JPH0434533B2 - - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula (In the formula, R¹may be protected
group, formyl group or optionally protected carboxyl group
Indicates a cy group, R²and R³are the same or different hydrogen
Indicates a protecting group for an atom or hydroxyl group, R^Fouris alkeni
represents a group or a cycloalkyl group, and n is 1 to 6
The dotted line indicates the double bond at the 2nd or 3rd position.
show. ) Novel carbacycline analogues with
and its pharmacologically acceptable salts. The above formula
During, R¹Protecting group for hydroxymethyl group, R²young
is R³It is usually used as a protecting group for the hydroxyl group of
There are no particular limitations as long as the group protects the hydroxyl group.
Acetyl, propionyl, butyryl, isobutylene
Lower fats like lil, benzoyl, and naphthoyl
group or aromatic acyl group; benzyl, p-nito
Ara such as lobenzyl, p-methoxybenzyl
Alkyl group; 2-tetrahydropyranyl, 2-tet
Lahydrofuranyl, 4-methoxytetrahydropi
Ran-4-yl, 2-tetrahydrothiopyranyl
It has an alkoxy group as a substituent, such as
Contains oxygen or sulfur atoms in the ring
5- to 6-membered cyclic heterocyclic group; methoxymethyl,
Acids such as toxymethyl, benzyloxymethyl
Substituted with a rukoxy group or aralkyloxy group
Methyl group having as; 1-methoxyethyl, 1
-1-alkoxyethyl such as ethoxyethyl
group or trimethylsilyl, triethylsilyl,
Phosphorus n-propylsilyl, t-butyldimethylsilyl
Tri-lowers such as biphenyl t-butylsilyl, biphenyl t-butylsilyl
alkyl or diaryl lower alkyl silicate
R groups can be mentioned, preferably R¹in
The protecting group for the hydroxymethyl group is an aralkyl group.
R, R²and R³The hydroxyl protecting group is 2-tetrahydrogen.
Dropyranyl group or 2-tetrahydrofuranyl group
It is. R¹As a protecting group for the carboxy group of
There are no particular restrictions on the carboxyl protecting group used.
No, but for example methyl, ethyl, n-propyl,
such as isopropyl, n-butyl, t-butyl
Lower alkyl group; benzyl, p-bromobenzyl
Aralkyl group such as phenyl, tolyl
aryl group; benzhydryl group or phenacyl
Examples include lower alkyl groups, preferably lower alkyl groups.
It is. R^FourAs the alkenyl group, 1-butyl vinyl
Allyl, 2-propylallyl, 2-butenyl
, 3-pentenyl, 4-pentenyl, 2-methyl
-3-pentenyl, 4-methyl-3-pentenyl
1-methyl-4-pentenyl, 4-hexenyl
1,4-dimethyl-3-penyl, 5-hexenyl,
tenyl, 5-heptenyl, 1-methyl-5-heptenyl
xenyl, 6-methyl-5-heptenyl, 2,6
-dimethyl-5-heptenyl, 1,1,6-tri
Methyl-5-heptenyl, 6-methyl-5-oc
tenyl, 2,6-dimethyl-5-octenyl, 6
-ethyl-5-octenyl, 2-methyl-6-ethyl
thyl-5-octenyl, 2,6-diethyl-5-
Direct carbon atoms with 3 to 12 carbon atoms such as octenyl
List of chain or branched alkenyl groups
and preferably 1-butylvinyl, 3-pene.
tenyl, 4-pentenyl, 2-methyl-3-pene
tenyl, 4-methyl-3-pentenyl, 1-methy
-4-pentenyl, 4-hexenyl, 5-hexenyl
Cenyl, 1,4-dimethyl-3-pentenyl, 5
-heptenyl, 1-methyl-5-hexenyl, 6
-Methyl-5-heptenyl, 2,6-dimethyl-
Aluminum containing 5 to 9 carbon atoms such as 5-heptenyl
It is a kenyl group. R^FourAs the cycloalkyl group, for example, cycloalkyl group is
lopropyl, cyclobutyl, cyclopentyl, 3
-Methylcyclopentyl, cyclohexyl, 4-
like ethylcyclohexyl, cycloheptyl
3 which may have a lower alkyl group as a substituent
It is possible to list up to 7-membered cycloalkyl groups.
preferably a cyclopentyl group or a cyclohexyl group
is a group. n is preferably an integer from 1 to 4. Compounds of the present invention having the general formula ()
T-R¹is a carboxyl group, if necessary.
It can be in the form of a pharmacologically acceptable salt.
Examples of pharmacologically acceptable salt forms include sodium chloride.
um, potassium, magnesium, and calcium.
salts of alkali metals or alkaline earth metals;
ammonium salt; tetramethylammonium, tet
Laethylammonium, benzyltrimethylammonium
monium, phenyltriethylammonium
Una quaternary ammonium salt; methylamine, ethylamine
amine, dimethylamine, diethylamine,
Limethylamine, triethylamine, N-methyl
hexylamine, cyclopentylamine, dicycline
lohexylamine, benzylamine, dibenzyl
Amine, α-phenylethylamine, ethylenedi
Lower aliphatic, lower cycloaliphatic and lower
Salts of aromatic aliphatic amines; piperidine, morpholin
pyrrolidine, piperazine, pyridine, 1-methane
such as tilpiperazine, 4-ethylmorpholine
Heterocyclic amines and their lower alkyl derivatives
Body salts; monoethanolamine, ethyldietano
amines, 2-amino-1-butanol, etc.
Examples include salts of amines containing hydrophilic groups.
can. Moreover, the compound () of the present invention has α-, β-, γ
- Host compounds and packaging such as cyclodexrin
A junction compound can also be formed and used. In addition, in the compound having the general formula ()
The coordination of the hydroxyl group on the side chain of the cyclopentane ring, etc.
R^Fourdouble bond when is an alkenyl group
Stereoisomers based on as well as within the cyclopentene ring
Positional isomers based on double bonds exist. accordingly
The compound having the above general formula () has these steric
If obtained as a mixture of isomers, separate them by conventional methods.
separation and resolution to obtain each isomer
I can do it. In the general formula () above, these
All mixtures of optical isomers and stereoisomers are single
The description of the present invention is expressed by the formula:
The range of is not limited. Also, in the general formula (), as a suitable compound
Well, (1) R¹is a carboxy group, hydroxymethyl group or
is a lower alkoxycarbonyl group, R²as well as
R³is a hydrogen atom and R^Fourhas 5 to 9 carbons
alkenyl group or 5- to 6-membered cycloa
A compound which is an alkyl group and where n is 1 to 4, (2) R¹is a carboxy group, a hydroxymethyl group,
or a methoxycarbonyl group, R²and R³
is a hydrogen atom and R^Fourhas 5 to 9 carbon atoms
Alkenyl group, cyclopentyl group or cyclohexyl group
List the compounds in which it is a xyl group and n is 4.
be able to. Recently, a protein that exhibits a strong platelet aggregation inhibitory effect has been developed.
Stacycline (PGI)₂) was discovered and its physiology
Its effects have attracted attention, and many groups have
Although research on related compounds has been conducted, the present inventors
is a new carbasa represented by the above general formula ()
We synthesized icrin analogs and examined their pharmacological activity.
However, these derivatives have excellent platelet aggregation inhibition.
action, coronary vasodilator action, bronchodilator action, antiulcer action
Inhibiting effects, especially platelet aggregation inhibition.
and/or exhibit strong activity.
Excellent sustainability and synthesis of active compounds
We discovered that it is an important intermediate for
Completed Ming. having the general formula () obtained by the present invention.
For example, the compounds listed below are
can give. 【table】 【table】 ｜ ｜

CH₃ CH₃

【table】 【table】 【table】 The compound () according to the present invention can be prepared by the method shown below.
Therefore, it can be manufactured. In the above formula, R¹,R²,R³,R^Four, n and dotted line are before
Indicates the same meaning as stated above, R^Fiveeven if it is protected
a good hydroxymethyl group or a group that may be protected.
Indicates a ruboxy group, R⁶and R⁷are the same or different
represents a hydroxyl protecting group, and R⁸is a protected hide
Roxymethyl group or optionally protected carboxy
Indicates a group, R⁹is a carboxy group that may be protected
shows. The first step of method A is an unsaturated compound having the general formula ().
In the process of manufacturing ton derivatives,
General formula for aldehyde derivatives (R^Ten)₃ P − C HCOR^Four () or general formula (In the formula, R^Fourhas the same meaning as above, and R^Ten
Aryl groups such as phenyl are methyl, n-butyl
Indicates an alkyl group such as til, M is lithium,
Alkali metal atoms such as sodium and potassium
shows. ) with Uitetsuhi or modified Uitetsu
This is achieved by reacting the reagents. The above general formula () or () used in the reaction
Wittetsug or modified Wittetsuchi reagent having
In the presence of a solvent according to a conventional method, the general formula (R^Ten)₃ P −CH₂−COR^Four・X (′) or general formula (In the formula, R^Fourand R^Tenhas the same meaning as above
and X represents a halogen atom such as chlorine or bromine.
vinegar. ) Compounds with sodium hydride and potassium hydride
Alkali metal hydrides such as um or sodium
ummethoxide, sodium ethoxide, potassium
Alkali metal alcohols such as tert-butoxide
oxide, sodium amide, potassium amide, etc.
Alkali metal amide, n-butyl lithium
Alkyl alkali metals, such as sodium dimethy
Alkali metal dioxins such as sulfoxide anions
Alkali metals such as methyl sulfoxide anion
can be obtained by reacting with a base.
Ru. The solvent used is the general formula Uitetsuhi reaction.
Any suitable solvent may be used without particular limitation, e.g.
For example, ethyl ether, tetrahydrofuran,
Ethers such as xane and dimethoxyethane;
Cyclic sulfones such as sulfolane; benzene,
Hydrocarbons such as toluene and hexane; dimethylene
Dialkyl sulfoxides such as Rusulfoxide
Class; dimethylformamide, dimethylacetamide
Fatty acid dialkylamides such as dichloro
Halogenated hydrocarbons such as methane and chloroform
Elemental class; hexamethylphosphortriamide
Inert phosphoric acid triamides such as (HMPA)
Examples include organic solvents. Also, the reaction
in an inert gas such as hydrogen, argon, or helium.
This is preferably done. There are no particular limitations on the reaction temperature.
It is usually carried out at -10℃ or the reflux temperature of the solvent.
This is preferably carried out at around room temperature. The reaction time is
It varies depending on the reaction temperature, etc., but usually 6 to 50
It's time. After the reaction is complete, the target compound of the Uitteg reaction is always
from the reaction mixture according to the method. For example, against
After the reaction is complete, add ice water to the reaction mixture and then
Depending on the acid treatment, organic
Add a solvent and extract, and wash the resulting organic solvent layer with water.
After drying, the solvent is distilled off from the organic solvent layer.
Obtained by. The second step is an alcohol derivative having the general formula ().
In the process of manufacturing conductors, the compound () is reduced.
This is achieved by The reaction is usually carried out in an inert solvent using a reducing agent.
It is done by. Only carbonyl groups are used as reducing agents.
There is no particular limitation as long as it is a reducing agent that converts into hydroxyl groups.
For example, sodium borohydride, borohydride
potassium, lithium borohydride, borohydride
Zinc, hydrogenated tri-tert-butoxyaluminum
Trimethoxy aluminum hydride
water, such as sodium cyanoborohydride
Nitrogenized metal compound or aluminum isopropoxy
diisobutyl-(2,6-di-t-butyl-
4-methylphenoxy) aluminum such as
Luminium compounds can be mentioned, but preferred
is sodium borohydride. In addition, in order to suppress the reduction of double bonds,
It is also possible to add lium etc. The inert solvent used must not participate in the reaction.
Although not particularly limited, for example, methanol, ethanol, etc.
alcohol, n-propanol, n-butanol, t-
alcohols or ethers such as butanol,
ethers such as tetrahydrofuran and zooxane
solvents or mixed solvents thereof.
However, alcohols, especially methanol are preferred.
Ru. The reaction temperature is usually 0°C to room temperature, and the reaction temperature is
The time required varies depending on the reaction reagent, reaction temperature, etc.
The duration is 10 minutes to 2 hours. After the reaction is completed, the target compound of this step is obtained according to the conventional method.
from the reaction mixture. For example, the reaction ends
After that, the solvent was distilled off under reduced pressure, and ice water was added to make the water immiscible.
extraction with a compatible organic solvent and distilling off the organic solvent
obtained by. In addition, in the raw material compound () of this step,
R^Fiveis a hydroxymethyl group, the necessary
Used in this reaction after protecting its hydroxyl group according to
can do. A reaction that introduces a protecting group into a hydroxyl group.
The reaction is carried out in the same manner as the reaction in the third step of method A described below.
It will be done. The third step is to produce a compound having the general formula ()
A step in which a compound having the general formula ()
This is achieved by protecting the hydroxyl groups of substances.
The reaction is to form a protecting group on the compound () according to a conventional method.
carried out by contacting with a compound that
Ru. The compounds forming the protecting groups used are:
For example, acetic acid, propionic acid, butyric acid, benzoic acid, sodium
Carboxylic acids such as phthalic carboxylic acid or
Its reactive derivatives; benzyl chloride, benzyl
Bromide, p-nitrobenzyl bromide, p-meth
Aralkyl hala such as toxybenzyl bromide
compound; dihydropyran, dihydrothiopyra
dihydrothiophene, 4-methoxy-5,6
-dihydro-(2H)pyran-like 5 or 6
Member cyclic heterocyclic compound; methoxymethyl chloride
ethoxyethyl chloride, benzyloxime
Alkoxy or aral like chloride
Kyloxy-substituted alkyl halide compound; methyl
Vinyl ether, such as ethyl vinyl ether
Unsaturated ethers; hexamethyldisilazane,
Limethylsilyl chloride, tri-n-propyl chloride
Lyl chloride, t-butyldimethylsilylchloride
Diphenyl t-butylsilyl chloride
Suitable compounds include silyl compounds, etc.
be able to. When using carboxylic acid compounds,
Presence of a condensing agent such as lohexane carbodiimide
This is preferably done below. Examples of reactive derivatives of carboxylic acids include vinegar.
Acid chloride, acetate bromide, benzoyl chloride
of benzoyl bromide, naphthoyl chloride
Acid halide compounds such as acetic anhydride, pro-anhydride
Include acid anhydrides such as pionic acid and benzoic anhydride.
When using this derivative,
ethylamine, pyridine, 4-dimethylamino
Pyridine, quinoline, N,N-dimethylaniline
This is preferably carried out in the presence of an organic base such as. This reaction is carried out in the presence of a solvent. used
Examples of solvents include benzene, toluene, and
hydrocarbons such as urethane, n-hexane, chloride
Tyrene, chloroform, carbon tetrachloride, chlorobene
halogenated hydrocarbons such as zene, ethers,
ethers such as tetrahydrofuran and dioxane
chemicals such as alcohols, acetone, and methyl ethyl ketone.
water, preferably hydrocarbon water.
It is an elementary class. The reaction temperature is usually 0°C to 100°C, and the reaction temperature is
The time required varies depending on the reaction reagent, reaction temperature, solvent, etc.
However, it takes between 30 minutes and 6 hours. Aralkyl halide compound, alkoxy or
is an aralkyloxy-substituted alkyl halide compound
or when using silyl compounds, inert solvents.
The compound () in the agent is added to sodium hydride, carbon hydride, etc.
Reacts with alkali metal hydrides such as
After producing the alkali metal salt of compound ()
, corresponding halide compounds or disilazane, etc.
Achieved by reacting with a silylation reagent
be done. The inert solvent used is
For example, but not limited to, ether, tetrahydride
ethers such as lofuran, dioxane,
Chylformamide, dimethylacetamide, hexa
Amides such as samethylphosphoryltriamide
nitric acid, such as acetonitrile, benzonitrile, etc.
Tolyls or sulfurs such as dimethyl sulfoxide
Phoxides can be mentioned, but preferably
They are amides. The reaction temperature is 0°C to 100°C, and the reaction temperature is
The waiting time varies depending on the reaction reagent, reaction temperature, etc., but is generally
Usually 10 minutes to 3 hours. Also, triethylamine, pyridine, 4-dimethy
Organic bases such as fluoraminopyridine or sodium hydroxide
Like thorium, potassium hydroxide, potassium carbonate
In the presence of an inorganic base, the compound () corresponds to
A halide compound can also be reacted. 5 years old
or a 6-membered cyclic heterocyclic compound or an unsaturated ether
When using solvents, the reaction is carried out in the presence of an inert solvent.
Small amounts of acids, e.g. hydrochloric acid, bromide, in the presence or absence of
Mineral acids like hydrogen acid or picric acid, triflic acid
Oroacetic acid, benzenesulfonic acid, p-toluene
Organic acids such as sulfonic acid and camphorsulfonic acid
carried out in the presence of The solvent used must not be involved in the reaction.
Although not particularly limited, for example, ether, tetrahydrogen
Dorofuran, ethers such as dioxane, salts
such as methylene chloride, chloroform, carbon tetrachloride
halogenated hydrocarbons or benzene, toluene,
Listing aromatic hydrocarbons such as xylene
However, halogenated hydrocarbons are preferred.
Ru. Also, in the absence of an inert solvent, it can also act as a solvent.
Excessive use of bare ring compounds or vinyl ether compounds
The reaction can also be carried out by using The reaction temperature is usually 0°C to 50°C, depending on the reaction temperature.
The time required varies depending on the reaction reagent, reaction temperature, etc.
However, the duration is from 30 minutes to 3 hours. After each of the above reactions, the protected purpose of the hydroxyl group is
The compounds were collected from the reaction mixture according to conventional methods.
Ru. For example, pour the reaction mixture into ice water and remove any insoluble matter.
If the solution is acidic or alkaline,
In case of potash, neutralize as appropriate and add water-immiscible organic solvent.
Obtained by distilling off the solvent after extraction with a solvent.
be able to. In addition, if necessary, use conventional methods, e.g.
