JPH0466853B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [In the formula, R ¹ represents an optionally protected hydroxymethyl group, an optionally protected formyl group, an optionally protected carboxy group, or an optionally substituted carbamoyl group, and R ² and R ³ are the same or Differently represents a protecting group for a hydrogen atom or a hydroxyl group, ^R4 is an optionally substituted alkyl group, alkenyl group, alkynyl group, an optionally substituted cycloalkyl group,
or a group of the formula -CH ₂ -Q-R ⁵ (wherein Q is a single bond,
represents an oxygen atom, a sulfur atom, or a methylene group,
R ⁵ represents an optionally substituted cycloalkyl group or aryl group. ), A represents an oxymethylene group (-O-CH ₂ -), a thiomethylene group (-S-
CH ₂ -) or a vinylene group, B represents an ethylene group, a trans-vinylene group, or an ethynylene group, n represents an integer of 2 to 4, n' represents an integer of 0 to 4, and the dotted line represents the 2-position Or it shows a double bond at the 3rd position. However, when A represents a vinylene group, n' represents 0. ] and a pharmacologically acceptable salt thereof. In the above formula, R ¹ is a protecting group for the hydromethyl group, R ² or R ³
The hydroxyl-protecting group is not particularly limited as long as it is a commonly used hydroxyl-protecting group, but examples include acetyl, propionyl, butyryl, isobutyryl,
Lower aliphatic or aromatic acyl groups such as benzoyl, naphthoyl; aralkyl groups such as benzyl, p-nitrobenzyl, p-methoxybenzyl; 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 4-methoxytetrahydropyran-
5-6 containing an oxygen atom or a sulfur atom in the ring with or without an alkoxy group as a substituent such as 4-yl, 2-tetrahydrothiopyranyl
Member cyclic heterocyclic group; Methyl group having an alkoxy group or aralkyloxy group as a substituent such as methoxymethyl, ethoxymethyl, and benzyloxymethyl; 1-alkoxyethyl group such as 1-methoxyethyl and 1-ethoxyethyl or tri-lower alkyl or diaryl-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl, tri-n-propylsilyl, t-butyldimethylsilyl, diphenyl-t-butylsilyl, and preferably the hydroxymethyl group in R ¹ The protecting group is an aralkyl group, and R ²
and the protecting group for the hydrogen group of R ³ is a 2-tetrahydropyranyl group or a 2-tetrahydrofuranyl group. The protecting group for the formyl group in R ¹ is not particularly limited as long as it is a commonly used protecting group for the formyl group, but for example,

[Formula] Group or formula

[Formula] Group (wherein R represents a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and T represents ethylene, propylene, trimethylene, butylene, tetramethylene, 2,2-dimethyl It represents an alkylene group having 2 to 5 carbon atoms such as trimethylene, and Y represents an oxygen atom or a sulfur atom). The carboxyl group-protecting group for R ¹ is not particularly limited as long as it is a commonly used carboxy group-protecting group, but examples include methyl, ethyl, n-propyl,
Preferred examples include lower alkyl groups such as isopropyl, n-butyl, and t-butyl; aralkyl groups such as benzyl and p-bromobenzyl; aryl groups such as phenyl and tolyl; benzhydryl group or phenacyl group. is a lower alkyl group. Examples of the optionally substituted carbamoyl group for R ¹ include a carbamoyl group and a mono- or di-substituted carbamoyl group, and examples of the substituent include methyl, ethyl, n-propyl, isopropyl, and n-butyl. Preferred examples include lower alkyl groups such as phenyl, aryl groups such as tolyl, acyl groups such as acetyl, trifluoroacetyl, and benzoyl, and sulfonyl groups such as methanesulfonyl, benzenesulfonyl, and p-toluenesulfonyl. is a carbamoyl group or a methanesulfonylcarbamoyl group, particularly preferably a methanesulfonylcarbamoyl group. Examples of the alkyl group of R ⁴ which may be substituted include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n
-bentyl, isopentyl, 1-methylpentyl, 2-methylpentyl, n-hexyl, n-heptyl, 1,1-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 2-ethylpentyl, n-octyl, 2 -methyloctyl, n-
Examples include alkyl groups having 1 to 12 carbon atoms such as nonyl, 2-methylnonyl, 2-ethyloctyl, n-decyl, 2-methyldecyl, and 2-ethyldecyl, preferably 4 to 10 carbon atoms.
, such as n-butyl, isobutyl, n-pentyl, isopentyl, 1-methylpentyl, 2-methylpentyl, n-hexyl, n-heptyl, 1,1-dimethylpentyl,
1-methylhexyl, 2-methylhexyl, 2-
Ethylpentyl, n-octyl, 2-methyloctyl or 2-ethyloctyl group, more preferably n-pentyl, 1-methylpentyl, n
-hexyl, 1,1-dimethylpentyl, 1-methylhexyl group or 2-methylhexyl group. Examples of the optionally substituted alkyl group of ^R4 include halogen atoms such as fluorine, chlorine, and bromine, and lower alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. Preferably, it is a fluorine atom, a chlorine atom, or a methoxy group. Examples of the alkenyl group for R ⁴ include 1-butylvinyl, allyl, 2-propylaryl, 2-butenyl, 2-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl -4-pentenyl, 4-hexenyl, 5-hexenyl, 1,4-dimethyl-3-pentenyl, 5-heptenyl, 1-methyl-5-hexenyl, 6-methyl-5-heptenyl, 2,6
-dimethyl-5-heptenyl, 1,1,6-trimethyl-5-heptenyl, 6-methyl-5-octenyl, 2,6-dimethyl-5-octenyl, 6
-ethyl-5-octenyl, 2-methyl-6-ethyl-5-octenyl, 2,6-diethyl-5-
Examples include linear or branched alkenyl groups having 3 to 12 carbon atoms such as octenyl, preferably 1-butylvinyl, 2-propylaryl, 2-pentenyl, 4-pentenyl,
2-methyl-3-pentenyl, 4-methyl-3-
Pentenyl, 1-methyl-4-pentenyl, 4-
Carbon numbers such as hexenyl, 5-hexenyl, 1,4-dimethyl-3-pentenyl, 5-heptenyl, 1-methyl-5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl 5 to 9 alkenyl groups. Examples of the alkynyl group for ^R4 include propargyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl , 1,1-dimethyl-2-pentynyl, 1,1-dimethyl-3-pentynyl,
Examples include alkynyl groups having 3 to 8 carbon atoms such as 1,1-dimethyl-2-hexynyl, and preferably alkynyl groups having 4 to 6 carbon atoms, such as 2-butynyl and 2-pentynyl. , 3-pentynyl, 1-methyl-2-pentynyl group or 1-methyl-3-pentynyl group, and more preferably 1-methyl-3-pentynyl group. Examples of the optionally substituted cycloalkyl group for R ⁴ and R ⁵ include lower alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, 3-ethylcyclopentyl, cyclohexyl, 4-methylcyclohexyl, and cycloheptyl. Examples include a 3- to 7-membered cycloalkyl group, which may be a cyclopentyl group or a cyclohexyl group. The aryl group for ^R5 is phenyl, o-tolyl, m-tolyl, p-tolyl, p-ethylphenyl, m-n-propylphenyl, m-methoxyphenyl, p-methoxyphenyl, o-ethoxyphenyl. enyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, m-chlorophenyl, p-chlorophenyl, p-bromophenyl, p-trifluoromethylphenyl, 3,4-
A phenyl group which may have 1 or 2 lower alkyl, lower alkoxy, halogen atoms or trifluoromethyl as a substituent, such as dimethylphenyl, 3-fluoro-4-methylphenyl, 2,4-dichlorophenyl. Among these, a phenyl group which may be substituted with methyl, a fluorine atom, a chlorine atom, or a trifluoro group is preferred, and a phenyl group is more preferred. Q is preferably a single bond, an oxygen atom or a methylene group, and more preferably a single bond or an oxygen atom. Further, suitable _-CH2- Q- ^R5 groups include, for example, cyclopentylmethyl, cyclohexylmethyl, 4-methylcyclohexylmethyl, benzyl, p-methylbenzyl, m-trifluorobenzyl, 2-cyclopentylethyl, 2-( 3-methylcyclopentylethyl), 2-cyclohexylethyl, 2-phenylethyl, 2-(p-fluorophenyl)ethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, phenoxymethyl, m-tolyloxymethyl, p-chlorophenoxymethyl, Alternatively, phenylthiomethyl can be mentioned. A is preferably an oxymethylene group or a thiomethylene group. B is preferably a trans-vinylene group. n is preferably an integer of 2 and n' is preferably 0.
or 2, more preferably 0. The double bond within the ring is preferably at the 2-position. Among the compounds of the present invention having the general formula (), the compound in which R ¹ is a carboxy group can be converted into a pharmacologically acceptable salt form, if necessary.
Examples of pharmacologically acceptable salt forms include salts of alkali metals or alkaline earth metals such as sodium, potassium, magnesium, and calcium; ammonium salts; tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, and phenyltriethylammonium; Quaternary ammonium salts such as methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, N-methylhexylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, ethylenediamine salts of lower aliphatic, lower alicyclic and aralkyl amines; piperidine, morpholine,
Salts of heterocyclic amines and their lower alkyl derivatives such as pyrrolidine, piperazine, pyridine, 1-methylpiperazine, 4-ethylmorpholine; hydrophilic salts such as monoethanolamine, ethyldiethanolamine, 2-amino-1-butanol Examples include salts of amines containing groups such as Moreover, the compound () of the present invention has α-, β-, γ
- It is also possible to form an inclusion compound with a host compound such as cyclodexrin and use it. In addition, in the compound having the above general formula (), the coordination of the hydroxyl group on the side chain of the cyclopentane ring, etc.
When R ⁴ is an alkenyl group, there are stereoisomers based on the double bond as well as positional isomers based on the double bond within the cyclopentene ring. Therefore, when the compound having the general formula () is obtained as a mixture of these stereoisomers, each isomer can be obtained by separation and resolution using conventional methods. In the general formula (), a mixture of these optical isomers and stereoisomers is all represented by a single formula, but the scope of the description of the present invention is not limited thereby. In addition, in the general formula (), suitable compounds include (1) a hydroxymethyl group in which R ¹ may be protected;
A compound that is an optionally protected carboxy group or an optionally substituted carbamoyl group, (2) R ¹ is a hydroxymethyl group, an optionally protected carboxy group, or a methanesulfonylcarbamoyl group, and R ² and R ³ are Compounds in which R ⁴ is a hydrogen atom, (3) an alkyl group having 4 to 10 carbon atoms which may be substituted with a halogen atom or a lower alkoxy group, an alkenyl group having 3 to 12 carbon atoms, and an alkenyl group having 4 to 12 carbon atoms; an alkynyl group having 6 atoms, a 5- to 6-membered cycloalkyl group, or a group of the formula -CH ₂ -Q-R ⁵ (wherein, Q is a single bond, an oxygen atom, or a methylene group, and R ⁵ is 5 to 6 A is a membered cyclic cycloalkyl group or a phenyl group optionally substituted with a lower alkyl group, a halogen atom, or a lower alkoxy group. ) A compound in which the double bond is at the 2-position, (6) a compound in which n' is 0, (7) a compound in which R ¹ is a hydroxymethyl group, an optionally protected carboxy group, or a methanesulfonylcarbamoyl group, and R ² and R ³ is a hydrogen atom,
an alkyl group having 4 to 10 carbon atoms, an alkenyl group having 3 to 12 carbon atoms, an alkynyl group having 4 to 6 carbon atoms, where R ⁴ may be substituted with a halogen atom or a lower alkoxy group;
5- to 6-membered cycloalkyl group or formula -
CH ₂ -Q-R ⁵ (wherein, Q is a single bond, an oxygen atom or a methylene group, and R ⁵ is substituted with a 5- to 6-membered cycloalkyl group, a lower alkyl group, a halogen atom, or a lower alkoxy group) ), A is an oxymethylene group, a thiomethylene group or a vinylene group, and B is a trans-vinylene group,
A compound in which n' is 0, (8) R ¹ is a hydroxymethyl group or a carboxy group that may be protected, R ² and R ³ are hydrogen atoms, and R ⁴ is a fluoro atom, a chlorine atom, or a methoxy group 4 to 10 carbon atoms, which may be substituted with
an alkyl group having 3 to 12 carbon atoms, an alkynyl group having 4 to 6 carbon atoms, a 5- to 6-membered cycloalkyl group, or a cycloalkyl group of the formula -CH ₂ -Q-R ⁵ (in the formula, Q is a single bond or an oxygen atom, and R ⁵ is a 5- to 6-membered cyclic cycloalkyl group or a phenyl group that may be substituted with a methyl group, a fluoro atom, a chloro atom, or a methoxy group), and A is an oxymethylene group or a thiomethylene group, and B is a trans-
A compound that is a vinylene group, n is an integer from 2 to 4, and n' is 0, (9) R ¹ is a hydroxymethyl group, carboxy group, or methoxycarbonyl group, and R ² and R ³ are hydrogen atoms. and R ⁴ is an alkyl group having 4 to 10 carbon atoms, an alkenyl group having 3 to 12 carbon atoms, an alkynyl group having 4 to 6 carbon atoms, a 5- to 6-membered cycloalkyl group, or - CH ₂ -Q-R ⁵ group (wherein R ⁵ is a cyclopentyl group, cyclohexyl group or phenyl group, and Q is a single bond or an oxygen atom),
A is an oxymethylene group or a thiomethylene group, B is a trans-vinylene group, and n is 2
is an integer, n' is 0, and the double bond in the ring is in the 2nd position. Recently, prostacyclin (PGI ₂ ), which exhibits a strong platelet aggregation inhibitory effect, has been discovered and its physiological effects have attracted attention, and many groups have been conducting research on related compounds. When novel carbacycline derivatives represented by the general formula () were synthesized and their pharmacological activities were investigated, these derivatives showed excellent platelet aggregation inhibiting action, coronary vasodilatory action, bronchodilator action, anti-ulcer action, etc. The present invention was developed based on the discovery that prostacyclins exhibit particularly strong activity in inhibiting platelet aggregation, have remarkable persistence of activity compared to conventional prostacyclins, and are important intermediates for the synthesis of active compounds. completed. Examples of the compound having the general formula () obtained by the present invention include the compounds described below.

