JPS60181041A - Carbacyclin derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is hydroxymethyl, formly, carboxy, etc.; R<2> and R<3> are H, or OH-protecting group; R<4> is alkyl, alkenyl, alkynyl, -CH2-Q-R<5> (Q is single bond, O, s, or CH2; R<5> is cycloalkyl, or aryl), etc.; A is oxymethylene, vinylene, etc.; B is ethylene, trans-vinylene, ethynylene; n is 2-4; n' is 0-4] and its salt. EXAMPLE:3-(3-Oxa-4-carboxybutyl)-6beta-( 3alpha-hydroxyoct-1-enyl )-7alpha-hydroxybicyclo [3,3,0]oct-2-ene. USE:A drug having improved inhibitory action on blood platelet aggregation, vasodilating action on coronary vessel, bronchodilatory action, antiulcervaction, etc. Showing improved sustained release activity. PREPARATION:For example, a compound (shown by the formula I a) shown by the formula I where A is oxymethylene is obtained by reactions of three processes from a compound shown by the formula II as a raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [wherein R1 is a hydroxymethyl group that may be mined,
Represents an optionally protected formyl group, an optionally protected carboxy group, or an optionally substituted carbamoyl group, and R
2 and R3 are the same or different and represent a hydrogen atom or a hydroxyl group, and R4 is an optionally substituted alkyl group, alkenyl group, alkynyl group, an optionally substituted cycloalkyl group, or a group of the formula -〇 H2-Q-R5 group (wherein Q represents a single bond, oxygen atom, sulfur atom, or methylene group, R5
represents an optionally substituted cycloalkyl group or aryl group. ), A is an oxymethylene group (-〇-CH2
-), a thiomethylene group (-s-an2-), or a vinylene group, B represents an ethylene group, a trans-vinylene group, or an ethynylene group, n represents an integer from 2 to 4, and n represents an integer from O to 4. , and the dotted line indicates the double bond at the 2nd or 3rd position.

The present invention relates to carbacycline derivatives having the following and pharmacologically acceptable salts thereof.

In the above formula, the protecting group for the hydromethyl group of R or the protecting group for the hydroxyl group of R3 is not particularly limited as long as it is a commonly used hydroxyl protecting group, but for example, acetyl, propionyl,
Lower aliphatic or aromatic acyl groups such as butyryl, isobutyryl, benzoyl, naphthoyl: benzyl, p
-Aralkyl group of nitrobenzyl, p-methoxybenzyl; 2-tetrahydrobyl, nil, 2-tetrahydrofinyl, 4-methoxytetrahydrobilane-4
5- to 6-membered heterocyclic group containing an oxygen atom or a sulfur atom in the ring with or without an alkoxy group as a substituent such as -yl, 2-tetrahydrothiopyranyl; methoxymethyl, ethoxymethyl, benzyl Methyl group having an alkoxy group or aralkyloxy group as a substituent such as oxymethyl; 1-methoxyethyl, 1-
1-alkoxyethyl groups such as ethoxyethyl or trimethylsilyl, triethylsilyl, tri-n-propylsilyl, t,-butyldimethylsilyl, diphenyl t
- tri-lower alkyl or diaryl-lower alkylsilyl groups such as -butylsilyl, preferably the protecting group for the hydroxymethyl group in R1 is an aralkyl group, and the protecting group for the hydroxyl groups in R2 and R is 2-tetrahydropyrani. or 2-tetrahydrobilanyl group.

R'ID The formyl group protecting group is not particularly limited as long as it is a commonly used formyl group protecting group.R represents a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, are ethylene, propylene,
It represents an alkylene group having 2 to 5 carbon atoms such as trimethylene, butylene, tetramethylene, λ2-dimethyltrimethylene, and Y represents an oxygen atom or a sulfur atom. ) can be mentioned.

The carboxyl group-protecting group for R1 is not particularly limited as long as it is a commonly used carboxy group-protecting group, but examples include lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl: benzil,
Aralkyl groups such as p-bromobenzyl; phenyl;
Aryl groups such as tolyl include benzhydryl or phenacyl groups, preferably lower alkyl groups.

Examples of the optionally substituted carbamoyl group for R1 include a carbamoyl group and a mono- or di-substituted carbamoyl group, and examples of the substituent include methyl,
Lower alkyl groups such as ethyl, n-propyl, isopropyl, n-butyl, aryl groups such as phenyl, tolyl, acyl groups such as acetyl, trifluoroacetyl, benzoyl, or methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl. Among them, a carbamoyl group or a methanesulfonylcarbamoyl group is preferable, and the methanesulfonylcarbamoyl group is particularly preferable.

Examples of the alkyl group of R4 which may be substituted include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobuty/L/, n-pentyl, impentyl, 1-methylpentyl, 2-methylpentyl. ,n
-hexyl, n-heptyl, -1,1-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 2-
Ethylpentyl, n-octyl, 2-methyloctyl,
n-nonyl, 2-methylnonyl, 2-ethyloctyl,
Mention may be made of alkyl groups having 1 to 12 carbon atoms such as n-decyl 2-methyldecyl or 2-ethyldecyl, preferably alkyl groups having 4 to 10 carbon atoms, such as n-butyl, isobutyl, n -pentyl, impentyl, 1-methylpentyl, 2-methylpentyl,
n-hexyl, n-hebutyl, 1.1-dimethylpentyl, 1-methylhexyl, 2-methylhexyl, 2-ethylpentyl, n-:t/butyl 2-methyloctyl or 2-ethyloctyl group, More preferably n-
Pentyl, 1-methylpentyl, nihexyl, 1.1
-dimethylpentyl, 1-methylbexyl group or 2-
It is a methyl bexyl group.

As the substituents of the optionally substituted alkyl group of R4,
For example, halos such as fluorine, chlorine, and bromine.

Mention may be made of a gun atom or a lower alkoxy group such as methoxy, ethoxy, n-propoxy, impropoxy, or n-methoxy, preferably a fluorine atom, a chlorine atom, or a methoxy group.

Examples of the alkenyl group for R4 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-hebutenyl, 1-methyl-5
-hexenyl, 6-m+-5-hephthynyl, 246-
Dimethyl-5-hebutenyl, 1.1.6-)dimethyl-
5-hebutenyl, 6-methyl-5-octenyl, 2,6
-dimethy/L/+ 5-octenyl, 6-ethyl-5-
Straight-chain or branched alkenyl groups having 3 to 12 carbon atoms such as octenyl, 2-methyl-6-ethyl-5-octenyl, and λ6-ethyl-5-octenyl can be mentioned, and are preferably is 1-butylvinyl, 2
-propylaryl, 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
-Heftynyl, 1-methyl-5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-hebutenyl, and other alkenyl groups having 5 to 9 carbon atoms.

Examples of the alkynyl group for R4 include propargyl, 2
-butynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexenyl, 1-methyl-2
-pentynyl, 1-methyl-3-benzonyl, 1,1-
Examples include alkynyl groups having 3 to 8 carbon atoms, such as dimethyl-2-pentynyl, 111-dimethyl-3-pentenyl, and 1.1-dimethy/l/-2-hexynyl, and preferably carbon atoms. Alkynyl groups having number 4 to 6, such as 2-butynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-henthynyl J! lt, :ha1
-methyl-3-pentynyl group, more preferably 1
-Methyl-3-pentynyl group.

Examples of the optionally substituted cycloalkyl group for R4 and R5 include cyclopropyl, cyclobutyl, cyclopentyl, 3-ethylcyclopentyl, cyclohexyl,
Examples include 3- to T-membered cycloalkyl groups which may have a lower alkyl group as a substituent such as 4-methylcyclohexyl and cycloheptyl, preferably cyclopentyl or cyclohexyl.

The aryl group of R5 is phenyl, 〇-tolyl, m
-tolyl, p-tolyl, p-ethylphenyl, m-n-
Propylphenyl, m-methoxyphenyl, p-methoxyphenyl, 0-ethoxyphenyl, 0-fluorophenyl, m-fluorophenyl, p-fluorophenyl,
m-chlorophenyl, p-chlorophenyl, p-bromophenyl, p-)! J fluoromethylphenyl, 3,4
Examples include phenyl groups which may have one or two substituents such as lower alkyl, lower alkoxy, halogen atoms, or trifluoromethyl, such as -dimethylphenyl, 3-fluoro-4-ethylphenyl, and λ4-dichlorophenyl. However, it is preferably a phenyl group which may be substituted with methyl, a fluorine atom, a chlorine atom, or a trifluoro group, and more preferably a phenyl group.

Q is preferably a single bond, an oxygen atom or a methylene group,
More preferably, it is a single bond or an oxygen atom.

Further, suitable -CH2-Q-R groups include, for example, cyclopentylmethyl, cyclohexylmethyl, 4-methylcyclohexylmethyl, benzyl, p-methylbenzyl,
m-) Lifluorobenzyl, 2-cyclopentylethyl, 2-(3-methylcyclopentylethyl), 2-cyclohexylethyl, 2-phenylethyl, 2 (p-fluorophenyl)ethyl, cyclopentyloxymethyl, cyclohexyloxymethyl , phenoxymethyl, m
-tolyloxymethyl, p-chlorophenoxymethyl, or phenylthiomethyl.

A is preferably an oxymethylene group or a thiomethylene group.

B is preferably a trans-vinylene group.

n is preferably an integer of 2, n is preferably 0 or 2, and more preferably 0. The double bond within the ring is preferably at the 2-position.

Among the compounds having the general formula (I) of the present invention, the compound in which R is a carboxy group can be converted into a pharmacologically acceptable salt form, if necessary. Examples of pharmacologically acceptable salts include sodium, potassium, magnesium,
Salts of alkali metals or alkaline earth metals such as calcium; ammonium salts; tetramethylammonium,
Quaternary ammonium salts such as tetraethylammonium, benzyltrimethylammonium, phenyltriethylammonium; methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, N-) IflLp hexylamine, cyclopentylamine, dicyclohexylamine, benzylamine, di Salts of lower aliphatic, lower cycloaliphatic and lower araliphatic amines such as benzylamine, α-phenylethylamine, ethylenediamine; such as piperidine, morpholine, pyrrolidine, piperazine, pyridine, 1-methylbiperazine, 4-ethylmorpholine Salts of heterocyclic amines and their lower alkyl derivatives; salts of amines containing hydrophilic groups such as mono-ethanolamine, ethyl jetanolamine, and 2-amino-1-butanol;

Moreover, the compound (1) of the present invention can also be used by forming an inclusion compound with a host compound such as α-1β-, r-cyclodexrin.

In addition, in the compound having the general formula (1), the stereoisomer based on the coordination of the hydroxyl group of the cyclopentane side chain, the double bond when R4 is an alkenyl group, and the double bond within the cyclopentene ring. Based on positional isomers exist. Therefore, when the compound having the general formula (1) is obtained as a mixture of these stereoisomers, the respective isomers can be obtained by separation and resolution using conventional methods. In the general formula (1), a mixture of these optical isomers and stereoisomers is all represented by a single formula, but the scope of the present invention is not limited thereby.

In addition, in general formula (■), suitable compounds include l) a compound in which R is an optionally protected hydroxymethyl group, an optionally protected carboxy group, or an optionally substituted carbamoyl group; 2) R is a hydroxymethyl group, an optionally protected carboxy group or a methanesulfonylcarbamoyl group,
A compound in which R2 and R3 are hydrogen atoms, 3) an alkyl group having 4 to 10 carbon atoms, an alkenyl group having 3 to 12 carbon atoms, or an alkenyl group having 3 to 12 carbon atoms, in which R4 may be substituted with a halogen atom or a lower alkoxy group; an alkynyl group having 4 to 6 members, a 5- to 6-membered cycloalkyl group or a cycloalkyl group having the formula, =H2-Q-R5 (in the formula, Q
is a single bond, an oxygen atom or a methylene group, and R5 is a phenyl group which may be substituted with a 5- to 6-membered cyclic cycloalkyl group, a lower alkyl group, a halogen atom, or a lower alkoxy group. ), 4) Compounds where A is an oxymethylene group or thiomethylene group, 5) Compounds where A is at the double bond or the 2nd position, 6) Compounds where n is 0, 7) Compounds where R is a hydroxymethyl group, protected a carboxy group or a methanesulfonylcarbamoyl group which may be
R2 and R3 are hydrogen atoms, and R4 has 4 to 1 carbon atoms, which may be substituted with a halogen atom or a lower alkoxy group
an alkyl group having 0 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 ape-like cycloalkyl group, or a formula -CH-Q
-R5 (wherein, Q is a single bond, an oxygen atom, or a methylene group, and R5 is a phenyl group optionally 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, thiomethylene group, or vinylene group, B i)E) is a lance-vinylene group, and n is 0
8) A compound in which R1 is a hydroxymethyl group or a carboxyl group that may be protected, R2 and R5 are hydrogen atoms, and R
an alkyl group having 4 to 10 carbon atoms, which may be substituted with a fluoro atom, a chlorine atom, or a methoxy group, an alkenyl group having 3 to 12 carbon atoms, an alkynyl group having 4 to 6 carbon atoms, 5 to 6 A membered cyclic cycloalkyl group or the formula -〇H2-Q-RC, where Q is a single bond or an oxygen atom, and R5 is a 5- to 6-membered cyclic cycloalkyl group, a methyl group, a fluoro atom, a chloro atom, or a methoxy It is a phenyl group which may be substituted with a group. ), A is an oxymethylene group or a thiomethylene group, B is a trans-vinylene group, n is an integer from 2 to 4, and n
is 0, 9) R is a hydroxymethyl group, a carboxy group or a methoxycarbonyl group, and R2 and R are hydrogen atoms,
R4 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 -〇H2-Q -R5 group (wherein R5 is a cyclopentyl group, cyclohexyl group or phenyl group, Q
is a single bond or an oxygen atom. ), A is an oxymethylene group or a thiomethylene group, B is a trans-vinylene group, n is an integer of 2, n' is 0, and the double bond in the ring is at the 2-position. , can be given.