Lamb chromatography, thin layer chromatography
- further purification using recrystallization method etc.
can. In addition, in compound (), the coordination of the hydroxyl group is
If a considerable amount of β-position compound is produced, the necessary
Depending on the hydroxyl protecting group R⁶By removing, the usual method,
For example, by recrystallization or column chromatography.
Then, remove the compound whose hydroxyl group is in the β position, and then
It can also be used in process reactions. The fourth step is a step performed as desired, and R⁸Included in
Protecting group for hydroxyl group or protecting group for carboxy group
Protecting group removal reaction, R⁶and/or R⁷Preservation of hydroxyl group
Protecting group removal method, R⁸Protecting groups for hydroxyl groups contained in
The hydroxymethyl group obtained by removing
or reaction to convert into carboxyl group or carboxyl group
It involves a reaction that esterifies an xy group. The protecting group for the hydroxyl group is a lower aliphatic or aromatic aliphatic group.
In the case of sil groups, their removal can be accomplished by conventional hydrolysis reactions.
This is done depending on the situation. acid or base used
It is an acid used in general hydrolysis reactions or
A base is used without particular limitation, but usually, for example,
Lithium hydroxide, sodium hydroxide, potassium hydroxide
barium, calcium hydroxide, and barium hydroxide.
Alkali metal and alkaline earth metal hydroxides
This is preferably carried out under basic conditions using a chemical compound.
The solvent used is the one used in the hydrolysis reaction.
Any solvent can be used without particular limitation, such as methanol.
alcohol, ethanol, n-propanol, isopropyl
Alcohols such as alcohol; ethyl ether
tel, tetrahydrofuran, dioxane, dimeth
Ethers such as xyethane; dimethyl sulfonate
Dialkyl sulfoxides such as oxides and
List the mixed solvents of these organic solvents and water.
I can do it. There is no particular restriction on the reaction temperature, and it is usually
It is carried out at around room temperature to the reflux temperature of the solvent. reaction
The time varies depending on the reaction temperature, etc., but is usually 1
The duration is between 12 hours and 12 hours. At this time, protection of the carboxy group
The same applies when the group is a lower alkyl group or an aryl group.
removed at times. Aralkyl group as a protecting group for hydroxyl group
In the case of the corresponding compound in an inert solvent with a reducing agent
This is achieved by contacting. The inert solvent and reducing agent used are lithium
Alkali golds such as umum, sodium, and potassium
genus or sodium sulfide or potassium sulfide.
Alkali metal sulfides can be listed.
is preferably an alkali metal. alkali metal
The reaction with liquid ammonium or
and ethers, such as tetrahydrofuran.
It is preferably carried out in a mixed solvent with esters, and alkaline
Reactions with metal sulfides include methanol and ethanol.
alcohols such as tetrahydrofuran,
Ethers such as xane or their organic solvents
This is preferably carried out in a mixed solvent of water and water. The reaction temperature is -78°C for reaction with alkali metals.
-20℃, and the reaction with alkali metal sulfides causes
The temperature range is from 0℃ to 100℃, and the time required for the reaction is generally
Usually 20 minutes to 6 hours. In this case, the protecting group for the carboxy group is aralkyl,
Simultaneously in the case of benzhydryl or phenacyl group
will be removed. Protecting group of hydroxyl group is heterocyclic group, alkoxy or
is methyl having aralkyloxy as a substituent
group or 1-alkoxyethyl group, contact with acid
This can be easily achieved by used
Examples of acids include formic acid, acetic acid, and trifluoroacetic acid.
acids, propionic acid, butyric acid, oxalic acid, malonic acid,
Methanesulfonic acid, benzenesulfonic acid, p-t
Luenesulfonic acid, camphorsulfonic acid, etc.
Organic acids; mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid are preferred.
used appropriately. Reactions can occur in the presence or absence of solvent
Although the reaction is carried out in
It is preferable to use a solvent, and the solvent used
For example, there is no limitation as long as it does not participate in this reaction.
Water; alcohol such as methanol and ethanol
Acids; acids such as tetrahydrofuran and dioxane
esters; such as acetone and methyl ethyl ketone
Ketones or mixed solutions of these organic solvents and water
Agents are preferably used. There are no particular restrictions on the reaction temperature.
The reaction is carried out at room temperature to the reflux temperature of the solvent. The time required for the reaction is 30 minutes to 10 hours.
Ru. Protecting group for hydrogen group is tri-lower alkyl or
Water is present in the case of diaryl lower alkylsilyl group
or contact with water containing acids or bases.
easily achieved by Containing acids or bases
When using water that contains acids or bases,
For example, formic acid, acetic acid, propionic acid, butyric acid,
Organic acids such as oxalic acid and malonic acid; hydrochloric acid and bromide water
acids, such as mineral acids such as sulfuric acid, or hydroxides.
Alkali metals such as aluminum and calcium hydroxide
and alkaline earth metal hydroxides; potassium carbonate
alkali metals such as aluminum, calcium carbonate, and
Particularly limited to bases such as alkaline earth metal carbonates
used without. The reaction uses water as a solvent.
Other solvents are not particularly necessary. Use other solvents
For example, use tetrahydrofuran, dioxa
Ethers such as methanol, ethanol, etc.
Mixed solvents of organic solvents such as alcohols and water
is used. There is no particular limit to the reaction temperature, but
It is usually suitably carried out at room temperature. Time required for reaction
is 30 minutes to 5 hours. Also, the protecting group is t-butyl
In the case of dimethylsilyl group, tetrahydrofuran
In the presence of ethers such as
To be treated with tetrabutylammonium tsunide
It will be achieved even if it is difficult. After the reaction is completed, the reaction to remove the hydroxyl protecting group is performed.
The target compound was collected from the reaction mixture according to a conventional method.
It will be done. For example, after the reaction is complete, the solvent is distilled off under reduced pressure.
or pour the reaction mixture into ice water without distilling it off.
Neutralize if necessary, then add an appropriate organic solvent.
After extracting and washing the extract with water and drying,
Obtained by distilling off the solvent from the extract.
Ru. R⁸The hydroxyl protecting group contained in R⁶and R⁷is the same
In the case of one protecting group, the above protecting group removal reaction is performed.
removed at the same time. Also, select the protecting group appropriately.
It is also possible to selectively deprotect by
Ru. The protecting group for the carboxyl group is a lower alkyl group or an alkyl group.
In the case of a lyl group, its removal is a normal hydrolysis reaction.
It is carried out by. This reaction protects the hydroxyl group.
This is done in the same way as when the group is an acyl group. Carboxy group protecting group is aralkyl group, benzene
In the case of a hydryl group or phenacyl group, its removal
The elimination reaction is performed when the above-mentioned hydroxyl protecting group is an aralkyl group.
The reaction is similar to that of the case. After the reaction is completed, the target compound of the hydrolysis reaction is treated in a conventional manner.
from the reaction mixture according to. For example, reaction
After completion, the reaction mixture is made acidic and then added with a suitable alcohol.
Extraction is performed by adding a solvent, and the extract is washed and dried.
After drying, the solvent is distilled off from the extract.
can be obtained. Reaction that converts hydroxymethyl group to formyl group
The reaction usually involves oxidizing a primary alcohol to an aldehyde.
It is carried out according to the method. At this time R²and R³is water
It needs to be a protecting group for acid groups. Examples of oxidizing agents used include anhydrous chromium
Acid, chromic anhydride-pyridine complex salt (Collins test)
medicine), chromic anhydride-concentrated sulfuric acid-water (Jones reagent),
Sodium dichromate, potassium dichromate, etc.
Chromic acids; N-bromoacetamide, N-bromoacetamide,
romsuccinimide, N-bromphthalimide,
N-chromium-p-toluenesulfonamide, N-
Organic active compounds such as chlorobenzenesulfonamide
chloride compound; aluminum-tert-butoxy
aluminum, such as aluminum isopropoxide, aluminum isopropoxide, etc.
Nium alkoxides; dimethyl sulfoxide
Dicyclocarbodiimide; pyridine-sulfuric anhydride-
Dimethyl sulfoxide and the like are preferably used. The reaction is suitably carried out in an inert organic solvent,
The solvent used is, for example, methylene chloride.
Halogens such as carbon, chloroform, and carbon tetrachloride
hydrocarbons, ethers, tetrahydrofuran,
Ethers such as dioxane, acetone, methane
Ketones such as ethyl ketone or dimethyls
Giving sulfoxides such as sulfoxide
I can do it. The reaction temperature is 0°C to room temperature, and the reaction temperature is 0°C to room temperature.
The time is usually 30 minutes to 3 hours. After the reaction is complete, the desired formyl compound is prepared according to a conventional method.
from the reaction mixture. For example, the reaction ends
After that, if there are any insoluble substances, put them in ice water separately.
After opening and neutralizing as appropriate, extract with a water-immiscible organic solvent.
It can be obtained by removing the solvent and distilling off the solvent.
Wear. The reaction that converts formyl group to carboxy group is a
Following the usual method of oxidizing a dehyde to a carboxylic acid.
It is carried out at the same time. At this time, R²and R³is the retention of hydroxyl groups.
It needs to be a guardian group. An example of the oxidizing agent used is chromic anhydride.
- concentrated sulfuric acid - water (Jones reagent), potassium permanganate
Sodium hydroxide or sodium carbonate
silver oxide, potassium dichromate-sulfuric acid, etc.
can be done. The reaction is usually carried out using ketones such as acetone, water or
Water and alcohols such as methanol and ethanol
It is carried out in a mixed solvent with. The reaction temperature is -30℃ to 100℃, and the reaction temperature is -30℃ to 100℃.
The time required for this is usually 30 minutes to 5 hours. Or, using hydroxymethyl compounds as raw materials,
Performing the reaction, you can directly obtain the carboxy compound
You can also do it. In addition, in the case of Jones reagent, the amount of reagent and reaction
Alcohol can be removed by adjusting conditions.
Selective carboxylic acid from dehyde or alcohol
You can also get it. After the reaction is complete, the desired carboxy compound is prepared in a conventional manner.
It is therefore taken from the reaction mixture. For example, reaction mixture
Pour the mixture into ice water, and if the solution is alkaline,
Acidified with dilute acid, then extracted with water-immiscible organic solution
and can be obtained by distilling off the solvent.
Ru. The reaction to esterify a carboxy group requires the presence of a solvent.
contact with an esterifying agent in the presence or absence of
It is done by Esterification used
As an agent, a normal carboxyl group can be replaced with an alkoxy group.
Esters used in converting to carbonyl groups
A curing agent can be used without particular limitation. S used
Examples of tellurizing agents include diazomethane, azizo
Ethane, diazo-n-propane, diazoisopropane
Diazo alkanes such as pan and diazo-n-butane
Class; methanol, ethanol, n-propanol
alcohol, isopropyl alcohol, n-butanol, etc.
Which alcohols and hydrochloric acid form ester groups,
Mineral acids such as hydrobromic acid or sulfuric acid or methane
Sulfonic acid, benzenesulfonic acid or p-t
Organic acids such as luenesulfonic acid; methyl bromide, odor
Lower alkyl halides such as ethyl chloride and hydroxide
of sodium, potassium hydroxide, and sodium carbonate.
Such bases are preferably used. diazoalkane
When using compounds, the reaction is preferably carried out in the presence of a solvent.
be called. The solvent used is not involved in this reaction.
If not, there is no particular limitation, for example, ethyl ether.
Ethers such as dioxane and dioxane are suitable.
There is no limit to the reaction temperature, but side reactions should be suppressed and dia
The process is carried out at a relatively low temperature to prevent the decomposition of zoalkanes.
It is preferable to carry out the test under ice cooling.
Ru. When using alcohols in the presence of acids,
Excess alcohol is preferably used as a regular solvent.
It will be done. The reaction temperature is not particularly limited, but room temperature or
This is preferably carried out near the reflux temperature of the ercols used.
be exposed. The reaction time mainly depends on the reaction temperature and the reaction temperature used.
Approximately 1 to 2 hours depending on the type of alcohol
It is days. After the reaction is complete, the target compound of the esterification reaction is always
from the reaction mixture according to the method. For example, against
After the reaction is complete, the solvent is distilled off from the reaction mixture.
Therefore, if necessary, the product may be further treated with an organic solvent.
Dissolve the organic solvent layer in an aqueous solution of sodium bicarbonate.
Alkali carbonate such as sodium carbonate aqueous solution
After washing with an aqueous solution and drying, remove the organic solvent layer.
It is obtained by distilling off the solvent. In the fifth step of method B, in the target compound (),
R′ is an optionally protected hydroxymethyl group or
A carboxyl group that may be protected, where n is 1 and
It is a process to obtain a certain compound (′) separately, and
The compound () is treated with a base in an inert solvent and extracted with
After isomerizing the double bond at the so position, if necessary,
Reduction reaction of optionally protected carboxy group, its
Hydroxymethyl group obtained by reduction reaction
When indicating a protecting reaction or a protecting group for a hydroxyl group,
R²and/or R³By carrying out the removal reaction of
achieved. Used in reactions that can isomerize the double bond at the exo position
The base to be used is preferably diisopropyl alcohol.
Minolithium, isopropylcyclohexylamine
Norithium, dicyclohexylaminolithium
Aminolithiums such as
The inert solution used should be one that does not participate in the reaction.
Although not particularly limited, ether and ether are preferably used.
Ethanols such as trahydrofuran, dimethoxyethane
-I can give you some information. The reaction temperature is -78℃ to 0℃, and the reaction temperature is -78℃ to 0℃.
The time required is 30 minutes to 3 hours. After the reaction is complete, the target compound is extracted from the reaction mixture using a conventional method.
Collected according to the following. For example, dilute the reaction mixture in ice water
and extract with a water-immiscible organic solvent to remove the solvent.
It can be obtained by distillation. Sara
If necessary, column chromatography,
It can also be purified by a recrystallization method or the like. The optionally protected carboxy group is replaced by a hydroxyl group.
The reaction to reduce to the chill group is carried out in an inert solvent, corresponding to
carried out by contacting the compound with a reducing agent
Ru. The reducing agents used include carboxy groups,
Reducing agent that converts stellate groups to hydroxymethyl groups
Although not particularly limited, boron hydride is preferably used.
Lithium, sodium borohydride - aluminum chloride
Ni, boron trihydride-cyclohexylamine
Boron compounds such as or lithium aluminum hydride
Lithium aluminum hydride-aluminum chloride
Minium, diisobutylaluminum hydrogen, etc.
We can list some aluminum compounds,
Particularly preferred is lithium aluminum hydride.
Ru. The inert solvent used is one that does not participate in the reaction.
If not, there is no particular limitation, but it is preferable that
Chemicals such as fluorine, tetrahydrofuran, and dioxane
- Teru type. The reaction temperature is 0°C to 50°C, and the reaction temperature is 0°C to 50°C.
The time is usually 30 minutes to 3 hours. After the reaction is complete, the reaction target product is mixed with the reaction mixture according to a conventional method.
It is collected from compounds. For example, dilute water in the reaction mixture
Add sodium oxide aqueous solution or ice water to make water immiscible.
extraction with a compatible organic solvent and distilling off the organic solvent
It can be obtained by Reaction to protect hydroxymethyl group or hydroxyl group
The removal reaction is a reaction corresponding to the fourth step of method A described above.
can be done similarly. The raw material compound () for this step can be prepared using a known method, e.g.
It can be easily manufactured according to the method disclosed in Japanese Patent Application Laid-open No. 53-462.
can be built. In addition, the raw material compounds () in Method A are as follows:
It can be manufactured by the method. In the above formula, R²,R^Five,R⁶,R⁸, n and dotted line are before
Indicates the same meaning as stated above, R¹¹is a protected
Indicates a droxymethyl group, R¹²is a hydrogen atom or metal
Like thyl, ethyl, n-propyl, n-butyl
represents a lower alkyl group, Z is the formula [formula] or is [formula] (where R¹³indicates a lower alkyl group , Y represents an oxygen atom or a sulfur atom, and A represents an ethyl atom.
Ren, propylene, trimethylene, butylene, te
Tramethylene, 2,2-dimethyltrimethylene
represents an alkylene group having 2 to 5 carbon atoms. )
represents a carbonyl group-protecting group having
Indicates an integer between 5 and 5. The sixth step is an alcohol derivative having the general formula ().
In the process of manufacturing conductors, the general formula
A ketone derivative with the general formula () XMg(CH₂)_o−R¹¹ () (In the formula, R¹¹, X and n have the same meanings as above.
shows. ) is reacted with Grignard reagent with
This is achieved by The inert solvent used must not participate in the reaction.
Although not particularly limited, ether, tetra
Ethers such as hydrofuran, dimethoxyethane
hexamethylphosphoryltriamide or
It is a mixed solvent of these. The reaction temperature is 0°C to 100°C, and the reaction temperature is
The time required is usually 30 minutes to 3 hours. The seventh step is to prepare a compound having general formula (XII).
Te, R¹is a protected hydroxymethyl group
In the process of producing compound (XII′), compound ()
This is achieved by dehydrating the The reaction involves treating compound (X) with an acid in an inert solvent.
It is done by doing. Acids used include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.
Inorganic acids such as phosphoric acid or acetic acid, trifluoroacetic acid
acid, methanesulfonic acid, benzenesulfonic acid, p
-Toluenesulfonic acid, camphorsulfonic acid, etc.
Examples include organic acids such as p, but preferably p
-Toluenesulfonic acid, camphorsulfonic acid
Ru. The inert solvent used does not participate in the reaction.
Although not particularly limited, benzene,
With aromatic hydrocarbons such as toluene and xylene
be. In addition, the phase used for the protective group of the carbonyl group
By coexisting with the corresponding alcohol, the
The reaction can be carried out without removing the protecting group.
Ru. The reaction temperature is 50℃ to 150℃, and the reaction temperature is 50℃ to 150℃.
The time required is 1 to 5 hours. The eighth step is the exo-position having the general formula (XI).
