JPH0364493B2 - - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula (In the formula, R¹may be protected
represents a carboxy group or a carboxy group that may be protected,
R²represents a hydrogen atom or a hydroxyl group protecting group, and n is
Indicates an integer from 1 to 6, and the dotted line indicates the second or third place.
Indicates a double bond. ) with carbacyclines green
Concerning body intermediates. In the above formula, R¹Protecting group for hydromethyl group, R²of the hydroxyl group of
As a protecting group, a commonly used hydroxyl group protecting group is used.
If so, there are no particular limitations, but for example, acetyl, pro-
pionyl, butyryl, isobutyryl, benzoy
lower aliphatic or aromatic such as
Group acyl group; benzyl, p-nitrobenzyl, p
-aralkyl group such as methoxybenzyl; 2-
Tetrahydropyrahil, 2-tetrahydrofurani
4-methoxytetrahydropyran-4-y
alkaline compounds such as 2-tetrahydrothiopyranyl,
In the ring with or without a koxy group as a substituent
5- to 6-membered ring containing oxygen or sulfur atom
Heterocyclic group; methoxymethyl, ethoxymethyl,
Alkoxy group such as benzyloxymethyl or
or a metal having an aralkyloxy group as a substituent.
Thyl group; 1-methoxyethyl, 1-ethoxyethyl
1-alkoxyethyl group such as
lucilyl, triethylsilyl, tri-n-propyl
Silyl, t-butyldimethylsilyl, diphenyl
Tri-lower alkyl such as t-butylsilyl or
or diallyl lower alkylsilyl group.
, preferably R¹hydroxymethyl in
The protecting group of the group is an aralkyl group, and R²hydroxyl group of
The protecting group is 2-tetrahydropyranyl group or 2-
It is a tetrahydrofuranyl group. 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. n is preferably an integer from 1 to 4. In addition, in the compound having the general formula ()
Based on the coordination of the hydroxyl group on the side chain of the cyclopentane ring, etc.
stereoisomers and double bonds within the cyclopentene ring
Positional isomers exist based on the combination. Therefore, the above
Compounds with the general formula () are these stereoisomers
If obtained as a mixture of
can be separated to obtain each isomer.
Ru. In the general formula () above, these optical differences
Mixtures of isomers and stereoisomers are all in a single formula
However, this does not limit the scope of the description of the present invention.
is not limited. Also, in the general formula (), as a suitable compound
Well, (1) R¹is a carboxy group that may be protected or
protected hydroxymethyl group, R²is water
Compounds that are protective groups for acid groups and where n is 1 to 4
thing, (2) R¹is a lower alkoxycarbonyl group,
R²is a hydroxyl protecting group and n is 4
I can give you a compound. 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 chlorophyll compounds has been carried out, the present inventors
The compound represented by the above general formula () is carboxylic acid.
Found to be a synthetic intermediate for cyclin-like green bodies.
The present invention was completed. In addition, the compound () is
Tetsuhi reaction, carbonyl group reduction, and further as necessary.
Therefore, by removing the protecting group, an excellent
Platelet aggregation inhibition, coronary vasodilation, bronchodilation
Tonic effect, anti-ulcer effect, etc. (especially platelet aggregation inhibitory effect)
Calcium, which has excellent long-lasting activity
Vacyclines can lead to plastids. The compound () of the present invention can be prepared according to the following method.
Manufactured. In the above formula, R¹,R², n and dotted lines are as described above.
Indicates the same meaning as R⁶indicates a hydroxyl protecting group,
R⁸is a protected hydroxymethyl group or
Indicates a carboxy group that may be¹¹is protected
represents a hydroxymethyl group, and R¹²is a hydrogen atom or
is methyl, ethyl, n-propyl, n-butyl
represents a lower alkyl group such that Z is the formula
[Formula] or [Formula] (where R¹³is low Y is an oxygen atom or a sulfur atom
and A is ethylene, propylene, trimethylene
butylene, tetramethylene, 2,2-dimethylene
Alkyl having 2 to 5 carbon atoms such as rutrimethylene
Indicates a ren group. ) protecting group for carbonyl group
, and m represents an integer from 0 to 5. The first 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 () XM_g(CH₂)_o−R¹¹ () (In the formula, R¹¹and n have the same meaning as above.
and X represents a halogen atom such as chlorine or bromine.
vinegar. ) can be reacted with a Grignard reagent having
This is accomplished 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 second step is to prepare a compound having the general formula ().
R¹is a protected hydroxymethyl group.
In the process of manufacturing compound ('), the compound
This is achieved by dehydrating (). The reaction is to treat the compound () 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 should not be involved in the reaction.
Although not particularly limited, benzene,
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 third step is at the exo position with the general formula ()
In the process of manufacturing compounds with double bonds, the compound
Thing () as a general formula (R^Ten)₃P○＋ -C○- H(CH₂)_nR¹ () or general formula (In the formula, R¹and m have the same meaning as above.
,R^Tenis an aryl group such as phenyl or methyl
represents an alkyl group such as n-butyl, M is
Alkalas such as lithium, sodium, and potassium
Shows re-metal. ) with Wittetsug reagent or modified
Achieved by reacting with Wittetsug reagent
be done. The general formula () or () used in the reaction
) or a modified Witetsch reagent with
is prepared by the general formula in the presence of a solvent according to a conventional method. (R^Ten)₃P −CH₂(CH₂)_nR¹X (′) or general formula (In the formula, R¹,R^Ten, X and m are the same as above.
Show meaning. ) in a compound with sodium hydride
alkali metal hydrides such as potassium hydroxide
Or sodium methoxide, sodium ethoxide
oxide, alkaline compounds such as potassium tert-butoxide
Potash metal alkoxide, sodium amide, potassium
Alkali metal amides such as umamide, n-butylamide
Alkyl alkali metals such as chilllithium, sodium
like thorium dimethyl sulfoxide anion
Alkali metal dimethyl sulfoxide anion, etc.
obtained by reacting an alkali metal base of
can be done. General solvents are used.
There are no particular restrictions on the solvent used in the Wittetsug reaction.
used, e.g. ethyl ether, tetrahydro
such as furan, dioxane, dimethoxyethane
Ethers; cyclic sulfones such as sulfolane
Class; carbonization such as benzene, toluene, hexane
Hydrogens; dialkyls such as dimethyl sulfoxide
Rusulfoxides; dimethylformamide, dimethylformamide
Fatty acid dialkylamides such as tylacetamide
Chemicals: Chemicals such as dichloromethane and chloroform
Logenated hydrocarbons; hexamethylphosphorotri
Phosphate triamides such as amide (HMPA)
Inert organic solvents such as Also
Reacts with inert gases like nitrogen, argon, and helium
Preferably carried out in gas. There are no particular restrictions on the reaction temperature.
There is no fixed temperature, but it is usually carried out at -10℃ or the reflux temperature of the solvent.
It is preferably carried out at around room temperature. During reaction
The time varies depending on the reaction temperature, etc., but it is usually 6 to
50 hours. 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. Also, R¹is 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 involves the reaction of the corresponding compound in an inert solvent.
This is done by contacting with a reducing agent. 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 In addition, the protection reaction of this hydroxyl group was carried out according to a conventional method.
A compound with a corresponding hydroxyl group is used to form a protecting group.
This is done by contacting the compound with the compound.
Examples of compounds that form the protecting group used are
Acetic acid, propionic acid, butyric acid, benzoic acid, naphtha
Carboxylic acids such as phosphocarboxylic acids or
Reactive derivatives; benzyl chloride, benzyl bromine
mido, p-nitrobenzyl bromide, p-methoxy
Aralkyl halides such as shibenzyl bromide
Compound; dihydropyran, dihydrothiopyran,
Dihydrothiophene, 4-methoxy-5,6-di
5- or 6-membered rings such as hydro-(2H)pyran
Heterocyclic compounds such as methoxymethyl chloride,
Toxyethyl chloride, benzyloxymethylchloride
Alkoxy or aralkylo such as lorido
Oxy-substituted alkyl halide compound; methylvinyl
Unsaturated like ether, ethyl vinyl ether
Ethers; hexamethyldisilazane, trimethy
lucilyl chloride, tri-n-propylsilyl chloride
loride, t-butyldimethylsilyl chloride, di
silyl chloride, such as phenyl t-butylsilyl chloride.