Recently, prostacyclin (pG), 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 its green compounds. We synthesized novel carnocyclin derivatives represented by the general formula (1) and examined their pharmacological activities, and found that these derivatives had excellent platelet aggregation inhibiting, coronary vasodilatory, and bronchodilatory effects.
It exhibits anti-ulcer effects, particularly strong activity in inhibiting platelet aggregation, has remarkable persistence of activity compared to conventional prostacyclins, and is an important intermediate for the synthesis of active compounds. The present invention was completed after discovering the following.

Examples of the compound having the general formula (1) obtained by the present invention include the compounds described below.

1 Co2HHH-CH20CH2Ph-c! H-CH
,22Co2HHH-CH(\/\cH,\Cu-CM
, 23 Co2H1,,) 0-CHrΔcH,”C
H-CH\24 CH20HHH-CH Lead CMH3”
CH-CH\ 25 CH20HHH-cHr△CH,
-CH2CH, -20H.

6 Co2HI(H-CH2/'w"!'!"(!H
-CH-27Co2HHH-CH2/VVcH5'c)
i-CH\20H.

8 Co2HHH-CH$CH,"CH-CH% 29
C02H[1lci1 to Hρ via CH3XH-CH\3C
H.

10 Co2C! H,HH-0M2haha4CH,'cH
-CH, 2CH.

11 Co2HHH-CH 2 people CH5'cH-CH\
2CH, CH.

CH3 15-Co2H)I H-CHl5JXcHゝCM-C
! HN216 -CMH20HHH iiH (ψsoocH3
XH-Akebono\217 -Co2HHH-CH2haVVOC
H5CH""CH\2 number R'12R'R' B
n I5 CH3 23C02HHH-CH/VV”CH-CH,2CH5 CM.

28 Co2m(HH-CH2Δ-”-Cl-CH,2
2tj Co2CH,"[j 1LlU-CH2~"5
ゝCH-CHN430 Co2HHH-CH2PVc
I~ Be=C-2=C-231CHH-CH2Δ~”
-CH-CH\232 CH20CH2Ph ``C) TsubeH2ΔicH,''Q14噌\2M3 CH.

H5 38CO2HHH-cH/'V'V'cH-cH\21 CH3 39CO2CH3HH ijH/'S/VXH-CH-2
5 CH.

CH5 Number R'R2R'R' B n CH3 STCO2HHH-cH2C/VCH''CH-CHS2
1 CH2 CH2 CH3 63C! 021 (HH-CH=-CH35cH<H\
2 shoes 660H20H'C) tsu ri ゝCH-CH\ 2e
r co2a HH-CI'ca-CH,268Co
2HHH-C1-CH20M2- 269 CH20H
HHOゝCH謬CH＼2To ca2oca2pb'c
) O() 'CH-(!H\371 CH20H'C
) 'C) -C> -c=c-272C02)! O
OO5CH\2 ys co2cH3HH() χHwCHN' 474
Co2HHH-C)-C15ゝCH-CH\ 275
CH20HHH-C>ゝCH-CH,2'16 C
o2HHH() 'CH-CH\ 277 C1120
H Tsutsu Be R2 Re 1H E＼ 2711 Co2H
HH-cH2() ′cH-(!H\279 Co2H
HH-CH2-8-■ ゝCH-CH＼280 CH2
0Hlf H-QH2÷OゝCM-CH, 281Co2
HHH-CH2toQ++CM-CH-282co2n
HH-CH247\CH-CH\ 2t sa co2HHH-cao4 ゝCH<H\20c!
H5 114CH20HHH-CH2-0-11) ゝCH\2 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, compounds in which R is a carboxyl group include its sodium salt or potassium salt.

Furthermore, in all the compounds in the above table, n represents 0.
．． n for 40, 41.51.63, 67 and 16
Compounds in which is an integer of 2 are also suitable.

Compound (1) according to the present invention can be produced according to the following method.

ω) (To) Q/ (Ia) B method (V) (B) (Ib) (II') (VIA) In the above formula, R, R, R, R, B, n, n and the dotted line are It has the same meaning as above, R6 represents a carboxyl group which may be protected, R' and R8 represent a hydroxyl protecting group, R is an alkanesulfonyl group such as methanesulfonyl or ethanesulfonyl, or benzenesulfonyl, p
- represents an arylsulfonyl group such as toluenesulfonyl, RlG represents a lower alkyl group or an aryl group,
W represents a sulfur atom or a xelene atom, and m represents an integer of 1 to 3.

Method A is a method for producing compound (Ia) in which A is an oxymethylene group in compound (1).

The first step is to produce an alcohol derivative having the general formula 2, which is achieved by contacting the compound 2 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, and aluminum compounds such as lithium aluminum hydride, lithium aluminum hydride-aluminum chloride, and diisobutylaluminum hydrogen, with lithium aluminum hydride being particularly preferred.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, but ethers such as ether, tetrahydrofuran, and dioxane are preferred.

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.

Moreover, the compound (-) can also be produced separately through the 11th to 22nd steps described below.

The second step is a step of producing a compound having the general formula (conversion), in which the compound (conversion) is treated with a base in an inert solvent, and then
General formula % formula % () (wherein, R6 and n' have the same meanings as described above,
X represents a halogen atom such as chlorine, bromine, or iodine. )
or an alkali metal salt thereof.

Bases used include, for example, alkali metal hydrides such as lithium hydrogen, sodium hydrogen and potassium hydrogen; alkaline earth metal hydrides such as calcium hydrogen and barium hydrogen; methyllithium, n-butyllithium,
Organolithium compounds such as phenyllithium; or sodium methoxide, sodium methoxide, potassium ethoxide, sodium n-proposite, potassium t
Alkali metal alkoxides such as -butoxide, sodium t-bento, and the like can be used, but are preferably alkali metal hydrides.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, but for example, hydrocarbons such as heyasan, benzene, toluene, and xylene; ethers such as ether, tetrahydrofuran, dimethoxyethane, and diglyme; Amides such as formamide, dimethylacetamide, hexamethylphosphoryltriamide; or sulfoxides such as dimethyl sulfocarbonate, or a mixed solvent thereof can be mentioned, but amides, sulfocarbons or a mixture thereof are preferably used. It is a solvent.

The reaction temperature is -78°C to 50°C in the reaction with a base.
In the reaction with compound (1), the temperature is 0°C to 50°C. The time required for the reaction is 10 minutes for the reaction with a base.
The reaction time is from 1 minute to 1 hour, and in the reaction with compound
hours to 48 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, making it acidic if necessary, 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 third step is a step that is performed as desired, and is a step in which R7 and/or R
Removal reaction of the protecting group of the hydroxyl group contained in 8, Removal reaction of the protecting group of the carboxy group contained in R6, Reaction of converting R6 into a dimethyl group in a mash, and reaction of converting the obtained hydroxymethyl group to a formyl group (including reaction to protect ), a reaction to esterify a simple carboxy group, or a reaction to convert a carboxy or ester to an optionally substituted 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 methanol, ethanol, n
-Alcohols such as propatool and isopropyl alcohol; ethers such as ethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; dialkyl sulfoxides such as dimethyl sulfoxide, and mixed solvents of these organic solvents and water. can.

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 to 12 hours. On this occasion,
When 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 agents used include lithium,
Alkali metals such as sodium and potassium or alkali metal sulfides such as sodium sulfide or potassium sulfide can be mentioned, but alkali metals are preferred. 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 tetrahydro-7rane, and the reaction with an alkali metal sulfide is preferably carried out in an alcohol such as methanol or ethanol. It is suitably carried out in an ether such as tetrahydrofuran or dioxane, or a mixed solvent of these organic solvents and water.

The reaction temperature is -78℃ to -2℃ for reactions with alkali metals.
In the reaction with an alkali metal sulfide, the temperature is 0°C to 100°C, and the time required for the reaction is usually 20 minutes to 6 hours.

At this time, if the carboxyl group is an aralkyl, benzhydryl or phenacyl group, it is removed at the same time.

Furthermore, when the protecting group is a p-methoxybenzyl group, it can also be removed by treatment with cerium ammonium fluoride in aqueous acetone at around room temperature, or with an oxidizing agent such as dichlorodicyanoquinone or sodium persulfate. It is also removed by

When the protecting group for the hydroxyl group is a heterocyclic group, a methyl group or a 1-alkoxyethyl group having an alkoxy or aralkyl group 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, methanesulfonic acid, benzenesulfonic acid, p
- Organic acids such as 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 absence of a solvent, but in order to carry out the reaction smoothly, it is preferable to use a solvent, and the solvent to be used is not particularly limited as long as it does not play a role in this reaction, such as water. ; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; or mixed solvents of these organic solvents and water are preferably used. The reaction temperature is not particularly limited and is 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, contact with water or water containing an acid or base, or in an inert solvent. This is easily achieved by reaction with fluorides such as tributylammonium fluoride. When water containing acids or bases is used, 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, sulfuric acid, etc. 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 any 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, a mixed solvent of water and an organic solvent such as ethers such as tetrahydrofuran or dioxane; or alcohols such as methanol or ethanol is 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 completion of the reaction, 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, the solvent is distilled off from the extract.

When R6 and R7 are the same protecting group, they are removed simultaneously by the above-mentioned protecting group removal reaction. In addition, by appropriately selecting a protecting group, deprotection can also be carried out in an appropriate manner.

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 the same manner 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 reaction is completed, 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 R6 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, R2 and R3 need to be hydroxyl-protecting groups.

Examples of the oxidizing agent used include chromic anhydride, chromic anhydride-pyridine complex salt (Co11ins reagent), chromic anhydride-concentrated sulfuric acid-water (Jonea reagent), chromic acids such as sodium dichromate, potassium dichromate; N-
Bromoacetamide, N-promusuccinimide, N-
Organic active halogen compounds such as glomphthalimide, IJ-/rolu-p-toluenesulfonamide, and N-chlorobenzenesulfonamide; aluminum-tart-
Aluminum alkoxides such as butoxide and aluminum isopropoxide; dimethyl sulfoxide-dicyclocarbodiimide; pyridine-sulfuric anhydride and the like are preferably used.

The reaction is preferably carried out in an inert organic solvent, examples of which include halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ethers such as ether, tetrahydrofuran, dioxane, etc. Mention may be made of 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, if insoluble matter is present after the reaction is completed, separate the r.

It can be obtained by pouring into ice water, neutralizing as appropriate, extracting with a water-immiscible organic solvent, and distilling off the solvent.

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-)luenesulfonic acid or phorontrifluoride.

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. Esterifying agents used include, for example, diazomethane,
Diazoalkanes such as diazoethane, diazo-n-propane, diazoisopropane, and diazo-n-butane; alcohols that form ester groups such as methanol, ethanol, n-globanol, isopropyl alcohol, and n-butanol, and hydrochloric acid, odor Mineral acids such as hydrohydric acid or sulfuric acid or methanesulfonic acid, benzenesulfonic acid
li! Organic acids such as <trip-)luenesulfonic acid, lower alkyl halides such as methyl bromide and ethyl bromide, and bases such as sodium hydroxide, potassium hydroxide, and sodium carbonate are 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 ethers such as ethyl ether and dioxane are suitable. There is no limit to the reaction temperature, but in order to suppress side reactions and prevent decomposition of the diazoalkanes, it is desirable to carry out the reaction at a relatively low temperature, and it is usually preferably carried out under water 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 ranges from room temperature to the temperature of the alcohol used.
A good JK is performed near the l1 school temperature. The reaction time 8 takes approximately 1 hour to 2 days, depending on the reaction temperature and the type of alcohol-71 used.