In the process of manufacturing compounds with heavy bonds, the compound
() is a general formula (R^Ten)₃ P − CH (CH₂)_nR^Five () or general formula (In the formula, R^Five,R^Ten, M and m are the same as above.
Show meaning. ) with Wittetsug reagent or modified method
Achieved by reacting with Wittetsug reagent
It will be done. This reaction is expressed by the general formula (R^Ten)₃ P −CH₂(CH₂)_nR^FiveX (′) or general formula (In the formula, R^Five,R^Ten, X and m are the same as above.
Show meaning. ) using a compound having the above A
The method is carried out in the same manner as the first step. Also, R^Fiveis a carboxyl group that may be protected.
by reducing the corresponding compound.
Compounds with hydroxymethyl groups, and water
Hydroxy protected by protecting the acid group
Can be converted into compounds with methyl group
Ru. This reduction reaction corresponds to the fifth step of method B above.
The reaction to protect the hydroxyl group is carried out in the same manner as described above.
This is carried out in the same manner as the third step of Method A. The ninth step is the end position having the general formula (XII).
In the process of manufacturing compounds with heavy bonds, inert
By treating compound (XI) with an acid in a solvent,
achieved. Examples of acids used include hydrochloric acid, nitric acid, and sulfuric acid.
Inorganic acids such as acetic acid, trifluoroacetic acid,
Zozoic acid, methanesulfonic acid, benzenesulfone
acid, p-toluenesulfonic acid, camphorsulfonate
organic acids such as phosphoric acid, but preferred
Suitably p-toluenesulfonic acid, camphorsul
It is phonic acid. The inert solvent used is one that does not participate in the reaction.
There is no particular limitation, but for example, benzene,
Aromatic hydrocarbons such as toluene and xylene,
Ether, tetrahydrofuran, dioxane etc.
Eel ethers, methylene chloride, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride,
ketones, such as methyl ethyl ketone,
Alcohols such as tanol, ethanol, water
Alternatively, a mixed solvent of the above organic solvent and water can be used.
However, aromatic hydrocarbons are preferred. The reaction temperature is 50℃ to 150℃, and the reaction temperature is 50℃ to 150℃.
The time required is usually 1 to 10 hours. R^Fiveis a protected hydroxymethyl group
In this case, the protective group for the hydroxyl group may be removed by acid.
for example heterocyclic groups, alkoxy or aral
Kyloxymethyl group, 1-alkoxyethyl group or
is a silyl group or Z is removed by acid
protecting groups such as [Formula] group or [Formula] Group (in the formula, R¹³and A are as mentioned above. indicates the same meaning. ), the above protection is usually applied.
The groups are also removed at the same time. However, Z is [formula] group or [formula] group (In the formula, R¹³and A have the same meaning as above.
vinegar. ), the phase forming the protecting group
Aromatic hydrocarbons
Protection of carbonyl groups by carrying out the reaction in
The main isomerization reaction can also be carried out while retaining the group.
Wear. The 10th step is ketone induction with the general formula ()
In the process of manufacturing compound (XII), the carbonyl
The protective group of the group is removed according to the usual method.
It is achieved by doing so. The protecting group for the carbonyl group has an oxygen atom.
In some cases, the corresponding compounds may be combined, for example in acetic acid-water, dilute
Hydrochloric acid-hydrated acetone, diluted hydrochloric acid-hydrated acetonitrile
Acids such as dilute sulfuric acid-hydrated acetone and aqueous
Contact with solvent for 30 minutes to 3 hours at 0℃ to 100℃.
It is removed by In this reaction, R^Fivehydroxymethyl group of
If the protecting group is a heterocyclic group, alkoxy group or
Methyl group having alkyloxy group as a substituent or
is tri-lower alkyl or diaryl-lower alkyl
In the case of a kylsilyl group, the protecting group is usually
is also removed at the same time. Also, if necessary, the generated
The droxymethyl group was added in the same manner as in the third step of method A above.
It can also be protected with a desired protecting group. The protecting group for the carbonyl group has a sulfur atom.
In some cases, the corresponding compound is
ethers, methylene chloride,
halogenated hydrocarbons such as chlorine, chloroform, etc.
alcohols such as alcohols, methanol, and ethanol
or water or a mixed solvent thereof, mercury acetate,
Contact with mercury chloride or mercury oxide (red) at 0℃ to 60℃
removed by touching it. In this reaction
Boron trifluoride-ether complex if necessary
Lewis acids such as
Ru. The 11th step is carboxy with general formula ()
Or a process for producing an alkoxycarbonyl compound
In the presence of a base, compound () in an inert solvent
Carbon dioxide gas, dry ice or general formula (In the formula, R¹³has the same meaning as above,
R¹⁴represents a lower alkoxy group or a halogen atom.
vinegar. ) with a carbonate derivative having
This is achieved by Used in reactions with carbon dioxide or dry ice
The base used is di-t-butyl-p-crete.
Organic lithium in the presence of cresols such as sol
compounds such as methyllithium, n-butyl
Lithium, s-butyllithium, phenyllithium
organic potassium compounds such as triphenylmethylene
potassium or metal hydrides such as sodium hydride
Give umum, potassium hydrate, and calcium hydride.
be able to. In reactions with carbonate derivatives, used
Bases include sodium methoxide, sodium
Lithium ethoxide, potassium t-butoxide, sodium
Alkali metals such as thorium t-pentoxide
Alkoxide or sodium hydride, potassium hydride
Alkali metals such as calcium hydride, calcium hydride, etc.
or alkaline earth hydrides.
Ru. Inert solvents used include ether, tet
Lahydrofuran, dioxane, dimethoxyetha
Ethers such as chlorine and diglyme are preferred.
Ru. The reaction temperature is -20℃ to 80℃, and the reaction temperature is -20℃ to 80℃.
The time required is 1 hour to 24 hours. The 12th step is hydroxyl having the general formula ()
In the process of manufacturing a compound, the compound () is reduced
This is achieved by doing. This reaction is carried out in the same manner as the second step of method A. The 13th step is hydroxyl having general formula (X)
In the process of manufacturing methyl compounds, the compound ()
After protecting the hydroxyl group, carboxyl is used as a raw material.
Reducing an xy group or an alkoxycarbonyl group
This is accomplished by The protective group for the hydroxyl group is prepared in the same manner as in the third step of method A.
be exposed. R⁸is a protected hydroxymethyl group or carboxyl group.
is a boxy group, R¹²is a lower alkyl group
In this case, the reduction reaction can be carried out using ether, tetrahydrofuran
in an inert solvent such as toluene.
Lithium aluminum hydride, borohydride compound
30 at -40℃ to 70℃ with elemental lithium, bitride, etc.
This is done by contacting for minutes to 5 hours.
At this time, the amount of lithium aluminum hydride is excessive.
By using it in such a way that it does not become
It will be done. R⁸is a protected carboxy group and R¹²is water
In the case of elementary atoms, the reduction reaction is ether,
In an inert solvent such as tetrahydrofuran, the equivalent
The compound is mixed with diborane at 0°C to room temperature for 30 minutes to
This is done by contacting for up to 3 hours. The 14th step is the process of manufacturing the compound (),
Oxidizing the hydroxymethyl group of compound ()
This is accomplished by This reaction is carried out using hydroxyl in the fourth step of method A.
Similar to the reaction that converts a methyl group to a formyl group
It will be done. Additionally, if necessary, R⁸protected hide
Protecting group for hydroxyl group in case of roxymethyl group and/or
is R⁶selectively removing the hydroxyl protecting group of
You can also do it. After the completion of the reaction in each step above, the target compound of the reaction
is collected from the reaction mixture according to conventional methods. example
For example, if there are insoluble materials, pour the reaction mixture into ice water.
If the solution is acidic or alkaline,
If necessary, neutralize and extract with a water-immiscible organic solvent.
After that, it can be obtained by distilling off the solvent.
Wear. If necessary, use conventional methods such as column chromatography.
Matography, thin layer chromatography, reconsolidation
It can be further purified using crystallization methods and the like.
The target compound obtained in this way is
mixture of isomers, geometric isomers and optical isomers
If available, this may be added at the appropriate synthesis step.
The isomers can be separated and resolved. Compounds having the above general formula () and their pharmacology
The above-acceptable salts are useful as antiplatelet agents in thrombotic diseases.
It can be used as a treatment and prophylactic for diseases.
Ru. Its dosage forms include tablets, capsules, etc.
Oral administration via tablets, granules, powders, syrups, etc.
Examples include parenteral administration by administration or intravenous injection.
I can do it. The amount used depends on your symptoms, age, weight, etc.
Although it varies depending on the person, it is usually about 1 day for adults.
0.0001mg to 1000mg, preferably about 0.01mg to 1000mg per day
100mg, administered once or in divided doses
be able to. Next, examples and reference examples will be given to further explain the present invention.
This will be explained in detail. Example 1 3-(4-carboxybutyl)-6β-(3α-hydro
(roxy-4-methylnona-1,8-dienyl)
-7α-hydroxybicyclo[3.3.0]octo-
Mixture of 2-ene and oct-3-ene (1a) 3-(5-benzyloxypentyl)-6β-(3
-oxo-4-methylnona-1,8-dienyl)
-7α-(2-tetrahydropyranyloxy)bisi
Chlo [3.3.0] oct-2-ene and oct-3
- mixture of enes The oil content of 0.41g of oily sodium hydride is
After washing with xane, add 60ml of tetrahydrofuran and
Chil 2-oxo-3-methyl-7-octenylpho
Add 2.70 g of sulfonate and stir for 30 minutes. then
3.24 g of the aldehyde obtained in Reference Example 8 was added to 20 ml of Tet
Dissolve in hydrofuran and stir at room temperature for 30 minutes.
Ru. The reaction solution was diluted with ice water and extracted with ethyl acetate.
Wash the effluent with water, dry with anhydrous sodium sulfate, and remove the solvent.
The residue obtained after successive distillation under reduced pressure was
Column chromatograph using silica gel (95.7g)
By subjecting to roughy, the target compound becomes oily 3.74
I got g. IR spectrum (Liq) ν_naxcm^-1: 1624, 1670, 1696 NMR spectrum (CDl₃) δ: 1.09 (3H, d, J=7.2Hz, -CH₃), 3.47 (2H, t, J=7.0Hz, -CH₂ CH ₂OBz), 4.51(2H,s,OCH ₂Ph), 4.8-5.2 (2H, m, olefin-H), 5.30 (1H, br, s, olefin-H), 6.26 (1H, dd, J=15.0Hz, 5.0Hz, olefin
-H), 6.70-7.10 (1H, m, Orufin-H), 7.35 (5H, s, aryl-H) (1b) 3-(5-benzyloxypentyl)-6β-(3α
-Hydroxy-4-methylnona-1,8-dieny
)-7α-(2-tetrahydropyranyloxy)
Bicyclo [3.3.0] Oct-2-ene and Octo
-3-enes as well as their 6β-(3β-hynes)
droxy) isomer Methylalcohol of the enone form (3.70g) obtained in (1a)
Coal solution (25 ml) was added to cesium chloride/7 water under ice cooling.
Methyl alcohol solution (30ml) of hydrate (3.1g)
plus sodium borohydride (393mg)
Add. After stirring for 30 minutes at an internal temperature of 5 to 10°C, start the reaction.
Pour the liquid into water and extract with ethyl acetate.
Ru. Wash the extract with saturated saline and dilute with anhydrous sodium sulfate.
After drying over a vacuum, the solvent was distilled off to obtain 3.90 g of a residue.
Purify by silica gel column chromatography
1.22g of target compound than the less polar part
[6β-(3β-hydroxy)-isomer] and more
2.03g of the target compound [6β-
(3α-hydroxy)-isomer] is an oily substance.
obtained as. [6β-(3α-hydroxy-)isomer]: IR spectrum (Liq) ν_naxcm^-1: 1024, 1120, 1454, 1642, 3460 NMR spectrum (CDCl₃) δ: 0.83~0.97 (3H, m, -CH₃), 3.47 (2H, t, J=7.0Hz, -CH₂ CH ₂OBz), 4.53 (2H, S,CH ₂−OPh), 4.70 (1H, br, s, [formula]), 4.83-5.20 (2H, m, olefin-H), 5.30 (1H, br, s, olefin-H), 5.47-6.20 (3H, m, olefin-H), 7.37 (5H, s, aryl-H) 6β-(3β-hydroxy-)isomer: IR spectrum (Liq) ν_naxcm^-1: 1023, 1120, 1454, 1642, 3460 MNR spectrum (CDCl₃) δ: 0.90 (3H, m, CH₃), 3.47 (2H, t, J=7.0Hz, CH₂ CH ₂OBz), 4.53 (2H, S,CH ₂OPh), 4.70 (1H, br, s, [formula]), 4.83-5.20 (2H, m, olefin-H), 5.30 (1H, br.s, −CH=,) 5.47-6.20 (3H, m, olefin-H) (1c) 3-(5-benzyloxypentyl)-6β-[3α
-(2-tetrahydropyranyloxy)-4-methy
-nona-1,8-dienyl]-7α-(2-tet
lahydropyranyloxy)bicyclo[3.3.0]o
Mixture of ct-2-ene and oct-3-ene The alcohol (2.02g) obtained in (1b) was added to the chloride solution.
Dissolved in tyrene (20 ml) and added 2,3-dihyde under ice cooling.
Ropyran (0.62ml) and catalytic amount of p-toluene
Add sulfonic acid and stir at an internal temperature of 2°C for 1 hour.
After the reaction is complete, add 5% aqueous sodium hydrogen carbonate solution.
After cooling, add saturated brine and extract with ethyl acetate.
put out Acetate ethyl ester extract is saturated saline solution
After washing with water and drying with anhydrous sodium sulfate, reduce
The solvent was distilled off under pressure to obtain 3.90 g of a residue. this thing
Purified by silica gel column chromatography
By doing this, 2.09g of the target product was obtained as an oily substance.
Ta. IR spectrum (Liq) ν_naxcm^-1: 1018, 1120, 1198, 1450, 1638 NMR spectrum (CDCl₃) δ: 0.80~1.03 (3H, m, -CH₃), 3.47 (2H, t, J=7.0Hz, CH₂ CH ₂OBz), 4.52(2H,s,CH ₂OPh), 4.70 (2H, br.s, [formula]), 4.83-6.20 (8H, m, olefin-H), 7.37 (5H, s, aryl-H) (1d) 3-(5-hydroxypentyl)-6β-[3α-
(2-tetrahydropyranyloxy)-4-methyl
nona-1,8-dienyl]-7α-(2-tetrahydryl
Dropyranyloxy)bicyclo[3.3.0]octo
-2-ene and oct-3-ene mixture Obtained with (1c) under nitrogen atmosphere at internal temperature of -70℃.
Liquid ammonia containing benzylpyranyl compound (2.07g)
A solution of A (40ml) and tetrahydrofuran (30ml)
When excess sodium metal is added to the solution, the solution becomes concentrated.
Appears blue. After stirring for 30 minutes at -70℃,
Add a large excess of ammonium chloride. Next, room
After returning to temperature and distilling off the ammonia, add water to the residue.
was added, extracted with diethyl ether, and the extract was diluted with water.
After washing with water, dry with anhydrous sodium sulfate and reduce
The solvent was distilled off under pressure to obtain 2.00 g of a residue.
was purified using silica gel column chromatography.
1.53g of the desired product was obtained as an oily substance. IR spectrum (Liq) ν_naxcm^-1: 1642, 3450 NMR spectrum (CDCl₃) δ: 0.80~1.01 (3H, m, -CH₃), 3.30~4.30 (8H, m) 4.67 (2H, br, s, [formula]), 4.83-6.20 (6H, m, olefin-H) (1e) 3-(4-carboxybutyl)-6β-[3α-(2
-tetrahydropyranyloxy)-4-methyl
-1,8-dienyl)-7α-(2-tetrahydride
ropyranyloxy)bicyclo[3.3.0]octo-
Mixture of 2-ene and oct-3-ene Aceto of the alcohol (1.51g) obtained in (1d)
Jones reagent (anhydrous
Dilute 26.7 g of romic acid and 23 ml of concentrated sulfuric acid with water to make a whole
2.8ml (prepared as 100ml) was added dropwise at the same temperature.
Stir for 1 hour. 5% sodium bicarbonate after the reaction
Neutralize with um aqueous solution and distill off acetone under reduced pressure.
Ru. Add water to the residue and extract with diethyl ether.
do. The extract was washed with water and diluted with anhydrous sodium sulfate.
After drying in a vacuum chamber, the solvent was distilled off under reduced pressure to remove 1.63 g of residue.
obtain. This product was subjected to silica gel column chromatography.
- to obtain 1.30g of the target product as an oil.
Ru. IR spectrum (Liq) ν_naxcm^-1: 1638, 1708, 1732 NMR spectrum (CDCl₃) δ: 0.80~1.01 (3H, m, -CH₃), 4.67 (2H, br.s, [formula]), 4.83-6.20 (6H, m, olefin-H) 7.70~8.60 (1H, br.s, COOH) (1f) 3-(4-carboxybutyl)-6β-(3α-hydro
Roxy-4-methylnona-1,8-dienyl)-
7α-Hydroxybicyclo[3.3.0]oct-2-
mixture of ene and oct-3-ene 0.52g of the tetrahydropyranyl compound obtained in (le)
In a solution of acetone (15.6 ml) and water (8 ml), add d-
Add camphor arsulfonic acid (28 mg) and reduce the internal temperature.
Stir at 40-45°C for 2 hours. After the reaction is complete, the reaction solution
Pour into water and extract with ethyl acetate.
After washing the liquid with water, dry it with anhydrous sodium sulfate.
