformamide, or a mixture of these in proportions. be able to. There is no particular restriction on the amount used, but a 1 tbsp dose, for example, about 5 to about 40 times the amount of the compound of formula (T-1ab) can be exemplified. Further, examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and acetic acid. This deprotecting group reaction can be carried out, for example, at about -10' to about 150°C for about 2 to about 72 hours. Furthermore, for example, the formula (1
In 1, the compound of formula (T-2) or the compound of formula <r-1) which can be obtained as described above, in which R3 represents a hydrogen atom, can be obtained by subjecting it to a hydrolysis reaction. ,
Easily represented by the formula (in Tl, below, -self formula (1-3) O, where X represents a halogen atom, and R represents an alkyl group or a group -COOR5 [where,
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, R7 represents an acyloxy group, and in the formula, == τ 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; I can do it. This hydrolysis can be carried out either by acid or alkali hydrolysis or enzymatic hydrolysis, but enzymatic hydrolysis is preferred. Examples of enzymes that benefit in this preferred manner include enzymes such as lipase and esterase. Such enzymes can be used regardless of their origin;
available on the market. When carrying out hydrolysis by an enzymatic method, it is preferable to use a buffer solution with a pH of about 4 to about 9 as the reaction solution, such as phosphate buffer, Mcllvain buffer, etc. . Additionally, organic solvents can be added to these buffers to the extent that they do not significantly affect the enzyme activity. There is no particular restriction on the amount used, but in the compound of formula (1-2) or formula (1-1), It. represents a hydrogen atom, for example, about 50 to about 20
An example of a case where 0 times the capacity is used can be exemplified. The reaction conditions can be changed appropriately depending on the enzyme used, but for example, about 20°~! ? :) For example, about 20 ~ at 40℃
Conditions such as about 40 hours can be exemplified. The method for producing the compound of the formula (m) of the present invention has been described in detail in the embodiment shown in the process diagram above. For example, the compound of the formula (1) of the present invention that can be obtained in this manner may be Then, it can be subjected to purification operations such as silica gel column chromatography, silica gel thin layer chromatography, and high performance liquid chromatography for fractional purification. The compound of the present invention can be used in the form of a free acid [in which R1 is a hydrogen atom] or in a pharmaceutically acceptable metal salt thereof, such as Na salt, K salt, Ca salt, Mg salt, etc. metal salts like
It can be used in the form of salts such as ammonium salts and quaternary ammonium salts, or esters. Such compounds of formula (I) can be used in the form of pharmaceutically acceptable salts or esters. Formation of such pharmaceutically acceptable salts of the compound of formula (1) or esters thereof can be carried out by means known per se. For example, the compound (wherein R1 represents a hydrogen atom)
The aqueous solution obtained by neutralizing the aqueous solution by adding an alkali metal or alkaline earth metal hydroxide such as Na, K, Cas Mg, etc., or ammonia or amine, etc., is subjected to freeze-drying by a conventional method. Pharmaceutically acceptable salts of the compound of formula (1) can be produced by the following steps. The raw material formula (II) compound used in the embodiment of the production of the formula m compound of the present invention described in detail above can be produced using the method described in detail in Japanese Patent Application No. 60-45735 filed by the same applicant. , a new ruling has been invented for the case where R in formula (U) is a group -COOR, , and will be described in detail below, including that ruling. The compound of the raw material formula (111) can be produced, for example, in the manner shown in the process diagram below. In the above aspect, the compounds CX, R, and R
The known compound 4-hydroxy-2-cyclohentenone (■), in which 4 is a starting material compound of the formula (same meaning as described for Il), is described, for example, in the literature Terahedron Let
ters, 759 (1976). Then, this formula (Ilr
) Compound is subjected to a reaction to protect its hydroxyl group in a reaction solution σ to form a new compound of formula (VN) [However, R3 is 3
When R3 is a tertiary butyldimethylsilyl group, it can be converted into a known compound] which represents a hydroxyl group-protecting group such as a tertiary butyldimethylsilyl group, a tertiary butyldiphenylsilyl group, or a tribenzylsilyl group. Examples of the reaction solvent include methylene chloride, chloroform, N,N-dimethylformamide, and mixtures thereof in arbitrary proportions. 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. A linear ('I'm) compound can be produced by A novel compound of formula (~.]) [R represents an alkyl group] is produced by reacting the compound of formula (VIE), which can be obtained as described above, with, for example, an alkyl metal compound in a reaction solvent. be able to. Examples of reaction solvents used include ethyl ether, tetrahydrofuran, n
Examples include -hexane and mixtures thereof in arbitrary proportions. Further, examples of alkyl metal compounds include methyllithium, ethyllithium, n-propyllithium, n-butyllithium, n-pentyllithium, n-
Examples include organic lithium compounds such as -hexyllithium, n-heptyllithium, and n-octyllithium. The reaction may be carried out, for example, at about -70°C to about 60°C for 20 minutes to about 60°C.