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[Table] In the table, t-Bu represents a t-butyl group. Furthermore, among all the compounds in the above table, compounds in which A is an oxymethyl group, a thiomethyl group, or a vinylene group can be mentioned. Furthermore, for compounds where R ¹ is a carboxy group,
Mention may be made of its sodium or potassium salts. Furthermore, in all the compounds in the above table, n' represents 0, but also compounds 2, 8, 11, 38,
Regarding 40, 41, 51, 63, 67 and 76, compounds in which A is an oxymethyl group or a thiomethyl group and n' is an integer of 2 are also suitable. The compound () according to the present invention can be produced according to the following method. A law B method C law In the above formula, R ¹ , R ² , R ³ , R ⁴ , B, n, n' and the dotted line have the same meanings as described above, R ⁶ represents a carboxyl group that may be protected, R ⁷ and R ⁸ represents a hydroxyl protecting group, R ⁹ represents methanesulfonyl,
It represents an alkanesulfonyl group such as ethanesulfonyl or an arylsulfonyl group such as benzenesulfonyl or p-toluenesulfonyl, R ¹⁰ represents a lower alkyl group or an aryl group, W represents a sulfur atom or a zelene atom, and m represents 1 Indicates an integer between 3 and 3. Method A is a method for producing compound (Ia) in which A is an oxymethylene group. The first step is to produce an alcohol derivative having the general formula (), and is achieved by contacting the compound () with a reducing agent in an inert solvent. The reducing agent used is not particularly limited as long as it converts a carboxy group or ester group into a hydroxymethyl group, but lithium borohydride, sodium borohydride-aluminum chloride, and boron trihydride-cyclohexyl are preferably used. Examples include boron compounds such as amines or aluminum compounds such as lithium aluminum hydride, lithium aluminum hydride-aluminum chloride, and diisobutylaluminum hydrogen.
Particularly preferred is lithium aluminum hydride. The inert agent used is not particularly limited as long as it does not participate in the reaction, but preferably ether,
Ethers such as tetrahydrofuran and dioxane. The reaction temperature is 0°C to 50°C, and the time required for the reaction is usually 30 minutes to 3 hours. After the reaction is completed, the reaction target product is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding a dilute aqueous sodium hydroxide solution or ice water to the reaction mixture, extracting with a water-immiscible organic solvent, and distilling off the organic solvent. Furthermore, if necessary, it can be further purified by conventional methods such as column chromatography, recrystallization, etc. In addition, the compound () is used in the 11th to 22nd steps described below.
It can also be manufactured separately depending on the process. The second step is a step of producing a compound having the general formula (), in which the compound () is treated with a base in an inert solvent, and then the general formula X- _CH2- ( _CH2 ) _o' - ^R6 ... () (In the formula, R ⁶ and n' have the same meanings as defined above, and X represents a halogen atom such as chlorine, bromine, or iodine.) or an alkali metal salt thereof. It is achieved by doing so. Bases used include, for example, alkali metal hydride compounds such as lithium hydrogen, sodium hydrogen, and potassium hydrogen; alkaline earth metal hydride compounds such as calcium hydrogen and barium hydrogen; methyllithium, n-butyllithium, and phenyllithium. or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, potassium t-butoxide, and sodium t-pentoxide; preferably, It is an alkali metal hydride. The inert solvent used is not particularly limited as long as it does not participate in the reaction, but for example, hexane,
Hydrocarbons such as benzene, toluene, xylene; ethers such as ether, tetrahydrofuran, dimethoxyethane, diglyme; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoryltriamide;
Alternatively, sulfoxides such as dimethyl sulfoxide or mixed solvents thereof can be mentioned, but amides, sulfoxides or mixed solvents thereof are preferable. The reaction temperature is -78℃ to 78℃ for reactions with bases.
50℃, and 0 in the reaction with compound ()
℃ to 50℃. The time required for the reaction is 10 minutes to 1 hour for the reaction with a base, and 1 hour to 48 hours for the reaction with the compound (). After the reaction is completed, the reaction target product is collected from the reaction mixture according to a conventional method. For example, it can be obtained by pouring the reaction mixture into water, making it acidic if necessary, extracting it with a water-immiscible organic solvent, and distilling off the organic solvent. Furthermore, if necessary, it can be further purified by conventional methods such as column chromatography, recrystallization, etc. The third step is a step carried out as desired, including a reaction for removing the protecting group for the hydrogen group of R ⁷ and/or R ⁸ , a reaction for removing the protecting group for the carboxy group contained in R ⁶ , and a reaction for removing the protecting group for the carboxy group contained in R ⁶ .
reaction to convert the obtained hydroxymethyl group into a formyl group (including reactions to protect it), reaction to esterify the carboxy group of ^R6 , or carboxy or ester may be substituted. Includes a reaction that converts into a carbamoyl group. When the hydroxyl protecting group is a lower aliphatic or aromatic acyl group, its removal is carried out by a conventional hydrolysis reaction. As the acid or base used, acids or bases used in general hydrolysis reactions are used without particular limitation, but usually, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, hydroxide It is preferably carried out under basic conditions using alkali metal and alkaline earth metal hydroxides such as barium.
The solvent used is not particularly limited to those used in hydrolysis reactions, such as alcohols such as methanol, ethanol, n-propanol, and isopropyl alcohol; ethers such as ethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. Examples include dialkyl sulfoxides such as dimethyl sulfoxide and mixed solvents of these organic solvents and water. The reaction temperature is not particularly limited, and is usually carried out at around room temperature to the reflux temperature of the solvent. The reaction time varies depending on the reaction temperature, etc., but is usually 1
The duration is between 12 hours and 12 hours. At this time, if the protecting group for the carboxy group is a lower alkyl group or an aryl group, it is removed at the same time. In the case of an aralkyl group protecting a hydroxyl group, this is achieved by contacting the corresponding compound with a reducing agent in an inert solvent. The reducing agent used may include alkali metals such as lithium, sodium, potassium or alkali metal sulfides such as sodium sulfide or potassium sulfide, preferably alkali metals. The reaction with an alkali metal is preferably carried out in liquid ammonia or a mixed solvent of liquid ammonia and an ether such as ether or tetrahydrofuran, and the reaction with an alkali metal sulfide is preferably carried out in an alcohol such as methanol or ethanol, tetrahydrofuran, It is suitably carried out in an ether such as dioxane or a mixed solvent of these organic solvents and water. The reaction temperature is -78°C to -20°C for the reaction with an alkali metal, and 0°C to 100°C for the reaction with an alkali metal sulfide, and the time required for the reaction is usually 20 minutes to 6 hours. In this case, the protecting group for the carboxy group is aralkyl,
In the case of benzhydryl or phenacyl groups, they are removed at the same time. Furthermore, when the protecting group is a p-methoxybenzyl group, it is removed by treatment in cerium ammonium fluoride and aqueous acetone at around room temperature, or by treatment with an oxidizing agent such as dichlorodicyanoquinone or sodium persulfate. is also removed. When the protecting group for the hydroxyl group is a heterocyclic group, a methyl group or a 1-alkoxyethyl group having alkoxy or aralkyloxy as a substituent, this can be easily achieved by contacting it with an acid. Examples of acids used include formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, oxalic acid, malonic acid,
Organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid; mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid are preferably used. The reaction is carried out in the presence or subpresence of a solvent, but in order to carry out the reaction smoothly, it is preferable to use a solvent, and the solvent used is not particularly limited as long as it is not involved in the reaction, such as water. Alcohols such as methanol and ethanol; ethers such as tetrahedrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; or a mixed solvent of these organic solvents and water are preferably used. The reaction temperature is not particularly limited, but is preferably carried out at room temperature to the reflux temperature of the solvent. Further, the time required for the reaction is 30 minutes to 10 hours. When the protecting group for the hydroxyl group is a tri-lower alkyl or diaryl-lower alkylsilyl group, by contacting with water or water containing an acid or a base, or by reacting with a fluoride such as tributylammonium fluoride in an inert solvent. easily achieved. When water containing acids or bases is used, examples of the acids or bases contained include organic acids such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, and malonic acid; hydrochloric acid, hydrobromic acid, and sulfuric acid. Acids such as mineral acids or alkali metal and alkaline earth metal hydroxides such as potassium hydroxide, calcium hydroxide; bases such as alkali metal and alkaline earth metal carbonates such as potassium carbonate and calcium carbonate. Used without particular restrictions. If water is used as a solvent in the reaction with an acid or base, no other solvent is particularly required. When using other solvents, for example, mixed solvents of water and organic solvents such as ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol are used. Solvents used in the reaction with the fluoride are, for example, ethers such as ether, tetrahydrofuran, dioxane. The reaction temperature is not particularly limited, but it is usually suitably carried out at room temperature. The time required for the reaction is 30 minutes to 5 hours. After the reaction is completed, the target compound of the reaction for removing the hydroxyl protecting group is collected from the reaction mixture according to a conventional method. For example, after the reaction is complete, the solvent is distilled off under reduced pressure, or the reaction mixture is poured into ice water without distillation, neutralized as necessary, and then an appropriate organic solvent is added to perform extraction, and the extract is washed with water. After drying,
Obtained by distilling off the solvent from the extract. When R ⁶ and R ⁷ are the same protecting group, they are removed simultaneously by the above-mentioned protecting group removal reaction. Moreover, selective deprotection can also be performed by appropriately selecting a protecting group. When the protecting group for the carboxy group is a lower alkyl group or an aryl group, its removal is carried out by a conventional hydrolysis reaction. This reaction is carried out in the same manner as in the case where the protecting group for the hydroxyl group is an acyl group. When the carboxyl-protecting group is an aralkyl group, benzhydryl group or phenacyl group, the removal reaction is carried out in accordance with the same reaction as in the case where the hydroxyl-protecting group is an aralkyl group. After the reaction is completed, the target compound of the hydrolysis reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the reaction mixture is made acidic, then an appropriate organic solvent is added to perform extraction, the extract is washed and dried, and then the solvent is distilled off from the extract. The reaction for converting R ⁶ into a hydroxymethyl group is carried out in the same manner as in the first step of method A described above. The reaction for converting a hydroxymethyl group into a formyl group is carried out according to the conventional method of oxidizing a primary alcohol to an aldehyde. In this case, R ² and R ³ need to be hydroxyl-protecting groups. Examples of the oxidizing agent used include chromic anhydride, chromic anhydride-pyridine complex salt (Collins reagent), chromic anhydride-concentrated sulfuric acid-water (Jones reagent),
Chromic acids such as sodium dichromate and potassium dichromate; N-bromoacetamide, N-bromsuccinimide, N-bromphthalimide,
N-chloro-p-toluenesulfonamide, N-
Organic active halogen compounds such as chlorobenzenesulfonamide; aluminum alkoxides such as aluminum tert-butoxide and aluminum isopropoxide; dimethyl sulfoxide
Dicyclocarbodiimide; pyridine-sulfuric anhydride, etc. are preferably used. The reaction is suitably carried out in an inert organic solvent,
Solvents used include, for example, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, ether, tetrahydrofuran,
Mention may be made of ethers such as dioxane, ketones such as acetone, methyl ethyl ketone, or sulfoxides such as dimethyl sulfoxide. The reaction temperature is 0°C to room temperature, and the time required for the reaction is usually 30 minutes to 3 hours. After the reaction is completed, the desired formyl compound is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, it can be obtained by pouring into ice water, appropriately neutralizing, extracting with a water-immiscible organic solvent, and distilling off the solvent, unless insoluble matter is present. Furthermore, if necessary, the formyl group is converted into an acetal or thioacetal protecting group according to conventional methods. For example, this can be achieved by reacting the corresponding thiol or alcohol with an acid such as p-toluenesulfonic acid or boron trifluoride. The reaction of esterifying a carboxy group is carried out by contacting it with an esterifying agent in the presence or absence of a solvent. The esterifying agent to be used is not particularly limited, and may be an esterifying agent that is commonly used for converting a carboxyl group into an alkoxycarbonyl group. Examples of the esterifying agent used include diazoalkanes such as diazomethane, diazoethane, diazo-n-propane, diazoisopropane, and diazo-n-butane; methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, etc. alcohols and hydrochloric acid that form an ester group,
Mineral acids such as hydrogen bromide or sulfuric acid or organic acids such as methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; lower alkyl halides such as methyl bromide, ethyl bromide and sodium hydroxide, potassium hydroxide, A base such as sodium carbonate is preferably used. When diazoalkanes are used, the reaction is preferably carried out in the presence of a solvent. The solvent used is not particularly limited as long as it does not participate in this reaction, and examples include ethyl ether,
Ethers such as dioxane are preferred. There is no limit to the reaction temperature, but in order to suppress side reactions and prevent decomposition of diazoalkanes, it is desirable to carry out the reaction at a relatively low temperature, and it is usually preferably carried out under ice cooling. When using an alcohol in the presence of an acid, an excess of the alcohol is usually preferably used as a solvent.
The reaction temperature is not particularly limited, but it is preferably carried out at room temperature or around the reflux temperature of the alcohol used. The reaction time varies mainly depending on the reaction temperature and the type of alcohol used, but is about 1 hour to 2 days. Alternatively, the sodium salt of a carboxylic acid can be combined with a halide such as benzyl bromide, p-methoxybenzyl chloride, phenacyl bromide, benzhydryl chloride and a base such as triethylamine, pyridine, 4-(N,N-dimethylamino)pyridine. The corresponding esters are also prepared by conventional treatment in the presence of . After the reaction is completed, the target compound of the esterification reaction is collected from the reaction mixture according to a conventional method. For example, after the completion of the reaction, the solvent is distilled off from the reaction mixture, and if necessary, the product is further dissolved in an organic solvent, and the organic solvent layer is dissolved in an aqueous alkali carbonate solution such as an aqueous sodium bicarbonate solution or an aqueous sodium carbonate solution. The organic solvent layer is then washed and dried, and then the solvent is distilled off from the organic solvent layer. The reaction of converting the ester into an optionally substituted carbamoyl group is carried out by contacting it with an amine compound in the presence of a solvent. The amine compound used is not particularly limited as long as it is used when amidating an ester group. Amine compounds used include, for example, ammonia or methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, aniline, p-methylaniline, dimethylamine,
Methylethylamine, diethylamine, N-methylaniline, N-ethylaniline, N-methyl-
Primary or secondary amines such as m-methylaniline can be mentioned. The solvent used is not particularly limited as long as it does not take part in the reaction, and examples thereof include water and ethers such as ether, tetrahydrofuran, and dioxane. The reaction is usually carried out at 0°C to 100°C, and the time required for the reaction is 1 to 24 hours. The reaction of converting a carboxy group to an N-acylcarbamoyl group is carried out in an inert solvent by contacting with an acyl isocyanate such as acetyl isocyanate, trifluoroacetyl isocyanate, benzoyl isocyanate. The solvents used are, for example, hydrocarbons such as bezene, toluene, xylene or ethers such as ethers, tetrahydrofuran, dimethoxyethane. The reaction temperature is usually room temperature, and the time required for the reaction is 30 minutes to 10 hours. The reaction for converting a carboxyl group into an N-sulfonylcarbamoyl group involves converting it into an active amide derivative in an inert solvent, and then reacting it with a sulfonic acid amide such as methanesulfonic acid amide, benzenesulfonic acid amide, or p-toluenesulfonic acid amide. It is done by letting Activated amide derivatives are prepared by converting the corresponding compound into N-hydroxylamide such as N-hydroxysucciamide, N-hydroxyphthalamide, etc. in the presence of a condensing agent such as dicyclohexylcarbodiimide.
-Hydroxyamide and usually around room temperature for 30 hours to
Produced by reacting for 10 hours. The reaction between the active amide derivative and the sulfonic acid amide is carried out in the presence of a base such as sodium methoxide, sodium ethoxide or potassium t-butoxide at around room temperature for 30 minutes to 15 hours. Both of the above reactions are preferably carried out in an inert solvent, and the solvents used include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ether, tetrahydrofuran and dimethoxyethane; dimethyl Amides such as formamide and dimethylacetamide; or sulfoxides such as dimethylsulfoxide can be mentioned. After the reaction is completed, the desired amide compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by pouring the reaction mixture into ice water, neutralizing if necessary, extracting with a water-immiscible organic solvent, and distilling off the solvent. Further, if necessary, it can be purified by conventional methods such as silica gel column chromatography and recrystallization. Method B is a method for producing a compound (b) in which A is a thiomethylene group. The fourth step of Method B is a step for producing a sulfonyloxy derivative having the general formula (), and is achieved by reacting the compound () with a sulfonyl halide in an inert solvent. The sulfonyl halide used has the formula R ^9
R9 and X have the same meanings as described above. ), but preferred are methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl bromide, and p-toluenesulfonyl chloride. The reaction is preferably carried out in the presence of a base, and the base used is preferably triethylamine,
N,N-dimethylaniline, pyridine, 4-(N,
N-dimethylamino)pyridine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), and 1,8-diazabicyclo[5.4.0]undecene-7 (DBU). The inert solvent used is not particularly limited as long as it does not participate in the reaction, but examples include hydrocarbons such as n-hexane, cyclohexane, benzene, toluene, and xylene; ethers such as ether, tetrahydrofuran, and dimethoxyethane. or halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride, preferably aromatic hydrocarbons or halogenated hydrocarbons such as benzene and toluene. The reaction temperature is usually around room temperature, and the time required for the reaction is 30 minutes to 10 hours. After the reaction is completed, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by pouring the reaction mixture into ice water, neutralizing if necessary, extracting with a water-immiscible organic solvent, and distilling off the solvent. Further, if necessary, it can be purified by conventional methods such as silica gel column chromatography and recrystallization. The fifth step is a step of producing a compound having the general formula (), in which the compound () is converted to the general formula HS- _CH2- ( _CH2 ) _o' - ^R6 ...() in the presence of a base in an inert solvent. (wherein R ⁶ and n' have the same meanings as defined above). The base and inert solvent used are as described in Method A 2 above.
This is the same as that exemplified in the process. The reaction temperature is 0°C to 100°C, and the time required for the reaction is 30 minutes to 5 hours. After the reaction is completed, the reaction target product is collected from the reaction mixture according to a conventional method. For example, it can be obtained by pouring the reaction mixture into ice water, making it acidic if necessary, extracting it with a water-immiscible organic solvent, and distilling off the organic solvent. Further, if necessary, it can be further purified by conventional methods such as column chromatography, recrystallization, etc. The sixth step is a step carried out as desired, including a reaction for removing the protecting group for the hydroxyl group of R ⁷ and/or R ⁸ , a reaction for removing the protecting group for the carboxy group contained in R ⁶ , and a reaction for removing the protecting group for the carboxyl group contained in R ⁶ .
reaction to convert into a hydroxymethyl group, reaction to convert the obtained hydroxymethyl group into a formyl group (including reaction to protect), reaction to esterify the carboxy group of R ⁶ , or carboxy or ester may be substituted. Includes a reaction that converts into a carbamoyl group. This step is carried out in the same manner as the third step of method A. Method C is a method for producing a compound (c) in which A is a vinylene group and n' is O. The seventh step of method C is a step of producing a compound having the general formula (), in which the general formula (') is prepared in an inert solvent.
After treating a compound having the general formula R ¹⁰ -W-W-R ¹⁰ ... (XI) or R ¹⁰ -W-X ... (XII) with a base, R ¹⁰ , W and X are as described above. This is achieved by reacting with a compound having the same meaning as R ⁶ in compound (') is preferably a protected carboxy group. R ¹⁰ is preferably an aryl group. Examples of the base used include methyllithium, n-butyllithium, s-butyllithium,
Organolithium compounds such as phenyllithium;
dialkylaminolithium such as diisopropylaminolithium, dicyclohexylaminolithium, isopropyl-cyclohexylaminolithium; or bis-such as bis(trimethylsilyl)lithium amide, bis(triethylsilyl)lithium amide, bis(diphenylmethylsilyl)lithium amide Examples include silyllithium amides, and dialkyllithium amides are preferred. Examples of the inert solvent used include ethers such as ether, tetrahydrofuran, dimethoxyethane, and diglyme, and aromatic hydrocarbons such as benzene, toluene, and xylene. Preferably, ethers are used. be. The reaction temperature is -100°C to room temperature for the reaction with a base, and 0°C to 50°C for the reaction with compound (XI) or (XII), and the time required for the reaction is 10 minutes for the former reaction. The reaction time ranges from 30 minutes to 5 hours in the latter reaction. After the reaction is completed, the reaction target product is collected from the reaction mixture according to a conventional method. For example, it can be obtained by pouring the reaction mixture into water, extracting with a water-immiscible organic solvent, and distilling off the organic solvent. Furthermore, if necessary, it can be further purified by conventional methods such as column chromatography, recrystallization, etc. The eighth step is a step of producing a compound having the general formula (), and is achieved by treating the compound () with an oxidizing agent in an inert solvent, followed by heating if necessary. The oxidizing agent used can be, for example, hydrogen peroxide or an organic peracid such as peracetic acid, perpropionic acid, perbenzoic acid, metachloroperbenzoic acid, preferably hydrogen peroxide or metachloroperbenzoic acid. Benzoic acid. Inert solvents used include, for example, aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as ether, tetrahydrofuran, dimethoxyethane and diglyme. ; esters such as ethyl acetate; alcohols such as methanol, ethanol, and n-propanol; water; or a mixed solvent of these solvents, but preferably hydrogen peroxide is used. It is a mixed solvent of water-alcohols-esters, and when an organic peracid is used, it is a halogenated hydrocarbon. The reaction temperature is usually -50°C to 50°C, the time required for the reaction is 30 minutes to 5 hours, and if necessary, to promote the formation of double bonds,
The treatment can also be carried out at 50°C to 100°C for 1 to 5 hours. After the reaction is completed, the reaction target product is collected from the reaction mixture according to a conventional method. For example, it can be obtained by pouring the reaction mixture into water and, if necessary, filtering any insoluble materials that arise, then extracting with a water-immiscible organic solvent, and distilling off the organic solvent. Furthermore, if necessary, it can be further purified by conventional methods such as column chromatography, recrystallization, etc. The ninth step is a step carried out as desired, including a reaction for removing the protecting group for the hydroxyl group of R ⁷ and/or R ⁸ , a reaction for removing the protecting group for the carboxyl group contained in R ⁶ , and a reaction for removing the protecting group for the carboxyl group contained in R ⁶ .
reaction to convert into a hydroxymethyl group, reaction to convert the obtained hydroxymethyl group into a formyl group (including reaction to protect), reaction to esterify the carboxy group of R ⁶ , or carboxy or ester may be substituted. Includes a reaction that converts into a carbamoyl group. This step is carried out in the same manner as the third official step of method A. The raw material compounds () and (′) of the present invention are:
According to the following method, publications having the general formula () (for example, JP-A-54-95552, JP-A-54-
No. 130543, JP-A-55-57559 or JP-A-55-
28945) with a base or acid in an inert solvent. In the above formula, R ⁴ , R ⁶ , R ⁷ , R ⁸ , B, n' and the dotted line have the same meanings as described above, and p represents an integer from 0 to 5. In the reaction of treating the compound () with a base, preferred bases include aminolithiums such as diisopropylaminolithium, isopropylcyclohexylaminolithium, and dicyclohexylaminolithium, and the inert base used The solution is not particularly limited as long as it does not participate in the reaction, but suitable examples include ethers such as ether, tetrahydrofuran, and dimethoxyethane. The reaction temperature is -78°C to 0°C, and the time required for the reaction is 30 minutes to 3 hours. This reaction is particularly suitable when p is an integer of 0 and n' is an integer of 0 in the compound (). Examples of the acid used in the reaction of treating compound () with an acid include inorganic acids such as hydrochloric acid, nitric acid, and sulfuric acid, acetic acid, trifluoroacetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p
Organic acids such as -toluenesulfonic acid and camphorsulfonic acid can be mentioned, and p-toluenesulfonic acid and camphorsulfonic acid are preferred. The inert solvent used is not particularly limited as long as it does not participate in the reaction, but for example, benzene,
Aromatic hydrocarbons such as toluene and xylene,
Ethers such as ether, tetrahydrofuran, dioxane, methylene chloride, chloroform,
halogenated hydrocarbons such as carbon tetrachloride, ketones such as acetone, methyl ethyl ketone,
alcohols such as methanol and ethanol,
Water or a mixed solvent of the above-mentioned organic solvent and water can be used, but aromatic hydrocarbons are preferable. The reaction temperature is 50°C to 150°C, and the time required for the reaction is usually 1 to 10 hours. a protecting group in which R ⁷ and/or R ⁸ are removed by acid;
For example, when it is a heterocyclic group, an alkoxy or aralkyloxymethyl group, a 1-alkoxyethyl group, or a trisubstituted silyl group, the above-mentioned protecting group is usually removed at the same time. In this case, the hydroxyl group can be removed by a conventional method, for example, by reaction with a cyclic unsaturated ether or alkoxy vinyl ether in the presence of an acid, or with an aralkyloxymethyl halide or a trisubstituted silyl halide in the presence of a base. can be protected. This reaction is suitable when p is an integer of 1 to 5 in compound (). After the reaction is completed, the target compound is collected from the reaction mixture in a conventional manner. For example, it can be obtained by pouring the reaction mixture into ice water, extracting with a water-immiscible organic solvent, and distilling off the solvent. In addition, if necessary, column chromatography,
It is also possible to purify by a recrystallization method or the like and to separate isomers at the 2-position and 3-position regarding the double bond in the ring. Compounds (), (') and () can also be produced, for example, from known compounds having the general formula () by the following method. In the above formula, R ⁴ , R ⁷ , R ⁸ , n', p or the dotted line have the same meanings as described above, R ¹¹ represents an aralkyl group, and R ¹² represents a hydrogen atom or a lower alkyl group. The compound () has the general formula Br-Mg-( _CH2 )p- _CH2 - _CH2 (C
H ₂ ) _o ′−OR ¹¹ ...() (wherein R ¹¹ , n′ and p have the same meanings as described above),
An alcohol having the general formula (),
Step 11), acid (e.g. p-toluenesulfonic acid)
to produce a compound having the general formula () (12th step), and treatment with an acid (for example, hydrochloric acid) to obtain an oxo compound having the general formula () (13th step). Compound () is reacted with a carboxylating agent (e.g. carbon dioxide, di-lower alkyl carbonate) in the presence of a base (e.g. sodium hydride) to obtain a compound having the general formula () (14th step), and a reducing agent (e.g. sodium borohydride);
After producing a compound having the general formula ()
Step 15), the hydroxyl group is protected according to a conventional method (e.g., dihydropyran-p-toluenesulfonic acid), leading to a compound having the general formula () (Step 16)
process). Compound () is treated with a reducing agent (for example, lithium aluminum hydride) to obtain a compound having general formula (XI) (step 17), which is oxidized with anhydrous sulfuric acid-pyridine to formyl having general formula (XII). After manufacturing the body (18th step), the general formula (In the formula, R ⁴ has the same meaning as described above, and Me
indicates a methyl group. ) is reacted with a compound having
Lead to a compound having the general formula () (19th step). Compound () is treated with a reducing agent (e.g., sodium borohydride) to form a compound having general formula () (20th step), and the hydroxyl group is protected according to a conventional method to obtain a compound having general formula (). (21st step) and removing ^R11 according to a conventional method (e.g., sodium-liquid ammonia or cerium ammonium fluoride, etc.) to produce a hydroxymethyl compound having the general formula (). I can do it. Furthermore, the compound () can be prepared using a conventional method (for example,
By oxidation according to Jones reagent: chromic anhydride-sulfuric acid), carboxy compounds having the general formula () can be prepared. Furthermore, the raw material compound (), (′) or ()
Among them, the compound having a double bond at the 2-position is obtained by first producing a compound (') having a double bond at the 2-position from the compound () according to the method shown below. Compound(
') can be produced separately by reacting in the same manner as in the 17th to 23rd steps. In the above formula, R ⁷ , R ¹¹ , R ¹² , n' and p have the same meanings as described above, and Ms represents a methanesulfonyl group. The compound () is treated with a peracid (eg, metachloroperbenzoic acid) to obtain an epoxide having the general formula () (24th step). Compound () is treated with a Lewis acid (e.g., boron trifluoride-ether complex) to obtain an oxo compound having general formula (XI) (step 25), and a reducing agent (e.g., sodium borohydride)
to obtain an alcohol having the general formula (XII) (26th step), and treating with an acid (eg, hydrochloric acid) to produce a compound having the general formula (27th step). treating compound () with a brominating agent (e.g. carbon tetrabromide-triphenylphosphine);
A bromine compound having the general formula () was obtained (28th
Step), the ring is closed using a base (for example, 1,8-diazabicyclo[5.4.0]undecene-7) to form a tricyclo compound having the general formula () (step
Step 29), in the presence of a base (e.g. sodium hydride), a carboxylating agent (e.g. carbon dioxide,
dimethyl carbonate) and the general formula ()
(30th step). compound () with an acid catalyst (e.g. sulfuric acid)
in the presence of a carboxylic acid (e.g. formic acid) to obtain a compound having the general formula ()
Step 31) and a reducing agent (e.g., sodium borohydride) to produce a compound having the general formula () (Step 32). ) to lead to a compound having the general formula () (33rd step). Compound () is treated with an alkali (e.g. potassium carbonate) to form a compound having general formula (L) (34th step), which is mesylated with methanesulfonyl chloride-triethylamine to form general formula (
L) is obtained (step 35) and treated with a weak base (e.g. phenylzelenosodium),
Produce a compound having the general formula (') (No.
36 steps). If the target compound thus obtained is a mixture of various positional, geometric and optical isomers, these isomers can be separated and resolved in an appropriate synthetic step. The compound having the general formula () and its pharmacologically acceptable salts are useful as antiplatelet agents and can be used as therapeutic and preventive agents for thrombotic diseases. Examples of the administration form include oral administration using tablets, capsules, granules, powders, syrups, etc., and parenteral administration via intravenous injection. The amount used varies depending on symptoms, age, weight, etc., but it is usually about 1 day per day for adults.
0.0001mg to 1000mg, preferably about 0.01mg to 1000mg per day
The dose is 100 mg and can be administered once or in divided doses. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. Example 1 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-5β,9-dimethyldec-1,8-dienyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-3
-ene(1a) 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
-5β,9-dimethyldeca-1,8-dienyl]
-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-
(2-tetrahydropyranyloxy)-5β,9
-dimethyldeca-1,8-dienyl]-7α-
105 mg of a mixture of (2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene was dissolved in dimethyl sulfoxide (1.5
ml) and dimethylformamide (1.5 ml), add 55% oily sodium hydrogen (96 mg), and stir at room temperature for 30 minutes. Next, 596 mg of lithium chloroacetate was added and stirred for 22 hours. Thereafter, the reaction solution was poured into ice water, acidified with acetic acid, and extracted with ethyl acetate. The extract is washed with brine and then with water, and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by thin layer chromatography (2 mm thickness, 20 cm x 20 cm: silica gel). The developing solvent used was hexane-ethyl acetate (1:1) containing a small amount of acetic acid. 38 mg of raw material was recovered from the less polar portion, and 28 mg of the target compound was obtained as an oil from the more polar portion. IR spectrum (Liq.) νmaxcm ^-1 : 1720,
1750 NMR spectrum ( _CDCl3 ) δppm: 0.92 (3H, m, _CH3 ) 3.63 (2H, t; J=7Hz, _-CH2O- ) 4.07 (2H, s, _-OCH2- ) 4.68 (2H, br ,