Then, the solvent was distilled off under reduced pressure to obtain 460 mg of a residue. child
into silica gel column chromatography
By refining the target product as an oil, 250
Get mg. IR spectrum (Liq) ν_naxcm^-1: 1640, 1708, 3340 NMR spectrum (CDCl₃) δ: 0.90 (3H, m, CH₃), 3.30~4.10 (2H, m), 4.80~6.10 (9H, m, Olefin-H x 6+
OH×2+COOH) Mass spectrum, m/e: 358 (M-18) Example 2 3-(4-carboxybutyl)-6β-(3α hydro
xy-5(R),9-dimethyl-1,8-decadi
enyl)-7α-hydroxybicyclo[3.3.0]o
Mixture of ct-2-ene and oct-3-ene (2a) 3-(5-benzyloxypentyl)-6β-(3
-oxo-5(R),9-dimethyl-1,8-deca
dienyl)-7α-(2-tetrahydropyranyl)
oxy)bicyclo[3.3.0]oct-2-ene and
mixture of oct-3-enes Crude aldehyde (compound of Reference Example 8: 3.05g) and
dimethyl 2-oxo-4(R),8-dimethylno
Example 1a
When the reaction is carried out in the same manner as above, 3.50g of the target compound becomes oil.
It was obtained as a solid substance. IR spectrum (Liq) ν_naxcm^-1: 1625, 1670, 1695 NMR spectrum (CDCl₃) δ: 0.89 (3H, d, J=7Hz, CH₃), 3.48 (2H, t,CH ₂OCH₂Ph), 4.50(2H,s,CH ₂Ph), 4.8~5.4 (2H, m, = CH−×2), 6.18 (1H, dd, J=16.3Hz, =CH-), 6.5~7.2 (1H, m, =CH-), 7.29 (5H, s, aryl-H) (2b) 3-(5-benzyloxypentyl)-6β-(3α
-Hydroxy-5(R),9-dimethyl-1,8-
(decadienyl)-7α-hydroxybicyclo
[3.3.0] Oct-2-ene and oct-3-ene
as well as their 6β-(3β-hydroxy
−) Isomers Experimental using ketone (compound of Example 2a: 3.50 g)
When the reaction is carried out in the same manner as in Example 1b, the corresponding hydrocarbon
A xyl body is obtained. This compound is suitable for thin layer chromatography.
It gives a roughy upper 3-spot, so it is not necessary to refine it.
Dissolve in 50 ml of acetic acid, 30 ml of water and tetrahydride
Add 20ml of Lofuran (THF) and stir at 50℃ for 2.5 hours.
Stirred. During that time, 15 ml of water was added. Reaction completed
After that, add an aqueous solution of sodium hydroxide (40g) and
The mixture was extracted with diluted ethyl acetate. extract liquid
After washing with saline, dry with anhydrous sodium sulfate.
Ru. The solvent was distilled off and the resulting residue was purified using silica gel.
It was purified by column chromatography. 20〜
1.15g from the 25% ethyl acetate/n-hexane outflow
oily 6β-(3β-hydroxy) form (thin chroma
2 spots) were obtained by tography. 30-50
% ethyl acetate/n-hexane from the outflow part.
Oily 6β-(3α-hydroxy) form (thin layer chromatography)
2 spots) were obtained on graphie. 6β-(3β-hydroxy) form: IR spectrum (Liq) ν_naxcm^-1:3370 NMR spectrum (CDCl₃) δ: 0.90 (3H, d, CH₃), 1.60 (3H, s, CH₃), 1.68(3H,s,CH₃), 3.45 (2H, t, -CH₂O
−), 4.50 (2H, s, CH₂O−), 5.10 (1H, t, = CH
−), 5.28 (1H, br.s, = CH−) 5.60 (2H, m, -CH=CH-) 6β-(3α-hydroxy) form: IR spectrum (Liq) ν_naxcm^-1:3360 NMR spectrum (CDCl₃) δ: 0.90 (3H, m, CH₃), 1.60 (3H, s, CH₃), 1.65(3H,s,CH₃), 3.50 (2H, t, 6Hz, -CH₂O−), 4.50(2H,s,-CH₂O−), 5.12 (1H, br.t, = CH−), 5.28 (1H, br.s, = CH−), 5.50 (2H, m, -CH=CH-) (2c) 3-(5-benzyloxypentyl)-6β-[3α
-(2-tetrahydropranyloxy)-5(R),
9-dimethyl-1,8-decadienyl]-7α-
(2-tetrahydropyranyloxy)bicyclo
[3.3.0] Oct-2-ene and oct-3-ene
mixture of Alcohol (6β-(3α-hydroxy of Example 2b)
C) body: 1.50 g) was subjected to reaction treatment in the same manner as in Example 1c.
2.10g of the target compound was obtained as an oil.
It was. IR spectrum (Liq) ν_naxcm^-1: 1022, 1035 NMR spectrum (CDCl₃) δ: 0.90 (3H, m, CH₃), 3.46 (2H, t, -CH₂O
−), 4.50(2H,s,-CH₂O−), 4.70 (2H, br.s, [formula]), 4.90~5.8 (4H, m, = CH−×4) (2d) 3-(5-hydroxypentyl)-6β-[3α-
(2-tetrahydropyranyloxy)-5(R),9
-dimethyl-1,8-decadienyl]-7α-(2
-tetrahydropyranyloxy]bicyclo
[3.3.0] Oct-2-ene and oct-3-ene
mixture of Using the benzylic compound (2.10 g of the compound of Example 2c)
When the reaction was carried out in the same manner as in Example 1d, 1.46 g of oily
The target compound was obtained. IR spectrum (Liq) ν_naxcm^-1: 3350 NMR spectrum (CDCl₃) δ: 0.92 (3H, m, CH₃), 2.63 (3H, s, CH₃), 2.69(3H,s,CH₃), 3.64 (2H, t, -CH₂O
−), 4.82 (2H, br.s, [formula]), 5.0~5.8 (4H, m, -CH=x4) (2e) 3-(4-carboxybutyl)-6β-[3α-(2
-tetrahydropyranyloxy)-5(R),9-
dimethyl-1,8-decadienyl]-7α-(2-
Tetrahydropyranyloxy)bicyclo [3.3.0]
Mixture of oct-2-ene and oct-3-ene Alcohol form (compound of Example 2d: 1.20 g)
When treated in the same manner as in Example 1e, 737 mg of oil was obtained.
The desired compound was obtained. NMR spectrum (CDCl₃) δ: 0.92 (3H, m, CH₃), 1.62 (3H, s, CH₃), 1.69(3H,s,CH₃), 4.72 (2H, br.s, [formula]), 5.0~5.8 (4H, m, = CH-×4) (2f) 3-(4-carboxybutyl)-6β-(3α-hydro
Roxy-5(R),9-dimethyl-1,8-decadi
enyl-7α-hydroxybicyclo[3.3.0]oc
Mixture of to-2-ene and oct-3-ene Using pyranyl compound (compound of Example 2e: 730 mg)
When the reaction was carried out in the same manner as in Example 1f, 394 mg of oil was obtained.
The target compound was obtained. IR spectrum (Liq) ν_naxcm^-1: 3350, 1710 NMR spectrum (CDCl₃) δ: 0.91 (3H, m, CH₃), 1.62 (3H, s, CH₃), 1.70(3H,s,CH₃), 3.72 (1H, m, >
CHOH), 4.15 (1, m, > CHOH), 5.11 (1H, t, = CH
−), 5.34 (1H, br.s, =CH−), 5.50 (2H, m, -CH=CH-) This compound is easily treated with diazomethane.
Corresponding methyl ester (IR spectrum: 1725
cm^-1) was converted to Example 3 3-(5-hydroxybentyl)-6β-(3α-hydoxybentyl)
Droxy-5(R),9-dimethyl-1,8-de
cadienyl)-7α-hydroxybicyclo
[3.3.0] Oct-2-ene and oct-3-ene
mixture of ingredients Using pyranyl compound (compound of Example 2d: 250 mg)
When the reaction was carried out in the same manner as in Example 1f, 121 mg of oil was obtained.
The target compound was obtained. This compound is a thin layer of chlorine.
Two spots are shown on the matograph. IR spectrum (CHCl₃) ν_naxcm^-1: 3370,975 NMR spectrum (CDCl₃) δ: 0.91 (3H, d, CH₃), 1.59 (3H, s, CH₃), 1.66(3H,s,CH₃), 5.02 (1H, t, = CH-), 5.19 (1H, br.s, = CH−), 5.40 (2H, m, -CH=CH-) Example 4 3-(4-carboxybutyl)-6β-(3α-hydro
Roxy-3-cyclopentyl-1-propenylate
)-7α-hydroxy-cis-bicyclo
[3.3.0] Oct-2-ene and oct-3-ene
mixture of ingredients (4a) 3-(5-benzyloxypentyl)-6β-(3
-oxo-3-cyclopentyl-1-propenylate
)-7α-(2-tetrahydropyranyloxy)-
cis-bicyclo[3.3.0]oct-2-ene and
3-ene mixture 0.41g of 55% oily sodium hydride oil is n-
After washing with hexane, add 60ml of tetrahydrofuran.
Dimethyl (2-oxo-2-cyclopentyl ethyl
) - Add 2.39 g of phosphonate and stir for 30 minutes.
Ru. Next, 3.05 g of the aldehyde obtained in Reference Example 8 was added to
Dissolve in 20ml of tetrahydrofuran and add to room temperature.
Stir for 30 minutes. Dilute the reaction solution with ice water and add ethyl acetate.
extraction, washing the extract with water, drying anhydrous sodium sulfate, and reducing the solvent.
The residue obtained after distillation under pressure is
Subjected to licage gel column chromatography
3.50 g of the target compound was obtained. IR spectrum (Liq) ν_naxcm^-1: 1030, 1120, 1626, 1693 NMR spectrum (CDCl₃) δ: 3.48 (2H, t, J=6Hz, -CH ₂OBz), 4.52(2H,s,OCH₂Ph), 5.30 (1H, br.s, olefin-H), 6.23 (1H, m, olefin-H), 6.90 (1H, m, olefin-H), 7.38 (5H, s, aryl-H) Mass spectrum, m/e: 506 (M⁺, ), 422 (M-84) (4b) 3-(5-benzyloxypentyl)-6β-(3α
-Hydroxy-3-cyclopentyl-1-prope
(2-tetrahydropyranyloxy)-7α-(2-tetrahydropyranyloxy)
-cis-bicyclo[3.3.0]oct-2-ene and
mixture of Enone form (compound of Example 4a: 3.40 g) was carried out.
Treated as in Example 1b, 1.91 g of the target compound and 6β-
1.07 g of (3β-hydroxy) compound was obtained. IR spectrum (Liq) ν_naxcm^-1: 1025, 1075, 1120, 3450 NMR spectrum (CDCl₃) δ: 3.47 (2H, t, J=6Hz, -CH ₂OBz), 4.52 (2H, s, -O-CH ₂Ph), 4.70 (1H, br.s, [formula]), 5.28 (1H, br.s, olefin-H), 5.65 (2H, m, olefin-H), 7.36 (5H, s, aryl-H) Mass spectrum, m/e: 406 (M-102) (4c) 3-(5-benzyloxypentyl)-6β-[3α
-(2-tetrahydropyranyloxy)-3-cyc
Lopentyl-1-propenyl]-7α-(2-tet
(rahydropyranyloxy)-cis-bicyclo
[3.3.0] Oct-2-ene and oct-3-ene
blend Hydroxy form (compound of Example 4b: 1.85 g)
2.18 g of the target compound was obtained in the same manner as in Example 1c.
Ta. IR spectrum (Liq) ν_naxcm^-1: 978, 1023, 1078, 1120 NMR spectrum (CDCl₃) δ: 3.46 (2H, t, J=6Hz, -CH ₂OBz), 4.51 (2H, s, -O-CH ₂Ph), 4.74 (2H, br.s, [formula]), 5.27 (1H, br.s, olefin-H), 5.62 (2H, m, olefin-H), 7.36 (5H, S, aryl-H) Mass spectrum, m/e: 490 (M-102) (4d) 3-(5-hydroxypentyl)-6β-[3α-
(2-tetrahydropyranyloxy)-3-cyclo
pentyl-1-propenyl]-7α-(2-tetra
hydropyranyloxy)-cis-bicyclo
[3.3.0] Oct-2-ene and oct-3-ene
blend The benzylic compound (compound of Example 4c: 2.12 g) was produced.
By processing as in Example 1d, 1.50 g of objective
The compound was obtained. IR spectrum (Liq) ν_naxcm^-1: 970, 1020, 1075, 1120, 1130, 3430 NMR spectrum (CDCl₃) δ: 4.75 (2H, br.s, [formula]), 5.30 (1H, br.s, olefin-H), 5.65 (2H, m, olefin-H) Mass spectrum, m/e: 400 (M-102) (4e) 3-(4-carboxybutyl)-6β-[3α-(2
-tetrahydropyranyloxy]-3-cyclope
ethyl-1-propenyl]-7α-(2-tetrahydryl)
Dropyranyloxy)-cis-bicyclo [3.3.0]
Mixture of oct-2-ene and oct-3-ene Hygiroxy compound (compound of Example 4d: 1.36 g)
By processing in the same manner as in Example 1e, 0.7 g of
A target compound was obtained. IR spectrum (Liq) ν_naxcm^-1: 980, 1022, 1130, 1710, 1738, 3000~3200 NMR spectrum (CDCl₃) δ: 4.73 (2H, br.s, [formula]), 5.30 (1H, br.s, olefin-H), 5.60 (2H, m, olefin-H) Mass spectrum, m/e: 414 (M-102) (4f) 3-(4-carboxybutyl)-6β-(3α-hydro
(roxy-3-cyclopentyl-1-propenyl)
-7α-hydroxy-cis-bicyclo[3.3.0]o
Mixture of ct-2-ene and oct-3-ene Dipyranyl compound (compound of Example 4e: 0.57 g)
The resulting residue was treated in the same manner as in Example 1f and treated with acetic acid.
By recrystallizing from ethyl and n-hexane
Obtained 0.17g of the target compound with a melting point of 104-106.5℃.
Ta. IR spectrum (kBr) ν_naxcm^-1: 970, 1080, 1235, 1710, 3350, 3480 NMR spectrum (CDCl₃) δ: 5.60~5.90 (2H, m, [formula]), 5.30 (1H, br.s, olefin-H), 5.54 (2H, m, olefin-H) Mass spectrum, m/e: 330 (M-18), 312 (M-36) Example 5 3-(5-hydroxypentyl)-6β-(3α-hydoxypentyl)
Droxy-3-hydroxypentyl-1-propenylate
)-7α-hydroxy-cis-bicyclo
[3.3.0] Oct-2-ene and oct-3-ene
mixture of Dipyranyl compound (compound of Example 4d: 0.30 g)
The resulting residue was treated in the same manner as in Example 1f and treated with acetic acid.
By recrystallizing from ethyl and n-hexane
Obtained 0.13g of the target compound with a melting point of 108-110℃.
Ta. IR spectrum (kBr) ν_naxcm^-1: 1243, 1434, 3420, NMR spectrum (CDCl₃) δ: 3.55~3.85 (4H, m, [formula] 【formula】), 5.30 (1H, br.s, olefin-H), 5.54 (2H, m, olefin-H) Mass spectrum, m/e: 316 (M-18), 298 (MM-36) Example 6 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-5(R),9
-dimethyl-deca-1,8-dienyl]-7α-
(2-tetrahydropyranyloxy)bicyclo
[3.3.0] Oct-2-ene and oct-3-ene
mixture (6a) 3-(methoxycarbonylmethyl)-6β-[3α-
(2-tetrahydropyranyloxy)-5(R),9
-dimethyl-deca-1,8-diethyl]-7α-(2-
Tetrahydropyranyloxy)bicyclo [3.3.0]
Mixture of oct-2-ene and oct-3-ene 3-Methoxycarbonylmethylidene-6β-[3α
-(2-tetrahydropyranyloxy)-5(R),
9-dimethyl-deca-1,8-dienyl]-7α-
(2-tetrahydropyranyloxy)bicyclo
[3.3.0] 1.95 g of octane in tetrahydrofuran
Diisopropylamino
Lithium (diisopropylamine 935 mg, 15% n
-Butyllithium-n-hexane solution 5.43ml and
Prepared from 1.6ml of hexamethylphosphoryltriamide.
10 ml of tetrahydrofuran solution of
added. After reacting at the same temperature for 1 hour, saturated aqueous chloride
Pour into ammonium aqueous solution and extract with ethyl acetate.
Ta. After drying the extract with sodium sulfate, the solvent was distilled off.
and purified by column chromatography to achieve the desired
1.30g of the compound was obtained. IR spectrum (Liq) ν_naxcm^-1:1737 NMR spectrum (CDCl₃) δ: 0.92 (3H, m, CH₃), 0.62 (3H, s, CH₃), 0.68(3H,s,CH₃), 3.10 (2H, s, -CH₂
−), 3.69(3H,s,COOMe), 4.82 (2H, br, s, [formula]), 5.12 (1H, t, = CH-), 5.3~5.8 (3H, m, =CH-, -CH=CH-) (6b) 3-(2-hydroxyethyl)-6β-[3α-
(2-tetrahydropyranyloxy)-5(R),
9-dimethyl-deca-1,8-dienyl]-7α
-(2-tetrahydropyranyloxy)bisic
B [3.3.0] Octo-2-ene and Octo-3
- mixture of enes The ester form (compound of Example 6a: 510 mg) was
Lithium aluminum hydride dissolved in 20ml
Add 500mg under ice cooling. After 1 hour, add 2 ml of 4% caustic acid.
Add sodium chloride water and stir to remove the precipitate and concentrate the liquid.
Upon contraction, an oily residue was obtained. silica gel color
When purified by muchromatography, 430 mg of oil is obtained.
The target compound was obtained. IR spectrum (Liq) ν_naxcm^-1:3350 NMR spectrum (CDCl₃) δ: 0.91 (3H, m, CH₃), 2.62 (3H, s, CH₃), 2.69(3H,s,CH₃), 4.80 (2H, br.s, [formula]), 5.0~5.8 (4H, m, = CH-×4) Example 7 3-(4-carboxybutyl)-6β-(3α-hydro
Roxy-3-cyclopentyl-1-propenylate
)-7α-hydroxybicyclo[3.3.0]oct
-2-en (7a) 3-(5-benzyloxypentyl)-6β-(3
-oxo-3-cyclopentyl-1-propenylate
)-7α-(2-tetrahydropyranyloxy)
Bicyclo [3.3.0] Oct-2-ene 74mg of 55% oily sodium hydride oil to n-
After washing with xane, dilute with 10ml of tetrahydrofuran.