Suitable compounds include compounds such as
can. When using carboxylic acid compounds,
In the presence of a condensing agent such as lohexycarbodiimide
This is preferably carried out. 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 corresponding hydroxy compound in sodium hydride
Alkali metal hydrogen such as um, potassium hydride
After reacting with compounds to produce alkali metal salts
, 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
Examples include phoxides, but preferred are ophoxides.
It is a mead. 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, hydroxy compounds and
It is also possible to react with a halide compound.
5- or 6-membered heterocyclic compound or unsaturated ester
When using esters, the reaction is carried out in an inert solvent.
in the presence or absence of a small amount of acid, e.g. hydrochloric acid, odor
Mineral acids such as hydrohydric acid or picric acid, trif
fluoroacetic acid, benzenesulfonic acid, p-toluene
Organics like sulfonic acid, camphor sulfonic acid
Performed in the presence of acid. 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 present, filter it out and make sure the solution is acidic or alkaline.
In the case of water-immiscible organic solvent, neutralize as appropriate.
Obtained by distilling off the solvent after extraction
I can do it. Further, if necessary, use conventional methods, e.g. column
chromatography, thin layer chromatography,
It can be further purified using methods such as recrystallization.
Ru. The fourth step is the end position with the general formula ()
In the process of manufacturing compounds with double bonds, inert
By treating the compound () with an acid in a neutral solvent,
It is achieved by doing so. Examples of acids used include
Inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, acetic acid,
Fluoroacetic acid benzoic acid, methanesulfonic acid, ben
Zenesulfonic acid, p-toluenesulfonic acid, can
Organic acids such as fursulfonic acid can be given.
However, p-toluenesulfonic acid, carbon
It is fluorofuronic acid. Inert solution used
As agents, there are no particular restrictions unless they are involved in the reaction.
However, for example, benzene, toluene, xylene
aromatic hydrocarbons such as ethers, tetrahydrides
Ethers such as lofuran, dioxane, chloride
Chemicals such as methylene, chloroform, and carbon tetrachloride
Rogenated hydrocarbons, acetone, methyl ethyl chloride
Ketones like ton, methanol, ethanol
Alcohols such as alcohol, ethylene glycol,
Water or a mixed solvent of the above solvents can be used.
However, aromatic hydrocarbons are preferred. reaction temperature
The temperature is between 50℃ and 150℃, and the time required for the reaction is generally
Usually 1 to 10 hours. R¹is 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 the same as mentioned above. Indicates the same meaning as . ), the above guarantee is usually applied.
Protecting groups are also removed at the same time. However, Z
[Formula] group or [Formula] group (wherein R¹³ and A have the same meanings as above. ) is
In some cases, the corresponding alcohol forming the protecting group
The reaction is carried out in aromatic hydrocarbons with
The protective group of the carbonyl group was retained by
The main isomerization reaction can also be carried out as is. The fifth step is ketone induction with the general formula ()
In the process of manufacturing compounds, the carbonyl
Removal of the protecting group of the group according to the usual method.
achieved by. 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, R¹hydroxymethyl 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 is replaced with the corresponding one in the third step.
Protect with the desired protecting group in the same manner as the reaction described above.
You can also 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 sixth step is carboxylic acid having the 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, R¹³indicates the same meaning as above and R¹⁴
represents a lower alkoxy group or a halogen atom. )
In reacting with a carbonate derivative having
It is achieved by doing so. 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
um, potassium hydride, and calcium hydride.
can be done. 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 90℃, and the reaction temperature is -20℃ to 90℃.
The time required is 1 hour to 24 hours. The seventh step is hydroxyl having the general formula ()
In the process of manufacturing a compound, the compound () is reduced
This is achieved by doing. 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 hydrogen 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. If the inert solvent used does 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 dioxane
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, at the end of the reaction
After completion, the solvent was distilled off under reduced pressure, and ice water was added to remove water.
Extract with a miscible organic solvent and distill off the organic solvent.
Obtained by. The eighth step is hydroxyl having the general formula ()
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 carried out in the same manner as in the third step.
Ru. 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 9th step is the step of manufacturing the compound (),
Oxidizing the hydroxymethyl group of compound ()
This is accomplished by This reaction oxidizes primary alcohol to aldehyde.
It is carried out according to the usual method. 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-chloro-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 target compound () is prepared according to a conventional method.
taken from the reaction mixture. For example, after the reaction is complete,
If insoluble matter is present, filter it out and add it to ice water.
After neutralization, extract with a water-immiscible organic solvent.
and can be obtained by distilling off the solvent.
Ru. 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. Also, the 1st, 2nd, 4th, 5th, 6th and 8th construction
After the completion of the reaction, the target compound of each reaction is prepared according to the conventional method.
from the reaction mixture. For example, reaction mixture
Pour the mixture into ice water and filter if any insoluble matter is present.
After that, if the solution is acidic or alkaline,
After neutralization and extraction with a water-immiscible organic solvent,
It can be obtained by distilling off the agent. Sara
If necessary, use conventional methods, e.g. column chromatography.
e, thin layer chromatography, recrystallization method, etc.
can be used for further purification. in this way
The target compound obtained by
How many isomers and optical isomer mixtures can be obtained?
In cases where these isomers are
can be separated and divided. The compound () according to the present invention can be prepared by the method shown below.
Therefore, it has an excellent platelet aggregation inhibitory effect, etc.
Can lead to carbacycline derivatives ()
Ru. In the above formula, R¹,R²,R⁶,R⁸, n and dotted line are before
Indicates the same meaning as stated above, R³is a hydrogen atom or
Indicates a protecting group for hydroxyl group, R^Fouris an Alkenia group or
Indicates a cycloalkyl group, R^Fivemay be protected
a hydroxymethyl group or a carboxyl group that may be protected.
Indicates a boxy group, R⁷represents a hydroxyl-protecting group. The 10th step is an unsaturated ketone with the general formula ()
In the process of producing derivatives, having the general formula ()
General formula for aldehyde derivatives (R^Ten)₃P○＋ -C○- HCOR^Four () or general formula (In the formula, R^Four,R^Tenand M have the same meaning as above.
shows. ) with Uitetsuhi or modified Uitetsu
This is achieved by reacting the H reagent. This reaction is expressed by the general formula (R^Ten)₃P○＋ −CH₂−COR^Four.X (′) or general formula (In the formula, R^Four,R^Tenand X have the same meaning as above.
shows. ) using a compound having
It is done in the same way. The 11th step is an alcoholic derivative having the general formula ().
In the process of manufacturing conductors, the compound () is reduced
This is achieved by This reaction is carried out in the same manner as the seventh step. In addition, in the raw material compound () of this step,
R¹is 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 corresponding reaction in the third step.
Ru. The 12th step produces a compound with the general formula ()
A step in which a compound having the general formula ()
This is achieved by protecting the hydroxyl groups of substances. This reaction is similar to the corresponding reaction in the third step above.
It is done. The 13th step is a step that is 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 reaction, 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. In the case of an aralkyl group as a protecting group for a hydroxyl group,
by contacting the compound with a reducing agent in an inert solvent.
This is accomplished by 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 ammonia or with liquid ammonia
Ethers, such as tetrahydrofuran
It is preferably carried out in a mixed solvent with alkali metals.
Reactions with sulfides include methanol and ethanol.
alcohols, tetrahydrofuran, dioxy
ethers such as or a mixture of these organic solvents and water.
It is suitably carried out in a solvent mixture. 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 a methyl group having as an aralkyloxy substituent
or in the case of a 1-alkoxyethyl group, when contacted with an acid.
This can be easily achieved by acid used
For example, formic acid, acetic acid, trifluoroacetic acid,
Propionic acid, butyric acid, oxalic acid, malonic acid, meth
Benzene sulfonic acid, benzene sulfonic acid, p-toluene
Organic compounds such as sulfonic acid and camphorsulfonic acid
Acids; Mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid are preferred.
used. Reactions can occur in the presence or absence of solvent
It is carried out in
It is preferable to use, and the solvent used is
There is no particular limitation as long as it is not involved in this reaction, for example
Water; alcohol such as methanol and ethanol
-Agents 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. The protecting group for the hydroxyl 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
Bases such as carbonates of alkaline earth metals are particularly limited.
used indefinitely. The reaction uses water as a solvent.
If so, no other solvent is required. Use other solvents
For example, tetrahydrofuran, dioxin
Ethers such as san; methanol, ethanol
A mixed solution of organic solvents such as alcohols and water.
agent is used. There is no particular restriction on the reaction temperature.