[Formula] x 2) 5.07 (1H, br.t; J = 6Hz, = CH-) 5.2-5.8 (3H, m, -HC = x 3) (1b) 3-(3-oxa-4-carboxybutyl )−
6β-(3α-hydroxy-5β,9-dimethyldec-1,8-dienyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-3
-ene 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
-5β,9-dimethyldeca-1,8-dienyl]
-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene in an acetone solution of 200 mg (6
ml) was added with 20 mg of camphorsulfonic acid, water was further added until the mixture became cloudy, and the mixture was heated and stirred at 50°C. After 3 hours and 30 minutes, saline solution was added and extracted with ethyl acetate. After washing the extract with brine, it is dried with anhydrous sodium sulfate. The solvent was distilled off and the resulting residue was purified using silica gel (5 g).
From the hexane containing 20% ethyl acetate-ethyl acetate outflow, 137 mg of an oily mixture of oct-2-ene and oct-3-ene was obtained. Mixture of oct-3-ene and oct-2-ene IR spectrum (Liq) νmaxcm ^-1 ; 1735, 3360, 975 NMR spectrum (CDCl ₃ ) δppm; 0.92 (3H, d; J=6Hz, CH ₃ ) 1.61 ( 3H, s, CH ₃ ) 1.69 (3H, s, CH ₃ ) 3.4-4.5 (2H, m, > CH OH x 2) 3.77 (2H, t; J=6Hz, -CH ₂ -) 4.08 (2H, s, -CH ₂ -) 5.11 (1H, t; J=6Hz, =CH-) 5.39 (1H, br.s, =CH-) 5.53 (2H, m, -CH=CH-) This mixture is It was purified by chromatography to obtain pure oct-2-ene and oct-3-ene. (Column: ocdecyl chemically bonded silica gel, solvent: 0.05M phosphoric acid water/
Acetonitrile = 45/55) Oct-2-ene body: IR spectrum (CHCl ₃ ) νmaxcm ^-1 ; 1735, 3370, 973 NMR spectrum (CDCl ₃ ) δppm; 0.92 (3H, d; J=6Hz, CH ₃ ) 1 , 61 (3H, s, CH ₃ ) 1.69 (3H, s, CH ₃ ) 3.4-4.5 (2H, m, > CH OH x 2) 3.77 (2H, t; J = 6 Hz, -CH ₂ O-) 4.08 (2H, s, -CH ₂ O-) 5.11 (1H, t; J=6Hz, =CH-) 5.39 (1H, s, =CH-) 5.53 (2H, m, -CH=CH-) Oct- 3-ene body IR spectrum (CHCl ₃ ) νmaxcm ^-1 ; 1735, 3370, 973 NMR spectrum (CDCl ₃ ) δppm; 0.92 (3H, d; J=6Hz, CH ₃ ) 1.61 (3H, s, CH ₃ ) 1.69 (3H, s, CH ₃ ) 3.4-4.5 (2H, m, >CH −OH ×2) 3.77 (2H, t; J=6Hz, −CH ₂ O−) 4.08 (2H, s, −CH ₂ O -) 5.11 (1H, t; J=6Hz, =CH-) 5.39 (1H, s, =CH-) 5.53 (2H, m, -CH=CH-) Example 2 3-(3-oxa-4- carboxybutyl)-
6β-(3α-hydroxyoct-1-enyl)-
7α-hydroxybicyclo[3.3.0]octo-2
-Mixture of -ene and oct-3-ene (2a) 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
oct-1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-
Mixture of 2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-
(2-tetrahydropyranyloxy)octo-
When 110 mg of a mixture of 1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene was treated in the same manner as in Example 1a, 31 mg of oily The target compound was obtained. IR spectrum (Liq) νmaxcm ^-1 ; 1720,
1750 NMR spectrum ( _CDCl3 ) δppm; 0.90 (3H, t, _CH3 ) 3.62 (2H, t; J=7Hz, _-CH2O- ) 4.07 (2H, s, _-CH2O- ) 4.67 (2H, br.s,