Methyl (2-oxo-2-cyclopentyl ethyl
Add phosphonate (418 mg) and stir for 30 minutes.
do. Then, 3-(5-benzyl obtained in Reference Example 14)
(oxypentyl)-6β-formyl-7α-(2-te
trahydropyranyloxy)bicyclo [3.3.0]
Oct-2-ene (469 mg) in 3 ml of tetrahydride
Dissolve and add to Lofuran and stir at room temperature for 1 hour.
do. After the reaction is complete, pour the reaction solution into ice water and add acetic acid ethyl chloride.
Extract with chill ester. After washing the drying liquid with water,
Dry over sodium sulfate and remove the solvent under reduced pressure.
Then, 937 mg of residue is obtained. Siri this thing
Purified by Kagel column chromatography,
503 mg of the target substance was obtained as an oily substance. IR spectrum (Liq) ν_naxcm^-1: 1120, 1625, 1665, 1690 NMR spectrum (CDCl₃) δppm: 3.48 (2H, t, J=6.0Hz, -CH ₂OCH₂Ph), 4.52(2H,s,-OCH₂Ph), 5.30 (1H, S, = CH-), 6.23 (1H, d.d, J=17.0, 5.0Hz, =CH−), 6.90 (1H, m, = CH−), 7.38 (5H, s, ph) (7b) 3-(5-benzyloxypentyl)-6β-(3α
-Hydroxy-3-cyclopentyl-1-prope
(2-tetrahydropyranyloxy)-7α-(2-tetrahydropyranyloxy)
Bicyclo [3.3.0] Oct-2-ene Methyl enone (compound of Example 7a: 484 mg)
cerium chloride solution under ice-cooling.
Methyl alcohol (430 mg)
ml) into the solution. Cool the solution after reaction to -20℃ and add water.
Add sodium borohydride (62 mg) and bring to the same temperature.
Stir for 15 minutes. After the reaction is complete, pour the reaction solution into water and add ethyl acetate.
Extract with stel. Wash the extract with saturated saline.
After cleaning and drying with anhydrous sodium sulfate, dissolve under reduced pressure.
The medium was distilled off to obtain 498 mg of residue. This product was subjected to silica gel column chromatography.
262mg from the more polar part
The desired product was obtained as an oily substance. Also, more
184mg of 3β-hydroxy compound was obtained from the less polar part.
It was done. IR spectrum (Liq) ν_naxcm^-1: 1025, 1075, 1120, 3450 NMR spectrum (CDCl₃) δppm: 3.47 (2H, t, J=6.0Hzz, CH₂ CH
₂OCH₂Ph), 4.52(2H,s,-OCH ₂Ph), 4.70 (1H, br.s, [formula]), 5.28 (1H, br.s, = CH−), 5.65 (2H, m, = CH−×2), 7.36 (5H, s, Ph) 3β-hydroxy form IR spectrum (Lip) ν_naxcm^-1: 1025, 1074, 1120, 3450 (7c) 3-(5-benzyloxypentyl)-6β-[3α
-(2-tetrahydropyranyloxy)-3-cyc
Lopentyl-1-propenyl]-7α-(2-tet
lahydropyranyloxy)bicyclo[3.3.0]-o
Cut-2-en 3α-hydroxy form (compound of Example 7b: 379
mg) in methylene chloride (4 ml) and cooled on ice.
2,3-dihydropyran (0.1 ml) and a catalytic amount of
Add para-toluenesulfonic acid and stir for 30 minutes.
Ru. After the reaction is complete, add 5% aqueous sodium hydrogen carbonate solution.
Neutralize with water and add water to make acetic acid ethyl ester.
Extract. The extract was washed with water and treated with sulfuric anhydride.
After drying with sodium, the solvent was distilled off under reduced pressure and the remaining
Obtain 482 mg of residue. This product is used for silica gel column chromatography.
By refining with E, the target product becomes an oily substance.
425mg was obtained. IR spectrum (Liq) ν_naxcm^-1: 1025, 1080, 1120 NMR spectrum (CDCl₃) δppm: 3.46 (2H, t, J=6.0Hz, -CH ₂OCH₂Ph), 4.51 (2H, s, -OCH ₂Ph), 4.74 (2H, br, s, [formula]), 5.27 (1H, br.s, =CH−), 5.62 (2H, m, -CH=CH-), 7.36 (5H, s, Ph) (7d) 3-(5-hydroxypentyl)-6β-[3α-
(2-tetrahydropyranyloxy)-3-cyclo
pentyl-1-propenyl]-7α-(2-tetra
hydropyranyloxy)bicyclo[3.3.0]-oc
To-2-ene Benzyl ether at an internal temperature of -70°C under a nitrogen atmosphere.
Liquid ammonium of the compound (compound of Example 7c: 415 mg)
Monia (20ml) and tetrahydrofuran (14ml)
When excess sodium metal is added to a solution, the solution
exhibits a deep blue color. Stir at -70℃ for 30 minutes.
Then add a large excess of ammonium chloride. reaction
After returning the solution to room temperature and distilling off the ammonia, remove the remaining
Add water to the residue and extract with diethyl ether.
After washing the extract with water, wash it with anhydrous sodium sulfate.
Dry and remove the solvent under reduced pressure to obtain 372 mg of residue.
This is subjected to silica gel column chromatography.
339 mg of the target product was obtained as an oily substance. IR spectrum (Liq) ν_naxcm^-1:3430 NMR spectrum (CDCl₃) δppm: 4.75 (2H, br.s, [formula]), 5.30 (1H, br.s, =CH−), 5.65 (2H, m, =CH−×2) (7e) 3-(4-carboxybutyl)-6β-[3α-(2
-tetrahydropyranyloxy)-3-cyclope
ethyl-1-propenyl]-7α-(2-tetrahydryl)
Dropyranyloxy)bicyclo[3.3.0]-octo
-2-en Jones reagent (same reagent as in Example 1e: 0.6 ml)
Dissolve in 10 ml of acetone and cool to -25°C.
The alcohol compound (compound of Example 7d: 329 mg) was added to
Add a solution dissolved in 15 ml of setone dropwise, and at the same temperature
Stir for 20 minutes. After the reaction is complete, add isopropyl alcohol.
After adding cole, add 5% sodium bicarbonate in water.
Neutralize with solution, add saturated saline, and add diethyl ether.
Extract with tel. Wash the extract with water and make it anhydrous.
After drying with sodium sulfate, the solvent was distilled off under reduced pressure.
to obtain 342 mg of residue. This product was subjected to silica gel column chromatography.
203 mg of the target product was obtained as an oil. IR spectrum (Liq) ν_naxcm^-1: 980, 1025, 1120, 1135, 1710, 1735, 3100 NMR spectrum (CDCl₃) δppm: 4.73 (2H, br.s, [formula]), 5.30 (1H, br.s, =CH−), 5.50 (2H, m, -CH=CH-) (7f) 3-(4-carboxybutyl)-6β-(3α-hydro
(roxy-3-cyclopentyl-1-propenyl)
-7α-hydroxybicyclo[3.3.0]-octo-2
−en Tetrahydropyranyl compound (compound of Example 7e:
207mg) in acetone (8ml) and water (3ml)
Add 2-camphorsulfonic acid (20 mg) to
Stir for 2 hours at a temperature of 40-45°C. After the reaction is complete, the reaction
Pour the liquid into water and extract with ethyl acetate.
Ru. The extract was washed with water and treated with anhydrous sodium sulfate.
After drying, the solvent was distilled off under reduced pressure to obtain a residue of 180 mg.
Ru. This product was subjected to silica gel column chromatography.
After purification at
By recrystallizing from a mixed solvent of xane,
75 mg of the target compound having a temperature of 108-110°C was obtained. IR spectrum (CHCl₃) ν_naxcm^-1: 975, 1710, 3300 NMR spectrum (CDCl₃) δppm: 5.33 (1H, br.s, −CH=), 5.50 (5H, m, -CH=CH−, OH×2, COO
H) Example 8 3-(4-carboxybutyl-6β-[3α-hydroxy-5(R), 9-dimethyl-1,8-decadienyl]-7α-hydroxybicyclo[3.3.0]
Oct-2-ene (8a) 3-(5-benzyloxypentyl)-6β-(3
-Oxo-5(R),9-dimethyl-1,8-decadienyl)-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene Crude aldehyde (Compound of Reference Example 14: 2.91 g) and dimethyl 2-oxo-4,8-dimethyl nona-
The 1-enylphosphonate was treated in the same manner as in Example 7a to obtain 3.16 g of the desired compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1625, 1665, 1690 NMR spectrum ( _CDCl3 ) δppm: 0.90 (3H, m, _CH3 ), 3.48 (2H, t, _-CH2O- ), 4.50 (2H , s, -CH ₂ -), 4.8-5.4 (2H, m, = CH - × 2), 6.18 (1H, dd, J = 16.5Hz, = CH -), 6.5-7.2 (1H, m, = CH -) (8b) 3-(5-benzyloxypentyl)-6β-(3α
-Hydroxy-5(R),9-dimethyl-1,8-
Decadienyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene and its 6β-(3β-hydroxy-) isomer Reaction treatment using ketone (compound of Example 8a: 3.1 g) in the same manner as in Example 7b The obtained hydroxy compound was then dissolved in acetic acid (45 ml), 25 ml of water and tetrahydrofuran (17 ml) were added, and the mixture was stirred at 50°C for 2.5 hours. During that time, 15 ml of water was added. After the reaction is completed, an aqueous solution of 36 g of sodium hydroxide is added to neutralize the mixture, and the mixture is extracted 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 silica gel column chromatography. 1.01g of oily 6β- from the hexane outflow containing 20-25% ethyl acetate.
A (3β-hydroxy) compound (having 2 spots in thin layer chromatography) was obtained. 30-50%
1.31 from the hexane outlet containing acetic acid ethyl ester
An oily 6β-(3α-hydroxy) form (having 2 spots on thin layer chromatography) of g was obtained. 6β-(3β-hydroxy) form IR spectrum (Liq) ν _nax cm ^-1 : 3380 NMR spectrum (CDCl ₃ ) δppm: 0.91 (3H, s, CH ₃ ), 1.60 (3H, s, CH ₃ ), 1.68 ( 3H, s, CH ₃ ), 3.45 (2H, t, -CH ₂ O-), 4.50 (2H, s, -CH ₂ -), 5.11 (1H, t, =CH-), 5.29 (1H, br. s, =CH-), 5.60 (2H, m, -CH=CH-) 6β-(3α-hydroxy) form IR spectrum (Liq) ν _nax cm ^-1 :3360 NMR spectrum ( _CDCl3 ) δppm: 0.91 (3H , m, CH ₃ ), 1.60 (3H, s, CH ₃ ), 1.66 (3H, s, CH ₃ ), 3.50 (2H, t, −CH ₂ −), 4.51 (2H, s, −CH ₂ −) , 5.12 (1H, t, =CH-), 5.28 (1H, br.s, =CH-), 5.50 (2H, m, -CH=CH-) (8c) 3-(5-benzyloxypentyl)- 6β−[3α
-(2-tetrahydropyranyloxy)-5(R),
9-dimethyl-1,8-decadienyl]-7α-
When (2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene alcohol [6β-(3α-hydroxy) form of Example 8b: 1.21 g] was treated in the same manner as in Example 7c, 1.71 g of An oily target compound was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 1022, ₁₀₃₅ NMR spectrum (CDCl3) δppm: 0.91 (3H, m, _CH3 ), 3.45 (2H, t, _-CH2- ), 4.50 (2H, s, −CH ₂ −), 4.70 (2H, br.s, [formula]), 4.90−5.8 (4H, m, =CH−×4), (8d) 3-(5-hydroxypentyl)-6β-[3α −
(2-tetrahydropyranyloxy)-5(R), 9
-dimethyl-1,8-decadienyl]-7α-(2
-Tetrahydropyranyloxy)bicyclo[3.3.0]oct-2ene benzyl derivative (compound of Example 8c: 1.62g) was reacted in the same manner as in Example 7d to obtain 1.06g of the target compound in the form of an oil. . IR spectrum (Liq) ν _nax cm ^-1 : 3350 NMR spectrum (CDCl ₃ ) δppm: 0.92 (3H, m, CH ₃ ), 2.62 (3H, s, CH ₃ ), 2.69 (3H, s, CH ₃ ), 4.82 (2H, br.s, -OCHO- x 2), 5.0-5.8 (4H, m, =CH- x 4), (8e) 3-(4-carboxybutyl-6β-[3α-(2-
Tetrahydropyranyloxy)-5(R),9-dimethyl-1,8-decadienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]
Oct-2-ene alcohol (compound of Example 8d: 1.0 g) was reacted in the same manner as in Example 7e to obtain 521 mg of the target compound in the form of an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1734, 1710 NMR spectrum (CDCl ₃ ) δppm: 0.92 (3H, m, CH ₃ ), 1.62 (3H, s, CH ₃ ), 1.69 (3H, s, CH ₃ ), 4.72 (2H, br.s, [formula]), 5.0-5.8 (4H, m, =CH-×4), (8f) 3-(4-carboxybutyl)-6β-[3α-hydroxy-5 (R), 9-dimethyl-1,8-decadienyl]-7α-hydroxybicyclo[3.3.0]oct-2-ene pyranyl derivative (compound of Example 8e: 505 mg) was used for reaction treatment in the same manner as in Example 7f. As a result, 190 mg of the target compound in the form of an oil was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 3350, 1710, 972 NMR spectrum ( _CDCl3 ) δppm: 0.91 (3H, d, _CH3 ), 1.62 (3H, s, _CH3 ), 1.69 (3H, s, _CH3 ), 3.72 (1H, m, > CH OH), 4.15 (1H, m, > CH −OH), 5.11 (1H, t, = CH−), 5.34 (1H, br.s, = CH−) , 5.50 (2H, m, -CH=CH-) This compound is easily converted to the corresponding methyl ester (IR spectrum: 1725
cm ^-1 ). Example 9 3-(5-hydroxypentyl)-6β-[3α-hydroxy-5(R),9-dimethyl-1,8-decadienyl]-7α-hydroxybicyclo[3.3.0]oct-2-ene pyranyl The compound of Example 8d (200 mg) was reacted in the same manner as in Example 7f to obtain 98 mg of the target compound in the form of an oil. IR spectrum ( _CHCl3 ) ν _nax cm ^-1 : 3370, 975 NMR spectrum ( _CDCl3 ) δppm: 0.91 (3H, d, _CH3 ), 1.59 (3H, s, _CH3 ), 1.66 (3H, s, CH ₃ ), 5.02 (1H, t, =CH-), 5.19 (1H, br.s, =CH-), 5.40 (2H, m, -CH=CH-) Example 10 3-(4-carboxybutyl) -6β-(3α-hydroxy-4-methylnona-1,8-dienyl)
-7α-hydroxybicyclo[3.3.0]octo-
2-ene (10a) 3-(5-benzyloxypentyl)-6β-(3
-oxo-4-methylnona-1,8-dienyl)
-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene formyl compound (compound of Reference Example 14: 540 mg) and dimethyl (2-oxo-3-methyl-7-octenyl) ) phosphonate in the same manner as in Example 7a to obtain 639 mg of the target compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1034, 1078, 1120, 1624, 1666, 1692 NMR spectrum ( _CDCl3 ) δppm: 1.09 (3H, d, J=7.0Hz, _-CH3 ) 3.47 (2H, t , J=6.0Hz, _-CH2O- ) 4.51 (2H, s, _-OCH2- ) 4.60~6.10 (5H, m, =CH-×4,
[Formula]) 5.29 (1H, br.s, = CH-), 6.25 (1H, dd; J = 17.0, 6.0Hz, = CH-), 6.90 (1H, m, = CH-) 7.35 (5H, s , Ph) (10b) 3-(5-benzyloxypentyl)-6β-(3α
-Hydroxy-4-methylnona-1,8-dienyl)-7α-(2-tetrahydropyranyloxy)-
Cis-bicyclo[3.3.0]oct-2-ene enone (compound of Example 10a: 630 mg) was reacted in the same manner as in Example 7b to obtain 270 mg of the target compound in the form of an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1020, 1072, 1118, 1640, 3450 NMR spectrum ( _CDCl3 ) δppm: 0.89 (3H, m, _CH3 ) 3.47 (2H, t, J=6.0Hz, -CH ₂ O−) 4.51 (2H, s, −OCH ₂ −) 4.68 (1H, br.s, [formula]) 4.77 to 6.10 (6H, m, = CH− × 6) 7.37 (5H, s, Ph) ( 10c) 3-(5-benzyloxypentyl)-6β-[3α
-(2-tetrapyranyloxy)-4-methylnona-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene 3α-hydroxy form ( Compound of Example 10b: 336
mg) was treated in the same manner as in Example 7c to obtain 392 mg of the target compound in the form of an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1020, 1120, 1640 NMR spectrum ( _CDCl3 ) δppm: 0.88 (3H, m, _CH3 ) 3.47 (2H, t, J=6.0Hz, _-CH2O- ) 4.51 (2H, s, −OCH ₂ −) 4.6 to 6.2 (8H, m, =CH−×6;
[Formula]) 7.37 (5H, s, Ph) (10d) 3-(5-hydroxypentyl)-6β-[3α-
(2-Tetrahydropyranyloxy)-4-methylnona-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]
Oct-2-ene benzyl derivative (compound of Example 10c: 382 mg) was subjected to reaction treatment in the same manner as in Example 7d to obtain 308 mg of the target compound in the form of an oil. IR spectrum (Liq) ν _nax cm ^-1 : 972, 1020,
1032, 1074, 1118, 1130, 1640, 3450 NMR spectrum ( _CDCl3 ) δppm: 0.88 (3H, m, _CH3 ) 4.73 (2H, br.s, [formula]) 4.83-6.10 (6H, m, = CH -×6) (10e) 3-(4-carboxybutyl)-6β-[3α-(2
-tetrahydropyranyloxy)-4-methylnon-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene hydroxy form (compound of Example 10d) :291mg)
222 by the same reaction treatment as in Example 7e.