Usually, it is suitably carried out at room temperature. time required for reaction
The duration ranges from 30 minutes to 5 hours. Also, the protecting group is t-butyl
In the case of tildimethylsilyl group, tetrahydrof
In the presence of ethers such as ethers and dioxane,
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.
Selective deprotection can also be achieved by 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 R³teeth
It needs to be a hydroxyl protecting group. 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-chloro-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
Which is 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 like dioxy, acetone, methyl
Ketones such as ethyl ketone or dimethyl sulfur
Sulfoxides such as phoxide can be given.
can. 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 any insoluble matter is present, filter it out and add it to ice water.
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. The oxidizing agent used is, for example, 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
By adjusting the conditions, alcohol can be
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 calcareous,
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.
Ethanol used in conversion to koxycarbonyl group
Stellifying agents can be used without particular limitation. used
Examples of esterification agents include diazomethane,
Diazoethane, diazo-n-propane, diazoi
Diazoas such as sopropane and diazo-n-butane
Lukans; methanol, ethanol, n-propane
alcohol, isopropyl alcohol, n-butanol
Alcohols and salts that form ester groups such as
acids, mineral acids or methane such as hydrobromic acid or sulfuric acid.
Tansulfonic acid, benzenesulfonic acid or p
-Organic acids such as toluenesulfonic acid; methyl bromide
, lower alkyl halides such as methyl bromide and
Sodium hydroxide, potassium hydroxide, sodium carbonate
Bases such as um are preferably used. Diazoa
When using lucans, the reaction is preferably carried out in the presence of a solvent.
It is done properly. In this reaction as the solvent used
There is no particular limitation as long as it is not involved, for example, ethyl ether.
Ethers such as ether and dioxane are suitable.
Ru. There is no limit to the reaction temperature, but it is necessary to suppress side reactions and
At a relatively low temperature to prevent the decomposition of diazoalkanes.
It is desirable to carry out this procedure, and it is usually carried out under ice cooling.
It will be done. When using alcohols in the presence of acids
Excess alcohol is usually used as a solvent.
be done. The reaction temperature is not particularly limited, but can range from room temperature to
The process is preferably carried out near the reflux temperature of the alcohol used.
be called. The reaction time mainly depends on the reaction temperature, which is used
It takes about 1 hour depending on the type of alcohol.
It will be 2 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 purified product can be 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. Next, examples and reference examples will be given to illustrate the present invention.
Explain in detail. Example 1 3-(4-carboxybutylidene)-7,7-e
ethylenedioxy-cis-bicyclo[3.3.0]o
Coutan 7,7-ethylenedioxy-3-oxo-
Cis-bicyclo[3.3.0]octane (36.0g)
Methyl sulfoxide (400ml) solution was added to triphenate.
Nylphosphine-4-carboxybutyl bromide
(440g) and dimethyl sulfoxide anion
(75.0g of 55% oily sodium hydride and dimethic acid)
prepared from Rusulfoxide (3))
Ylide solution made from methyl sulfoxide solution
and leave it at room temperature under nitrogen atmosphere for 48 hours.
Ru. After the reaction is complete, neutralize with acetic acid and add saturated sodium chloride.
Pour into water and extract with ethyl acetate.
The liquid was washed with saturated saline and then with anhydrous sodium sulfate.
After drying, the solvent was distilled off under reduced pressure to obtain 164.3 g of a residue.
This is subjected to silica gel column chromatography.
By refining the target product as an oily substance,
49.10g was obtained. IR spectrum (Liq) νmaxcm^-1:1710 NMR spectrum (CDCl₃) δ: 3.88 (4H, s,
OCH₂CH₂O), 5.23 (1H, t, J = 6.0Hz, I
Finn-H), 10.36 (1H, s, COOH) Mass spectrum, m/e: 266 (M⁺) Example 2 3-(5-hydroxypentylidene)-7,7-
Ethylenedioxy-cis-bicyclo [3.3.0]
octane 3-(4-carboxybutylidene)-7,7-e
ethylenedioxy-cis-bicyclo[3.3.0]oc
Tan (49.10g) in tetrahydrofuran (150ml)
Cool the solution on ice and add lithium aluminum hydride.
(10.50g) suspended in tetrahydrofuran (675ml)
Add dropwise to the solution, then heat under reflux for 1 hour and 20 minutes. reaction
After finishing, add 4% aqueous sodium hydroxide solution (42ml).
Then, stir at room temperature. Filter the white precipitate that forms.
After evaporation, the filtrate was concentrated under reduced pressure to obtain 46.90 g of residue.
Ru. This item is silica gel column chromatographed.
By refining with E, the target product becomes oily.
40.10g was obtained. IR spectrum (Liq) νmaxcm^-1:3320, 1430,
1330, 1110 NMR spectrum (CDCl₃) δ: 3.81 (4H, s,
OCH₂CH₂O), 5.14 (1H, t, J = 6.0Hz, I
Huynh-H), Mass spectrum, m/e: 252 (M⁺) 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]o
Cutane (10.0g) in dimethylformamide (20
ml) solution in 55% oily sodium hydride under ice-cooling and stirring.
(2.60 g) of dimethylformamide (35 ml)
dropwise into the suspension, then stirred at room temperature for 30 minutes.
Ru. Add benzyl bromide (7.1ml) to this.
Add dropwise at room temperature and stir for 30 minutes. After the reaction is complete,
Pour the reaction solution into ice water 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 22.0 g of the residue.
obtain. This product was subjected to silica gel chromatography.
By refining the target product as an oily substance,
12.30g was obtained. IR spectrum (Liq) νmaxcm^-1:1455, 1330,
1110 NMR spectrum (CDCl₃) δ: 3.47 (2H, t,
J = 6.0Hz, CH₂ CH ₂ OBz), 3.88 (4H, s,
OCH₂CH₂O), 4.48 (2H, s, OCH ₂ Ph), 5.20
(1H, t, J=6.0Hz, Olefin-H), 7.35
(5H, s, aryl-H) 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]
In a solution of octane (17.8g) in benzene (300ml)
p-Toluenesulfonic acid (1.50g) and ethylene
Add Recall (2.9 ml) and remove water azeotropically.
Heat and stir for 2.5 hours. After the reaction is complete, the reaction solution
Washed with water, dried with anhydrous sodium sulfate, and dried under reduced pressure.
The solvent was distilled off to obtain 18.20g of the target product as an oil.
Ta. This product can be used in the next reaction without purification.
Ru. IR spectrum (Liq) νmaxcm^-1:1455, 1320,
1110, 1020 NMR spectrum (CDCl₃) δ: 3.42 (2H, t,
J = 6.0Hz, CH₂ CH ₂ OBz), 3.84 (4H, s,
OCH₂CH₂O), 4.44 (2H, s, OCH ₂ Ph), 5.15
(1H, br, s, olefin-H), 7.28 (5H,
s, aryl-H) Mass spectrum, m/e: 342 (M⁺) Example 5 3-(5-benzyloxypentyl)-7-oxy
sosis-bicyclo [3.3.0] oct-2-ene 3-(5-benzyloxypentyl)-7,7-
Ethylenedioxy-cis-bicyclo[3.3.0]o
Ct-2-ene (6.65g) in acetone (120ml),
Add to a mixture of water (45 ml) and concentrated hydrochloric acid (1.0 ml).
Then, stir at room temperature for 2 hours. After the reaction is complete, carbonic acid
After neutralizing by adding sodium hydrogen, add acetone under reduced pressure.
To leave. Add saturated brine to the residue and add ethyl acetate.
Extract to ester. 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 6.00 g of a residue, which was poured into a silica gel.
Purification by column chromatography
5.33g of the target product was obtained as an oily substance. IR spectrum (Liq) νmaxcm^-1:1725, NMR spectrum (CDCl₃) δ: 3.42 (2H, t,
J=6.0Hz−CH₂CH₂OCH₂Ph) 4.43 (2H, s,
O.C.H ₂Ph), 5.14 (1H, br.s, olefin-H),
4.24 (5H, s, aryl-H) Mass spectrum, m/e: 298 (M⁺) Example 6 3-(5-benzyloxypentyl)-6β-ka
ruboxy-7α-hydroxy-cis-bicyclo
[3.3.0] Oct-2-ene and 3-(5-ben
Zyloxypentyl)-6β-carboxy-7α-
Hydroxy-cis-bicyclo[3.3.0]octo
-3-ene mixture 1,2- of 55% oily sodium hydrogen (1.91 g)
A suspension of 2,6-dimethoxyethane (170 ml)
-Add t-butyl-p-cresol (9.60g)
Stir vigorously for 1 hour at an internal temperature of 40°C. Then the internal temperature
After cooling to 30℃, cool it inside while introducing carbon dioxide gas.