Also, benzyl bromide% carboxylic acid sodium salt
Corresponding esters are also prepared with halides such as p-methoxybenzyl chloride, phenacylbromide, penthydryl chloride and bases such as triethylamide.

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 reaction product and the reagent are distilled off, and if necessary, the product is further dissolved in an organic solvent, and the organic solvent layer is dissolved in an aqueous solution of sodium bicarbonate or nine thorium carbonate. After washing with an aqueous alkali carbonate solution and drying.

It is obtained by distilling off the solvent 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 bath agent. The amine compound used is not particularly limited as long as it is used when amidating an ester group.

Examples of the amine compounds used include ammonia, L-methylamine, ethylamine, n-propylamine,
Isopropylamine, n-butylamine, aniline, p
- 1 such as methylaniline, dimethylamine, methylethylamine, diethylamine, N-methylaniline, N-ethylaniline, N-methyl-m-methylaniline
or secondary amines. The solvent to be used is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as aqueous ether, tetra-hydrofuran, 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 benzene, toluene, xylene or ethers such as ether, tetrahydrofuran, dimethoxyethane. The reaction temperature is room temperature with electricity applied, and the reaction time is 30 minutes to 10 hours.

The reaction for converting a carboxy group into an N-sulfonylcarbamoyl group is carried out in an inert solvent, after conversion to an active amide derivative, a sulfonic acid such as methanesulfonic acid amide, benzenesulfonic acid amide, p-)luenesulfonic acid amide, etc. This is done by reacting with an amide. The activated amide derivatives are prepared by combining the corresponding compound with an N-hydroxyamide such as N-hydroxysucciamide or N-hydroxyphthalamide in the presence of a condensing agent such as dicyclohexylcarbodiimide, usually at around room temperature for 30 to 16 hours. Produced by time reaction. The reaction between the activated amide spinner 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; Amides such as dimethylformamide, dimethylacetamide; or sulfoxides such as dimethylsulfoxide can be used.

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 neutralizing the reaction mixture in ice water, if necessary, and then 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 xemography and recrystallization.

Method B is a method for producing compound (lb) in which %A in compound (I) is a thiomethylene group.

The fourth step of method B is a step of producing a sulfonyloxy derivative having the general formula (V), in which compound (2) is prepared in an inert solvent.
is achieved by reacting with a sulfonyl halide.

The sulfonyl halide used has the formula R9X, where R
9 and X have the same meanings as described above. )In Although,
Preferred are methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and p-)toluenesulfonyl chloride.

The reaction line is preferably carried out in the presence of a base, and the bases used are preferably triethylamine, N,N-dimethylaniline, and pyridine%'-(N,N-dimethylamino).
Pyridine, 1,5-diazapicic E2 (4,3,0)
/Nen-5 (DBN), 1. It-diazabicyclo[5,4,0]]undecene-1DBLJ).

The inert solvent used is not particularly limited as long as it does not participate in the reaction, but includes hydrocarbons such as n-hexane, cyclohexane, benzene, toluene, and xylene; ethers such as ether, tetrahydrofuran, and dimethoxyethane. or halogenated hydrogen members such as methylene chloride, chloroform, and carbon tetrachloride, but aromatic hydrocarbons and halogenated hydrocarbons such as benzene and toluene are preferred. .

The reaction temperature is usually around room temperature, and the time required for the reaction is 3
The duration ranges from 0 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 (9), in which compound (V) of the general formula % formula % (wherein R6 and n' are as described above) is added in the presence of a base in an inert solvent. Show the same meaning.

) is achieved by reacting with a compound having

The base and inert solvent used are the same as those exemplified in the second step of the above-mentioned method.

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 6th step is a step that is carried out as desired for P9T, and includes a reaction for removing the protecting group for the hydroxyl group of R' and/or R8, a reaction for removing the protecting group for the carboxy group contained in R6, and converting R6 into a hydroxymethyl group. Reaction, reaction of converting the obtained human sekidimethyl group into formyl group (including reaction to protect), R6
It includes a reaction of esterifying a carboxy group of and a reaction of converting a carboxy or ester into an optionally substituted 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 (IC) in which the compound (1) is a vinylene group.

Step 7 of method C is a process for producing a compound having the general formula (e), in which the compound having the general formula (II') is treated with a base in an inert solvent, and then the general formula % formula % () ) (In the formula, R, W and X have the same meanings as described above.

) is achieved by reacting with a compound having

R6 in compound (■') is preferably a protected carboxy group.

R'' is preferably an aryl group.

Examples of bases used include methyllithium, n-
organolithium compounds such as butyllithium, β-butyllithium, phenyllithium; dialkylaminolithium such as diisopropylaminolithium, dicyclohexylaminolithium, impropyl-cyclohexylaminolithium; or bis(trimethylsilyl)lithium amide, bis Bis-silyl lithium amides such as (triethylsilyl) lithium amide and bis(diphenylmethylsilyl) lithium amide can be mentioned, but di-dialkyl lithium amide is 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 1100°C to room temperature for the reaction with the base, and 0°C to 50°C for the reaction with the compound O1) or (Xll), and the time required for the reaction is 10°C for the former reaction. The reaction time ranges from minutes to 2 hours, and for the latter reaction from 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 water, extracting 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 eighth step is a step for producing a compound having the general formula (■), which is achieved by treating the compound (■) with an oxidizing agent in an inert solvent, and then 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, but preferably hydrogen peroxide or Metachloroperbenzoic acid.

Inert solvents used include, for example, aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform; ether, tetrahydrofuran, dimethoxyethane,
Ethers such as diglyme; artificial acids such as ethyl acetate; alcohols such as methanol, ethanol, n-propanol; water; When hydrogen oxide is used, a mixed solvent of water-alcohol-esters is used, and when an organic peracid is used, a halogenated hydrocarbon is used.

The reaction temperature is usually -50°C to SOC, and the reaction time is 30 minutes to 5 hours).
The treatment can also be carried out at 0° 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, filtering if necessary if insoluble matter is generated, extracting 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 ninth step is a step carried out as desired, and is a step performed as desired.
Removal reaction of the protecting group of the hydroxyl group in 8, Removal reaction of the protective group of the carboxy group present in R6 Reaction of converting R6 into a hydroxymethyl group, Reaction of converting the obtained hydroxymethyl group into a formyl group (reaction to protect) ), a reaction of esterifying the carboxy group of R6, or a reaction of converting carboxy or ester into an optionally substituted carbamoyl group.

This step is carried out in the same manner as the third step of the mining law.

The raw material compounds (M) and (II') of the present invention can be obtained from publications having the general formula (XI) (for example, JP-A-54-95552, JP-A-54-130543) according to the following method.
No., JP-A-55-5755.9 or JP-A-55-28
945) with a base or acid in an inert solvent.

In the above formula, R', R', R', R8,B
, n' and the dotted line have the same meanings as described above, and p represents an integer from 0 to 5.

In a reaction in which compound (XI[) is treated with a base.

The bases used can include aminolithiums such as Ktli diisopropylaminolithium, isopropylcyclohexylaminolithium, dicyclohexylaminolithium, and the inert solutions used include aminolithiums such as Ktli diisopropylaminolithium, isopropylcyclohexylaminolithium, dicyclohexylaminolithium; Although not particularly limited, ethers such as ether, tetrahydrofuran, and dimethoxyethane can be preferably used.

The reaction temperature is -18°C to 0°C ('hj), and the time required for the reaction is 30 minutes to 3 hours.

This reaction is particularly suitable in the case where p is an integer of O and ze is an OoliL number in the compound (Xlll).

Examples of acids used in the reaction of treating compound 0If) include inorganic acids such as hydrochloric acid, nitric acid, and sulfuric acid;
Organic acids such as acetic acid, trifluoroacetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-)luenesulfonic acid, and camphorsulfonic acid can be mentioned, and preferred are 11C hap-)luenesulfonic acid and camphor sulfonic acid. It is sulfonic acid.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, but examples include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as ether, tetrahydrofuran, and dioxane, methylene chloride, and chloroform. , halogenated hydrocarbons such as carbon tetrachloride, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, water or a mixed solvent of the above-mentioned organic solvents and water, preferably. are aromatic hydrocarbons.

The reaction temperature is from SaC to 150°C, and the time required for the reaction is usually from 1 hour to 10 hours.

Protecting groups from which R' and/or R8 are removed by acid, such as heterocyclic groups, alkoxy or ara, are also removed at the same time. In this case, the conventional method 1, for example, reaction with an aralkyloxymethylnolide or a trisubstituted silylnolide in the presence of an acid base, or a reaction with an aralkyloxymethylnolide or a trisubstituted silylnolide in the presence of a base. The hydroxyl group can be protected by h''-.

This reaction is carried out in compound (X[) from p bL l to 5
It is suitable when the value is an integer of .

After completion of the reaction, the target compound is collected by using an anti-silicone mixture in accordance with a conventional method. For example, it can be obtained by extracting the reaction mixture in ice water with a water-immiscible organic solvent and distilling off the solvent.

Furthermore, if necessary, it is also possible to perform purification by column chromatography, recrystallization, etc., and to separate isomers at the 2- and 3-positions with respect to the double bond in the ring.

Compounds (1), (1') and (2) can also be obtained by the following method from known compounds having the general formula (X[V) (W) (XV) CXK) (X's 0 (blade) H (XK) (XX) (X)I) RoR7 (xQl) (xxm) oaav) (XXV) RoR7δR8 (xXvl) OtsuR7OtsuR8 (Ω) In the above formula, R'JR',R',n', p
The dotted line also has the same meaning as described above, aSl represents an aralkyl group, and R12 represents a hydrogen atom or a lower alkyl group.

Compound (W) is reacted with a Grignard reagent having the general formula % (in the formula, njl, n' and pH have the same meanings as above) to form an alcohol having the general formula (XV). , (11th engineering 8
), # (e.g. p-)luenesulfonic acid);
General formula (12th step to produce a compound with 1% ri)
, and an acid (for example, hydrochloric acid) to obtain an oxo compound having general formula (b) (13th step).

A compound (expletive) is reacted with a carboxylating agent (e.g., carbon dioxide, di-lower alkyl carbonate) in the presence of a base (e.g., water-enriching compound) to obtain a compound having the general formula ((e)). 14th step) and a reducing agent (for example, sodium borohydride) to produce a compound having the general formula (U) (15th step).
dihydropyran-p-toluenesulfonic acid)
The mixture is incubated and a compound having the general formula (XX) is obtained (first step).

Compound (XX) is treated with a reducing agent (for example, sodium aluminum hydride) to obtain a compound having the general formula 0Di (step 1T), which is oxidized with sulfuric anhydride-pyridine to obtain a formyl compound having the general formula (coupling). After manufacturing (18th step)
, reacted with a compound having the general formula (MeO)2]''%-(J)-R'4 (XXK) (wherein R4 has the same meaning as described above, and Me represents a methyl group). , general formula (XX
III) (step 19).

Treat the compound (xxm) with a reducing agent (e.g., sodium borohydride) to obtain a compound having the general formula (XXIV) (Step 20), protect the hydroxyl group according to a conventional method,
Obtaining a compound having general formula (XXV) (21st step)
, R11 according to a conventional method (for example, sodium-liquid ammonia or cesylium ammonium fluoride), a hydroxymethyl compound having the general formula (XXW) can be produced.

Furthermore, compound (XXM) was prepared by a conventional method (for example, Jqnes
A carboxy compound having the general formula (xxvn) can be produced by oxidation according to reagent: chromic anhydride-sulfuric acid).

Furthermore, among the starting compounds (1), (I') or (2), a compound having a knee double bond at the 2-position is the compound (x
vi) to compound (XX
), a compound (XX') having a double bond at the 2-position
It is also possible to produce the compound (XX') separately by reacting the obtained compound (XX') in the same manner as in the 17th to 23rd steps.

(Xi) (XXX) (XXXI) (xxxn) υ (XXX[V) δH (XIOIIlf) MiR' (XL) CIR' (XLI) δR7 (XX') In the above formula, R7, R11, R12, nt and pB has the same meaning as above, and M8 represents a methanesulfonyl group.

The compound (X%K) is treated with perbenzoic acid (for example, methac-n-perbenzoic acid) to obtain an epoxide having the general formula (XXX) (24th step).

