JPS5852991B2 - Method for producing cyclopentane derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [wherein R is hydrogen or lower alkyl; R1 is hydrogen, lower alkyl, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl or the group -C-CH2 -X-CH31; R4 is hydrogen, lower alkyl or fluorine, R5 is hydrogen or lower alkyl, and the dotted bond can be hydrogenated; provided that when R4 and R5 are both hydrogen, R1 is lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl or the group -C-(I
The present invention relates to a novel cyclobencune derivative, as well as enantiomers and racemates thereof.

A particular subgroup of novel cyclopenkune derivatives of formula I are those in which each symbol also represents: R is hydrogen, R is hydroxymethyl or lower alkoxymethyl, and the dotted bond is hydrogenated. Not yet.

When R1 in a compound of formula I is hydroxymethyl or lower alkoxymethyl, preferred compounds are those in which at least one of R4 and R6 is other than hydrogen.

When R1 in a compound of formula I is lower alkoxycarbonyl, suitable compounds are those in which at least one of R4 and R6 is other than hydrogen.

Preferred compounds of formula I are nia-(5ct-hydroxy-2β-(3G-hydroxy4-fluoro-1-trans-octenyl)-1α-
Cyclopentyl-iosis-5-heptenoic acid (hepte)
noic acid) near-(3α-(methylsulfinyl acetyl)-5a-hydroxy-2β-(3α-
Methyl 7-(3α-(methylsulfinyl acetyl)-
5α-hydroxy-2β-(3α-hydroxy-1-trans-octenyl)-1α-cyclopentyliosis-5-heptenoate; 7-(3α-hydroxymethyl-5α-hydroxy-2β-(3α-hydroxy-1-
4lans-octenyl)-1α-cyclopentyl]-hebutenoic acid (ll-homo-prostaglandin F1a);
7-(3α-methoxycarbonyl-5α-hydroxy-
2β-(4,4-dimethyl-3α-hydroxy-1-trans-octenyl)-1-〇-cyclopentyl]-cis-5-heptenoic acid; Methyl 7-(3α-methoxycarbonyl-50-hydroxy-2β-(3α -Hydroxy-1-transoctenyl)-1α-cyclopentyliosis-5-heptenoate.

The method according to the invention for preparing the cyclopenkune derivatives of formula I comprises a compound of the general formula and R and o are hydrogen, lower alkyl, carboxy, lower alkoxycarbonyl, lower alkoxymethyl, or a hydroxymethyl group protected with a hydrolyzable ether or ester group; provided that when R4 and R5 are both hydrogen , Rlo is lower alkoxycarbonyl, lower alkoxymethyl or a hydroxymethyl group protected with a hydrolyzable ether or ester group] or its enantiomer! Alternatively, the racemate may be prepared as necessary in the presence of dimethyl sulfoxide when Rlo is carboxy or central alkoxycarbonyl, with a base and general [in the formula, R7, R70
and R71 is aryl or di(lower alkyl)-amino, and Y is halogen]; if necessary, the resulting general formula [wherein R4, R5 and R6 are has the meaning of R1
1 is as above RIO, and further the group 5-
The heptenoic acid derivative or its enantiomer or racemate is subjected to saturation by hydrogenation of the double bond in the side chain containing the carboxy group; the reaction product is then combined in the desired order with the protected hydroxy group R6 and the group R1.
Conversion of the protected hydroxy group present in 1 into a hydroxy group; optionally conversion of the present carboxy group to the corresponding lower alkoxycarbonyl group by esterification; and optionally the present lower alkoxycarbonyl group. It is then subjected to conversion to a carboxy group by chlorinated hydrolysis.

As used herein, the term "lower alkyl" includes:
Both straight-chain and branched alkyl groups having 1 to 7 carbon atoms are included, such as methyl, ethyl and propyl, with methyl being preferred.

The term "lower alkoxy" includes groups having from 1 to 7 carbon atoms, such as methoxy and ethoxy.

The term "lower alkanoic acid" as used herein also includes alkanoic acids of 1 to 7 carbon atoms, such as formic acid and acetic acid.

Further, as used herein, the term "halogen" or "halo" is intended to include fluorine, chlorine, bromine and iodine, unless otherwise specified.

In the process of the invention, all compounds with one or more asymmetric carbon atoms can be prepared as semimixtures.

This resulting racemic mixture can be resolved at the appropriate step in the process of the invention by methods well known in the art for the time being described in more detail below, whereupon the following products are separated by the corresponding optical It can be obtained as a pure enantiomer.

In the structural formula representation of the compound shown in this specification, the filled tapered line ←-) indicates a substituent in the β-coordination (at the surface of the molecule), and the brush line (1111111111) indicates the α-coordination. (below the plane of the molecule) and the wavy line (to) indicates a substituent in either the α- or β-configuration or isomeric mixtures thereof.

The representations of structural formulas for compounds shown herein are for simplicity and should be construed to include other forms, including enantiomers and racemates, and are limited to the specific forms shown. It should be understood that it should not be construed as

The term "aryl" as used herein may also be unsubstituted or substituted in one or more positions with lower alkylenedioxy, halogen, nitro, lower alkyl, or lower alkoxy substituents. It represents a mononuclear aromatic hydrocarbon group, such as phenyl, tolyl, etc., and a polynuclear aryl group, which may be substituted with one or more of the above groups, such as naphthyl, anthryl, phenanthryl, azuryl, etc.

Suitable aryl groups are substituted and unsubstituted mononuclear aryl groups, especially phenyl groups.

The term "aryl lower alkyl" embraces the radicals where aryl and lower alkyl are as defined above;
Especially benzyl.

The term "aryl lower alkanoic acid" includes acids where "aryl" and "lower alkanoic acid" are as defined above, particularly benzoic acid.

Furthermore, as used herein, the term "carboxy protected with a group hydrolytically convertible to a carboxy group" includes conventional organic acid protecting groups that are hydrolytically removable.

A preferred organic acid protecting group is an ester.

Conventional ester groups which can yield acids on hydrolysis can be used as protecting groups.

Examples of esters that can be used for this purpose are lower alkyl esters, especially methyl and ethyl esters, aryl esters, especially phenyl esters, and aryl lower alkyl esters, especially benzyl esters.

As used herein, the term "hydrolyzable ester or ether group" refers to an ester or ether group that can be hydrolyzed to yield a hydroxy group.

Examples of ester groups that can be used for this purpose are those in which the acyl moiety is derived from lower alkanoic acids, aryl lower alkanoic acids, phosphoric acids, carbonic acids or lower alkanedicarboxylic acids.

Among the acids that can be utilized to form such ester groups are acid anhydrides and acid halides, preferably chlorides or bromides, lower alkanoic anhydrides such as acetic anhydride and caproic anhydride, aryl lower alkanes. Preferred are acid anhydrides such as benzoic anhydride, lower alkanedicarboxylic acid anhydrides such as succinic anhydride, and chloroformates such as trichloroethyl chloroformate.

Additional ether-forming protecting groups are, for example, tetrahydropyranyl ether or 4-methoxy-5,6-cyhydro 2H-pyranyl ether.

Others include arylmethyl ethers such as benzyl, benzhydryl, trityl ethers or α-lower alkoxy lower alkyl ethers such as methoxymethyl or allyl ether, or triallylsilyl ethers such as trimethylsilyl ether or dimethyl-t-butylsilyl ether. There is.

When R6 is an ether group, suitable ether groups are 2-tetrahydropyranyloxy and dimethyl-t-butylsilyloxy.

1Rtt and R1 are each a group -C-CH2-S-CH
% R, in preparing intermediates of formula (1) representing 31 and desired products of formula I.

is carboxy or lower alkoxycarbonyl in the presence of dimethyl sulfoxide and a base, preferably an alkali metal hydride.
react with the phosphonium salt of

In this reaction, dimethyl sulfoxide can be used as both a solvent and a reactant.

- As the organic solvent medium, customary inert organic solvents can be used in a mixture with dimethyl sulfoxide.

Alkali metal hydrides are preferably used as bases in carrying out this reaction.

In this reaction, on the other hand, alkali metal hydrides can be combined with dimethyl sulfoxide in the form of alkali metal methylsulfinyl methylides.

Temperature and pressure are not critical in carrying out this reaction, and the reaction can be carried out at room temperature and atmospheric pressure.

On the other hand, temperatures higher or lower than room temperature can be used.

It is generally preferred to carry out this reaction at a temperature of -100C to +50C.

R11 and R1 are each a group -C-CH2-X-CH2
1 The preparation of the intermediates of the formula (I) different from 1 and the target products of the formula I is preferably carried out in an inert organic solvent, in particular hexamethylphosphoric triamide.

Common inert organic solvents can be mixed with hexamethylphosphoric triamide.

A preferred base is sodium bis-trimethylsilylamide.

When this reaction is carried out using sodium bis-trimethylsilylamide as the base in a solvent medium containing hexamethylphosphoric triamide, acid chain
) to produce a compound of formula (1) having primarily a cis-double bond at the 5-position.

Temperature and pressure are not critical in carrying out the reaction, and the reaction can be carried out at room temperature and atmospheric pressure.

However, temperatures higher or lower than room temperature can be used if desired.

It is generally preferred to carry out this reaction at a temperature of 0 to 50C.

The above reaction leads to an intermediate compound of general formula (1).

This intermediate is further reacted, if necessary in the desired order, to (1) saturate the double bond in the side chain containing the carboxy group by hydrogenation, and (2) convert the carboxy group present to a lower alkoxy group by esterification. (3) the lower alkoxycarbonyl group present can be converted to a carboxy group by basic hydrolysis.

In order to obtain the final product of formula I, the protected hydroxy group and group R11 of the intermediate of formula 1 or the product obtained by the above reactions (1), (2) and/or (3)
Converts the protected hydroxy group present in to a hydroxy group.

Conversion reaction (1) is carried out before removal of this protecting group, while reactions (2) and (3) can be carried out before as well as after removal of the protecting group.

The above reaction (1), ie, the saturation of the double bond in the side chain containing a carboxy group, is carried out by hydrogenation.

Conventional hydrogenation methods such as catalytic hydrogenation can be utilized in carrying out this reaction.

Among the preferred methods of hydrogenation is reaction with hydrogen in the presence of a blue metal catalyst such as platinum or palladium under conditions customary for such hydrogenations.

The existing carboxy group can be converted to lower alkoxycarbonyl by a conventional esterification method [reaction (2) above].

As esterification agents, for example diazomethane, lower alkanols or reactive derivatives thereof, such as lower alkyl halides, are used.

Conventional reaction conditions can be used for this esterification reaction.

The above reaction (3), ie, the conversion of the lower alkoxycarbonyl group present, is carried out by basic hydrolysis in a conventional manner.

Removal of the above protecting groups can be carried out in conventional manner, yielding free hydroxy groups.

If the hydroxy group is protected via a hydrolysable ether bond, conventional ether hydrolysis can be used, preferably treatment with aqueous acids.

Lower alkyl is not a normal hydrolyzable ether group; thus, when R11 is lower alkoxymethyl, the lower alkyl group is not removed by normal ether hydrolysis.

Hydrolyzable ester groups can be dissociated in conventional manner via treatment with base in an aqueous medium.

Such treatment will also convert the lower alkoxycarbonyl group R11 to carboxy.

Starting compounds of formula H where RIO is hydrogen, lower alkyl, carboxy or lower alkoxycarbonyl can be prepared according to the following reaction scheme.

[In the formula, R12 is hydrogen, lower alkyl or carboxy, R05 is hydrogen, lower alkyl or lower alkoxycarbonyl, R14 is hydrogen, lower alkyl,
carboxy or lower alkoxycarbonyl, R
8 is 2-propenyl; produced from a compound of formula V.

This reaction can be carried out in an aqueous medium containing an alkali metal hydroxide and in the presence of a powdered steel catalyst.

In carrying out this reaction, common alkali metal hydroxides can be used, with potassium hydroxide being preferred.

In this reaction, the alkali metal hydroxide may be present in an amount of about 10 to 30 pounds by weight of the aqueous medium.

Temperature and pressure are not critical in carrying out this reaction, and generally the reaction can be carried out at room temperature and atmospheric pressure.

Preferably the reaction is carried out under an inert gas atmosphere at about -1O
It is carried out at a temperature of from 0.degree. C. to about 65.degree.

Customary inert gases such as nitrogen or alkones can be used in carrying out this reaction; it is particularly preferred to bubble the inert gas into the reaction mixture and at the same time stir the reaction mixture vigorously.

Carboxy substituents in compounds of formula (1) are protected by esterification in the usual manner.

Compounds of formula (II) are prepared in a lower alcoholic reagent using conventional inert organic solvents such as lower alkanols, lower alkyl ethers, acetone, tetrahydrofuran, dioxane, diglyme, or aliphatic or aromatic hydrocarbons, preferably in an excess of alcoholic reagents. Preference is given to reacting with alkanol or benzyl alcohol.

Preferably, the treatment is carried out in the presence of a catalytic amount of an inorganic acid.

Common inorganic acids can be used, with sulfuric acid being preferred.

Temperature and pressure are not critical, and generally the reaction can be carried out at room temperature and atmospheric pressure.

However, it is generally preferred to use a temperature of about 0°C to about 150'C, with reflux temperature of the reaction mixture being preferred.

A compound of formula (1) can be obtained by chlorination or bromination of a compound of formula (2).

Conventional chlorinating or brominating agents can be used in carrying out this reaction.

Among the suitable chlorinating agents are chlorine dissolved in chlorinated hydrocarbons, tert-butyl-hypochloride and N-chlorosuccinimide, especially tert-butyl-hypochloride.

This reaction can be carried out in an inert organic solvent.

In carrying out this reaction, customary inert organic solvents such as halogenated hydrocarbons, lower alkanols, diethyl ether and tetrahydrofuran can be used.

When using tert-butyl-hypochloride,
Lower alkanols, especially methanol, are preferred solvents.

