JPH10182598A - Production of fluorine-containing prostaglandin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a fluorine-containing prostaglandin derivative having high activities as a medicine and further having fluorine atom at 15-position having no side effect by allowing specific phosphoranes to act on a specified fluorine-containing lactols. SOLUTION: Alcohols of formula I (A is ethylene, etc.; R<1> is a 3-8C alkyl, etc.; R<3> is H or a protecting group of OH) is fluorinated by a trifluorinated dialkylaminosulfur derivative, which is a nucleophilic fluorinating agent, etc., e.g. morpholinosulfur trifluoride to provide fluorine-containing lactones of formula II, and the lactones is reduced by diisobutylaluminum hydride, etc., to provide a fluorine-containing lactones of formula III. The objective compound having a structure of formula V is obtained by reacting 1 equivalent compound of formula III with 0.1-20 equivalents phosphoranes of formula IV [R<2> is a protecting group of H or OH; X is CH2 , O or S; Z is OR<4> , etc., (R<4> is H, an alkyl, etc.); R<10> is an aryl, an alkyl, etc.] by a so-called Wittig-type reaction to provide the objective compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a fluorinated prostaglandin derivative having a fluorine atom at the 15-position, a novel intermediate useful for producing the fluorinated prostaglandin derivative, and a method for producing the same. .

[0002]

2. Description of the Related Art Natural prostaglandins (PGs) are a group of physiologically active substances synthesized in vivo, and regulate local cell functions of various tissues in the body as local hormones having various physiological activities. PGF, a kind of natural PG
Since they have a uterine contractile action, an anti-pregnancy action and an estrous cycle controlling action, they have been used as a labor-inducing agent and an animal sexual cycle synchronizing agent. Therefore, the development of PGF derivatives which are more effective as these pharmaceuticals and have no side effects is being studied in Japan and overseas.

[0003] PGF2α having a natural skeleton is a derivative in which fluorine is introduced at the 15-position, 15-fluoro-15.
-Deoxy PGF2α has been reported by Bezglov et al. 15-Fluoro-15-deoxy PGF2α
Is 100% of native PGF2α on respiratory smooth muscle.
A remarkable pharmacological action has been reported in which it exhibits a contractile activity of 1000 times and a relaxation activity of 1000 times, and has a similar effect to natural PGF2α on digestive and circulatory system smooth muscles (Izv. Akad). . Nauk SSSR, Ser. Biol., 6,831 (198
9)).

However, in the synthesis of 15-fluoro-15-deoxy PGF2α, natural PGA2 is fluorinated at position 15 and then converted to 15-fluoro-15-deoxy PGE2, and the carbonyl group at position 9 is reduced to form 15-fluoro-15-deoxy PGF2α. -Fluoro-15-deoxy PGF2α by a very impractical method (Dokl. Akad. Nauk,
SSSR, 250, 468 (1980)). There is no known prostaglandin F derivative having a fluorine atom at the 15-position other than 15-fluoro-15-deoxy PGF2α, and 15-fluoro-15-deoxy PGF having a non-natural side chain.
A versatile production method that can also synthesize 2α derivatives has been strongly desired.

[0005]

The present invention provides a versatile and practical method for producing a prostaglandin derivative having a fluorine atom at the 15-position of prostaglandin.

[0006]

DISCLOSURE OF THE INVENTION The present invention provides a novel method for producing a prostaglandin derivative having a fluorine atom at the 15-position of prostaglandin, a novel intermediate related to the production method, and a method for producing the intermediate. The present invention relates to a manufacturing method.

A fluorine-containing lactol represented by the following general formula (2) is reacted with a phosphorane represented by the following general formula (3) to produce a fluorine-containing lactol represented by the following general formula (1). A method for producing a prostaglandin derivative. A method for producing a fluorine-containing lactone represented by the following general formula (2), comprising reducing a fluorine-containing lactone represented by the following general formula (4). A method for producing a fluorinated lactone represented by the following general formula (4), comprising fluorinating an alcohol represented by the following general formula (5). Fluorine-containing lactol represented by the following general formula (2). Fluorine-containing lactones represented by the following general formula (4).

[0008]

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(General formulas (1), (2), (3),
In (4) and (5), A: ethylene group, vinylene group, ethynylene group, -OCH
_2- or -SCH _2- , R ¹ : substituted or unsubstituted alkyl group having 3 to 8 carbon atoms, substituted or unsubstituted alkenyl group having 3 to 8 carbon atoms, substituted or unsubstituted 3 to 8 carbon atoms An alkynyl group, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxyalkyl group, R ² and R ³ each independently represent a hydroxyl group X: CH ₂ , O, or S, Z: OR ⁴ , NR ⁵ COR ⁶ , NR ⁷ SO ₂ R ⁸ , or SR ⁹ , R ⁴ : hydrogen atom, alkyl group, alkenyl group, alkynyl group, a cycloalkyl group, an aryl group, an aralkyl group or a metal ^{ion,, R 6, R 8,} R 9: each independently, a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, Black alkyl group, an aryl group or an aralkyl group,, R ^5, R ^7: each independently a hydrogen atom or a metal ion, R ^10: a substituted or unsubstituted aryl group, a substituted or unsubstituted alkyl group, substituted or non A substituted aralkyl group or a dialkylamino group; an overlapping portion of a solid line and a broken line: a single bond or a cis or trans double bond. )

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the following description of the present specification,
When the organic group is “lower”, it means 1 to 6 carbon atoms. More preferred lower organic groups are organic groups having 1 to 4 carbon atoms. The “alkyl group” may be linear or branched, and a lower alkyl group is preferable unless otherwise specified.
Suitable examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like.

The "alkenyl group" is preferably a lower alkenyl group unless otherwise specified, more preferably a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and one unsaturated group. Suitable examples include vinyl, allyl, 1-propenyl, isopropenyl, 3-butenyl, 3-pentenyl, 4-hexenyl and the like.

The "alkynyl group" is preferably a lower alkynyl group unless otherwise specified, more preferably a straight-chain or branched alkynyl group having 2 to 6 carbon atoms and one unsaturated group. Examples include 1-propynyl, 2-propynyl, 3-butynyl, 3-pentynyl, 4-hexynyl and the like.

As the "alkoxy group", a wide range of general alkoxy groups is used, but a lower alkoxy group is preferable, and a linear or branched alkoxy group having 1 to 4 carbon atoms is more preferable. Examples include methoxy, ethoxy, propoxy, butoxy and the like.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. “Aryl group” refers to a monovalent aromatic hydrocarbon group, which may have a substituent (eg, a lower alkyl group, a halogen atom, a lower alkoxy group, a lower alkylamino group, etc.),
Preferable are phenyl groups and derivatives thereof. For example, phenyl groups, tolyl groups, p-halophenyl groups (for example, p-
Examples thereof include a chlorophenyl group and a p-bromophenyl group, and an alkoxyphenyl group (eg, a methoxyphenyl group and an ethoxyphenyl group).

The "aralkyl group" refers to an alkyl group substituted with an aryl group. The aryl group as the substituent includes those described above, and the alkyl group has 1 carbon atom.
To 4 are preferable. Suitable examples thereof include a benzyl group,
Examples include a benzhydryl group, a trityl group, and a phenethyl group.

"Cycloalkyl group" represents an unsubstituted or substituted 3- to 8-membered cycloalkyl group. When substituted, examples of the substituent include a lower alkyl group, a halogen atom, and an alkoxy group. Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a methylcyclohexyl group, a dimethylcyclopentyl group, a dimethylcyclohexyl group, a chlorocyclohexyl group, a dichlorocyclohexyl group, and the like.

"Halogenated alkyl group" means a lower halogenated alkyl group halogenated with one or more halogen atoms. Fluoromethyl group, difluoromethyl group, trifluoromethyl group, trifluoroethyl group,
Examples include a pentafluoroethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, and a bromomethyl group.

The term "acyl group" refers to a monovalent or polyvalent group formed by removing a hydroxyl group from all carboxyl groups of a carboxylic acid. The carboxylic acids include saturated or unsaturated aliphatic carboxylic acids, carbocyclic carboxylic acids, and heterocyclic carboxylic acids. The carbocyclic carboxylic acids include saturated or unsaturated cyclic aliphatic carboxylic acids and aromatic carboxylic acids.

In the general formula (1), the overlap between the solid line and the broken line represents a single bond, a cis or trans double bond, and a cis double bond is most preferred. In the above general formulas (1), (2), (4) and (5), A is preferably a vinylene group or an ethylene group, particularly preferably a vinylene group. Vinylene groups include cis and trans vinylene groups. A is particularly preferably a vinylene group of trans. In the above general formulas (1) and (3), X
Is particularly preferably CH ₂ .

The general formulas (1), (2), (4),
In (5), an organic group corresponding to X-chain of the organic groups and various PGF ₂ alpha acids corresponding to the X chain portion of native PGF ₂ alpha is preferred as R ^1. Examples of such an organic group include an alkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, an alkynyl group having 3 to 8 carbon atoms, and a ring having 3 to 8 carbon atoms.
There are aryloxy groups with aryl such as 8 cycloalkyl groups, aralkyl groups, phenyl groups, and these groups with various substituents.

The substituent may be a cycloalkyl group or an aryl group, such as a cycloalkyl-substituted alkyl group, a cycloalkyl-substituted alkenyl group, or an aryl-substituted alkenyl group. Further, an organic group in which a carbon atom of a chain organic group is substituted by an oxygen atom or a sulfur atom, or an organic group having a ring such as a cycloalkylene group or an arylene group between the chain organic groups may be used. Examples of the substituent for R ¹ include the above-mentioned substituents, a halogen atom, an oxygen atom-containing substituent, a sulfur atom-containing substituent, a nitrogen atom-containing substituent, and the like.

As the chain-like R ¹ , an alkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, and
And alkynyl groups of 8 and especially 5 to 6 linear groups and their monomethyl or dimethyl substituents.

Specific examples of these groups include n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl,
1-methylpentyl group, 1,1-dimethylpentyl group,
1-methylhexyl group, 2-methylpentyl group, 2-methylhexyl group, 3-pentenyl group, 1-methyl-3-
Pentenyl group, 1-methyl-3-hexenyl group, 1,1
-Dimethyl-3-pentenyl group, 1,1-dimethyl-3
-Hexenyl group, 2-methyl-3-pentenyl group, 2-
Methyl-3-hexenyl group, 3-pentynyl group, 1-methyl-3-pentynyl group, 1-methyl-3-hexynyl group, 2-methyl-3-pentynyl group, 2-methyl-3-
Hexynyl group, 1,1-dimethyl-3-pentynyl group,
A 1,1-dimethyl-3-hexynyl group and the like are preferable.
Among them, n-pentyl group, 2-methylhexyl group, 1
-Methyl-3-pentynyl, 1-methyl-3-hexynyl, and 1,1-dimethyl-3-hexynyl are particularly preferred.

As R ¹ which is a substituted or unsubstituted cycloalkyl group, a cycloalkyl group having 3 to 8 carbon atoms and a lower alkyl-substituted cycloalkyl group are preferable, and an unsubstituted cyclopentyl group, an unsubstituted cyclohexyl group, A cyclopentyl group substituted with an alkyl group having 1 to 4 carbon atoms and a cyclohexyl group substituted with an alkyl group having 1 to 4 carbon atoms are preferable.

R ¹ which is a substituted or unsubstituted aralkyl group includes a benzene ring substituted with a halogen atom, a halogenated alkyl group, an alkoxy group, a hydroxyl group, etc.
Aralkyl groups containing a furan ring, a thiophene ring, a naphthalene ring and the like are preferred. The alkyl portion of the aralkyl group (that is, the alkylene group) preferably has 1 to 4 carbon atoms. Particularly preferred aralkyl groups are phenyl groups or C1-C2 alkyl groups having a mono- or disubstituted phenyl group.

Specifically, phenylmethyl group, 2-phenylethyl group, 3-methylphenylmethyl group, 2- (3
-Methylphenyl) ethyl group, 3-trifluoromethylphenylmethyl group, 2- (3-trifluoromethylphenyl) ethyl group, 3-chlorophenylmethyl group, 2-
(3-Chlorophenyl) ethyl, 3,5-dichlorophenylmethyl, 3,4-dichlorophenylmethyl and the like are preferred.

R ¹ which is a substituted or unsubstituted aryloxyalkyl group includes a benzene ring, a furan ring, a thiophene ring, a naphthalene ring and the like substituted with a halogen atom, a halogenated alkyl group, an alkoxy group, a hydroxyl group and the like. Aryloxyalkyl groups are preferred. The number of carbon atoms in the alkyl group moiety that can be substituted with the aryloxy group is preferably 1 to 3.

Particularly preferred aryloxyalkyl groups are phenoxymethyl, 3-chlorophenoxymethyl, 3-fluorophenoxymethyl, 3-trifluoromethylphenoxymethyl, 3,5-dichlorophenoxymethyl, 3,4 A dichlorophenoxymethyl group,
A 3,5-difluorophenoxymethyl group, a 3,4-difluorophenoxymethyl group, a 3,5-bis (trifluoromethyl) phenoxymethyl group, and a 3,4-bis (trifluoromethyl) phenoxymethyl group.

As R ¹ other than the above, an alkyl group having 1 to 4 carbon atoms, which is substituted by the above cycloalkyl group, which is a kind of substituted alkyl group, is preferable. As the cycloalkyl group, a cyclopentyl group and a cyclohexyl group are preferable, and as the alkyl group, an alkyl group having 1 to 2 carbon atoms is preferable.

Of these R ¹ , particularly preferred R ¹ is CH ₂ O among the above aryloxyalkyl groups.
An aryloxymethyl group represented by Ar. Here, Ar represents a phenyl group or a monovalent heteroaromatic group having two or more substituents. The heteroaromatic ring refers to an aromatic heterocycle such as a furan ring and a thiophene ring. Ar
Is preferably a halogen atom, a lower alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkyloxy group, an alkylthio group, a halogenated alkylthio group, an acylamino group, or the like. Particularly preferred substituents are halogen atoms, especially chlorine and fluorine atoms.