Stir for 30 minutes at 30℃. Cooled to internal temperature 10℃
Then, 7-(5-benzyloxypentyl)-3-o
xo-cis-bicyclo[3.3.0]oct-2-e
(4.32 g) of 1,2-dimethoxyethane (20
ml) solution was added dropwise and stirred for 2 hours at an internal temperature of 10°C.
Next, add sodium borohydride to this product.
(820mg) of t-butyl alcohol (40ml) and water
(13ml) solution was added dropwise and stirred for 1 hour at an internal temperature of 10℃.
Stir. After the reaction is complete, pour the reaction solution into water and add hexane.
The aqueous layer was acidified with 10% hydrochloric acid, and then washed with vinegar.
Extract with acid ethyl ester. Extract is saturated food
After washing with salt water, dry with anhydrous sodium sulfate.
After drying, the solvent was distilled off under reduced pressure to obtain 5.42 g of a residue. child
into silica gel column chromatography
By refining the target product as an oil, 4.28
g was obtained. IR spectrum (Liq) νmaxcm^-1:3350, 1710 NMR spectrum (CDCl₃) δ: 3.49 (2H, t,
J=6.0Hz, CH₂CH ₂OBz), 4.52 (2H, s,
CH₂O.C. _H2 Ph), 7.08 (2H, s, OH, COOH),
7.37 (5H, s, aryl-H) Mass spectrum, m/e: 344 (M⁺) Example 7 3-(5-benzyloxypentyl)-6β-hy
Droxymethyl-7α-(2-tetrahydropyra
Nyloxy)-cis-bicyclo[3.3.0]oct
-2-ene and oct-3ene mixture A mixture of hydroxycarboxylic acids (example 6)
Compound: 4.28g) was dissolved in methylene chloride (10ml).
and dihydropyran (3.4 ml) and a catalytic amount of pyrane.
Add gin hydrochloride and stir at room temperature for 2 hours. Two
This material was cooled on ice and placed in an aluminum lily under hydrogen.
Tetrahydrofuran (300ml) in Tetrahydrofuran (500mg)
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. white precipitate formed
After filtering off the substance, the filtrate was concentrated under reduced pressure to obtain a residue of 7.60
get g. Apply this to silica gel column chromatography
The target product becomes oily by refining it with Graphee.
4.840g of product was obtained. IR spectrum (Liq) νmaxcm^-1:3430, 1455,
1120 NMR spectrum (CDCl₃) δ: 3.47 (2H, t,
J=6.0Hz, CH₂CH ₂OBz), 4.53 (2H, s, OC
H ₂ Ph), 5.30 (1H, br.s, olefin-H),
7.37 (5H, s, aryl-H) Mass spectrum, m/e: 414 (M ⁺ ) Example 8 3-(5-benzyloxypentyl)-6β-formyl-7α-(2-tetrahydropyranyloxy)- Mixture of cis-bicyclo[3.3.0]oct-2-ene and oct-3-ene Mixture of alcohols (compound of 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 for the next reaction without being purified. IR spectrum (Liq) νmaxcm ^-1 : 1725 NMR spectrum (CDCl ₃ ) δ: 4.45 (2H, s,
OC H ₂ Ph), 5.23 (1H, br.s, olefin-H),
7.26 (5H, s, aryl-H), 9.68 (1H, t,
J=4.0Hz, CHO) Example 9 3-(5-benzyloxypentyl)-6β-ethoxycarbonyl-7-oxo-cis-bicyclo[3.3.0]oct-2-ene and oct-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 solution of 150 mg of 3-(5benzyloxypentyl)-7-oxo-cis-bicyclo[3.3.0]oct-2-ene (compound of Example 5) in dioxane (3 ml) was added dropwise to the reaction mixture.
After dropping, the reaction was carried out for 1 hour at an external temperature of 90°C.
A solvent 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 chromatography. 72mg from hexane outflow containing 3% ethyl acetate
An oily oct-2-ene is obtained, followed by 5
% ethyl acetate-containing hexane, 57 mg of oily oct-3-ene compound was obtained. Oct-2-ene: IR spectrum (Liq) νmaxcm ^-1 : 698, 735,
1620, 1657, 1725, 1753, Oct-3-ene: IR spectrum (Liq) νmaxcm ^-1 : 698, 735,
1620, 1658, 1723, 1751 Example 10 3-(5-benzyloxypentyl)-6β-ethoxycarbonyl-7α-hydroxy-cis-
Bicyclo[3.3.0]oct-2-ene 6β-ethoxycarbonyl oct-2-ene compound (compound of Example 9: 62 mg) was dissolved in 3 ml of ethanol, and heated at -40 to -20°C with sodium borohydride.
50 mg 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. Wash the extract with water,
After drying, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography to yield 48 mg.
The desired oily compound was obtained. IR spectrum (Liq) νmaxcm ^-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) Example 11 3-(5-benzyloxypentyl)-6β-ethoxycarbonyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene hydroxy form (Example 10 Dihydropyran (0.3 ml) was added to a methylene chloride solution (1 ml) of the compound (47 mg), and a catalytic amount of p-toluenesulfonic acid was added under ice cooling, and the mixture was reacted 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. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel to obtain 55 mg of the target compound as an oil. IR spectrum (Liq) νmaxcm ^-1 : 699, 738,
977, 1028, 1039, 1730. Example 12 3-(5-benzyloxypentyl)-6β-hydroxymethyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene To an ether solution (5 ml) of the pyranyl compound (compound of Example 11: 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. The precipitate is collected by filtration and the filtrate is concentrated. 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) νmaxcm ^-1 : 1120, 1455,
3430 NMR spectrum (CDCl ₃ ) δ: 3.47 (2H, t),
4.53 (2H, s), 5.30 (1H, br.s), 7.37 (5H,
s) Example 13 3-(5-benzyloxypentyl)-6β-holomyl-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene 3-(5-benzyloxypentyl)- To a solution of 6β-hydroxymethyl-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene (1.06 g) in dimethyl sulfoxide (8 ml) is added 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. The extract was washed with water, dried over anhydrous sodium sulfate, and 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) νmaxcm ^-1 : 1725 NMR spectrum (CDCl ₃ ) 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) Example 14 3-(5-benzyloxypentyl) -7,7-
Ethylenedioxy-3-hydroxy-cis-bicyclo[3.3.0]octane 5-benzyleoxypentyl bromide 1.00
g [The method of AWBurgstahler et al. (J.Org.Chem.,
42, 566 (1977). 5-benzyloxypentamethylenemagnesium bromide prepared from pentamethylene bromide and benzyl alcohol] and metallic magnesium (100 mg) in diethyl ether (5 ml) was added to 5-benzyloxypentamethylene magnesium bromide at room temperature. Oxy-3-oxo-cis-
A solution of bicyclo[3.3.0]octane (501 mg) in diethyl ether (5 ml) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. After the reaction is 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) νmaxcm ^-1 : 3480, 1470,
1330, 1110 NMR spectrum (CDCl ₃ ) δ: 3.47 (2H, t,
J=6.0Hz, CH ₂ C H ₂ OBz), 3.91 (4H, s,
OCH ₂ CH ₂ O), 4.52 (2H, s, OCH ₂ Ph), 7.36
(5H, s, aryl-H) mass spectrum, m/e: 360 (M ⁺ ), 342 (M -
18) Example 15 3-(5-benzyloxypentyl)-7,7-
Ethylenedioxy-cis-bicyclo [3.3.0]
Oct-2-ene 3-(5-benzyloxypentyl)-7,7-
Ethylene glycol (0.05 ml) and p-toluenesulfonic acid (10 mg) were added to a solution of ethylene dioxy-3-hydroxy-cis-bicyclo[3.3.0] octane (209 mg) in benzene (2 ml), and the water was azeotroped. Heat and stir for 3.5 hours while removing. After the reaction was completed, the reaction solution was neutralized with a 5% aqueous sodium bicarbonate solution, 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 column chromatography to obtain 142 mg of the desired product as an oil. IR spectrum (Liq) νmaxcm ^-1 : 1445, 1320,
1100, 1020 NMR spectrum (CDCl ₃ ) δ: 3.42 (2H, t,
J=6.0Hz, CH ₂ C H ₂ OBz), 3.84 (4H, s,
OCH ₂ CH ₂ O), 4.44 (2Hs, OCH ₂ Ph), 5.15
(1H, br.s, olefin-H), 7.28 (5H, s,
Aryl-H). Mass spectrum, m/e: 342 (M ⁺ ) Example 16 3-(5-hydroxypentyl)-7,7-ethylenedioxy-cis-bicyclo[3.3.0]oct-2-ene Compound of Example 15 (1.20g), Reference Example 1d
When the reaction was carried out in the same manner as above, 0.67 g of the desired oily compound was obtained. IR spectrum (Liq) νmaxcm ^-1 : 3350 NMR spectrum (CDCl ₃ ) δ: 3.85 (4H, s,
OCH ₂ CH ₂ O), 5.15 (1H, br.s, = CH-) When this compound is treated with 10% hydrochloric acid/acetone (3:7), the corresponding ketone form (IR spectrum:
3350, 1725cm ^-1 ). Example 17 3-(4-methoxycarbonylbutyl)-7,7
-ethylenedioxy-cis-bicyclo[3.3.0]
Oct-2-ene Dissolve 1.56 g of 3-(4-hydroxypentyl)-7,7-ethylenedioxy-cis-bicyclo[3.3.0]oct-2-ene in 45 ml 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 ethyl acetate is extracted. 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) νmaxcm ^-1 : 1725 NMR spectrum (CDCl ₃ ) δ: 3.63 (3H, s,
COOCH ₃ ), 3.84 (4H, s, OCH ₂ CH ₂ O), 5.15
(1H,br.s,=CH-) Example 18 3-(4-methoxycarbonylbutyl)-6β-
Formyl-7α-(2-tetrahydropyranyloxy)-cis-bicyclo-[3.3.0]oct-2
-ene and oct-3-ene The carboxylic acid prepared according to the first part of Example 17 was treated in the same manner as in Example 5 to remove the protecting group of the carbonyl group, and dimethyl carbonate was used to treat the carboxylic acid prepared according to the first part of Example 17. The reaction was carried out in the same manner as in Example 10 to perform methoxycarbonylation, and then the reduction reaction was carried out in the same manner as in Example 10.