The reaction can be carried out under conditions such as 0 minutes, and can be converted into a compound of formula (1) [R represents an alkyl group]. The compound of formula (~'II) that can be obtained as described above is subjected to a reaction that protects its hydroxyl group in a reaction solvent to form a new compound of formula (vl) [R and R are the same as defined above, R4 represents a hydroxyl group protecting group]. Examples of the reaction solvent include methylene chloride, chloroform, tetrahydrofuran, and mixtures thereof in arbitrary proportions. In addition, examples of reagents used for introducing protecting groups include 2,3-dihydropyran, 2,
Examples include 3-dihydrofuran, vinyl ethyl ether, and hivinyl n-butyl ether. The above reaction can be carried out, for example, at room temperature for about 90 minutes in the presence of an acid such as hydrochloric acid, radruenesulfonic acid or camphorsulfonic acid. The thus obtained compound of formula (Vl) is subjected to a reaction in which a protecting group such as a tertiary butyldimethylsilyl group, a tertiary butyldiphenylsilyl group or a tribedylsilyl group is removed in a reaction solvent to form a novel compound of formula (Vl). ) compound [R and R4 have the same meanings as above]. This detachment 4i
The group reaction is carried out in a solvent such as tetrahydrofuran,
For example, at about 60°C to room temperature, for example, about 60 minutes to about 150°C.
This can be carried out by allowing tetrabutylammonium fluoride to act on the chain formula (Vl) compound under conditions such as minutes. Next, a novel formula (
IV) Compound [R is an alkyl group, R.4' is a hydroxyl group protecting group] can be obtained. Examples of the reaction solution to be used include methylene chloride, chloroform, dichloroethane, 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 compound of formula (IV) obtained in this way can be prepared by reacting with the raw material formula (formula (■-1) in the reaction solution 24, for example, by reacting with nitrogen and then with a base. It can be converted into a compound (where X is a rogen atom and Rlz is a hydrogen atom). Examples of the reaction solvent to be used include methylene chloride, chloroform, and mixtures thereof in arbitrary proportions. Examples of the above-mentioned nitrogen include fluorine, chlorine, bromine, and iodine rings. Although the number used is equivalent to the amount of the necessary mole relative to the compound of formula (IV), in actual reactions, for example, about 1 to about]0 times the mole .tau.1 can be used. Furthermore, examples of the base used in the reaction include aliphatic amines such as triethylamine and triisopropylamine. The reaction can be carried out under conditions such as, for example, at about -20° C. to room temperature for about 1 to about 4 hours. Then, the formula (II-
1') A novel compound of formula (n-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, tetrahydrofuran, NlN-dimethylformamide, or a mixture of these in arbitrary proportions. Examples of reagents for protecting hydroxyl groups include 2,3-dihydropyran, 2,3-dihydrofuran, vinyl ethyl ether, vinyl n-butyl ether, and alkylchlorosilanes such as trimethylchlorosilane, triethylchlorosilane, and tertiary-butyldimethylchlorosilane. The following examples can be given. 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, halatoluenesulfonic acid, and camphorsulfonic acid. Further, when using an alkylchlorosilane reagent, for example, imidazole can be added as a base for further treatment. In addition, in the compound of formula (ff-1) above, R is a group -COOR
, CR, <synonymous with the case where mK:%- and R represents -COOR],
Formula O as a readily available starting material compound
劃) Can be produced using compounds. A novel f (
Xn) (wherein, X represents a halogen atom). Examples of reaction solvents typically include water, methanol, and acetic acid. The reaction is carried out by dissolving 4-halophenol in, for example, an aqueous solution of caustic soda, and then adding bromine to the solution at a temperature of about 10 to about 1 at about 10°C to about 10°C.
A nuclear formula (Xrl) compound can be produced by adding to the reaction for 0 minutes. The compound of formula (XI) that can be obtained as described above is dissolved in an alcohol and treated with an acid to form a new compound of formula (XT
) Compound [X dimension] represents a rogene atom, and R5 represents a linear or branched alkyl group, a cycloalkyl group, or an optionally substituted benzyl group] can be produced. Examples of reaction conditions include conditions such as about 60° to about 150° C. for about 20° to about 10 hours. Thus obtained 11. A novel formula (X) compound [X
and R1 have the same meanings as described above]. Acetone is usually exemplified as the reaction solvent to be used. Further, as an example of the oxidizing agent, John's reagent (a mixture of chromium trioxide, sulfuric acid, and water) can be exemplified. This reaction is carried out, for example, at a temperature of about 10° to about 60°C.
This can be carried out for about 4 hours. The thus obtained compound of formula (X) is reacted with a debrominating agent in a reaction solvent to form a novel compound of formula (i-1) [X represents a rogen atom, and R is a group -cooa. and R3 has the same meaning as above] can be produced. Examples of the reaction solvent used include methanol,
Examples include lower alcohols such as ethanol, a mixture of dilute hydrochloric acid and acetone, and the like. Examples of the debrominating agent include zinc-copper couple and chromium dichloride. The reaction conditions are, for example, about 20° to about 60°
Examples include conditions such as about 10 to about 10 minutes at ℃. Culture experiments using cultured L1210 mouse leukemia cells were conducted for several representative examples of the formula m compounds of the present invention. The results are shown in Table 1 below. As shown in the results of Table 1, the compound of the present invention exhibits a growth-inhibitory effect on L1210 mouse leukemia cells at extremely low concentrations, and therefore,
It can be seen that the compound of formula (1) of the present invention is a promising compound for the prevention and treatment of human tumors as an antitumor agent. Mouse leukemia cell growth inhibition test Knee leukemia cells Flow Laboratories
L1210 mouse leukemia cultured cells maintained by the company were used. 10% cultured cells in logarithmic growth phase
F C8+RP MI 1640 Medium 'T! IX
Prepared to 10' cells/1 and indicated by 2 m
-Halo 2-cyclobentenone derivative 0.01-1μE
The cells were statically cultured for 4 days at 37° C. and 5% CO1 in the presence of /Ml. After culturing, Trivan blue staining solution was added and unstained cells were counted. IC3o (μg/−1) after 4 days of treatment is shown below. Table 1 Example 1 2-chloro-4-methyl-4-tetrahydropyranyloxy-5-((4几)-4-acetyloxy-6-medoxycarbonyl-2-hexenylidene)-2-cyclobentenone argon 0.0% hexamethyldisilazane under air flow.
