JPH08143560A - Method for producing difluorolactone - Google Patents

Abstract

(57) [Summary] [Object] To provide a method for producing difluorolactones useful as a synthetic intermediate such as difluoroprostacyclins having two fluorine atoms at the 7-position. [Structure] The lactone represented by the formula (1) [particularly, corey lactone] is fluorinated with an electrophilic fluorinating agent in the presence of a metal compound reactant such as a transition metal halide to obtain the formula (2). A difluorolactone represented by is produced. However, n is 0 to 10 [preferably 1], R ^{1 to} R
⁴ is a hydrogen atom, a halogen atom, a protected hydroxyl group, etc.
It represents a hydrocarbon group or the like, or R ² and R ³ are combined to form 2
Represents a valent hydrocarbon group, and R ¹ and R ⁴ each represent the above. Embedded image

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing difluorolactone, which is useful as an important intermediate for difluoroprostaglandins, especially for pharmaceuticals and agricultural chemicals.

[0002]

BACKGROUND OF THE INVENTION Difluorolactones are important compounds as medicines and agricultural chemicals or their intermediates.
406 (1988)), and intermediates of difluoroprostaglandins (Table 56-501319).

However, in all of these production methods, the raw materials are difficult to obtain, the reaction control is difficult due to the use of severe reaction conditions, and the methods are not general, so that difluorolactones are used. It was strongly desired to develop a practical manufacturing method for.

On the other hand, as the fluorinating agent, fluorine gas,
Electrophilic fluorinating agents such as xenon fluoride and perchloryl fluoride have been known for a long time.
In recent years, electrophilic fluorinating agents such as N-fluorosulfonimide and N-fluorosulfonamide have also been used. Electrophilic fluorinating agents such as N-fluorosulfonimide and N-fluorosulfonamide are described in USP 3,917,68.
8, DHR Barton et al., J. Chem. Soc. Perkin I., 732 (1
974), USP 4,479,901, EP 311,086, E.Differding et
al., Synlett, 187 (1991), DE 3,623,184, JP 62-26.
264, FADavis et al., Tetrahedron Lett., 32,1631 (19
91) and the like.

An example of directly difluorinating the α-position of a carbonyl group such as a ketone or ester using these compounds is described in E. Di.
fferding et al., Tetrahedron Lett., 32, 1779 (1991), and there were problems in yield, selectivity and versatility. Up to now, there have been no known examples of direct difluorination of lactones.

[0006]

The present invention provides a novel method for the direct difluorination of lactones which solves the above problems.

[0007]

The present inventors have found a practical production method for efficiently producing difluorolactones. The present invention is the following invention relating to a method for producing difluorolactones which are useful as an important intermediate for medical and agricultural chemicals or their intermediates, particularly difluoroprostaglandins.

A lactone represented by the following formula (1) is fluorinated by causing an electrophilic fluorinating agent to act under basic conditions and in the presence of a metal compound reactant. The manufacturing method of the difluoro lactones represented by these.

[0009]

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[0010]

[Chemical 6]

[Wherein R ¹ , R ² , R ³ and R ⁴ are the same or different, and (a) individually represent a hydrogen atom, a halogen atom, a protected hydroxyl group, a protected amino group and a protected carboxyl group; A group or a monovalent hydrocarbon group having 20 or less carbon atoms, which may have a substituent, or

(B) Any two selected from n R ¹ , n n R ² , R ³ and R ⁴ are bonded to each other and have a carbon number of 10 or less, which may have a substituent. Represents a divalent hydrocarbon group, and the other R ^{1 to} R ⁴ are individually a hydrogen atom, a halogen atom, a protected hydroxyl group, a protected amino group,
Represents a protected carboxyl group or a monovalent hydrocarbon group having 20 or less carbon atoms which may have a substituent, and n
Represents an integer of 0 to 10. ]

As the lactone represented by the formula (1), the lactone represented by the following formula (3) is preferable, and the lactone represented by the formula (2)
The difluorolactone represented by the following formula (4)
The difluorolactones represented by are preferred. The difluorolactone represented by the formula (4) is useful as an important intermediate for difluoroprostaglandins.

[0014]

[Chemical 7]

[0015]

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[Wherein R ⁵ is an alkyl group having 14 or less carbon atoms, which may have a substituent, an alkenyl group having 14 or less carbon atoms, which may have a substituent, or a substituent. Represents an optionally alkynyl group having 14 or less carbon atoms, and R ⁶ represents a hydrogen atom or a protecting group. ]

In the following description of the present specification, the "lower" organic group means 1 to 6 carbon atoms. A more preferred lower organic group is an organic group 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 thereof include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, n-hexyl group and the like.

Unless otherwise specified, the "alkenyl group" is preferably a lower alkenyl group, more preferably a linear or branched alkenyl group having 2 to 6 carbon atoms and one unsaturated group. Suitable examples include vinyl group, allyl group, 1-propenyl group, isopropenyl group, 3-butenyl group, 3-pentenyl group, 4-hexenyl group and the like. Unless otherwise specified, the "alkynyl group" is preferably a lower alkynyl group, more preferably a linear or branched alkynyl group having 2 to 6 carbon atoms and one unsaturated group, and a suitable example thereof is , 1-propynyl group, 2-propynyl group, 3-butynyl group, 3-pentynyl group, 4-hexynyl group and the like.

The "alkoxy group" is preferably a lower alkoxy group, more preferably a linear or branched alkoxy group having 1 to 4 carbon atoms, and suitable examples thereof include a methoxy group and an ethoxy group. Examples include propoxy group and butoxy group. "Alkoxyalkyl group"
Is preferably a lower alkyl group whose alkoxy group moiety is a lower alkoxy group, and suitable examples thereof include a methoxyethyl group, a 3-methoxypropyl group, and a 2-methoxypropyl group.
Examples thereof include an ethoxyethyl group.

Further, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The "aryl group" refers to a monovalent aromatic hydrocarbon group, which may have a substituent (eg, lower alkyl group, halogen atom, lower alkoxy group, lower alkylamino group, etc.), and is preferably phenyl. A group or a derivative thereof, for example, a phenyl group, a tolyl group, a p-halophenyl group (for example, p-chlorophenyl group, p-bromophenyl group, etc.), an alkoxyphenyl group (for example, methoxyphenyl group, ethoxyphenyl group, etc.), etc. Is mentioned.
The "aralkyl group" refers to an aryl group-substituted alkyl group, and examples of the aryl group as the substituent include those described above. The alkyl group preferably has 1 to 4 carbon atoms. Suitable examples thereof include benzyl group, benzhydryl group, trityl group, phenethyl group and the like.

The "protecting group" is a group for temporarily protecting a reactive functional group such as a hydroxyl group, and as will be described in detail later, for example, as a hydroxyl protecting group,
There are triorganosilyl groups, acyl groups, alkyl groups, alkoxyalkyl groups, aralkyl groups, and the like. Examples of amino group protecting groups include acyl groups, alkoxycarbonyl groups, alkyl groups, alkenyl groups, aralkyl groups, and triorganosilyl. Examples of the protective group for the carboxyl group include an alkyl group, an alkenyl group, an aralkyl group, and a triorganosilyl group.