Preferred Ar is a phenyl group having two or more substituents, and particularly preferred is a phenyl group having two halogen atoms (particularly, chlorine atoms) or two trifluoromethyl groups. Specific examples of particularly preferable Ar include 3,5-dichlorophenyl group, 3,4-dichlorophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 3,5-difluorophenyl group,
Examples include a 3,4-difluorophenyl group, a 2,4-difluorophenyl group, a 3,5-bis (trifluoromethyl) phenyl group, and a 3,4-bis (trifluoromethyl) phenyl group. Particularly, a 3,5-dichlorophenyl group and a 3,4-dichlorophenyl group are preferable.

The above general formulas (1), (2), (4),
In (5), R ² and R ³ are each independently a hydrogen atom or a hydroxyl-protecting group. In the reactions described below, it may be preferable that R ² and R ³ in the reacting compound are protecting groups. In such a case, the compound in which R ² or R ³ is a hydrogen atom can be subjected to the reaction by protecting its hydroxyl group. R ² and R ³ in the compound formed by such a reaction can be subsequently deprotected if necessary, and when the resulting compound is further subjected to the next reaction,
² and R ³ may remain as protecting groups. in this way,
When R ² or R ³ is a hydrogen atom, it can be converted to a protecting group as needed, and when R ² or R ³ is a protecting group, deprotection may be performed as necessary to make R ² or R ^{3 a} hydrogen atom. Can be converted to a compound. The general formulas (1), (2), (4),
R ³ may be different or the same between (5).

A fluorine-containing prostaglandin derivative represented by the general formula (1) is produced by a Wittig reaction between a fluorine-containing lactol represented by the general formula (2) and a phosphorane represented by the general formula (3). When a conversion reaction is performed, R
² is usually a hydrogen atom. This reaction product in which R ² is a hydrogen atom can then optionally convert R ² to a protecting group. For example, as described below, the carboxylic acid moiety (Z)
Is converted from Z in the reaction product to another Z in some cases, for example, a hydrogen atom R ² may be converted into a protecting group in advance. In the fluorination reaction for converting an alcohol represented by the general formula (5) into a fluorine-containing lactone represented by the general formula (4), R ³ usually needs to be a protecting group. In this case, if R ³ is a hydrogen atom, the hydroxyl group may be fluorinated.

When R ² or R ³ is a protecting group (protecting group for a hydroxyl group), the protecting group is not particularly limited, and a known or well-known protecting group used as a protecting group for a hydroxyl group can be employed. Examples of the protecting group include a triorganosilyl group, an acyl group, an alkyl group, an aralkyl group, and a cyclic ether group. Also, R ² and R ^{3 work} together as 1
It may be one protecting group. Examples of such a protecting group include a cyclic acetal, a cyclic ketal, a cyclic orthoester, a cyclic silyl ether, a cyclic carbonate, a cyclic boronate, which are general protective groups having a 1,3-diol structure.

The triorganosilyl group is a group in which three organic groups such as an alkyl group, an aryl group, an aralkyl group and an alkoxyl group are bonded to a silicon atom, and in particular, at least one selected from a lower alkyl group and an aryl group. A triorganosilyl group having three groups of the above is preferred. Specifically, for example, t-butyldimethylsilyl group, t-
A butyldiphenylsilyl group, a triethylsilyl group, a triphenylsilyl group, a triisopropylsilyl group and the like are preferable.

The acyl group is preferably an acetyl group, a trifluoroacetyl group, a pivaloyl group, a benzoyl group, a p-phenylbenzoyl group, and the like, and the cyclic ether group is preferably a tetrahydropyranyl group or a tetrahydrofuranyl group. Further, the alkyl group or the aralkyl group may have a substituent, for example, a methoxymethyl group,
-Alkoxyalkyl groups such as -ethoxyethyl group and 2-methoxyethoxymethyl group, and benzyl group, methoxybenzyl group and trityl group.

The cyclic acetal or cyclic ketal is preferably methylene acetal, ethylidene acetal, isopropylidene acetal, and the like, and the cyclic orthoester is preferably methoxymethylene acetal, dimethoxymethylene acetal, or the like. As the cyclic silyl ether, a 1,3- (1,1,3,3-tetraisopropyldisiloxanilidene) derivative or the like is preferable, and as the cyclic boronate, phenylboronate or the like is preferable.

Usually, such a protecting group as described above can be converted into a hydroxyl group by a conventional method. For example, "New Experimental Chemistry Course 14: Synthesis and Reaction of Organic Compounds (I), (II), (V)" (Maruzen), "Protective Groups in Organic Synthesis" (TW Greene, JW
iley & Sons).
It can be easily converted to a hydroxyl group.

In the above general formulas (1) and (3), Z represents OR ⁴ , NR ⁵ COR ⁶ , NR ⁷ SO ₂ R ⁸ , or S
Represents R ⁹ . Z between the general formulas (1) and (3)
May be different or the same. For example,
A compound represented by the general formula (1) is produced from the compound represented by the general formula (3) (both Zs are usually the same at this stage), and then a compound represented by the general formula (1) is obtained. May be converted to another Z.

R ⁴ represents a hydrogen atom, a metal ion, a linear or branched alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group or aralkyl group.

The alkyl group as R ⁴ preferably has 1 to 8 carbon atoms. Specific chain hydrocarbon groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-decyl group,
1-methylpentyl group, 1,1-dimethylpentyl group,
Examples thereof include a 1-methylhexyl group, a 2-methylpentyl group, a 2-methylhexyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group.

Examples of the alkenyl group as R ⁴ include an allyl group, 2-butenyl group, 3-pentenyl group, 1-methyl-3-pentenyl group, 1-methyl-3-hexenyl group,
Examples thereof include a 1,1-dimethyl-3-pentenyl group and a 1,1-dimethyl-3-hexenyl group.

Examples of the alkynyl group as R ⁴ include a propargyl group, a 3-pentynyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group, a 1,1-dimethyl-3-pentynyl group, and , 1-dimethyl-3-hexynyl group and the like.

The cycloalkyl group as R ⁴ preferably has 10 or less carbon atoms. Specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-dimethylcyclopropyl, 3
-Cyclopentenyl group, 3-cyclohexynyl group, cyclooctanyl group and the like.

The aryl group as R ⁴ is preferably a substituted or unsubstituted phenyl group. As the substituent, an alkyl group (preferably having 4 or less carbon atoms), a halogenated methyl group, a halogen atom, an alkoxy group, an acyl group, an acylamino group, a nitro group, and the like are preferable. Specifically, a phenyl group, a 4-methylphenyl group, a 4- (t-butyl) phenyl group, a 3-trifluoromethylphenyl group, a 4-trifluoromethylphenyl group, a 4-chlorophenyl group,
4-acetylphenyl group, 4-benzoylphenyl group,
Examples thereof include a 4-acetylaminophenyl group, a 4-benzoylaminophenyl group, a 3-nitrophenyl group, and a 4-nitrophenyl group.

The aralkyl group as R ⁴ is preferably an aralkyl group comprising a phenyl group and an alkyl group having 4 or less carbon atoms (preferably having 1 or 2 carbon atoms). The phenyl group in these may have a substituent such as an alkyl group (preferably having 4 or less carbon atoms), a halogenated methyl group, a halogen atom, an alkoxy group, an acyl group, an acylamino group, a nitro group and the like. The alkyl group portion of the aralkyl group may have a branch.

Specifically, a benzyl group, a phenethyl group,
Diphenylmethyl group, (3-methylphenyl) methyl group, (3-chlorophenyl) methyl group, (3-fluorophenyl) methyl group, (3-bromophenyl) methyl group, (3-trifluoromethylphenyl) methyl group, 1
-(3-methylphenyl) ethyl group, 1- (3-chlorophenyl) ethyl group, 1- (3-trifluoromethylphenyl) ethyl group, 1- (3-fluorophenyl) ethyl group, 1- (3-bromo Phenyl) ethyl group, 2- (3
-Methylphenyl) ethyl group, 2- (3-chlorophenyl) ethyl group, 2- (3-trifluoromethylphenyl) ethyl group, 2- (3-fluorophenyl) ethyl group, 2- (3-bromophenyl) ethyl Group, 1-methyl-2- (3-methylphenyl) ethyl group, 1-methyl-
2- (3-chlorophenyl) ethyl group, 1-methyl-2
-(3-trifluoromethylphenyl) ethyl group, 1-
Methyl-2- (3-fluorophenyl) ethyl group, 1-
And a methyl-2- (3-bromophenyl) ethyl group.

The metal ion as R ⁴ is a metal ion capable of forming a salt with a carboxyl group. For example, there are alkali metal ions and a half amount of alkaline earth metal ions, and particularly, alkali metal ions such as lithium, sodium, and potassium are preferable.

R ⁵ and R ⁷ each independently represent a hydrogen atom or a metal ion. The metal ion is preferably a metal ion selected from alkali metals and alkaline earth metals. In particular, alkali metal ions such as lithium, sodium, and potassium are preferable. Such a metal ion is usually an ion of the same metal species as a metal species contained in a base used when converting a phosphonium salt described later into a phosphorane. These metal ions are usually present in the reaction system for producing phosphoranes from phosphonium salts or in the reaction system of the Wittig reaction. When it is converted into a fluorinated prostaglandin derivative represented by the general formula (1) and isolated after the Wittig reaction, it becomes a hydrogen atom by hydrolysis or the like.

R ⁶ , R ⁸ and R ⁹ each independently represent a hydrogen atom, a linear or branched alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group,
It represents an aralkyl group, the alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, those described in the explanation for the above R ⁴ is preferably a aralkyl group. Further, as R ⁸ , a halogenated alkyl group is also preferable in addition to the alkyl group described for R ⁴ . As the halogenated alkyl group, a lower perfluoroalkyl group such as a trifluoromethyl group and a pentafluoroethyl group is preferable.

Z is NR ⁵ COR ⁶ , wherein R ⁴ is the above-mentioned alkyl group or aralkyl group, OR ⁴ , R ⁵ is a hydrogen atom and R ⁶ is the above-mentioned alkyl group, aryl group or aralkyl group. , R ⁷ is a hydrogen atom and R ⁸
Is NR ⁷ SO ₂ R ^{8 which} is the above-mentioned alkyl group, aryl group or aralkyl group, and SR is where R ⁹ is the above-mentioned alkyl group, aryl group or aralkyl group
⁹ is preferred. More preferred Z is OR ⁴ , in which case R ⁴ is an alkyl group having 1 to 8 carbon atoms, particularly 1 to 8 carbon atoms.
Preferred are alkyl groups of 4 to 4.

In the above formula (3), R ¹⁰ represents an aryl group, an alkyl group, an aralkyl group, a dialkylamino group, or a group having a substituent, and X and Z each represent the above-mentioned groups.

The aryl group which may have a substituent as R ¹⁰ is preferably a phenyl group, a naphthyl group or a derivative thereof. As the substituent, for example,
There are a lower alkyl group, a halogen atom, a lower alkoxy group, a lower alkylamino group, a nitro group and the like. Examples of the aryl group include a phenyl group, a naphthyl group, a tolyl group, a p-chlorophenyl group, a p-methoxyphenyl group, a p-nitrophenyl group, an o-chlorophenyl group,
-Methoxyphenyl group, o-nitrophenyl group and the like are preferable, and phenyl group and tolyl group are particularly preferable.

As the alkyl group which may have a substituent as R ¹⁰ , an alkyl group having 20 or less carbon atoms is preferable, and among them, a methyl group, an ethyl group, an n-propyl group,
Preferred are linear alkyl groups such as n-butyl group, n-pentyl group and n-hexyl group, and branched alkyl groups such as isopropyl group and t-butyl group.

As the aralkyl group which may have a substituent as R ¹⁰ , the alkyl portion of the aralkyl group (that is, the alkylene group) has 1 to 4 carbon atoms;
An aralkyl group in which the aryl portion of the aralkyl group is a benzene ring or a naphthalene ring is preferred. As the substituent, a halogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group and the like are preferable. A particularly preferred aralkyl group is a C1 to C2 alkyl group having a phenyl group.

The dialkylamino group may have 1 to 1 carbon atoms.
A dialkylamino group having 6 alkyl groups is preferred, and the two alkyl groups may be different. Particularly preferred dialkylamino groups are dialkylamino groups having the same alkyl group having 1 to 4 carbon atoms, such as a dimethylamino group, a diethylamino group and a dibutylamino group.

The phosphoranes represented by the general formula (3) can be produced from the phosphonium salts represented by the general formula (6) in an inert solvent in the presence of a base. It is used for the Wittig reaction with the fluorine-containing lactol represented by the formula (2). In the general formula (6), Y represents a halogen atom, and X, Z, R
¹⁰ represents the same as in the general formula (3). As the halogen atom as Y, a chlorine atom, a bromine atom or an iodine atom is preferable.

[0058]

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Specific examples of the compound represented by the general formula (6) include, but are not limited to, the following compounds. (4-carboxybutyl) triphenylphosphonium bromide, (4-carboxy-3-oxabutyl) triphenylphosphonium bromide, [4- (N-methanesulfonylcarbamoylbutyl)] triphenylphosphonium bromide, [4- (N-benzoylcarbamoyl) Butyl)] triphenylphosphonium bromide.

The fluorine-containing prostaglandin derivative represented by the general formula (1) of the present invention (hereinafter referred to as fluorine-containing prostaglandin derivative (1)) can be produced by the following method. That is, by fluorinating an alcohol represented by the general formula (5) (hereinafter, referred to as alcohol (5)), a fluorinated lactone represented by the general formula (4) (hereinafter, fluorinated lactone ( 4))
Next, the fluorinated lactone (4) is reduced to produce a fluorinated lactol represented by the general formula (2) (hereinafter referred to as a fluorinated lactol (2)). On the other hand, a phospholane represented by the general formula (3) (hereinafter referred to as a phosphorane (3)) is produced from a phosphonium salt represented by the general formula (6) (hereinafter referred to as a phosphonium salt (6)). By reacting the phosphoranes (3) with the fluorinated lactols (2), the fluorinated prostaglandin derivative (1) can be produced. Hereinafter, these methods will be described.