The hydroxyl group of the alcohol of the resulting mixture of 2-ene and 3-ene was reacted in the same manner as in Example 11, treated with water instead of aqueous sodium bicarbonate, and then treated with a slight excess of lithium aluminum hydride. 3-(4-methoxycarbonylbutyl)-6β-hydroxymethyl-7α obtained by reacting in the same manner as above, post-treating with weak acidity, and esterifying with diazomethane.
-(2-tetrahydropyranyloxy)-cis-bicyclo-[3.3.0]oct-2-ene and oct-
Using 165 mg of the 3-ene mixture, the reaction was carried out in the same manner as in Example 8 to obtain 163 mg of the crude target compound. IR spectrum (Liq) νmaxcm ^-1 : 2700, 1735,
1030, 1020 Example 19 3-(methoxycarbonylmethylidene)-7,7
-ethylenedioxy-cis-bicyclo-
[3.3.0] Octane After washing 14.19 g of 55% oily sodium hydrogen with hexane, 1.8 g of dimethoxyethane was added.
To this suspension, 74.02 g of trimethylphosphonoacetate was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Next, a solution of 74 g of 3-oxo-7,7-ethylenedioxy-cis-bicyclo-[3.3.0]octane in dimethoxyethane (370 ml) was added dropwise to the reaction solution for 10 minutes at room temperature.
Stir for hours. After the reaction is complete, acetic acid and saturated brine are added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is washed with saturated saline and dried with sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain 75 g of the target compound as an oil. IR spectrum (Liq) νmaxcm ^-1 : 730, 878,
1028, 1130, 1367, 1440, 1660, 1720, 2900,
2960 Example 20 3-(methoxycarbonylmethyl)-7,7-ethylenedioxy-cis-bicyclo-[3.3.0]oct-2-ene ester (compound of Example 19: 15.26 g) was added to Example 4 Similarly, treatment with p-toluenesulfonic acid gave 15.05 g of the desired compound as an oil. IR spectrum (Liq) νmaxcm ^-1 : 730, 800,
953, 1110, 1240, 1330, 1440, 1743, 2900,
2970 Example 21 3-(2-Hydroxyethyl)-7,7-ethylenedioxy-cis-bicyl-[3.3.0]oct-2-ene Suspension of lithium aluminum hydride (3.57 g) in ether (250 ml) An ether solution (125 ml) of the ester (compound of Example 20: 14.96 g) was added dropwise to the solution at -3 to 8°C. After stirring for 25 minutes, add 4 to the reaction solution.
% caustic soda water (15 ml) was added and stirred for 60 minutes. The precipitate is collected by filtration, the filtrate is concentrated, and the resulting residue is purified by silica gel column chromatography.
12.42 g of the desired oily compound was obtained. IR spectrum (Liq) νmaxcm ^-1 : 722, 795,
950, 985, 1045, 1110, 1330, 1432, 1480,
2900, 3450 Example 22 3-(2-hydroxyethyl)-7-oxo-cis-bicyclo-[3.3.0]oct-2-ene 7,7-ethylenedioxy-3-(2-hydroxyethylene)- A solution of cis-bicyclo[3.3.0]oct-2-ene (3.00 g) in a mixture of acetone (30 ml) and water (12 ml) was added with concentrated hydrochloric acid (0.5 g).
ml) and stirred at room temperature for 1 hour. After the reaction is completed, saturated brine is added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
2.61 g of the obtained residue was purified by silica gel column chromatography to obtain 1.97 g of the target product as an oily substance. IR spectrum (Liq) νmaxcm ^-1 : 1047, 1400,
1740, 2850, 2900, 3430 Example 23 3-(2-dimethyl-t-butylsilyloxyethyl)-7-oxo-cis-bicyclo-
[3.3.0] Oct-2-ene 3-(2-hydroxyethyl)-7-oxo-cis-bicyclo-[3.3.0] Oct-2-ene (1.90
g) in dimethylformamide (10 ml), add t
-butyldimethylsilyl chloride (2.58g),
Add imidazole (1.17 g) and 4-dimethylaminopyridine (0.20 g), and stir at room temperature for 30 minutes.
After the reaction is complete, the reaction solution is poured into saturated brine and extracted with ethyl acetate. After washing the extract with saturated saline,
Dry with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue (5.80 g) was purified by silica gel column chromatography to obtain 3.02 g of the desired product as an oily substance. IR spectrum (Liq) νmaxcm ^-1 : 775, 839,
1100, 1257, 1745, 2860, 2900, 2940, 2970 Example 24 3-(2-dimethyl-t-butylsilyloxyethyl)-6β-ethoxycarbonyl-7-oxo-cis-bicyclo-[3.3.0]oct -2-ene and oct-3-ene Under a nitrogen atmosphere, 1,4-dioxane (10 ml) and diethyl carbonate (1 ml) were added to 55% oily sodium hydrogen (200 mg) and heated to an internal temperature of 80°C.
To this, 3-(2-dimethyl-t-butylsilyloxyethyl)-7-oxo-cis-
A solution of bicyclo[3.3.0]oct-2-ene (157 mg) in 1,4-dioxane (5 ml) was added dropwise, followed by stirring at the same temperature for 30 minutes. After the reaction was completed, the reaction solution was cooled on ice, neutralized with acetic acid, and saturated brine was added.