Temperature and pressure are not critical in carrying out this reaction, and generally the reaction can be carried out at room temperature and atmospheric pressure.

In carrying out this reaction, generally from about -10'c to about 100'c
Temperatures of 0.degree. C. are used, with temperatures of 00.degree. C. to 20.degree. C. being particularly preferred.

A cyclopentenyl compound of formula (2) can be obtained by ring contraction of a compound of formula (2).

In carrying out this ring contraction, the compound of formula (1) is heated to an elevated temperature, preferably in the presence of a non-hydroxyl base.

Conventional non-hydroxyl bases can be used in carrying out this reaction.

In general, anhydrous alkali metal carbonates, sodium bis-trimethylsilylamide, lithium diisopropylamide and powdered glass are suitable non-hydroxyl bases, especially anhydrous sodium carbonate.

This reaction can be carried out in a high boiling inert organic solvent, preferably under an inert gas atmosphere such as nitrogen or argon.

In carrying out this reaction, customary high-boiling inert organic solvents can be used, aromatic hydrocarbons being preferred, especially xylene and mesitylene.

Elevated temperatures of about 100'C to about 200C can be used in carrying out this reaction.

It is generally preferred to conduct the reaction at the reflux temperature of the reaction mixture, with temperatures from about 40°C to about 170°C being particularly preferred.

A compound of formula X can be obtained by treating a compound of formula (1) with nitromethane in the presence of a base.

Conventional bases can be used in carrying out this reaction.

Among the suitable bases are lower alcoholates, especially alkali metal lower alcoholates, amines, especially tertiary and quaternary amines, and pyridine.

Particularly preferred as base is benzyl) IJ methylammonium hydroxide.

This reaction can be carried out in an inert organic solvent.

The customary inert organic solvents such as lower alkanols, lower alkyl ethers, tetrahydrofuran, dioxane or diglyme can be used in this reaction.

When carrying out this reaction, it is preferred to use an excess of nitromethane as a solvent.

Temperature and pressure are not critical in carrying out this reaction, and generally the reaction can be carried out at room temperature and atmospheric pressure.

It is preferred to use a temperature of about -30°C to the reflux temperature of the reaction mixture in carrying out the reaction, with temperatures of about 1000°C being particularly preferred.

In forming the compound of formula

On the other hand, the nitromethane substituent is attached to the molecule on the opposite side of the plane as substituents R3 and R13.

This coordination is maintained throughout the process, thereby allowing the formula
is converted into a compound of formula I.

Compounds 2M are obtained from compounds of formula X by changing the 2-propenyl group R8 to a carboxymethyl group.

This conversion can be carried out in conventional manner by oxidative decomposition.

Optionally, the compound is represented by the formula ■ where R14 is carboxy
can be hydrolyzed to obtain the compound.

In carrying out the oxidative decomposition of compounds of formula X, conventional oxidizing agents that selectively oxidize 2-propenyl groups to form carboxymethyl groups can be used.

In general, alkali metal permanganates, osmium tetroxide/periodide and ozone are preferred oxidizing agents, with potassium permanganate being particularly preferred.

This oxidative decomposition can be carried out in an inert solvent.

In carrying out this reaction, customary inert solvents can be used, such as water and the organic solvents mentioned above, acetone being preferred.

Temperature and pressure are not critical in carrying out the reaction, and generally a temperature of about -70°C to the reflux temperature of the reaction mixture can be used, with about -40°C to about +2000°C being particularly preferred, and even more preferably about 0°C. be.

Hydrolysis can be carried out using a conventional well water decomposition method.

It is generally preferred to use dilute aqueous inorganic acids such as sulfuric acid or aqueous alkalis such as hydroxide sulfur IJ wams.

The nigari compound can be obtained by selective reduction of the niM compound.

In carrying out this reaction, the compound of formula M can be treated with a reducing agent.

It is generally preferred to convert the compound of 2M to the corresponding alkali metal carboxylate before its reduction.

Conversion of the alkali compound to its alkali metal carboxylate can be suitably carried out by treating the aliphatic compound with an alkali metal lower alcoholide, with sodium methylate being preferred.

In carrying out this reaction, conventional methods for converting carboxylic acids or carboxylic acids into their alkali metal salts can be used.

When selectively reducing the compound of 2M to produce the compound of the formula can.

Generally hydride reducing agents such as alkali metal hydrides or borohydrides are preferred.

A particularly preferred reducing agent is lithium perhydro-9b-boraphenaryl hydride.

Temperature and pressure are not critical in carrying out this reaction;
This reaction can be carried out at room temperature and atmospheric pressure.

Generally, the reaction is preferably carried out at about -100'C to the reflux temperature of the reaction mixture, with temperatures below about 0C being particularly preferred, and about -78C being more preferred.

This reaction can be carried out in the presence of an inert organic solvent.

In carrying out this reaction, conventional inert organic solvents such as those mentioned above can be used.

Compounds of formula can be converted to compounds of formula XIII by heating a compound of known formula in an inert organic solvent.

In carrying out this conversion, temperature and pressure are not critical;
Generally, the reaction can be carried out at a temperature of about 50 DEG C. to about 100 DEG C. and atmospheric pressure, with reflux temperature being preferred.

This reaction can be carried out in a conventional inert organic solvent such as those mentioned above, preferably tetrahydrofuran.

The compound of formula X■ is obtained by oxidizing the compound of formula
It can be directly converted into a compound of V.

Preferred oxidizing agents are alkali metal permanganates, with sodium permanganate being particularly preferred.

In carrying out this reaction, the compound of formula X■ is converted to its aci-nitro salt prior to treatment with permanganate.

A compound of formula X can be converted to its aci-nitro salt by treatment with an alkali metal lower alcoholate, preferably lithium metholeate.

Temperature and pressure are not critical in carrying out this reaction, and generally the reaction can be carried out at room temperature and atmospheric pressure.

This reaction can be carried out in an inert organic solvent.

In this reaction, conventional inert organic solvents such as those mentioned above can be used, with methanol being preferred.

The oxidation of the aci-nitro salt of the compound of formula X can be carried out in the presence of an inert organic solvent or water.

In this reaction, customary inert organic solvents such as tetrahydrofuran, dioxane, acetone, diglyme or lower alkyl ethers can be used.

Temperature and pressure are not critical in carrying out this reaction, and the reaction can be carried out at room temperature and atmospheric pressure.

It is generally preferred to conduct the reaction at a temperature of about -10C to about +75C, with temperatures of about 0C being particularly preferred.

Prior to conversion to the aci-nitro salt, the compound of formula X■ in which RI4 is carboxy is preferably first protected with a conventional protecting group which can be converted into a carboxy group by hydrolysis.

The conversion of the group R14 which can be converted from carboxy to a carboxy group can be carried out in a conventional manner by esterification, preferably by esterification of the compound of formula (1) above.

The resulting product of formula XIV can be subjected to hydrolysis as described in connection with the preparation of compounds of formula M to produce compounds of formula XIV where R14 is carboxy.

The compound of the formula X■ is prepared by first converting the compound of the formula
4; R5J R7J R70j lR'yt and Y are as above] Phosphonium salt of ** or formula [wherein R4 and R5 are as above, and R7
2 and R73 are aryl, aryloxy or lower alkoxy].

The preparation of compounds of formula Xv by reaction of compounds of XIV with phosphonium salts of formula
t t i g) is carried out through a reaction.

In carrying out this reaction, any of the conditions conventional in Witteigh reactions can be used.

The preparation of a compound of formula X■ by reaction of a compound of formula XIV with a phosphonate of formula xx is carried out via a Hornet reaction.

Any of the conditions conventional in Horner type reactions can be used in carrying out this reaction.

A compound of formula X■ can be obtained by treating a compound of formula Xv with a reducing agent.

In carrying out this reaction, conventional reducing agents which selectively reduce keto groups to hydroxy groups can be used.

Suitable reducing agents are water** hydrides, especially aluminum hydrides, such as alkali metal aluminum hydrides, and borohydrides, such as alkali metal borides, with zinc borohydride being particularly preferred.

Temperature and pressure are not critical in carrying out this reaction;
This reaction can be carried out at room temperature and atmospheric pressure, or at elevated or lowered temperature and elevated or reduced pressure.

It is generally preferred to carry out the reaction at -10°C to the reflux temperature of the reaction mixture.

This reduction reaction can be carried out in the presence of an inert organic solvent.

In carrying out this reaction, conventional inert organic solvents such as those mentioned above or water can be used.

Among the suitable solvents are dimethoxyethylene glycol and ethers such as tetrahydrofuran, diethyl ether and dioxane.

A compound of formula can be done.

When performing this separation, conventional separation methods such as column chromatography, gas phase chromatography, etc. can be used.

Any of these isomers can be used to prepare compounds of Formula I according to the present reaction.

The configuration of the hydroxy groups on the octenyl side chain is maintained throughout the process of the invention, so that the hydroxy groups on the octenyl side chain in compounds of formula I also have similar configurations as in compounds of formulas XVI-A and XVI-B, respectively. .

Compounds of formulas XVI, XVI-A and XVI-B can be converted to compounds of formula X■ by esterification or etherification of the free hydroxy group with an ether or ester protecting group capable of hydrolysis at the edge.

This esterification or etherification can be carried out by conventional esterification or etherification methods.

Preferred hydrolysable ester groups are lower alkanoyls, with acetyl being particularly preferred.

Suitable hydrolyzable ether groups include tetrahydropyranyl.

RI4 is lower alkoxycarbonyl, and R6
A compound of the formula A compound of X■ can be produced.

The compound of formula X■ can be converted to the compound of W-A by treating the compound of formula X■ with a reducing agent.

In carrying out this reaction, conventional reducing agents which selectively reduce keto groups to hydroxy groups can be used.

Suitable reducing agents are hydrides, especially aluminum hydrides, such as alkali metal aluminum hydrides, and borohydrides, such as alkali metal borohydrides, with diisobutylaluminum hydride being particularly preferred.

This reaction can also be carried out using di(branched lower alkyl)borane such as bis-(3-methyl-2-butyl)-borane.

Temperature and pressure are not critical in carrying out this reaction; the reaction can be carried out at room temperature and atmospheric pressure, or at elevated or falling temperatures and elevated or reduced pressures.

It is generally preferred to carry out the reaction at a temperature of -100C to the reflux temperature of the reaction mixture.

This reduction reaction can be carried out in the presence of an inert organic solvent.

Conventional inert organic solvents can be used in carrying out this reaction.

Among the suitable solvents are dimethoxyethylene glycol and ethers such as tetrahydrofuran, diethyl ether and dioxane.

A starting compound of formula (1) in which RIO is lower alkoxymethyl or a hydroxymethyl group protected with a hydrolyzable ether or ester group can be prepared from a compound of formula (X) in which R14 is carboxy by treatment with borane. , thereby converting the carboxy group R14 to hydrodimethyl.

Temperature and pressure are not critical in carrying out this reaction, and the reaction can be carried out at room temperature and atmospheric pressure.

On the other hand, elevated or low temperatures can be used.

It is generally preferred to carry out this reaction at a temperature of -20°C to +50°C.

This reaction is generally carried out in the presence of an inert organic solvent.

Conventional inert organic solvents can be used in carrying out this reaction.

Suitable solvents are ether solvents f11 such as diethyl ether, tetrahydrofuran, dioxane and the like.

The hydroxymethyl group of the thus obtained compound of the formula [wherein s R4+ R5 and R6 are as described above] is converted into an ether or an ester capable of hydrolyzing the hydroxymethyl group by etherification or esterification by a conventional method. Protect with base.

A preferred protecting group is tetrahy**dropyranyl.

On the other hand, this hydroxymethyl group can be converted into lower alkoxymethyl by etherification with a lower alkyl halide.

Conventional conditions for producing lower alkyl ethers can be used during this conversion.

The thus obtained formula [wherein R15 is lower alkoxymethyl or a hydroxymethyl group protected with a hydrolyzable ether or ester group, and % R4+ R5 and R6 are as described above.

) is treated with a reducing agent in a manner similar to that used for converting the compound of formula It can be converted into a compound with 2H, which is a hydroxymethyl group protected by .

Phosphonates of formula XX, where R4 is fluorine, are lithium salts of the formula: [wherein R72 and R73 are as above] of [wherein R9 is lower alkyl and R3 is as above] Manufactured by reacting with a compound.

In this reaction, conditions conventional for producing addition products by the reaction of lithium salts and esters can be used.

Compounds of formula Xx, where R4 is alkyl, can be obtained by reacting a compound of formula can be manufactured.

In carrying out this reaction, conditions conventional in the reaction of lithium salts with acid chlorides to form adducts can be used.

A phosphonium salt of the formula [wherein R41
is hydrogen, lower alkyl or fluorine, R5 is lower alkyl or hydrogen, with the proviso that R41 and R5
At least one of 1 is other than hydrogen, and
is as described above] with a compound of the formula [wherein R7, R7o and R71 are as described above].

Compounds of formula I are dietary (a l imen t a r
y) and reproductive (1ve) modulating the activity of the plagiarismus muscle and inhibiting mucus and enzyme secretion by the stomach;
It has the ability to stimulate the synthesis of adrenal corticoids, as well as regulate blood pressure and lipolysis.

Additionally, the compounds are useful for inducing labor and for therapeutically terminal pregnancy in women.
The compounds of No. 6, which are active against agonizing pregnancies, can be used in the pharmaceutical and veterinary pharmaceutical fields as various pharmaceutical or veterinary pharmaceutical preparations.

In these preparations, the compounds may be incorporated into tablets, emulsions, powders, capsules, injectables, solutions, suppositories, emulsions,
Administer in the form of dispersions, feed premixes and other suitable formulations.

The medicament or veterinary medicament containing the compound of formula (II) is advantageously formulated with a non-toxic pharmaceutical organic carrier or a non-toxic pharmaceutical inorganic carrier.