The alcohols (5) are basically known compounds and can be produced by a known method. As the fluorinating agent for fluorinating the alcohol (5), a nucleophilic fluorinating agent is used. In this fluorination, usually, a fluorine atom is easily introduced into a configuration in which the configuration is inverted with respect to the hydroxyl group to be fluorinated, and such a fluorinated product is obtained as a main product. Therefore, in order to efficiently obtain a fluorinated product having the same configuration as a natural hydroxyl group, it is preferable to use an alcohol (5) having a non-natural type hydroxyl group as a starting material. When the alcohols (5) have a functional group which may be fluorinated during the fluorination reaction, it is preferable to protect the functional group with a protecting group in advance. For example, when R ³ is a hydroxyl group, it is protected with a protecting group to perform a fluorination reaction, and then deprotection is performed as appropriate.

The fluorinating agent for fluorinating the alcohol (5) is not particularly limited, and a known or well-known nucleophilic fluorinating agent can be employed. For example, nucleophilic fluorinating agents described in books such as "Chemistry of Fluorine" by Tomoya Kitazume, Takashi Ishihara and Takeo Taguchi (Kodansha Scientific) can be used. Specifically, there are the following nucleophilic fluorinating agents.

Dialkylaminosulfur trifluoride derivative. Tetrafluorophenylphosphorane. Fluoroalkylamine reactants such as diethylamine-chlorotrifluoroethene adduct and diethylamine-hexafluoropropene adduct; Hydrogen fluoride amine complexes such as HF-pyridine and HF-triethylamine. Silicon tetrafluoride or sulfur tetrafluoride. Metal fluorides such as potassium fluoride, cesium fluoride, and silver fluoride. Ammonium salts and phosphonium salts such as tetrabutylammonium fluoride, tetraethylammonium fluoride and tetrabutylfluorophosphorane.

The hydroxyl group of alcohols (5) may be directly fluorinated with these nucleophilic fluorinating agents to form a fluoride. Further, in order to increase the reactivity of the hydroxyl group or suppress the side reaction, the hydroxyl group may be converted to a derivative such as sulfonate or silyl ether and then fluorinated. As these sulfonates, methanesulfonate, p-toluenesulfonate, benzenesulfonate, trifluoromethanesulfonate and the like are preferable, and as the silyl ether, trimethylsilyl ether and the like are preferable.

In view of yield and selectivity, particularly preferred nucleophilic fluorinating agents are dialkylaminosulfur trifluoride derivatives, specifically, morpholinosulfatrifluoride, piperidinosulfatrifluoride, diethylaminosulfur Trifluoride, dimethylaminosulfur trifluoride and the like are preferred.

The amount of the fluorinating agent is usually 0.5 to 1 part by weight of the alcohol (5) as a substrate.
About 20 parts by weight, preferably about 1 to 5 parts by weight. The above fluorination reaction is preferably carried out in an inert solvent. Further, it is preferable to carry out the reaction after this reaction in an inert solvent. The amount of the inert solvent is usually 5 to 5 parts by weight based on 1 part by weight of the reaction substrate in common in reactions such as the fluorination reaction and the subsequent reduction reaction.
The amount is about 1000 parts by weight, preferably 10 to 100 parts by weight.

As the inert solvent, a halogen solvent, an ether solvent, a hydrocarbon solvent, a polar solvent, or a mixed solvent thereof is preferable. Examples of the halogen-based solvent include methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene, 1,1,2-trichloro-
1,2,2-trifluoroethane and the like, and ether solvents such as diethyl ether and tetrahydrofuran [TH
F], 1,4-dioxane, dimethoxyethane, diglyme, t-butyl methyl ether and the like; hexane, toluene, benzene, pentane, xylene, petroleum ether and the like as hydrocarbon solvents; dimethylformamide as a polar solvent; Dimethylacetamide, dimethylsulfoxide, nitromethane, hexamethylphosphoramide [HMPA], 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone [DMPU],
1,3-dimethyl-2-imidazolidinone [DMI],
N, N, N ', N'-tetramethylethylenediamine [TMEDA] and the like are preferable. In addition, [] is an abbreviation (the same applies hereinafter).

The above fluorination reaction may be carried out in the presence of a base. As the base, amines such as tertiary amines and aromatic amines, and salts of alkali metals and alkaline earth metals are preferable. Specific examples include triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and the like. The reaction temperature of the above fluorination reaction is usually about -150 to + 100 ° C, and -80 to +4
0 ° C. is preferred.

The fluorinated lactone (4) obtained by the fluorination reaction is then reduced to produce a fluorinated lactol (2). As this method, a method of reacting a reducing agent in an inert solvent is usually used. For example, "New Experimental Chemistry Course 15 Oxidation and Reduction (II)" (Maruzen), "No.
Edition Chemistry Course 26 Organic Synthesis VIII, Asymmetric Synthesis / Reduction / Sugar / Labeled Compounds "(Maruzen) and the like.

The amount of the reducing agent used in this reduction reaction is usually 0.01 to 50 equivalents per 1 equivalent of the fluorinated lactone (4), and usually 5 to 2 equivalents.
0 equivalents are preferred. The reaction temperature is preferably about -150 to + 100C, particularly preferably -80 to 0C.

Examples of the reducing agent include diisobutylaluminum hydride [DIBAH], dialkylaluminum alkoxide, lithium aluminum hydride, tributyltin hydride, triphenyltin hydride, triethylsilane, trichlorosilane, dimethylphenylsilane, diphenylsilane, and hydrogenated hydrogen. Sodium borohydride, sodium trimethoxyborohydride, lithium tri (s-butyl) borohydride, potassium tri (s-butyl) borohydride, lithium lithium triethylborohydride, lithium trisiamilborohydride, potassium trithiamylborohydride , Zinc borohydride, calcium borohydride, trialkoxyaluminum lithium hydride, sodium bis (2-methoxyethoxy) aluminum hydride, diborane, disiamilbo Emissions, thexylborane, 9-borabicyclo [3.3.1] nonane and the like, diisobutylaluminum hydride [DIBAH], sodium bis (2-methoxyethoxy) aluminum hydride is preferred.

The inert solvent used for the reduction reaction is preferably an ether solvent, a hydrocarbon solvent, a polar solvent, or a mixed solvent thereof. As specific examples of the ether solvent, the hydrocarbon solvent, and the polar solvent, the ether solvents, hydrocarbon solvents, and polar solvents described as specific examples in the description of the fluorination reaction are preferable. Among them, diethyl ether, THF, t-butyl methyl ether, toluene and benzene are particularly preferred. The configuration of the hydroxyl group of the fluorinated lactols (2) generated by the reduction reaction is not particularly limited.

As described above, the phosphoranes (3) are produced from the corresponding phosphonium salts (6) in an inert solvent in the presence of a base. The generated phosphoranes (3) are not isolated and usually used as Wittig with fluorine-containing lactols (2).
Used for reaction. The method for producing the phosphoranes (3) from the corresponding phosphonium salts (6) is described in, for example, "New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (I)" (Maruzen), "4th Edition Experimental Chemistry Course 19" Organic Synthesis I, Hydrocarbon and Halogen Compounds ”(Maruzen), and the method of Schaaf et al. (J. Med. Chem. 22, 1340 (1
979)).

Z in the phosphoranes (3) and the phosphonium salts (6) may be any of the above Z, but is usually a hydroxyl group in these compounds (ie, OR ^{4 in} which R ⁴ is a hydrogen atom). is there. By reacting this phosphorane (3) with a fluorinated lactol (2), a fluorinated prostaglandin derivative (1) in which Z is a hydroxyl group is obtained. When producing a fluorine-containing prostaglandin derivative (1) in which Z is a group other than a hydroxyl group, it is preferable to use a method of converting Z of the fluorine-containing prostaglandin derivative (1) into Z other than a hydroxyl group. Prior to the phosphoranes (3), a fluorine-containing prostaglandin derivative (1) in which Z is a group other than a hydroxyl group and Z is a group other than a hydroxyl group can also be produced.

The amount of the phosphorane (3) to be used is usually 0.1 to 1 equivalent of the fluorinated lactol (2).
About 1 to 20 equivalents is suitable, and 1 to 10 equivalents is preferred. Phosphoranes (3) to fluorinated lactols (2)
Is a reaction generally called a Wittig-type reaction. For the reaction of the fluorinated lactols (2) and the phosphoranes (3) in the present invention, the conditions usually used for this Wittig type reaction can be adopted. In particular, it is preferable to carry out the reaction under basic conditions and further to carry out in an inert solvent. The reaction temperature is usually from -150 to +2
About 00 ° C. is appropriate, and preferably −80 to + 100 ° C.

The amount of the base is usually about 0.1 to 20 equivalents, preferably 1 to 10 equivalents, per equivalent of the fluorinated lactol (2). The type of the base is appropriate in consideration of the acidity of hydrogen bonded to the carbon at the α-position of the phosphorus atom of the phosphonium salt (6) of the raw material of the phosphoranes (3), the stability of the generated phosphoranes (3), and the like. Use different types of bases. Such a base can be selected, for example, from the following bases.

Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, diazabicyclononene, diazabicycloundecene, potassium t -Butoxide, lithium amide, sodium amide, potassium amide, lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, lithium isopropylcyclohexylamide, lithium-2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilazide, sodium Diethylamide, sodium hexamethyldisilazide, potassium-3-aminopropylamide, potassium hexamethyldisilazide, hydrogen hydride Lithium, sodium hydride, potassium hydride, dimesyl sodium, n-butyllithium, s-butyllithium, t-butyllithium, methyllithium, phenyllithium, lithium naphthalenide,
Lithium biphenylide, sodium trityl.

Of these bases, potassium carbonate, potassium t-butoxide, lithium amide, sodium amide, potassium amide, lithium diisopropylamide,
Lithium diethylamide, lithium dicyclohexylamide, lithium isopropylcyclohexylamide, lithium-2,2,6,6-tetramethylpiperidine, lithium hexamethyldisilazide, sodium diethylamide, sodium hexamethyldisilazide, potassium-
3-Aminopropylamide, potassium hexamethyldisilazide, and dimsyl sodium are preferred, and potassium t
-Butoxide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and sodium dimsyl are particularly preferred.

Examples of the inert solvent include ether solvents, hydrocarbon solvents, polar solvents, aqueous solvents, alcohol solvents,
Alternatively, a mixed solvent thereof is preferable. The amount of the inert solvent used is usually a fluorine-containing lactol (2)
The amount is suitably about 5 to 1000 parts by weight, preferably 10 to 100 parts by weight, based on 1 part by weight. Ether solvents,
As specific examples of the hydrocarbon solvent and the polar solvent, the ether solvents, hydrocarbon solvents and polar solvents described as specific examples in the description of the fluorination reaction are preferable. As the aqueous solvent, water or a mixed solvent of water and an alcohol solvent is preferable. As the alcohol solvent, methanol, ethanol, t-butanol, t-amyl alcohol and the like are preferable. Particularly preferred solvents include diethyl ether,
There are THF, 1,2-dimethoxyethane, t-butyl methyl ether, toluene, and benzene.

The obtained fluorinated prostaglandin derivative (1) can convert its Z into another Z, if necessary, as described above. For example, when Z is a hydroxyl group, it can be appropriately converted into an ester, a salt of a carboxylic acid, an acylamide, a sulfonamide, a thioester, or the like by a conventional method.

The esterification of Z can be carried out by a conventional method, for example, “New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (I
I) ”(Maruzen) and other methods described in written books. For example, methods such as esterification by condensation with alcohols and phenols, esterification with an O-alkylating agent, esterification with alkenes and alkynes, and esterification with dialkyl sulfates and halogenated hydrocarbons are used. Can be

For conversion into acylamides or sulfonamides, for example, the method of Tithereley et al. (J. Chem. So
c. 85, 1673 (1904)) and the method of Lynch et al. (Can. J. Chem. 5
0,2143 (1972)) and the method of Davidson et al. (J. Am. Chem. So
c.80,376 (1958)). Also, after converting the carboxylic acid to an acid halide or active ester, it is directly subjected to a condensation reaction with amides or sulfonamides, or reacted with amines, and once converted to amides, then acylated or sulfonylated. And the like.

To convert Z into thioesters, “New Experimental Chemistry Course 14: Synthesis and Reaction of Organic Compounds (III)” (Maruzen), “Protective Groups in Organic Synthesis” (TW Greene, J. .Wi
ley & Sons). For example, a method of converting a carboxylic acid into an acid halide or an active ester and then reacting with a thiol is used.

Fluorine-containing prostaglandin derivative (1)
Are shown below, but are not limited thereto.

15-deoxy-15-fluoroprostaglandin F2α methyl ester, 15-deoxy-
15-fluoroprostaglandin F2α ethyl ester, 15-deoxy-15-fluoroprostaglandin F2α isopropyl ester, 16- (3,5-
Dichlorophenoxy) -15-deoxy-15-fluoro-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15-fluoro-
17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15-fluoro-1
7,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15-fluoro-
17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15-fluoro-1
7,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15-fluoro-17,
18,19,20-tetranorprostaglandin F2
α-isopropyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15-fluoro-17,18,19,20-
Tetranorprostaglandin F2α methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15-fluoro-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16-
(3-chlorophenoxy) -15-deoxy-15-fluoro-17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16-
(3,5-difluorophenoxy) -15-deoxy-
15-fluoro-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16-
(3,5-difluorophenoxy) -15-deoxy-
15-fluoro-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16-
(3,5-difluorophenoxy) -15-deoxy-
15-fluoro-17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 1
6- (3,4-difluorophenoxy) -15-deoxy-15-fluoro-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16
-(3,4-difluorophenoxy) -15-deoxy-15-fluoro-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16-
(3,4-difluorophenoxy) -15-deoxy-
15-Fluoro-17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

16- (3-fluorophenoxy) -15
-Deoxy-15-fluoro-17,18,19,20
-Tetranorprostaglandin F2α methyl ester, 16- (3-fluorophenoxy) -15-deoxy-15-fluoro-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16
-(3-Fluorophenoxy) -15-deoxy-15
-Fluoro-17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16-
[3,5-bis (trifluoromethyl) phenoxy]-
15-deoxy-15-fluoro-17,18,19,
20-tetranorprostaglandin F2α methyl ester, 16- [3,5-bis (trifluoromethyl)
Phenoxy] -15-deoxy-15-fluoro-1
7,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- [3,5-bis (trifluoromethyl) phenoxy] -15-deoxy-15
-Fluoro-17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16-
[3,4-bis (trifluoromethyl) phenoxy]-
15-deoxy-15-fluoro-17,18,19,
20-tetranorprostaglandin F2α methyl ester, 16- [3,4-bis (trifluoromethyl)
Phenoxy] -15-deoxy-15-fluoro-1
7,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- [3,4-bis (trifluoromethyl) phenoxy] -15-deoxy-15
-Fluoro-17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

16- [3- (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-17,1
8,19,20-tetranor prostaglandin F2α
Methyl ester, 16- [3- (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-
17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- [3- (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-17,18,19,20-tetranorprostagland Gin F2α isopropyl ester, 16-phenoxy-15-deoxy-15-fluoro-17,18,
19,20-tetranorprostaglandin F2α methyl ester, 16-phenoxy-15-deoxy-1
5-fluoro-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16-phenoxy-15-deoxy-15-fluoro-17,1
8,19,20-tetranor prostaglandin F2α
Isopropyl ester.