Compound (XXX) is treated with a Lewis acid (e.g., porontrifluoride-ether complex) to give the general formula (XXM)
The oxo compound having the general formula (x
xxi) is obtained (step 26) and treated with an acid (eg, hydrochloric acid) to produce a compound having the general formula (nxw) (step 21).

Compound (xxxit) is treated with a brominating agent (e.g. carbontetrabromide s-triphenylphosphine) to give the general formula (XX
XyI) was obtained (28th step), and the base (
For example, using 1,8-diazabicyclo[5,4,0]]undecene-1, the ring is closed to obtain a tricyclo compound having the general formula (XXXV) (Step 29), a base (e.g.
It is reacted with a carboxylating agent (e.g., carbon dioxide gas, dimethyl carbonate) in the presence of sodium hydride) to form a compound of the general formula 00
001) is produced (30th step).

Compound (xxxw) is reacted with a carboxylic acid (e.g., formic acid) in the presence of an acid catalyst (e.g., sulfuric acid) to form the general formula (W
A compound having the general formula (W
After producing the compound having the formula (2) (step 32), the hydroxyl group is protected according to a conventional method (e.g., dihydropyran-p-toluenesulfonic acid), leading to the compound having the general formula (XXX[) (step 32). 33 steps).

Compound (xxxx) is treated with an alkali (e.g., potassium carbonate) to obtain a compound having the general formula CXE-), which is mesylated with methanesulfonylxeride-triethylamine and has the general formula (XI-I). A compound is obtained (35th step) and treated with a weak base (eg, phenylzeleno sodium) to produce a compound having general formula (XX') (36 steps).

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1゜(1a) 3-(3-oxa-4-carboxybutyl)-6β-[
3α-(2-tetrahydropyranyloxy)-5β, S
-dimethyldeca-1,8-genyl]-1α-(2-tetrahydropyranyloxy)bicyclo[3,3,0]]
A mixture of oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-′[3α-(2
-tetrahydropyranyloxy)-5βI9-dimethyldeca-1,8-genyl)-yα-(2-tetrahydropyranyloxy)bidiclo(3,&O)oct-2-
A mixture of ene and oct-3-ene (105m#) was dissolved in dimethyl sulfoxide (1,5d) and dimethylformamide (1,5m) and 55% oily sodium hydrogen (
Add sssl and stir at room temperature for 30 minutes. Next, chloroacetic acid lithium salt sssmp 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. After washing the extract with saline and then with water,
Dry with anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to thin layer chromatography (2M thickness, 29cm
Purification was performed using Nijiri gel (m×20 cm). The developing solvent used was hexane-ethyl acetate (1:1) containing a small amount of acetic acid.

The less polar part (38f) was recovered, and the more polar part (l) 28 mg of the target compound was obtained as an oil.

IR spectrum (Liq,) sma:c Ql-':
1720, 175ONMR spectrum (CDCts
) δppm = o, i12 (3H, m, CH5)
! 6! (2H, t i J = 7 Hz, -C
H20-)4-01 (2H, a, -0CH2-)
4.68 (2H, br, -0CHO-X2)5
．． 07 (I H, br, t; J-6H2,<H-
) 5.2-5.8 (3H, m, -HC-X3)
(1b) 3-(3-oxa-4-carboxybuty/I/)-6β
-(3α-hydroxy-5β, S-dimethyldeca-1,
8-genyl)-1α-hydroxybisic* (& 3
．． O) Oct-2-ene and oct-3-ene 3-(3-oxa-4-carboxybutyl)-6β-[
3α-(2-tetrahydropyranyloxy)-5β, 9
-Dimethyldec-1,8-genyl]-Tα-(2-tetrahydropyranyloxy)bicyclo(&&O)Mixture of oct-2-ene and oct-3-ene 200 If
Camphorsulfonic acid 20% in the a7tone solution (6sd) of
(2) was added, and water was further added until the mixture became cloudy, and the mixture was heated and stirred at SO°C. After 3 hours and 30 minutes, saline was added and extracted with ethyl acetate. After washing the extract with brine, it is dried with anhydrous sodium sulfate. The solvent is distilled off L7 and the resulting residue is purified using silica gel (sy). 18189 oily mixture of oct-2-ene and oct-3-ene was obtained from the ethyl acetate outlet to hexane containing 20% ethyl acetate.

IR spectrum of mixture of oct-3-ene and oct-2-ene (Liq) νfQ&xCIl +1735,
3360, 97! I NMR spectrum (cDct6) δppm; 0.9
2 (3)! , d:J-6H@, CH8)1
．． 61 (3H, s, CM, 41) 1.69 (
3H, a, CHA) 3.4-4.5 (2H, m
, >Cdan0HX2 )3,TT (2H,tiJ-
6Hz, -CH2-)4.08 (2H, s, -C
H2-)ri, 11 (I H, * t i J ” 6
H4jIl1wca-)5.39 (I H, br,
a, -CH-)5.53 (2H, m, -CH
-C! H-,) This mixture was purified by high performance liquid chromatography to obtain pure oct-2-ene and oct-3
- Obtained en-en form. (Column: octadecyl chemical bonding shop silica gel, solvent: 0.05 M phosphoric acid water/acetonitrile-4515,) Oct-2-ene body: IR spectrum J' (C) IC4) II maXcl
k +1735, 33TO, 973 NMR spectrum (CDC4) δppfll: 0, i
12 (311, d; J+w6Hz, CHy,
)1.61 (3H, s, CHB)1.1!9
(3H, a, CHB) 14-45 (2H, m
, >Cdan01HX2)3.77(2H,i;Jri6
Hz, -CH20-)408 (2H, a,
-CH20-)Lll(lu,i:J驕6H1,□H-
)1311 (III, s, -CM-)5.
53 (2H, m, -cn=cH-) oct-3-ene body IR spectrum AI (cncza) νmtLX (ML-'
;1735. 3370. 973 NMR, (vector<cDctsnδpp*;0.9
2 (3H, d i J-6Hz, CH5) 1.6
1 (3H, s, CH3) 1.69 (3H, a, CH5) 3.4-4.5 (2H, m, >C!!-0HX2
)&? 7 (2) 1, t; J=6Hz,
-C! H20-)4.08 (2H,s, -CH2
O-)5.11 (I H, t i J=6Hz,
=CH-)5.39 (IH,m, -CI-)5.
53 (2H,m, -CH-CH-)Example 2゜(2a) 3-(3-oxa-4-carboxybutyl)-6β-[
3α-(2-tetrahydropyranyloxy)octo-1
-enyl]-11α-(2-tetrahydropyranyloxy)bicyclo[image O]oct-2-ene and oct-
Mixture of 3-enes 3-(2-hydroxyethyl A/) -8β-[3α-(
Example 1a Using a mixture of 110 ■2-tetrahydropyranyloxy)oct-1-enyl]-1α-(2-tetrahydropyranyloxy)bicyclo(3,1O)oct-2-ene and oct-3-ene The reaction was carried out in the same manner as above to obtain 31 .mu.m of the target compound in the form of an oil.

IR spectrum (Liq) rnaxctx-'s
1720, 175ONMR spectrum (CDC15)
δppm; agG (3H, t, CH5) &@2 (zH, t; J-IHg5.-CH20-
)40F (2)1, a, -CH20-)46
7 (2H, br, s, -0CHO-X2)5.
2-5.8 (3H, m, -CH-X3) (2b
) 3-(3-oxa-4-carboxybutyl)-6β-(
3α-hydroxyoct-1-endyl)-7α-hydroxybicyclo(&&O)oct-2-ene and oct-
Mixture of 3-enes 3-(3-oxa-4-carboxybutyl)-6β-[3α-(2-tetrahydropyranyloxy)oct-1-dynyl]-1α-(2-tetrahydropyranyloxy) Bicyclo (a, a.

O] Mixture 1 of oct-2-ene and oct-3-ene
When 521Ig was used and treated in the same manner as in Example 1b, 9
5119 of the desired oily compound was obtained.

IR spectrum (Liq) νBs1zcit.

1733, 3360, 973 NMR spectrum (cDct6) δppm; 0.90
(3H,t;caB) 3.75 (2H,*;J==6Hz, -ca2o-
)4.08 (2H, s, -CH2O-)5.41
(I H,br,a, =C11-)5,sa (2
H, Ill, -CH-CM-) Example 3 3-(2-hydroxyethyl)-6β-[3α-(2-
Tetrahydropyranyloxy)-4-methyloct-1
-enyl)-7α-(2-tetrahydropyranyloxy)bicyclo(S, a, O) Example 1a using a mixture of oct-2-ene and oct-3-ene 162η,
Then, reaction treatment was carried out in the same manner as in Example 1b to obtain 36 capes of the target compound in the form of an oil.

! R spectrum (Liq) νmax cm':
173G.

3360, 974 Example 4 Mixture of oct-2-ene and oct-3-ene 3-(
2-Hydroxyethyl)-6β-[3α-(2-tetrahydropyranyloxy)-5-,71thynona-1-
enyl]-7α-(2-tetrahydropyranyloxy)
Bicyclo(3,3,0)oct-2-ene and oct-
Example 18 using 105η of a mixture of 3-enes The reaction treatment was then carried out in the same manner as in Example 1b to obtain 23ml119 of the target compound.

IR spectrum (OHOJ3) vmax am'
: 1730°3350, 972 Example 5 (5a) 3-(3-oxa-4-carboxybutyl)-6β-[
3α-(2-tetrahydropyranyloxy)-4-methylnona-1,8-genyl]-7α-(2-tetrahydropyranyloxy)bicyclo(3,a.

0] Mixture of oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-(2-
Tetrahydropyranyloxy)-4-methylnona-1,
8-genyl]-γα-(2-tetrahydropyranyloxy)bicyclo(3,3,0]]oct-2-ene and oct-3-ene mixture (430 μ) was treated in the same manner as in Example 1a, 102 ml of the target compound in the form of an oil was obtained.

IR spectrum (Liq) vmax cm':
1720° IT4S, 164O NMR spectrum (0DOJ 5 ) δp: 0.91
(3H, m, 0H3) 3.62 (2H, t, -ol(2o-)4, Or
(2H,S, -0H20-)4.70 (2H,b
r, s, -00HO-)4-82640 (6H,
m, 0H=OH, '5=OH2=Ql(-) (5b) 3-(3-oxa-4-carboxybutyl)-6β-(
3α-hydroxy-4-methylnona-1,8-genyl)-Tα-hydroxybicyclo(3,3,0)octo-
A mixture of 2-ene and oct-3-ene 3-(3-oxa-4-carboxybutyl)-6β-[3α-(2-f
Trahydropyranyloxy]-4-methylnona-1,8
-genyl]-Tα-(2-tetrahydropyranyloxy)bicyclo(3,3°0)oct-2-ene and oct-3-ene mixture was obtained as an oily substance.

IR spectrum (Liq) vmax cm-': 9
73. 1638°1735, 337G NMR spectrum (ODOj5) δppm: 0.90
(3H, m, OH5) 3.76 (2H, t, -0H20-)4.08 (
2H,8,0H20) 3.4-4.3 (2H,m,)OHOHX2)5.
32 (IH, br, s, =OH-)5.53 (2
H, m, -0H=OH-)4.3-6.2 (3H,
m, -0H=OH2) When this compound is treated with diazomethane, the methyl ester form (IR spectrum (LiQ) ν
maX Cm 1 :973, 1638. 174θ
, 3380) were obtained.

Example 6 (6a) 3-(3-oxa-4-carboxybutyl)-6β-[
3α-(2-tetrahydropyranyloxy-4,1-dimethyloct-1,6-genyl]-7α-(2-tetrahydropyranyloxy)bicyclo0(3,3,0)oct-2-ene and oct- A mixture of 3-enes 3-(2-hydroxyethyl)-6β-[3α-(2-
mixture of oct-2-ene and oct-3-ene The reaction treatment was carried out in the same manner as in Example 1a using 150 ml, to obtain 53 mg of the target compound.

IR spectrum (Liq) νmax cm': 1
72G, 175ONM spectrum (CDC13) δ
ppm: 0.90 (3H, m, OH3) 3.45 (2H, t, -〇H2O-) 4.51 (
2H, s, 0H20) 4.70 (2H, br, s, -00HOX2)5
．． 0 to 5.8 (4H, m, =OH-X2.-0H=
OH-)(6b) 3-(3-oxa-4-carboxybutyl)-6β-(
3α-Hydroxy-4,7-dimethylocto1,6-
genyl)-7α-hydroxybicyclo(3,3,O)
Mixture of oct-2-ene and oct-3-ene 3-(3-oxy"j-4-carboxybutyl)-6β-
[3α-(2-tetrahydropyranyloxy-4,7-
Mixture of dimeteroct-1,6-genyl]-1α-(2-tetrahydropyranyloxy)bicyclo(3,3,0)oct-2-ene and oct-3-ene 124q
The reaction treatment was carried out in the same manner as in Example 1b, using 75 cm of the desired compound.