Representative pharmaceutically acceptable carriers include water, gelatin, lactose, starch, magnesium stearate,
Talc, vegetable oils, polyalkylene glycols, yellow petrolatum, and other pharmaceutically acceptable carriers commonly used include amethyst.

Pharmaceutical preparations may also contain non-toxic auxiliary substances, such as emulsifiers,
Preservatives and wetting agents such as sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan, dioctyl sodium sulfosacunate, etc. can be included.

The daily dosage at which the compounds are administered will, of course, vary depending on the specific compound employed, depending on the compound's specific potency, the chosen route of administration, and the size of the receptor.

The dosage administered is not defined in a precise range, but will usually be within the pharmacologically functional effective amount of the prostaglandin.

An example of a typical method for administering prostaglandin compounds of Formula I is by an injectable type of route of administration.

By this route, a sterile solution containing the prostaglandin of formula I was prepared at 0.01μ, 9-0.15μg/min,/k.
g of body weight can be administered intravenously.

Compounds administered by the injectable route are in a form suitable for injection, eg, mixed with a sterile aqueous solution containing reagents that slow recovery, such as aluminum monostearate and the like.

When administering the compound of formula I to livestock or laboratory animals, the compound is prepared in the form of a feed premix by mixing it with, for example, dried fish meat, oatmeal, etc., and the prepared premix is added to the normal feed. Additionally, the compound is thereby administered to livestock or laboratory animals in the form of feed.

The following experimental examples illustrate the invention, but are not intended to limit the scope thereof.

All temperatures are in degrees Celsius. The ether used in the examples was diethyl ether.

Example 1 3.3aβ, 4,5,6,6aβ-hexahydro4β
-[3α-(2-tetrahydropyranyloxy)-1-
1-Lance-octenyl]-5αcarbomethoxy-2H
-Cyclopenc (b) 414m9 of furanol 2-ol was converted into hexamethylphosphoric acid triamide 151' under an alkone.
The mixture was heated with 2.8 equivalents of Witzteich's reagent, produced by the reaction of sodium bis-trimethylsilylamide and (4-carboxyphthyl)triphenyl phosphonium bromide, in Ill.

After 1 hour, the reaction mixture was neutralized with acetic acid and the solvent was removed under high vacuum at 40-50°.

The remaining material was column chromatographed on silica gel to give 7-[3α-carbomethoxy-5α-hydroxy-
2β-[3α-(2-tetrahydropyranyloxy)-
1-trans-octenylio1α-cyclopentyl]
-cis-5heptic acid was obtained.

7-(3α-carbomethoxy-5α-hydroxy-2β
-[3α-(2-tetrahydropyranyloxy)-1-
1-Lance-octenylo1α-cyclopentyl]-
100 μl of cis-5-heftenoic acid were heated to 35° for 16 hours in 3 ml parts by volume of 2:1 acetic acid-water.

The extruded components were evaporated at 25° and 0.5 mm, Hji to give the crude 7-[3α-carbomethoxy-5α-hydroxy-2β-(3α-hydroxy-1-trans-octenyl)-1α-cyclopentylz- 5-Heptenoic acid was purified by column chromatography on silica gel.

The starting materials 3,3aβ,4,5,6,6aβ-hexahydro-4β-[3α-(2-tetrahydropyranyloxy)-1-1-lans-octenyl]-5α-carbomethoxy-2H-cyclopenta(b ) Furan-2-ol could be prepared as follows: α in 264 rul of a 20 mt aqueous solution of potassium hydroxide.
-dihydroresorsilic acid93.6. ? Copper powder 1 in a solution of
, 8g and allyl bromide 7FH1 were added.

The mixture was sparged with nitrogen and stirred vigorously at room temperature for 50,000 hours.

Add 600ml of sodium hydroxide aqueous solution by weight, and remove unreacted allyl bromide with 100ml each of diethyl ether.
1 and removed by extraction twice.

The basic solution was carefully brought to pH'H2O2 with 20 weight polysulfuric acid while cooling on ice.

The mixture was then extracted six times with 300 ml each of diethyl ether and dried over anhydrous magnesium sulfate.

The combined dry ether extracts were evaporated leaving a partially solid residue.

Crystallization from ethyl acetate petroleum ether yielded a first product of 4-(2-propenyl)-3,5-cyclohexanedione carboxylate, mp 163-165° and a second product, mp 143-152°. Ta.

55.8 g of 4-(2-furobenyl)-cyclohexanedione carboxylate were dissolved in 700 ml of methanol, 2 g of concentrated sulfuric acid were added and the mixture was heated under reflux for 4 hours.

Upon evaporation, the residue was dissolved in 200 ml of tetrahydrofuran and 1001 rLl of water and stirred for 1 hour at room temperature.

Concentrate this mixture to half its volume and add 200,771 liters of water.
Upon adding 1 and extracting 5 times with 250 g each of methylene chloride and evaporating the dried (over magnesium sulfate) organic extract, a crude product was obtained which was crystallized from ethyl acetate-petroleum ether. After the melting point is 130-132
methyl 4-(2-propenyl)-3°5-cyclohexanedionecarboxylate was obtained.

)l f-4-(2-propenyl)-3,5-cyclohexanedionecarboxylate-1-38,71 was dissolved in 300 ml of t-butanol, and 50 TI of t-butanol was added.
t-Butyl/\Ivochlorite l-2<1 in Ll was added.

The mixture was heated to 50° C. and stirred at this temperature for 31 hours.

Evaporate and dry under reduced pressure as a viscous oil (boiling point 95-10
o'10. o 1 mm, HEl) methyl 4-chloro-4-(2-propenyl)-3°5-cyclohexanedione carboxylate was obtained.

A three-necked flask equipped with a Dean-8tark separator, a vibratory mixer, and a gas inlet was charged with 600 ml of dry mesitylene and 75 g of anhydrous sodium carbonate.

A gentle stream of alcohol was bubbled into the reaction mixture during the entire operation.

This suspension is then heated under reflux for 2 hours, but not before heating methyl 4-chloro-
A solution of 45 g of 4-(2-7'lopenyl)-3,5-cyclohexanedione carboxylate was added dropwise to the boiling mixture over a period of 15 minutes.

Reflux and vigorous stirring were continued for 16 hours.

After cooling, the solvent was evaporated and purified by distillation to give 1-methoxycarbonyl-3-(2-propenyl)-
4-oxo-cyclobent-2-ene was obtained; boiling point 10
6-111'/0.75mmHg01-Methoxycarbonyl-3-(2-7'ropenyl)-4-oxo-cyclobent-2-ene 20.15g nitromethane 20
011L, and 3 liters of a 40 wt φ methanolic solution of benzyltrimethylammonium hydroxide were added.

The mixture was then heated on a steam bath for 3 hours, cooled and
Acidified with cold 2N aqueous sulfuric acid.

This mixture was extracted with diethyl ether (300 mJ).

The ether solution was dried (M g S 04 ) and the solvent was removed under reduced pressure.

The residue was distilled to obtain 4α-methoxycarbonyl-3β-nitromethyl-2α-(2-propenyl)-cyclopentanone (boiling point 125-130° 10.15 H,y)
.

4α-methoxycarbonyl-3β in 75ml acetone
-Ditromethyl-2α-(2--10benyl)-cyclopentanone 9.42.9 75 I71 water
An ice-cold solution of 5.8 g of concentrated sulfuric acid in solution was added.

A solution of 21.6 g of potassium permanganate in 400 ml of water was added dropwise to the reaction mixture over a period of 10 minutes while cooling and stirring vigorously.

This entire operation was carried out under an argon atmosphere.

The reaction mixture was stirred for 5 minutes.

The mixture was then bubbled with sulfur dioxide until a clear solution was obtained.

Extract with methylene chloride containing 20 wt φ of acetone, dry (over magnesium sulfate), evaporate the organic solvent,
-Methoxycarbonyl-3β-nitromethyl-2α-carboxymethyl-cyclopentanone was obtained.

The crude product was taken up with diethyl ether and filtered: mp 148-150'.

To an ice-cold solution of 4.66.9 g of 2α-carboxymethyl-3β-nitromethyl-4α-methoxycarbonylcyclopentanone in 2501 rL of methanol was added 0.94 g of sodium methylate, followed by 0.0 g of sodium borohydride.
．． Added 5g.

The mixture was stirred at 0° for 1 hour and then acidified with IN aqueous sulfuric acid.

The methanol was evaporated, leaving 2α-carboxymethyl-3β-nitromethyl-4α-methoxycarbonyl-cyclopentanol as a liquid residue, which was extracted with 20 volumes of acetone in 80% ethyl acetate solution.

The solution was dried and the solvent removed under reduced pressure.

The residue was dissolved in tetrahydrofuran and refluxed for 2 hours.

Then remove the solvent and add 15 ml of water containing 2 g of potassium bicarbonate.
The residue was treated at 7.

Filter solid valve, 3,3a with melting point 100-101.5°
β,4,5,6,6aβ-hexahydro-4β-nitromethyl-2-oxo-2H-cyclopenta(b)furan-5α-carboxylic acid methyl ester was obtained.

Recrystallized from ethyl acetate-petroleum ether, melting point 102
The temperature rose to ~103°.

3.3aβ, 4,5,6,6aβ-hexahydro-4-
Nitromethyl-2-oxo-2H-cyclopenta(b)
Furan-5α-carboxylic acid methyl ester 2437n9
and 20 methanol with 1 equivalent of lithium methylate added.
It was dissolved in m1.

The clear solution containing the acinitro salt was evaporated, the residue was taken up in 5 liters of cold water and 2 drops of 20% by weight aqueous potassium hydroxide solution were added.

While cooling on ice and stirring, a solution of 130 ml of sodium permanganate trihydrate in 5 TL of water was added dropwise over 3 minutes.

The reaction mixture was then quickly filtered and the residue was washed with methylene chloride.

Solution F was further extracted with methylene chloride. Dry (MgS
O,i) Evaporation of the organic solvent gives the aldehyde, 3,3aβ,4,5,6°6aβ-hexahydro-4β-carboxaldehyde-2-oxo-2H-, with a melting point of 94-96°.
Cyclopenta(b,l furan-5α-carboxylic acid methyl ester was obtained.

The aldehyde 2,4-d-nitrophenyl-hydrazone had a melting point of 187-189°.

Dimethyl in 20 ml of dimethoxyethylene glycol (
To a solution of 433 ml of 2-oxoheptyl)phosphonate under an argon atmosphere were added 12 ml of a 1,6M solution of n-butyllithium in hexane.

After 10 minutes, 3,3aβ,4,5,6,6aβ-hexahydro-4β-carboxaldehyde-2-oxo-2H
-Cyclopenta(b) Furan-5α-carboxylic acid methyl ester 400Tn9 was added and the mixture was stirred for 2 hours.

Water (25ml) was then added and the mixture was extracted with methylene chloride.

Dry the methylene chloride solution (M g S 04)
, activated charcoal treatment, solvent removed under reduced pressure, brown oil 600
Obtained T19.

The product was taken up in a small amount of ethyl acetate and filtered through a small column of silica gel, and the eluent was treated with petroleum ether.

After 2 days at 0°, 3°3aβ,4,5,6aβ-hexahydro-
4β-(3-oxo-1-trans-octenyl)-2
-Oxo-2H-cyclopenta(b)furan-5α-carboxylic acid methyl ester crystallized.

3.3aβ, 4,5,6.6aβ-hexahydro-4β
-(3-oxo-1-transoctenyl)-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid methyl ester (5 g) at room temperature (25°) for 30 minutes.
Treated with excess zinc borohydride in 50 rrLl of dimethoxyethylene glycol.

After carefully adding 30 ml of dilute sulfuric acid while cooling on ice, the mixture was extracted four times with diethyl ether.

Evaporation of the ether gave a mixture which, when chromatographed on silica gel (diethyl ether as eluent), produced pure 3,3aβ with a melting point of 58-61°.
, 4,5,6,6aβ-hexahydro-4β-(3α-
Hydroxy-1-trans-octenyl)-2-oxo-2H-cyclopenta(b) furan-5α-carboxylic acid methyl ester was obtained.

3,3aβ, as a colorless oil by chromatography.
4,5,6,6aβhexahydro-4β-(3β-hydroxy-1-transoctenyl)-2-oxo-2H
-Cyclopenta(b)furan-5α-carboxylic acid methyl ester was obtained.

3.3aβ, 4,5,6,6αβ-hexahydro-4β
-(3α-hydroxy-1-trans-octenyl)-
2-Oxo-2H-cyclopenta(b)furan-5α-
Carboxylic acid methyl ester 1.90. F was mixed with freshly distilled dihydropyran 1.0aβ and methylene chloride 501111 containing trace amounts of p-toluenesulfonic acid.

After 30 min, the solvent was evaporated and the remaining oil was purified by column chromatography on silica gel to obtain 3,3aβ,4,
5,6゜6aβ-hexahydro-4β-[3α-(2-
Tetrahydropyranyloxy)-1-trans-octenyl-5α-carbomethoxy-2-oxo-2)1-
Cyclopenta(b)furan was obtained.

3.3aβ, 4,5,6.6aβ-hexahydro-4β
-[3α-(2-tetrahydropyranyloxy)-1-
trans-octenylo5α-carbomethoxy-2-
Oxo-2H-cyclopenta(b)furan 3181n9
(0.8mM) for 20 hours at Oo under argon.
Bis-(3-methyl-
Reacted with a 10% excess of 2-butyl)-borane.

After this period, 5 TL of a 2N aqueous sodium chloride acetate solution and 1 α by weight of hydrogen peroxide were added and the reaction mixture was allowed to reach room temperature.

After 1 hour, the mixture was cooled to Oo and the organic layer was separated by addition of anhydrous potassium carbonate.

After evaporation of the dried (MgSO+) organic layer and column chromatography on silica gel, pure 3°3aβ,
4,5,6,6aβ-hexahydro-4β-[3α-[
2-tetrahydropyranyloxy)-i-trans-octenyl-5α-carbomethoxy-2H-cyclopenta(b)furan-2-ol was obtained.