Add 41d to 1211/l of tetrahydrofuran and make 150
Cooled to ℃. Then, 1.19 at of a 10% n-butyllithium hexane solution was added and the mixture was heated at -50°C to 0°C.
Stir for 5 minutes. After cooling to -60°, a solution of 2-chloro-4-methyl-4-tetrahydropyranyloxy-2-cyclobentenone 0.40B, 9 and tetrahydrofuran 3D was added and stirred at the same temperature for 60 minutes. Then, a solution of 0.504 M of trilopuryltin chloride and 3 d of tetrahydrofuran was added, and the mixture was stirred at the same temperature for 40 minutes. Then at -65°C 0.38 methyl (4R)-4-acetyloxy-7-oxo-5-hebutenoate
0,9. Add 3d of tetrahydrofuran to -65°~-
60 minutes at 40°C, then 40 minutes at -40°C to -20°C.
The mixture was stirred for a minute. Add saturated ammonium chloride aqueous solution 39 to the reaction solution.
After addition of at at about 0° C., extraction was performed with methylene salt. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography (silica gel, Merck, 7734, n-hexane-
ethyl acetate) to obtain 0.23 (l) of a viscous oil of the title compound. NMR (CDCI, -TM8) δ: 0.7-4.1 (18H, m ) 3. 7 (3'HX s) 4.1-4.9 (IH, m) 5.3-5.7 (LH, m) 5.8-7.9 (4H,, m) Example 2 2-chloro -4-hydroxy-4-methyl-5-((4
B) -4-Acetyloxy-6-medoxycarbonyl-2-hexenylidene)-2-7 Clopentenone 0.22 (l) of the product of Example 1 is dissolved in 8 d of acetone and 1 drop of 6N-HCI is added to approx. The mixture was stirred at 25°C for 60 minutes.Then, the solvent was distilled off, and 8 d of saturated saline was added to the resulting residue, followed by extraction with methylene chloride.The extract was dried over anhydrous magnesium sulfate, and the dissolved pancreas was distilled off. The resulting residue was subjected to column chromatography (silica gel, Merck, 7734, n-hexane-ethyl acetate (2:1)).
) to obtain 0.07'l of the title compound.
I got it. This was then subjected to thin layer chromatography (Merck 5717
, n-hexane-ethyl acetate (2:1) and then methylene chloride-acetone (10:1)) to obtain 0.064.9 g of the title compound as a viscous oil. NMR (CDCI, -TMS) a: 1.5-17 (IOH, m) 3.2-3.6 (IH, m, OH) 3.7 (3H, s) 5.2-5.6 (IH ,m) 5.8-7.8 (4H,m) Example 3 2-chloro-4-hydroxy-4-methoxycarbonyl-5-((4FL)-4-acetoxy-1-hydroxy-6,-methoxy carbonyl-2-hexenyl)-2-
Cyclobentenone 1.11 M of hexamethyldisilazane was dissolved in 15 a/ml of tetrahydrofuran under an argon stream and cooled to -50°C. Then 10% n-butyllithium hexane solution 3
．． 41417 was added and stirred at -50° to -5°C for 60 minutes. Then, after cooling to -70°C, 2-chloro-4-
A solution of 0.507.9 mL of hydroxy-4-methoxycarbonyl-2-cyclobentenone and 2 ν of tetrahydrofuran was added, and the mixture was stirred at the same temperature for 60 minutes. Then methyl (4R
A solution of 0.570 # of )-4-acetyloxy-7-oxo-5-heptenoate and 2 ml of tetrahydrofuran was added, and the mixture was stirred at -60°C to -50°C for 3 hours. To the reaction mixture was added 30 liters of saturated ammonium chloride aqueous solution, and the mixture was extracted with methylene chloride. The extract was washed with saturated 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, Merck, 7734, n-hexane-ethyl acetate) to obtain 0.16 (l) of the title compound as a viscous oil. NMR (CDCI) , -TMS) δ: 1.7-3.5 (9H,m) 3.7 (3H,s) 3.3 (3H,s) 4.3-4.8 (2H,m,%OH)5 .1-5.4
(IH, m) 5.5. -6.3 (2H,m) 7.2-7.4 (LH,m) Example 4 2-chloro-4-hydroxy-4-methoxycarbonyl-5-((4FL) -4-acetyloxy- 6-Medoxycarbonyl-2-hexenylidene)-2-cyclobentenone 0.160.9 of the product of Example 3 was dissolved in 3d of methylene chloride. Then, under water cooling, triethylamine 0.22
211/, methanesulfonylchlorih” 0.306d
was added and stirred at the same temperature for 60 minutes. The residue obtained by concentrating the reaction solution was subjected to thin layer chromatography (Merck, 57
17, was separated and purified using n-hexane-ethyl acetate (1:1) and then methylene chloride-acetone (10:1) to obtain 0.0475 ml of the title compound as a viscous oil. Yield 31.1% NMR (CDCI, -TMS) δ: 1.8-2.7 (7HXm) 3.7. (3H, s) 3.7-3.8 (3H, m) 4.5 (IH, bs, 0H) 5.2-5.6 (I H, m) 5.9-7.8 (4H, m) Example 5 2-Fluoro-4-hydroxy-4-methoxycarbonyl-5-((4R)-4-acetyloxy-1-hydroxy-6-medoxycarbonyl-2-hexenyl)-2
- Cyclobentenone 1.22 d of hexamethyldisilazane was dissolved in 15 m/ml of tetrahydrofuran under an argon stream and cooled to -45°C. Then 10% n-butyllithium hexane solution 3.