16- [3- (methyl) phenyl] -15
-Deoxy-15-fluoro-17,18,19,20
-Tetranorprostaglandin F2α methyl ester, 16- [3- (methyl) phenyl] -15-deoxy-15-fluoro-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16
-[3- (methyl) phenyl] -15-deoxy-15
-Fluoro-17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16-
[3- (trifluoromethyl) phenyl] -15-deoxy-15-fluoro-17,18,19,20-tetranorprostaglandin F2α methyl ester, 1
6- [3- (trifluoromethyl) phenyl] -15
Deoxy-15-fluoro-17,18,19,20-
Tetranorprostaglandin F2α ethyl ester, 16- [3- (trifluoromethyl) phenyl]-
15-deoxy-15-fluoro-17,18,19,
20-tetranorprostaglandin F2α isopropyl ester.

16-phenyl-15-deoxy-15-
Fluoro-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16-phenyl-15-deoxy-15-fluoro-17,18,1
9,20-tetranorprostaglandin F2α ethyl ester, 16-phenyl-15-deoxy-15-
Fluoro-17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 17-phenyl-15-deoxy-15-fluoro-18,1
9,20-trinorprostaglandin F2α methyl ester, 17-phenyl-15-deoxy-15-fluoro-18,19,20-trinorprostaglandin F2α ethyl ester, 17-phenyl-15-deoxy-15- Fluoro-18,19,20-trinorprostaglandin F2α isopropyl ester.

15-deoxy-15-fluoro-11-
Benzoyl prostaglandin F2α methyl ester, 15-deoxy-15-fluoro-11-benzoyl prostaglandin F2α ethyl ester, 15-
Deoxy-15-fluoro-11-benzoyl prostaglandin F2α isopropyl ester, 16-
(3,5-dichlorophenoxy) -15-deoxy-1
5-fluoro-11-benzoyl-17,18,19,
20-tetranorprostaglandin F2α methyl ester, 16- (3,5-dichlorophenoxy) -15
-Deoxy-15-fluoro-11-benzoyl-1
7,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15-fluoro-11-
Benzoyl-17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15-fluoro-11-benzoyl-
17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15-fluoro-11
-Benzoyl-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16-
(3,4-dichlorophenoxy) -15-deoxy-1
5-fluoro-11-benzoyl-17,18,19,
20-tetranorprostaglandin F2α isopropyl ester, 16- (3-chlorophenoxy) -15
-Deoxy-15-fluoro-11-benzoyl-1
7,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostagland Gin F2α ethyl ester, 16- (3-chlorophenoxy) -15-deoxy-15-fluoro-11-
Benzoyl-17,18,19,20-tetranorprostaglandin F2α-isopropyl ester.

16- (3,5-difluorophenoxy)
-15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3,5-difluorophenoxy) -15-deoxy-15-fluoro-
11-benzoyl-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16-
(3,5-difluorophenoxy) -15-deoxy-
15-Fluoro-11-benzoyl-17,18,1
9,20-tetranorprostaglandin F2α isopropyl ester, 16- (3,4-difluorophenoxy) -15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostaglandin F2α Methyl ester, 16- (3,4-
Difluorophenoxy) -15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostaglandin F2α ethyl ester,
16- (3,4-difluorophenoxy) -15-deoxy-15-fluoro-11-benzoyl-17,1
8,19,20-tetranor prostaglandin F2α
Isopropyl ester, 16- (3-fluorophenoxy) -15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostaglandin F2α methyl ester.

16- (3-fluorophenoxy) -15
-Deoxy-15-fluoro-11-benzoyl-1
7,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3-fluorophenoxy) -15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostagland Gin F2α isopropyl ester, 16- [3,5
-Bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11-benzoyl-17,1
8,19,20-tetranor prostaglandin F2α
Methyl ester, 16- [3,5-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostaglandin F2α ethyl ester,
16- [3,5-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

16- [3,4-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-
11-benzoyl-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16-
[3,4-bis (trifluoromethyl) phenoxy]-
15-deoxy-15-fluoro-11-benzoyl-
17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- [3,4-bis (trifluoromethyl) phenoxy] -15-deoxy-1
5-fluoro-11-benzoyl-17,18,19,
20-tetranorprostaglandin F2α isopropyl ester, 16- [3- (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11-
Benzoyl-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- [3-
(Trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11-benzoyl-17,18,1
9,20-tetranorprostaglandin F2α ethyl ester, 16- [3- (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostagland Gin F2α isopropyl ester.

16-phenoxy-15-deoxy-15
-Fluoro-11-benzoyl-17,18,19,2
0-tetranorprostaglandin F2α methyl ester, 16-phenoxy-15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostaglandin F2α ethyl ester,
16-phenoxy-15-deoxy-15-fluoro-
11-benzoyl-17,18,19,20-tetranorprostaglandin F2α isopropyl ester,
16- [3- (methyl) phenyl] -15-deoxy-
15-fluoro-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16-
[3- (methyl) phenyl] -15-deoxy-15-
Fluoro-11-benzoyl-17,18,19,20
-Tetranorprostaglandin F2α ethyl ester, 16- [3- (methyl) phenyl] -15-deoxy-15-fluoro-11-benzoyl-17,18,
19,20-tetranorprostaglandin F2α isopropyl ester.

16- [3- (trifluoromethyl) phenyl] -15-deoxy-15-fluoro-11- (2
-Tetrahydropyranyloxy) -17,18,19,
20-tetranorprostaglandin F2α methyl ester, 16- [3- (trifluoromethyl) phenyl] -15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostaglandin F2α Ethyl ester, 16- [3- (trifluoromethyl) phenyl] -15-deoxy-15-
Fluoro-11-benzoyl-17,18,19,20
-Tetranorprostaglandin F2α isopropyl ester, 16-phenyl-15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-
Tetranorprostaglandin F2α methyl ester, 16-phenyl-15-deoxy-15-fluoro-11-benzoyl-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16
-Phenyl-15-deoxy-15-fluoro-11-
Benzoyl-17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

17-phenyl-15-deoxy-15-
Fluoro-11-benzoyl-18,19,20-trinorprostaglandin F2α methyl ester, 17
-Phenyl-15-deoxy-15-fluoro-11-
Benzoyl-18,19,20-trinorprostaglandin F2α ethyl ester, 17-phenyl-15
-Deoxy-15-fluoro-11-benzoyl-1
8,19,20-trinorprostaglandin F2α
Isopropyl ester, 15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) prostaglandin F2α methyl ester, 15-deoxy-15
-Fluoro-11- (2-tetrahydropyranyl) prostaglandin F2α ethyl ester, 15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) prostaglandin F2α isopropyl ester.

16- (3,5-dichlorophenoxy)-
15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16-
(3,5-dichlorophenoxy) -15-deoxy-1
5-fluoro-11- (2-tetrahydropyranyl)-
17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15-fluoro-11
-(2-tetrahydropyranyl) -17,18,19,
20-tetranorprostaglandin F2α isopropyl ester, 16- (3,4-dichlorophenoxy)
-15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16
-(3,4-dichlorophenoxy) -15-deoxy-
15-fluoro-11- (2-tetrahydropyranyl)
-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15-fluoro-1
1- (2-tetrahydropyranyl) -17,18,1
9,20-tetranorprostaglandin F2α isopropyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3-
(Chlorophenoxy) -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,
19,20-tetranorprostaglandin F2α ethyl ester, 16- (3-chlorophenoxy) -15
-Deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16
-(3,5-difluorophenoxy) -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3 5-difluorophenoxy) -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,1
8,19,20-tetranor prostaglandin F2α
Ethyl ester, 16- (3,5-difluorophenoxy) -15-deoxy-15-fluoro-11- (2
-Tetrahydropyranyl) -17,18,19,20-
Tetranorprostaglandin F2α isopropyl ester.

16- (3,4-difluorophenoxy)
-15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16
-(3,4-difluorophenoxy) -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3 4-difluorophenoxy) -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,1
8,19,20-tetranor prostaglandin F2α
Isopropyl ester, 16- (3-fluorophenoxy) -15-deoxy-15-fluoro-11- (2
-Tetrahydropyranyl) -17,18,19,20-
Tetranorprostaglandin F2α methyl ester, 16- (3-fluorophenoxy) -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α Ethyl ester, 16- (3-fluorophenoxy) -15-deoxy-15-fluoro-1
1- (2-tetrahydropyranyl) -17,18,1
9,20-tetranorprostaglandin F2α isopropyl ester.

16- [3,5-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-
11- (2-tetrahydropyranyl) -17,18,1
9,20-tetranorprostaglandin F2α methyl ester, 16- [3,5-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-
11- (2-tetrahydropyranyl) -17,18,1
9,20-tetranorprostaglandin F2α ethyl ester, 16- [3,5-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-
11- (2-tetrahydropyranyl) -17,18,1
9,20-tetranorprostaglandin F2α isopropyl ester, 16- [3,4-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,1
8,19,20-tetranor prostaglandin F2α
Methyl ester, 16- [3,4-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,1
8,19,20-tetranor prostaglandin F2α
Ethyl ester, 16- [3,4-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,1
8,19,20-tetranor prostaglandin F2α
Isopropyl ester.

16- [3- (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11-
(2-tetrahydropyranyl) -17,18,19,2
0-tetranorprostaglandin F2α methyl ester, 16- [3- (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11- (2-
Tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α ethyl ester,
16- [3- (trifluoromethyl) phenoxy] -1
5-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester,
6-phenoxy-15-deoxy-15-fluoro-1
1- (2-tetrahydropyranyl) -17,18,1
9,20-tetranorprostaglandin F2α methyl ester, 16-phenoxy-15-deoxy-15
-Fluoro-11- (2-tetrahydropyranyl) -1
7,18,19,20-tetranorprostaglandin F2α ethyl ester, 16-phenoxy-15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprosta Grangein F2α isopropyl ester.

16- [3- (methyl) phenyl] -15
-Deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- [3
-(Methyl) phenyl] -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,1
8,19,20-tetranor prostaglandin F2α
Ethyl ester, 16- [3- (methyl) phenyl]
-15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16- [3- (trifluoromethyl) phenyl]-
15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16-
[3- (trifluoromethyl) phenyl] -15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- [3 -(Trifluoromethyl) phenyl] -15-deoxy-15
-Fluoro-11- (2-tetrahydropyranyl) -1
7,18,19,20-tetranorprostaglandin F2α isopropyl ester.

16-phenyl-15-deoxy-15-
Fluoro-11- (2-tetrahydropyranyl) -1
7,18,19,20-tetranorprostaglandin F2α methyl ester, 16-phenyl-15-deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprosta Glandin F2α ethyl ester, 16-phenyl-15
-Deoxy-15-fluoro-11- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α-isopropyl ester, 17-
Phenyl-15-deoxy-15-fluoro-11-
(2-tetrahydropyranyl) -18,19,20-trinorprostaglandin F2α methyl ester, 1
7-phenyl-15-deoxy-15-fluoro-11
-(2-tetrahydropyranyl) -18,19,20-
Trinor prostaglandin F2α ethyl ester,
17-phenyl-15-deoxy-15-fluoro-1
1- (2-tetrahydropyranyl) -18,19,20
-Trinor prostaglandin F2α isopropyl ester.

15-deoxy-15-fluoro-11-
(T-butyldimethylsilyl) prostaglandin F2
α-methyl ester, 15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) prostaglandin F2α ethyl ester, 15-deoxy-15-
Fluoro-11- (t-butyldimethylsilyl) prostaglandin F2α isopropyl ester, 16-
(3,5-dichlorophenoxy) -15-deoxy-1
5-fluoro-11- (t-butyldimethylsilyl)-
17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15-fluoro-11
-(T-butyldimethylsilyl) -17,18,19,
20-tetranorprostaglandin F2α ethyl ester, 16- (3,5-dichlorophenoxy) -15
-Deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16-
(3,4-dichlorophenoxy) -15-deoxy-1
5-fluoro-11- (t-butyldimethylsilyl)-
17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15-fluoro-11
-(T-butyldimethylsilyl) -17,18,19,
20-tetranorprostaglandin F2α isopropyl ester, 16- (3-chlorophenoxy) -15
-Deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3
-Chlorophenoxy) -15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,1
8,19,20-tetranor prostaglandin F2α
Ethyl ester, 16- (3-chlorophenoxy)-
15-Deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

16- (3,5-difluorophenoxy)
-15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16
-(3,5-difluorophenoxy) -15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3 5-difluorophenoxy) -15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,1
8,19,20-tetranor prostaglandin F2α
Isopropyl ester, 16- (3,4-difluorophenoxy) -15-deoxy-15-fluoro-11
-(T-butyldimethylsilyl) -17,18,19,
20-tetranorprostaglandin F2α methyl ester, 16- (3,4-difluorophenoxy) -1
5-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16-
(3,4-difluorophenoxy) -15-deoxy-
15-fluoro-11- (t-butyldimethylsilyl)
-17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

16- (3-Fluorophenoxy) -15
-Deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3
-Fluorophenoxy) -15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,1
8,19,20-tetranor prostaglandin F2α
Ethyl ester, 16- (3-fluorophenoxy)
-15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16- [3,5-bis (trifluoromethyl) phenoxy ] -15-Deoxy-15-fluoro-11-
(T-butyldimethylsilyl) -17,18,19,2
0-tetranorprostaglandin F2α methyl ester, 16- [3,5-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11-
(T-butyldimethylsilyl) -17,18,19,2
0-tetranorprostaglandin F2α ethyl ester, 16- [3,5-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11-
(T-butyldimethylsilyl) -17,18,19,2
0-tetranorprostaglandin F2α isopropyl ester.