IR spectrum (Liq) νmax cm-':
971, 1707°35O NMR spectrum (0DOJ 5 ) δppm: 0.
90 (3H, m, OR3,) 3.75 (2H, t, -0H20-) 4.09 (
2H,8,-0H20-)34~4.4 (2H,m,
>O! ! 0HX2 )5.11 (IH,t, =Q
l(-)5.38 (IH, br, s, =OH-)
5.53 (2H, m, -0 leg H-) Example 1 Mixture 3-(2-hydroxyethyl)-6β-[3α-(2-
Tetrahydropyranyloxy)-9-methyldeca-1,
8-genyl)-7c! =(2-tetrahydropyranyloxy)bicyclo(3,3,0) A mixture of 150 IIy of oct-2-ene and oct-3-ene was reacted in the same manner as in Example 1a and then in Example 1b, and 39 The desired compound was obtained.

IR spectrum A/ (Liq) νmax cm'
: 1735°3350, 974 Example 8 (8a) 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 mixture of -enes 3-(2-hydroxyethyl)-6β-[3α-(2-tetrahydropyranyloxy)-4-methyloct-1-
Example 1 using a mixture 103η of en-6-ynyl]-7α-(2-tetrahydrobylanyloxy)bicyclo(3,,3,0)oct-2-ene and oct-3-ene
The reaction treatment was carried out in the same manner as in a to obtain the target compound of Cape 41.

In spectrum (LiQ) νmax cm-': 1
71B.

75O NMB spectrum (oDoJ5) δppm: 0.9
5 (3H, m, OH3) 1.79 (3H, t; J-1,5H,, OH,)
3.1i1 (2H, t; J=7H2, -0H20
-)4.06 (2H,8,-0H20-)4.67
(2H,br,s, -00110X2)5.2~5
．． 8 (3H,m, =OL!-,-0H=OH-)(
8b) 3-(3-oxa-4-carboxybutyl)-6β-(
3α-hydroxy-4-methyloct-1-ene-6-
mixture of 3-(3-oxa-4-carboxybutyl)-6β-1
3α-(2-tetrahydropyranyloxy)-4-methyloctonin-1-en-6-ynyl]-Tα-(2-tetrahydropyranyloxy)bicyclo(3,3,0)oct-2-ene and oct-3 A reaction treatment was carried out in the same manner as in Example 1b using 100q of a mixture of -ene to obtain 5911 g of the target compound as an oil.

IR spectrum (LiQ) νmax cm-': 1
735+3360, 974 NMR spectrum (aaoj13) δppm: 0.
95 (3H, m, 0H3) 1.78 (3H, t; J=1.5H2,OH,)3.
4-4.5 (2H, m, )or+oItx2)3.
76 (2H,t; J-6H,, -0H20-)4.
08 (2H,S,CH2O) 5.39 (IH,br,s,:OH-)5.54 (
2H,m, -0H=011-) Example 9 Compound 3-(2-hydroxyethyl)-6β-[3α-(2-
Mixture of tetrahydropyraninot-oxy)-4-cycloben-1-butenyl]-Tα-(2-tetrahydropyranyloxy)bicyclo(3,3,0)oct-2-ene and oct-3-ene 181η Example 1a using
Then, the reaction treatment was carried out in the same manner as in Example 1b to obtain the target compound of 41η.

IR spectrum (cHaJ3) νmax cm':
1735.

3360, 974 Example 10 -1-7'lovenyl)-Tα-hydroxybidiclon mixture (10a) Compound a-(2-hydroxyethyl)-6β-[3α-(2-
Tetrahydropyranyloxy)-3-cyclohexyl-
1-propenyl]-Tα-(2-f was reacted in the same manner as in Example 1a to obtain the target compound in the form of an oil with a compound size of 79 capes.

IR spectrum/l/ (Liq) νmax crn
': 1720.

174? NMR spectrum (ODOJ5) δppm: 3.64
(2H, t, -on2o-)4.06 (2H,S,
-0H20-)4.70 (2H,br,s,-00H
O-X2-)5.2-5.8 (3H,m,-0H=O
H-, =OH-) (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-(2-tetrahydropyranyloxy)bicyclo(3,3,0)oct-2-ene and oct-3-ene Mixture 312■- was reacted in the same manner as in Example 1b to obtain the desired compound of 136η.

IR spectrum (oucjt3) νmax cm'
: 972.

1.735, , 335G NMR spectrum (0DOJ 5 ) δppm: 3.
76 (2H,t, -0H20-)4.08 (2H
,S, -0H20-)3.4~4.3 (2H,m,
>0HOHX2 )5.38 (IH,br,s,=O
H-) 5.52 (2H, m, -〇H=OH-)Example 11 Mixture C11a) 3-(2-methanesulfonyloxyethyl)-6β-[
3α-(2-tetrahydropyranyloxy) = 5βl
9-dimethyldeca-1,8-genyl]-7α-(2-
tetrahydropyranyloxy)bicyclo(a, s,
o) Mixture of oct-2-ene and oct-3-ene 3-(2-hydroxyethyl)-6β-[3α-(2-
tetrahydropyranyloxy)-5β,9-dimethyldec-1,8-genyl)-yα-(2-tetrahydropyranyloxy)bicyclo(3,3,0)oct-2-ene and oct-3-ene Tri-reacted with a methylene chloride solution (1 (1 m/)) of Mixture 294 Q. After the reaction was completed, ethyl acetate was added, and the mixture was washed successively with brine, acetic acid water, diluted aqueous aqueous solution, and then brine, and dried with anhydrous sodium sulfate. When the solvent was distilled off, 303η of the target compound was obtained as an oil.

NMR/C vector (oDoJ3) δppm: 0-9
3 (3H, m, 0H5) 2.92 (3H, s, OH5) 4.70 (2H, m, -00HO-) 5.05 (
IH, t; J-6H2,=CH-)5.2-5.8 (
3H,m, :0H-X3)(11b) 3-(3-thia-4-carboxybutyl)-6β-[3
α-(2-tetrahydropyranyloxy)-5β,9-
Dimethyldec-1,8-genyl]-1α-(2-tetrahydropyranyloxy)bicyclo(3,3,0]]oct-2-ene and oct-3-ene mixture 55% oily) IJium hydrogen ( After washing 400 q) with hexane, 15 g of dimethyl sulfoxide and 400 g of thioglycolic acid were added, and the mixture was stirred at room temperature until no bubbles appeared. 3α-(2-tetrahydropyranyloxy)-5β,9-dimethyldec-1,8-genyl]-7α-(2-tetrahydropyranyloxy)bicyclo(3,3,0)oct-2-ene and oct -3-
303 # of a mixture of ene was 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, dry with anhydrous sulfuric acid and IJum. The residue obtained by distilling off the solvent was purified by silica gel-S.
The developing solvent is purified by layered chromatography (23);
50% hexane-ethyl acetate containing 0.25% acetic acid), 1
87% oily target compound was obtained @ IR spectrum (Liq) ymax cm':
1725°T1O NMR spectrum (ODOJ5) δppm: 0.90
(3H, rn, OH5) 3.20 (2H, S, 8C!H2) 4.65 (
2H,br, -00HO-)5.01 (IH,t;
J-6H2,OH,)5.2~5.7 (3H,m,=
OH-X3)(11c) 3-(3-thia-4-carboxybutyl)-6β-(3
α-hydroxy-5β,9-dimethyldeca-1,8-genyl)-7α-hydroxybicyclo(a, a, O
) A mixture of oct-2-ene and oct-3-ene 3-(3-thia-4-carboxytyl)-6β-[3α
-(2-tetrahydropyranyloxy)-5β,9-dimethyldec-1,8-genyl]-7α-(2-tetrahydropyranyloxy)bicyclo(3,s,o)oct-2-ene and oct- 3-ene mixture 180■
The reaction was carried out in the same manner as in Example 1b.

The resulting residue is purified by silica gel column chromatography. From the hexane-ethyl acetate outflow containing 30% ethyl acetate, 120 μm of an oily mixture of oct-2-ene and oct-3-ene was obtained.

East IR spectrum (Li(1)vmax cm':
975. 1705°35O NMR spectrum (oDOJ3) δppm: 0.9
4 (3H, d; J-6H2, 0H5) LFr2 (3
H, S, OH5) 1.70 (3H, S, , OH3) 3.22 (
2H,S, -0H2-)3.4~4.5 (,zn,
br, , >0HOHX2 )5.08 (IH, b
r, t; J-6H2,=Ql(-)5.36 (IH,
br, s, =OH-)5.60 (2H, m, -0
H=OH-) This mixture was purified by high performance liquid chromatography to obtain pure oct-2-ene and oct-3-ene.
6 (column: octadecyl chemically bonded silica gel, solvent: 0.05M phosphoric acid water/acetonitrile = 45155) oct-2-ene form; ■R spectrum (aHo15) vmax cm-'
: 974.

1705, 335O NMR spectrum (CDa15) δppm: 0.94
(3H, d; J-6H2, -0H5) 1.62 (3
H,8,0H3) 1.70 (3H,S,0H3) 3.22 (2H,s,0H28-) 3.4~4.5 (2H,br,7ononxz)
.

5.08 (IH,t; Jro6H,,=OH-)5
．． 36 (IH, br, s, =OH-)5.60
(2H,,m, -〇H=OH-)oct-3-ene body; IR spectrum C0HO15) vmax cm'
: 974.

1705, 335O NMR spectrum (0DO), )δpptn: 0.9
4 (3H,a; J=6H,,aH5)1.62 (3
H,S,on,) 1.70 (3H,s,OH3) 3.22 (2H,8,-0H2B-)3.4-4.
5 (2H,br, ,)OHOHX2)5.08
(IH,t;Jhi6H2,:0H-)5.36 (IH
,br,s,=OH−)s,so(2H,rrl,
0H=OH) Example 12 3-(2-methanesulfonyloxyethyl)-6β-[
3α-(2-tetrahydropyranyloxy)-3-cyclohexyl-1-propenyl]-Tα-(2-tetrahydropyranyloxy)bicyclo(3,3,0)octo-
Example (11b) was then treated in the same manner as in Example (11c) using 237η of a mixture of 2-ene and oct-3-ene to obtain 102q of the target compound.

! R spectrum (anoJ5) vmax cm-':
975.

1101, 3350 Example 13 (13a) 3-(4-phenylsereno-4-methoxycarbonylbutyl)-6β-[3α-(2-ftrahydropyranyloxy)-5β,9-dimethyldeca-1,8 -genyl]-Tα-(2-ftrahydropyranyloxyfubicyclo(3,3,O) mixture of oct-2-ene and oct-3-ene diisopropylamine (084 fl) in tetrahydrofuran (14 ml) and 3-(4-Methoxycarbonylbutyl)-6β-[3α-(2-tetrahydropyranyloxy)- 5β,9-dimethyldeca-
A tetrahydrofuran solution of a mixture (1,41) of 1,8-genyl]-1α-(2-tetrahydropyranyloxy)bicycloC3,3゜0]oct-2-ene and oct-3-ene (C6fll) is added dropwise. . Same temperature K for 20 minutes
After stirring fA, diphenyl diselenide (1
, 611) in tetrahydrofuran (Sg+/) was added and 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 brine, it is dried with anhydrous sodium sulfate. The solvent is distilled off and the residue is purified by silica gel column chromatography. From the hexane outflow containing 10 to 20% ethyl acetate, an oily target compound of 1.74 F was obtained.

IR spectrum (Liq) vmax cm':
1580.