[Formula] x 2) 5.2-5.8 (3H, m, = CH- x 3) (2b) 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxyoct-1-enyl)-
7α-hydroxybicyclo[3.3.0]octo-2
-Mixture of -ene and oct-3-ene 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
Oct-1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene 152
When the reaction is treated in the same manner as in Example 1b using mg
95 mg of oily target compound was obtained. IR spectrum (Liq) νmaxcm ^-1 ; 1733, 3360, 973 NMR spectrum ( _CDCl3 ) δppm; 0.90 (3H, t; _CH3 ) 3.75 (2H, t; J=6Hz, _-CH2O- ) 4.08 (2H , s, _-CH2O- ) 5.41 (1H, br.s, =CH-) 5.53 (2H, m, -CH=CH-) Example 3 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-4-methyloct-1
-enyl)-7α-hydroxybicyclo [3.3.0]
Mixture of oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-4-methyloct-1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-
Using 162 mg of a mixture of ene and oct-3-ene, the reaction was carried out in the same manner as in Example 1a and then in Example 1b to obtain 36 mg of the target compound in the form of an oil. Spectrum (Liq) νmaxcm ^-1 : 1730, 3360,
974 Example 4 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-5-methylnona-1-
mixture of oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-(2
-Tetrahydropyranyloxy)-5-methylnon-1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0] Performed using 105 mg of a mixture of oct-2-ene and oct-3-ene. Example 1a Then, reaction treatment was carried out in the same manner as in Example 1b to obtain 23 mg of the target compound. IR spectrum (CHCl ₃ ) νmaxcm ^-1 : 1730,
3350, 972 Example 5 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-4-methylnona-1,
8-dienyl)-7α-hydroxybicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene (5a) 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
-4-methylnona-1,8-dienyl]-7α-
Mixture of (2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-
(2-tetrahydropyranyloxy)-4-methylnona-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]
Mixture of oct-2-ene and oct-3-ene
Using 430 mg, reaction treatment was carried out in the same manner as in Example 1a,
102 mg of the target compound as an oil was obtained. IR spectrum (Liq) νmaxcm ^-1 : 1720,
1745, ₁₆₄₀ NMR spectrum (CDCl3) δppm: 0.91 (3H, m, _CH3 ) 3.62 (2H, t, _-CH2O- ) 4.07 (2H, s, _-CH2O- ) 4.70 (2H, br. s,