As the lactone in the present invention, general lactones are widely used. N in formulas (1) and (2)
Represents an integer of 0 to 10. That is, the lactone ring has 4 to
Form a 14-membered ring. Particularly, lactones having a 5- to 8-membered ring [n is 1 to 4] are preferable. This lactone may have another ring which is condensed or not condensed (when two of R ^{1 to} R ⁴ represent a divalent hydrocarbon group as described later). Other rings include an aliphatic ring and an aromatic ring. As this ring, a ring which is not fluorinated in the fluorination of the present invention, particularly an aliphatic ring is preferable. The lactone represented by the formula (3) is one of the lactones having the condensed aliphatic ring.

[0023] Equation (1), (2), and when R ¹ to R ⁴ are identical or different, representing individually a monovalent radical, R ¹
In some cases, two of R ⁴ to R ⁴ represent a divalent hydrocarbon group (other R ^{1 to} R ⁴ represent a monovalent group). In the case of the former (a) and the latter as (b), the former case will be described first.

In the case of (a), R ¹ , R ² , R ³ , R ⁴
Are the same or different and are independently a hydrogen atom, a halogen atom, a protected hydroxyl group, a protected amino group, a protected carboxyl group, or a monovalent group having 20 or less carbon atoms which may have a substituent. Represents a hydrocarbon group of. As shown in the formula, there are n R ¹ and R ² each, and when n is 2 or more, a plurality of R ¹ may be different from each other (R
^{2 is} also the same).

As the protected hydroxyl group, a hydroxyl group protected by a known or known protecting group used as a hydroxyl protecting group can be adopted. As the protecting group, for example,
A triorganosilyl group, an acyl group, a cyclic ether group, an optionally substituted alkyl group or an aralkyl group is used. The triorganosilyl group is a group in which three organic groups such as an alkyl group, an aryl group, an aralkyl group and an alkoxy group are bonded to a silicon atom, and particularly at least one group selected from a lower alkyl group or an aryl group is selected. A triorganosilyl group having 3 is preferable.

Specifically, for example, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triethylsilyl group, triphenylsilyl group, triisopropylsilyl group and the like are preferable. The acyl group is preferably an acetyl group, a benzoyl group or a p-phenylbenzoyl group. The cyclic ether group is preferably a tetrahydropyranyl group or a tetrahydrofuranyl group. The alkyl group and aralkyl group which may have a substituent include an alkoxyalkyl group such as a methoxymethyl group, a 1-ethoxyethyl group and a 2-methoxyethoxymethyl group, a benzyl group, a methoxybenzyl group and a trityl group. There are groups.

As the protected amino group, an amino group protected by a known or known protecting group used as a protecting group for an amino group can be adopted. Examples of the protecting group include an acyl group, an alkoxycarbonyl group, an alkyl group, an alkenyl group, an aralkyl group, a triorganosilyl group and a sulfonyl group, and examples of the acyl group include an acetyl group, a benzoyl group and a trifluoroacetyl group. Is preferred. The alkoxycarbonyl group is preferably t-butoxycarbonyl group, benzyloxycarbonyl group or the like, and the alkyl group, the alkenyl group or the alkynyl group is preferably methoxymethyl group, allyl group, benzyl group, trityl group or methoxybenzyl group. . As the triorganosilyl group, a t-butyldimethylsilyl group,
t-butyldiphenylsilyl group, triethylsilyl group,
A triphenylsilyl group and a triisopropylsilyl group are preferable. As the sulfonyl group, a p-toluenesulfonyl group, a benzenesulfonyl group, a p-chlorobenzenesulfonyl group, a p-nitrobenzenesulfonyl group, a methanesulfonyl group and the like are preferable.

As the protected carboxyl group, a carboxyl group protected by a known or known protecting group used as a protecting group for a carboxyl group can be adopted. As the protecting group, an alkyl group, an alkenyl group, an aralkyl group, a triorganosilyl group and the like are preferable. As the alkyl group, alkenyl group and aralkyl group, methoxymethyl group, allyl group, benzyl group, trityl group, methoxybenzyl group and the like are preferable. As the triorganosilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a triethylsilyl group, a triphenylsilyl group, a triisopropylsilyl group and the like are preferable.

The monovalent hydrocarbon group having 20 or less carbon atoms which may have a substituent is a linear or branched saturated or unsaturated hydrocarbon group, and in the case of an unsaturated hydrocarbon group, it is The number of saturated groups (carbon-carbon double bond or triple bond) is 4 or less, particularly preferably 1 or 2. The monovalent hydrocarbon group preferably has 10 or less carbon atoms.

Examples of the monovalent hydrocarbon group having 20 or less carbon atoms include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group and n- Octyl group, n-nonyl group, n-decyl group, n
-Undecyl group, n-dodecyl group, n-tetradecyl group, n-hexadecyl group, n-octadecyl group, n-eicosyl group, and other linear saturated hydrocarbon groups, isopropyl group, isobutyl group, t-butyl group, neopentyl group Group, 1
-Methylpentyl group, 1,1-dimethylpentyl group, 1
-Methylhexyl group, 2-methylpentyl group, branched saturated hydrocarbon group such as 2-methylhexyl group, allyl group,
Butenyl group, 3-pentenyl group, 1-methyl-3-pentenyl group, 1,1-dimethyl-hexenyl group, propargyl group, 3-pentynyl group, 1-methyl-3-hexynyl group, 1,1-dimethyl-3 -Pentynyl group, 1,1-
Examples thereof include saturated or unsaturated hydrocarbon groups such as dimethyl-3-hexynyl group.

Examples of the substituent bonded to the monovalent hydrocarbon group include a cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group, a halogen atom, a protected hydroxyl group, and a protected amino group. Substituents such as protected carboxyl group, nitro group, cyano group, oxime group, and alkoxyme group can be mentioned.

The cycloalkyl group having 3 to 10 carbon atoms is preferably a cycloalkyl group having 3 to 8 carbon atoms or a cycloalkyl group having a lower alkyl, and particularly, an unsubstituted cyclopentyl group, an unsubstituted cyclohexyl group, and a carbon number of 1 to 1 Four
Cyclopentyl group substituted with an alkyl group having 1 carbon atom
A cyclohexyl group substituted with an alkyl group of 4 is preferred.

As the substituted or unsubstituted aryl group,
Preferably, it is a phenyl group, a naphthyl group or a derivative thereof, and may have a substituent such as a lower alkyl group, a halogen atom, a lower alkoxyl group, a lower alkylamino group or a nitro group, for example, a phenyl group, Naphthyl group, tolyl group, p-chlorophenyl group, p-bromophenyl group, p-fluorophenyl group, p-methoxyphenyl group, p-ethoxyphenyl group, p-nitrophenyl group, o-chlorophenyl group, o-bromophenyl group A group, an o-methoxyphenyl group, an o-ethoxyphenyl group, an o-nitrophenyl group and the like are preferable.

Protected hydroxyl group, protected amino group,
As the protected carboxyl group, the above-mentioned ones are preferable.

In the case of (b), n R ¹ , n R ² ,
Any two selected from R ³ and R ⁴ are combined with each other to represent a divalent hydrocarbon group having 10 or less carbon atoms which may have a substituent, and other R ^{1 to} R ⁴ Are individually a hydrogen atom, a halogen atom, a protected hydroxyl group, a protected amino group, a protected carboxyl group, or a monovalent hydrocarbon group having 20 or less carbon atoms which may have a substituent. Represent R ^{1 to} R ⁴ which do not form a ring are the same as those described in the case of (a) above.