Extract 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) νmaxcm ^-1 : 775, 838,
1100, 1232, 1252, 1623, 1662, 1730, 1757 Oct-3-ene: IR spectrum (Liq) νmaxcm ^-1 : 778, 838,
1100, 1238, 1258, 1623, 1662, 1728, 1757 Example 25 3-(2-dimethyl-t-butylsilyloxyethyl)-6β-ethoxycarbonyl-7α-hydroxy-cis-bicyclo-[3.3.0]oct -2
Dissolve -ene 6β-ethoxycarbonyloct-2-ene compound (compound of Example 24: 108 mg) in ethyl alcohol (2 ml), add sodium borohydride (50 mg) at -40 to -30°C, and stir for 30 minutes. do. After the reaction is complete, acetic acid and then saturated brine are added, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
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) νmaxcm ^-1 : 775, 840,
1100, 1258, 1730, 3460 Example 26 3-(2-dimethyl-t-butylsilyloxyethyl)-6β-ethoxycarbonyl-7α-(2
-tetrahydropyranyloxy)cis-bicyclo-[3.3.0]oct-2-ene hydroxy compound (compound of Example 25: 95 mg) was dissolved in methylene chloride (2 ml), and 2,3-dihydropyran was added under ice cooling. (0.05 ml) and para-toluenesulfonic acid (2 mg), and stirred for 50 minutes. After the reaction is completed, 5
% sodium bicarbonate water to neutralize, add saturated brine, and extract with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure to obtain a residue. This product was purified by silica gel column chromatography,
110 mg of the target product was obtained as an oily substance. IR spectrum (Liq) νmaxcm ^-1 : 777, 838,
975, 1023, 1039, 1100, 1258, 1730 Example 27 3-(2-dimethyl-t-butylsilyloxyethyl)-6β-hydroxymethyl-7α-(2-
Tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene pyranyl compound (compound of Example 26: 115 mg) is dissolved in 15 ml of methylene chloride. −70 to this solution
0.9 ml of a 20% toluene solution of diisobutylaluminum hydride was added at °C, and the mixture was 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. The solvent was distilled off, and the resulting residue was purified using a silica gel column to obtain 86 mg of the target compound as an oil. IR spectrum (Liq) νmaxcm ^-1 : 780, 840,
982, 1024, 1040, 1100, 1260, 3470 Example 28 3-(2-dimethyl-t-butylsilyloxyethyl)-6β-formyl-7α-(2-tetrahydropyranyloxy)cis-bicyclo-
[3.3.0] Add 2 ml of triethylamine to a dimethyl sulfoxide solution (6 ml) of oct-2-ene hydroxy compound (compound of Example 27: 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 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) νmaxcm ^-1 : 781, 842,
1104, 1262, 1730, 2740 NMR spectrum (CDCl ₃ ) δ: 9.64 (1H, d),
5.28 (1H, brs), 4.58 (1H, br), 0.88 (9H,
s), 0.2 (6H, s) Example 29 3-(2-benzoyloxyethyl)-6β-hydroxymethyl-7α-hydroxy-cis-bicyclo-[3.3.0]oct-2-ene hydroxy form (Example 27 compound: 3.96 g) and dihydropyran (1.24 g), 4.57 g of dipyranyl compound obtained by reaction treatment in the same manner as in Reference Example 1c.
Dissolve in 40 ml of tetrahydrofuran, add 30 ml of room temperature 1M tetrabutylammonium fluoride,
After stirring at room temperature for 30 minutes, add saturated saline,
Extract with ethyl acetate. After drying the extract and distilling off the solvent, it was purified by silica gel column chromatography to obtain 2.11 g of oily alcohol. 2.11g of this alcohol and 15ml of pyridine
1.15 g of benzoyl chloride was added to the solution, and the mixture was left to stand at room temperature for 4 hours, then water was added and extracted with ethyl acetate. After washing the extract with saturated saline, cooled 3% hydrochloric acid, sodium bicarbonate, and then saturated saline,
Dry 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. Dissolve 5.2 g of this benzoyl compound in 52 ml of methanol and add 13 ml of water and 1.3 g of p-toluenesulfonic acid.
Stir at 30-35°C for 1.5 hours. Next, the reaction solution
Dilute with 100 ml of water and extract with ethyl acetate, wash the extract with water, dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure. The resulting crystalline residue is washed and filtered with cyclohexane to obtain 2.8 g of the target compound. Ta. IR spectrum (KBr) νmaxcm ^-1 : 1080, 1120,
1280, 1715, 3220 NMR spectrum (CDCl ₃ ) δ: 4.43 (2H, t),
5.46 (1H, s), 7.48 (3H, m), 8.05 (2H, m) Example 30 3-(2-benzoyloxyethyl)-6β-hydroxymethyl-7α-(2-tetrahydropyranyloxy)-cis -Bicyclo-[3.3.0]oct-2-ene dihydroxy form (compound of Example 29) 3.0 g and triethylamine 2.61 ml were dissolved in benzene 60 ml, and under ice cooling and stirring, trichloroacetyl chloride 1.16 ml was added to the benzene. Dissolve in 30ml, 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. 50% of this residue
3.05 g of mono-trichloroacetyl compound was obtained by purification by column chromatography using silica gel. 3.05g of mono-trichloroacetyl compound and 2,3-
Dissolve 0.93 ml of dihydropyran in 10 ml of methylene chloride and add a small amount of p-toluenesulfonic acid.
Stir for 10 minutes at room temperature. 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 sequentially 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. The target compound was obtained. IR spectrum (Liq) νmaxcm ^-1 : 970, 1020,
1070, 1110, 1270, 1600, 1715, 3420 Example 31 3-(2-benzoyloxyethyl)-6β-formyl-7α-(2-tetrahydropyranyloxy)cis-bicyclo-[3.3.0]octo-2 2.50 g of the -ene hydroxy compound (compound of Example 30) was dissolved in 25 ml of dimethyl sulfoxide, 8.97 ml of triethylamine was added thereto, and the sulfur-ene hydroxy compound (compound of Example 30) was dissolved under stirring at 20°C.
Dissolve 5.15 g of trioxide-pyridine complex in 17 ml of dimethyl sulfoxide and dropwise add
Stir for a minute. The reaction solution was diluted with ice water and 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) νmaxcm ^-1 : 715, 975,
1030, 1120, 1280, 1720 NMR spectrum (CDCl ₃ ) δ: 4.64 (1H, s),
5.46 (1H, s), 9.78 (1H, d) Reference example 1 3-(4-carboxybutyl)-6β-(3α-hydroxy-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)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene 0.41 g of oily The oil content of sodium under hydrogen
-After washing with hexane, 60ml of tetrahydrofuran
and 2.70 g of dimethyl 2-oxo-3-methyl-7-octenylphosphonate were added and stirred for 30 minutes. Next, 3.24 g of the aldehyde obtained in Example 8
Dissolve in 20ml of tetrahydrofuran and add.
Stir for 30 minutes at room temperature. The reaction solution was diluted with ice water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography using silica gel (95.7 g). By subjecting the mixture to e.g., 3.74 g of the desired oily compound was obtained. IR spectrum (Liq) νmaxcm ^-1 : 1624, 1670,
1696 NMR spectrum (CDCl ₃ ) δ: 1.09 (3H, d,
J=7.2Hz, _-CH3 )3.47(2H,t,J=7.0
Hz, CH ₂ CH ₂ OBz), 4.51 (2H, s, O CH ₂
Ph), 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, olefin-H)
H), 7.35(5H,s,aryl-H) (1b) 3-(5-benzyloxypentyl)-6β-
(3α-hydroxy-4-methylnona-1,8-
mixtures of dienyl)-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene and their
A methyl alcohol solution (25 ml) of the enone form obtained from 6β-(3β-hydroxy-)isomer (1a) (3.70 g) was added to a methyl alcohol solution (30 ml) of cesium chloride heptahydrate (3.1 g) under ice cooling.
in addition to sodium borohydride (393
mg). After stirring for 30 minutes at an internal temperature of 5 to 10°C, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off, leaving a residue of 3.90
get g. By purifying with silica gel column chromatography,
1.22 g of target compound [6β-(3β-hydroxy)-
isomer] and the more polar part of the target compound [6β-(3α-biloxy)-isomer]
were obtained as oils. 6β-(3α-hydroxy-)isomer: IR spectrum (Liq) νmaxcm ^-1 : 1024, 1120,
1454, 1642, 3460 NMR spectrum ( _CDCl3 ) δ: 0.83~0.97
(3H, m, −CH ₃ )3.47 (2H, t, J=7.0Hz,
CH ₂ CH ₂ OBz), 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) νmaxcm ^-1 : 1023, 1120,
1454, 1642, 3460 NMR spectrum (CDCl ₃ ) δ: 0.90 (3H, m,
CH ₃ ) 3.47 (2H, t, J = 7Hz, CH ₂ HC ₂
OBz), 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, -CH=),
5.47-6.20 (3H, m, olefin-H) (1c) 3-(5-benzyloxypentyl)-6β-
[3α-(2-tetrahydropyranyloxy)-4
-Methyl-nona-1,8-dienyl]-7α-
(2-tetrahydropyranyloxy)bicyclo[3.3.0]The alcohol compound (2.02 g) obtained from the mixture (1b) of oct-2-ene and oct-3-ene was dissolved in methylene chloride (20 ml), and While cooling, 2,3-dihydropyran (0.62 ml) and a catalytic amount of p-toluenesulfonic acid were added, and the mixture was stirred at an internal temperature of 2°C for 1 hour. After the reaction is completed, the mixture is neutralized with a 5% aqueous sodium bicarbonate solution, saturated brine is added, and the mixture is extracted with ethyl acetate. The acetic acid ethyl ester extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.90 g of a residue. This product was purified by silica gel column chromatography to obtain 2.09 g of the desired product as an oil. IR spectrum (Liq) νmaxcm ^-1 : 1018, 1120,
1198, 1450, 1638 NMR spectrum ( _CDCl3 ) δ: 0.80~1.03
(3H, m, −CH ₃ )3.47 (2H, t, J=7.0Hz,
CH ₂ CH ₂ OBz), 4.52 (2H, s, CH ₂ OPh),
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-methylnona-1,8-dienyl)-7α-(2-tetrahydropyranyloxy)bicyclo [3.3.0]
Mixture of oct-2-ene and oct-3-ene Under a nitrogen atmosphere at an internal temperature of -70°C, the benzylpyranyl compound (2.07 g) obtained in (1c) was mixed with liquid ammonia (40 ml) and tetrahydrofuran (30 ml). When excess sodium metal is added to a solution of , the solution takes on a dark blue color. After stirring for 30 minutes at -70°C, a large excess of ammonium chloride was added.