[Formula] 4.82−6.20 (6H, m, −CH=CH−,

[Formula]=CH-) (5b) 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-4-methylnona-1,
8-dienyl)-7α-hydroxybicyclo[3.3.0] mixture of oct-2-ene and oct-3-ene 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
-4-methylnona1,8-dienyl]-7α-
100 mg of a mixture of (2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene was treated in the same manner as in Example 1b to obtain 59 mg of the target compound as an oily substance. IR spectrum (Liq) νmaxcm ^-1 : 973,
1638, 1735, ₃₃₀ NMR spectrum ( _CDCl3 ) δppm: 0.90 (3H, m, CH3) 3.76 (2H, t, _-CH2O- ) 4.08 (2H, s, _-CH2O- ) 3.4-4.3 ( This _compound When treated with diazomethane, the methyl ester form (IR spectrum (Liq) νmaxcm
^-1 : 973, 1638, 1740, 3380) were obtained. Example 6 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-4,7-dimethyloct-1,6-dienyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-
Mixture of 3-enes (6a) 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy-4,7-dimethyloct1,6-dienyl]
-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-
(2-tetrahydropyranyloxy)-4,7-
dimethyloct-1,6-dienyl]-7α-
150 mg of a mixture of (2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene was reacted in the same manner as in Example 1a to obtain 53 mg of the target compound. IR spectrum (Liq) νmaxcm ^-1 : 1720,
1750 NMR spectrum ( _CDCl3 ) δppm: 0.90 (3H, m, _CH3 ) 3.45 (2H, t, _-CH2O- ) 4.51 (2H, s, _-CH2O- ) 4.70 (2H, br.s,

[Formula] x 2) 5.0 to 5.8 (4H, m, = CH - x 2, -CH = CH
-) (6b) 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-4,7-dimethyloct-1,6-dienyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-
Mixture of 3-enes 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy-4,7-dimethyloct-1,6-dienyl]-7α-(2-tetrahydropyranyloxy)
124 mg of a mixture of bicyclo[3.3.0]oct-2-ene and oct-3-ene was reacted in the same manner as in Example 1b to obtain 75 mg of the target compound. IR spectrum (Liq) νmaxcm ^-1 : 971,
1707, 3350 NMR spectrum ( _CDCl3 ) δppm: 0.90 (3H, m, _CH3 ) 3.75 (2H, t, _-CH2O- ) 4.09 (2H, s, _-CH2O- ) 3.4-4.4 (2H, m, >C H OH x 2) 5.11 (1H, t, = CH-) 5.38 (1H, br.s, = CH-) 5.53 (2H, m, -CH=CH-) Example 7 3 (3- Oxa-4-carboxybutyl)-6β
-(3α-hydroxy-9-methyldeca-1,8
-dienyl)-7α-hydroxybicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-9-methyldeca-1,8-dienyl)-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-
Using 150 mg of a mixture of ene and oct-3-ene, the reaction was carried out in the same manner as in Example 1a and then in Example 1b,
39 mg of the target compound was obtained. IR spectrum (Liq) νmaxcm ^-1 : 1735, 3350,
974 Example 8 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-4-methyl-octo-
1-en-6-ynyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-
Mixture of 3-enes (8a) 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
-4-methyloct-1-en-6-ynyl]
-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.1]oct-2-ene and -3-
mixture of enes 3-(2-hydroxyethyl)-6β-[3α-(2
-Tetrahydropyranyloxy)-4-methyloct-1-en-6-ynyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene
Using 103mg, reaction treatment was carried out in the same manner as in Example 1a, and 41mg
The desired compound was obtained. IR spectrum (Liq) νmaxcm ^-1 : 1718, 1750 NMR spectrum (CDCl ₃ ) δppm: 0.95 (3H, m, CH ₃ ) 1.79 (3H, t; J = 1.5Hz, CH ₃ ) 3.61 (2H, t; J =7Hz, -CH ₂ O-) 4.06 (2H, s, -CH ₂ O-) 4.67 (2H, br.s,

[Formula]×2) 5.2-5.8 (3H, m, =CH-, CH=CH-) (8b) 3-(3-oxa-4-carboxybutyl)-
6β(3α-hydroxy-4-methyloct-1-
(en-6-ynyl)-7α-hydroxybicyclo[3.3.0] mixture of oct-2-ene and oct-3-ene 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
-4-methyloct-1-en-6-ynyl]
-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and -3-
A reaction treatment was carried out in the same manner as in Example 1b using 100 mg of a mixture of enes to obtain 59 mg of the target compound as an oily substance. IR spectrum (Liq) νmaxcm ^-1 : 1735,
3360, ₉₇₄ NMR spectrum (CDCl3) δppm: 0.95 (3H, m, _CH3 ) 1.78 (3H, t; J=1.5Hz, _CH3 ) 3.4-4.5 (2H, m, >CHOH x 2) 3.76 (2H , t; J=6Hz, -CH2O-) 4.08 (2H, s, _-CH2O- ) _5.39 (1H, br.s, =CH-) 5.54 (2H, m, -CH=CH-) Implementation Example 9 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-4-cyclopentyl-
Mixture of 1-butenyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-4-cyclopentyl-1-butenyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octo-2
Using 181 mg of a mixture of -ene and oct-3-ene, the reaction was carried out in the same manner as in Example 1a and then in Example 1b to obtain 41 mg of the target compound. IR spectrum (CHCl ₃ ) νmaxcm ^-1 : 1735,
3360, 974 Example 10 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-3-cyclohexyl-
1-propenyl)-7α-hydroxybicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene (10a) 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
-3-cyclohexyl-1-propenyl]-7α
-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3
-Mixture of -enes 3-(2-hydroxyethyl)-6β-[3α-
(2-Tetrahydropyranyloxy)-3-cyclohexyl-1-propenyl-7α-(2-tetrahydropyranyloxy)bicyclo [3.3.0]
A reaction treatment was carried out in the same manner as in Example 1a using 273 mg of a mixture of oct-2-ene and oct-3-ene,
79 mg of the target compound as an oil was obtained. IR spectrum (Liq) νmaxcm ^-1 : 1720,
1747 NMR spectrum ( _CDCl3 ) δppm: 3.64 (2H, t, _-CH2O- ) 4.06 (2H, s, _-CH2O- ) 4.70 (2H, br.s,

[Formula]×2) 5.2-5.8 (3H, m, -CH=CH-, =CH-) (10b) 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-3-cyclohexyl-
1-propenyl)-7α-hydroxybicyclo[3.3.0] mixture of oct-2-ene and oct-3-ene 3-(3-oxa-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
3-cyclohexyl-1-propenyl]-7α-
312 mg of a mixture of (2-terolahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene was reacted in the same manner as in Example 1b to obtain 136 mg of the target compound. IR spectrum (CHCl ₃ ) νmaxcm ^-1 : 972,
1735, 3350 NMR spectrum ( _CDCl3 ) δppm: 3.76 (2H, t, _-CH2O- ) 4.08 (2H, s, _-CH2O- ) 3.4-4.3 (2H, m, > CH2Ox2 ) 5.38 (1H, br.s, =CH-) 5.52 (2H, m, -CH=CH-) Example 11 3-(3-thia-4-carboxybutyl)-6β
-(3α-hydroxy-5β,9-dimethyldeca-
1,8-dienyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-3-ene compound (11a) 3-(2-ethanesulfonyloxyethyl)-
6β-[3α-(2-tetrahydropyranyloxy)
-5β,9-dimethyldeca-1,8-dienyl]
-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-
(2-tetrahydropyranyloxy)-5β,9
-dimethyldeca-1,8-dienyl]-7α-(2-
A mixture of 294 mg of tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene in methylene chloride (10
ml), triethylamine (87 mg) was added thereto, 97 mg of methanesulfonyl chloride was added under ice cooling, and the mixture was reacted for 2 hours under ice cooling. After the reaction is complete, ethyl acetate is added, and the mixture is washed successively with brine, acetic acid, dilute sodium bicarbonate, and then brine, and dried with anhydrous sodium sulfate. When the solvent is distilled off, an oily target compound is obtained.
303 mg was obtained. NMR spectrum ( _CDCl3 ) δppm: 0.93 (3H, m, _CH3 ) 2.92 (3H, s, _CH3 ) 4.70 (2H, m,

[Formula]) 5.05 (1H, t; J=6Hz, =CH-) 5.2-5.8 (3H, m, =CH-×3) (11b) 3-(3-thia-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
-5β,9-dimethyldeca-1,8-dienyl]
-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene mixture After washing 55% oily sodium hydrogen (400 mg) with hexane, 15 ml of dimethyl sulfoxide and thioglycol Add 400 mg of acid and stir at room temperature until almost no bubbles appear. 3-(2-methanesulfonyloxyethyl)-6β-[3α-(2-tetrahydropyranyloxy)-5β,9-dimethyldec-1.8-dienyl] -7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octo-2
303 mg of a mixture of -ene and oct-3-ene were added. After stirring at room temperature for 1 hour, the mixture was poured into ice water, acidified with acetic acid, and extracted with ethyl acetate. After washing the extract with brine, it is dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel thin layer chromatography (2 mm) (developing solvent: 50% hexane monoethyl acetate containing 0.25% acetic acid) to obtain 187 mg of the target compound in the form of an oil. IR spectrum (Liq) νmaxcm ^-1 : 1725,
1710 NMR spectrum ( _CDCl3 ) δppm: 0.90 (3H, m, _CH3 ) 3.20 (2H, s, _-SCH2- ) 4.65 (2H, br.

[Formula]) 5.01 (1H, t; J=6Hz, CH ₃ ) 5.2-5.7 (3H, m, =CH-×3) (11c) 3-(3-thia-4-carboxybutyl)-
6β-(3α-hydroxy-5β,9-dimethyldec-1,8-dienyl]-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-3
-Mixture of ene 3-(3-thia-4-carboxybutyl)-
6β-[3α-(2-tetrahydropyranyloxy)
-5β,9-dimethyldeca-1,8-dienyl]
180 mg of a mixture of -7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene was reacted and treated in the same manner as in Example 1b, and the resulting residue was applied to a silica gel column. Purify by chromatography. From the hexane monoethyl acetate outlet containing 30% ethyl acetate
120mg oily oct-2-ene and oct-2-ene
A mixture of 3-enes was obtained. Mixture of oct-2-ene and oct-3-ene IR spectrum (Liq) νmaxcm ^-1 : 975,
1705, 3350 NMR spectrum ( _CDCl3 ) δppm: 0.94 (3H, d; J=6Hz, _CH3 ) 1.62 (3H, s, _CH3 ) 1.70 (3H, s, _CH3 ) 3.22 (2H, s, -CH ₂ −) 3.4 to 4.5 (2H, br., >CHOH×2) 5.08 (1H, br.t; J=6Hz, =CH−) 5.36 (1H, br.s, =CH−) 5.60 (2H, m , -CH=CH-) This mixture was purified by high performance liquid chromatography to obtain pure oct-2-ene and oct-3-ene bodies. (Column: octadecyl chemically bonded silica gel, solvent: 0.05M phosphoric acid water/acetonitrile = 45/55) Oct-2-ene body; IR spectrum (CDCl ₃ ) νmaxcm ^-1 : 974,
1705, 3350 NMR spectrum ( _CDCl3 ) δppm: 0.94 (3H, d; J=6Hz, _-CH3 ) 1.62 (3H, s, _CH3 ) 1.70 (3H, s, _CH3 ) 3.22 (2H, s, - CH ₂ S−) 3.4 to 4.5 (2H, br, >C H OH×2) 5.08 (1H, t; J=6Hz, =CH−) 5.36 (1H, br.s, =CH−) 5.60 (2H, m, -CH=CH-) oct-3-ene body; IR spectrum ( _CDCl3 ) νmaxcm ^-1 : 974,
1705, 3350 NMR spectrum ( _CDCl3 ) δppm: 0.94 (3H, d; J=6Hz, _CH3 ) 1.62 (3H, s, _CH3 ) 1.70 (3H, s, _CH3 ) 3.22 (2H, s, -CH ₂ S−) 3.4 to 4.5 (2H, br., >C H OH×2) 5.08 (1H, t; J=6Hz, =CH−) 5.36 (1H, br.s, =CH−) 5.60 (2H, m, -CH=CH-) Example 12 3-(3-thia-4-carboxybutyl)-6β
-(3α-hydroxy-3-cyclohexyl-1
-propenyl)-7α-hydroxybicyclo[3.3.0] mixture of oct-2-ene and oct-3-ene 3-(2-methanesulfonyloxyethyl)-
6β-[3α-(2-tetrahydropyranyloxy)-
3-cyclohexyl-1-propenyl]-7α-
Mixture of (2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene [compound obtained by reacting the alcohol form of Reference Example 10 in the same manner as in Example (11a) 〕237mg
Example (11b) was then reacted in the same manner as in Example (11c) to obtain 102 mg of the target compound. IR spectrum ( _CDCl3 ) νmaxcm ^-1 : 975,
1707, 3350 Example 13 3-(4-methoxycarbonyl-3-butenyl)
-6β-(3α-hydroxy-5β,9-dimethyl-
1,8-decadienyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-
Mixture of 3-enes (13a) 3-(4-phenylseleno-4-methoxycarbonylbutyl)-6β-[3α-(2-tetrahydropyranyloxy)-5β,9-dimethyldec-
1,8-dienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octo-
Mixture of 2-ene and oct-3-ene A diisopropylaminolithium solution prepared from a solution of diisopropylamine (0.84 g) in tetrahydrofuran (14 ml) and a hexane solution of 15% n-butyllithium (3.07 ml) was added with 3 at -70°C. -(4
-methoxycarbonylbutyl)-6β-[3α-(2-
mixture of (tetrahydropyranyloxy)-5β,9-dimethyldec-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene ( A solution of 1.4 g) in tetrahydrofuran (6 ml) is added dropwise. After stirring at the same temperature for 20 minutes, a solution of diphenyl diselenide (1.61 g) in tetrahydrofuran (5 ml) was added at -78°C, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. After washing the extract with saline,
Dry with anhydrous sodium sulfate. The solvent is distilled off and the residue is purified by silica gel column chromatography. 1.74 g of oily target compound was obtained from the hexane outflow containing 10-20% ethyl acetate. IR spectrum (Liq) νmaxcm ^-1 : 1580, 1735 NMR spectrum (CDCl ₃ ) δppm: 0.91 (3H, m, CH ₃ ) 1.61 (3H, s, CH ₃ ) 1.66 (3H, s, CH ₃ ) 3.62 (3H , s, CH ₃ ) 4.70 (2H, br.