Example 2 3.3aβ, 4,5,6,6aβ-hexahydro-4β
-(3α-dimethyl-t-7'thylsilyloxy-1-
trans-octenyl)-5α-carbomethoxy-2H
-cyclopenta[b]furan-2-ol 213rr1
9 with 2.8 equivalents of Witzteich's reagent produced by reaction of sodium bis-trimethylsilylamide with (4-carboxybutyl)-triphenylphosphonium bromide in 15 ml of hexamethylphosphoric triamide at 25° under argon. Made it react.

After 1 hour, the reaction mixture was mixed with 50 parts by volume of a 1:1 part by volume mixture of saturated aqueous sodium chloride solution and 30% by weight aqueous acid solution.
Pour into m1.

The resulting mixture was extracted with cyclohexane.

The dried (Na2S04) extract was evaporated to give the crude 7-(3α-carbomethoxy-5α-hydroxy-2β-(3α-dimethyl-t-butylsilyloxy-1-trans-octenyl)-1α -cyclopentyliosis-5-heptenoic acid was obtained, which was purified by column chromatography on silica gel.

By the method of Example 1, 7-[3α-carbomethoxy-
5α-hydroxy-2β-(3α-dimethyl-t-butylsilyloxy-1-trans-octenyl)-1α-
Cyclopentyliosis-5-heptenoic acid is converted to 7-[3α
-carbomethoxy-5α-hydroxy-2β-(3α-
hydroxy-1-trans-octenyl)-1α-cyclopentyliosis-5-heptenoic acid.

Starting material 3,3αβ,4,5,6,6aβ-hexahydro-4β-(3α-dimethyl-t-butylsilyloxy-1-trans-octenyl)-5α-carbomethoxy-2H-cyclopenta[b]furan- 2-ol could be prepared as follows: 3.3aβ, 4,5,6,6aβ-hexahydro-4β
-(3α-hydroxy-1-trans-octenyl)-
2-Oxo-2H-cyclopenta(b)furan-5α-
Carboxylic acid methyl ester 683172p (2,13m
M) as dimethyl-t-butylsilyl chloride 393■
(2,56m'M), imidazole 362■ (5,33
(door extraction) and N,N-dimethylformamide (3TL1).

After 20 hours at 35°, the reaction mixture was diluted with methylene chloride, washed with water and dried (MgSO4). The solvent was evaporated and the 3,3aβ,4,5,6,6aβ-hexahydro-4β-( 3α-dimethyl-t-butylsilyl-oxy-1-trans-octenyl)-5α-carbomethoxy-2-oxo-2H-cyclopenta(b)furan was obtained; mp 87-89: crystallized from hexane.

3.3aβ, 4,5,6.6aβ-hexahydro-4β
-(3α-dimethyl-4-butylsilyloxy-1-trans-octenyl)-5α-carbomethoxy-2-oxo-2H-cyclopenta(b) Furan 1.49 (3
mM) in tetrahydrofuran at Oo under argon.
Reacted with 100% excess of bis-(3-methyl-2-butyl)-borane in m1.

After 20 hours, the mixture was diluted with 3N aqueous sodium acetate solution 30T.
30% by weight aqueous hydrogen oxide solution 6T in the presence of Ll
Oxidized with rLl.

After addition of anhydrous potassium carbonate at Oo, the organic layer is separated, dried (MgSO4), evaporated and purified by column chromatography on silica gel, followed by 3,3aβ,
4゜5.6.6aβ-hexahydro-4β-(3α-dimethyl-1-butylsilyloxy-1-trans-octenyl)-5α-carbomethoxy-2H-cyclopenta(b) Furan-2-ol was obtained .

Example 3 7-(3α-carbomethoxy-5α-hydroxy-2β
-(3α-hydroxy-1-trans-octenyl)-
1α-Cyclopentyliosis-5-heptenoic acid was treated with a 50% molar excess of diazomethane in diethyl ether.

The solvent was removed with a stream of nitrogen to yield methyl 7-[3α-carbomethoxy-5α-hydroxy-2β-(3α-hydroxy-1-trans-octenyl)-1α-cyclopentyliosis-5-hebutenoate.

Example 4 7-[3α-carbomethoxy-5α-hydroxy-2β
-(3α-hydroxy-1-trans-octenyl)-
1α-cyclopentylthosis-5-heptenoic acid 100
r/u/ was treated with 2.5 equivalents of lithium hydroxide in 10:1 parts by weight of methanol-water-5 for 5 hours at 25°.

This mixture was mixed with an excess of Dowex 50
After treatment with a W-x 8 acid ion exchange resin, filtration, evaporation of the solvent and purification by column chromatography on silica gel, the 7-[3α-
Carboxy-5α-hydroxy-2β-(3α-hydroxy-1-trans-octenyl)-1α-cyclopentylcus-5-heptenoic acid was obtained.

Example 5 3.3aβ, 4,5,6,6αβ-hexahydro-4β
-[3α-(2-tetrahydropyranyloxy)-1-
1-Lance-octenyl]-5α-carbomethoxy-2
H-cyclopenta(b)furan-2-ol 400rn
9 was reacted in 151 rLl of dimethyl sulfoxide at 25°C with 2.8 equivalents of Witzteich's reagent produced by the reaction of sodium methylsulfinyl methylide and (4-carboxybutyl)-triphenylphosphonium bromide.

After 5 hours, the solvent was evaporated at 25° (0.1% Hg) and the remaining paste was mixed with 31 liters of water and 6 TIlls of acetic acid.

The mixture was held at 35° for 16 hours and then the volatile components were removed at 25° (0,1iiHg).

The remaining material was purified by column chromatography on silica gel to obtain 7-(3α-(methylsulfinyl acetyl)-
Isolation of 5α-hydroxy-2β-(3α-hydroxy-1-trans-octenyl)-1α-cyclopentyl]-cis-5-heptenoic acid.

Example 6 7-(3α-(methylsulfinylacetyl)-5α-
Hydroxy-2β-(3α-hydroxy-1-h lance-octenyl)-1α-cyclopentylthosis-5-
100 m9 of heptenoic acid to 1:1 parts by volume of methylene chloride/
Dissolved in ethyl ether and treated with a 50% molar excess of diazomethane.

The solvent was removed with a stream of nitrogen and the methyl 7-[3α-methylsulfinyl acetyl-5α-hydroxy-2β-
(3α-hydroxy-1-trans-octenyl)-1
α-Cyclopentyl-iosis-5-hebutenoate was obtained, which was purified by column chromatography on silica gel.

Example 7 (4-
To a solution of 666 m9 (1,48 mmol) of triphenylphosphonium (carboxybutyl)-triphenylphosphonium phytophyto were added 550 ml of sodium bis-trimethylsilylamide (2,96 mmol) in 30 ml hexamethylphosphoric triamide.

Then, hexamethylphosphoric acid triamide 107 was added to the above solution.
3,3aβ in 7Il.

4.5,6.6aβ-hexahydro-4β-[3α-(
240 m9 (0.53 mM) of 2-tetrahydropyranyloxy)-1-trans-octenyl-5α-[(tetrahydropyranyloxy)methyl)-2H-cyclopenta(b) furan-2-ol were added.

After stirring at room temperature for 2 hours, the reaction mixture was poured into 100 g of ice-water.
The mixture was poured into acetic acid, adjusted to pH 3.5 with dilute sulfuric acid, and extracted with cyclohexane (four times).

The cyclohexane extract was washed with saturated aqueous sodium chloride solution and the Na25O4) solvent was removed to give an oil which was chromatographed on silica gel and 11-homo-prostaglandin F2αlla, 15
-bis-(tetrahydropyranyl ether)(7-(3
α-[(2-tetrahydropyranyloxy)-methyl]
-5α-hydroxy-2β-[3α-(2-tetrahydropyranyloxy)-1-trans-octenyl-1
α-cyclopentyl]-cis-5-heptenoic acid) was obtained.

A solution of 200 μl of 11-homo-prostaglandin F2alla, 15 (tetrahydropyranyl ether) in 5 ml of a 3:1 volume acetic acid/water solution was kept at 35° for 15 hours.

The solvent was removed under high vacuum and the residue was purified by column chromatography to obtain 11-homo-prostaglandin F2α.
I got it.

The starting materials 3,3aβ, 4,5,6.6aβ-hexahydro-4β-[3α-(2-tetrahydropyranyloxy)-1-4 lance-octenyl]-5α-[(2-tetrahydropyranyloxy) ) Methyl)-2H-cyclopenta(b) Furan-2-ol could be prepared as follows; 3,3 in 150 TILl of methylene chloride.
aβ, 4, 5゜6.6aβ-hexahydro-4β-
(3α-hydroxy-1-trans-octenyl)-2
-Oxo-2H-cyclopenta(b)furan-5α-carboxylic acid methyl ester2. i, dihydropyran 6.9
A solution of 25g and p-toluenesulfonic acid 14rn9
The mixture was stirred for 3 hours at °C.

The solution was washed with saturated sodium bicarbonate and the volatile components were evaporated to give an oil.

This oil was dissolved in 1:1 parts by volume ethyl ether-hexane and stored at -17°.

After 1 day, 3.3 aβ as needles with melting point 64-65°.

4.5,6,6aβ-hexahedro-4β-[3α-(
2-tetrahydropyranyloxy)-1-trans-octenyl-2-oxo-2H-cyclopenta(b,l
Furan-5α-carboxylic acid methyl ester crystallized.

3.3aβ, 4,5,6,6aβ-hexahydro-4β
-[3α-(2-tetrahydropyranyloxy)-1-
4 lance-octenyl-2-oxo-2H-cyclopenta(b,l furan-5α-carboxylic acid methyl ester 188 g, 6 weight polyaqueous solution of sodium hydroxide 8.3
ml and 331 rLl of tetrahydrofuran.
Refluxed for an hour.

The mixture was cooled to 0°, neutralized with 2N aqueous sulfuric acid, saturated with sodium chloride, and extracted with ethyl acetate.

Evaporate ethyl acetate to obtain 2β-
[3α-(2-tetrahydropyranyloxy)-1-1
-rance-octenyl)-3α-carboxymethyl-4
α-Hydroxy-cyclopencune-1α-carboxylic acid was obtained.

Benzene 50mA! and the mixture was refluxed for 4 hours.

Evaporate benzene, 3°3aβ, 4,5,6,6aβ
-hexahydro-4β-[3α-[2-tetrahydropyranyloxy)-1-trans-octenyl-2-oxo-2H-cyclopenta[b]furan-5α-carboxylic acid was obtained; melting point 73-74°, ethyl Crystallized from ether/hexane.

10ml dry tetrahydrofuran kept at water bath temperature
3,3aβ, 4,5,6,6aβ-hexahydro-
4β-[3α-(2-tetrahydropyranyloxy)-
1-trans-octenyl-5α-carboxy-2H
-cyclopenta[b]furan-2-one 0.90 g (
2,36mM) in tetrahydrofuran.
．． 20 ml of 146 molporane solution was added.

After stirring at this temperature for 1 hour and at room temperature for 25 minutes, the reaction mixture was taken up with 5 ml of water and saturated with sodium chloride.

The tetrahydrofuran layer was decanted from the aqueous solution, and the aqueous solution was extracted with ethyl acetate.

The ethyl acetate extract was combined with the tetrahydrofuran extract, dried with sodium sulfate, and the solvent was removed under reduced pressure.

The residue was shown to be homogeneous by thin layer chromatographic analysis and was used directly in the next experiment.

The product was passed through a silica gel column and 3,3aβ4.
5,6,6aβ-hexahydro-4β-[3α-(2-
An analytical sample of (tetrahydropyranyloxy)-1-trans-octenyl-5α-hydroxymethyl-2H-cyclopenta(b) furan-2one was obtained.

3,3aβ, 4°5.6,6aβ-hexahydro-4β-[3α-(2-
(tetrahydropyranyloxy)-1-trans-octenyl-5α-hydroxymethyl 2H-cyclopenta(
b) To a solution of 0.95 g (2.6 mM) of furan-2-one was added 0.35 g of freshly distilled dihydropyran and 4 μl of p-++-luenesulfonic acid.

The mixture was stirred at room temperature for 10 minutes and then washed with 5 parts by weight aqueous sodium carbonate solution.

The methylene chloride solution was dried (Na25O4) and the solvent and excess hydropyran were removed under vacuum.

3°3aβ, 4,5,6.
6aβ-hexahydro-4β-[3α-(2-tetrahydropyranyloxy)-1-1-lans-octenyl]
An analytical sample of -5α-[(2-tetrahydropyranoloxy)methyl]-2H-cyclopenta[b]furan-2-one was obtained.

3,3aβ, 4,5,6゜6aβ in 60m7 of toluene
-hexahydro-4β-[3α-(2tetrahydropyranyloxy)-1-trans-octenyl]-5α-[
(2-tetrahydropyranyloxy)methyl)-2H-
20 rrtl of toluene was removed by distillation from a solution of 1.144 g of cyclopenta[b]furan-2-one.

To the above solution kept in a dry ice-acetone bath under argon was added 3 ml of a 2.3 M solution of diisobutylaluminum hydride in hexane.

After stirring for 20 minutes at dry ice temperature, the reaction mixture was decomposed with three portions of methanol and allowed to reach room temperature.

After addition of 171 Ll of water and 3 g of diatomaceous earth, the reaction mixture was stirred for a further 30 min, filtered and dried (Na2SO
2).

The solvent was removed under vacuum.

The crude material was chromatographed on silica gel and 3
,3aβ,4,5゜6.6aβ-hexahydro-4β-
[3α-(2-tetrahydropyranyloxy)-1-trans-octenyl]-5α-[(2-tetrahydropyranyloxy)methylyocyclopenta[b]furan-
2-ol was obtained.