Then, the temperature was returned to room temperature, ammonia was distilled off, water was added to the residue, extracted with diethyl ether, the extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. residue 2.00
This product was purified by silica gel column chromatography to obtain 1.53 g of the desired product as an oil. IR spectrum (Liq) νmaxcm ^-1 : 1642, 3450 NMR spectrum ( _CDCl3 ) δ: 0.80~1.01
(3H, m, −CH ₃ ) 3.30 to 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-methylnona-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]
Acetate of alcohol (1.51g) obtained from mixture (1d) of oct-2-ene and oct-3-ene
2.8 ml of Jones reagent (prepared by diluting 26.7 g of chromic anhydride and 23 ml of concentrated sulfuric acid with water to make a total of 100 ml) was added dropwise to the 175 ml solution at an internal temperature of -25°C, and the mixture was stirred at the same temperature for 1 hour. After the reaction is completed, the mixture is neutralized with a 5% aqueous sodium hydrogen carbonate solution, and acetate is distilled off under reduced pressure. Water was added to the residue and extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.63 g of a residue. This product was purified by silica gel column chromatography to obtain 1.30 g of the target product as an oil.
obtain. IR spectrum (Liq) νmaxcm ^-1 : 1638, 1708,
1732 NMR spectrum ( _CDCl3 ) δ: 0.80~1.01
(3H, m, −CH ₃ ), 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-hydroxy-4-methylnona-18-dienyl)-
7α-hydroxybicyclo[3.3.0]octo-2
In a solution of 0.52 g of the tetrahydropyranyl compound obtained from the mixture (1e) of -ene and oct-3-ene in acetone (15.6 ml) and water (8 ml), d
- Add camphorsulfonic acid (28 ml) and stir at an internal temperature of 40-45°C for 2 hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to leave a residue of 460
Get mg. This product is purified by silica gel column chromatography to obtain 250 mg of the desired product as an oil. IR spectrum (Liq) νmaxcm ^-1 : 1640, 1708,
3340 NMR spectrum (CDCl ₃ ) δ: 0.90 (3H, m,
CH ₃ ), 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) Reference example 2 3-(4-carboxybutyl)-6β-(3α-hydroxy-5(R), 9-dimethyl-1,8decadienyl) -7α-Hydroxybicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene (2a) 3-(5-benzyloxypentyl)-6β-
(3-oxo-5(R), 9-dimethyl-1,8
-decadienyl)-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2
-ene and oct-3-ene mixture Crude aldehyde (compound of Example 8: 3.05 g)
and dimethyl 2-oxo-4(R), 8-dimethylnona-1,8-dienylphosphonate were treated in the same manner as in Reference Example 1a to obtain 3.50 g of the target compound as an oil. IR spectrum (Liq) νmaxcm ^-1 : 1625, 1670,
1695 NMR spectrum (CDCl ₃ ) δ: 0.89 (3H, d,
J = 7Hz, CH ₃ ) 3.48 (2H, t, CH ₂
OCH ₂ Ph), 4.50 (2H, s, CH ₂ Ph) 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)-α-hydroxybicyclo[3.3.0]oct-2-ene and oct-
A mixture of 3-enes and their 6β-(3β-hydroxy-)isomers A corresponding hydroxy compound is obtained by using a ketone (compound of Reference Example 2a: 3.50 g) and reacting in the same manner as in Reference Example 1b. This compound gives a 3-spot on thin layer chromatography, so it was dissolved in 50 ml of acetic acid without purification, and 30 ml of water and 20 ml of tetrahydrofuran (THF) were added.
Stirred at ℃ for 2.5 hours. During that time, 15 ml of water was added. After the reaction is completed, an aqueous solution of sodium hydroxide (40 g) 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 column chromatography using silica gel. 1.15 g of oily 6β-(3β-hydroxy) compound (2 spots determined by thin layer chromatography) was obtained from the 20-25% ethyl acetate/n-hexane outflow. 30-50% ethyl acetate/n
-1.54g of oily 6β-(3α
-hydroxy) form (2 spots by thin layer chromatography) was obtained. 6β-(3β-hydroxy) form: IR spectrum (Liq) νmaxcm ^-1 : 3370 NMR spectrum (CDCl ₃ ) δ: 0.90 (3H, d,
CH ₃ ) 1.60 (3H, s, CH ₃ ), 1.68 (3H, s,
CH ₃ ) 3.45 (2H, t, -CH ₂ O-), 4.50 (2H, s,
CH ₂ O−), 5.10 (H, t, = CH−), 5.28
(1H, br.s, = CH−), 5.60 (2H, m, −CH=
CH-) 6β-(3α-hydroxy) form: IR spectrum (Liq) νmaxcm ^-1 : 3360, NMR spectrum ( _CDCl3 ) δ: 0.90 (3H, m,
CH ₃ ) 1.60 (3H, s, CH ₃ ), 1.65 (3H, s, CH ₃ ) 3.50 (2H, t, 6Hz, -CH ₂ O-), 4.50 (2H,
s, -CH ₂ O-), 5.12 (1H, br.t, = CH-),
5.28 (1H, br.s, = CH-) 5.50 (2H, m, -
CH=CH-) (2c) 3-(5-benzyloxypentyl)-6β-
[3α-(2-tetrahydropyranyloxy)-5
(R),9-dimethyl-1,8-decadienyl]
-7α-(2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene mixture Using alcohol (6β-(3α-hydroxy) form of Reference Example 2b: 1.50 g) When the reaction was carried out in the same manner as in Reference Example 1c, 2.10 g of the target compound was obtained as an oil. IR spectrum (Liq) νmaxcm ^-1 : 1022, 1035 NMR spectrum (CDCl ₃ ) δ: 0.90 (3H, m,
CH ₃ ) 3.46 (2H, t, -CH ₂ O-), 4.50 (2H,
s, -CH ₂ O-) 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-
A mixture of (2-tetrahydropyranyloxy)bicyclo[3.3.0]oct-2-ene and oct-3-ene When the benzylic compound (2.10 g of the compound of Reference Example 2C) is reacted in the same manner as in Reference Example 1d, 1.46 g of the target compound in the form of an oil was obtained. IR spectrum (Liq) νmaxcm ^-1 : 3350 NMR spectrum (CDCl ₃ ) δ: 0.92 (3H, m,
CH ₃ ), 2.63 (3H, s, CH ₃ ), 2.69 (3H, s,
CH ₃ ), 3.64 (2H, t, −CH ₂ O−) 4.82 (2H, br.s, [formula]), 5.0 to 5.8 (4H, m, = CH = × 4) (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 Reference Example 2b: 1.20g)
When treated in the same manner as in Reference Example 1e, 737mg was obtained.