[Formula]) 5.0-5.8 (4H, m, = CH-×4) 7.30 (3H, m, aromatic proton) 7.59 (2H, m, aromatic proton) (13b) 3-(4-methoxycarbonyl-3 -butenyl)-6β-[3α-(2-tetrahydropyranyloxy)-5β,9-dimethyl-1,8-decadienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octo-2 -ene and oct-3-ene mixture 3-(4-phenylseleno-4-methoxycarbonylbutyl)-6β-[3α-(2-tetrahydropyranyloxy)-5β,9-dimethyldec-
1,8-dienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octo-
0.70g mixture of 2-ene and oct-3-ene
Add 4 ml of methanol to 6 ml of ethyl acetate solution of
0.85 ml of 30% hydrogen peroxide was added dropwise at 20°C, and the mixture was stirred at room temperature for 40 minutes. After the reaction is complete, add 100ml of ethyl acetate.
After washing with saturated sodium bicarbonate solution and brine, dry with anhydrous sodium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography. 338 mg of oily target compound was obtained from the hexane outflow containing 5 to 10% ethyl acetate. IR spectrum (Liq) νmaxcm ^-1 : 1655,
1730 NMR spectrum ( _CDCl3 ) δppm: 0.89 (3H, m, _CH3 ) 3.69 (3H, s, _CH3 ) 4.67 (2H, br.,

[Formula] × 2) 4.85-5.90 (5H, m, = CH- × 5) 6.87 (1H, d, t; J = 15, 7 Hz, = CH-) (13c) 3-(4-methoxycarbonyl-3 -butenyl)-6β-(3α-hydroxy-5β-,9-dimethyl-1,8-decadienyl)-7α-hydroxybicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene -methoxycarbonyl-3-bitenyl)-6β-[3α-(2-tetrahydropyranyloxy)-5β,9-dimethyl-1,8-decadienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3. 0] 400 mg of mixture of oct-2-ene and oct-3-ene, 6 ml of acetic acid,
A mixture of 4 ml of water and 1 ml of tetrahydrofuran for 60
Stir for 1 hour at °C. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The extract is diluted with a saturated sodium bicarbonate solution and then with a saline solution, and then dried with anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography. 230 mg of oily target compound was obtained from the hexane outflow containing 40% to 60% ethyl acetate. IR spectrum (Lip) νmaxcm ^-1 : 1650,
1725, 3355 NMR spectrum ( _CDCl3 ) δppm: 0.93 (3H, d; J=6Hz, _CH3 ) 1.62 (3H, s, _CH3 ) 1.68 (3H, s, _CH3 ) 3.70 (3H, s, _CH3) ) 4.90-5.90 (5H, m, = CH- x 5) 6.88 (1H, d, t; 15, 7Hz, = CH-) Example 14 3-(3-oxa-5-hydroxypentyl)-
6β-(3α-hydroxy-5β,9-dimethyldec-1,8-dienyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-3
-ene mixture (14a) 3-(3-oxa-5-hydroxypentyl)
-6β-[3α-(2-tetrahydropyranyloxy-5β,9-dimethyldeca-1,8-dienyl)-7α-(2-tetrahydropyranyloxy]
Bicyclo[3.3.0] Mixture of oct-2-ene and oct-3-ene Dipyranyl compound (compound of Example 1a: 310 mg)
in ether with excess diazomethane at room temperature for 30 min.
321 mg of methyl ester was obtained (IR spectrum (Lip) νmaxcm ^-1 : 1720). Dissolve 250 mg of this ester in 10 ml of ether,
250 mg of lithium aluminum hydride was added and stirred at room temperature for 30 minutes. After the reaction is completed, 1 ml of 4% caustic soda water is added, the precipitate is removed, and the liquid is concentrated. The obtained residue was purified by column chromatography to obtain 187 mg of the target compound as an oil. IR spectrum (Liq) νmaxcm ^-1 : 340,
1120, 1076, 1022 (14b) 3-(3-oxa-5-hydroxypentyl)
-6β-(3α-hydroxy-5β,9-dimethyldec-1,8-diethyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and oct-
3-ene mixture alcohol form (compound of Example 14a: 180 mg)
was dissolved in 5 ml of acetic acid-water-tetrahydrofuran mixed solvent (5:3:1) and reacted at 40°C for 3 hours. After the reaction is complete, add saturated brine and extract with ethyl acetate. After washing the extract with water and drying (sodium sulfate), the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography to obtain 91 mg of the target compound as an oil. IR spectrum (Liq) νmaxcm ^-1 : 3350, 971 Example 15 3-(3-oxa-4-formylbutyl)-6β
-(3α-hydroxy-5β,9-dimethyldeca-
Compound alcohol of 1,8-dienyl)-7α-hydroxybicyclo[3.3.0]oct-5-ene and oct-3-ene (compound of Example 14a: 171 mg)
Dissolve in 50 ml of methylene chloride, add 2.5 g of pyridine-chromic anhydride complex (Collins reagent) under ice cooling, and stir for 30 minutes. After the reaction is complete, excess ether is added and the reaction mixture is washed with saturated saline.
After drying the organic layer with sodium sulfate, the solvent was distilled off and 3-(3-oxa-4-formylbutyl)-
6β-[3α-(2-tetrahydropyranyloxy-
5β,9-dimethyldeca-1,8-dienyl]-7α
-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene compounds (161 mg) were obtained (IR spectrum (Liq)
νmaxcm ^-1 : 2720, 1710). This formyl compound was deprotected in the same manner as in Example 14b to obtain 75 mg of the target compound. IR spectrum ( _CHCI3 ) νmaxcm ^-1 : 2710,
1710 Example 16 3-(4-methoxycarbonyl-3-butenyl)
-6β-(3α-hydroxy-4-methyl-1-octenyl)-7α-hydroxybicyclo[3.3.0]
Mixture of oct-2-ene and oct-3-ene Methyl ester (compound in the second half of Reference Example 26,
1.02g) was sequentially reacted and treated in the same manner as in Example 13 to obtain 164mg of the target compound in the form of an oil. IR spectrum (Liq) νmaxcm ^-1 : 1650, 1725, ₃₃₅₄ NMR spectrum (CDCl3) δppm: 0.7-1.1 (6H, m, _CH3 × 2) 3.68 (3H, s, _CO2CH3 ) _5.0-5.9 ( 4H, m, CH-×4) 6.88 (1H, d, t; J=15, 7Hz=CH-) Example 17 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-4,4-dimethyloct-1-enyl)-7α-hydroxybicyclo[3.3.0] mixture of oct-5-ene and oct-3-ene 3-(2-hydroxyethyl)- 6β−[3α−(2
350 mg of a mixture of oct-2-ene and oct-3-ene
The reaction was carried out in the same manner as in Example 1a and then in Example 1b using
Work-up gave 71 mg of the desired compound as an oil. IR spectrum (Liq) νmaxcm ^-1 : 975, 1718, 3400 NMR spectrum ( _CDCl3 ) δppm: 0.7-1.1 (6H, m) 4.08 (2H, s) 5.40 (1H, br.s) 5.59 (2H, m) Example 18 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-3-cyclopentyl-
Mixture of 1-propenyl)-7α-hydroxybicyclo[3.3.0]oct-3-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-(2
265 mg of mixture of oct-2-ene and oct-3-ene
When the reaction was carried out in the same manner as in Example 1a and then in Example 1b, 49 mg of the target compound was obtained. IR spectrum ( _CHCl3 ) νmaxcm ^-1 : 975, 1735, 3400 NMR spectrum ( _CDCl3 ) δppm: 3.0 (1H, br) 3.5-4.0 (4H, m) 4.08 (2H, s) 5.40 (1H, br, s ) 5.52 (2H, m) Example 19 3-(3-oxa-4-carboxybutyl)-
6β-(3α-hydroxy-4-phenoxy-1-
butenyl)-7α-hydroxybicyclo[3.3.0]
Mixture of oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-4-phenoxy-1-butenyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]-octo-2-
310 mg of ene and oct-3-ene compounds were reacted in the same manner as in Example 1a and then in Example 1b to obtain 57 mg of the target compound in the form of an oil. IR spectrum (Liq) νmaxcm ^-1 : 1130, 1242, 1740, 3350 NMR spectrum ( _CDCl3 ) δppm: 3.5-4.2 (7H, m) 4.48 (1H, br) 5.40 (1H, br, s) 5.80 (2H, m) 6.8 to 7.5 (5H, m) Reference example 1 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-5(R),9
-dimethyl-deca-1,8-dienyl]-7α-
(2-Tetrahydropyranyloxy)picyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene (1a) 3-(methoxycarbonylmethyl)-6β-[3α
-(2-tetrahydropyranyloxy)-5
(R),9-dimethyl-deca-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)
Bicyclo[3.3.0] Mixture of oct-2-ene and oct-3-ene 3-methoxycarbonylmethylidene-6β-
[3α-(2-tetrahydropyranyloxy)-5
(R), 9-dimethyl-deca-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)
Dissolve 1.95 g of bicyclo[3.3.0]octane in tetrahydrofuran (5 ml) and heat the mixture at -60°C with diisopropylaminolithium (diisopropylamine).
A 10 ml solution of 935 mg of 15% n-butyllithium (prepared from 5.43 ml of n-hexane solution and 1.6 ml of hexamethylphosphoryltriamide) in tetrahydrofuran was added. After reacting at the same temperature for 1 hour, the mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. After drying the extract over sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography to obtain 1.30 g of the target compound. IR spectrum (Liq) νmaxcm ^-1 : 1737 NMR spectrum (CDCl ₃ ) δppm: 0.92 (3H, m, CH ₃ ) 1.62 (3H, s, CH ₃ ) 1.68 (3H, s, CH ₃ ) 3.10 (2H, s , −CH ₂ −) 3.69 (3H, s, COOCH ₃ ) 4.82 (2H, br.s,

[Formula]) 5.12 (1H, t, =CH-) 5.3-5.8 (3H, m, =CH-, -CH=CH-) (1b) 3-(2-hydroxyethyl)-6β-[3α-
(2-terahydropyranyloxy)-5(R),9
-dimethyl-deca-1,8-dienyl]-7α-
(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene mixture ester (compound of Reference Example 1a: 510 mg) was dissolved in 20 ml of ether, and 500 mg of lithium aluminum was added under hydrogen. Add on ice. After 1 hour, 2ml
4% aqueous sodium hydroxide solution was added and stirred to remove the precipitate, and the liquid was concentrated to obtain an oily residue. Purification by silica gel column chromatography yielded 430 mg of the target compound as an oil. IR spectrum (Liq) νmaxcm ^-1 : 3350 NMR spectrum (CDCl ₃ ) δppm: 0.91 (3H, m, CH ₃ ) 1.62 (3H, s, CH ₃ ) 1.69 (3H, s, CH ₃ ) 4.80 (2H, br .s,