Example 8 A 0.6M solution of sodium methylsulfinyl methylide in dimethylsulfoxide (4-carboxybutyl)- in 2rrLl of dry dimethylsulfoxide to 4rul
Triphenylphosphonium bromide 0.53 g (1
, 2mM) was added.

Add 10 ml of dimethyl sulfoxide to this Witzteich reagent.
3,3aβ in the middle.

4.5,6.6aβ-hexahydro-4β-[3α-(
2-tetrahydropyranyloxy)-1-trans-octenyl]-5α-[(2-tetrahydropyranyloxy)methyl)-2H-cyclopenta(b)furan-2-
All O,' 25 g (0.5 mM) was added.

The reaction mixture was stirred at room temperature for 30 minutes, then cooled in a water bath and decomposed with 101 rLl of 0.2N sulfuric acid and then 2 mA' of 5% by weight aqueous sodium bicarbonate solution.

The solvent was removed under vacuum and the residue was dissolved in 10 ml of water.

The reaction mixture was adjusted to a pH value of 4 with dilute sulfuric acid at ice temperature and extracted three times with ethyl acetate.

The combined extracts were washed with saturated sodium chloride solution, and N
Dry over a2S04 and remove solvent.

The residue was chromatographed on silica gel to give most of the product, 2α-(3-methylsulfinyl-2hydroxypropyl)-4α-((2-tetrahydropyranyloxy)methyl]-3β-[3α(2-tetrahydro pyranyloxy)-1-trans-octenylo-1α-cyclopentanol and the lesser product, 11-homo-
Prostaglandin F2α, lla, 15-bis-(tetrahydropyranyl ether) was obtained.

In a similar manner to the method described in Example 7, 11-homo-prostaglandin F11a15-bi2αtsu (tetrahydropyranyl ether) was
It was possible to convert it to prostaglandin F2a.

Example 9 11-Homo-prostaglandin F2α, lla, 15-bis-(tetrahydropyra,
5 weight palladium catalyst 15 supported on charcoal in a cooled (-20') solution of 0.50.9
0 m9 was added and the mixture was hydrogenated under 1 atmosphere of hydrogen.

After absorbing 1 mole of hydrogen, the mixture was passed through a diatomist's bed.

After removing the solvent, the residue was treated with a 3:1 part by weight acetic acid/water solution at 35° for 15 hours.

The solvent was removed under high vacuum and the residue was purified by column chromatography to give 7-(3α-hydroxymethyl-5α-
hydroxy-2β-(3α-hydroxy-1-transoctenyl)-1α-cyclopentyl]-hebutanoic acid,
That is, 11-homo-prostaglandin Fl (1) was obtained.

Example 10 By the method of Example 1, 3,3aβ, 4,5°6.6a
β-Ichinohe・xahydro-4β-[4,4-dimethyl-3α
-(2-tetrahydropyranyloxy)-1-1-lanse-octenyl-5α-carbomethoxy-2H-cyclopenta(b) furan-ol with 7-[3α-carbomethoxy-5α-hydroxy-2β-[4,4 -dimethyl-3α-(2-tetrahydropyranyloxy)-1-t
-lance-octenyl-1α-cyclopentyl]-cis-5-heptenoic acid.

By the method of Example 1, 7-[3α-carnemethoxy-
5α-hydroxy-2β-[4,4-dimethyl-3α-
(2-tetrahydropyranyloxy)-1-trans-
Octenyl-1α-cyclopentyl]-cis-5-heptenoic acid was converted to 7-[3α-carbomethoxy-5α-hydroxy-2β-(4,4-dimethyl-3α-hydroxy-
1-trans-octenyl)-1α-cyclopentyl]
- changed to cis-5-heptenoic acid.

Starting materials 3,3aβ,4,5,6,6aβ-hexahydro-4β-C4,4-dimethyl-3α-[2-tetrahydropyranyloxy)-1-4lans-octenyl-5α-carbomethoxy-2H-cyclopenta (b) Furan-2-ol could be prepared as follows; a solution of 464 g of dimethylmethyl-phosphonate in 900 ml of tetrahydrofuran was cooled to -78° under argon (dry ice-acetone bath), hexane Part 1.
220 ml of 54Mn-butyllithium was added dropwise.

After 5 minutes, 2,2-dimethylhexanoyl chloride (boiling point 68-7σ/19m group; prepared from 2,2-dimethylhexanoic acid and excess oxalyl chloride) 27
．． Fl was added dropwise.

The mixture was stirred at -78° for 3 hours and allowed to reach 0° for 30 minutes.

The mixture was poured into a separatory funnel containing 50 ml of water and 2.5 A of diethyl ether.

Separate each layer and combine the organic layer with saturated sodium chloride solution 4X1
00 ml, dried (Mg504) and the ether was evaporated at 40°.

The remaining oil was distilled under reduced pressure to yield dimethyl (3,3-dimethyl-2-oxo-heptyl)phosphonate; boiling point 97-103°/0.06 mmHg.

Dry dimethoxyethane 500171. 35 g of sodium hydride/mineral oil (55 parts by weight of sodium hydride) in l
A solution of 20.0 g of dimethyl (3,3-dimethyl-2-oxo-heptyl)phosphonate in 100 ml of dimethoxyethane was added to the mixture under argon.

The mixture was stirred vigorously for 2 hours at room temperature.

Dimethoxyethane 120mA! 3゜3aβ, 4,5 in the middle
,6,6aβ-hexahydro-4β-formyl-5α-
Carbomethoxy-2-oxo-2H-cyclopenta(b
) Franc 16. (Bi' solution was added and the mixture was stirred at room temperature for 3 hours.

After this period, 300 rnl of water were added and the mixture was poured into a separatory funnel containing 21 mL of ethyl ether.

The layers were separated, the ethereal layer was washed with saturated sodium chloride solution, dried over Na2SO4 and the ether was evaporated at 40°.

The remaining oil solidified upon cooling and was recrystallized from diethyl ether hexane (7:3) to give a melting point of 71-72.
6 of 3゜3aβ, 4,5,6.6aβ-hexahydro-
4β-(4,4-dimethyl-3-oxo-1-trans-octenyl)-5α-carbomethoxy-2H-cyclopenta(b)furan was obtained.

1.3゜3aβ in 1001 nl of 2-dimethoxyethane
, 4,5,6,6aβ-hexahydro-4β-(4,4
-dimethyl-3-oxo-1-trans-octenyl)
-5α-Carbomethoxy-2H-cyclopenta[b]furan-2-one in a solution of 4.4 g (13.1 mM)
, 1 zinc borohydrate in 150 m9 of 2-dimethoxyethane
A 5mM solution was added.

The mixture was stirred for 5 hours, 5 ml of 4N aqueous sulfuric acid, 1 ml of water,
00 g and 300 ml of diethyl ether.

The layers were separated and the aqueous layer was extracted with 2 x 200 ml of ether.

The combined ether extracts were washed with 3 x 30 TL of saturated sodium chloride aqueous solution (N a2 S 04 ),
Evaporation of the solution gave a colorless oil which, when column chromatographed on silica gel, yielded pure 3,3aβ,4,5,6.6aβ-hexahydro-4β-(4 ,4-dimethyl-3α-hydroxy-1
-trans-octenyl)-5αcarbomethoxy-2H
- cyclopenta(b) furan-2-one (melting point 61-6
2°) and 3,3aβ.

4.5,6.6aβ-hexahydro-4β-(4゜4-
Dimethyl-3β-hydroxy-1-transoctenyl)-5α-carbomethoxy-2H-cyclopenta(b)
Furan-2-one was obtained.

By the method of Example 1, 3,3aβ, 4,5°6.6
aβ-hexahydro-4β-(4,4-dimethyl-3α
-hydroxy-1-trans-ocy-nyl)-5α
-Carbomethoxy-2H-cyclopenta(b)furan-
2-one to 3,3aβ, 4゜5.6.6aβ-hexahydro-4β-[4,4-dimethyl-3α-(2-tetrahydropyranyloxy)-1-1-lans-octenylo5αcarbomethoxy- 2H-cyclopenta(b,l
Changed to furan-2-one.

By the method of Example 1, 3,3aβ, 4,5°6.6
aβ-hexahydro-4β-[4,4-dimethyl-3α
-(2-tetrahydropyranyloxy)-1-4 lance-octenylcou 5α-carbomethoxy-2H-cyclopent(b)furan-2-one with 3,3aβ,4,5,
6.6aβ-hexahydro-4β-[4,4-dimethyl-3α-(2-tetrahydropyranyloxy)-1-trans-octenyl-5α-carbomethoxy2H-cyclopentaCb)furan-2-ol.

Example 11 By the method of Example 1, 3,3aβ, 4, 5゜6
．． 6aβ-hexahydro-4β-[4-fluoro-3α
-(2-tetrahydropyranyloxy)-1-trans-octenyl-5α-carbomethoxy-2H-cyclopenta(b)furan-2ol to 7-(3α-carbomethoxy-5α-hydroxy-2β-[4-fluoro- 3
α-(2-tetrahydropyranyloxy)-1-transoctenyl-1α-cyclopentyl]-cis-5-
changed to heptenoic acid.

By the method of Example 1, 7-[3α-carbomethoxy-5α-hydroxy-2β-[4-fluoro-3α-(
7-(3αcarbomethoxy-5α-hydroxy-2β-(4-fluoro-3α-hydroxy-1 -trans-octenyl)-1α-cyclopentyliosis-
Changed to 5-heptenoic acid.

Starting materials 3,3aβ,4,5,6,6aβ-hexahydro-4β-[4-fluoro-3α-(2-tetrahydropyranyloxy)-1-h lance-octenylcou5
α-Carbomethoxy2H-cyclopenta(b)furan-
2-ol could be prepared as follows: in a solution of 7.7 g (0.06M) of tetrahydrof9f80 at 73°C.
A 1.42M solution of butyllithium in hexane at 43.
4 ml was added dropwise.

After stirring for 5 minutes, 4 g of ethyl 2-fluorohexanoate (0.03 M
) solution was added dropwise.

The resulting solution was left to Oo and then acidified with 2N sulfuric acid (
The pH value was adjusted to 3).

The mixture was extracted with hexane, the hexane solution was washed with saturated sodium chloride solution and dried (M gs 0
4).

The solvent was removed under reduced pressure and the residue was distilled to a boiling point of 116-1
Dimethyl (2-oxo-3-fluoroheptyl)phosphonate was obtained at 18 DEG 10.4 Hg.

3,3aβ, 4, 5 by the method of Example 10.

6,6aβ-hexahydro-4β-formyl-5α-carbomethoxy-2-oxo-2H-cyclopenta (b)
Furan was reacted with dimethyl (2-oxo-3-fluoroheptyl)phosphonate for 10 hours to produce 3,3aβ,4,
5,6.6aβ-hexahydro-4β-(4-fluoro-3-oxo-1-trans-octenyl)-5α-carbomethoxy-2H-cyclopenta(b)furan-2-
On was generated.

3,3aβ, 4, 5 by the method of Example 10.

6,6aβ-hexahydro-4β-(4-fluoro-3
3.3aβ, 4,5,6
．． 6aβ-hexahydro 4β-(4-fluoro-3α-
hydroxy-1trans-octenyl)-5α-carbomethoxy-2H-cyclopent(b) furan-2-one and 3,3aβ,4,5,6.6aβ-hexahydro-
A mixture of 4β-(4-fluoro-3β-hydroxy 1-trans-octenyl)-5α-carbomethoxy-2H-cyclopenta[b]furan-2one was produced, which was separated by column chromatography on silica gel.

By the method of Example 1, 3,3aβ, 4,5°6.6a
β-hexahydro-4β-(4-fluoro-3α-hydroxy-■-trans-octenyl)-5α-carbomethoxy-2H-cyclopenta[b]furan-2-one with 3,3aβ+4+'5+6.6aβ-hexahydro -4
It was changed to β-[4-fluoro-3α-(2-tetrahydropyranyloxy)l-trans-octenyl-5α-carbomethoxy-2H-cyclopenta[b]furan-2one.

By the method of Example 1, 3,3aβ, 4,5°6.6a
β-Hexahydro-4β-[4-Flu-3α-(2
-tetrahydropyranyloxy)■-trans-octenyl]-5α-carbomethoxy-2H-cyclopenta[
b] Furan-2one as 3,3aβ+ 4 + 5 +
6 + 6 aβ-hexahydro-4β-[4-fluoro-3α-(2-tetrahydropyranyloxy)-1-
4 lance-octenylo 5α~carbomethoxy-2H
-Cyclopenta(b) was changed to furan-2-ol.

Example 12 21 equivalents of Wittstein reagent, produced by the reaction of sodium bis-trimethylsilylamide and (4carboxybutyl)-triphenylphosphonium bromide in hexamethylphosphoric triamide 3001'Ll, were added at 25° under argon. 3.3aβ, 4,5,6.6a
β-hexahydro 4β-[4,4-dimethyl-3α-(
2-tetrahydropyranyloxy)-1-1-lans-
octenyl]-5α-((2-tetrahydropyranyloxy)methyl)-2H-cyclopenta[b]furan-2
~A solution of 5.67 g of hexamethylphosphoric triamide was added.

After 30 minutes, excess Witzteig reagent was decomposed with glacial acetic acid and
Volatile components at 6° to 75°70. It was removed by distillation with O4 mmHg.

3.0 g of sodium hydroxide was added to the residue, which was dissolved in 250 ml of water, filtered and stirred at 25° under argon for 36 hours.

This solution was made acidic with IN sulfuric acid to a pH value of 4 and
Saturated with IJum, ethyl ether 5 x 200TfL
Extracted with l.

Evaporation of the ether solution gave a residue which, upon purification by dry column chromatography on silica gel, yielded 7-(3α-(2-tetrahydropyranyloxina-methyl-5α-hydroxy 2β-[4, 4-dimethyl-3α-(2-tetrahydropyranyloxy)-1-
Trans-octenyl io lα-cyclopentyl]-cis-5 heptenoic acid was obtained.