T35 NMR spectrum (oDOJ3) δppm: 0.91
('3H, m, 0H3) 2.61 (3H, s, OH5) 2.66 (3H, s, OH5) 3.62 (3H, s, OH3) 4.70 (2H, br, -00HO)5 .0~5.
8 (4H, m, =OH-X 4 )7.3[1(3H
, m, aromatic proton) 1.59 (2H, m, aromatic proton) (13b) 3-(4-methoxycarbonyl-3-butenyl)-6β
-[3α-(2-tetrahydropyranyloxy)-5β
, 9-dimethyl-1,8-decajenyl]-7α-(2
-tetrahydropyranyloxy)bicyclo(3,3,0
) Mixture of oct-2-ene and oct-3-ene 3C47xNylseleno-4-methoxycarbonylbutyl)-6β-[3α-(2-tetrahydropyranyloxy)-5β,9-dimethyldec-1,8-genyl )=7
α-(2-tetrahydropyranyloxy)bicyclo(3
,3,0) A mixture of oct-2-ene and oct-3-ene in 0.7 ml of ethyl acetate solution and 4 ml of methanol.
me then 20% hydrogen peroxide 0.8.5 ysl
It was added dropwise at room temperature and stirred for 40 minutes at room temperature. After the reaction was completed, it was diluted with ethyl acetate (100 gtτ), washed with saturated dehydrated water and brine, and dried with anhydrous sodium sulfate. The solvent was distilled off to obtain The residue was purified by silica gel column chromatography. From the hexane outflow containing 5 to 10% ethyl acetate, the target compound in the form of a 33B oil was obtained.

IR spectrum (jiq) vmax cm': 1
655°13O NMR spectrum (ODOJ13) δppm: 0.8
9 (3H, m, OH3) 3.69 (3H, s, OH5) - a, sr (2H, br, , -00HO-82) 4
．． 85-5.90 (5H, m, =OH-X5)6
．． 87 (IH, d, t; J snow 15. 7H,,=OH
-)(13C) a-(4-methoxycarbonyl-3-butenyl)-6β
-(3α-hydroxy-5β,9-dimethyl-1,8-
Decadienyl)-Tα-hydroxybicyclo(3,3,
0) Mixture of oct-2-ene and oct-3-ene 3-(4-methoxycarbonyl-3-butenyl)-6β
-[3α-(2-tetrahydropyranyloxy)-5β
, 9-dimethyl-1,8-decajenyl]-Tα-(2
-tetrahydropyranyloxy)bicyclo(3,3,0
) mixture of oct-2-ene and oct-3-ene 40
A mixture of 0 q, 6 ml of acetic acid, 4 ml of water, and 1 ml of tetrahydrofuran is stirred at 60° C. for 1 hour. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The extract is washed with water and then with brine, and then dried with anhydrous sodium sulfate.

The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography. From the hexane outflow containing 40% to 60% ethyl acetate, 230 μm of the desired oily compound was obtained.

IR spectrum (LiQ) vmax cm': 1
650°1725, 3355 NMR spectrum (0DOJ 5 ) δppm: Q,
113 (3) t, d; J-6H,, OH3) 1.6
2 (3H,S,OH,) 1.68 (30,8,OH3) 3.70 (3H,S,0H3) 4.90~5.90 (5H,m,=OH-X5)6
．． 88 (IH, d, t; J-15,7H2,=OH-
) Example 14 (14a) 3-(3-oxa-5-hydroxypentyl)-6β-
[3α-(2-tetrahydropyranyloxy-5β,9
-dimethyldeca-1,8-genyl)-Tα-(2-tetrahydropyranyloxy]bicyclo(a, S, O
) Dipyranyl mixture of oct-2-ene and oct-3-ene (compound of Example 1a: 310Wfl) was treated with excess diazomethane in ether for 30 minutes at room temperature to give the methyl ester of 321η (IR spectrum (t, iq) pmax cm': 1720 J
o This ester body 250Q was dissolved in ether 10-, 250q of lithium aluminum hydride was added, and the mixture was heated at room temperature.
Stirred for 0 minutes. After the reaction is completed, 1 g of 4% caustic soda water is added, the precipitate is collected, and the liquid is concentrated. The obtained residue was purified by column chromatography to obtain 1874 of the target compound as an oil.

IR spectrum (Liq) pmax cm':
3410°1120, 1076, 1022 (14b) 3-(3-oxa-5-hydroxypentyl)-6β-
(3α-hydroxy-5β, 9-dimethyldeca-1,8
-genyl)-7α-hydroxybicyclo(3,3,0
) Mixture alcohol of oct-2-ene and oct-3-ene (compound of Example 14a: 180 Mg)
in a mixed solvent of acetic acid, water, tetrahydrofuran (5:3:
1) The mixture was dissolved for 5 hours 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 the target compound 91119 as an oil.

IR spectrum (Liq) pmax cm':
3350, 971 Example 15 Alcohol mixture (compound of Example 14a: 171-methylene chloride is dissolved in 50 ml of C, 2.5 F of pyridine-chromic acid anhydride complex (Collins reagent) is added under water cooling, and stirred 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 sulfuric acid), the solvent was distilled off, and 3-(3-oxa-4-formylbutyl)-6β-[
3α-(2-tetrahydropyranyloxy-5β, 9-
dimethyldec-1,8-genyl]-1α-(2-tetrahydropyranyloxy)bicyclo(3,3,01 mixture of oct-2-ene and oct-3-ene (161
■) Obtained (Inspect A/ (Liq) vma
x cm-': 2720. 1710). This formyl compound was deprotected in the same manner as in Example 14b to obtain the target compound 75*.

IR spectrum (CHOJ3) I'maX C1n-
': 2710.

T10 Reference Example 1 Mixture (1a) of 3-(methoxycarbonylmethyl)-6β-[3α-[
2-tetrahydropyranyloxy)-5(2).

9-dimethyl-deca-1,8-genyl]-1α-(2
-tetrahydropyranyloxy)1. Bicyclo (3, &
0 ) Mixture of oct-2-ene and oct-3-ene 3-methoxycarbonylmethylidene-6β-[3α-(
2-tetrahydropyranyloxy)-5(2).

9-dimethyl-deca-1,8-genyl]-7α-(2
-tetrahydropyranyloxy)bicyclo(3,3:
O') octane 1.95F in tetrahydrofuran (5m
diisopropylamine lithium (diisopropylamine 935111F, 15% n
10 g of tetrahydrofuran (prepared from 5.43 d of -butyllithium-n-hexane solution and 6 ml of hexamethylphosphoryl triamide) 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 1.3011 of the target compound.

IR spectrum (Liq) vmax cm':
1737 NMR spectrum (0DOJ5) δppm
:0.92 (aH, In, OHs) 0.62 (3H, S, OH3) 0.68 (3H, S, , OH3) 3.10 (2
H,S,-cn2-)319 (3H,S,0O00
H3) 4.82 (2H,br,s,-00HO-X2)5
．． 12 (IH,t,=Q)l-)5.3~58 (
3H,m,=OH+,-Ql(=Q)I-)(1b) 3-(2-hydroxyethyl)-6β-[3α-(2-
tetrahydropyranyloxy)-5(2),9-dimethyl-dec-1,8-genyl]-1α-(2-tetrahydropyranyloxy)bicyclo(3,3,0)octo-
A mixed ester of 2-ene and oct-3-ene (compound of Reference Example 1a: 510111F) was dissolved in 20 ml of ether, and 500 ml of lithium aluminum hydride was added under water cooling. After 1 hour, 2 ml of 4%
Caustic soda water was added and stirred to remove the precipitate and the P solution was concentrated to give an oily residue. Purification by silica gel column chromatography yielded 430 wg of the target compound as an oil.

IBx vector (Liq) ymax cm':
335ONMR spectrum (ODOJ15) δppn
:0.91 (3H, m, 0H5) 2.62 (3H, S, 0H3) 2.69 (3H, S, OH5) 4.80 (2H1br, s, -00HO-X2)5
．． 0 to 5.8 (4H, m, =OH-X4) Reference example 2 3-methoxycarbonylmethylidene-6β-[3α-(
2-tetrahydropyranyloxy)oct-1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[λS, O) Using 520η of octane, Reference Example 1
React and process in the same manner as a and 1b to obtain the target product at 194η
Obtained.

IR spectrum (Liq) vmax cm-':
3350°1032, 1022. 974 Reference Example 3 3-Methoxycarbonylmethylidene-6β-[3α-(
Using 712q of 2-tetrahydropyranyloxy)-4-methyloct-1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3,a,O)octane, the reaction was carried out in the same manner as in Reference Examples 1a and 1b. , 287 # of the target product was obtained.

IR spectrum (Liq) vmax cm':
3350.

1032, 1022. 974 Reference Example 4 3-methoxycarbonylmethylidene-6β-[3α-(
2-tetrahydropyranyloxy)-5-methylnona-
1-enyl]-7α-(2-tetrahydropyranyloxy)bicyclo(3,3,0)', tcutane 7111.9
The reaction and treatment were carried out in the same manner as in Reference Examples 1a and 1b, to obtain 286 w1g of the target product.

IR spectrum A (Liq) vmax cm-1:
3350.

1032, 1022. 974 Reference Example 5 3-Methoxycarbonylmethylithene-6β-[3α-(
2-tetrahydropyranyloxy) to 4-methylnonar1,8-genyl]-7α-(2-tetrahydropyranyloxy)bicyclo(3,3゜0)octane 512tR
Using g, reaction and treatment were carried out in the same manner as in Reference Examples 1a and 1b to obtain 196 of the target product.

IR spectrum (Liq) vmax cm-':
3350°1032, 1022. 974 Reference Example 6 Mixture 3-methoxycarbonylmethyf')te:/-6β-[3α
-(2-tetrahydropyranyloxy)-4゜T-dimethylockl,6-genyl]-1α-(2-tetrahydropyranyloxy)bicyclo(3,3,0)octane 457 # was used for reference example 1a. The reaction and treatment were carried out in the same manner as in 1b and 159η of the desired product was obtained.

X'PL Schect/l/ (Liq) vmax c
m': 3350.

1032, 1022. 974 Reference Example 7 3-(2-hydroxyethyl)-6β-[3α-3-methoxycarbonylmethyIJ y' y -6β-[3α
-(2-tetrahydropyranyloxy)-9-methyldeca-1,8-genyl)-rα-(2-tetrahydropyranyloxine bicyclo(3,3°0)octane 941
Using "y", the reaction and treatment were carried out in the same manner as in Reference Examples 1a and 1b to obtain the target product 3871'9.

IR spectrum (Liq) vmax cm':
3350°1032, 1022. 973 Reference Example 8 Compound 3-methoxycarbonylmethylidene-6β-[3α-(
2-tetrahydropyranyloxy)-4-methyloct-1-en-6-ynyl]-Tα-(2-tetrahydropyranyloxy)bicyclo(3,3,0)octane 54
311f! The reaction and treatment were carried out in the same manner as in Reference Examples 1a and 1b, to obtain 210 ml of the desired product.

IR spectrum (Liq) vmax cm':
3350°1G32. 1022.974 Reference Example 9 3-methoxycarbonylmethylidene-6β-[3α-(
2-tetrahydropyranyloxy)-4-cyclopentyl-1-ph? Nyl)-Tα-(2-tetrahydropyranyloxy)pisicc2j3.3゜0〕octane 412■
The reaction and treatment were carried out in the same manner as in Reference Examples 1a and 1b, and 194 target products were obtained.

Ins vector (Liq) vmax cm':
3350°1032, 1022. 973 Reference Example 10 3-Methoxycarbonylmethylidene-6β-[3α-(
2-tetrahydropyranyloxy)-3-cyclohexyl-1-7'robenyl]-7α-(2-tetrahydropyranyloxy)bicyclo(3,3゜0)octane 117
Using 1N, reaction and treatment were carried out in the same manner as in Reference Examples 1a and 1b to obtain 387W of the target product.

IR spectrum (Liq) vmax cm':
3350.

1032, 1022. 974 Reference Example 11 Cyclo(3,3,O]]octane 5-benzyloxybentylbromide 10Of(A
, W. Burgstahler et al.'s method (J, Org,
chem, 42° 566 (1977), from pentamethylene bromide and benzyl alcohol] and 5-benzyloxypentamethylene magnesium bromide prepared from metallic magnesium (100η) in diethyl ether (5*/). , 7-ethylenedioxy-3-oxosysupicic I:I (3,3,0) octane (501M9) nochetyl ether (5*/) solution was added dropwise at room temperature, and 1° was added at room temperature. Stir for .5 hours. After the reaction is complete, 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 a residue of 1.4Tf. .

This product was purified by silica gel column chromatography to obtain the desired product as an oil.

I<c>t h (Liq) vmax cm':
34B0.

1470, 1330. 111O NMR spectrum (0DOJ 3 ) δppm: 3.
47 ('2H,t, J=6.OH,,0H20H20
B2) 3.91 (4H,S,0OH20H20)4.
52 (2H, s, 0 2ph) 7.36 (5H,
s, aryl-H) mass spectrum h0m/e: 36
0 (M+), 342 (M-18) Reference Example 12 3-(5-hensyloxypentyl)'-L7,7-ethylenedioxy-3-hydroxy-cis-bicyclo(3
,3,0) octane (209η) benzene (2s+l
) solution with ethylene glycol (0.05 ml) and p-
Toluenesulfonic acid (10119) was added, and the mixture was heated and stirred for 3.5 hours while water was removed azeotropically. After the reaction is completed, 5
% hydrogen carbonate), wash the reaction solution with water, dry with anhydrous sulfuric acid, and remove the solvent under reduced pressure to obtain a residue of 193jlf. This product was purified by silica gel column chromatography to obtain 142fflF of the desired product as an oil.