16- [3,4-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-
11- (t-butyldimethylsilyl) -17,18,1
9,20-tetranorprostaglandin F2α methyl ester, 16- [3,4-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-
11- (t-butyldimethylsilyl) -17,18,1
9,20-tetranorprostaglandin F2α ethyl ester, 16- [3,4-bis (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-
11- (t-butyldimethylsilyl) -17,18,1
9,20-tetranorprostaglandin F2α isopropyl ester, 16- [3- (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-
11- (t-butyldimethylsilyl) -17,18,1
9,20-tetranorprostaglandin F2α methyl ester, 16- [3- (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11-
(T-butyldimethylsilyl) -17,18,19,2
0-tetranorprostaglandin F2α ethyl ester, 16- [3- (trifluoromethyl) phenoxy] -15-deoxy-15-fluoro-11- (t-
(Butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

16-phenoxy-15-deoxy-15
-Fluoro-11- (t-butyldimethylsilyl) -1
7,18,19,20-tetranorprostaglandin F2α methyl ester, 16-phenoxy-15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprosta Glandin F2α ethyl ester, 16-phenoxy-15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16- [3- Methylphenyl] -15-deoxy-
15-fluoro-11- (t-butyldimethylsilyl)
17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- [3-methylphenyl] -15-deoxy-15-fluoro-11- (t-
Butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α ethyl ester,
16- [3-methylphenyl] -15-deoxy-15
-Fluoro-11- (t-butyldimethylsilyl) -1
7,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16- [3- (trifluoromethyl) phenyl] -15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,
18,19,20-tetranorprostaglandin F2
α methyl ester, 16- [3- (trifluoromethyl) phenyl] -15-deoxy-15-fluoro-1
1- (t-butyldimethylsilyl) -17,18,1
9,20-tetranorprostaglandin F2α ethyl ester, 16- [3- (trifluoromethyl) phenyl] -15-deoxy-15-fluoro-11- (t
-Butyldimethylsilyl) -17,18,19,20-
Tetranorprostaglandin F2α isopropyl ester.

16-phenyl-15-deoxy-15-
Fluoro-11- (t-butyldimethylsilyl) -1
7,18,19,20-tetranorprostaglandin F2α methyl ester, 16-phenyl-15-deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprosta Glandin F2α ethyl ester, 16-phenyl-15
-Deoxy-15-fluoro-11- (t-butyldimethylsilyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 17-
Phenyl-15-deoxy-15-fluoro-11-
(T-butyldimethylsilyl) -18,19,20-trinorprostaglandin F2α methyl ester, 1
7-phenyl-15-deoxy-15-fluoro-11
-(T-butyldimethylsilyl) -18,19,20-
Trinor prostaglandin F2α ethyl ester,
17-phenyl-15-deoxy-15-fluoro-1
1- (t-butyldimethylsilyl) -18,19,20
-Trinor prostaglandin F2α isopropyl ester.

15-deoxy-15-fluoro-13,
14-dihydroprostaglandin F2α methyl ester, 15-deoxy-15-fluoro-13,14-
Dihydroprostaglandin F2α ethyl ester,
15-deoxy-15-fluoro-13,14-dihydroprostaglandin F2α isopropyl ester,
16- (3,5-dichlorophenoxy) -15-deoxy-15-fluoro-13,14-dihydro-17,1
8,19,20-tetranor prostaglandin F2α
Methyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15-fluoro-13,14-
Dihydro-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3,5
-Dichlorophenoxy) -15-deoxy-15-fluoro-13,14-dihydro-17,18,19,20
-Tetranorprostaglandin F2α isopropyl ester, 16- (3,4-dichlorophenoxy) -1
5-deoxy-15-fluoro-13,14-dihydro-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15-fluoro- 1
3,14-dihydro-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16
-(3,4-dichlorophenoxy) -15-deoxy-
15-fluoro-13,14-dihydro-17,18,
19,20-tetranorprostaglandin F2α isopropyl ester.

16- (3-chlorophenoxy) -15-
Deoxy-15-fluoro-13,14-dihydro-1
7,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3-chlorophenoxy) -15-deoxy-15-fluoro-13,14-
Dihydro-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3-chlorophenoxy) -15-deoxy-15-fluoro-
13,14-dihydro-17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 16-phenoxy-15-deoxy-15-fluoro-13,14-dihydro-17,18,19,20-
Tetranorprostaglandin F2α methyl ester, 16-phenoxy-15-deoxy-15-fluoro-13,14-dihydro-17,18,19,20-
Tetranorprostaglandin F2α ethyl ester, 16-phenoxy-15-deoxy-15-fluoro-13,14-dihydro-17,18,19,20-
Tetranorprostaglandin F2α isopropyl ester.

17-phenyl-15-deoxy-15-
Fluoro-13,14-dihydro-18,19,20-
Trinorprostaglandin F2α methyl ester,
17-phenyl-15-deoxy-15-fluoro-1
3,14-dihydro-18,19,20-trinorprostaglandin F2α ethyl ester, 17-phenyl-15-deoxy-15-fluoro-13,14-dihydro-18,19,20-trinorprostaglandin F2α isopropyl ester, 16- (3,5-dichlorophenoxy) -15-deoxy-15-fluoro-3-oxa-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3
5-dichlorophenoxy) -15-deoxy-15-fluoro-3-oxa-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16-
(3,5-dichlorophenoxy) -15-deoxy-1
5-fluoro-3-oxa-17,18,19,20-
Tetranorprostaglandin F2α isopropyl ester.

16- (3,4-dichlorophenoxy)-
15-deoxy-15-fluoro-3-oxa-17,
18,19,20-tetranorprostaglandin F2
α-methyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15-fluoro-3-oxa-
17,18,19,20-tetranor prostaglandin F2α ethyl ester, 16- (3,4-dichlorophenoxy) -15-deoxy-15-fluoro-3-oxa-17,18,19,20-tetranor Prostaglandin F2α-isopropyl ester, 16- (3-chlorophenoxy) -15-deoxy-15-fluoro-
3-oxa-17,18,19,20-tetranorprostaglandin F2α methyl ester, 16- (3-
Chlorophenoxy) -15-deoxy-15-fluoro-3-oxa-17,18,19,20-tetranorprostaglandin F2α ethyl ester, 16- (3
-Chlorophenoxy) -15-deoxy-15-fluoro-3-oxa-17,18,19,20-tetranorprostaglandin F2α isopropyl ester, 1
6-phenoxy-15-deoxy-15-fluoro-3
-Oxa-17,18,19,20-tetranorprostaglandin F2α methyl ester.

16-phenoxy-15-deoxy-15
-Fluoro-3-oxa-17,18,19,20-tetranorprostaglandin F2α ethyl ester,
16-phenoxy-15-deoxy-15-fluoro-
3-oxa-17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

Specific examples of the fluorinated lactols (2) are shown below, but are not limited thereto.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-
Fluoro-1-octenyl] -bicyclo [3.3.0]
Octane, (1S, 5R, 6R, 7R) -2-oxa-
7-benzoyloxy-3-hydroxy-6-[(1
E, 3R) -3-Fluoro-1-octenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7
R) -2-oxa-7-p-phenylbenzoyloxy-3-hydroxy-6-[(1E, 3R) -3-fluoro-1-octenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy)-
6-[(1E, 3R) -3-fluoro-1-octenyl] -bicyclo [3.3.0] octane, (1S, 5
R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(1E,
3R) -3-Fluoro-1-octenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R)
-2-oxa-3,7-dihydroxy-6-[(1E,
3R) -3-Fluoro-4- (3,5-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R) -2-oxa-7-
Benzoyloxy-3-hydroxy-6-[(1E, 3
R) -3-Fluoro-4- (3,5-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-7-p-phenylbenzoyloxy-3-hydroxy-6-[(1E, 3R) -3-fluoro-4- (3,5
-Dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R)
-2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3-fluoro-4- (3,5-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5
R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(1E,
3R) -3-Fluoro-4- (3,5-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-
Fluoro-4- (3,4-dichlorophenoxy) -1-
Butenyl] -bicyclo [3.3.0] octane, (1
S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(1E, 3R) -3-
Fluoro-4- (3,4-dichlorophenoxy) -1-
Butenyl] -bicyclo [3.3.0] octane, (1
S, 5R, 6R, 7R) -2-oxa-7-p-phenylbenzoyloxy-3-hydroxy-6-[(1E,
3R) -3-Fluoro-4- (3,4-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R) -2-oxa-3-
Hydroxy-7- (2-tetrahydropyranyloxy)
-6-[(1E, 3R) -3-fluoro-4- (3,4
-Dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R)
-2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(1E, 3R) -3-fluoro-4- (3,4-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S,
5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-fluoro-4- (3-
Chlorophenoxy) -1-butenyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-7-benzoyloxy-3-hydroxy-6-
[(1E, 3R) -3-Fluoro-4- (3-chlorophenoxy) -1-butenyl] -bicyclo [3.3.0]
Octane.