The ring formed is basically R ¹ ~
Two of R ⁴ bonded to the same carbon atom (eg R ³
And R ⁴ ), a ring formed by two (eg, R ² and R ³ when n is 1) bound to adjacent carbon atoms, and two non-adjacent carbons. Two attached to an atom (eg, R at the 4-position when n is 2)
There are three types, a ring formed by R ³ ) at the ^2- and 6-positions.
Particularly preferred in the present invention is a ring formed by two bonded to adjacent carbon atoms.

The divalent hydrocarbon group formed by bonding two of R ^{1 to} R ⁴ to each other may have an unsaturated group.
Preferred is a saturated hydrocarbon group. The carbon number is preferably 6 or less, and particularly preferably 2 to 4.

The hydrocarbon ring formed by bonding two of R ^{1 to} R ⁴ to each other may have a substituent. As a substituent, a halogen atom, a protected hydroxyl group,
A protected amino group, a protected carboxyl group, or a monovalent hydrocarbon group having 20 or less carbon atoms which may have a substituent is preferable. These substituents are the above R ¹ to
Those described as R ⁴ are suitable.

As the lactone represented by the formula (1) in the present invention, the lactone represented by the formula (3) is most preferable. The lactone represented by the formula (3) has the formula (1) in which n is 1, R ¹ and R ⁴ are both hydrogen atoms, and R ² and R ³ are bonded to form a trimethylene group, and A compound having a structure in which the substituents R ⁵ and OR ⁶ are bound to the trimethylene group and has the specific configuration shown in formula (3) is obtained. The lactone represented by the formula (3) is a prostaglandin I ₂ (hereinafter referred to as PGI ₂ )
It is a compound having the same skeleton as the above-mentioned class and known as an intermediate for the synthesis of PGI ₂ [a so-called Corey lactone derivative].

R ⁵ in equations (3) and (4) is
Organic groups corresponding to the ω chain of natural PGI ₂ and various P
An organic group corresponding to the ω chain portion of GI ₂ or an organic group that can be easily converted into these is preferable. It is preferably a hydrocarbon group having 14 or less carbon atoms which may have a substituent. Specifically, it has 1 to 1 carbon atoms which may have a substituent.
4 alkyl groups, optionally substituted carbon atoms 2-1
And the alkynyl group having 4 to 14 carbon atoms which may have a substituent. Particularly preferred is a hydrocarbon group having a protected hydroxyl group. The most preferable R ⁵ is a group represented by —A—CH (OR ⁸ ) —R ⁷ and a group represented by —CH ₂ OR ⁹ .

A in --A--CH (OR ⁸ )-R ⁷
Is a vinylene group, an ethynylene group, or an ethylene group, preferably a vinylene group or an ethynylene group, and most preferably a vinylene group similar to that corresponding to A of natural PGI ₂ .

R ⁷ is preferably an organic group corresponding to the ω chain portion of natural PGI ₂ or an organic group corresponding to the ω chain portion of various PGI ₂ . Examples of such an organic group include an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 1 to 10 carbon atoms, an alkynyl group having 1 to 10 carbon atoms, and a ring having 3 to 8 carbon atoms.
Are cycloalkyl groups, aryloxy groups having aryl groups such as phenyl groups, and these groups having various substituents. The substituent may be a cycloalkyl group or an aryl group, for example, a cycloalkyl group-substituted alkyl group, a cycloalkyl group-substituted alkenyl group, an aryl group-substituted alkenyl group, or the like.
Further, it may be an organic group in which a carbon atom of the chain organic group is substituted with 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. In addition to the above-mentioned substituents, the substituent for R ⁷ includes a halogen atom, an oxygen atom-containing substituent, a sulfur atom-containing substituent, a nitrogen atom-containing substituent, and others.

R ⁷ is preferably a chain hydrocarbon group, particularly preferably an alkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, and an alkynyl group having 3 to 8 carbon atoms. Most preferably, these are straight-chain groups having 5 to 6 carbon atoms and their monomethyl or dimethyl substituents. Specific examples of these groups include n-propyl group and n
-Butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-decyl group, 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, 1,1-dimethyl-3-hexynyl group Groups and the like. Of these, an n-pentyl group, a 2-methylhexyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group and a 1,1-dimethyl-3-hexynyl group are preferable.

When it is a substituted or unsubstituted cycloalkyl group, R ⁷ is preferably a cycloalkyl group having 3 to 8 carbon atoms which may be substituted with a lower alkyl group,
Particularly, 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.

When R ⁷ is a substituted or unsubstituted aralkyl group, R ⁷ is a benzene ring, furan ring, thiophene ring or naphthalene substituted with a halogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyl group or the like. An aralkyl group containing a ring or the like is preferable. The alkyl moiety of the aralkyl group (that is, the alkylene group) preferably has 1 to 4 carbon atoms. Particularly preferred aralkyl groups are
It is an alkyl group having 1 to 2 carbon atoms having a phenyl group.

In the case of a substituted or unsubstituted aryloxy group, R ⁷ is a benzene ring, a furan ring, a thiophene ring, a naphthalene ring substituted with a halogen atom, a halogenated alkyl group, an alkoxy group, a hydroxyl group or the like. Aryloxy groups containing are preferred. A particularly preferred aryloxy group is a phenoxy group.

R ⁷ other than the above is preferably an alkyl group having 1 to 4 carbon atoms substituted with the above cycloalkyl group. The cycloalkyl group is preferably a cyclopentyl group and a cyclohexyl group, and the alkyl group is preferably an alkyl group having 1 to 2 carbon atoms.

When R ⁶ , R ⁸ and R ⁹ are each a protective group (hydroxyl protecting group), the protecting group is not particularly limited, and a known or well known protecting group used as a hydroxyl protecting group is adopted. it can. These protecting groups may be the same or different. Examples of the protective group include the above-mentioned triorganosilyl group, acyl group, alkyl group,
Examples include aralkyl groups and cyclic ether groups. These protecting groups are adopted depending on the purpose. This is because, for example, when it is necessary to selectively deprotect only one protecting group of a compound having two protecting groups, it is preferable to use protecting groups having different reactivities. Specifically, for example, R
⁶ and R ⁸ are preferably a triorganosilyl group, a cyclic ether group and an acyl group, and R ⁹ is a triorganosilyl group, a cyclic ether group and an acyl group, which have different reactivity from other protecting groups. preferable.

The triorganosilyl group is a group in which three organic groups such as an alkyl group, an aryl group, an aralkyl group and an alkoxy group are bonded to a silicon atom, and at least one selected from a lower alkyl group and an aryl group. A triorganosilyl group having 3 groups is preferable. Specifically, for example, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triethylsilyl group, triphenylsilyl group, triisopropylsilyl group and the like are preferable.

The acyl group is preferably an acetyl group, a benzoyl group or a p-phenylbenzoyl group, and the cyclic ether group is preferably a tetrahydropyranyl group or a tetrahydrofuranyl group. Further, the alkyl group and aralkyl group which may have a substituent include a methoxymethyl group, an alkoxyalkyl group such as a 1-ethoxyethyl group and a 2-methoxyethoxymethyl group, and a benzyl group.
Examples include methoxybenzyl group and trityl group.