IR spectrum (Liq) vmax cm': 1
445°1320, 1100. 1010 2ON spectrum (ODC13) δppm: 3.42
(2H, t; J=6.0H2,0H20!!20B,
)3.84 (4H,S,0OH20H20)4.4
4 (2H,S,00H2ph)5.15 (IH
,br,s,ole747-)1)7.28(5H
, s, aryl-H) mass spectrum, m/e:
342 (M10n Reference Example 13 Wang 22 3-(5-benzyloxypentyl)-7,7-ethylenedioxycis-bicyclo(3,3,0)oct-2
-x7 (6,651) acetoy (120+w/ )
.

Add to a mixture of water (45 g/') and concentrated hydrochloric acid (1,0 resistant) and stir at room temperature for 2 hours. After the reaction is complete, 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 leave a residue 6. OOf was obtained, and this product was purified by silica gel column chromatography.
Obtained.

IR spectrum (Liq) vmax cm':
1725% NMR spectrum (cDoJ, 5) δppm
:3.42 (2H,t;J=6.0H,,-0H
20H200H2Ph )4.43 (2H,S,0O
H2Ph) 5.14 (IH, br, s, olefin-H) 7.24 (5H, s, aryl-H) mass spectrum, m/e: 298 (M+) Reference example 14 -3-ene mixture 55% Suspension of oily sodium hydrogen (1,911) in 1,2-dimethoxyethane (170*/) 2.6-di-t
-Butyl-p-cresol (9, Hf) was added and the internal temperature was 4.
Stir vigorously for 1 hour at 0°C. Then, after cooling to an internal temperature of 30°C, it was heated for 3 hours at an internal temperature of 30°C while introducing carbon dioxide gas.
Stir for 0 minutes. Cool to internal temperature 10℃? , [,3-(5
-benzyloxypentyl)-7-oxo-cis-bicyclo(3,a,o)oct-2-ene(4,32f
) of 1,2-dimethoxyethane (20wl)! The liquid was added dropwise and stirred for 2 hours at an internal temperature of 10°C. Then, a solution of sodium borohydride (820 η), t-butyl alcohol (40 proof) and water (13 g +/-) was added dropwise to this mixture, and the mixture was stirred for 1 hour at an internal temperature of 10°C. After the reaction is completed, the reaction solution is poured into water, washed with hexane, and the aqueous layer is made acidic with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sulfuric acid, and the solvent was distilled off under reduced pressure to obtain 542 g of a residue. This product was purified by silica gel column chromatography to obtain 4.281 of the target product as an oil.

IR spectrum (Liq) vmax cm-':
3350.

71O NMR spectrum (onoJ3) δppm: a, 4s
(2H, t;, rs, oH2, 0H20H20B2)
4.52 (2H,S,0H200H2Ph)7.0
8 (2H,S,OH,0OOH)7.37 (SR,
s, ok-rou U) Mass spectrum, m/e: 3
44 (M+) Reference Example 15 Mixture of hydroxycarboxylic acids (Reference Example 14) Compound =
4.28 g) is dissolved in methylene chloride (10*/), dihydropyran (3,ts+/) and a catalytic amount of pyridine hydrochloride are added, and the mixture is stirred at room temperature for 2 hours. This material was then dissolved in lithium aluminum hydride (soOs) under water cooling.
The mixture was poured into a suspension of (w) in tetrahydrofuran (30 L) and stirred for 1 hour at an internal temperature of 18°C. After the reaction is complete, 4% aqueous sodium hydroxide solution (2 g+/) is added and stirred at room temperature. After removing the formed white precipitate, the liquid is concentrated under reduced pressure to obtain a residue 7.60f. By using silica gel column chromatography to purify the
4.84 of the target product was obtained as an oily substance.

IR spectrum (Liq) vmax cm-”: 3
43G.

1455, 112O NMB spectrum (oDa15>δppm: 3.4
7 (2H,t;J-6,OH,,0H20H20B2
) -4,53(2H,S,0012Ph)5.30
'(IH, br, s, 7-H) T, 3T (
SR, s, aryl-H) mass spectrum, m/e
: 414 (M'') Reference Example 16 Mixture of ene and oct-3-ene Mixture of alcohols (Compound of Reference Example 15: 482F
Triethylamine (13,5s+/) is added to a solution of ) in dimethylsulfoxide (42m), then a solution of pyridine-sulfuric anhydride complex (4,720f) in dimethylsulfoxide (22g/) is added, and the mixture is stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was poured into saturated brine 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 to obtain the desired product as an oil. 96F was obtained.

This substance is used in the next reaction without purification.

IR spectrum (Liq) vmax cm-1: 17
25 Reference Example 11 After washing the oil content of 55% oily sodium hydride of 043 fl with n-hexane, tetrahydrofuran 6011j
and dimethyl 2-oxo-4,8-dimethylnona-1,8-
Add 3.55 F (dienylphosphonate) and stir for 30 minutes. Next, the aldehyde compound &05F obtained in Reference Example 16
was dissolved in 10-tetrahydro7ran and added at room temperature.
Stir for 0 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 (80F). By this addition, 3.50 fl of the target compound as an oil was obtained.

IB spectrum (Liq) vmax cm-': 1
B25°1670, 1695 NMB spectrum (0DOJ 5 ) δppm: 0.
89 (3H, d; J-7H,, OH3) 3.48 (
2H,t ,0H200H2Ph )45G (2H,
S, O)! 2pH) 4.8-5.4 (2H,m, =OH-X2)6.
1 fl (IH, dd, J=16.3H,,=oii
-36,5~1.2 (IH,m, =OB-)7.2
9 (5H, s, aryl-H) Reference Example 18 C) Isomer A methyl alcohol solution (251 g/) of the enone form (3,50f) obtained in Reference Example 17 was added to cerium chloride/T under water cooling.
Add hydrate (3,61) to methyl alcohol solution (3o resistant), then add sodium borohydride (600q)
Add. After stirring for 3θ minutes at an internal temperature of 5 to 10°C, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the bath medium was distilled off to obtain an oily residue.

This compound gives 3-spots on thin layer chromatography, so it was dissolved in 50 l of fermentation without purification, and dissolved in 31 gl of water and tetrahydrofuran (THE')2.
0 g (was added and stirred at 50°C for 2.5 hours. During that time, 1
Added 5 water resistance. After the reaction is complete, add sodium hydroxide (
Add an aqueous solution of 401) to neutralize and extract with ethyl acetate. After washing the extract with brine, it is dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was purified by column chromatography using silica gel. A 1.15F oily 6β-(3β-hydroxy) body (thin layer chromatography: Q2 spot) was obtained from the 20-25% acetate ethyl/n-hexane outflow. 1.54 g of oily 6β was extracted from the 30-50% ethyl acetate/n-hexane outflow.
-(3α-hydroxy) form (2 spots by thin layer chromatography) was obtained.

6β-(3β-hydroxy) form: 1B spectrum/l/(Liq) vmax cm'
: 337ONMB spectrum (cncJ5) δpp
m: 0.90 (3H, d, OH,) 1.60 (3H, S, OH3) 1.68 (3H, s, OH, 5) 3.45 (2H, t, -0H20-) 4-50 (
2H, s, 0H20) 5.1o (IH, t, =0) (-) 5.28 (IH, br, s, =011-)5.
60 (2H, m, -0H=OH-)IR spectrum (
Liq) vmax cm': 336ONMR spectrum (aDoA3) δppm: o, so (3H,
rn, 0H5) 1゜60 (3H, S, 0H3) 4.50 (2H, S, 0H20) 5.12 (I
H, br, t, =OH-)5.28 (IH, L+
r, S, = OII −)5.50 (2H, m, −0H
=OH-) Reference Example 18 0(3,3,0) Mixture alcohol of oct-2-ene and oct-3-ene (6β-(3α-hydroxy) of Example 1a)
2,3-dihydropyran (0,95jI) was dissolved in methylene chloride (10gl) and cooled with water.
t) and a catalytic amount of 6′ p-toluenesulfonic acid;
Stir for 1 hour at an internal temperature of 2°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 solvent was distilled off under reduced pressure to obtain a residue. This product was purified by silica gel column chromatography to obtain the desired product 2.10f as an oil.

IR spectrum (Liq) vmax cm-1: 10
2L035 NMR spectrum (opoJ4) δppm: 0.90
(3H, m, OH5) 1.46 (2H, t, -0H20-) 4.50 (2
H, s', -○! (20-)4.70 (2H,br,
s, -oo)1o-)4.90~5.8 (4H,
m, :0I(-X4) Reference Example 20 In a nitrogen atmosphere at an internal temperature of -70"C, the W-isomer of the benzylpyranyl compound (2,10y) obtained in Reference Example 19 7 ammonia C
40d) In a bath solution of h tetrahydrofuran (30 m/),
When excess sodium metal is added, the solution takes on a dark blue color. After stirring for 30 minutes at -7°C, a large excess of ammonium chloride was added.Then, the temperature was returned to room temperature, and ammonia was distilled off. Water was added to the residue, extracted with diethyl ether, and the extract was diluted with water. After washing, it was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. This residue was purified by silica gel column chromatography to obtain the desired product as an oily product (1.41').

IR spectrum (Liq) vmax cm':
335ONMR,'(vector (oDo15)δppm
:0.92 (3H,m,,OH,) 2.63 (3H,'8,OH5)2.69 (3
H0s, 01(3) 3.64 (2H, t, -0H20-) 4.82 (2H, br, s, -00HO-) 5.0~
5.8 (4H,m, -Ql (=x4) Reference Example 21 Add Rones reagent (anhydrous (Prepared by diluting 26.Tl of chromic acid and 23 ml of concentrated sulfuric acid with water to make a total volume of 100 ml) 15 g 1 k
Add 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 the desired product as an oil.

IR spectrum (LiQ) νmax cm': 1
735°71O NMR spectrum (cnoj5) δppm: 0.92
(3H, m, cfH5) 1.62 (3H, s, OH3) 1.69 (3H, S, OH,) 4.72 (2H, br, s, -00HO-) 5.0
~5.8 (4H, m, =OH-X4) This compound 251 was reacted with excess diazomethane in ether at room temperature to give the corresponding methyl ester of 253.

11% spectrum (Liq) νmax cm-1: 9
70.

1740, 3360 Applicant Sankyo Co., Ltd. Representative Patent Attorney Izusho Kashi Procedural Amendment (spontaneous) April S, 1980 Commissioner of the Patent Office Kazuo Wakasugi 1981 Patent Application No. 38151 2, Title of Invention Carbacycline Derivative 3, Relationship with the Person Making Amendment Case Address of Patent Applicant: 6 Name, 3-1 Nihonbashi Honmachi, Chuo-ku, Tokyo 103 (185) Sankyo Co., Ltd. Representative Director and President Yoshinori Kawamura 4 Address of Agent: Sankyo Co., Ltd., 1-2-58 Hiromachi, Honbunagawa-ku, Tokyo 140, page 74 of the specification, line 1, insert the following sentence next to "Process)."

"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 (1) 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 in the form of tablets, capsules, granules, powders, syrups, etc., and parenteral administration by intravenous injection. The amount used varies depending on the symptoms, age, weight, etc., but it is usually about 0.00 mg per day for adults.
00011v to 1000q, preferably about 0.01 per day
~ to 1001 Rg, and can be administered once or in divided doses. ” Above ■, Indication of the case Patent Application No. 38151 filed in 1982, 2, Name of the invention: Carbacycline derivative 3, Relationship with the person making the amendment Patent applicant address: 3-1 Nihonbashi Honmachi, Chuo-ku, Tokyo 103 6 Name (185) Sankyo Co., Ltd. Representative Director and President: Yoshinori Kawamura 4, Agent address: 1-2-58 Hiromachi, Honbunagawa-ku, Tokyo 1, within Sankyo Co., Ltd. The scope of the claims in the specification is as follows: Correct to shi.