(1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3-fluoro-4-
(3-Chlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R)
-2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(1E, 3R) -3-fluoro-4- (3-chlorophenoxy) -1-butenyl] -bicyclo [3 .3.0] octane, (1S, 5
R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-fluoro-4- (3,5
-Difluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R)
-2-oxa-7-benzoyloxy-3-hydroxy-6-[(1E, 3R) -3-fluoro-4- (3,5
-Difluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R)
-2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3-fluoro-4- (3,5-difluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(1E, 3R) -3-fluoro-4-
(3,5-difluorophenoxy) -1-butenyl]-
Bicyclo [3.3.0] octane, (1S, 5R, 6
R, 7R) -2-oxa-3,7-dihydroxy-6-
[(1E, 3R) -3-fluoro-4- (3,4-difluorophenoxy) -1-butenyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-7-benzoyloxy-3-hydroxy-6-
[(1E, 3R) -3-fluoro-4- (3,4-difluorophenoxy) -1-butenyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3-fluoro-
4- (3,4-Difluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(1E, 3R) -3-fluoro-4-
(3,4-difluorophenoxy) -1-butenyl]-
Bicyclo [3.3.0] octane, (1S, 5R, 6
R, 7R) -2-oxa-3,7-dihydroxy-6-
[(1E, 3R) -3-fluoro-4- (3-fluorophenoxy) -1-butenyl] -bicyclo [3.3.
0] octane, (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-
[(1E, 3R) -3-fluoro-4- (3-fluorophenoxy) -1-butenyl] -bicyclo [3.3.
0] octane, (1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3-fluoro-4-
(3-Fluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7
R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(1E, 3R) -3-
Fluoro-4- (3-fluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-
Fluoro-4- (3,5-bis (trifluoromethyl)
Phenoxy) -1-butenyl] -bicyclo [3.3.
0] octane, (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-
[(1E, 3R) -3-fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) -1-butenyl]
-Bicyclo [3.3.0] octane, (1S, 5R, 6
(R, 7R) -2-oxa-3-hydroxy-7- (2-
Tetrahydropyranyloxy) -6-[(1E, 3R)
-3-Fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-7- (t-butyldimethylsilyloxy) -3
-Hydroxy-6-[(1E, 3R) -3-fluoro-
4- (3,5-bis (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-
Fluoro-4- (3,4-bis (trifluoromethyl)
Phenoxy) -1-butenyl] -bicyclo [3.3.
0] octane, (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-
[(1E, 3R) -3-fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) -1-butenyl]
-Bicyclo [3.3.0] octane, (1S, 5R, 6
(R, 7R) -2-oxa-3-hydroxy-7- (2-
Tetrahydropyranyloxy) -6-[(1E, 3R)
-3-Fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-7- (t-butyldimethylsilyloxy) -3
-Hydroxy-6-[(1E, 3R) -3-fluoro-
4- (3,4-bis (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-
Fluoro-4- (3- (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3 -Hydroxy-6-[(1E, 3
R) -3-Fluoro-4- (3- (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3-fluoro-
4- (3- (trifluoromethyl) phenoxy) -1-
Butenyl] -bicyclo [3.3.0] octane, (1
(S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-
[(1E, 3R) -3-Fluoro-4- (3- (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-
Fluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R)
-2-oxa-7-benzoyloxy-3-hydroxy-6-[(1E, 3R) -3-fluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R , 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy)-
6-[(1E, 3R) -3-fluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octane,
(1S, 5R, 6R, 7R) -2-oxa-7- (t-
Butyldimethylsilyloxy) -3-hydroxy-6-
[(1E, 3R) -3-fluoro-4-phenoxy-1
-Butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-
Fluoro-4- (3-methylphenyl) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5
R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(1E, 3R) -3-fluoro-4- (3-methylphenyl) -1-butenyl] -bicyclo [3 .3.0] octane, (1S, 5R, 6R,
7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3
-Fluoro-4- (3-methylphenyl) -1-butenyl] -bicyclo [3.3.0] octane, (1S, 5
R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(1E,
3R) -3-Fluoro-4- (3-methylphenyl)-
1-butenyl] -bicyclo [3.3.0] octane,
(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-fluoro-4
-(3- (trifluoromethyl) phenyl) -1-butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(1
E, 3R) -3-Fluoro-4- (3- (trifluoromethyl) phenyl) -1-butenyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3-fluoro-
4- (3- (trifluoromethyl) phenyl) -1-butenyl] -bicyclo [3.3.0] octane, (1S,
5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(1
E, 3R) -3-Fluoro-4- (3- (trifluoromethyl) phenyl) -1-butenyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-3,7-dihydroxy-6-[(1E, 3R)
-3-Fluoro-4-phenyl-1-butenyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(1
E, 3R) -3-Fluoro-4-phenyl-1-butenyl] -bicyclo [3.3.0] octane, (1S, 5
R, 6R, 7R) -2-oxa-3-hydroxy-7-
(2-tetrahydropyranyloxy) -6-[(1E,
3R) -3-Fluoro-4-phenyl-1-butenyl]
-Bicyclo [3.3.0] octane, (1S, 5R, 6
(R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(1E, 3R)
-3-fluoro-4-phenyl-1-butenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7
R) -2-oxa-3,7-dihydroxy-6-[(1
E, 3R) -3-fluoro-5-phenyl-1-pentenyl] -bicyclo [3.3.0] octane, (1S, 5
R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(1E, 3R) -3-fluoro-5-phenyl-1-pentenyl] -bicyclo [3.
3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3-fluoro-5-phenyl-1 -Pentenyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R) -2-oxa-7
-(T-butyldimethylsilyloxy) -3-hydroxy-6-[(1E, 3R) -3-fluoro-5-phenyl-1-pentenyl] -bicyclo [3.3.0] octane, (1S, 5R , 6R, 7R) -2-oxa-3,7
-Dihydroxy-6-[(3R) -3-fluorooctyl] -bicyclo [3.3.0] octane, (1S, 5
(R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluorooctyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluorooctyl] -bicyclo [3.3 .0] octane, (1S, 5R, 6R,
7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(3R) -3-fluorooctyl] -bicyclo [3.3.0] octane;
(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4-
(3,5-dichlorophenoxy) butyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R)
-2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluoro-4- (3,5-dichlorophenoxy) butyl] -bicyclo [3.3.0] octane, (1S , 5R, 6R, 7R) -2-oxa-3
-Hydroxy-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-4- (3,5-
Dichlorophenoxy) butyl] -bicyclo [3.3.
0] octane, (1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(3R) -3-fluoro-4- (3,
5-dichlorophenoxy) butyl] -bicyclo [3.
3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4- (3,4-dichlorophenoxy) butyl] -bicyclo [3 .3.0] octane, (1S, 5R, 6R,
7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluoro-4- (3,4
-Dichlorophenoxy) butyl] -bicyclo [3.3.
0] octane, (1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-4- (3,
4-dichlorophenoxy) butyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-7- (t-butyldimethylsilyloxy) -3
-Hydroxy-6-[(3R) -3-fluoro-4-
(3,4-Dichlorophenoxy) butyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4- (3-chlorophenoxy) butyl] -bicyclo [3.3 .0] octane, (1S, 5R, 6R, 7R)
-2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluoro-4- (3-chlorophenoxy) butyl] -bicyclo [3.3.0] octane, (1S, 5R , 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy)-
6-[(3R) -3-fluoro-4- (3-chlorophenoxy) butyl] -bicyclo [3.3.0] octane,
(1S, 5R, 6R, 7R) -2-oxa-7- (t-
Butyldimethylsilyloxy) -3-hydroxy-6-
[(3R) -3-fluoro-4- (3-chlorophenoxy) butyl] -bicyclo [3.3.0] octane, (1
S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4- (3,5
-Difluorophenoxy) butyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-7-benzoyloxy-3-hydroxy-6-
[(3R) -3-Fluoro-4- (3,5-difluorophenoxy) butyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-4- (3,5
-Difluorophenoxy) butyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-7- (t-butyldimethylsilyloxy) -3
-Hydroxy-6-[(3R) -3-fluoro-4-
(3,5-difluorophenoxy) butyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R)
-2-oxa-3,7-dihydroxy-6-[(3R)
-3-fluoro-4- (3,4-difluorophenoxy) butyl] -bicyclo [3.3.0] octane, (1
(S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluoro-4- (3,4-difluorophenoxy) butyl]-
Bicyclo [3.3.0] octane, (1S, 5R, 6
(R, 7R) -2-oxa-3-hydroxy-7- (2-
Tetrahydropyranyloxy) -6-[(3R) -3-
Fluoro-4- (3,4-difluorophenoxy) butyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(3R) -3-fluoro-4- (3,4
-Difluorophenoxy) butyl] -bicyclo [3.
3.0] octane, (1S, 5R, 6R, 7R) -2-
Oxa-3,7-dihydroxy-6-[(3R) -3-
Fluoro-4- (3-fluorophenoxy) butyl]-
Bicyclo [3.3.0] octane, (1S, 5R, 6
(R, 7R) -2-oxa-7-benzoyloxy-3-
Hydroxy-6-[(3R) -3-fluoro-4- (3
-Fluorophenoxy) butyl] -bicyclo [3.3.
0] octane, (1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-4- (3-
Fluorophenoxy) butyl] -bicyclo [3.3.
0] octane, (1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(3R) -3-fluoro-4- (3-
Fluorophenoxy) butyl] -bicyclo [3.3.
0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) butyl ] -Bicyclo [3.3.0] octane,
(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) butyl ] -Bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy)-
6-[(3R) -3-fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7
R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(3R) -3-fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) butyl] -Bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) butyl ] -Bicyclo [3.3.0] octane,
(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) butyl ] -Bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy)-
6-[(3R) -3-fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7
R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(3R) -3-fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) butyl] -Bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4- (3- (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0] octane, (1S, 5
(R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluoro-4
-(3- (trifluoromethyl) phenoxy) butyl]
-Bicyclo [3.3.0] octane, (1S, 5R, 6
(R, 7R) -2-oxa-3-hydroxy-7- (2-
Tetrahydropyranyloxy) -6-[(3R) -3-
Fluoro-4- (3- (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0] octane, (1
(S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-
[(3R) -3-fluoro-4- (3- (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.
0] octane, (1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4-phenoxybutyl] -bicyclo [3.3.
0] octane.

(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3
R) -3-Fluoro-4-phenoxybutyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7
R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-4-phenoxybutyl] -bicyclo [3.3.0]
Octane, (1S, 5R, 6R, 7R) -2-oxa-
7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(3R) -3-fluoro-4-phenoxybutyl] -bicyclo [3.3.0] octane, (1S,
5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4- (3-methylphenyl) butyl] -bicyclo [3.3.0] octane, ( 1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3
-Fluoro-4- (3-methylphenyl) butyl] -bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-4- (3-methylphenyl ) Butyl] -Bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R) -2-oxa-7-
(T-butyldimethylsilyloxy) -3-hydroxy-6-[(3R) -3-fluoro-4- (3-methylphenyl) butyl] -bicyclo [3.3.0] octane,
(1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4- (3
-(Trifluoromethyl) phenyl) butyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7
R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluoro-4- (3- (trifluoromethyl) phenyl) butyl] -bicyclo [3.3.0] Octane.

(1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-4- (3-
(Trifluoromethyl) phenyl) butyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R)
-2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(3R) -3-fluoro-4- (3- (trifluoromethyl) phenyl) butyl] -bicyclo [3. 3.0] octane, (1S, 5
R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-4-phenylbutyl] -bicyclo [3.3.0] octane, (1S, 5
(R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluoro-4
-Phenylbutyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy)-
6-[(3R) -3-fluoro-4-phenylbutyl]
-Bicyclo [3.3.0] octane.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(3R) -3-fluoro-4-phenylbutyl] -bicyclo [3.3.0] octane, (1S,
5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(3R) -3-fluoro-5-phenylpentyl] -bicyclo [3.3.0] octane, (1S, 5
R, 6R, 7R) -2-oxa-7-benzoyloxy-3-hydroxy-6-[(3R) -3-fluoro-5
-Phenylpentyl] -bicyclo [3.3.0] octane, (1S, 5R, 6R, 7R) -2-oxa-3-hydroxy-7- (2-tetrahydropyranyloxy)-
6-[(3R) -3-fluoro-5-phenylpentyl] -bicyclo [3.3.0] octane, (1S, 5
(R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -3-hydroxy-6-[(3R)
-3-Fluoro-5-phenylpentyl] -bicyclo [3.3.0] octane.

Specific examples of the fluorinated lactones (4) are shown below, but are not limited thereto.