mg of the target compound as an oil was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 980, 1022,
1038, 1080, 1120, 1138, 1642, 1712, 1740 NMR spectrum (CDCl3) δppm: 0.87 (3H, m, _CH3 ) 4.73 ₍ 2H, br.s, [formula]) 3.83-6.07 (6H, m, =CH-×6) (10f) 3-(4-carboxybutyl)-6β-(3α-hydroxy-4-methylnona-1,8-dienyl)-
7α-Hydroxy-cis-bicyclo[3.3.0]oct-2-ene dipyranyl compound (compound of Example 10e: 212 mg) was treated in the same manner as in Example 7f to obtain 91 mg of the target compound in the form of an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1640, 1708, 3340 NMR spectrum ( _CDCl3 ) δppm: 0.90 (3H, m, _CH3 ) 3.50-4.1 (2H, m, >CHOH x 2) 5.30 (1H, br.s, =CH-) 5.52 (2H, m, -CH=CH-) 4.4-6.1 (3H, m, -CH= _CH2 ) Example 11 3-(4-carboxybutyl)-6β-(3α -hydroxy-3-cyclohexyl-1-propenyl)-7α-hydroxy-cis-bicyclo[3.3.0]oct-2-ene 3-(5-benzyloxypentyl)-6β-(3
-oxo-3-cyclohexyl-1-propenyl)-7α-(2-tetrahydropyranyloxy)-
Cis-bicyclo[3.3.0]oct-2-ene formyl compound (compound of Reference Example 14: 515 mg) and dimethyl (2-oxo-2-cyclohexylethyl) phosphonate were reacted in the same manner as in Example 7a to give 548 mg. The desired oily compound was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 1622, 1666, 1692 NMR spectrum ( _CDCl3 ) δppm: 3.47 (2H, t; J=6.0Hz, _-CH2O- ) 4.51 (2H, s, _-OCH2 -) 5.28 (1H, br.s, =CH-) 6.24 (1H, d, d; J = 15.0Hz, 4.0Hz, =CH
−) 6.88 (1H, m, =CH−) 7.36 (5H, s, Ph) (11b) 3-(5-benzyloxypentyl)-6β-(3α
-hydroxy-3-cyclohexyl-1-propenyl)-7α-(2-tetrahydropyranyloxy)
-cis-bicyclo[3.3.0]oct-2-ene enone (compound of Example 11a: 530 mg) was treated in the same manner as in Example 7b to obtain 295 mg of the oily target compound and its (3β-hydroxy) isomer. The body (140 mg of oil) was obtained. (3α-hydroxy) isomer IR spectrum (Liq) ν _nax cm ^-1 : 1022, 1076, 1120, 3450 NMR spectrum (CDCl ₃ ) δppm: 3.47 (2H, t; J=6.0Hz, -CH ₂ O-) 4.51 (2H, s, -OCH ₂ - 4.69 (1H, br.s, [formula]) 5.27 (1H, br.s, =CH-) 5.61 (2H, m, -CH=CH-) 7.37 (5H, s, Ph) (3β-hydroxy) isomer IR spectrum (Liq) ν _nax cm ^-1 : 1022, 1077, 1120, 3450 NMR spectrum (CDCl ₃ ) δppm: 3.46 (2H, t; J = 6.0Hz, -CH ₂ O−) 4.50 (2H, s, −CH ₂ O−) 4.72 (1H, br.s, [formula]) 5.29 (1H, br.s, =CH−) 5.63 (2H, m, −CH=CH -) 7.38 (5H, s, Ph) (11c) 3-(5-benzyloxypentyl)-6β-[3α
-(2-tetrahydropyranyloxy)-3-cyclohexyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene (3α-hydroxy) form 445mg When (compound of Example 11b) was treated in the same manner as in Example 7c, 435mg
The desired compound was obtained as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 975, 1022, 1035 NMR spectrum ( _CDCl3 ) δppm: 3.47 (2H, t; J=6Hz, _-CH2O- ) 4.51 (2H, s, _-CH2O -) 4.75 (2H, br.s, [formula]) 5.0 ~ 5.8 (3H, m, = CH- × 3) 7.33 (5H, s, Ph) (11d) 3-(5-hydroxypentyl)-6β- [3α−
(2-Tetrahydropyranyloxy)-3-cyclohexyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene 420 mg of benzylic compound (Example 11c) Compound) was reacted in the same manner as in Example 7d to obtain 317 mg of the target compound in the form of an oil. IR spectrum (Liq) ν _nax cm ^-1 : 3450 NMR spectrum (CDCl ₃ ) δppm: 4.72 (2H, br.s, [formula]) 5.1 to 5.8 (3H, m, = CH−×3) (11e) 3 -(4-carboxybutyl)-6β-[3α-(2
-tetrahydropyranyloxy)-3-cyclohexyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]
Oct-2-ene hydroxy form (compound of Example 11d: 300 mg)
was reacted in the same manner as in Example 7e to obtain 211 mg of the target compound in the form of an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1705, 1738 NMR spectrum (CDCl ₃ ) δppm: 4.73 (2H, br.s, [formula]) 5.1 to 5.8 (3H, m, =CH-, -CH=CH -) (11f) 3-(4-carboxybutyl)-6β-[3α-hydroxy-3-cyclohexyl-1-propenyl]
-7α-Hydroxy-cis-bicyclo[3.3.0]oct-2-ene pyranyl compound (compound of Example 11e: 195 mg) was treated in the same manner as in Example 7f to obtain 94 mg of the target compound in the form of an oil. Furthermore, this compound was left in a refrigerator to obtain a crystalline substance. Melting point 77-79℃ IR spectrum (CHCl ₃ ) ν _nax cm ^-1 : 976, 1709, 3350 NMR spectrum (CDCl ₃ ) δppm: 5.34 (1H, br.s, =CH-) 5.50 (2H, m, -CH =CH-) Example 12 3-(4-carboxybutyl)-6β-(3α-hydroxy-4,7-dimethyloct-1,6-dienyl)-7α-hydroxybicyclo[3.3.0]octo-2- Ene (12a) 3-(5-benzyloxypentyl)-6β-(3
-oxo-4,7-dimethyloct-1,6-dienyl)-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene Crude aldehyde (290 mg of the compound of Reference Example 14) and dimethyl 2-Oxo-3,6-dimethyloct-5-enylphosphonate was treated in the same manner as in Example 7a to obtain 310 mg of the target compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1624, 1665, 1692 NMR spectrum ( _CDCl3 ) δppm: 3.47 (2H, t, _-CH2O- ) 4.50 (2H, s, _-CH2O- ) 4.8~ 5.4 (2H, m, =CH-×2) 6.17 (1H, dd; J=17Hz, 5Hz, =CH-) 6.5-7.2 (1H, m, =CH-) (12b) 3-(5-benzyloxy Pentyl-6β-(3α
-Hydroxy-4,7-dimethyloct-1,6
-dienyl)7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene ketone (compound of Example 12a: 310 mg) was treated in the same manner as in Example 7b to yield 157 mg of the target compound in the form of an oil. and 61 mg of its 3β-hydroxy isomer were obtained. 3α-hydroxy isomer IR spectrum (Liq) ν _nax cm ^-1 :3450 NMR spectrum ( _CDCl3 ) δppm: 0.88 (3H, m, _CH3 ) 3.47 (2H, t, _-CH2O- ) 4.50 (2H, s, -CH ₂ O-) 4.70 (1H, br.s, [formula]) 5.0-5.6 (4H, m, = CH- x 4) 7.37 (5H, s, Ph) (12c) 3- (5- benzyloxybentyl)-6β-[3α
-(2-tetrahydropyranyloxy)-4,7-dimethyloct-1,6-dienyl]-7α-(2-
Tetrahydropyranyloxy)bicyclo [3.3.0]
Oct-2-ene 3α-hydroxy form (compound of Example 12b: 300
mg) was treated in the same manner as in Example 7c to obtain 327 mg of the target compound in the form of an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1020, ₁₁₂₀ NMR spectrum (CDCl3) δppm: 0.89 (3H, m, _CH3 ) 3.46 (2H, t, _-CH2O- ) 4.51 (2H, s, - CH ₂ O−) 4.70 (2H, br.s, [formula]) 4.90-5.8 (4H, m, =CH−×4) (12d) 3-(5-hydroxypentyl)-6β-[3α-
(2-tetrahydropyranyloxy)-4,7-dimethyloct-1,6-dienyl]-7α-(2-
Tetrahydropyranyloxy)bicyclo [3.3.0]
Oct-2-ene pyranyl compound (compound of Example 12c: 380 mg) was treated in the same manner as in Example 7d to obtain 297 mg of the target compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 3350 NMR spectrum (CDCl ₃ ) δppm: 0.91 (3H, m, CH ₃ ) 2.61 (3H, s, CH ₃ ) 2.69 (3H, s, CH ₃ ) 4.80 (2H , br.s, [Formula]) 5.0-5.8 (4H, m, = CH-×2, -CH=CH-) (12e) 3-(4-carboxybutyl)-6β-[3α-(2
-tetrahydropyranyloxy)-4,7-dimethyloct-1,6-dienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]
Using 556 mg of oct-2-ene alcohol (compound of Example 12d), reaction treatment was carried out in the same manner as in Example 7e to obtain 241 mg of the target compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1734, 1709 NMR spectrum ( _CDCl3 ) δppm: 0.91 (3H, m, _CH3 ) 1.62 (3H, s, _CH3 ) 1.69 (3H, s, _CH3 ) 5.0-5.8 (4H, m, = CH- x 2, -CH=CH-) (12f) 3-(4-carboxybutyl)-6β-(3α-hydroxy-4,7-dimethyloct-1,6-dienyl)-7α-hydroxybicyclo[3.3.0]octo- The 2-ene pyranyl compound (compound of Example 12e: 231 mg) was reacted in the same manner as in Example 7f to obtain 99 mg of the target compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 972, 1709, 3350 NMR spectrum (CDCl ₃ ) δppm: 0.90 (3H, m, CH ₃ ) 1.62 (3H, s, CH ₃ ) 1.68 (3H, s, CH ₃ ) 3.71 (1H, m, >C H OH) 4.14 (1H, m, <C H OH) 5.11 (1H, t, =CH-) 5.34 (1H, br.s, =CH-) 5.52 (2H, m, -CH=CH-) Example 13 3-(4-carboxy mixture of oct-2-ene and oct-3-ene (13a) 3-( 5-benzyloxypentyl)-6β-(3
-oxo-3-cyclohexyl-1-propenyl)-7α-(2-tetrahydropyranyloxy)-
A mixture of cis-hycyclo[3.3.0]oct-2-ene and oct-3-ene formyl compound (compound of Reference Example 8: 2.92 g) and dimethyl 2-oxo-2-cyclohexylethylphosphonate were prepared in the same manner as in Example 1a. Reaction treatment to
3.59 g of oily target compound was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 1622, 1664, 1692 NMR spectrum ( _CDCl3 ) δppm: 3.47 (2H, t; J=6.0Hz, _-CH2O- ) 4.51 (2H, s, _-OCH2 ) 5.29 (1H, br.s, =CH−) 6.25 (1H, dd; J=17.0, 5.0Hz, =CH−) 6.90 (1H, m, =CH−) 7.36 (5H, s, Ph) (13b ) 3-(5-benzyloxypentyl)-6β-(3α
-hydroxy-3-cyclohexyl-1-propenyl)-7α-(2-tetrahydropyranyloxy)
-Cis-bicyclo[3.3.0] Mixture of oct-2-ene and oct-3-ene The enone compound (compound of Example 13a: 3.56 g) was treated in the same manner as in Example 1b to obtain 1.65 g of oily 1.25 g of the target compound and its 3β-hydroxy isomer were obtained. 3α-hydroxy isomer IR spectrum (Liq) ν _nax cm ^-1 : 1022, 1078, 1120, 3450 NMR spectrum (CDCl ₃ ) δppm: 3.45 (2H, t, J=8.0Hz, -CH ₂ O-) 4.50 ( 2H, s, -OCH ₂ -) 4.67 (1H, br.s, [formula]) 5.27 (1H, br.s, =CH-) 5.60 (2H, m, -CH=CH-) 7.33 (5H, s , Ph) 3β-hydroxy isomer IR spectrum (Liq) ν _nax cm ^-1 : 1022, 1078, 1120, 3450 NMR spectrum ( _CDCl3 ) δppm: 3.46 (2H, t, _-CH2O- ) 4.51 (2H, s, -CH ₂ O-) 4.67 (1H, br.s, [formula]) 5.29 (1H, br.s, =CH-) 5.62 (2H, m, -CH=CH-) 7.34 (5H, s, Ph) (13c) 3-(5-benzyloxypentyl)-6β-[3α
-(2-tetrahydropyranyloxy)-3-cyclohexyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene and oct-3-ene Mixture hydroxy form (compound of Example 13b: 1.63 g)
was treated in the same manner as in Example 1c to obtain 1.89 g of the desired oily compound. IR spectrum (Liq) ν _nax cm ^-1 : 1022, 1080, 1120 NMR spectrum ( _CDCl3 ) δppm: 3.47 (2H, t; J=6.0Hz, _-CH2O- ) 4.50 (2H, s, _-OCH2 −) 4.70 (2H, br.s, [Formula]) 5.1-6.0 (3H, m, = CH-×3) 7.33 (5H, s, Ph) (13d) 3-(5-benzyloxypentyl)-6β −[3α
-(2-tetrahydropyranyloxy)-3-cyclohexyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene and oct-3-ene Mixture: 1.36 g of benzylic compound (compound of Example 13c: 1.88 g) was treated in the same manner as in Example 1d.
The desired oily compound was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 978, 1022, 1078, 1120, 1134, 3450 NMR spectrum ( _CDCl3 ) δppm: 4.70 (2H, br.s, [formula]) 5.28 (1H, br.s, =CH-) 5.1~5.8 (2H, m, -CH=CH-) (13e) 3-(4-carboxybutyl)-6β-[3α-(2
-tetrahydropyranyloxy)-3-cyclohexyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]
Mixture of oct-2-ene and oct-3-ene hydroxy form (compound of Example 13d: 1.34 g)
1.16 by reacting in the same manner as in Example 1e.
g of the target compound in the form of an oil was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 978, 1020, 1078, 1120, 1134, 1705, 1738 NMR spectrum (CDCl ₃ ) δppm: 4.73 (2H, br.s, [formula]) 5.30 (1H, br. s, =CH-) 5.10-5.80 (2H, m, -CH=CH-) (13f) 3-(4-carboxybutyl)-6β-(3α-hydroxy-3-cyclohexyl-1-propenyl)
-7α-Hydroxy-cis-bicyclo[3.3.0] Mixture of oct-2-ene and oct-3-ene Dipyranyl compound (compound of Example 13e: 1.14 g)
0.46 by reacting in the same manner as in Example 1f.
g of the target compound in the form of an oil was obtained. IR spectrum (CHCl ₃ ) ν _nax cm ^-1 : 1705, 3400 NMR spectrum (CDCl ₃ ) δppm: 3.50-3.95 (2H, m, > CH OH x 2) 5.30 (1H, br.s, = CH-) 5.50 (2H, m, -CH=CH-) Example 14 3-(2-hydroxyethyl)-6β-[3-(2
-tetrahydropyranyloxy)-3-cyclopentyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene (14a) 3-(2-benzoyloxy ethyl)-6β-(3
-oxo-3-cyclopentyl-1-propenyl)-7α-(2-tetrahydropyranyloxy)-
Cis-bicyclo[3.3.0]oct-2-ene 0.24g of 55% oily sodium hydride was converted into n-
After washing with hexane, 50 ml of tetrahydrofuran and 1.29 g of dimethyl (2-oxo-2-cyclopentylethyl)-phosphonate were added, and the mixture was stirred at room temperature for 1 hour. Next, 1.5 g of 3-(2-benzoyloxyethyl)-6β-formyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene (compound of Reference Example 28) was added. Ten
Dissolve in 30 ml of tetrahydrofuran and add at room temperature.
Stir for a minute. The reaction solution was diluted with ice water, made weakly acidic with dilute hydrochloric acid, extracted with ethyl acetate, and the extract was washed with water.
After drying over anhydrous sodium sulfate, the solvent was successively distilled off under reduced pressure to obtain 2.33 g of an oily residue. 30g of this residue
Column chromatography using silica gel was performed using ethyl acetate in n-hexane for 5, 10,
15% and 20%, and poured 200 ml at a time to obtain 1.79 g of the target compound from the portion that flowed out with the 10-15% mixed solvent. IR spectrum (Liq) ν _nax cm ^-1 : 710, 1120, 1270, 1625, 1665, 1690, 1720 NMR spectrum ( _CDCl3 ) δppm: 4.42 (2H, t), 5.45 (1H, s), 6.23 (1H, q), 6.85 (1H, m), 7.50 (3H, m), 8.05 (2H, m) (14b) 3-(2-benzoyloxyethyl)-6β-(3
-hydroxy-3-cyclopentyl-1-propenyl)-7α-(2-tetrahydropyranyloxy)
-cis-bicyclo[3.3.0]oct-2-ene 1.7 g of the enone compound (compound of Example 14a) and 1.39 g of cerium chloride were dissolved in 30 ml of methanol, cooled to 0°C, and 135 mg of sodium borohydride was added. hand
Stir for 10 minutes. The reaction solution was diluted with 150 ml of ice water, 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 1.7 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 710, 1025, 1120, 1270, 1720, 3450 NMR spectrum (CDCl ₃ ) δppm: 4.43 (2H, t), 4.67 (1H, s), 5.44 (1H, s) , 5.60 (2H, m), 7.50 (3H, m), 8.05 (2H, m) (14c) 3-(2-benzoyloxyethyl)-6β-[3
-(2-tetrahydropyranyloxy)-3-cyclopentyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene hydroxy form (Example 14b) compound) 1.7g and 2,3-dihydropyran 0.61ml in methylene chloride 5
ml, a small amount of p-toluenesulfonic acid was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was diluted with 150 ml of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.0 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 710, 975, 1020, 1075, 1110, 1270, 1720 NMR spectrum ( _CDCl3 ) δppm: 4.43 (2H, t), 4.72 (2H, s), 5.43 (1H, s), 5.57 (2H, m), 7.50 (3H, m), 8.05 (2H, m) (14d) 3-(2-hydroxyethyl)-6β-[3-(2
-tetrahydropyranyloxy)-3-cyclopentyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]
Oct-2-ene benzoyloxy form (compound of Example 14c) 2.0
Dissolve g in 50 ml of methanol to obtain 1.0 potassium carbonate.
g and stirred at 40°C for 30 minutes. 200% reaction solution
The extract was diluted with 1 ml of water, 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 1.8 g of an oily residue. This residue, 30
Column chromatography using 10 g of silica gel was carried out using 10 g of ethyl acetate in n-hexane.