80117 was added and stirred at -45° to -5°C for 60 minutes. Then, it was cooled to -65°C and 0.512% of 2-fluoro-4-hydroxy-4-methoxycarbonyl-2-cyclobentenone was added. ! 9. A solution of 2d of tetrahydrofuran was added and stirred at the same temperature for 60 minutes. Then methyl (4R)
A solution of 0.630E of -4-acetyloxy-7-oxo-5-heptenoate and 2d of tetrahydrofuran was added, and the mixture was stirred at -50°C to -60°C for 3 hours. To the reaction mixture was added 3Qm of a saturated aqueous solution of hydrogen tartrate, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solution was subjected to column chromatography (silica gel, Merck, 7734, n-hexane-ethyl acetate (1:
The title compound was subjected to separation and purification operation according to 1)) to obtain 0.1009 viscous oil. NMR (CDCI, -TMS) δ: 1.7-3.
5 (9H, m) 3.7 (3H, s) 3.8 (3H, s) 4.3-4.8 (2I-T, m, 0H) 5.2-5.
4 (IH,m) 5.5-6.0 (28Xm) 6.7-6.9 (IH,m) Example 6 2-Fluoro-4-hydroxy-4-methoxycarbonyl-5-((4R) -4-acetyloxy-6-medoxycarbonyl-2-hexenylidene)-2-cyclobentenone 0.1009 of the product of Example 5 was dissolved in methylene chloride 2
Triethylamine 0.140d dissolved in d and cooled with water,
Methanesulfonyl chloride (0.020 m) was added to the mixture and the mixture was stirred at the same temperature for 60 minutes. The residue obtained by concentrating the reaction solution was subjected to thin layer chromatography (Merck, 5717, n
-hexane-ethyl acetate (1:1) and then methylene chloride-acetone (10:1)) to obtain a viscous oil of the title compound at 0.022.9. NMR (CDCI, -TMS) δ: 1.7-2.7 (2H, m) 3.7 (3H, s) 3.7-3.8 (3H, m) 4.2 (1) TXbs, 0H ) 5.2-5.6 (IH,m) 5.9-7.8 (4H,m) Example 7 2-Chloro-4-1::)"Ro*C4-1+Rue5-
((4R)-4-acetyloxy-6-carboxy-2
-hexenylidene)-2-cyclobentenone O Product of Example 2 63m9.7-1r) yo, 4a#,
Phosphate buffer 4a/pH8, pig liver esterase 0
．． A mixture of 2jI/(310 units, sigma 10η/-7) was stirred at about 25<0>C for 40 hours. The reaction solution was then extracted with ethyl acetate. The extract 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 5717, methylene chloride-methanol (5:1
)) to obtain 17 cm of the title compound as a viscous oil. NMR (CDCI, -TMS) δ: 1.5-2.7 (IOH, m) 5.2-5.6 (LH, m) 5.8-7.8 (4H, m) 7.7 (2H , bs, OH, C00H) Reference Example 1 4-tertiary butyldimethylsilyloxy-2-cyclobentenone (Vl). 32.96 g of 4-hydroxy-2-cyclobentenone,
In a solution of 69.63 g of 3R butyldimethylchlorosilane and 300 m of methylene chloride, 33.70 g of imidazole,
9. A solution of 500% methylene chloride was added dropwise at room temperature over 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. The obtained residue was subjected to separation and purification by column chromatography (silica gel, n-hexane: ethyl acetate) to obtain the title compound 70 as an oil.
．． 8 g was obtained. bp75-77℃(15Torr) IR,fl Irn-(max ryn 3350.2920.2850
, Reference Example 2 l-n-butyl-4-tertiary butyldimethylsilyloxy-2-cyclopenten-1-ol (Vll). A mixture of 64.7 ml of n-hexane solution (r, eM solution) of n-butyllithium and ethyl ether/I/30 d was cooled to -55°C, and 4-tert-butyldimethylsilyloxy-2-cyclobentenone 19 A solution of .50.9 and 30 ml of ethyl ether 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 give the title compound as an oil, 25.89 g.