(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(1E, 3R) -3-fluoro-1-octenyl] -bicyclo [3.3.0] octane-3 -One, (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E, 3R) -3
-Fluoro-1-octenyl] -bicyclo [3.3.
0] octan-3-one, (1S, 5R, 6R, 7R)
-2-oxa-7-p-phenylbenzoyloxy-6
-[(1E, 3R) -3-fluoro-1-octenyl]
-Bicyclo [3.3.0] octan-3-one, (1
S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3
-Fluoro-1-octenyl] -bicyclo [3.3.
0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6
[(1E, 3R) -3-fluoro-1-octenyl]-
Bicyclo [3.3.0] octan-3-one, (1S,
5R, 6R, 7R) -2-oxa-7-hydroxy-6
-[(1E, 3R) -3-fluoro-4- (3,5-dichlorophenoxy) -1-butenyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-benzoyloxy-6-[(1
E, 3R) -3-Fluoro-4- (3,5-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0]
Octane-3-one, (1S, 5R, 6R, 7R) -2
-Oxa-7-p-phenylbenzoyloxy-6-
[(1E, 3R) -3-fluoro-4- (3,5-dichlorophenoxy) -1-butenyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3-fluoro-4-
(3,5-Dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6
[(1E, 3R) -3-fluoro-4- (3,5-dichlorophenoxy) -1-butenyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-hydroxy-6-[(1E, 3
R) -3-Fluoro-4- (3,4-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa -7-benzoyloxy-6-[(1E, 3R) -3
-Fluoro-4- (3,4-dichlorophenoxy) -1
-Butenyl] -bicyclo [3.3.0] octane-3-
ON, (1S, 5R, 6R, 7R) -2-oxa-7-
p-phenylbenzoyloxy-6-[(1E, 3R)
-3-fluoro-4- (3,4-dichlorophenoxy)
-1-butenyl] -bicyclo [3.3.0] octane-
3-one, (1S, 5R, 6R, 7R) -2-oxa-
7- (2-tetrahydropyranyloxy) -6-[(1
E, 3R) -3-Fluoro-4- (3,4-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0]
Octane-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6
[(1E, 3R) -3-fluoro-4- (3,4-dichlorophenoxy) -1-butenyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-hydroxy-6-[(1E, 3
R) -3-Fluoro-4- (3-chlorophenoxy)-
1-butenyl] -bicyclo [3.3.0] octane-3
-On, (1S, 5R, 6R, 7R) -2-oxa-7
-Benzoyloxy-6-[(1E, 3R) -3-fluoro-4- (3-chlorophenoxy) -1-butenyl]
-Bicyclo [3.3.0] octan-3-one, (1
S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3
-Fluoro-4- (3-chlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one,
(1S, 5R, 6R, 7R) -2-oxa-7- (t-
Butyldimethylsilyloxy) -6-[(1E, 3R)
-3-Fluoro-4- (3-chlorophenoxy) -1-
Butenyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(1E, 3R) -3-fluoro-4- (3,5-difluorophenoxy) -1-butenyl]- Bicyclo [3.3.0] octan-3-one,
(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E, 3R) -3-fluoro-4
-(3,5-difluorophenoxy) -1-butenyl]
-Bicyclo [3.3.0] octan-3-one, (1
S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6-[(1E, 3R) -3
-Fluoro-4- (3,5-difluorophenoxy)-
1-butenyl] -bicyclo [3.3.0] octane-3
-On, (1S, 5R, 6R, 7R) -2-oxa-7
-(T-butyldimethylsilyloxy) -6-[(1
E, 3R) -3-Fluoro-4- (3,5-difluorophenoxy) -1-butenyl] -bicyclo [3.3.
0] octan-3-one, (1S, 5R, 6R, 7R)
-2-oxa-7-hydroxy-6-[(1E, 3R)
-3-Fluoro-4- (3,4-difluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E, 3R) -3-
Fluoro-4- (3,4-difluorophenoxy) -1
-Butenyl] -bicyclo [3.3.0] octane-3-
ON, (1S, 5R, 6R, 7R) -2-oxa-7-
(2-tetrahydropyranyloxy) -6-[(1E,
3R) -3-Fluoro-4- (3,4-difluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-
Oxa-7- (t-butyldimethylsilyloxy) -6
-[(1E, 3R) -3-fluoro-4- (3,4-difluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6
R, 7R) -2-oxa-7-hydroxy-6-[(1
E, 3R) -3-Fluoro-4- (3-fluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa -7-benzoyloxy-6-[(1E, 3R)-
3-fluoro-4- (3-fluorophenoxy) -1-
Butenyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6
[(1E, 3R) -3-fluoro-4- (3-fluorophenoxy) -1-butenyl] -bicyclo [3.3.
0] octan-3-one, (1S, 5R, 6R, 7R)
-2-oxa-7- (t-butyldimethylsilyloxy) -6-[(1E, 3R) -3-fluoro-4- (3
-Fluorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6
R, 7R) -2-oxa-7-hydroxy-6-[(1
E, 3R) -3-Fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5
R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E, 3R) -3-fluoro-4- (3,5
-Bis (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6
[(1E, 3R) -3-fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) -1-butenyl]
-Bicyclo [3.3.0] octan-3-one, (1
S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6-[(1E, 3R) -3
-Fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-hydroxy-6-[(1E, 3
R) -3-Fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6
(R, 7R) -2-oxa-7-benzoyloxy-6-
[(1E, 3R) -3-fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) -1-butenyl]
-Bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6
[(1E, 3R) -3-fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) -1-butenyl]
-Bicyclo [3.3.0] octan-3-one, (1
S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6-[(1E, 3R) -3
-Fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-hydroxy-6-[(1E, 3
R) -3-Fluoro-4- (3- (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-benzoyloxy-6-[(1
E, 3R) -3-Fluoro-4- (3- (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6
[(1E, 3R) -3-fluoro-4- (3- (trifluoromethyl) phenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R,
6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6-[(1E, 3R) -3-fluoro-4- (3- (trifluoromethyl) phenoxy) -1
-Butenyl] -bicyclo [3.3.0] octane-3-
ON, (1S, 5R, 6R, 7R) -2-oxa-7-
Hydroxy-6-[(1E, 3R) -3-fluoro-4
-Phenoxy-1-butenyl] -bicyclo [3.3.
0] octan-3-one, (1S, 5R, 6R, 7R)
-2-oxa-7-benzoyloxy-6-[(1E,
3R) -3-Fluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6
[(1E, 3R) -3-fluoro-4-phenoxy-1
-Butenyl] -bicyclo [3.3.0] octane-3-
ON, (1S, 5R, 6R, 7R) -2-oxa-7-
(T-butyldimethylsilyloxy) -6-[(1E,
3R) -3-Fluoro-4-phenoxy-1-butenyl] -bicyclo [3.3.0] octan-3-one,
(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(1E, 3R) -3-fluoro-4- (3
-Methylphenyl) -1-butenyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-benzoyloxy-6-[(1
E, 3R) -3-Fluoro-4- (3-methylphenyl) -1-butenyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6
[(1E, 3R) -3-fluoro-4- (3-methylphenyl) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2 −
Oxa-7- (t-butyldimethylsilyloxy) -6
-[(1E, 3R) -3-fluoro-4- (3-methylphenyl) -1-butenyl] -bicyclo [3.3.0]
Octane-3-one, (1S, 5R, 6R, 7R) -2
-Oxa-7-hydroxy-6-[(1E, 3R) -3
-Fluoro-4- (3- (trifluoromethyl) phenyl) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa-7 -Benzoyloxy-6-[(1E, 3R) -3
-Fluoro-4- (3- (trifluoromethyl) phenyl) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa-7 -(2-tetrahydropyranyloxy) -6-
[(1E, 3R) -3-Fluoro-4- (3- (trifluoromethyl) phenyl) -1-butenyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6
[(1E, 3R) -3-fluoro-4- (3- (trifluoromethyl) phenyl) -1-butenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6
R, 7R) -2-oxa-7-hydroxy-6-[(1
E, 3R) -3-fluoro-4-phenyl-1-butenyl] -bicyclo [3.3.0] octan-3-one;
(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E, 3R) -3-fluoro-4
-Phenyl-1-butenyl] -bicyclo [3.3.0]
Octane-3-one, (1S, 5R, 6R, 7R) -2
-Oxa-7- (2-tetrahydropyranyloxy)-
6-[(1E, 3R) -3-fluoro-4-phenyl-
1-butenyl] -bicyclo [3.3.0] octane-3
-On, (1S, 5R, 6R, 7R) -2-oxa-7
-(T-butyldimethylsilyloxy) -6-[(1
E, 3R) -3-Fluoro-4-phenyl-1-butenyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(1E, 3R) -3-fluoro-5-phenyl-1-pentenyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-benzoyloxy-6-[(1
E, 3R) -3-fluoro-5-phenyl-1-pentenyl] -bicyclo [3.3.0] octan-3-one;
(1S, 5R, 6R, 7R) -2-oxa-7- (2-
Tetrahydropyranyloxy) -6-[(1E, 3R)
-3-fluoro-5-phenyl-1-pentenyl] -bicyclo [3.3.0] octan-3-one, (1S, 5
R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6-[(1E, 3R) -3-fluoro-5-phenyl-1-pentenyl] -bicyclo [3.3. 0] octane-3-one, (1S, 5R, 6
R, 7R) -2-oxa-7-hydroxy-6-[(3
R) -3-Fluorooctyl] -bicyclo [3.3.
0] octan-3-one, (1S, 5R, 6R, 7R)
-2-oxa-7-benzoyloxy-6-[(3R)
-3-fluorooctyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6
[(3R) -3-fluorooctyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7- (t-butyldimethylsilyloxy) -6-[(3R) -3-fluorooctyl] -bicyclo [3.3.0] octan-3-one, (1S, 5
R, 6R, 7R) -2-oxa-7-hydroxy-6-
[(3R) -3-fluoro-4- (3,5-dichlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa- 7-benzoyloxy-6-[(3R) -3-fluoro-4- (3,5-dichlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5
(R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-
4- (3,5-Dichlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6
[(3R) -3-fluoro-4- (3,5-dichlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa- 7-hydroxy-6-[(3R) -3-fluoro-4
-(3,4-dichlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6
(R, 7R) -2-oxa-7-benzoyloxy-6-
[(3R) -3-fluoro-4- (3,4-dichlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa- 7- (2-tetrahydropyranyloxy) -6
[(3R) -3-fluoro-4- (3,4-dichlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa- 7- (t-butyldimethylsilyloxy) -6
[(3R) -3-Fluoro-4- (3,4-dichlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(3R) -3-fluoro-4
-(3-chlorophenoxy) butyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-benzoyloxy-6-[(3
R) -3-Fluoro-4- (3-chlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one;
(1S, 5R, 6R, 7R) -2-oxa-7- (2-
Tetrahydropyranyloxy) -6-[(3R) -3-
Fluoro-4- (3-chlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5
(R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6-[(3R) -3-fluoro-
4- (3-Chlorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(3R) -3-fluoro-4
-(3,5-difluorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R,
6R, 7R) -2-oxa-7-benzoyloxy-6
-[(3R) -3-fluoro-4- (3,5-difluorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa -7- (2-tetrahydropyranyloxy) -6
[(3R) -3-fluoro-4- (3,5-difluorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa- 7- (t-butyldimethylsilyloxy) -6
[(3R) -3-fluoro-4- (3,5-difluorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa- 7-hydroxy-6-[(3R) -3-fluoro-
4- (3,4-Difluorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(3R) -3-fluoro-4- (3,4-difluorophenoxy) butyl]-
Bicyclo [3.3.0] octan-3-one, (1S,
5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-4- (3,4-difluorophenoxy) butyl] -bicyclo [3. 3.0] octane-3-one, (1S, 5
(R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6-[(3R) -3-fluoro-
4- (3,4-difluorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5
R, 6R, 7R) -2-oxa-7-hydroxy-6-
[(3R) -3-fluoro-4- (3-fluorophenoxy) butyl] -bicyclo [3.3.0] octane-3
-On, (1S, 5R, 6R, 7R) -2-oxa-7
-Benzoyloxy-6-[(3R) -3-fluoro-
4- (3-Fluorophenoxy) butyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6
[(3R) -3-fluoro-4- (3-fluorophenoxy) butyl] -bicyclo [3.3.0] octane-3
-On, (1S, 5R, 6R, 7R) -2-oxa-7
-(T-butyldimethylsilyloxy) -6-[(3
R) -3-Fluoro-4- (3-fluorophenoxy)
Butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(3R) -3-fluoro-4- (3 ,
5-bis (trifluoromethyl) phenoxy) butyl]
-Bicyclo [3.3.0] octan-3-one, (1
S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(3R) -3-fluoro-4- (3,5
-Bis (trifluoromethyl) phenoxy) butyl]-
Bicyclo [3.3.0] octan-3-one, (1S,
5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) butyl] -Bicyclo [3.3.0] octane-3-
on.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6
[(3R) -3-fluoro-4- (3,5-bis (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6
R, 7R) -2-oxa-7-hydroxy-6-[(3
R) -3-Fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.
0] octan-3-one, (1S, 5R, 6R, 7R)
-2-oxa-7-benzoyloxy-6-[(3R)
-3-Fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0]
Octane-3-one, (1S, 5R, 6R, 7R) -2
-Oxa-7- (2-tetrahydropyranyloxy)-
6-[(3R) -3-fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6
[(3R) -3-fluoro-4- (3,4-bis (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6
R, 7R) -2-oxa-7-hydroxy-6-[(3
R) -3-Fluoro-4- (3- (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-
Oxa-7-benzoyloxy-6-[(3R) -3-
Fluoro-4- (3- (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0] octane-3-
ON, (1S, 5R, 6R, 7R) -2-oxa-7-
(2-tetrahydropyranyloxy) -6-[(3R)
-3-Fluoro-4- (3- (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6
[(3R) -3-fluoro-4- (3- (trifluoromethyl) phenoxy) butyl] -bicyclo [3.3.
0] octan-3-one, (1S, 5R, 6R, 7R)
-2-oxa-7-hydroxy-6-[(3R) -3-
Fluoro-4-phenoxybutyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-benzoyloxy-6-[(3
R) -3-Fluoro-4-phenoxybutyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R,
6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-4-
Phenoxybutyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6
[(3R) -3-fluoro-4-phenoxybutyl]-
Bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(3R) -3-fluoro-4
-(3-methylphenyl) butyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-benzoyloxy-6-[(3
R) -3-Fluoro-4- (3-methylphenyl) butyl] -bicyclo [3.3.0] octan-3-one;
(1S, 5R, 6R, 7R) -2-oxa-7- (2-
Tetrahydropyranyloxy) -6-[(3R) -3-
Fluoro-4- (3-methylphenyl) butyl] -bicyclo [3.3.0] octan-3-one, (1S, 5
(R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6-[(3R) -3-fluoro-
4- (3-methylphenyl) butyl] -bicyclo [3.
3.0] octan-3-one, (1S, 5R, 6R, 7
R) -2-oxa-7-hydroxy-6-[(3R)-
3-Fluoro-4- (3- (trifluoromethyl) phenyl) butyl] -bicyclo [3.3.0] octane-3
-ON.

(1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(3R) -3-fluoro-4- (3- (trifluoromethyl) phenyl) butyl] -bicyclo [ 3.3.0] octan-3-one,
(1S, 5R, 6R, 7R) -2-oxa-7- (2-
Tetrahydropyranyloxy) -6-[(3R) -3-
Fluoro-4- (3- (trifluoromethyl) phenyl) butyl] -bicyclo [3.3.0] octane-3-
ON, (1S, 5R, 6R, 7R) -2-oxa-7-
(T-butyldimethylsilyloxy) -6-[(3R)
-3-fluoro-4- (3- (trifluoromethyl) phenyl) butyl] -bicyclo [3.3.0] octane-
3-one, (1S, 5R, 6R, 7R) -2-oxa-
7-hydroxy-6-[(3R) -3-fluoro-4-
Phenylbutyl] -bicyclo [3.3.0] octane-
3-one, (1S, 5R, 6R, 7R) -2-oxa-
7-benzoyloxy-6-[(3R) -3-fluoro-4-phenylbutyl] -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6
[(3R) -3-fluoro-4-phenylbutyl] -bicyclo [3.3.0] octan-3-one, (1S, 5
(R, 6R, 7R) -2-oxa-7- (t-butyldimethylsilyloxy) -6-[(3R) -3-fluoro-
4-phenylbutyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(3R) -3-fluoro-
5-phenylpentyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(3R) -3-fluoro- 5-phenylpentyl] -bicyclo [3.3.
0] octan-3-one, (1S, 5R, 6R, 7R)
-2-oxa-7- (2-tetrahydropyranyloxy) -6-[(3R) -3-fluoro-5-phenylpentyl] -bicyclo [3.3.0] octan-3-one, (1S, 5R, 6R, 7R) -2-oxa-7-
(T-butyldimethylsilyloxy) -6-[(3R)
-3-Fluoro-5-phenylpentyl] -bicyclo [3.3.0] octan-3-one.

The fluorine-containing prostaglandin derivative (1) of the present invention, the fluorine-containing lactols (2),
Since each of the fluorine-containing lactones (4) has an asymmetric carbon in its structure, there are various stereoisomers and optical isomers, and these compounds of the present invention include all of these stereoisomers and optical isomers , And mixtures thereof.

In the fluorine-containing prostaglandin derivative (1) of the present invention, when R ² or R ³ is a protecting group for a hydroxyl group, the protecting group is removed by a known deprotection reaction to obtain ^Each of R ² and R ³ can be a hydrogen-containing fluorine-containing prostaglandin derivative (1) having a physiological activity. The derivative having this bioactivity has almost the same bioactivity as the natural prostaglandin F2α and has few side effects. In the living body, it is hard to be decomposed by metabolism such as hydrolysis and oxidation, and is very useful as a medicine because it is stable and has high absorbability in the living body. When at least one of R ² and R ³ is an acyl group which is one kind of a protecting group for a hydroxyl group, it may be deacylated in a living body to form a derivative having a physiological activity. Is also useful as a prodrug.

[0174]

The present invention will be described in more detail with reference to the following specific examples, but the present invention is not limited to these examples. Examples 1-2
Shows a synthesis example, and Examples 3 to 8 show examples.

Example 1 (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E) -4- (3,5-dichlorophenoxy) -3-oxo-1- Synthesis of butenyl] -bicyclo [3.3.0] octan-3-one

Sodium hydride (60% dispersion in mineral oil,
2-oxo-3- (3,5-dichlorophenoxy)-to a suspension of 8.02 g) in THF (1000 ml) under ice-cooling.
Dimethyl propylphosphonate (70.0 g) in THF
(750 ml) solution was added. After stirring for 1 hour, (1
A solution of (S, 5R, 6R, 7R) -6-formyl-7-benzoyloxy-2-oxa-bicyclo [3.3.0] octan-3-one (52.4 g) in THF (750 ml) was added. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour, adjusted to pH 5 to 6 by adding acetic acid, poured into water, extracted with ethyl acetate, washed with saturated saline, and dried and concentrated.
Purify by silica gel column chromatography (hexane / ethyl acetate 2 / 1-3 / 2) to give the title compound 53.4.
I got

¹ H NMR (CDCl ₃ ): δ 2.31 (ddd, J = 2.0, 4.9, 1
5.6Hz, 1H), 2.51 (m, 1H), 2.65 (dt, J = 6.5,15.6Hz, 1H), 2.87
-2.98 (m, 3H), 4.67 (s, 2H), 5.11 (dt, J = 2.0,6.5Hz, 1H), 5.3
5 (m, 1H), 6.54 (d, J = 16.1Hz, 1H), 6.77 (d, J = 2.0Hz, 2H), 6.9
2 (dd, J = 7.8,16.1Hz, 1H), 6.99 (t, J = 2.0Hz, 1H), 7.45 (m, 2
H), 7.60 (m, 1H), 7.98 (m, 2H).