By the method of Example 1, 7-(3α-(2-tetrahydropyranyloxy)-methyl-5α-hydroxy-2β
-[4,4-dimethyl-3α[2-tetrahydropyranyloxy)-t-trans-octenylio1α-cyclopentyl]cis-5-heptenoic acid in 7. It was changed to (3α-hydroxymethyl-5α-hydroxy-2β-(4,4-dimethyl-3α-hydroxy-t-trans-octenyl)-1α-cyclopentyl]-cis-5-heptenoic acid.

Starting material 3,3αβ,4,5,6,6αβhexahydro-4β-(4,4-dimethyl-3α-(2-tetrahydropyranyloxy)-1-trans-octenyl)-
5α-[(2-tetrahydropyranyloxy)-methyl)-2H-cyclopenta[b]furan-2-ol could be produced as follows.

3,3αβ, 4,5,66α in 50TLl methanol
β-hexahydro-4β-[4,4-dimethyl-3α-
(2-tetrahydropyranyloxy)L-1-lans-
Octenylo5α-carbomethoxy-2H-cyclopenta[b]furan-2off5,9! l (14,1mM
) was added 5 TL of 7N aqueous sodium hydroxide solution.

The mixture was refluxed for 5 hours and then solidified to a white solid under vacuum.

Dissolve this solid in 50 ml of water and add 50 ml of ethyl ether.
711, acidified with 4N aqueous sulfuric acid to a pH value of 1,
Saturated with sodium chloride.

An oil separated which immediately solidified to give a white solid (melting point 147-150°).

This solid was mixed with 3:7 (V/V) ethyl acetate/benzene 4
00rnl and the solution was refluxed for 8 hours in a water collector.

The solvent was evaporated under reduced pressure and purified by column chromatography on silica gel to give 3,
3αβ, 4,5,6,6αβ, hexahydro-4β-[
4,4-dimethyl-3α-[2-tetrahydropyranyloxy)-t-trans-octenylo5α-carboxy 2H cyclopent(b) furan-2-one was obtained.

3°3α in 20 orrll of dry tetrahydrofuran
β, 4,5,6,6αβ-hexahydro 4β-[4,4
-dimethyl-3α-(2-tetrahydropyranyloxy)-■-1-lansuoctenyl]-5α-carboxy-2H-cyclopenta[b]furan-2-one 7.5
1.14 M boranetetrahydrofuran complex 17.6 g (18.4 mM) was added to an ice-cooled solution of 1.14 M boranetetrahydrofuran complex under an argon atmosphere.
ml (20mM).

After 1 hour, 50 ml of methanol were added and the mixture was condensed to an oil under vacuum.

This oil was taken up in 200 ml of ethyl ether, washed with saturated aqueous sodium chloride solution 2×1 OrrL11 saturated aqueous sodium chloride solution LOrrtl and dried (MgSO3).

Evaporation of the solvent under vacuum gave an oil which, when purified by column chromatography on silica gel,
Pure 3°3αβ,4,5,6,6αβ-hexahydro-4β-[4,4-dimethyl-3α-(2-tetrahydropyranyloxy)-t-t-lans-octenylo5α-hydroxy-methyl- as a viscous oil. 2H-cyclopenta(b)furan-2-one was obtained.

By the method of Example 1, 3,3αβ, 4,5°6.6α
β-hexahydro-4β・[4,4-dimethyl・3α-
(2-tetrahydropyranyloxy)-th-lance-
Octenyl-5α-hydroxymethyl-2H-cyclopenta[b]furan-2-one is reacted with dihydropyran to form a viscous oil, 3,3αβ,4,5,6,6αβ-hexahydro-4β-[4,4-dimethyl- 3α-(2-
Tetrahydropyranyloxy)-1-transoctenyl].5α-[(2.tetrahydropyranyloxy)methyl"]-]2H-cyclopentab) furan-2-one was obtained.

By the method of Example 1, 3,3αβ, 4,5°6.6α
β-hexahydro-4β-[4,4-dimethyl-3α-
(2-tetrahydropyranyloxy)-t-trans-
octenyl]-5α-[(2tetrahydropyranyloxy)methylyo2Hcyclopenc[b]6.35 g of furan-2-one was reacted with bis-(3-methyl-2-butyl)-borane, and after purification, the viscosity 3,3aβ as oil
.

4.5,6.6aβ-hexahydro-4β-[4゜4-
Dimethyl-3α-(2-tetrahydropyranyloxy)
-1-trans-octenyl]-5α[(2-tetrahydropyranyloxy)methyl]2H-cyclopenc[b
] Furan-2-ol was obtained.

Example 13 7-t:3α-hydroxymethyl-5α-hydroxy-
2β-(4,4-dimethyl-3α-hydroxy-t-trans-octenyl)1α-cyclopentyliosis-
An ethereal solution of 5-heptenoic acid was treated with a solution of diazomethane in diethyl ether until the yellow color persisted for more than 10 minutes.

The solvent was evaporated and methyl 7-[3α-hydroxymethyl-5α-hydroxy-2β-(4゜4-dimethyl-3
α-hydroxy-t-trans-octenyl)-1α-
Cyclopentyl iosis 5-heptenoate was obtained.

Example 14 11-Homo-prostaglandin F2α, L L a , 15-bis-(2-tetrahydropyranyl ether) was converted to 11-homo-prosfuglandin F2α, lla, 15-bis according to Example 13θ) method. (2-tetrahydropyranyl ether) methyl ester.

By the method of Example 7, 11-homo-prosufuglandin F2α, 11. a, 15-bis-(2-tetrahydropyranyl ether) methyl ester was hydrolyzed to 11-homo-prostaglandin F2α methyl ester.

Example 15 3°3aβ,4,5,6,6aβ-hexahydro4β-[3 in hexamethylphosphate triamide 1507rLl
α-(2-tetrahydropyranyloxy)-4-fluoro-t-trans-octenyl]5α-methyl-2H-
Cyclopenc (b) Furan-2-ol 3.29 (8
, 6mM), 7.0g (0,0384M) of sodium bistrimethylsilylamide and 8.4g (4,carboxybutyl)-triphenylphosphonium bromide.
The mixture was reacted with 2.2 equivalents of Witzteig reagent, which was formed by reaction with g (0,019M).

After stirring for 30 minutes, the hexamethylphosphoric triamide was removed under high vacuum.

The residue was treated with IN sodium hydroxide and the mixture was stirred at room temperature for 2 hours.

The mixture was then extracted with ether and the aqueous layer was separated and carefully acidified.

The aqueous mixture was extracted with ether.

The ether solution was dried (Na2804) and the solvent was removed under reduced pressure.

The residue was chromatographed on silica gel and 7-(3
α-Methyl-5α-hydroxy-2β-[3α-(2-
Tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl)-1α-cyclopentyl)-cis-5-heptenoic acid was obtained.

7-[3α-methyl-5α-hydroxy-2β-[3α(2-tetrahydropyranyloxy)-4-fluoro-t-trans-octenylo-1-cyclopentyl]-cis in 5 ml of a 3:1 volume acetic acid/water solution. A solution of 200 μl of -5-heptenoic acid was held at 35° for 15 hours.

The solvent was then removed under high vacuum and the residue was purified by column chromatography to give 7-[3α-methyl-5α-hydroxy-2β-(3α-hydroxy-4-fluoro-t-
Trans-octenyl)-1α-cyclopentyliosis-5-heptenoic acid was obtained.

The starting materials 3,3aβ, 4,5,6.6aβhexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4-fur-t-t-lans-octenyl]-5
α-Methyl-2H-cyclopenta[b]furan-2-ol could be produced as follows.

3.3aβ, 4,5,6.6aβ-hexahydro-4β
-Formyl-5α-methyl-2-oxo 2H-cyclopenta[b]furan was first prepared essentially as described in Example 28 for the preparation of the homolog without the methyl at position 5. .

Sodium hydroxide 0.72 in 150ml dry grime
g suspension in dimethyl (2-oxo-3-fluoro1), after stirring for 5 hours, dissolved in Glyme 307IL1.

3aβ, 4, 5. , 6, 6 aβ-hexahydro-4β-formyl-5α-methyl-2-oxo-
5 g of 2H cyclopenta[b]furan was added dropwise at 00.

After stirring at room temperature for 3 hours, 500 ml of diethyl ether
The mixture was washed with water.

Dry the organic layer with M. 9SO4), the solvent was removed under reduced pressure.

The residue was washed with 75g of silica gel and 3.3aβ~
4,5,6,6aβ1hexahydro-4β-(3-oxo-4-fluoro-1-trans-octenyl)-5α
-Methyl-2-oxo2H-cyclopenta[b]furan was obtained.

3,3aβ-4,5 in dry Grim lOO1rLl.

6,6aβ-hexahydro-4β-(3-oxo-4-
Fluoro-1-trans-octenyl)5α-methyl-
2-oxo-2H-cyclopenta[b]furan 4.5g
An excess of zinc borohydride in 50 ml of grime was added to the solution and the resulting solution was stirred for 3 hours.

Cool the solution to Oo, 200 ml of water, 40 ml of ether.
07111 and 10 TLl of 0.5N sulfuric acid.

The ether was separated and dried (MgSO4), the solvent was removed under reduced pressure, and the 3,3aβ,4,5,6.

6aβ-hexahydro-4β-(3-hydroxy-4-
Fluoro-1-trans-octenyl)5α-methyl-
2-oxo-2H-cyclopenta[b]furan was obtained.

Column chromatography on silica gel using diethyl ether/hexane (70:30 parts by volume) first produced 3,3aβ4,5,6.6aβ-hexahydro-4β (
3a-Hydroxy-4-fluoro-1-trans-octenyl)-5α-methyl-2-oxo2H-cyclopenta(b) Furan and 3,3aβ.

4,5,6,6aβ-hexahydro-4β-(3
βhydroxy-4-fluoro-1-trans-octenyl)-5α-methyl-2-oxo-2Hcyclopenta(
b) Furan was obtained.

3,3aβ,4,5 in 200 mg of methylene chloride.

6,6aβ-hexahydro-4β-(3α-hydroxy-4-fluoro-1-trans-o'7tenyl)-5α
-Methyl-2-oxo-2H-cyclopenta(b) 25 g of a solution of 5 g of furan, 1.2 g of dihydropyran and 25 m9 of p-h luenesulfonic acid.

The mixture was stirred for 3 hours.

The solution was washed with saturated sodium bicarbonate solution, the methylene chloride solution was dried (MgSO4), and the volatile components were evaporated under reduced pressure. (2-Tetrahydropyranyloxy)-4-fluoro-1-trans-octenylo5α-methyl-2-oxo-2H-cyclopenta[b
] Obtained a franc.

3,3aβ,4,5,6°6aβ-hexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4-fluoro-l trans-octenyl-5α-methyl-2oxo-2H-cyclopenta in 150TrLl of toluene (b) One equivalent of diisobutylaluminum hydride in the same solvent was added dropwise to a solution of 53 g of furan at -78°.

The reaction mixture was stirred at the above temperature for 2 hours, after which 20 TLl of methanol was slowly added and the mixture was stirred at room temperature for 2 hours.

The mixture was then filtered through a bed of charcoal, the charcoal was washed with ethyl acetate, and the solvent was removed under reduced pressure.

The residue was washed through a silica gel column and the 3,3aβ
, 4,5,6.6aβhexahydro-4β-[3α-(
2-tetrahydrohyranyloxy)-4-fluoro-1
-trans-octenyl]-5α-methyl-2H-cyclopenta(b)furan-2-ol was obtained.

Example 16 By the method of Example 15, 3,3aβ, 4, 5゜6
．． 6aβ-hexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4-fluoro4-methyl-1
-trans-octenyl]5α-methyl-2H-cyclopenta[b]furan-2-ol to 7-[3-methyl-5
α-hydroxy-2β-[3α-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]-■α-cyclopentyl]-cis-
Changed to 5-heptenoic acid.

7-(3α-methyl-5α-
Hydroxy-2β-(3a-(2-tetrahydropyranyloxy)-4-fluoro-4methyl-1-trans-
Octenyl]-lα-cyclopentyl]-cis-5-heptenoic acid was converted to 7[3α-methyl-5α-hydroxy-2β
-(3αhydroxy-4-fluoro-4-methyl-l-
trans-octenyl)-1α-cyclopentyl]cis-5-heptenoic acid.

Starting material 3,3αβ,4,5,6.6aβhexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-1-trans-octenyl]5α-methyl 2H-cyclopenta (t)) Furan-2-ol could be produced as follows.

By the method of Example 11, lithium dimethylmethylphosphonate was reacted with ethyl 2-methyl-2-fluorohexanoate to form dimethyl (2-oxo-3-methyl-3-fluoroheptyl) with a boiling point of 106'10.2 mm H& ) The phosphonate was removed.

By the method of Example 15, 3,3aβ, 4, 5゜6
．． 6aβ-hexahydro-4β-formyl 5α-methyl-2-oxo-2H-cyclopenta[b]furan to dimethyl (2-oxo-3-methyl 3-fluoroheptyl)
Reacted with phosphonate, 3.3aβ, 4,5,6.6
aβ-hexahydro 4β-(3-oxo-4-methyl-
4-fluoro-1-trans-octenyl)-5α-methyl 2-oxo-2H-cyclopenta[b] was obtained.

By the method of Example ■5, 3,3aβ, 4, 5゜6
．． 6aβ-hexahydro-4α-(3-oxo-4-fluoro-4-methyl-l-trans-octenyl)-5
α-Methyl-2-oxo-2H=cyclopenta[b] is converted into furan by 3,3aβ, 4°5.6.6aβ-hexahydro-4β-(3α-hydroxy-4-fluoro-4-methyl-1-trans -octenyl)5α-methyl-2-
Oxo-2H-cyclopenta(1))furan and 3,3
aβ.