! I got j. NMR (CDCI, -TMS) δ: 0110 (6H, s) 0.90 (9H, s) 0.80-0.85 (9H, m) 2.15-2. ．． 50 (3H, m) 4.50-4.
80 (IH, m) 5.65-5.90 (2H, m) IRI/"mCrn-': 3350.2900.14
60, max 1360.1250.1090. 1050.1010.900. 840.780 Reference Example 3 3-n-butyl-5-tertiary butyldimethylsilyloxy-3-(tetrahydropyran-2-(ruoxy)cyclopentene (Vl). 1-n-butyl-4-tertiary butyldimethylsilyl Oxy-2-cyclopenten-1-ol 25.89 g, methylene chloride 100 ml 1% 2.3-dihydropyran 11.6
A mixture of 1 s and 0.1559 halatoluenesulfonic acid monohydrate was stirred at room temperature for 30 minutes. After stirring, the mixture was washed with an aqueous sodium bicarbonate solution and a saline solution in that order, dried over anhydrous magnesium sulfate, and then 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 oily title compound 26,
04.9 was obtained. Yield 80% NMR (CDCI, -TMS) δ: Q, 10 (61-1, s) 0.90 (9H, s) 1.10-2.00 (15H1m) 2.10-2.
40 (2H, m) 3.30-4.20 (2)1. +n) 4.50-
5.00 (2H, m) 5.50-6.00 (2H, m) fi! m IRv cm-': 2900.1460.1
360, aX 1250, 1100.1020. 900.840.780 Reference Example 4 4-n-Butyl-4(tetrahydropyran-2-yloxy)-2-cyclopentene-]-ol ('V)
. 3-n-butyl-5-tertiary butyldimethylsilyloxy-3-(tetrahydropyran-2-yloxy)cyclopentene 26.04Q, tetrahydrofuran 8011/
Tetrabutylammonium fluoride (1M
Add 130 ml of tetrahydrofuran solution and stir at room temperature.
Stirred for 0 minutes. After the completion of the reaction, the solution G 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 (CDCI, -TMS) δ: 0.70-3
．． 00 (17H, m) 3.20-5.10 (5H, m) 5.60-6.40 (2H, m) i1m IRv α-': 3300.2900.1430,
ax 1350.1240.1100. 1060.1020.860. 830.760 Reference Example 5 4-n-butyl-4-(tetrahydropyran-2-yloxy)-2-cyclopenten-1-one (IV'). 4-n-Butyl-4-(tetrahydropyran-2-yloxy)-2-cyclopenten-1-ol 1.55.
! 3.61/J of pyridium dichromate was added to a solution of 3 (1/g) of methylene chloride and stirred at room temperature for 4 hours. The reaction solution was filtered and the solution obtained was concentrated. The resulting residue was Column chromatography (silica gel, n-hexane: E
This was subjected to a separation and purification operation using ethyl monate (ethyl)K to obtain 1.27μ of the title compound as an oil. Yield 82.6% NMR (CDCI, -TMS) δ: 0.30-3
．． 00 (17H1m) 3.00-4.90 (38, m) 6.00-6.30 (IH, m) 7.30-7.70 (IH, m) Reference example 6 4- n-butyl-2 -chloro-4-hydroxy-2-
Cyclopenten-1-one (II-1). 4-n-Butyl-4-(tetrahydropyran-2-yloxy)-2-cyclopenten-1-one 3.27! j
, chlorine 2.9. to a solution of methylene chloride 6517. ! 9 was blown at -10°C to 0°C for 90 minutes. Then add 2.839 g of triethylamine and heat at 0°C for 15 min.
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 a separation and purification operation using silica gel and n-hexane:ethyl acetate) to obtain 48 g of the title compound 1 in the form of an oil. Yield 56.9% NMR (CDCI, -TMS) δ: 0.30-15
0 (9H,m) Z67 (2)(,S) 3.20 (IH,s') 7.43 (IH,s) Reference Example 7 4-n-Butyl-2-chloro-4-(tetrahydropyran- 2-yloxy)-2-cyclopenten-1-one (If-2). 4-n-7'thyl-2-chloro-4-hydroxy-
2-cyclopenten-1-one 7,10.9, methylene chloride 100117, 2,3-dihydropyran 4.759
, 30 m9 of paratoluenesulfonic acid monohydrate (Da metal) 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 gel,
The mixture was separated and purified using n-hexane:ethyl acetate) to obtain 6.15 g of the title compound as an oil. Yield 59.9
%NMR(CDCIsTMS)δ:0
．． 70-3.00 (17H, m) 3.00-5.5
0 (3H, m) 7.30-7.60 (IH, m) Reference example 8 5.5-dibromo-1,4-dihydroxy-3-fluoro-2-cyclopentenecarboxylic acid (Xll) 4-fluorophenol 50 g was dissolved in 800 d of 5N aqueous sodium hydroxide solution and heated to about 10°C to dissolve bromine 285.19. f9
was added dropwise, followed by stirring at the same temperature for 20 minutes. Then, the reaction solution was mixed with a mixture of ethyl acetate and ethyl ether (1:1).