Example 2 (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E, 3S) -3-hydroxy-
4- (3,5-dichlorophenoxy) -1-butenyl]
Synthesis of -Bicyclo [3.3.0] octan-3-one

53.3 g of the enone synthesized in Example 1 was dissolved in a mixed solvent of methylene chloride (250 ml) and methanol (500 ml), and 16.85 g of cerium trichloride heptahydrate was added. After cooling to −78 ° C., 3.41 g of sodium borohydride was added, and the mixture was stirred for 2.5 hours. After adding 1N hydrochloric acid to adjust the pH to about 3, the mixture was once concentrated, diluted with ethyl acetate, and diluted with saturated saline. Washed with 3% citric acid aqueous solution. After drying, concentration and purification by silica gel column chromatography (hexane / ethyl acetate 3/2), 26.2 g of the title compound was obtained.

¹ H NMR (CDCl ₃ ): δ 2.27 (ddd, J = 2.0, 5.9, 1
5.1Hz, 1H), 2.52 (d, J = 16.1Hz, 1H), 2.63 (dt, J = 6.8,15.1H
z, 1H), 2.7-2.9 (m, 3H), 3.76 (dd, J = 7.3,9.3Hz, 1H), 3.90 (d
d, J = 3.4,9.3Hz, 1H), 4.50 (m, 1H), 5.07 (dt, J = 2.0,6.3Hz, 1
H), 5.28 (dd, J = 5.9,12.2Hz, 1H), 5.70 (dd, J = 5.4,15.6Hz, 1
H), 5.80 (ddd, J = 0.97,7.8,15.6Hz, 1H), 6.74 (d, J = 2.0Hz, 1
H), 6.97 (t, J = 2.0Hz, 1H), 7.44 (m, 2H), 7.57 (m, 1H), 7.99
(m, 2H).

Example 3 (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(1E, 3R) -3-fluoro-4
-(3,5-dichlorophenoxy) -1-butenyl]-
Synthesis of Bicyclo [3.3.0] octan-3-one

To a solution of 19.2 g of the alcohol synthesized in Example 2 in 500 ml of methylene chloride was added 25.0 g of morpholinosulfatrifluoride at -78 ° C. After stirring for 1 hour, the mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. Purification by silica gel column chromatography (hexane / ethyl acetate 3/1) gave 12.5 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 2.3-3.0 (m, 5H), 4.00
(m, 2H), 5.08-5.31 (m, 3H), 5.73-5.88 (m, 2H), 6.74 (m, 2H),
6.97 (m, 1H), 7.42 (m, 2H), 7.56 (m, 1H), 7.96 (m, 2H) 19 F NMR (CDCl 3):. -182.8 (m).

Example 4 (1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(1E, 3R) -3-fluoro-4-
Synthesis of (3,5-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one

12.5 g of the fluoride synthesized in Example 3 was dissolved in 120 ml of methanol, and 3.04 g of potassium carbonate was dissolved.
Was added and stirred at room temperature for 2 hours. After adjusting the pH to about 7 with 2N hydrochloric acid, water was added, and the mixture was extracted with ethyl acetate. Silica gel column chromatography (hexane / ethyl acetate 3
/ 2-1 / 3) to give 9.7 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 2.00 (dd, 2.7, 6.6 Hz, 1
H), 2.43-2.82 (m, 6H), 4.03-4.12 (m, 3H), 4.95 (m, 1H), 5.13
-5.29 (m, 1H), 5.70-5.84 (m, 2H), 6.82 (m, 2H), 6.98 (m, 1H) 19 F NMR (CDCl 3):. -182.4 (m).

Example 5 (1S, 5R, 6R, 7R) -2-oxa-3,7-dihydroxy-6-[(1E, 3R) -3-fluoro-4
-(3,5-dichlorophenoxy) -1-butenyl]-
Synthesis of bicyclo [3.3.0] octane

Synthesized in Example 4 (1S, 5R, 6R, 7
R) -2-oxa-7-hydroxy-6-[(1E, 3
R) -3-Fluoro-4- (3,5-dichlorophenoxy) -1-butenyl] -bicyclo [3.3.0] octan-3-one (9.6 g) in a THF (250 ml) solution was -78. A toluene solution of diisobutylaluminum hydride (1 M, 97 ml) was added at 0 ° C., and the mixture was stirred for 1 hour. Then, water (150 ml) and 1N hydrochloric acid (150 ml) were added, and the mixture was extracted with ethyl acetate. After drying, the solvent was distilled off to obtain 9.4 g of a crude product of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.99-2.83 (m, 8H), 3.92
-4.10 (m, 3H), 4.63 (m, 1H), 5.14-5.27 (m, 1H), 5.56-5.86
. (m, 3H), 6.82 (m, 2H), 6.99 (m, 1H) 19 F NMR (CDCl 3): -181.1
(M).

Example 6 Synthesis of 16- (3,5-dichlorophenoxy) -15-deoxy-15-fluoro-17,18,19,20-tetranorprostaglandin F2α isopropyl ester

To a suspension of 44.0 g of 4-carboxybutyltriphenylphosphonium bromide in 500 ml of THF was added 22.3 g of potassium t-butoxide, and the mixture was stirred at room temperature for 1.5 hours. To the lactol crude product synthesized in Example 5, 9.40 g of THF (100 ml) was added.
Stirred for hours. The reaction was stopped by adding water, washed with diethyl ether, the aqueous layer was acidified, extracted with ethyl acetate, dried, and the solvent was distilled off to give 5.90 g of a crude carboxylic acid.
I got 5.90 g of the synthesized carboxylic acid in acetone (5
0 ml) 11.7 g of diazabicycloundecene in solution,
14.2 g of 2-iodopropane was added and the mixture was stirred for 3.5 hours. Aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate.
The extract was washed with a 10% aqueous citric acid solution and aqueous sodium hydrogen carbonate, dried and concentrated, and then purified by silica gel column chromatography (hexane / ethyl acetate 2/3) to obtain 4.1 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.23 (d, J = 6.4 Hz, 1 H),
1.57-1.75 (m, 3H), 1.84 (d, J = 13.7Hz, 1H), 2.07-2.46 (m, 8
H), 4.00-4.06 (m, 3H), 4.10-4.22 (m, 1H), 4.22 (m, 1H), 4.99
-5.04 (m, 1H), 5.13-5.28 (m, 1H), 5.37-5.42 (m, 2H), 5.70 (d
dd, J = 6.3,12.2,15.6Hz), 5.84 (ddd, J = 2.9,8.8,15.6Hz),
6.83 (d, J = 2.0Hz, 2H), 6.98 (t, J = 2.0Hz, 1H) 19 F NMR (CDCl 3):. -180.4 (m).

Example 7 (15RS) -15-deoxy-15-fluoro-16
-[3- (methyl) phenyl] -17,18,19,2
0-tetranorprostaglandin F2α methyl ester

(1S, 5R, 6R, 7R) -6-Formyl-7-benzoyloxy-2-oxa-bicyclo [3.3.0] octan-3-one and 2-oxo-3-one
The title compound was synthesized from dimethyl (3-methyl) phenylpropylphosphonate in the same manner as in Examples 1 to 6.

¹ H NMR (CDCl ₃ ): δ1.4-2.5 (m, 17H), 2.84
3.07 (m, 2H), 3.66 (s, 3H), 3.90 (m, 1H), 4.17 (m, 1H), 5.06
. (m, 1H), 5.37 (m, 2H), 5.50-5.68 (m, 2H), 6.97-7.30 (m, 4H) 19 F NMR (CDCl 3): -171.0 (m), - 170.6 (m) .

Example 8 (15RS) -15-deoxy-15-fluoro-16
-[3- (trifluoromethyl) phenyl] -17,1
8,19,20-tetranor prostaglandin F2α
Methyl ester

(1S, 5R, 6R, 7R) -6-Formyl-7-benzoyloxy-2-oxa-bicyclo [3.3.0] octan-3-one and 2-oxo-3-one
The title compound was synthesized from dimethyl [3- (trifluoromethyl) phenyl] propylphosphonate in the same manner as in Examples 1 to 6.

¹ H NMR (CDCl ₃ ): δ1.4-2.5 (m, 14H), 2.9-
3.2 (m, 2H), 3.66 (s, 3H), 3.93 (m, 1H), 4.19 (m, 1H), 5.08 (m,
. 1H), 5.3-5.5 (m, 2H), 5.55-5.70 (m, 2H), 7.35-7.60 (m, 4H) 19 F NMR (CDCl 3): -172.1 (m), - 171.7 (m), -63.1 (s).

[0199]

Industrial Applicability The present invention aims at producing a prostaglandin derivative having a fluorine atom at the 15-position useful as a medicament, a method for producing the same, a method for producing an intermediate therefor, and a novel intermediate It is. All of these production methods are excellent methods that do not require severe reaction conditions or long-time reactions and do not require special reaction reagents or reaction equipment. Furthermore, the starting compound is also
It is an easily available lactone that is a basic raw material in the production of prostaglandin derivatives. Therefore, the production method and intermediate of the present invention are excellent also in versatility and can be applied to the synthesis of many other derivatives.

Continuing on the front page (72) Inventor Yasushi Matsumura 1150 Hazawa-cho, Kanagawa-ku, Yokohama-shi, Kanagawa Prefecture Inside Asahi Glass Co., Ltd. (72) Inventor Yoshitomi Morisawa 1150 Hazawa-cho, Kanagawa-ku, Yokohama-shi, Kanagawa Asahi Glass Co., Ltd.

Claims (13)

[Claims] 1. A compound represented by the following general formula (1), wherein a phosphorane represented by the following general formula (3) is allowed to act on a fluorine-containing lactol represented by the following general formula (2). A method for producing a fluorine-containing prostaglandin derivative. Embedded image (In the general formulas (1), (2) and (3), A: ethylene group, vinylene group, ethynylene group, -OCH
_2- or -SCH _2- , R ¹ : substituted or unsubstituted alkyl group having 3 to 8 carbon atoms, substituted or unsubstituted alkenyl group having 3 to 8 carbon atoms, substituted or unsubstituted 3 to 8 carbon atoms An alkynyl group, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxyalkyl group, R ² and R ³ each independently represent a hydroxyl group X: CH ₂ , O, or S, Z: OR ⁴ , NR ⁵ COR ⁶ , NR ⁷ SO ₂ R ⁸ , or SR ⁹ , R ⁴ : hydrogen atom, alkyl group, alkenyl group, alkynyl group, a cycloalkyl group, an aryl group, an aralkyl group or a metal ^{ion,, R 6, R 8,} R 9: each independently, a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, Black alkyl group, an aryl group or an aralkyl group,, R ^5, R ^7: each independently a hydrogen atom or a metal ion, R ^10: a substituted or unsubstituted aryl group, a substituted or unsubstituted alkyl group, substituted or non A substituted aralkyl group or a dialkylamino group; an overlapping portion of a solid line and a broken line: a single bond or a cis or trans double bond. ) 2. A method for producing a fluorine-containing lactone represented by the following general formula (2), comprising reducing a fluorine-containing lactone represented by the following general formula (4). Embedded image (In the general formulas (2) and (4), A: ethylene group, vinylene group, ethynylene group, -OCH
_2- or -SCH _2- , R ¹ : substituted or unsubstituted alkyl group having 3 to 8 carbon atoms, substituted or unsubstituted alkenyl group having 3 to 8 carbon atoms, substituted or unsubstituted 3 to 8 carbon atoms An alkynyl group, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxyalkyl group; R ³ : a hydroxyl-protecting group or a hydrogen atom; Represents ) 3. A method for producing a fluorine-containing lactone represented by the following general formula (4), comprising fluorinating an alcohol represented by the following general formula (5). Embedded image (In the general formulas (4) and (5), A: ethylene group, vinylene group, ethynylene group, -OCH
_2- or -SCH _2- , R ¹ : substituted or unsubstituted alkyl group having 3 to 8 carbon atoms, substituted or unsubstituted alkenyl group having 3 to 8 carbon atoms, substituted or unsubstituted 3 to 8 carbon atoms An alkynyl group, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxyalkyl group; R ³ : a hydroxyl-protecting group or a hydrogen atom; Represents ) 4. The method according to claim 1, wherein A is a vinylene group. 5. The method according to claim 1, wherein X is CH ₂ . 6. The method according to claim 1, wherein Z is OR ^4.
Manufacturing method. 7. The method according to claim 1, wherein R ¹ is CH ₂ OAr (where Ar represents a phenyl group or a monovalent heteroaromatic group having two or more substituents). 4,5
Or the manufacturing method of 6. 8. The method according to claim 7, wherein Ar is a 3,5-dichlorophenyl group or a 3,4-dichlorophenyl group. 9. A fluorinated lactol represented by the following general formula (2). Embedded image (In the general formula (2), A: ethylene group, vinylene group, ethynylene group, -OCH
_2- or -SCH _2- , R ¹ : substituted or unsubstituted alkyl group having 3 to 8 carbon atoms, substituted or unsubstituted alkenyl group having 3 to 8 carbon atoms, substituted or unsubstituted 3 to 8 carbon atoms An alkynyl group, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxyalkyl group; R ³ : a hydroxyl-protecting group or a hydrogen atom; Represents ) 10. A fluorine-containing lactone represented by the following general formula (4). Embedded image (In the general formula (4), A: ethylene group, vinylene group, ethynylene group, -OCH
_2- or -SCH _2- , R ¹ : substituted or unsubstituted alkyl group having 3 to 8 carbon atoms, substituted or unsubstituted alkenyl group having 3 to 8 carbon atoms, substituted or unsubstituted 3 to 8 carbon atoms An alkynyl group, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxyalkyl group; R ³ : a hydroxyl-protecting group or a hydrogen atom; Represents ) 11. The compound according to claim 9, wherein A is a vinylene group. 12. R ¹ is CH ₂ OAr (although, Ar is 2
Represents a phenyl group or a monovalent heteroaromatic group having at least two substituents. 9), 10 or 1).
Compound of 1. 13. The compound according to claim 12, wherein Ar is a 3,5-dichlorophenyl group or a 3,4-dichlorophenyl group.