The protective group for the hydroxyl group as described above can be converted into the 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, J. Wiley & Sons)
It can be easily converted into a hydroxyl group by the method described in the textbooks such as.

The difluorolactones represented by the above general formula (2) can be produced by difluorinating known lactones represented by the general formula (1). The method for producing the difluorolactone represented by the general formula (2) by difluorinating the compound represented by the general formula (1) is, in the present invention, electrophilic in the presence of a metal compound reactant. A method of reacting with a fluorinating agent is adopted. It is believed that the metal compound reactant activates the active substance generated in the intermediate stage of the reaction with respect to the fluorination reaction. When fluorination is carried out in the absence of a metal compound reactant, a difluoride is scarcely produced even if a monofluoride is produced.

Examples of the metal compound reactant include organic metal compounds and metal salts. Examples of the metal in the metal compound include B, Mg, Al, Ca, Ti,
V, Mn, Fe, Co, Ni, Cu, Zn, Zr, S
Examples include metal species such as n, Ba, Hf, W, La, Ce and Sm.

The metal compound reactant is preferably a metal halide, an organic metal halide (particularly an alkyl metal halide), a metallocene halide, a trifluoromethanesulfonic acid metal salt and the like. A transition metal is preferable as the metal species. Specific examples of the metal compound reactant include the following metal compounds.

Boron trifluoride etherate, magnesium chloride, magnesium bromide, magnesium iodide, magnesium trifluoromethanesulfonate, aluminum chloride, dialkylaluminum chloride, alkylaluminum dichloride, calcium chloride, titanium tetrachloride,
Titanium trichloride isopropoxide, titanium dichloride diisopropoxide, titanium chloride triisopropoxide, titanium tetrabromide, titanium tribromide isopropoxide, titanium dibromide diisopropoxide, titanium bromide triisopropoxy Dehydrate, titanocene dichloride, vanadium chloride, manganese dichloride, manganese dibromide, iron trichloride, iron tribromide, iron triiodide, cobalt chloride, nickel chloride, nickel bromide, copper chloride, copper bromide, iodide Copper, zinc chloride, zinc bromide, zinc iodide, zinc trifluoromethanesulfonate, zirconium chloride, zirconium bromide, zirconocene dichloride,
Zirconocene chloride hydride, tin tetrachloride, tin dichloride, tin trifluoromethanesulfonate, barium chloride, barium bromide, barium iodide, hafnium chloride,
Hafnocene dichloride, tungsten chloride, lanthanum chloride, cerium chloride, samarium iodide.

The amount of the metal compound reactant is usually 0.01 to 20 parts by weight, preferably 0.1 to 20 parts by weight, based on 1 part by weight of the lactone represented by the formula (1). 10
About parts by weight is preferable.

The electrophilic fluorinating agent is not particularly limited, and a known or well-known electrophilic fluorinating agent can be adopted. For example, the electrophilic fluorinating agents described in the publications such as Tomoya Kitazume, Takashi Ishihara, Takeo Taguchi, "Chemistry of Fluorine" (Kodansha Scientific) can be used. In particular,
Fluorine gas, xenon fluoride, perchloryl fluoride, acetyl hypofluorite, N-fluoro sulfonamides and N-fluoro sulfonimides can be mentioned. N-fluorosulfonamide and N-fluorosulfonimide are preferred, and specifically, N-fluorobenzenesulfonimide, N-fluoro-p-fluorobenzenesulfonimide, N-fluoro-o-benzenedisulfonimide, N -Fluoro-p-toluenesulfonimide, N-fluoro-Nt-butylbenzenesulfonamide, N-fluoro-Nt-butyl-p-toluenesulfonamide, N-fluoro-N-methylbenzenesulfonamide, N- Fluoro-N-norbornyl-
Particularly preferred is p-fluorobenzenesulfonamide and the like.

The amount of the electrophilic fluorinating agent is usually 0.5 to 20 parts by weight per 1 part by weight of the lactone represented by the formula (1), About 10 parts by weight is preferable.

The above-mentioned difluorination reaction is preferably carried out under basic conditions and further preferably carried out in an inert solvent.
The base is preferably an amide of an alkali metal such as lithium, sodium or potassium and ammonia or a secondary amine, an alkali metal hydride, an alkali metal alkoxide, or an alkali metal organic compound. Specifically, for example, 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, lithium hydride, sodium hydride, potassium hydride, potassium t-butoxide, n-butyllithium, s-butyllithium, t-butyllithium, lithium naphthalenide, Examples include lithium biphenylide.

As the amount of the base, in the usual case, the amount of the formula (1)
0.5 to 20 relative to 1 part by weight of the lactone represented by
About 10 parts by weight is preferable, and about 2 to 10 parts by weight is preferable.

The inert solvent is preferably an ether solvent, a hydrocarbon solvent, a polar solvent, or a mixed solvent thereof. Ether-based solvents include diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, etc., and hydrocarbon-based solvents include hexane, toluene, benzene, pentane, xylene and petroleum. Ethers and the like are used as polar solvents such as dimethyl sulfoxide, 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), etc. Is preferred.

The amount of the inert solvent is usually 5 to 1 with respect to 1 part by weight of the lactone represented by the formula (1).
About 000 parts by weight is suitable, and 10 to 100 parts by weight is preferable. The reaction temperature of the above fluorination reaction is usually about -150 to + 100 ° C.
0- + 40 degreeC is preferable.

The compound represented by the formula (4) in the present invention is an important intermediate that can be induced into various difluoroprostacyclins. For example, R ⁵ is —CH ₂ O
This —CH ₂ OR ⁹ of the difluorolactone represented by the formula (4), which is the group represented by R ⁹ , can be converted into various ω chains. A group represented by ^{-A-CH (OR 8) -R} 7 is a preferred example of ω-chain. The method for introducing the ω chain into the lactone represented by the formula (3) in which R ⁵ is —CH ₂ OR ⁹ is basically known, and the corresponding formula (4 ) To difluorolactones represented by ω
Chains can be introduced.

Further, the α chain can be introduced into the difluorolactone represented by the formula (4) by a known method. A method for introducing an α chain into the lactone represented by the formula (3) is basically known, and α is introduced into the corresponding difluorolactone represented by the formula (4) by using this basically known method. Chains can be introduced. It is also possible to introduce the α chain before introducing the ω chain and then introduce the ω chain.

Regarding the introduction of the ω chain and the α chain as described above, for example, Japanese Patent Application No. 6-8064 of the present inventors.
It can also be carried out by the method described in Japanese Patent No. 1 and Japanese Patent Application No. 6-20450.

The compounds which are the starting materials for the compounds of the present invention are readily available compounds. The synthesis methods of the present invention are excellent methods that do not require severe reaction conditions or long-term reactions, and do not require special reaction reagents or reaction equipment. Therefore, the production method of the present invention is versatile and is an extremely excellent method applicable to the synthesis of many derivatives.