"General formula [wherein R1 is an optionally protected hydroxymethyl group,
optionally protected formyl group, optionally protected carboxyl group
1xy group or optionally substituted carbamoyl group
p2 and R5 are the same or different and represent a hydrogen atom or a hydroxyl group protecting group, and R4 is an optionally substituted alkyl group, alkenyl group, alkynyl group, optionally substituted cycloalkyl group, or the formula -CH2-Q -'R5 group (wherein Q represents a single bond, an oxygen atom, a sulfur atom, or an expanded methylene group,
t represents an optionally substituted cycloalkyl group or an aryl group. ), A is an oxymethylene group (-0-CH
2-), thiomethylene group (-8-CH2-) or vinylene group, B represents ethylene group, trans-vinylene group or ethynylene group, n represents an integer from 2 to 4, n
l represents an integer from O to 4, and a dotted line represents a double bond at the 2nd or 3rd position.

shows. ] A carbacycline derivative and a pharmacologically acceptable salt thereof. ” 2. “Indicates.” on page 3, line 10 of the specification. However, when A represents a vinylene group, nl represents 0. ]” and amend it.

3. “2-hexenyl” on page 9, lines 9 and 10
"2-hexynyl 1.!: Correct.

4. Correct "lower aromatic aliphatic" in line 3 of page 13 to "aralkyl." ◎ 5. Correct line 5 to line 7 of page 21.

6, page 22, line 2, 7, page 28, line 11, ``compounds where n' is an integer of 2'' are defined as ``a compound in which 8 is an oxymethyl group or a thiomethyl group''.
"Compounds where nl is an integer of 2" is corrected.

U') O's (4) (k) J (n') (VID α's (Ic) ttT Engineering 1 Ro. 1 9, "No particular limitations" on page 39, line 1 of the same page changed to "No particular limitations.""No, but preferably," he corrected.

10, on page 53, lines 14 and 15, "A is a vinylene group" is corrected to "A is a vinylene group, and n' is 0."

11. On page 67, line 11, "Cesylium" is corrected to "Cerium."

12. In the fourth line from the bottom of page 101, the word "mixture" is corrected to read "mixture [compound obtained by reacting the alcohol of Reference Example 10 in the same manner as in Example (lla)]".

13, same m 102 jf 4 lines from bottom [DrPl alignment J'
(Corrected to "made by i-ri14".

14, page 112, line 5, 15.3-58'' was changed to ``5.
3 to 5.8,” he corrected.

15. "r-4,s-" on page 128, line 2 of r-4@
.

8-” and correct it.

16, No. 84, line 5 from the bottom, page 96, line 7 from the bottom, #g page 98, line 5, page 109, line 4, page 133, 1
line, page 134, line 8 and page 135, negative line 5 from the bottom o
r -o6no-J t r -oδHO-X 2
Correct it with J.

Written amendment to the above procedure (spontaneous) March q, 1985 Commissioner of the Patent Office Gakudon Shiga 1, Indication of the case Patent Application No. 38151 filed in 1988 2゜Name of the invention Carbacycline derivative 3, Person making the amendment Case and Relationships Patent Applicant Address 1-6, 3-1 Nihonbashi Honmachi, Chuo-ku, Tokyo 103 Name (185) Sankyo Co., Ltd. Representative Director and President Yoshinori Kawamura 4, Agent Residence 1-2 Hiromachi, 140 Totori Honmonagawa-ku No. 58 Sankyo Co., Ltd. 6, subject of amendment 1. Detailed explanation of the invention in the specification column 7
, Contents of amendment 411 Arrow 1 Female 1 The following sentence is inserted next to "Example 15" spanning from page 109, line 4 to page 110, line 6 of the specification.

[Example 16 Mixture methyl ester compound (compound in the second half of Reference Example 26, 1.02
F) was sequentially reacted and treated in the same manner as in Example 13, and 16
4 rng of the target compound as an oil was obtained.

-1.

IP spectrum (Liq) ν. aXcrIL.

1650.1725.3354 NMR spectrum (CDCl2) δppm: 0.7~
1.1 (6H, m, ClHg X2) 3.68 (3H
, s, C02CH4)5.0~5.9 (4H, m
, =CH-x 4)6.88 (IH, d, t
; J=15.7Hz, =CH-) Example 17 A mixture of 3-(2-hydroxyethyl)-6β-[3α-(2-
mixture of oct-2-ene and oct-3-ene 350 Example 1a using ■
, and then reacted and treated as in Example 1b, yielding 71
q of oily target compound was obtained.

IR spectrum (Liq) νfoaXcFn.

975.1718.3400? , 1MR spectrum (CDCl2) δppm: 0.
7-1.1 (6H, m) 4.08 (2H, s) 5.40 (IH, br-s) 5.59 (2H, m) Example 18 3-(3-oxa-4-calgexybutyl) −6β−(
3α-hydroxy-3-cyclopentyl-1-propenyl)-7α-hydroxybicyclor3.3.0]oct-3-ene and mixture of oct-3-ene 3-(2-hydroxyethyl)-6β-[3α- (2-tetrahydropyranyloxy)-3-cyclopentyl-1-7'ropenyl]-7α-(2-tetrahydropyranyloxy)bicyclor3.3.0)oct-2-ene and oct-3
-Ene mixture 265~ was reacted and treated in the same manner as in Example 1a and then Example 1b to obtain the target compound 49~.

11 (spectrum (cHcts>ν]l[1axcrr
L.

975.1735.340O NMR spectrum (cDct3) 6 ppm: 3.
0 (IH, br ) 3.5-4.0 (4H, m ) 4.08 (2H, 5) 5-40 (I Hr br -s ) 5.52 (2H
, m) Example 19 3-(2-hydroxyethyl) -6/y-[3α-(
2-tetrahydropyranyloxy)-4-phenoxy-
Example 1a Using 310 μ of a mixture of 1-butenyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3,3,o]-:r-2-ene and oct-3-ene
, and then subjected to the same reaction treatment as in Example 1b, 57Il
An oily target compound of v was obtained.

IR spectrum (Llq) ν dl: ax 1130.1242.1740.335 ONMR spectrum pv (CDCLs) δppm: 3.5 to 4.2
(7H, m) 4.48 (IH, br) 5.40 (IH, br, s) 5.80 (2H, m) 6.8-7.5 (5H, m) J 2, same page 128 Correct "nona-1,8-genyl" in lines 2 and 3 to "-7-nonenyl."

3, page 136, line 2 r 1740.3360 J
is corrected to r1740J.

4. Insert the following sentence next to "Reference Example 21," which spans from line 10 of member 134 to two lines on page 136.

"Reference example 22 3-(5-benzyloxypentyl)-6β-(3-oxo-4-methyl-1-octenyl)-7α-(2-tetrahydropyranyloxy)bicyclo[3,:(,0]
] Mixture of oct-2-ene and oct-3-ene 0.41f 55% oily sodium hydride, dimethyl
2-oxo-3-methylheptylphosphonate) 3.5
6 r and the aldehyde obtained in Reference Example 16 2.98 f
was reacted and treated in the same manner as in Reference Example 17, and 3.21r
The desired oily compound was obtained.

Spectrum (Liq) νmaXa.

1625.1670,1696 NMI (spectrum (CDCt5) δppm: 1.0
7 (3H, d: J = 5Hz, CH5) 0.9
0(3H,br,t',CH3)3.47(2H,t
; J=7Hz, -CH20CH2Ph)4.
50 (2H, s, CH2Ph )5.30 (IH,
s, =CH-)6.20 (IH, dd; J=1
7,5Hz,=CH-)6.7~7.05 (I
H, no, =CH-) Reference example 23 Bicyclo[3,3,0)oct-2-ene and oct-
Mixture of 3-enes and their 6β-(3β-hydroxy) isomers Enones obtained in Reference Example 22 (3,2(1), cerium chloride heptahydrate (3,5v) and borohydride Using thorium (600 μl), the reaction and treatment were carried out in the same manner as in the first stage of Reference Example 18, and the resulting residue was purified using silica gel column chromatography without acid treatment. The 6β-(3β-hydroxy) form of was obtained, and then the 6β-(3α-hydroxy) form of 1.729 ml of hexane effluent containing ethyl thiacetate was obtained.

6β-(3β-hydroxy) form: IR spectrum (Liq) ν, aXcIIL・3450
．． 1450.1115 NMR spectrum (CDCl3) δppm: 0.7
~1.1 (6H, m, CH3X2)3.47
(2H,t:J=6.0)1z, -CH2O-C
)]zPh)4.53(2)1. s, C Ph) 5.28 (1) 1. br, s, =CH-)5.50~
5.74 (2'ki, m, -0H=CH-)
7.37 (5H,s, -Ph) 6β-(3α-hydroxy) form: IR spectrum (Liq) ν. aXcIrL.

3450.1455,111O NMR spectrum (CDCLs) δppIIll: 0
-7~1.1 (6Tl r m * CH5X 2
) 3.48 (2H, t; J = 6 Hz,
-CH20G12Ph )4.53 (2H, s, -
CH2Ph)5.28 (IH,br,s,=cH-)
5.50-5.80 (2H, m, -CH=CH-
) 7.38 (5H, s, -Ph) Reference Example 24 Reacted in the same manner as in Reference Example 19 using 1.72f of the alcohol [6β-(3α-hydroxy) form of Reference Example 23] and 0.91- of nohydrobilane. , to obtain 1.80 t of the target compound as an oil.

IR spectrum (Liq) νmax CIIL -14
60, 1355, 1205, 101025N spec)
pv (CDCLs) δppm: 3.47 (2H,
t: J=6Hz, -CHz-OCH2Ph4.
52 (2H, s, -CH2Ph)5.20~5
．． 80(3H,m,=4-X3)7.36(5B,s,
-Ph) Reference example 25 Dropyranyloxy]bicyclo[3,3,0]octo-
A benzylic compound of 2-ene and oct-3-ene (compound of Reference Example 24: 1.80f) and excess metal sodium were reacted and treated in the same manner as in Reference Example 20 to obtain 1.27
The target compound No. 9 was obtained as an oil.

IR spectrum (Liq) νmax” '3460.1
45 (1,120O NMR spectrum (cDczs) δppm: 0.7~
1.1 (6H+m, CHsX2) 4.72 (2H, br
, s, -o&o-x2) 5.20~5.80 (3H,
rn, =CH-X3) Reference example 26 3-(4-carboxybutyl)-6β-[3α-(2-
Tetrahydropyranyloxy)-4-methyl-1-octenyl]-7α-(2-tetrahydropyranyloxy)
Bicyclor3.3.0]oct-2-ene and oct-
The mixture alcohol of 3-ene (compound of Reference Example 25: 1.27P) and Soyones reagent 1.6- were reacted and treated in the same manner as in Reference Example 21 to obtain the target compound in the form of a 1.05F oil.

IR spectrum (Liq) ν1111aXcrIL.

1732.1707.1010 2ON spectrum (CDCl5) δppm: 4.7
3 (2H, br, s, -06HO-X 2 )5
．． 10-5.80 (3H, m, =CH-X3
)8-00~B-91(l He br, s*Co
ol) This compound was reacted with diazomethane to give the corresponding methylnisder.

IR spectrum (Liq) νInaXcIIL, 970
, 1740 Reference Example 27 (1titrahydrobilanyloxy)-4,4-dimethyl-
1-Octenyl]-7α-(2-tetra-2-ene and oct-3-ene mixture 2.99% of the aldehyde obtained in Reference Example 16 and tributyl 2-oxo-3,3
-A solution of 4.31f of methylhegetylphosphorane in nooxane (50) is 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 t of enone was obtained from the hexane outlet containing 10-ethyl thiacetate. This enone was sequentially treated in the same manner as in Reference Examples 18, 19 and 20 to obtain 921 .mu. of the target compound in the form of an oil.

I) 1 spectrum (Liq) ν9X me.

3460.1450,120O NMR spectrum # (CDC2s) a ppm: 0
．． 7-1.1 (9H, m, CHs X3)4
．． 70 (2H, br, s, -o&o X 2 )
5.20-5.80 (3H, m, =CH-x3) J or more

Claims (1)

[Claims] [In the formula, R1 is an optionally protected hydroxymethyl group,
Represents an optionally protected formyl group, an optionally protected carboxy group, or an optionally substituted carbamoyl group, and R
2 and R3 are the same or different and represent a hydrogen atom or a hydroxyl group, and R4 is an optionally substituted alkyl group, an alkenyl group, an alkynyl group, an optionally substituted cycloalkyl group, and -CH2 -Q-R5 group (wherein Q represents a single bond, oxygen atom, sulfur atom, or methylene group, R5
represents an optionally substituted cycloalkyl group or aryl group. ), A is an oxymethylene group (-0-OH2
-), a thiomethylene group (-8-OH2-), 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 is an integer of 0 to 4. , and the dotted line indicates the double bond at the 2nd or 3rd position. ] and a pharmacologically acceptable salt thereof.