4.5,6.6aβ-hexahydro-4β-(3βhydroxy-4-fluoro-4-methyl-l trans-octenyl)-3α-methyl-2-oxo-2H-cyclopenta(b), and this were separated by color chromatography in the method of Example 15.

By the method of Example 15, 3,3aβ, 4, 5゜6
．． 6aβ-hexahydro-4β-(3α-hydroxy-
4-fluoro-4-methyl-1-1-trans-octenyl)5α-methyl-2-oxo2H-cyclopenta(
b) 3,3aβ of furan.

4.5,6.6aβ-hexahydro-4β-[3α(2
-tetrahydropyranyloxy)-4-fluoro-4-
Methyl-1-trans-octenyl]5α-methyl-2
-Oxo-2H-cyclopenta[b]furan was changed.

By the method of Example 15, 3,3aβ, 4, 5゜6
．． 6aβ-hexahydro-4β-[3α-(2tetrahydropyranyloxy)-4-fluoro4-methyl-1-
trans-octenyl]5α-methyl-2-oxo-2
H-cyclopenta[b]furan as 3,3aβ,4,5,
6.6aβhexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-
It was changed to 1-trans-octenylio5α-methyl 2H-cyclopenta[b]furan-2-ol.

Example 17 By the method of Example 15, 3,3aβ, 4, 5゜6
．． 6aβ-hexahydro-4β-[3α-(2tetrahydropyranyloxy)-4,4,dimethyl-t-trans-octenyl]-5α-methyl-2H-cyclopenta[b]furan-2-ol with 7-[ 3α-methyl-5α
-hydroxy 2β-[3α-(2-tetrahydropyranyloxy)-4-4-dimethyl-1-trans-octenylio1α-cyclopentyl]-cis-5-heptenoic acid.

By the method of Example 15, 7-[3α-methyl5α-hydroxy-2β-[3α-(2-tetrahydropyranyloxy)-4,4-dimethylt-trans-octenylo1α-cyclopentyl]-cis-5- Heptenoic acid was converted into 7-(3α-methyl-5α-hydroxy-2β-(3α
-hydroxy-4-4-dimethyl-t-trans-octenyl)-1α-cyclopentyl]-cis-5-heptenoic acid.

Starting materials 3,3aβ,4,5,6,6aβhexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4,4-dimethyl-1-)lans-octenyl]-
5α-Methyl-2H-cyclopenta(b) Furan-C-
Or could be prepared as follows: 3,3aβ, 4,5°6.6 by the method of Example 15
aβ-hexahydro-4β-formyl-5α-methyl-
2-Oxo-2H-cyclopenta(b)furan is reacted with dimethyl (2-oxo-3,3 dimethylhebutyl)phosphonate to give 3°3aβ,4,5,6,6aβ-hexahydro-4β-(3- Oxo-4,4-dimethyl-1
-trans-octenyl)-5α-methyl-2-oxo-2H-cyclopenta[b]furan was obtained.

By the method of Example 15, 3,3aβ, 4,5°6.6
aβ-hexahydro-4β-(3-oxo4,4-dimethyl-t-h lance-octenyl)5α-methyl-2-
Oxo-2H-cyclopenta[b]furan is 3,3aβ
, 4,5,6゜6aβ-hexahydro-4β-(3α-
hydroxy-4,4-dimethyl-t-trans-octenyl)5α-methyl-2-oxo-2H-cyclopenta[b]furan and 3,3aβ,4,5,6°6aβ-hexahydro-4β-(3β- Hydroxy-4,4-dimethyl-1-trans-octenyl)-5α-methyl-2
-oxo-2H-cyclopenta[b]furan, which was separated by column chromatography in the manner of Example 5.

By the method of Example 15, 3-3aβ, 4,5°6.6
aβ-hexahydro-4β-(3α-hydroxy-4,
4-dimethyl-l-trans-octenyl)-5α-methyl-2H-cyclopenqua]furan to 3,3aβ,4
, 5.6.6aβ-hexahydro-4β-[3α-(2
-tetrahydropyranyloxy)-4,4-dimethyl-
It was changed to 1-trans-octenylo5α-methyl-2-oxo2H-cyclopenta(b)furan.

By the method of Example 15, 3,3aβ141516.6
aβ-hexahydro-4β-[3α-(2tetrahydropyranyloxy)-4,4-dimethyl-1-trans-
octenylo5α-methyl-2-oxo-2H-cyclopenta(b) furan 3,3aβ,4,5,6.6a
β-hexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4,4-dimethyl-1-transoctenyl]-5α-methyl-2H-cyclopenta(b)
Changed to furan-2-ol.

Example 18 By the method of Example 15, 3,3aβ, 4,5°6.6
aβ-hexahydro-4β-[3α-(2tetrahydropyranyloxy)-4-fluoro-trans-octenyl’)l-2H-cyclopenta(b) furan-2-ol to 7-(5α-hydroxy-2β- [3α-(2-
Tetrahydropyranyloxy)-4-fluoro-t-transoctenyl]-1α-cyclopentyl)-cis5
-Switched to heptenoic acid.

7-[5αhydroxy-2β-[3α-(2-tetrahydropyranyloxy)-4-fluoro-t-trans-octenyl)- in 5 ml of a 3:l volume acetic acid/water solution.
1α-cyclopentyliosis-5-heptenoic acid 200
The 7n9 solution was held at 35' for 15 hours.

The solvent was removed under high vacuum and the residue was purified by column chromatography to give 7[5α-hydroxy-2β-(3α
-Hydroxy-4-fluoro-t-trans-octenyl)1α-cyropentyl]-cis-heptenoic acid was obtained.

Starting materials 3,3aβ, 4,5,6.6aβhexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4-fluoro-t-transoctenyl)-2H
- Cyclopenta[b]furan-2-ol could be prepared as follows: dichlorohexanedione (165,9,1,47M), bronze (4,5,?) and 20% by weight hydroxide Allyl bromide (
195g, 1.62M) was boiled over 15 minutes.

After 6 hours, the reaction mixture was mixed with 1500 ml of 5% by weight aqueous sodium hydroxide solution and 10100 ml of ethyl nitrate, filtered and the dispersed aqueous layer was acidified with 4N hydrochloric acid to a pH value of 1.

A brown solid formed upon freezing to Oo.

This solid was taken up in ethyl acetate and the solution was dissolved in water (3x
Washed with 150 mO, dried (Mg504), treated with charcoal and concentrated until cloudy.

2-aryl/L/-1 with a melting point of 125-12r when cooled
, 3-cyclohexanedione was collected.

Oo to a solution of 2-allyl-1,3 cyclohexanedione (132,9,0,87M) in 550 ml of methanol
and t-butylhypochlora/ft(104,6,9,0
, 196M) was added dropwise.

The temperature was not allowed to rise above 20'.

The methanol was removed under vacuum in a 40° water bath and the remaining oil was taken up in benzene.

The benzene solution was diluted with 5% sodium thiosulfate (3x250T
rLl), 5% sodium bicarbonate (3 x 250 mA) and water (ix 250 mA).

The benzene was evaporated and the 2-chloro-2-
Allyl-1,3-cyclohexanedione was obtained.

Anhydrous powdered sodium carbonate (670 g) and 1300 TrL of dry (alumina) xylene were placed in a 31 volume three-necked flask equipped with a water trap, condenser, mixer, addition funnel, and argon inlet.

The flask was sparged with argon and the contents were brought to reflux.

2-chloro-2-allyl-1 in 200 ml of xylene,
A solution of 3-cyclohexanedione (147910, 78M) was added dropwise at such a rate that vigorous reflux was maintained.

After 45 hours, the reaction mixture was cooled, filtered, and added with sodium carbonate I
The Jum cake was thoroughly washed with ethyl acetate.

The solvent was evaporated and the remaining oil was carefully fractionated to a boiling point of 73.
2-allyl-2-cyclopenten-1-one of ˜84°/4.2 Hg was obtained.

2-allyl-2-cyclopenten-1-one (468g
, 0.38M), 180 ml of nitromethane and benzyltrimethylammonium hydroxide (35% by weight in methanol) was heated in oil to 60-65° for 4 hours.

The reaction mixture was cooled, acidified to pHHI3 with IN sulfuric acid, diluted with 500 TIL of ethyl ether, washed with saturated aqueous sodium chloride solution and dried (M, 9 SOa) (2 x 250 mA).

The solvent was evaporated to give 69 g (100%) of 2α-allyl-3β-nitromethylcyclopentanone as a yellow oil.

This compound could be further purified by distillation;
Boiling point 112° 10.025 mmHg.

Sodium permanganate (52,2,
9,0,26M) solution under argon.

2α-allyl-3β nitromethylcyclopentanone (18,3&, 0.1 M), 300 ml of acetone and 83 Tll of 10% (V/V) sulfuric acid for 1 hour at ~0°.
was added dropwise to the vigorously stirred mixture.

The reaction mixture was stirred for an additional 45 minutes at Oo, saturated with sodium chloride, and extracted with 3N tetrahydrofuran-methylene chloride.

The combined organic extracts were dried and evaporated to give crude 2α-carboxymethyl-3β-nitromethylcyclopencun-■-one as an oil, which was diluted with ethyl acetate-ethyl ether (L :4); melting point 88-90°.

2α-carboxymethyl-3β-nitromenalcyclopentan t-one (
2,10g, 10mM) solution in Albond.
A 1.06 M solution of lithium perhydro 9b boraphenaryl hydride in tetrahydrofuran 207111 (
21,6mM).

Ta.

The reaction mixture was stirred for 30 minutes and then allowed to warm to 0°.

At this point, use cyclohexane 2001rL11
The mixture was poured into a separatory funnel containing 50 TIL of ethyl acetate and 507,711 L of water.

The aqueous layer was separated and the organic layer was washed with water (2X20m0).

The combined aqueous extracts were immediately acidified to pHHI3 with 4N hydrochloric acid, saturated with sodium chloride, and extracted with 3 volumes of tetrahydrofuran-methylene chloride solution (3×50 mO).

The combined organic extracts were dried (Mg5O4) and concentrated to give an oil, which was taken up in 200 TfLl of benzene and refluxed in a water bucket for 2 hours.

The resulting benzene solution was washed with a 5% by weight aqueous solution of Mg5O
4), concentrated as a colorless oil, 3°3aβ,4,5,6
．． 6aβ-hexahydro-4β-nitromethyl-2-oxo-2H-cyclopenta[b]furan was obtained.

3,3aβ, 4,5゜6, in 35ml of anhydrous methanol
．． 6aβ-hexahydro-4β-nitromethyl-2-oxo-2H-cyclopenta(b)furan (1,08g,
4.85771M) at 0° under Alcon.
2.3M lithium methylate solution in methanol 2.6
treated with rrLl (6.0mM).

The solvent was evaporated and the remaining X solid was dried under vacuum at 25°.

This dry salt was diluted with -1O under argon. 15 ml of saturated borax solution were added at , followed by dropwise addition of sodium permanganate trihydrate (0.69 g, 35 mmol) in 6 ml of water.

The reaction mixture was immediately filtered through diatomaceous earth and
Extracted with 12 methylene chloride acetone (4 x 60 TIL0).

The dried (M,!7S04) organic extract was evaporated to give 3.3aβ,4,5,6,6aβ-hexahydro-4β-formyl-2-oxo-2H-cyclopenta(
b) Furan was obtained.

Dimethyl (2-oxo-3-
Fluoroheptyl)phosphonate 3゜3aβ,4,5
, 6.6aβ-hexahydro-4β-formyl-2-oxo-2H-cyclopenta(b) reacted with furan, 3
,3aβ,4,5゜6.6aβ-hexahydro-4β-
(3-oxo4-fluoro-1-trans-octenyl)2-oquinone 2H-cyclopenta(b)furan was produced.

By the method of Example 15, 3,3aβ141516.6
aβ-hexahydro-4β-(3-oxo-4-fluoro-■-trans-octenyl) = 2-oxo-2H-
3,3aβ,4 by reacting cyclopenta(b)furan
,5,6.6aβ-hexahydro-4β-(3-hydroxy-4-fluoro-1-1-lans-octenyl)-
2-oxo2H-cyclopenta[b]furan was produced.

Chromatographed on silica gel in the method of Example 15, first 3,3aβl 41516 +6aβ-
Hexahydro-4β-(3α-hydroxy-4-fluoro-1-trans-octenyl)2-oxo-2H-cyclopenta(b)furan was obtained.

Also 3,3aβ by chromatography. 4.5,6.
6aβ-hexahydro-4β-(3β-hydroxy-4
-fluoro-1-transoctenyl)-2-oxo-
2H-cyclopenta(b)furan was also obtained.

By the method of Example 15, 3,3aβ, 4,5°6.6
aβ-hexahydro-4β-[3α-hydroxy-4-
Fluoro-■-trans-octenyl]-2-oxo-
2H-cyclopenta[b]furan to 3,3aβ,4,5
, 6.6aβ-hexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl-2-oxo-2H-cyclopenta[
b] Changed to franc.

By the method of Example 15, 3,3aβ+4+5t6.6
aβ-hexahydro-4β-[3α-(2tetrahydropyranyloxy)-4-fluoro1-4lans-octenylo2-oxo2H-cyclopenta[b]furan to 3,3aβ.

4.5,6.6aβ-hexahydro-4β-[3α(2
-tetrahydropyranyloxy)-4-fluoro-1-
trans-octenyl)-2H-cyclopenta(b) furan-2-ol.

Example 19 3,3aβ141516.6 was prepared by the method of Example ■5.
aβ-hexahydro-4β-[3α-(2tetrahydropyranyloxy)-4-fluoro4-methyl-1-trans-octenyl]2H-cyclopenta(b)furan-
2-ol to 7-[5α-hydroxy-2β-[3α-
(2-tetrahydropyranyloxy)-4-fluoro4
-Methyl-t-trans-octenylo1αcyclopentyl]-cis-5-heptenoic acid.