Mix 15, 20, 25, 30% and pour 200ml each to make 15
1.53 g of the target compound was obtained from the portion that flowed out with the ~25% mixed solvent. IR spectrum (Liq) ν _nax cm ^-1 : 980, 1025, 1040, 1080, 1125, 1135, 3470 NMR spectrum ( _CDCl3 ) δppm: 4.69 (2H, s), 5.40 (1H, s), 5.58 (2H,
m) Example 15 3-(2-hydroxyethyl)-6β-[3-(2
-tetrahydropyranyloxy)-5,9-dimethyl-1,8-decadienyl]-7α-(2-
Tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene (15a) 3-(2-benzoyloxyethyl)-6β-(3
-oxo-5,9-dimethyl-1,8-decadienyl)-7α-(2-tetrahydropyranyloxy)
-cis-bicyclo[3.3.0]oct-2-ene aldehyde compound (compound of Reference Example 28) (2.30 g) was carried out using 2.32 g of dimethyl (2-oxo-4,8-dimethyl-7-nonenyl)-phosphonate. Example 14a
The mixture was treated in the same manner as above to obtain 2.51 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 710, 1115, 1270, 1625, 1670, 1690, 1720 NMR spectrum ( _CDCl3 ) δppm: 0.90 (3H, d), 4.43 (2H, t), 5.10 (1H, t), 5.45 (1H, b-s), 6.17 (1H, q), 6.8 (1H,
m), 7.5 (3H, m), 8.05 (2H, m) (15b) 3-(2-benzoyloxyethyl)-6β-(3
-Hydroxy-5,9-dimethyl-1,8-decadienyl)-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene enone (compound of Example 15a) 2.45 g was treated in the same manner as in Example 14b to obtain 2.47 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 715, 980, 1025, 1070, 1120, 1275, 1720,
3450 NMR spectrum (CDCl ₃ ) δppm: 0.90 (3H, d), 1.60 (3H, s), 1.68 (3H.s), 4.43 (2H, t), 4.67 (1H, s), 5.12 (1H, t) , 5.44 (1H, s), 5.6 (2H, m), 7.6 (3H, m),
8.05 (2H, m) (15c) 3-(2-benzoyloxyethyl)-6β-[3
-(2-tetrahydropyranyloxy)-5,9-
dimethyl-1,8-decadienyl]-7α-(2-
2.4 g of tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene hydroxy compound (compound of Example 15b) was treated in the same manner as in Example 14c to obtain 2.8 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 710, 970, 1020, 1030, 1070, 1110, 1270,
1720 NMR spectrum ( _CDCl3 ) δppm: 4.43 (2H, t), 4.70 (2H, s), 5.15 (1H, t), 5.44 (1H, b-s), 5.6 (2H, m), 7.5 (3H,
m), 8.05 (2H, m) (15d) 3-(2-hydroxyethyl)-6β-[3-(2
-tetrahydropyranyloxy)-5,9-dimethyl-1,8-decadienyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene benzoyloxy compound (Example 15c compound) 2.8
g was treated in the same manner as in Example 14d to obtain 2.2 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 975, 1020, 1030, 1075, 1120, 1123, 1200,
3450 NMR spectrum (CDCl ₃ ) δppm: 0.9 (3H, m), 2.32 (2H, t), 4.70 (2H, s), 5.13 (1H, t), 5.43 (1H, s), 5.6 (2H, m) Example 16 3-(2-hydroxyethyl)-6β-[3-(2
-tetrahydropyranyloxy)-4-methyl-1,8-nonadienyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene (16a) 3-(2- benzoyloxyethyl)-6β-(3
-oxo-4-methyl-1,8-nonadienyl)
-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2ene aldehyde (compound of Reference Example 28) (1.6 g) was converted into dimethyl (2-oxo-3-methyl-7-octenyl) -Processing in the same manner as in Example 14a using 1.27 g of phosphonate gave 1.81 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 710, 975, 1025, 1033, 1070, 1120, 1270,
1625, 1670, 1695, 1720 NMR spectrum ( _CDCl3 ) δppm: 1.10 (3H, d), 4.43 (2H, t), 4.9-5.1 (2H, m), 5.45 (1H, s), 5.6-6.0 (1H , m), 6.24 (1H, q), 6.85 (1H, m), 7.5 (3H, m), 8.05 (2H, m) (16b) 3-(2-benzoyloxyethyl)-6β-(3
-Hydroxy-4-methyl-1,8-nonadienyl)-7α-(2-tetrahydropyranyloxy)-
1.75 g of cis-bicyclo[3.3.0]oct-2-ene enone (compound of Example 16a) was treated in the same manner as in Example 14b to obtain 1.71 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 710, 975, 1025, 1070, 1120, 1275, 1725,
3460 NMR spectrum ( _CDCl3 ) δppm: 0.90 (3H, m), 4.45 (2H, t), 4.66 (1H, s), 4.9-5.1 (2H, m), 5.45 (1H, s), 5.5-6.1 ( 3H, m), 7.5 (3H, m), 8.05 (2H, m) (16c) 3-(2-benzoyloxyethyl)-6β-[3
-(2-tetrahydropyranyloxy)-4-methyl-1,8-nonadienyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene hydroxy form (Example 1.65 g of compound 16b) was treated in the same manner as in Example 14c to obtain 2.0 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 710, 975, 1025, 1075, 1115, 1270, 1720 NMR spectrum (CDCl ₃ ) δppm: 0.9 (3H, m), 4.44 (2H, t), 4.70 (1H, b-s), 4.9-5.1 (2H, m), 5.45 (1H, s), 5.4-6.05 (3H, m), 7.5 (3H, m), 8.05 (2H, m) (16d) 3-(2 -hydroxyethyl)-6β-[3-(2
-tetrahydropyranyloxy)-4-methyl-
1,8-nonadienyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene benzoyloxy form (compound of Example 16c)
1.95 g was treated in the same manner as in Example 14d to obtain 1.55 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 905, 975, 1000, 1020, 1030, 1073, 1120,
1130, 1200, 3450 NMR spectrum ( _CDCl3 ) δppm: 0.93 (3H, m), 4.70 (2H, s), 4.9-5.1 (2H, m), 5.43 (1H, s), 5.34-6.05 (3H, m ) Reference example 1 3-(4-carboxybutylidene)-7.7-ethylenedioxy-cis-bicyclo[3.3.0]octane 7.7-ethylenedioxy-3-oxo-cis-
A solution of bicyclo[3.3.0]octane (36.0 g) in dimethyl sulfoxide (400 ml) was mixed with triphenylphosphine-4-carboxybutyl bromide (440 g) and dimethyl sulfoxide anion (75.0 g of 55% oily sodium hydride and dimethyl sulfoxide). (3)) was added dropwise to the ylide solution prepared from the dimethyl sulfoxide solution and allowed to stand at room temperature under a nitrogen atmosphere for 48 hours. After completion of the reaction, neutralize with acetic acid, pour into saturated brine, extract with ethyl acetate, wash the extract with saturated brine, dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to leave a residue of 164.3 get g.
By purifying this product using silica gel column chromatography, the target product is obtained as an oil.
49.10g was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 1710 NMR spectrum (CDCl ₃ ) δppm: 3.88 (4H, s, OCH ₂ CH ₂ O), 5.23 (1H, t, J = 6.0 Hz, olefin-H), 10.36 (1H, s, COOH) Mass spectrum, m/e: 266 (M ⁺ ) Reference example 2 3-(5-hydroxypentylidene)-7.7-ethylenedioxy-cis-bicyclo[3.3.0]octane 3-( A solution of 4-carboxybutylidene)-7.7-ethylenedioxy-cis-bicyclo[3.3.0]octane (49.10 g) in tetrahydrofuran (150 ml) was mixed with lithium aluminum hydride (10.50 g) in tetrahydrofuran (675 ml) under ice cooling. The mixture was added dropwise to the suspension and then heated under reflux for 1 hour and 20 minutes. After the reaction is complete, 4% aqueous sodium hydroxide solution (42 ml) is added, and the mixture is stirred at room temperature. After removing the formed white precipitate, the liquid was concentrated under reduced pressure to obtain 46.90 g of a residue. This product was purified by silica gel column chromatography to obtain 40.10 g of the desired product as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 3320, 1430, 1330, 1110 NMR spectrum (CDCl ₃ ) δppm: 3.81 (4H, s, OCH ₂ CH ₂ O), 5.14 (1H, t, J = 6.0Hz, Olefin-H), mass spectrum, m/e: 252 (M ⁺ ) Reference example 3 3-(5-benzyloxypentylidene)-7.7
-ethylenedioxy-cis-bicyclo [3.3.0]
Octane 3-(5-hydroxypentylidene)-7.7-ethylenedioxy-cis-bicyclo[3.3.0]octane (10.0 g) in dimethylformamide (20 ml)
The solution was added dropwise to a suspension of 55% oily sodium hydride (2.60 g) in dimethylformamide (35 ml) under ice-cooling and stirring, and then stirred for 30 minutes at room temperature. Benzyl bromide (7.1 ml) was added dropwise to this mixture at room temperature, and the mixture was stirred for 30 minutes. After the reaction is completed, the reaction solution is poured into ice water and extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium acetate, and the solvent was distilled off under reduced pressure to obtain 22.0 g of a residue. By purifying this product using silica gel chromatography, 12.30g of the target product was obtained as an oily substance.
Obtained. IR spectrum (Liq) ν _nax cm ^-1 : 1455, 1330, 1110 NMR spectrum (CDCl ₃ ) δppm: 3.47 (2H, t, J=6.0Hz, CH ₂ CH ₂ OBz), 3.88 (4H, s, OCH ₂ CH ₂ O), 4.48 (2H, s, O CH ₂ Ph), 5.20 (1H, t, J=6.0Hz, olefin-H), 7.35 (5H, s, aryl-H) Reference example 4 3-(5 -benzyloxypentyl) -7.7-ethylenedioxy-cis-bicyclo[3.3.0]oct-2-ene 3-(5-benzyloxypentylidene) -7.7
-ethylenedioxy-cis-bicyclo[3.3.0]
Octane (17.8g) in benzene (300ml solution)
-Toluenesulfonic acid (1.50 g) and ethylene glycol (2.9 ml) are added, and the mixture is heated and stirred for 2.5 hours while removing water azeotropically. After the reaction was completed, the reaction solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 18.20 g of the desired product as an oil.
This product is used in the next reaction without purification. IR spectrum (Liq) ν _nax cm ^-1 : 1455, 1320, 1100, 1020 NMR spectrum (CDCl ₃ ) δppm: 3.42 (2H, t, J=6.0Hz, CH ₂ CH ₂ OBz), 3.84 (4H, s, _OCH2CH2O ), 4.44 (2H, s, OCH2Ph ), 5.15 (1H, br.s, _olefin -H), 7.28 (5H, s, aryl-H) Mass spectrum, m/ _e : 342 (M ⁺ ) Reference example 5 3-(5-benzyloxypentyl)-7-oxo-cis-bicyclo[3.3.0]oct-2-ene 3-(5-benzyloxypentyl)-7.7-ethylenedioxy- Add cis-bicyclo[3.3.0]oct-2-ene (6.65 g) to a mixture of acetone (120 ml), water (45 ml), and concentrated hydrochloric acid (1.0 ml),
Stir at room temperature for 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 obtain 6.00 g of a residue. This was purified by silica gel column chromatography to obtain the target product as an oil. 5.33g of product was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 1725 NMR spectrum (CDCl ₃ ) δppm: 3.42 (2H, t, J=6.0Hz, -CH ₂ CH
₂ OCH ₂ Ph), 4.43 (2H, s, O CH ₂ Ph), 5.14 (1H, br.s, olefin-H), 7.24 (5H, s, aryl-H) Mass spectrum, m/e: 298 ( M ⁺ ) Reference Example 6 3-(5-benzyloxypentyl)-6β-carboxy-7α-hydroxy-cis-bicyclo[3.3.0]oct-2-ene and 3-(5-benzyloxypentyl)-6β- Carboxy-7α-
Mixture of hydroxy-cis-bicyclo[3.3.0]oct-3-ene 1,2- in 55% oily sodium hydrogen (1.91 g)
2,6-di-t-butyl-p-cresol (9.60 g) was added to a suspension in dimethoxyethane (170 ml) and stirred vigorously for 1 hour at an internal temperature of 40°C. Then the internal temperature
After cooling to 30°C, stir for 30 minutes at an internal temperature of 30°C while introducing carbon dioxide gas. After cooling to an internal temperature of 10°C, 1,2-dimethoxyethane (20
ml) solution was added dropwise and stirred for 2 hours at an internal temperature of 10°C.
Then, a solution of sodium borohydride (820 mg) in t-butyl alcohol (40 ml) and water (13 ml) was added dropwise to this mixture, and the mixture was stirred at an internal temperature of 10°C for 1 hour. After the reaction was completed, the reaction solution was poured into water, washed with hexane, and the aqueous layer was made acidic with 10% hydrochloric acid.
Extract with ethyl acetate. After extraction, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 5.42 g of a residue.
By purifying this product using silica gel column chromatography, the target product is obtained as an oil.
4.28g was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 3350, 1710 NMR spectrum (CDCl ₃ ) δppm: 3.49 (2H, t, J=6.0Hz, CH ₂ CH ₂ OBz), 4.52 (2H, s, CH ₂ O CH ₂ Ph), 7.08 (2H, s, OH, COOH), 7.37 (5H, s, aryl-H) Mass spectrum, m/e: 344 (M ⁺ ) Reference example 7 3-(5-benzyloxypentyl)- 6β-Hydroxymethyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene Mixture of hydroxycarboxylic acids (compound of Reference Example 6: 4.28 Dissolve g) in methylene chloride (10 ml), add dihydropyran (3.4 ml) and a catalytic amount of pyridine hydrochloride, and stir at room temperature for 2 hours. Next, add lithium aluminum hydride (500 mg) to tetrahydrofuran (30 ml) under ice cooling.
Add to the suspension and stir for 1 hour at an internal temperature of 18°C.
After the reaction is complete, add 4% aqueous sodium hydroxide solution (2
ml) and stir at room temperature. After removing the formed white precipitate, the liquid was concentrated under reduced pressure to obtain a residue.
Obtain 7.60g. This product was purified by silica gel column chromatography to obtain 4.840 g of the desired product as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 3430, 1455, 1120 NMR spectrum (CDCl ₃ ) δppm: 3.47 (2H, t, J=6.0Hz, CH ₂ CH ₂ OBz), 4.53 (2H, s, O CH ₂ Ph), 5.30 (1H, br.s, olefin-H), 7.37 (5H, s, aryl-H) Mass spectrum, m/e: 414 (M ⁺ ) Reference example 8 3-(5-benzyloxypentyl )-6β-formyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene Mixture of alcohols (compound of Reference Example 7:
Triethylamine (13.5 ml) was added to a solution of 4.82 g) in dimethyl sulfoxide (42 ml), followed by a solution of pyridine-sulfuric anhydride complex (4.720 g) in dimethyl sulfoxide (22 ml), and the mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was poured into saturated brine, extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.96 g of the target product as an oil. Obtained. This substance is used in the next reaction without purification. IR spectrum (Liq) ν _nax cm ^-1 : 1725 NMR spectrum (CDCl ₃ ) δppm: 4.45 (2H, s, O CH ₂ Ph), 5.23 (1H, br.s, olefin-H), 7.26 (5H, s , aryl-H) 9.68 (1H, t, J = 4.0Hz, CHO) Reference example 9 3-(5-benzyloxypentyl)-7.7-ethylenedioxy-3-hydroxy-cis-bicyclo[3.3.0]octane 5-benzyloxypentyl bromide 1.00g
[The method of AWBurgstahler et al. (J.Org.Chem., 42 ,
566 (1977))] and magnesium metal (100 mg) in diethyl ether (5 ml) at room temperature.