Washed three times with 200 ml. Concentrated hydrochloric acid 200117 in the aqueous phase
was added, and further salt was added to saturate the mixture. The mixture was then extracted six times with 200 ml of ethyl acetate, and the mixture was dried over anhydrous magnesium sulfate. Residue obtained by distilling off the solvent 94.08
g by column chromatography (silica gel, Merck 7
734, n-hexane:ethyl acetate-1:1, formic acid 5%
) to separate and purify the title compound as a solid 43.
I got 09 f:. Yield 30.1% NMR (DM80-d
6TMS) δ: 4.97 (IH, d, J = 3H
z ) 5.40 (it(, bs ) 5.90 (3H, bs 0)1x2, C00H)
"j0'-' , 3400, H40.1620IRsimax fl"7F+ Reference Example 9 Methyl 5,5-dibromo-1,4-dihydroxy-3-
Fluoro-2-cyclopentenecarboxylate) (X
I) 20.62 m of acetyl chloride was added to a solution of 5.5-dibromo-1,4-dihydroxy-3-fluoro-2-cyclopentene carbon [43, OS 1 and 400 d of methanol, and the mixture was heated under reflux for 2 hours. Next, methanol was distilled off, and the resulting residue was subjected to separation and purification by column chromatography (silica gel Merck 7734, n-hexane-ethyl acetate) to obtain the title compound as a solid 43.5'H7.
I got it. Yield 96.7%. This was recrystallized from carbon tetrachloride to form crystals at mp, 8Q-80.5°C. NMR (CDCI, -TMS) δ: 3.0-4.0 (2H, bs, 0) IX2)3
．． 90 (3HXs) 4.95 (IH, dd, J = 1.5Hz, 3H
z) 5.35 (IH, t, J = 1.5) 1z
) Reference Example 10 Methyl 3-chloro-5,5-dibromo-1°4-dihydroxy-2-cyclopentenecarboxylate) (Xi
) H Parachlorophenol 2.5717 was dissolved in 2.5N aqueous sodium hydroxide solution 70a7 and brought to about 0°C. Bromine IZ785.9 was then added dropwise at about 0° C. over 30 minutes, and the mixture was further stirred at the same temperature for 10 minutes. Next, 50 ml of concentrated hydrochloric acid was added, and the mixture was extracted with ethyl acetate. After drying the extract over anhydrous magnesium sulfate, the solvent was distilled off to obtain 3-chloro-5,5-dibromo-1,4-dihydroxy-2-cyclopentenecarboxylic acid 117. Next, 50 d of methanol was added to this to dissolve it, and 0.92117 d of acetyl chloride was added and refluxed for 2 hours. The insoluble matter was filtered with 1 methanol and the solvent of the resulting slurry was distilled off, and the resulting residue was subjected to column chromatography (silica gel, Merck 7734, n-hexane-ethyl acetate (2:1)). After performing separation and purification operations, 2.438 g of crystals of the title compound were obtained. Yield 34%IRv nuj
"cm-': 3450.1720maX NMR (CDCI, -TMS) δ: 3.89 (3H, s) 4.20 (2H, bs, 0Hx2) 4.89
(IH,,d,J=1.8Hz)5.90 (IH
, d, J=1.8Hz) Reference Example 11 Methyl 5,5-dibromo-3-fluoro-1-hydroxy-4-oxo-2-cyclopentenecarboxylate (X) 〇Lithium trioxide 19.509.2 .5 M sulfuric acid 91a/
17) A solution of 43.57,9 methyl 5,5-dibromo-1,4-dihydroxy-3-fluoro-2-cyclopentenecarboxylate and 130 d of acetone was added to the solution, and the mixture was stirred at 40 to 50°C for 2 hours. Next, 5.47 at of Improper Tool was added and stirred. After distilling off the volume W of the reaction solution, common salt was added to saturate the solution. Next, extract with ethyl acetate, wash the extract with brine,
It was dried with anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography (silica gel,
Merck 7734, n-hexane-ethyl acetate (2:1)
) to obtain 23.00 g of the title compound as an oil. Yield 53% i1m IRv crn-': 3450,1740,
1650aX NMR (CDCI 3-TMS) δ: 3.90 (
3H,,S) 5.00 (IH, bs, 0H) 6.73 (IH, s) Reference example] 2 Methyl 3-chloro-5,5-dibromo-1-hydroxy-4-oxo-2-cyclopentenecarboxy rate(
X) 1.0449 chromium trioxide was dissolved in 5 d of 2.5 M sulfuric acid and added with water. Next, a vinegar solution of 4438 L of methyl 3-chloro-5,5-dibromo-1,4-dihydroxy-2-cyclobentencarboxylate (7 d of acetone) was added, and the mixture was stirred for 5 minutes while cooling with water. After further stirring for 60 minutes at room temperature, 1 ml of isopropanol was added and stirred. Then, after distilling off the acetone, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to column chromatography (silica gel, Merck 7734,
Separation and purification using n-hexane-ethyl acetate (2:1) gave 1.0797 crystals of the title compound. Yield 44.5%. mp106-107.5 °C I) also synnuj0'cm-': 3400,
1740, 1600laX NMR (CDCI, -TMS) δ: 3.85 (3H, s) 4.65 (IH, bs, 0H) 7.13 (IH, s) Reference Example 13 Methyl 3-fluoro-1-hydroxy- 4-oxo-2
- cyclopentene carboxylate zinc - copper casopurus 2.76, g+ in methanol 9 Q
Add at and stir, then add methyl 5,5-dibromo-
A solution of 9 Q ml of 11.619° methanol was added. Since it generated heat and reached 45°C, it was cooled to room temperature and stirred for 15 minutes. The reaction solution was then filtered. The obtained solution F was concentrated, and then 50 ml of water and 701 liters of 3N hydrochloric acid were added, and the mixture was further saturated with sodium chloride. It was extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography (silica gel Merck 7734, n-hexane-ethyl acetate (2
:1)) to obtain 2121 g of the title compound as a solid. Yield 32.0% i1m IRl'cm-': 3450.1760.