Specific examples of the compound represented by the formula (4) include the following compounds, but the object compound of the present invention is not limited thereto. The following compounds include various stereoisomers, optical isomers, and mixtures thereof.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-hydroxymethyl-bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7- (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0]
Octan-3-on. (1S, 5R, 6R, 7R) -2
-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octan-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldiphenylsiloxy) methyl-
Bicyclo [3.3.0] octane-3-one. (1S,
5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (triethylsiloxy) methyl-bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (2-tetrahydropyranyloxy)
Methyl-bicyclo [3.3.0] octan-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy)-
6-Benzyloxymethyl-bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (methoxybenzyloxy) methyl-bicyclo [3.3.0] octan-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy)-
6-Trityloxymethyl-bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-acetoxymethyl-bicyclo [3.
3.0] Octane-3-one. (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7-hydroxy-6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octan-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7- (t-butyldimethylsiloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0]
Octan-3-on. (1S, 5R, 6R, 7R) -2
-Oxa-4,4-difluoro-7- (triisopropylsiloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (acetoxy) -6- (t
-Butyldimethylsiloxy) methyl-bicyclo [3.
3.0] Octane-3-one. (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7- (benzoyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octan-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (4-phenylbenzoyloxy) -6
-(T-Butyldimethylsiloxy) methyl-bicyclo [3.3.0] octan-3-one. (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-acetoxymethyl-bicyclo [3.3.
0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-hydroxymethyl-bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3S, 5S)
-3-Hydroxy-5-methyl-E-1-nonenyl}-
Bicyclo [3.3.0] octane-3-one. (1S,
5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S, 4S) -hydroxy-4-methyl-E-1-octen-6-ynyl} -bicyclo [3 .3.0] Octane-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-hydroxy-6-{(3S, 4S) -hydroxy-
4-Methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3
S) -Hydroxy-4,4-dimethyl-E-1-nonene-6-ynyl} -bicyclo [3.3.0] octane-3
-On. (1S, 5R, 6R, 7R) -2-oxa-
4,4-difluoro-7-hydroxy-6-{(3S)
-3-Cyclopentyl-3-hydroxy-E-1-propenyl} -bicyclo [3.3.0] octan-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3S) -3-
Cyclohexyl-3-hydroxy-E-1-propenyl} -bicyclo [3.3.0] octane-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-E-1-octenyl} -bicyclo [3.3.
0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3
S) -3-Hydroxy-4,4-dimethyl-E-1-octenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3S) -3-
(3-Tolyl) methyl-3-hydroxy-E-1-propenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3S, 5S)
-3-Hydroxy-5-methyl-1-nonynyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3
S, 4S) -3-Hydroxy-4-methyl-1,6-octadiynyl} -bicyclo [3.3.0] octane-3
-On. (1S, 5R, 6R, 7R) -2-oxa-
4,4-difluoro-7-hydroxy-6-{(3S,
4S) -3-Hydroxy-4-methyl-1,6-nonadiynyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3S) -3-
Hydroxy-4,4-dimethyl-1,6-nonadiynyl} -bicyclo [3.3.0] octane-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-cyclopentyl-3-hydroxy-1-propynyl} -bicyclo [3.3. 0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3
S) -3-Cyclohexyl-3-hydroxy-1-propynyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3S) -3-
Hydroxy-4,4-dimethyl-1-octynyl} -bicyclo [3.3.0] octane-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-hydroxy-6-{(3S) -3- (3-tolyl)
Methyl-3-hydroxy-1-propynyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S, 5S) -3-hydroxy-5
-Methyl-nonyl} -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3
R, 5S) -3-Hydroxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octan-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3R, 4S)
-3-Hydroxy-4-methyl-E-1-octene-6
-Inyl} -bicyclo [3.3.0] octan-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3R, 4S)
-3-Hydroxy-4-methyl-E-1-nonene-6-
Inyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3R) -3-
Hydroxy-4,4-dimethyl-E-1-nonene-6-
Inyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3
R) -3-Cyclopentyl-3-hydroxy-E-1-
Propenyl} -bicyclo [3.3.0] octane-3-
on. (1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3R) -3
-Cyclohexyl-3-hydroxy-E-1-propenyl} -bicyclo [3.3.0] octane-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3R) -3-hydroxy-E-1-octenyl} -bicyclo [3.3.
0] Octane-3-one. (1S, 5R, 6R, 7R)
-2-oxa-4,4-difluoro-7-hydroxy-
6-{(3R) -3-hydroxy-4,4-dimethyl-
E-1-octenyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3
R) -3- (3-Tolyl) methyl-3-hydroxy-E
-1-Propenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3
R, 5S) -3-Hydroxy-5-methyl-1-nonynyl} -bicyclo [3.3.0] octan-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3R, 4S) -hydroxy-4-methyl-1,6-octadiynyl} -bicyclo [3. 3.0] Octane-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-hydroxy-6-{(3R, 4S) -hydroxy-
4-Methyl-1,6-nonadiynyl] -bicyclo [3.
3.0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6- (3-hydroxy-4,4-dimethyl-1,6-nonadiynyl)
-Bicyclo [3.3.0] octane-3-one. (1
S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3R) -3-cyclopentyl-3-hydroxy-1-propynyl} -bicyclo [3.3.0. ] Octan-3-on. (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3R) -3-cyclohexyl-3-
Hydroxy-1-propynyl} -bicyclo [3.3.
0] Octane-3-one. (1S, 5R, 6R, 7R)
-2-oxa-4,4-difluoro-7-hydroxy-
6-{(3R) -3-hydroxy-4,4-dimethyl-
1-octynyl} -bicyclo [3.3.0] octane-
3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3
R) -3- (2-phenylethyl) -3-hydroxy-
1-propynyl} -bicyclo [3.3.0] octane-
3-one. (1S, 5R, 6R, 7R) -2-oxa-
4,4-difluoro-7-hydroxy-6-{(3R,
5S) -3-Hydroxy-5-methyl-nonyl} -bicyclo [3.3.0] octane-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-Hydroxy-6-{(3S, 5R) -3-hydroxy-5-methyl-E-1-nonenyl} -bicyclo [3.
3.0] Octane-3-one. (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S, 4R) -3-hydroxy-4-methyl-E-1-octen-6-ynyl} -bicyclo [3.
3.0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3
S, 4R) -3-Hydroxy-4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3
R, 5R) -3-Hydroxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3R, 4R)
-Hydroxy-4-methyl-E-1-octen-6-ynyl} -bicyclo [3.3.0] octane-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3R, 4R) -hydroxy-4-methyl-E-1-nonene-6-ynyl}
-Bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3
R, 5R) -3-Hydroxy-5-methyl-1-nonynyl} -bicyclo [3.3.0] octan-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S, 5S) -3
-T-Butyldimethylsiloxy-5-methyl-E-1-
Nonenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] Octan-3-on.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-{(3
S, 5S) -3-t-Butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3. 0] Octane-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7- (2-tetrahydropyranyloxy) -6-{(3
S, 5S) -3-Hydroxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 5S) -3- (2-tetrahydropyrani Luoxy) -5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S, 5S) -3
-Acetoxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-acetoxy-6-{(3S, 5S) -3-acetoxy-5-methyl-E-1-nonenyl} -bicyclo [3.
3.0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S, 4S) -3-t-butyldimethylsiloxy-4- Methyl-E-1-octene-6-ynyl}
-Bicyclo [3.3.0] octane-3-one. (1
S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3
S, 4S) -3- (2-Tetrahydropyranyloxy)
-4-Methyl-E-1-octen-6-ynyl} -bicyclo [3.3.0] octan-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-t-butyldimethylsiloxy-6-{(3S, 4
S) -3-Acetoxy-4-methyl-E-1-octene-6-ynyl} -bicyclo [3.3.0] octane-3
-On.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 4S)-(2-tetrahydropyranyloxy ) -4-Methyl-E-1-octene-
6-Inyl} -bicyclo [3.3.0] octane-3-
on. (1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-t-butyldimethylsiloxy-6
-{(3S, 4S) -3-t-Butyldimethylsiloxy-4-methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R,
6R, 7R) -2-Oxa-4,4-difluoro-7-
(2-Tetrahydropyranyloxy) -6-{(3S,
4S) -3-t-Butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.3.
0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-{(3
S, 4S) -3-t-Butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.
3.0] Octane-3-one. (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 4S)-
3- (2-Tetrahydropyranyloxy) -4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.3.
0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-cyclopentyl-3-t-butyldimethylsiloxy- E-1-propenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R,
6R, 7R) -2-Oxa-4,4-difluoro-7-
(2-Tetrahydropyranoyloxy) -6-{(3
S) -3-Cyclopentyl-3-t-butyldimethylsiloxy-E-1-propenyl} -bicyclo [3.3.
0] Octane-3-one. (1S, 5R, 6R, 7R)
-2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-E-1-octenyl} -bicyclo [3.
3.0] Octane-3-one. (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3-
(2-Tetrahydropyranyloxy) -E-1-octenyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3
S, 5R) -3-t-Butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octan-3-one. (1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 5R) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3 .3.0] Octane-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-{(3S, 5R) -3
-T-Butyldimethylsiloxy-5-methyl-E-1-
Nonenyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 5R) -3-hydroxy-
5-Methyl-E-1-nonenyl} -bicyclo [3.3.
0] Octane-3-one. (1S, 5R, 6R, 7R)
-2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 5R) -3-
(2-Tetrahydropyranyloxy) -5-methyl-E
-1-Nonenyl} -bicyclo [3.3.0] octane-
3-one. (1S, 5R, 6R, 7R) -2-oxa-
4,4-Difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 5R) -3-acetoxy-5
-Methyl-E-1-nonenyl} -bicyclo [3.3.
0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3
S, 5R) -3-Acetoxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octan-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-acetoxy-6-{(3S, 5R)
-3-acetoxy-5-methyl-E-1-nonenyl}-
Bicyclo [3.3.0] octane-3-one. (1S,
5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S, 4
R) -3-t-Butyldimethylsiloxy-4-methyl-
E-1-octene-6-ynyl} -bicyclo [3.3.
0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-hydroxy-4-methyl-E
-1-octene-6-ynyl-bicyclo [3.3.0]
Octan-3-on. (1S, 5R, 6R, 7R) -2
-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S, 4R) -3- (2-tetrahydropyranyloxy) -4-methyl-E-1-octen-6-ynyl } -Bicyclo [3.3.0] octane-
3-one. (1S, 5R, 6R, 7R) -2-oxa-
4,4-Difluoro-7-t-butyldimethylsiloxy-6-{(3S, 4R) -3-acetoxy-4-methyl-E-1-octene-6-ynyl} -bicyclo [3.
3.0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3
S, 4R) -3- (2-Tetrahydropyranyloxy)
-4-Methyl-E-1-octen-6-ynyl} -bicyclo [3.3.0] octan-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7- (2-tetrahydropyranyloxy) -6-{(3
S, 4R) -3- (2-Tetrahydropyranyloxy)
-4-Methyl-E-1-octen-6-ynyl} -bicyclo [3.3.0] octan-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-acetoxy-6-{(3S, 4R) -3- (2
-Tetrahydropyranyloxy) -4-methyl-E-1
-Octene-6-ynyl} -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S, 4R) -3-t-butyldimethylsiloxy-4- Methyl-E-1-nonene-6-ynyl}-
Bicyclo [3.3.0] octane-3-one. (1S,
5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S, 4R) -3-t-butyldimethylsiloxy-4-methyl-E-1-nonene-
6-Inyl} -bicyclo [3.3.0] octane-3-
on. (1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 4R) -3-t-butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl}
-Bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-{(3
S, 4R) -3-t-Butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.
3.0] Octane-3-one. (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 4R)-
3- (2-Tetrahydropyranyloxy) -4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.3.
0] Octane-3-one. (1S, 5R, 6R, 7R)
-2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 4R) -3-
Hydroxy-4-methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 4R) -3-acetoxy-
4-Methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3R, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3 .3.0] Octane-3-one. (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7- (2-tetrahydropyranyloxy) -6-{(3
R, 5S) -3-t-Butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-{(3
R, 5S) -3-t-Butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octan-3-one. (1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 5S) -3-hydroxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] ] Octan-3-on. (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-
(2-Tetrahydropyranyloxy) -6-{(3R,
5S) -3- (2-Tetrahydropyranyloxy) -5
-Methyl-E-1-nonenyl} -bicyclo [3.3.
0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 5S) -3-acetoxy-
5-Methyl-E-1-nonenyl} -bicyclo [3.3.
0] Octane-3-one. (1S, 5R, 6R, 7R)
-2-oxa-4,4-difluoro-7-hydroxy-
6-{(3R, 5S) -3-acetoxy-5-methyl-
E-1-Nonenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-acetoxy-6-{(3
R, 5S) -3-Acetoxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3R, 4S) -3-t-butyldimethylsiloxy-4- Methyl-E-1-octene-6-ynyl}
-Bicyclo [3.3.0] octane-3-one. (1
S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3
R) -3-Hydroxy-4-methyl-E-1-octene-6-ynyl-bicyclo [3.3.0] octane-3-
on. (1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-t-butyldimethylsiloxy-6
-{(3R, 4S) -3- (2-Tetrahydropyranyloxy) -4-methyl-E-1-octen-6-ynyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3R, 4S) -3-acetoxy-4-methyl-E- 1-octene-6-ynyl} -bicyclo [3.
3.0] Octane-3-one. (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3R, 4S) -3- (2-tetrahydropyranyloxy) -4-methyl-E-1-octene-6-
Inyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 4S) -3- (2-tetrahydropyranyloxy) -4-methyl-E-1-octene-6
-Inyl} -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-
{(3R, 4S) -3- (2-Tetrahydropyranyloxy) -4-methyl-E-1-octen-6-ynyl}
-Bicyclo [3.3.0] octane-3-one. (1
S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3
R, 4S) -3-t-Butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.
3.0] Octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3
R, 4S) -3-t-Butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.
3.0] Octane-3-one. (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 4S)-
3-t-butyldimethylsiloxy-4-methyl-E-1
-Nonene-6-ynyl} -bicyclo [3.3.0] octan-3-one. (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-
{(3R, 4S) -t-Butyldimethylsiloxy-4-
Methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 4S) -3- (2-tetrahydropyrani Ruoxy) -4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.3.0] octane-3
-On. (1S, 5R, 6R, 7R) -2-oxa-
4,4-Difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 4S) -3-hydroxy-4
-Methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-
(2-Tetrahydropyranyloxy) -6-{(3R,
4S) -3-acetoxy-4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.3.0] octane-3
-On.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3R) -3-cyclopentyl-3-t-butyldimethylsiloxy- E-1-propenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R,
6R, 7R) -2-Oxa-4,4-difluoro-7-
Hydroxy-6-{(3R) -3-cyclopentyl-3
-T-butyldimethylsiloxy-E-1-propenyl}
-Bicyclo [3.3.0] octane-3-one. (1
S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-{(3R) -3-cyclopentyl-3-t-butyldimethylsiloxy-E-1-propenyl} -bicyclo [3.3.0] Octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7- (2-tetrahydropyranoyloxy) -6-{(3R) -3-cyclopentyl-3-t-
Butyldimethylsiloxy-E-1-propenyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranoyloxy) -6-{(3R) -3-cyclopentyl-
3-Hydroxy-E-1-propenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-
(2-Tetrahydropyranoyloxy) -6-{(3
R) -3-Cyclopentyl-3-acetoxy-E-1-
Propenyl} -bicyclo [3.3.0] octane-3-
on. (1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-t-butyldimethylsiloxy-6
-{(3R) -3-t-butyldimethylsiloxy-E-
1-octenyl} -bicyclo [3.3.0] octane-
3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-{(3
R) -3-t-Butyldimethylsiloxy-E-1-octenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-hydroxy-6-{(3R) -3-
t-butyldimethylsiloxy-E-1-octenyl}-
Bicyclo [3.3.0] octane-3-one. (1S,
5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-
{(3R) -3- (2-tetrahydropyranyloxy)
-E-1-octenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R) -3-acetoxy-E
-1-Octenyl} -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3
R, 5R) -3-t-Butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 5R) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3 .3.0] Octane-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-{(3R, 5R) -3
-T-Butyldimethylsiloxy-5-methyl-E-1-
Nonenyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 5R) -3-hydroxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3- on.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 5R) -3- (2-tetrahydropyrani Luoxy) -5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one. #
(1S, 5R, 6R, 7R) -2-oxa-4,4-
Difluoro-7- (2-tetrahydropyranyloxy)
-6-{(3R, 5R) -3-triethylsiloxy-5
-Methyl-E-1-nonenyl} -bicyclo [3.3.
0] Octane-3-one. (1S, 5R, 6R, 7R)
-2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 5R) -3-
Acetoxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3
R, 5R) -3-Acetoxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octan-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7-acetoxy-6-{(3R, 5R)
-3-acetoxy-5-methyl-E-1-nonenyl}-
Bicyclo [3.3.0] octane-3-one. (1S,
5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3R, 4
R) -3-t-Butyldimethylsiloxy-4-methyl-
E-1-octene-6-ynyl} -bicyclo [3.3.
0] Octane-3-one. (1S, 5R, 6R, 7R)
2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3R, 4R) -3- (2-tetrahydropyranyloxy) -4-methyl-E-1-octene-6 -Inyl} -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3R, 4R) -3-acetoxy-4-methyl-E- 1-octene-6-ynyl} -bicyclo [3.
3.0] Octane-3-one. (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3R, 4R) -3- (2-tetrahydropyranyloxy) -4-methyl-E-1-octene-6-
Inyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-oxa-4,4
-Difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 4R) -3- (2-tetrahydropyranyloxy) -4-methyl-E-1-octene-6
-Inyl} -bicyclo [3.3.0] octan-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-
{(3R, 4R) -3- (2-Tetrahydropyranyloxy) -4-methyl-E-1-octen-6-ynyl}
-Bicyclo [3.3.0] octane-3-one. (1
S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3
R, 4R) -3-t-Butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.
3.0] Octane-3-one. (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3R, 4R) -3-t-butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl}-
Bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 4R) -3-t-butyldimethylsiloxy -4-Methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octan-3-one.
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6-{(3R, 4R) -3
-T-butyldimethylsiloxy-4-methyl-E-1-
Nonene-6-ynyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 4R) -3- (2-tetrahydropyranyloxy) -4-Methyl-E-1-nonene-6-ynyl} -bicyclo [3.3.0] octane-
3-one.