[Formula]×2) 5.0 to 5.8 (4H, m, =CH−×4) Reference example 2 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)octo-1-
mixture of oct-2-ene and oct-3-ene 3-methoxycarbonylmethylidene-6β-[3α
-(2-tetrahydropyranyloxy)octo-
Using 520 mg of 1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octane, 194 mg of the desired product was obtained using the same reaction and treatment as in Reference Examples 1a and 1b. IR spectrum (Liq) νmaxcm ^-1 : 3350, 1032,
1022, 974 Reference example 3 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-4-methyloct-4-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene compounds Reden-6β-[3α
-(2-tetrahydropyranyloxy)-4-methyloct-1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octane
Using 712mg, react in the same manner as Reference Examples 1a and 1b.
After treatment, 287 mg of the target product was obtained. IR spectrum (Liq) νmaxcm ^-1 : 3350, 1032,
1022, 974 Reference example 4 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-5-methylnon-1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-
Mixture of 2-ene and oct-3-ene 3-methoxycarbonylmethylidene-6β-[3α
-(2-tetrahydropyranyloxy)-5-methylnona-1-ethyl]-7α-(2-tetrahydropyranyloxy)picyclo[3.3.0]octane 712
The reaction and treatment were carried out in the same manner as in Reference Examples 1a and 1b using 286 mg of the target product. IR spectrum (Liq) νmaxcm ^-1 : 3350, 1032,
1022, 974 Reference example 5 3-(2-hydroxyethyl)-6β-[3α-(2
3-Methoxy Carbonylmethylidene-6β-[3α
-(2-tetrahydropyranyloxy)-4-methylnona-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octane 512mg, same as Reference Examples 1a and 1b After reaction and treatment, 196 of the target product was obtained. IR spectrum (Liq) νmxcm ^-1 : 3350, 1032,
1022, 974 Reference example 6 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-4,7-dimethyloct-1,6-dienyl]-7α-(2
-Tetrahydropyranyloxy)bicyclo[3.3.3]Mixture of oct-2-ene and oct-3-ene 3-methoxycarbonylmethylidene-6β-[3α
-(2-tetrahydropyranyloxy)-4,7-
dimethyloct-1,6-dienyl]-7α-(2
-Tetrahydropyranyloxy)bicyclo[3.3.0]octane (457 mg), Reference Example 1a and
The reaction and treatment were carried out in the same manner as in 1b to obtain 159 mg of the desired product. IR spectrum (Liq) νmaxcm ^-1 : 3350, 1032,
1022, 974 Reference example 7 3-(2-hydroxyethyl)-6β-[3α-(2
-Tetrahydropyranyloxy)-9-methyldec-1.8-dienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene 3-methoxycarbonylmethylene Reden-6β-[3α
-(2-Tetrahydropyranyloxy)-9-methyldeca-1,8-dienyl]-7α-(2tetrahydropyranyloxy)bicyclo[3.3.0]octane, using 941 mg, in the same manner as in Reference Examples 1a and 1b. After reaction and treatment, 387 mg of the target product was obtained. IR spectrum (Liq) νmaxcm ^-1 ; 3350, 1032,
1022, 973 Reference example 8 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-4-methyloct-1-en-6-ynyl]-7α-(2-
Tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene 3-methoxycarbonylmethylidene-6β-[3α
-(2-tetrahydropyranyloxy)-4-methyloct-1-en-6-ynyl]-7α-(2-
Tetrahydropyranyloxy)bicyclo [3.3.0]
Using 543 mg of octane, the reaction and treatment were carried out in the same manner as in Reference Examples 1a and 1b to obtain 210 mg of the target product. IR spectrum (Liq) νmaxcm ^-1 : 3350, 1032,
1022, 974 Reference example 9 3-(2-hydroxyethyl)-6β-[3α-tetrahydropyranyloxy)-4-cyclopentyl-1-butenyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0 ]Octo-
Mixture of 2-ene and oct-3-ene 3-methoxycarbonylmethylidene-6β-[3α
Using 472 mg of -(2-tetrahydropyranyloxy)-4-cyclopentyl-1-butenyl]-7α-(2-tetrahydropyranyloxy)picyclo[3.3.0]octane, the reaction was carried out in the same manner as in Reference Examples 1a and 1b. , 194 mg of the target product was obtained. IR spectrum (Liq) νmaxcm ^-1 : 3350, 1032,
1022, 973 Reference example 10 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-3-cyclohexyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]
Mixture of oct-2-ene and oct-3-ene 3-methoxycarbonylmethylidene-6β-[3α
Using 871 mg of -(2-tetrahydropyranyloxy)-3-cyclohexyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]octane, the reaction was carried out in the same manner as in Reference Examples 1a and 1b. , and 387 mg of the target product was obtained. IR spectrum (Liq) νmaxcm ^-1 : 3350, 1032,
1022, 974 Reference example 11 3-(5-benzyloxypentyl)-7,7-
Ethylenedioxy-3-hydroxy-cis-bicyclo[3.3.0]octane 5-benzyloxypentyl bromide 1.00g
[The method of AWBurgstahler et al. (J.Org.Chem., 42 .
566 (1977). 5-benzyloxypentamethylenemagnesium bromide prepared from pentamethylene bromide and benzyl alcohol] and metallic magnesium (100 mg) in diethyl ether (5 ml) was added to 5-benzyloxypentamethylene magnesium bromide at room temperature. Oxy-3-oxosis-
A solution of bicyclo[3.3.0]octane (501 mg) in diethyl ether (5 ml) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. After the reaction is completed, an aqueous ammonium chloride solution is added to the reaction solution, extracted with diethyl ether, the extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain 1.47 g of a residue. This product was purified by silica gel column chromatography to obtain 556 mg of the desired product as an oil. IR spectrum (Liq) νmax cm ^-1 : 3480,
1470, 1330, 1110 NMR spectrum (CDCl ₃ ) δppm: 3.47 (2H, t, J=6.0Hz, CH ₂ C H ₂ OB _Z ) 3.91 (4H, s, OCH ₂ C H ₂ O) 4.52 (2H, s , OCH ₂ Ph) 7.36 (5H, s, aryl-H) Mass spectrum, m/e: 360 (M ⁺ ) 342 (M-18) Reference example 12 3-(5-benzyloxypentyl)-7,7-
Ethylenedioxisis-bicyclo [3.3.0]
Oct-2-ene 3-(5-benzyloxypentyl)-7,7-
Ethylenedioxy-3-hydroxy-cis-bicyclo[3.3.0]octane (209 mg) in benzene (2
ml) solution with ethylene glycol (0.05 ml) and p-
Add toluenesulfonic acid (10 mg), and heat and stir for 3.5 hours while removing water azeotropically. After the reaction is complete,
Neutralize with 5% aqueous sodium hydrogen carbonate solution, wash the reaction solution with water, and dry with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 193 mg of residue. This product was purified by silica gel chromatography to obtain 142 mg of the desired product as an oil. IR spectrum (Liq) νmaxcm ^-1 : 1445, 1320,
1100, 1020 NMR spectrum (CDCl ₃ ) δppm: 3.42 (2H, t; J = 6.0Hz, CH ₂ C H ₂ B _Z ) 3.84 (4H, s, OCH ₂ CH ₂ O) 4.44 (2H, s, OC H ₂ Ph) 5.15 (1H, br.s, olefin-H) 7.28 (5H, s, aryl-H) Mass spectrum, m/e: 342 (M ⁺ ) Reference example 13 3-(5-benzyloxypentyl)- 7-Oxo-cis-bicyclo[3.3.0]-oct-2-ene 3-(5-benzyloxypentyl)-7.7-ethylenedioxy-cis-bicyclo[3.3.0]oct-2-ene (6.65 g ) to a mixture of acetone (120 ml), water (45 ml), and concentrated hydrochloric acid (1.0 ml),
Stir at room temperature for 21 hours. After the reaction is completed, sodium hydrogen carbonate is added to neutralize the mixture, and the acetone is distilled off under reduced pressure. Add saturated brine to the residue and extract with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 6.00 g of a residue. This was purified by silica gel column chromatography to obtain the desired product as an oil. 5.33g of product was obtained. IR spectrum (Liq) νmaxcm ^-1 : 1725 NMR spectrum (CDCl ₃ ) δppm: 3.42 (2H, t; J=6.0Hz, -CH ₂ C H ₂ OCH ₂ ph) 4.43 (2H, s, OC H ₂ Ph) 5.14 (1H, br.s, olefin-H) 7.24 (5H, s, aryl-H) Mass spectrum, m/e: 298 (M ⁺ ) Reference example 14 3-(5-benzyloxypentyl)-6β-carboxy -7α-hydroxy-cis-bicyclo[3.3.0]oct-2-ene and 3-(5-benzyloxypentyl)6β-carboxy-7α-
Mixture of hydroxy-cis-bicyclo[3.3.0]oct-3-ene 1,2- in 55% oily sodium hydrogen (1.91 g)
(dimethoxyethane) 170ml) suspension to 2.6-di-
Add t-butyl-p-cresol (9.60 g) and stir vigorously for 1 hour at an internal temperature of 40°C. Then the internal temperature is 30
After cooling to ℃, increase the internal temperature while introducing carbon dioxide gas.
Stir for 30 minutes at 30°C. After cooling to an internal temperature of 10°C, 1,2-dimethoxyethane (20
ml) Remove the solution and stir for 2 hours at an internal temperature of 10°C.
Then, a solution of sodium borohydride (820 mg) in t-butyl alcohol (40 ml) and water (13 ml) was added dropwise to the mixture, and the mixture was stirred for 1 hour at an internal temperature of 10°C. After the reaction was completed, the reaction solution was poured into water, washed with hexane, and the aqueous layer was made acidic with 10% hydrochloric acid.
Extract with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.42 g of a residue.
By purifying this product using silica gel column chromatography, the target product is obtained as an oil.
4.28g was obtained. Sakae IR spectrum (Liq)
νmax cm ^-1 : 3350, 1710 NMR spectrum (CDCl ₃ ) δppm: 3.49 (2H, t; J=6.0Hz, CH ₂ C H ₂ OB _Z ) 4.52 (2H, s, CH ₂ OC H ₂ Ph) 7.08 ( 2H, s, OH, COOH) 7.37 (5H, s, aryl-H) Mass spectrum, m/e: 344 (M ⁺ ) Reference example 15 3-(5-benzyloxypentyl)-6β-hydroxymethyl-7α- Mixture of (2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene and oct-3-ene A mixture of hydroxycarboxylic acids (compound of Reference Example 14: 4.28 g) was mixed with methylene chloride (10 ml). ), add dihydropyran (3.4 ml) and a catalytic amount of pyridine hydrochloride, and stir at room temperature for 21 hours. Next, add lithium aluminum hydride (500 mg) to tetrahydrofuran (30 ml) under ice cooling.
Add to the suspension and stir for 1 hour at an internal temperature of 18°C.
After the reaction is complete, add 4% aqueous sodium hydroxide solution (2
ml) and stir at room temperature. After removing the formed white precipitate, the liquid was concentrated under reduced pressure to obtain a residue.
Obtain 7.60g. This product was purified by silica gel column chromatography to obtain 4.840 g of the desired product as an oil. I spectrum (Liq) νmaxcm ^-1 : 3430, 1455,
1120 NMR _spectrum ( _CDCl3 ) δppm: 3.47 (2H, t; J=6.0Hz, CH2CH2OBZ ) 4.53 (2H, s, OC _{H2Ph )} 5.30 (1H, _br.s , olefin-H ) 7.37 (5H, s, aryl-H) Mass spectrum, m/e: 414 (M ⁺ ) Reference example 16 3-(5-penzyloxypentyl)-6β-formyl 7α-(2-tetrahydropyranyloxy) -Mixture of cis-bicyclo[3.3.0]oct-2-ene and oct-3-ene Mixture of alcohols (compound of Reference Example 15:
Triethylamine (13.5 ml) was added to a solution of 4.82 g) in dimethyl sulfoxide (42 ml), followed by a solution of pyridine-sulfuric anhydride complex (4.720 g) in dimethyl sulfoxide (22 ml), and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was poured into saturated brine, extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.96 g of the target product as an oil. Obtained. This substance is used in the next reaction without purification. IR spectrum (Liq) νmaxcm ^-1 : 1725 Reference example 17 3-(5-benzyloxypentyl)-6β-(3
-oxo-5(R), -dimethyl-1,8-decadienyl)-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0] mixture of oct-2-ene and oct-3-ene 0.43 g After washing the oil content of 55% oily sodium hydride with n-hexane, add 60 ml of tetrahydrofuran.
and dimethyl 2-oxo-4(R), 8-dimethyl-
Add 3.55 g of 7-nonenylphosphonate and stir for 30 minutes. Next, the aldehyde compound 3.05 obtained in Reference Example 16
Dissolve g in 10 ml of tetrahydrofuran, add and stir at room temperature for 30 minutes. The reaction solution was diluted with ice water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography using silica gel (80 g). By subjecting the mixture to e.g., 3.50 g of the desired oily compound was obtained. IR spectrum (Liq) νmaxcm ^-1 : 1625, 1670,
1695 NMR _spectrum ( _CDCl3 ) δppm: 0.89 (3H, d; J=7Hz, _CH3 ) 3.48 (2H, t _, CH2O _CH2Ph ) 4.50 (2H, s, CH2Ph ) 4.8-5.4 (2H, m, =CH-×2) 6.18 (1H, dd, J=16.3Hz, =CH-) 6.5-7.2 (1H, m, =CH-) 7.29 (5H, s, aryl-H) Reference example 18 3-(5-benzyloxypentyl)-6β-(3α
-Hydroxy-5(R),9-dimethyl-1,8
Enone form obtained in Reference Example 17 (3.50 g ) methyl alcohol solution (25 ml) was added with cerium chloride under ice cooling.
Hydrate (3.6g) in methyl alcohol solution (30ml)
plus sodium borohydride (600mg)
Add. After stirring for 30 minutes at an internal temperature of 5 to 10°C, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain an oily residue.
This compound gives a 3-spot on thin layer chromatography, so it was dissolved in 50 ml of acetic acid without purification, mixed with 30 ml of water and tetrahydrofuran (THF).
20 ml was added and stirred at 50°C for 2.5 hours. Meanwhile 15
Added ml of water. After the reaction is complete, add an aqueous solution of sodium hydroxide (40 g) to neutralize and extract with ethyl acetate. The extract is washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by column chromatography using silica gel. 1.15g of oily 6β-(3β-hydroxy) from the 20-25% ethyl acetate/n-hexane outflow.
A body (2 spots by thin layer chromatography) was obtained. From the 30-50% ethyl acetate/n-hexane outflow, 1.54 g of oily 6β-(3α-hydroxy) compound (2 spots determined by thin layer chromatography) was obtained. 6β-(3β-hydroxy) form: IR spectrum (Liq) νmaxcm ^-1 : 3370 NMR spectrum (CDCl ₃ ) δppm: 0.90 (3H, d, CH ₃ ) 1.60 (3H, s, CH ₃ ) 1.68 (3H, s , CH ₃ ) 3.45 (2H, t, -CH ₂ O-) 4.50 (2H, s, CH ₂ O-) 5.10 (1H, t, = CH-) 5.28 (1H, br.s, = CH-) 5.60 (2H, m, -CH=CH-) 6β-(3α-hydroxy) body: IR spectrum (Liq) νmaxcm ^-1 : 3360 NMR spectrum (CDCl ₃ ) δppm: 0.90 (3H, m, CH ₃ ) 1.60 (3H , s, CH ₃ ) 1.65 (3H, s, CH ₃ ) 3.50 (2H, t, J=6Hz, -CH ₂ O-) 4.50 (2H, s, -CH ₂ O-) 5.12 (1H, br.t , =CH-) 5.28 (1H, br.s, =CH-) 5.50 (2H, m, -CH=CH-) Reference example 19 3-(5-benzyloxypentyl)-6β-[3α
-(2-tetrahydropyranyloxy)-5
(R), 9-dimethyl-1,8-decadienyl]
-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene mixture Alcohol (6β-(3α-hydroxy) form of Reference Example 18: 1.50 g) is chlorinated Dissolved in methylene (10 ml), added 2,3-dihydropyran (0.95 ml) and a catalytic amount of p-toluenesulfonic acid under ice cooling, and
Stir for 1 hour at °C. After the reaction is completed, the mixture is neutralized with a 5% aqueous sodium bicarbonate solution, saturated brine is added, and the mixture is extracted with ethyl acetate. The ethyl acetate extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the dissolved amount was distilled off under reduced pressure to obtain a residue. This product was purified by silica gel column chromatography to obtain 2.10 g of the desired product as an oil. IR spectrum (Liq) νmaxcm ^-1 : 1022, ₁₀₃₅ NMR spectrum (CDCl3) δppm: 0.90 (3H, m, _CH3 ) 1.46 (2H, t, _-CH2O- ) 4.50 (2H, s, _-CH2 O−) 4.70 (2H, br.s,