1650aX NMR (CDCI, -TMS) δ: 2.75 (
2T-I, q, J = 18.5Hz, 38Hz
) 3.80 (3H,s) 4.50 (n4, bs, 0H) 6.80 (IHLS) Preparation of zinc-copper couple Cupric acetate2. oo! q, acetic acid]QQa/100-1
It was heated to 05°C to dissolve it. Next, zinc powder 2o, o
o9 was added and refluxed for 2 minutes. Then, the solid zinc-copper couple obtained by hot filtration was diluted with 5Qaj of acetic acid.
After washing twice and then twice with ether 5Qs4,
Vacuum dried. 100% yield Reference J, O, C, .
39, 2300 (1974) Tetrahedron
Letters, 1539 Reference Example 14 Methyl 3-/Clo 1-hydroxy-4-oxo-2-
Cyclopentene carboxylate (■-1) Zinc-copper couple 0.108. ! ; 5d methanol to I
was added and stirred, and then 0.522E of methyl 3-chloro-5°5-dibromo-1-hydroxy-4-oxo-2-cyclopentenecarboxylate was added. Add a solution of 5 liters of methanol and stir for 15 minutes. During this time, he developed a fever of 40°C in the trench. Insoluble matter was separated from door to door. The residue obtained by distilling off the solvent of the P solution was subjected to separation and purification by column chromatography (silica gel, Merck, 7734, n-hexane-ethyl acetate (2:1)) to obtain the title compound 0.06519. I got it. Yield 23% NMR (CDCI, -TMS) δ: 2.86 (2H,q, J=18Hz) 3.50
(IH, bs, 0H) 3.85 (3HXs) 7.29 (IHl S) Licensed person: Japan Pharmaceutical Industry Co., Ltd. Representative Patent attorney: Taira Odajima 1 non-confessional procedural amendment letter May 10, 1986 Japan Patent Office *11 Letter 1 f Department 1, Indication of case 1985 %r+&fi 俤252E+25 2, Title of invention 2-Hello 2-Cyclobentenone conductor and mo kt Table 3, Amendment person case Relationship with Patent Applicant Name: b Hon Medical Products Co., Ltd. (Name) 4. Agent: 107 Phone: 585-2256
Name 1 Attachment (I) The statement in the “% Revised Claims” column of the specification,
The following corrections are made. 1. The following formula [11 In the formula, X represents a halogen atom;
represents a straight-chain or branched alkyl group, a cycloalkyl group, or a benzyl group which may have a substituent], 5 represents a hydrogen atom or a lower alkyl group, R2 represents an acyloxy group, R4 represents a hydrogen atom or a protecting group for a hydroxyl group, and in the formula, == represents a single bond or a double bond; when a single bond is shown, FiQ is OH; when it is a double bond, FiQ is OH; A 2-no-rho-2-cyclobentenone derivative represented by the following atoms and pharmaceutically acceptable salts thereof. 2, the following formula (III, where X represents a halokene atom, R represents an alkyl group or a group -COOR1 [where R
represents a straight-chain or branched alkyl group, a cycloalkyl group, or a pentyl group which may have a substituent], and 2-halo 4 represented by R, Fi represents a hydrogen atom or a protecting group for a hydroxyl group A formula characterized by reacting 4-i11-substituted-2-cyclobentenone with an aldehyde visiting conductor represented by the following formula [ml, where R1 represents a lower alkyl group and R1 represents an acyloxy group. In tIl, the following formula Cl-11, where X, R, R,, R, and R4 are as defined above,
In the formula, == indicates a single bond or a double bond, Q is OB when a single bond is indicated, and q is OB when a double bond is indicated.
is a hydrogen atom, and a method for producing a 2-halo-2-cyclobentenone derivative and its pharmaceutically acceptable salts. 6. In the formula [l-11, the following formula (I-1α) 0B However, in the formula, X represents a halokene atom, R is an alkyl group or a group -COOR,
5 represents a straight-chain or branched alkyl group, a cycloalkyl group, or a pentyl group which may have a substituent], R1 represents a lower alkyl group, 5 represents an acyloxy group, and R4 represents In formula (I-1), which is characterized by subjecting a 2-norlow 2-cyclobentenone derivative represented by which represents a protecting group for a hydrogen atom or a hydroxyl group to a dehydration reaction, the following formula (I
A method for producing a 2-halo-5-alkylidene-2-cyclobentenone derivative and its pharmaceutically acceptable salts, represented by -1b1, where XXR, R, , R, and R4 are as defined above. 4. In the formula tI-11, the following formula (I-1αb) is provided, where,
R1 represents a lower alkyl group, R3 represents an acyloxy group, R4 represents a hydroxyl group protection represents a group, and in the formula, =-1 represents a single bond or a double bond; when a single bond is represented, VCdQ is OH; when a double bond is represented, Q is a hydrogen atom; - Formula (I-1
1, the following formula (I-21, where X, R, R1, R, and 7τ= have the same meanings as above, 5. In the formula (I-11, the following formula (I-21), where
represents a straight-chain or branched alkyl group, a cycloalkyl group, or a benzyl group which may have a substituent], R1 represents a lower alkyl group, R1 represents an acyloxy group, and = represents a single Indicates a bond or double bond; when a single bond is indicated, it is QViOH, and when it is a double bond, it is QViOH.