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3R, 4R) -3-hydroxy-
4-Methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one. (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-
(2-Tetrahydropyranyloxy) -6-{(3R,
4R) -3-acetoxy-4-methyl-E-1-nonene-6-ynyl} -bicyclo [3.3.0] octane-3
-On.

The present invention will be specifically described below with reference to Examples and Reference Examples. However, the invention is not limited to these examples. Reference Examples 1 to 6 are examples in which the difluorolactones synthesized in Example 1 were used and the α chain and the ω chain were sequentially introduced to synthesize difluoro PGI _{2 s} . Reference Examples 7 to 10 are examples in which the difluorolactones (having an ω chain) synthesized in Example 6 are used, and an α chain is introduced thereinto to synthesize the same difluoro PGI ₂ compounds synthesized in Reference Examples 1 to 6. Indicates.

[0116]

【Example】

Example 1 (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy)-
Synthesis of 6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-one.

185 mg of anhydrous manganese bromide (1.5 mm
ol), anhydrous tetrahydrofuran [hereinafter referred to as THF] (3 ml) was added, and then 473 mg (1.5 mmol) of anhydrous THF was added to N-fluorobenzenesulfonimide.
The solution (3 ml) was added at room temperature and stirred for 1 hour. next,
(1S, 5R, 6R, 7R) -2-oxa at -78 ° C
7- (2-tetrahydropyranyloxy) -6- (t-
Butyldimethylsiloxy) methyl-bicyclo [3.3.
0] octan-3-one 185 mg of THF (3 ml)
The solution was added at -78 ° C, 4 ml of potassium hexamethyldisilazide (0.5 M toluene solution) was added, and the solution was added at -78 ° C.
The mixture was stirred for 1 hour at 0 ° C. for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and purified by silica gel column chromatography to give the title compound (110 mg).

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.06 (m, 6H), 0.89
(m, 9H), 1.2-2.3 (m, 8H), 2.6-2.7 (m, 1H), 3.09 (m, 1H), 3.4-
3.9 (m, 4H), 4.23 (m, 1H), 4.64 (m, 1H), 5.12 (m, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): -94 (m), -115 (m). Mass spectrum: 406 (M ⁺ ).

The title compound was synthesized under the same starting materials and conditions as above except that the kind of the metal compound reactant was changed.
Table 1 shows the kinds of metal compound reactants used and the yield of the title compound. The metal compound reactants abbreviated in the table are as follows. CpZrCl _2: zirconocene dichloride. Zn (OTf) ₂ : Zinc trifluoromethanesulfonate.

[0120]

[Table 1]

Example 2 (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-6-bicyclo [3.3.0] octene-3-
On synthesis. Using (1S, 5R, 6R, 7R) -2-oxa-6-bicyclo [3.3.0] octen-3-one 62 mg,
In the same manner as in Example 1, 55 mg of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.5-3.0 (m, 2H), 4.5-6.1 (m, 4H)
. ¹⁹ F-NMR (CDCl ₃ , ppm): -100 (m), -117 (m).

Example 3 Synthesis of 2,2-difluoro-7-heptanolide. 20 mg of the title compound was obtained in the same manner as in Example 1 using 64 mg of 7-heptanolide. ¹⁹ F-NMR (CDCl ₃ , ppm):-100 (m).