By the method of Example 18, 7-(5α-hydroxy-2
19-(3α-(2-tetrahydropyranyloxy)-
4-fluoro-4-methyl-1-trans-octenyl-1α-cyclopentyl]cis-5-heptenoic acid 7
-(5α-hydroxy-2β-(3α-hydroxy-4
-fluoro-4-methyl-t-+-lance-octenyl)-1αcyclopentyl]-cis-5-heptenoic acid.

The starting materials 3,3aβ, 4,5,6.6aβ-hexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl l-trans-octenyl)-2H-cyclopenta[ b] Furan-2-ol could be produced as follows; 3,3aβ+4y5+6.6 by the method of Example 15
aβ-hexahydro-4β-formyl-2oxo-2H
-cyclopenta[b]furan with dimethyl (2-oxo-
3-Methyl-3-fluoroheptyl)phosphonate to give 3,3aβ.

4.5,6.6aβ-hexahydro-4β-(3oxo-4-methyl-4-fluoro-1-trans-octyl)-2-oxo-2H-cyclopenta(b)furan was obtained.

By the method of Example 22, 3,3aβ+4+5t6.6
aβ-hexahydro-4β-[3-oxo4-fluoro-4-methyl-1-trans-octenyl)-2-oxo-2H-cyclopenta[b]furan with 3,3aβ,4
,5,6,6aβhexahydro-4β-(3α-hydroxy-4-fluoro-4-methyl-1-)lanth-octenyl)-2-oxo-2H-cyclopenta(b)furan and 3,3aβ,4,5 , 6.6aβ-hexahydro-4β-(3β-hydroxy-4-fluoro-4-methyl-■-trans-octenyl)-2-oxo-2H-
Example 1
Separation was performed by column chromatography in method 5.

By the method of Example 15, 3,3aβ141516.6
aβ-hexahydro-4β-(3α-hydroxy-4-
Fluoro-4-methyl-1-trans-octenyl)-
2-oxo-2H-cyclopenta(b”)furan with 3,
3aβff 4151616aβ-hexahydro-4β
-[3α-(2-tetrahydropyranyloxy)-4-
Fluoro-4methyl-t-trans-octenyl]-2
-Oxo2H-cyclopenta[b]furan.

By the method of Example 15, 3,3aβ, 4,5°6.6
aβ-hexahydro-4β-[3α-(2tetrahydropyranyloxy)-4-fluoro4-methyl-1-trans-octenyl]-2oxo2H-cyclopenta[
b] Furan to 3°3aβ,4,5,6.6aβ-hexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4-fluoro-4-methyl-l-transoctenyl)-2H-cyclopenta [b] Changed to furan-2-ol.

Example 20 By the method of Example 15, 3,3aβ141516.6
aβ-hexahydro-4β-[3α-(2tetrahydropyranyloxy)-4,4-dimethyl-t-t-lans-octenyl)-2H-cyclopenta[b]furan-2
-ol to 7-[5αhydroxy-2β-[3α-(2
-tetrahydropyranyloxy)-4,4-dimethyl-
1-4 lance-octenylo 1α-cyclopentyl]
It was changed to cis-5-heptenoic acid.

By the method of Example 18, 7-(5α-hydroxy-2
β-[3α-2-tetrahydropyranyloxy)-4
,4-dimethyl-1-transoctenyl-1α-cylopentylcis-5heptenoic acid and 7-(5α-hydroxy-2β(3α-hydroxy-4,4-dimethyl-
1-trans-octenyl)-1α-cyclopentyl]
Changed to cis-5-heptenoic acid.

Starting materials 3,3aβ,4,5,6.6aβhexahydro-4β-[3α-(2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl)-
2H-cyclopenta(b'1 furan-2-ol could be prepared as follows: 3,3aβ141DI6.6 by the method of Example 15.
aβ-hexahydro-4β-formyl-2oxo-2H
-cyclopenta[b]furan with dimethyl (2-oxo-
reacted with 3,3-dimethylheptyl)phosphonate,
3,3aβj 4 j 516,6aβ-hexahydro-4β-(3-oxo-4,4-dimethyl-1-trans-octenyl)2-oxo-2H-cyclopenta[b
] produced furan.

By the method of Example 15, 3,3aβ14. ”16.6
aβ-hexahydro-4β-(3-oxo-4,4-dimethyl-l-trans-octenyl) = 2-oxo-2
H-cyclopenta(b) furan to 3,3aβ, 4,5,
6,6aβ-hexahydro-4β-(3α-hydroxy-4,4-dimethyl-t-trans-octenyl)-2
-oxo2H-cyclopenta(b) furan and 3,3a
β.

Example 15 separated by chromatography in the method of

By the method of Example ■5, 3,3aβ, 4, 5゜6
．． 6aβ-hexahydro-4β-(3α-hydroxy-
4,4-dimethyl-1-trans-octenyl)-2H
-cyclopenta[b]furan-2-one 3,3aβ,
4,5,6.6aβ-hexahydro-4β-[3α-(
2-tetrahydropyranyloxy)-4,4-dimethyl-1-trans-octenyl)-2H-cyclopenta[
b] Changed to furan-2-one.

By the method of Example ■5, 3,3aβ, 4,5°6.6
aβ-hexahydro-4β-[3α-(2tetrahydropyranyloxy)-4,4-dimethyl-1-trans~
octenyl]-2-oxo2H-cyclopenta(b)furan to 3,3aβ.

4.5,6.6aβ-hexahydro-4β-[3α[2
-tetrahydropyranyloxy)-4,4dimethyl-t
-trans-octenyl)-2Hcyclopenta(b)furan-2-ol.

Example 2 was converted to 3,3aβj 41516.6 by the method of Example 1.
aβ-hexahydro-4β-[4,4-dimethyl-3α
-(2-tetrahydropyranyloxy)-t-h lance-octenyl]-5α-methoxymethyl-2H-cyclopentaCb)furan 2-ol in hexamethylphosphoric triamide and sodium bis-trimethylsilylamide and ( 7-[2β-(4,4-dimethyl 3α-(2-tetrahydropyranyloxy)-1-trans-otenyl] by Wittstein reagent derived from 4-carboxybutyl)triphenylphosphonium furomite
methyl 7-[2β-[4,4- Dimethyl 3α-
(2-Tetrahydropyranyloxy)-ltrans-octenyl]-3α-methoxymethyl-5α-hydroxy-1α-cyclopentyl]cis-5-heptenoate was obtained.

Mixture of acetic acid, water and acetonitrile (2:1:4) 5
7-[2β-[4,4-dimethyl-3α- in 0TLl
(2-(tetrahydropyranyloxy)1-trans-
A solution of 400 μl of [octenyl]-3α-methoxymethyl-5α-hydroxy-1α-cyclopentyltosis-5-hebutenoic acid was heated to 37° for 15 hours.

The solvent was evaporated and then purified by column chromatography on silica gel to give 7-[2β-(4,4-dimethyl 3α-hydroxy-1-trans-octenyl)3α
7-[2β-(4
,4-dimethyl3β-hydroxy-1-trans-octenyl)3α-methoxymethyl-5α-hydroxy1α
-Cyclopentyltosis-5-hephthenoate.

Starting materials 3,3aβ,4,5,6,6aβhexahydro-4β-(4,,4-dimethyl-3α(2-tetrahydropyranyloxy)-1-trans-octenyl)-
5α-Methoxymethyl 2H-cyclopenta(b) Furan-2-ol can be prepared as follows.
．． 6.6aβ-hexahydro-4β-[4,4dimethyl-3α-(2-tetrahydropyranyloxy)-1-1
-Lance-octenyl]-5αhydroxymethyl-2H
- A solution of 5.5 g of cyclopenta[b]furan-2-one in 40 ml of dimethoxyethane with 0.0% sodium hydroxide
Dropped into 34g of stirred slurry.

After 10 minutes, 2.0 g of methyl iodide was added and the mixture was stirred for 2 hours.

The mixture was then diluted with 100 ml of diethyl ether and 50 TL of hexane, washed with saturated aqueous sodium chloride solution and dried (Mg5O4), the solvent was evaporated and the crude 3
,3aβ,4,5,6.6aβ-hexahydro-4β-
[4,4-dimethyl-3α(2-tetrahydropyranyloxy)-1-+-lance-octenyl-5α-methoxymethyl 2H-cyclopent(b)furan-2-one was obtained, which was columned on silica gel. Purified by chromatography.

By the method of Example 1, 3,3aβ+ 4+ 5 +6
．． 6aβ-hexahydro-4β-[4,4-dimethyl-
3α-(2-tetrahydropyranyloxy)-t-trans-octenylo5α-methoxymethyl-2H-cyclopenta[b]furan 2-one was reduced with bis-(3methyl-2-butyl)-borane in tetrahydrofuran. , 3°3aβ, 4,5,6.6aβ-hexahydro4β
-[4,4-dimethyl-3α-(2-tetrahydropyranyloxy)-t-trans-octenyl-5α-methoxymethyl-2H-cyclopenta[b]furan-2-
I went all.

Example 22 By the method of Example 1, 3,3aβr 4+ 5 y6
．． 6aβ-hexahydro-4β-[3β-(2tetrahydropyranyloxy)-1-transoctenylcy5
α-Carbomethoxy-2Hcyclopenc[b]furan-
2-ol 7 [3α-carbomethoxy-5α-hydroxy 2β-[3β-(2-tetrahydropyranyloxy)-1-1-lans-octenyl]-1α-cyclopentyl]-1-cis-5-heptenoic acid When this product was decomposed by the method of Example 1, 7-(3α-
Carbomethoxy-5α-hydroxy 2β-(3β-hydroxy-1-trans-octenyl)1α-cyclopentyl]-cis-5 heptenoic acid was obtained.

Starting materials 3,3aβ, 4,5,6.6aβhexahydro-4β-[3β-(2-tetrahydropyranyloxy)-t-t-lans-octenyl]5α-carbomethoxy-2H-cyclopenta[b]furan -2-ol was prepared by the method of Example 1, 3,3aβ with a melting point of 55 to 57°,
4,5,6゜6aβ-hexahydro-4β-[3β-(
2-tetrahydropyranyloxy)-t-t-lans-
octenylo5α-carbomethoxy-2-oxo2H
- 3.3aβ via cyclopenta(b) furan intermediate
, 4,5,6.6aβ-hexahydro 4β-(3β-hydroxy-1-trans-octenyl)-5α-carbomethoxy-2-oxo2H-cyclopenta(b) could be prepared from furan.

Example 23 By the method of Example 15, 3,3aβ+4+5+6.6
aβ-hexahydro-4β-[3β-(2tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl)-5α-methyl-2H-cyclopenta[b]furan-2-ol with 7-(3α- Methyl-5α-hydroxy-2β[3β-(2-tetrahydropyranyloxy)4-fluoro-t-trans-octenyl]lα-cyclopentyl]-cis-5-heptenoic acid, which was further converted into 7-[3α -methyl 5α-hydroxy-2β-
(3β-hydroxy 4-fluoro-1-trans-octenyl-1■α-cyclopentyl)-cis-5-heptenoic acid.

Starting materials 3,3aβ, 4,5,6.6aβ hexahydro-4β-[3β-(2-tetrahydropyranyloxy)-4-fluoro-1-trans-octenyl]-5α
-Methyl-2H-cyclopenta[b]furan-2-ol was prepared by the method of Example 15 for 3,3aβ, 4,5,6
．． 6aβhexahydro-4β-(3β-hydroxy-4
Fluoro-1-trans-octenyl)-5α methyl-
2-oxo-2H-cyclopenta[b]furan to 3,
3aβ, 4,5,6.6aβ-hexahydro-4β-[
3β-(2-tetrahydropyranyloxy)-4-fluoro-t-t-lans-octenyl-5α-methyl-2
-Oxo-2H-cyclopenta(6) could be produced via a furan intermediate.

Claims (1)

[Scope of Claims] 1 General formula [wherein R is hydrogen or lower alkyl; R is hydrogen, lower alkyl, carboxy, lower alkoxycarbonyl, hydroxymethyl, lower a-C-CH-8-CH
3 Rukoxymethyl or the group 11 ↓OO; R4 is hydrogen, lower alkyl or fluorine; R5 is hydrogen or lower alkyl; the dotted bond can be hydrogenated; with the proviso that R4 and R5
are both hydrogen, R1 shall be lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl or the group -C-CH2-8-CH3]11
↓ In producing cyclopenkune derivatives of OO and their enantiomers and racemates, the general formula [where R4 and R
5 has the above meaning; R6 is a hydroxy group protected with an ether or ester group that can be decomposed by water;
RIO is hydrogen, lower alkyl, carboxy, lower alkoxycarbonyl, lower alkoxymethyl, or a hydroxymethyl group protected with a hydrolyzable ether or ester group; unless R4 and R5 are both hydrogen, % RIO is lower alkoxycarbonyl, lower alkoxymethyl, or a hydroxymethyl group protected with a hydrolyzable ether or ester group], or its enantiomer or racemate, if necessary, where RIO is a carboxy or **lower alkoxycarbonyl, in the presence of dimethyl sulfoxide, a base and the general formula [wherein R7s R70 and R71 are aryl or di(lower alkyl)-amino, and Y is halogen It is. if necessary, the resulting general formula [wherein R4y R5 and R6 have the above meanings and R1
1 is the same as RIO above, and furthermore the group -C-CH
2-8-CH3] ↓ 0 0 of the 5-heptenoic acid derivative or its enantiomer or racemate is subjected to saturation by hydrogenation of the double bond in the side chain containing the carboxy group; the reaction product is then Conversion of the protected hydroxy groups that may be present in the protected hydroxy groups R6 and R1, into hydroxy groups, optionally in any desired order; optionally, the carboxy groups present are converted by esterification. Cyclopencune derivatives of the above general formula (1) and their Method for producing enantiomers and racemates.