is a hydrogen atom, and the following formula (I-31, where X, R, R, and T-:= have the same meanings as above, and are expressed as 2-].] Process for producing rho-2-cyclobentenone derivatives and pharmaceutically acceptable salts thereof.'' [■] Specification 1
The description in the "Detailed Description of the Invention" column is corrected as follows. (1) On the last line of page 16 of the specification, the words "Rt, Rt and ==" are corrected to "RI and R7 are". do. (2) In the formula tIll on page 31, line 6 of the specification box, on the right end,
The part that says ``coOR,J'' is corrected to ``C'0OHJ.'' (3) In the fifth line from the bottom of page 51 of the specification, the phrase ``RI indicates a lower alkyl group'' is deleted. 14) On page 38, line 2 of the specification, “R4” is written,
(5) In the second line from the bottom to the last line of Specification No. 59, the phrase "R1 represents a hydrogen atom" is corrected to read "R represents an alkyl group." (6) Specification page 59, lines 4-5 and page 60, lines 13-14
In the rows, "3-looptyl-5-5-butyltmethylsilyloxy-3-" is replaced with "2-looptyl-5-5-butyltmethylsilyloxy-3-".
4-tertiary gtyltmethylsilyloxy-2-". (7) In line 2 of the 67th member of the specification, the phrase "・Zera chlorophenol" is corrected to "Zera chlorophenol."

Claims (1)

[Claims] 1. The following formula (I) ▲There are numerical formulas, chemical formulas, tables, etc.▼...(I) However, in the formula, X represents a halogen atom, and R represents an alkyl group or a group -COOR_3 [here So, 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 hydrogen atom or a lower alkyl group, R_2 represents an acyloxy group, R_4 represents a hydrogen atom or a protecting group for a hydroxyl group, and in the formula, ■ represents a single bond or a double bond, when a single bond is represented, Q is OH, and when a double bond is represented, Q is a hydrogen atom. A 2-halo-2-cyclopentynone derivative and pharmaceutically acceptable salts thereof, represented by the following. 2. Formula (II) below ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(II) 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 which may have a substituent], and R_4 represents a hydrogen atom or a hydroxyl group-protecting group, 2-halo- 4,4-Substituted-2-cyclopentenone and the following formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼...(III) However, in the formula, R_1 represents a lower alkyl group, and R_2 represents an acyloxy group. In the formula (I), which is characterized by reacting an aldehyde derivative represented by, the following formula (I-1)▲There are numerical formulas, chemical formulas, tables, etc.▼...(I-1) However, in the formula, X, R, R_1, R_2 and R_4 have the same meanings as above, 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 OH; Q is a hydrogen atom, A method for producing a 2-halo-2-cyclopentenone derivative and pharmaceutically acceptable salts thereof. 3. 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, 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 which may have a substituent], R_1 represents a lower alkyl group, R_2 represents an acyloxy group, and R_4 represents hydrogen In formula (I-1), the following formula (
I -1b), ▲There are mathematical formulas, chemical formulas, tables, etc.▼...( I -1b
) In the formula, X, R, R_1, R_2 and R_4 have the same meaning as above. A method for producing a 2-halo-5-alkylidene-2-cyclopentanone derivative and its pharmaceutically acceptable salts. 4. In formula (I-1), the following formula (I-1ab)▲mathematical formula,
There are chemical formulas, tables, etc.▼...(I-1ab) 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 which may have a substituent], R_1 represents a lower alkyl group, R_2 represents an acyloxy group, and R_4 represents 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; Formula (I-1) characterized by subjecting a 2-halo-2-cyclopentenone derivative to a deprotecting group reaction
), the following formula ( I -2) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼... ( I -2) However, in the formula, X, R, R_1, R_2 and ■ have the same meaning as above, and are represented by A method for producing a 2-halo-2-cyclopentenone derivative and its pharmaceutically acceptable salts. 5. 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 the group -COOR_3 [where 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, R_2 represents an acyloxy group, and in the formula 2-halo-2-cyclopentenone represented by: represents a single bond or a double bond, Q is OH when represents a single bond, and Q is a hydrogen atom when represents a double bond The formula (I-1) characterized in that a derivative is subjected to a hydrolysis reaction
), the following formula ( I -3) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼... ( I -3) However, in the formula, X, R, R_2 and ■ have the same meanings as above, 2- represented by A method for producing halo-2-cyclopentenone derivatives and pharmaceutically acceptable salts thereof.