A solution of 7.7-ethylenedioxy-3-oxo-cis-bicyclo[3.3.0]octane (501 mg) in diethyl ether (5 ml) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. After the reaction is 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 1.47 g of a residue. This product was purified by silica gel column chromatography to obtain 556 mg of the desired product as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 3480, 1470, 1330, 1110 NMR spectrum (CDCl ₃ ) δppm: 3.47 (2H, t, J=6.0Hz, CH ₂ CH ₂ OBz), 3.91 (4H, s, _OCH2CH2O ), 4.52 (2H, s, OCH2Ph ), 7.36 (5H, s, aryl-H) Mass spectrum _, m/e: 360 ₍ M ⁺ ), 3.42 (M-
18) Reference example 10 3-(5-benzyloxypentyl-7.7-ethylenedioxy-cis-bicyclo[3.3.0]oct-2-ene 3-(5-benzyloxypentyl)-7.7-ethylenedioxy-3 -Hydroxy-cis-bicyclo[3.3.0]octa (209 mg) in benzene (2 ml)
Ethylene glycol (0.05 ml) and p-toluenesulfonic acid (10 mg) were added to the solution, and the mixture was heated and stirred for 3.5 hours while removing water azeotropically. After the reaction is completed, 5
% aqueous sodium bicarbonate solution, the reaction mixture was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 193 mg of a residue. This product was purified by silica gel chromatography to obtain 142 mg of the desired product as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1445, 1320, 1110, 1020 NMR spectrum (CDCl ₃ ) δppm: 3.42 (2H, t, J=6.0Hz, CH ₂ CH ₂ OBz), 3.84 (4H, s, _OCH2CH2O ), 4.44 (2H, s, OCH2Ph ), 5.15 (1H, br.s, _olefin -H), 7.28 (5H, s, aryl-H) Mass spectrum, m/ _e : 342 (M ⁺ ) Reference Example 11 3-(5-hydroxypentyl)-7,7-ethylenedioxy-cis-bicyclo[3.3.0]oct-2-ene Example using the compound of Reference Example 10 (1.20 g) The reaction was carried out in the same manner as in 1d to obtain 0.67 g of the target compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 3350 NMR spectrum (CDCl ₃ ) δppm: 3.85 (4H, s, OCH ₂ CH ₂ O), 5.15 (1H, br.s, =CH−) This compound is 10% When treated with hydrochloric acid/acetone (3:7), the corresponding ketone body (IR spectrum:
3350, 1725cm ^-1 ). Reference example 12 3-(4-methoxycarbonylbutyl)-7.7-
Ethylenedioxy-cis-bicyclo [3.3.0]
Oct-2-ene 3-(5-hydroxypentyl)-7.7-ethylenedioxy-cis-bicyclo[3.3.0]oct-
Dissolve 1.56g of 2-ene in 45ml of acetone and -20~-
Add Jones reagent (4 ml) dropwise at 10°C. After the reaction is completed, the mixture is neutralized with 5% aqueous sodium hydrogen carbonate, and the acetone is distilled off under reduced pressure. The residue is acidified with acetic acid and extracted with ethyl acetate. The extract is dried with sodium sulfate, the solvent is distilled off, and the resulting residue (corresponding carboxylic acid: IR spectrum: 1705 cm ^-1 ) is esterified with ether of diazomethane. Purification by silica gel chromatography (30 g) gave the target compound as an oil. Furthermore, this ester is 1
It can be converted to the corresponding amide by heating with primary and secondary amines. IR spectrum (Liq) ν _nax cm ^-1 :1725 NMR spectrum ( _CDCl3 ) δ: 3.63 (3H, s, COOCH ₃ ), 3.84 (4H, s, OCH ₂ CH ₂ O), 5.15 (1H, br.s , =CH-) Reference example 13 3-(3-benzyloxypropyl)-7.7-ethylenedioxy-cis-bicyclo[3.3.0]oct-2-ene 3-oxo-7.7-ethylenedioxy-cis-
The reaction was carried out in the same manner as in Reference Examples 9 and 10 using 5 g of bicyclo[3.3.0] octane and 3-benzyloxypropylmagnesium bromide (1.2 moles) to obtain 3.1 g of the target compound as an oil. IR spectrum (Liq ₎ ν _nax cm ^-1 : 1445 NMR spectrum (CDCl ₃ ) δ: 3.41 (2H, t, CH 2 OCH ₂ Ph), 3.84 (4H, s, -OCH ₂ CH ₂ O-), 4.45 (1H, s, -CH ₂ Ph), 5.14 (1H, br.s, =CH-) Reference example 14 3-(5-benzyloxypentyl)-6β-formyl-7α-(2-tetrahydropyranyloxy) Bicyclo[3.3.0]oct-2-ene 3-(5-benzyloxypentyl)-6β-hydroxymethyl-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene (1.06 g ) in dimethyl sulfoxide (8 ml), add triethylamine (7.1 ml). Pyridine-
Add a solution of anhydrous sulfuric acid complex (2.04 g) in dimethyl sulfoxide (7 ml) and stir for 30 minutes. After the reaction is complete, the reaction solution is poured into saturated brine and extracted with ethyl acetate. Wash the extract with water,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.03 g of the desired product as an oil. This substance can be used in the next reaction without purification. IR spectrum (Liq) ν _nax cm ^-1 :1725 NMR spectrum ( _CDCl3 ) δ: 4.45 (2H, s, -O CH ₂ Ph), 5.23 (1H, br.s, =CH-), 7.26 (5H, s, Ph), 9.68 (1H, t; J=4.0Hz, CHO) Reference example 15 3-(4-methoxycarbonylbutyl)-6β-
Formyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-
mixture of ene and oct-3-ene 3-(4-methoxycarbonylbutyl)-6β-
Hydroxymethyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octo-
Using 165 mg of a mixture of 2-ene and oct-3-ene, the reaction was carried out in the same manner as in Reference Example 8 to obtain 163 mg of the crude target compound. IR spectrum (Liq) ν _nax cm ^-1 : 2700, 1735, 1030, 1020 Reference example 16 3-(5-benzyloxypentyl)-6β-ethoxycarbonyl-7-oxo-cis-bicyclo[3.3.0]octo- 2-ene and octo-3
-Ene 200 mg of 55% oily sodium hydrogen in dioxane 5
ml, add 1 ml of diethyl carbonate, and stir while heating to an external temperature of 90°C. A dioxane solution (3 ml) containing 150 mg of 3-(5-benzyloxypentyl)-7-oxo-cis-bicyclo[3.3.0]oct-2-ene (compound of Reference Example 5) was added dropwise to the reaction mixture. After dropping, the mixture was reacted for 1 hour at an external temperature of 90°C. During the dropwise addition, a catalytic amount of ethanol was added. After the reaction is complete, the reaction mixture is poured into ice water, acidified with acetic acid, and extracted with ethyl acetate. The extract was washed with saturated brine and then dried with sodium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography. 72 mg of oily oct-2-ene was obtained from the hexane outflow containing 3% ethyl acetate, and 57 mg of oily oct-3-ene was obtained from the hexane outflow containing 5% ethyl acetate. Oct-2-ene: IR spectrum (Liq) ν _nax cm ^-1 : 698, 735, 1620, 1657, 1725, 1753 Oct-3-ene: IR spectrum (Liq) ν _nax cm ^-1 : 698, 735 , 1620, 1658, 1723, 1751 Reference example 17 3-(5-benzyloxypentyl)-6β-ethoxycarbonyl-7α-hydroxy-cis-
Bicyclo[3.3.0]oct-2-ene 6β-ethoxycarbonyl oct-2-ene compound (compound of Reference Example 16: 62 mg) was dissolved in 3 ml of ethanol at -40 to -20°C with 50 mg of sodium borohydride.
was added and stirred for 45 minutes. After the reaction is complete, acetic acid is added to the reaction mixture and the mixture is allowed to warm to room temperature, then saturated brine is added and extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain 48 mg of the target compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 697, 735, 1300, 1728, 3450 NMR spectrum (CDCl ₃ ) δ: 3.45 (2H, t), 4.50 (2H, s), 5.29 (1H, br.s) , 7.36 (5H, s) Reference example 18 3-(5-benzyloxypentyl)-6β-ethoxycarbonyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene hydroxy Dihydropyran (0.3 ml) was added to a methylene chloride solution (1 ml) of the compound (compound of Reference Example 17: 47 mg), and a catalytic amount of p-toluenesulfonic acid was added under ice cooling, followed by reaction for 1 hour. After the reaction is complete,
Add sodium bicarbonate solution and extract with ethyl acetate. After washing the extract with saturated saline, it is dried with sodium sulfate. When the solvent is distilled off and the resulting residue is purified by column chromatography using silica gel,
55 mg of oily target compound was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 699, 738, 977, 1028, 1039, 1730 Reference example 19 3-(5-benzyloxypentyl)-6β-hydroxymethyl-7α-(2-tetrahydropyranyloxy) To an ether solution (5 ml) of -cis-bicyclo[3.3.0]oct-2-ene pyranyl compound (compound of Reference Example 18: 27 mg) was added 48 mg of lithium aluminum hydride at room temperature, and the mixture was stirred for 30 minutes. After the reaction is complete, add 0.2 ml of 4% caustic soda water and stir for 2 hours. Collect the precipitate and concentrate the liquid. The obtained residue was purified by column chromatography using silica gel to obtain 24 mg of the target compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 1120, 1455, 3430 NMR spectrum ( _CDCl3 ) δ: 3.47 (2H, t), 4.53 (2H, s), 5.30 (1H, br.s), 7.37 (5H , s) Reference example 20 3-(5-benzyloxypentyl)-7α-(2
-tetrahydropyranyloxy)-6β-hydroxymethyl-cis-bicyclo[3.3.0]oct-3-ene 6β-ethoxycarbonyloct-3-ene compound (compound of Reference Example 16: 75 mg) was used, Reference Example 17 ,
Sequential reaction treatment was carried out in the same manner as in 18 and 19 to obtain 24 mg of the target compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 697, 735, 980, 1025, 1040, 1120, 1455, 3430 Reference example 21 3-(2-dimethyl-t-butylsilyloxyethyl)-6β-ethoxycarbonyl-7 -Oxo-cis-bicyclo[3.3.0]oct-2-ene and oct-3-ene 1,4-dioxane (10 ml) and diethyl carbonate (1 ml) in 55% oily sodium hydride (200 mg) under nitrogen atmosphere Add and heat to an internal temperature of 80℃. To this, 3-(2-dimethyl-
t-butylsilyloxyethyl)-7-oxo-
cis-bicyclo[3.3.0]oct-2-ene (157
1,4-dioxane (5 ml) was added dropwise, followed by stirring at the same temperature for 30 minutes. After the reaction is completed, the reaction solution is ice-cooled, neutralized with acetic acid, saturated brine is added, and extracted with ethyl acetate.
The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain a residue. By purifying this product using silica gel column chromatography, 57 mg of the desired oct-2-ene compound was obtained as an oily substance from the less polar portion. In addition, 49 mg of oct-3-ene compound was obtained from the more polar portion. Oct-2-ene: IR spectrum (Liq) ν _nax cm ^-1 : 775, 838, 1100, 1232, 1252, 1623, 1662, 1730, 1757 Oct-3-ene: IR spectrum (Liq) ν _nax cm ^-1 : 778, 838, 1100, 1238, 1258, 1623, 1662, 1728, 1757 Reference example 22 3-(2-dimethyl-t-butylsilyloxyethyl)-6β-ethoxycarbonyl-7α-hydroxy-cis-bicyclo [3.3.0] Octo-2
-Ene 6β-ethoxycarbonyloct-2-ene compound (compound of Reference Example 21: 108 mg) was dissolved in ethyl alcohol (2 ml), and sodium borohydride (50 mg) was added at -40 to -30°C for 30 minutes. Stir. After the reaction is complete, acetic acid and then saturated brine are added, followed by extraction with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain a residue. This product was purified by silica gel column chromatography to obtain 101 mg of the desired product as an oily substance. IR spectrum (Liq) ν _nax cm ^-1 : 775, 840, 1100, 1258, 1730, 3460 Reference example 23 3-(2-dimethyl-t-butylsilyloxyethyl)-6β-ethoxycarbonyl-7α-(2
-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene hydroxy compound (compound of Reference Example 22: 95 mg) was dissolved in methylene chloride (2 ml), and 2,3-dihydropyran (0.05 ml) and para-toluenesulfonic acid (2 mg), and stirred for 50 minutes. After the reaction is completed, 5% sodium bicarbonate water is added to neutralize, saturated brine is added, and the mixture is extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain a residue. This product was purified by silica gel column chromatography to obtain 110 mg of the desired product as an oily substance. IR spectrum (Liq) ν _nax cm ^-1 : 777, 838, 975, 1023, 1039, 1100, 1258, 1730 Reference example 24 3-(2-dimethyl-t-butylsilyloxyethyl)-6β-hydroxymethyl-7α -(2-
Tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene pyranyl compound (compound of Reference Example 23: 115 mg) was dissolved in 15 ml of methylene chloride. −70 to this solution
At °C, 0.9 ml of a 20% toluene solution of diisobutylaluminum hydride was added and stirred for 2 hours and 30 minutes. After the reaction is complete, methanol, acetic acid, and saturated brine are added, followed by extraction with ethyl acetate. The extract is washed with saturated saline and dried over sodium sulfate. When the solvent was distilled off and the resulting residue was purified using a silica gel column, 86 mg was obtained.
The desired oily compound was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 780, 840, 982, 1024, 1040, 1100, 1260,
3470 Reference example 25 3-(2-dimethyl-t-butylsilyloxyethyl)-6β-formyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene hydroxy form ( Add 2 ml of triethylamine to a dimethyl sulfoxide solution (6 ml) of the compound of Reference Example 24 (80 mg). A solution of 450 mg of pyridine sulfuric anhydride complex in 3 ml of dimethyl sulfoxide was added dropwise to this reaction solution while stirring vigorously. After 45 minutes, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 94 mg of the target compound as an oil. IR spectrum (Liq) ν _nax cm ^-1 : 781, 842, 1104, 1262, 1730, 2740 NMR spectrum ( _CDCl3 ) δ: 9.64, (1H, d), 5.28 (1H, br.s), 4.58 (1H , br), 0.88 (9H, s), 0.2 (6H, s) Reference example 26 3-(2-benzoyloxyethyl-6β-hydroxymethyl-7α-hydroxy-cis-bicyclo[3.3.0]oct-2- 4.57 g of the dipyranyl compound obtained by the same reaction treatment as in Example 1c using the ene hydroxy compound (compound of Reference Example 24: 3.96 g) and dihydropyran (1.24 g) was dissolved in 40 ml of tetrahydrofuran and mixed with 1M tetrabutylammonium at room temperature. Add 30 ml of fluoride and stir at room temperature for 30 minutes, then add saturated brine and extract with ethyl acetate. The extract is dried, the solvent is distilled off, and purified by silica gel column chromatography to give 2.11 g. An oily alcohol was obtained. 2.11 g of this alcohol was dissolved in 15 ml of pyridine, 1.15 g of benzoyl chloride was added, and the solution was dissolved at room temperature.
After standing for a while, water was added and extracted with ethyl acetate. The extract is saturated saline, cooled 3% hydrochloric acid,
After washing with a sodium bicarbonate solution and then with a saturated saline solution, it is dried with sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 2.21 g of oily benzoyl compound.
5.2 g of this benzoyl derivative was dissolved in 52 ml of methanol, 13 ml of water and 1.3 g of p-toluenesulfonic acid were added, and the mixture was stirred at 30 to 35°C for 1.5 hours. Next, the reaction solution was diluted with 100 ml of water, extracted with ethyl acetate, the extract was washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, and the obtained crystalline residue was washed with cyclohexane to obtain 2.8 g of the target compound was obtained. IR spectrum (Liq) ν _nax cm ^-1 : 1080, 1120, 1280, 1725, 3220 NMR spectrum (CDCl ₃ ) δ: 4.43 (2H, t), 5.46 (1H, s), 7.48 (3H, m), 8.05 (2H, m) Reference example 27 3-(2-benzoyloxyethyl)-6β-hydroxymethyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene dihydroxy form ( Dissolve 3.0 g of the compound of Reference Example 26 and 2.61 ml of triethylamine in 60 ml of benzene, cool on ice, and add trichloroacetyl chloride while stirring.
Dissolve 1.16ml in 30ml of benzene, add dropwise and stir for 20 minutes. The reaction solution was diluted with ice water, extracted with ethyl acetate, the extract was washed with water, dried, and the solvent was evaporated under reduced pressure to obtain 4.9 g of an oily residue. This residue
The product was purified by column chromatography using 50 g of silica gel to obtain 3.05 g of mono-trichloroacetyl compound. 3.05g of mono-trichloroacetyl compound and 2,3-
Dissolve 0.93 ml of dihydropyran in 10 ml of methylene chloride, add a small amount of p-toluenesulfonic acid, and stir at room temperature for 10 minutes. The reaction solution was diluted with ethyl acetate, washed with water, dried, and the solvent was distilled off under reduced pressure to obtain 3.7 g of pyranyl compound. Dissolve 3.6 g of pyranyl compound in 70 ml of methanol and add 5 ml of saturated aqueous sodium bicarbonate solution to 30
Stir at ~40°C for 2 hours. The reaction solution was diluted with saturated brine and extracted with ethyl acetate. The extract was washed with water, dried, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 2.59 g of the target compound. Ta. IR spectrum (Liq) ν _nax cm ^-1 :970, 1020, 1070, 1110, 1270, 1600, 1715, 3420 Reference example 28 3-(2-benzoyloxyethyl)-6β-formyl-7α-(2-tetrahydropirani 2.50 g of hydroxy)-cis-bicyclo[3.3.0]oct-2-ene hydroxy compound (compound of Reference Example 27) was dissolved in 25 ml of dimethyl sulfoxide, 8.97 ml of triethylamine was added, and sulfur trioxide was dissolved under stirring at 20°C. - 5.15 g of pyridine complex is dissolved in 17 ml of dimethyl sulfoxide and added dropwise and stirred for 10 minutes. The reaction solution was diluted with ice water, extracted with ethyl acetate, the extract was washed with water, dried, and the solvent was distilled off under reduced pressure to obtain 2.34 g of the target compound. IR spectrum (Liq) ν _nax cm ^-1 : 715, 975, 1030, 1120, 1280, 1720 NMR spectrum (CDCl ₃ ) δ: 4.64 (1H, s), 5.46 (1H, s), 9.78 (1H, d)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents an optionally protected hydroxymethyl group, formyl group, or an optionally protected carboxy group, R ² and R ³ are the same or different and represent a hydrogen atom or a hydroxyl group-protecting group, and R ⁴ represents an alkenyl group or a cycloalkyl group, and n is 1 to 6
The dotted line indicates the double bond at the 2nd or 3rd position. ) and pharmacologically acceptable salts thereof.