The desired oily compound was obtained. IR spectrum (Liq) νmaxcm ^-1 : 1735, 1710 NMR spectrum (CDCl ₃ ) δ: 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) (2f) 3-(4-carboxybutyl)-6β-(3α-hydroxy-5( R),9-dimethyl-1,8-decadienyl)-7α-hydroxybicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene For reference using pyranyl compound (compound of Reference Example 2e: 730 mg) The reaction was carried out in the same manner as in Example 1f to obtain 394 mg of the target compound in the form of an oil. IR spectrum (Liq) νmaxcm ^-1 : 3350, 1710 NMR spectrum (CDCl ₃ ) δ: 0.91 (3H, m,
CH ₃ ) 1.62 (3H, S, CH ₃ ), 1.70 (3H, s,
CH ₃ ) 3.72 (1H, m, CHOH), 4.15 (1H,
m, CHOH) 5.11 (1H, t, = CH-),
5.34 (1H, br.s, = CH-) 5.50 (2H, m, -
CH=CH−) When treated with diazomethane, this compound readily transforms into the corresponding methyl ester (IR spectrum:
1725cm ^-1 ). Reference example 3 3-(5-hydroxybentyl)-6β-(3α-hydroxy-5(R),9-dimethyl-1,8-decadienyl)-7α-hydroxybicyclo[3.3.0]oct-2-ene A mixture of oct-3-ene and pyranyl compound (compound of Reference Example 2d: 250 mg) was reacted in the same manner as in Reference Example 1f to obtain 121 mg of the target compound in the form of an oil. This compound showed 2 spots on thin layer chromatography. IR spectrum (CHCl ₃ ) νmaxcm ^-1 : 3370, 975 NMR spectrum (CDCl ₃ ) δ: 0.91 (3H, d,
CH ₃ ), 1.59 (3H, s, CH ₃ ) 1.66 (3H, s,
CH ₃ ), 5.02 (1H, t, = CH−) 5.19 (1H, br.s,
=CH-), 5.40 (2H, m, -CH=CH-) Reference example 4 3-(4-carboxybutyl)-6β-(3α-hydroxy-3-cyclopentyl-1-propenyl)-7α-hydroxy-cis -Bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene (4a) 3-(5-benzyloxypentyl)-6β-
(3-oxo-3-cyclopentyl-1-propenyl)-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-
Mixture of ene and 3-ene 0.41 g of 55% oily sodium hydride
- After washing with hexane, tetrahydrofuran 60
ml and 2.39 g of dimethyl (2-oxo-2-cyclopentylethyl)-phosphonate and stirred for 30 minutes. Next, 3.05 g of the aldehyde obtained in Example 8 was dissolved in 20 ml of tetrahydrofuran, added and stirred at room temperature for 30 minutes. The reaction solution was diluted with ice water and extracted with ethyl acetate. The extract was washed with water, dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain the target compound 3.50. I got g. IR spectrum (Liq) νmaxcm ^-1 : 1030, 1120,
1626, 1693 NMR spectrum (CDCl ₃ ) δ: 3.48 (2H, t,
J=6Hz, _-CH2OBz )4.52(2H,s,-O
CH ₂ Ph) 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-
propenyl)-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octo-
Mixture of 2-ene and 3-ene The enone compound (compound of Reference Example 4a: 3.40g) was treated in the same manner as in Example 1b to obtain 1.91g of the target compound.
1.07 g of 6β-(3β-hydroxy) compound was obtained. IR spectrum (Liq) νmaxcm ^-1 : 1025, 1075,
1120, 3450 NMR spectrum (CDCl ₃ ) δ: 3.47 (2H, t,
J=6Hz, _-CH2OBz )4.52(2H,s,-O
CH ₂ Ph), 4.70 (1H, br.s,
[Formula]), 5.28 (1H, br.s, olefin-H), 5.65 (2H, m, olefin-H), 5.65 (2H, m, olefin-H),
H), 7.36 (5H,s,aryl-H) Mass spectrum, m/e: 406 (M-102) (4c) 3-(5-benzyloxypentyl)-6β-
[3α-(2-tetrahydropyranyloxy)-3
-cyclopentyl-1-propenyl]-7α-
(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]oct-2-ene and oct-
3-ene mixture hydroxy form (compound of Reference Example 4b: 1.85g)
was treated in the same manner as in Reference Example 1c to obtain 2.18 g of the target compound. IR spectrum (Liq) νmaxcm ^-1 : 978,
10231078, 1120 NMR spectrum (CDCl ₃ ) δ: 3.46 (2H, t,
J=6Hz, _-CH2OBz ), 4.51(2H,s,-O
CH ₂ Ph), 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-cyclopentyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene The benzylic compound (compound of Reference Example 4c: 2.12 g) was treated in the same manner as in Reference Example 1d to obtain 1.50 g of the target compound. IR spectrum (Liq) νmaxcm ^-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-cyclopentyl-1-propenyl]-7α-(2-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene Hydroxy form (compound of Reference Example 4d: 1.36g)
By processing in the same manner as Reference Example 1e, 0.7g
The desired compound was obtained. IR spectrum (Liq) νmaxcm ^-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- mixture of oct-2-ene and oct-3-ene Dipyranyl compound (reference example) 4e compound: 0.57g)
was treated in the same manner as in Reference Example 1f, and the resulting residue was recrystallized from ethyl acetate and n-hexane to obtain the target compound having a melting point of 104 to 106.5°C.
0.17g was obtained. IR spectrum (KBr) νmaxcm ^-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) Reference example 5 3-(5-hydroxypentyl)-6β-(3α-hydroxy-3-cyclopentyl-1-propenyl)-7α-hydroxy-cis-bicyclo[3.3.0]oct-2-ene A mixture of dipyranyl compound (compound of Reference Example 4d: 0.30 g) of 0.13 g of the target compound having a temperature of ~110°C was obtained. IR spectrum (KBr) νmaxcm ^-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 (M
-36) Reference example 6 3-(2-hydroxyethyl)-6β-[3α-(2
-tetrahydropyranyloxy)-5(R),9
-dimethyl-deca-1,8-dienyl]-7α-
(2-Tetrahydropyranyloxy)bicyclo[3.3.0]Mixture of oct-2-ene and oct-3-ene (6a) 3-(methoxycarbonylmethyl)-6β-[3α
-(2-tetrahydropyranyloxy)-5
(R),9-dimethyl-deca-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)
Bicyclo[3.3.0] Mixture of oct-2-ene and oct-3-ene 3-methoxycarbonylmethylidene-6β-
[3α-(2-tetrahydropyranyloxy)-5
(R),9-dimethyl-deca-1,8-dienyl]-7α-(2-tetrahydropyranyloxy)
Dissolve 1.95 g of bicyclo[3.3.0]octane in tetrahydrofuran (5 ml) and heat the mixture at -60°C with diisopropylaminolithium (diisopropylamine).
A 10 ml solution of 935 mg of 15% n-butyllithium (prepared from 5.43 ml of a 15% n-hexane solution and 1.6 ml of hexanemethylphosphoryltriamide) in tetrahydrofuran was added. After reacting at the same temperature for 1 hour, the mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. After drying the extract over sodium sulfate, the solvent was distilled off and purified by column chromatography to obtain 1.30 g of the target compound.
Obtained. IR spectrum (Liq) νmaxcm ^-1 : 1737 NMR spectrum (CDCl ₃ ) δ: 0.92 (3H, m,
CH ₃ ), 0.62 (3H, s, CH ₃ ), 0.68 (3H, s,
CH ₃ ), 3.10 (2H, s, -CH ₂ -) 3.69 (3H,
s, COOMe), 4.82 (2H, br.s,
[Formula]), 5.12 (1H, t, = CH -), 5.3 to 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)bicyclo[3.3.0]oct-2-ene and oct-3
-Ene mixture Ester form (compound of Reference Example 6a: 510 mg) is dissolved in 20 ml of ether, and 500 mg of lithium aluminum hydride is added under ice cooling. After 1 hour, 2 ml of 4% caustic soda water was added and stirred, the precipitate was filtered off, and the filtrate was concentrated to give an oily residue. Purification by silica gel column chromatography
430 mg of oily target compound was obtained. IR spectrum (Liq) νmaxcm ^-1 : 3350 NMR spectrum (CDCl ₃ ) δ: 0.91 (3H, m,
CH ₃ ), 2.62 (3H, s, CH ₃ ), 2.69 (3H, s,
CH ₃ ), 4.80 (2H, br.s,
[Formula]), 5.0 to 5.8 (4H, m, = CH−×4)

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents an optionally protected hydroxymethyl group or an optionally protected carboxy group,
R ² represents a hydrogen atom or a hydroxyl group-protecting group, n represents an integer of 1 to 6, and the dotted line represents a double bond at the 2- or 3-position. ) is a carbacycline plastid intermediate.