[Formula]) 4.90-5.8 (4H, m, =CH-×4) Reference example 20 3-(5-hydroxypentyl-6β-[3α-(2
-tetrahydropyranyloxy)-5(R), 9
-dimethyl-1,8-decadienyl]-7α-
(2-tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene The benzylpyranyl compound obtained in Reference Example 19 ( When excess sodium metal is added to a solution of 2.10 g) of liquid ammonia (40 ml) and tetrahydrofuran (30 ml), the solution develops a dark blue color. After stirring at -70°C for 30 minutes, a large excess of ammonium chloride was added. Then, the temperature was returned to room temperature, ammonia was distilled off, water was added to the residue, extracted with diethyl ether, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to form a residue. and this one,
It was purified by silica gel column chromatography to obtain 1.46 g of the desired product as an oil. IR spectrum (Lip) νmaxcm ^-1 : 3350 NMR spectrum (CDCl ₃ ) δppm: 0.92 (3H, m, CH ₃ ) 2.63 (3H, s, CH ₃ ) 2.69 (3H, s, CH ₃ ) 3.64 (2H, t , −CH ₂ O−) 4.82 (2H, br.s,

[Formula]) 5.0 to 5.8 (4H, m, -CH=×4) Reference example 21 3-(4-carboxybutyl)-6β-[3α-(2
-tetrahydropyranyloxy)-5(R), 9
-dimethyl-1,8-decadienyl]7α-(2
-Tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene Add Jones reagent to a 50 ml acetone solution of the alcohol (1.20 g) obtained in Reference Example 20 at an internal temperature of -25°C. Add 1.5 ml (prepared by diluting 26.7 g of chromic anhydride and 23 ml of concentrated sulfuric acid with water to make a total of 100 ml) dropwise and stir at the same temperature for 1 hour. After the reaction is completed, the mixture is neutralized with a 5% aqueous sodium hydrogen carbonate solution, and the acetone is distilled off under reduced pressure. Water was added to the residue and extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. This product was purified by silica gel column chromatography to obtain 0.737 g of the desired product as an oil. IR spectrum (Liq) νmaxcm ^-1 : 1735, 1710 NMR spectrum (CDCl ₃ ) δppm: 0.92 (3H, m, CH ₃ ) 1.62 (3H, s, CH ₃ ) 1.69 (3H, s, CH ₃ ) 4.72 (2H ,br.s,

5.0-5.8 (4H, m, =CH-x4) 251 mg of this compound was reacted with excess diazomethane in ether at room temperature to give 253 mg of the corresponding methyl ester. IR spectrum (Liq) νmaxcm ^-1 : 970, 1740 Reference example 22 3-(5-benzyloxypentyl)-6β-(3
-oxo-4-methyl-1-octenyl)-7α
-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3
-ene mixture 0.41 g 55% oily sodium hydride, dimethyl 2-oxo-3-methylheptylphosphonate
Using 3.56 g and 2.98 g of the aldehyde obtained in Reference Example 16, the same reaction treatment as in Reference Example 17 was carried out to obtain 3.21 g of the target compound in the form of an oil. IR spectrum (Liq) νmaxcm ^-1 : 1625, 1670, 1696 NMR spectrum ( _CDCl3 ) δppm: 1.07 (3H, d; J=5Hz, _CH3 ) 0.90 (3H, br.t, _CH3 ) 3.47 (2H, t; J=7Hz, -CH2OCH2Ph ) 4.50 (2H, s, CH2Ph) 5.30 (1H _, s, ₌ CH-) 6.20 ( 1H, dd; J=17.5Hz, = _CH- ) 6.7-7.05 (1H, m, =CH-) Reference example 23 3-(5-benzyloxypentyl)-6β-(3α
-hydroxy-4-methyl-1-octenyl)
-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene and their 6β-(3β-
Hydroxy) isomer The enone form obtained in Reference Example 22 (3.20 g), cerium chloride heptahydrate (3.5 g) and sodium borohydride (600 mg) were reacted and treated in the same manner as in the first step of Reference Example 18. The obtained residue was purified by silica gel column chromatography without treatment with acid. 850 from the hexane outlet containing 9% ethyl acetate
mg of 6β-(3β-hydroxy) form was obtained, and then
1.72 g of 6β- from the hexane outlet containing 10% ethyl acetate
(3α-hydroxy) form was obtained. 6β-(3β-hydroxy) form: IR spectrum (Liq) νmaxcm ^-1 : 3450, 1450, 1115 NMR spectrum (CDCl ₃ ) δppm: 0.7 to 1.1 (6H, m, CH ₃ ×2) 3.47 (2H, t; J=6.0Hz- CH2O -CH2Ph) 4.53 (2H _, s , CH2Ph) _5.28 (1H, br.s, ₌ CH-) 5.50~5.74 (2H, m, -CH=CH- ) 7.37 (5H, s, -Ph) 6β-(3α-hydroxy) form: IR spectrum (Liq) νmaxcm ^-1 : 3450, 1455, 1110 NMR spectrum (CDCl ₃ ) δppm: 0.7-1.1 (6H, m, CH ₃ × 2) 3.48 (2H, t; J=6Hz, -C H ₂ OCH ₂ Ph) 4.53 (2H, s, -C H ₂ Ph) 5.28 (1H, br.s, =CH-) 5.50~5.80 ( 2H, m, -CH=-CH-) 7.38 (5H, s, -Ph) Reference example 24 3-(5-benzyloxypentyl)-6β-[3α
-(2-tetrahydropyranyloxy)-4-methyl-1-octenyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0] Mixture of oct-2-ene and oct-3-ene Alcohol Using 1.72 g of [6β-(3α-hydroxy) form of Reference Example 23] and 0.91 ml of dihydropyran, the reaction and treatment were carried out in the same manner as in Reference Example 19 to obtain 1.80 g of the target compound in the form of an oil. IR spectrum (Liq) νmaxcm ^-1 : 1460, 1355, 1205, 1025 NMR spectrum ( _CDCl3 ) δppm: 3.47 (2H, t; J=6Hz, -CH2 _{- OCH2Ph} 4.52 (2H, s, -C H ₂ Ph) 5.20-5.80 (3H, m, = CH- x 3) 7.36 (5H, s, -Ph) Reference example 25 3-(5-hydroxypentyl)-6β-[3α-
(2-Tetrahydropyranyloxy)-4-methyl-1-octenyl]-7α-(2-tetrahydropyranyloxy]bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene Benzyl compound ( Using the compound of Reference Example 24 (1.80 g) and excess metal sodium, the reaction was carried out in the same manner as in Reference Example 20 to obtain 1.27 g of the target compound in the form of an oil. IR spectrum (Liq) νmax cm ^-1 : 3460, 1450 , 1200 NMR spectrum ( _CDCl3 ) δppm: 0.7-1.1 (6H, m, _CH3 × 2) 4.72 (2H, br.s

[Formula] x 2) 5.20-5.80 (3H, m, = CH- x 3) Reference example 26 3-(4-carboxybutyl)-6β-[3α-(2
-tetrahydropyranyloxy)-4-methyl-1-octenyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-
A mixture of 2-ene and oct-3-ene (compound of Reference Example 25; 1.27 g) was reacted in the same manner as in Reference Example 21 using 1.27 g of Johns reagent to obtain 1.05 g of the target compound in the form of an oil. . IR spectrum (Liq) νmaxcm ^-1 : 1732, 1707, 1020 NMR spectrum ( _CDCl3 ) δppm: 4.73 (2H, br.s,

[Formula] x2) 5.10-5.80 (3H, m, =CH- x3) 8.00-8.91 (1H, br.s, COOH) This compound was reacted with diazomethane to obtain the corresponding methyl ester. IR spectrum (Liq) νmaxcm ^-1 : 970, 1740 Reference example 27 3-(4-carboxybutyl)-6β-[3α-2-
Tetrahydropranyloxy)-4,4-dimethyl-1-octenyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene In Reference Example 16 A solution of 2.99 g of the obtained aldehyde and 4.31 g of tributyl 2-oxo-3,3-dimethylbutylphosphorane in dioxane (50 ml) was heated under reflux for 8 hours. After the reaction is completed, the solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography using silica gel. 3.57 g of enone was obtained from the hexane outflow containing 10% ethyl acetate. This enone was sequentially treated in the same manner as in Reference Examples 18, 19 and 20 to obtain 921 mg of the target compound in the form of an oil. IR spectrum (Liq) νmaxcm ^-1 : 3460, 1450, 1200 NMR spectrum ( _CDCl3 ) δppm: 0.7-1.1 (9H, m, CH3 _× 3) 4.70 (2H, br.s,

[Formula]×2) 5.20~5.80 (3H, m, =CH-×3)

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is an optionally protected hydroxymethyl group, an optionally protected formyl group, an optionally protected carboxy group, or an optionally substituted carbamoyl group (the substituent is a lower alkyl group, an aryl group) , represents an acyl group or a sulfonyl group),
R ² and R ³ are the same or different and represent a hydrogen atom or a hydroxyl group protecting group, and R ⁴ is an optionally substituted alkyl group (the substituent represents a halogen atom or a lower alkoxy group), an alkenyl group, an alkynyl group. basis,
An optionally substituted cycloalkyl group (the substituent represents a lower alkyl group) or a group of the formula -CH ₂ -Q-R ⁵ (wherein Q represents a single bond, an oxygen atom, a sulfur atom or a methylene group) , R ⁵ represents an optionally substituted cycloalkyl group (the substituent represents a lower alkyl group) or an aryl group)
, A is an oxymethylene group (-O-CH ₂ -),
Represents a thiomethylene group (-S- _CH2- ) or a vinylene group, B represents an ethylene group, a trans-vinylene group, or an ethynylene group, n represents an integer of 2 to 4, and n' represents an integer of 0 to 4. The dotted line indicates the double bond at the 2nd or 3rd position. However, when A represents a vinylene group, n' represents 0. ] A carbacycline derivative and a pharmacologically acceptable salt thereof.