Example 4 3,5-bis-O- (t-butyldimethylsilyl) -2
-Synthesis of deoxy-2,2-difluoro-1-oxoribose. 3,5-bis-O- (t-butyldimethylsilyl) -2
The title compound (75 mg) was obtained in the same manner as in Example 1 by using 190 mg of -deoxy-1-oxoribose. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.1-0.2 (m, 12H), 0.84 (s, 9H), 0.
91 (s, 9H), 3.81 (m, 1H), 3.96 (m, 1H), 4.28 (m, 1H), 4.55 (m, 1
H).

Reference Example 1 1- (4-iodobutyl) -4-methyl-2,6,7-
Synthesis of trioxabicyclo [2.2.2] octane.

EJCorey et al., Tetrahedron Lett., 24,
Synthesis was carried out in the same manner as described in 5571 (1983) as follows. To a solution of 4.21 g of 3-methyl-3-hydroxymethyloxetane in methylene chloride (20 ml) was added 0 ml of 5 ml of pyridine and 12.2 g of 5-iodopentanoic acid chloride.
The mixture was added at 0 ° C. and stirred for 2 hours. It was poured into aqueous sodium hydrogen carbonate, extracted with methylene chloride, and then purified by silica gel column chromatography to obtain 13.0 g of the corresponding ester. To a solution of 6.24 g of this ester in anhydrous methylene chloride (20 ml),
Boron trifluoride etherate 0.62 at -15 ° C
ml was added, and the mixture was stirred at -15 ° C for 4 hours, 0 ° C for 2 hours, and room temperature for 1 hour. 2.79 ml of triethylamine was added at 0 ° C.
The reaction solution was concentrated and purified by silica gel column chromatography to obtain 5.42 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.80 (s, 3H), 1.5-1.9 (m, 6H), 3.1
7 (t, J = 7.2Hz, 2H), 3.89 (s, 6H).

[Reference Example 2] (1S, 5R, 6R, 7R) -2-oxa-3- {4-
(4-methyl-2,6,7-trioxabicyclo [2.
2.2] Octanyl) butylidene} -4,4-difluoro-6- (t-butyldimethylsiloxymethyl) -7-
(2-Tetrahydropyranyloxy) bicyclo [3.
3.0] Synthesis of octane.

1- (4-iodobutyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane 195 mg of anhydrous ether (5
ml) solution was cooled to −78 ° C., 0.87 ml of t-butyllithium (1.48M pentane solution) was added,
The mixture was stirred at -78 ° C for 2 hours. In addition, (1S, 5R, 6R, 7R) -2-oxa-4,4-synthesized in Example 1
Difluoro-7- (2-tetrahydropyranyloxy)
-6- (t-Butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-one 209 mg of an ether solution (2 ml) was added at -78 ° C, and then -78 ° C.
The mixture was stirred for 1 hour at −60 ° C. for 1 hour. It was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated brine and then concentrated under reduced pressure.

2 ml of methylene chloride was added to the residue, 0.53 ml of triethylamine and 0.14 ml of methanesulfonyl chloride were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. It was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10) to obtain 263 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.05 (m, 6H), 0.8-2.9 (m, 28H), 3.
4-4.7 (m, 14H). ¹⁹ F-NMR (CDCl ₃ , ppm): -83 (m), -115 (m).

[Reference Example 3] 5- (1S, 5R, 6R, 7R) -2-oxa-4,4
Synthesis of methyl-difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate.

Synthesized in Reference Example 2 (1S, 5R, 6R,
7R) -2-oxa-3- {4- (4-methyl-2,
6,7-Trioxabicyclo [2.2.2] octanyl) butylidene} -4,4-difluoro-6- (t-butyldimethylsiloxy) methyl-7- (2-tetrahydropyranyloxy) bicyclo [3. 3.0] Octane 2
To a solution of 63 mg of 1,2-dimethoxyethane (5 ml), 0.5 ml of a 10% sodium hydrogensulfate aqueous solution was added at 0 ° C, and the mixture was stirred for 30 minutes. The mixture was poured into aqueous sodium hydrogen carbonate, extracted with ethyl acetate, the extract was concentrated under reduced pressure, 5 ml of methanol and 136 mg of potassium carbonate were added to the residue, and the mixture was stirred at room temperature for 2 hours. Pour into an aqueous solution of sodium hydrogen carbonate-ethyl acetate-hexane (1:
1), the extract was concentrated under reduced pressure, and subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
30-1: 10) to obtain 191 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.05 (m, 6H), 0.8-2.9 (m, 25H), 3.
67 (s, 3H), 3.4-4.7 (m, 8H). ¹⁹ F-NMR (CDCl ₃ , ppm): -83 (m), -115 (m).

[Reference Example 4] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0]
Synthesis of octane-3-ylidene] methyl pentanoate.

5- (1S, 5R, 6 synthesized in Reference Example 3
R, 7R) -2-Oxa-4,4-difluoro-7-
(2-Tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0]
Octane-3-ylidene] methyl pentanoate 340 mg
780 μl of tetrabutylammonium fluoride (1M THF solution) was added to a THF (10 ml) solution of 1 at 0 ° C. After stirring at room temperature for 2 hours, the solvent was evaporated and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1) to obtain 150 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3-2.9 (m, 16H), 3.67 (s, 3H), 3.
4-4.7 (m, 8H). ¹⁹ F-NMR (CDCl ₃ , ppm): -83 (m), -115 (m).

[Reference Example 5] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 5
S) -3-Hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of methyl pentanoate.

5-[(1S, 5R, synthesized in Reference Example 4
6R, 7R) -2-Oxa-4,4-difluoro-7-
Methyl (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-ylidene] pentanoate 150 mg benzene (3 ml)
Pyridine 29μl, dimethyl sulfoxide 30μ in the solution
1, trifluoroacetic acid 4 μl and dicyclohexylcarbodiimide 217 mg were added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was filtered, and the filtrate was washed with water and concentrated to obtain the corresponding crude aldehyde product.

37 mg of sodium hydride was added to a solution of 235 mg of dimethyl (4S) -4-methyl-2-oxooctanylphosphonate in 1,2-dimethoxyethane (5 ml), and the mixture was stirred for 10 minutes. To this solution was added a solution of the crude aldehyde above in 1,2-dimethoxyethane (3 ml).
The mixture was added at 0 ° C., stirred at room temperature for 30 minutes, poured into brine and extracted with ethyl acetate. After drying and concentration, silica gel column chromatography (ethyl acetate: hexane = 1: 4-1: 1:
Purification in 1) gave 120 mg of the corresponding enone. Cerium chloride heptahydrate 102 was added to this methanol (5 ml) solution.
mg and sodium borohydride (15 mg) were added at -40 ° C, the mixture was stirred at -40 ° C for 10 minutes and at 0 ° C for 30 minutes, poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate.

After concentration, the residue was dissolved in methanol (5 ml), 5 mg of p-toluenesulfonic acid monohydrate was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. After the methanol was distilled off, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added for extraction. The extract was dried, concentrated, and purified by silica gel column chromatography (methylene chloride: acetone = 1: 2) to give 39 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-3.0 (m, 25H), 3.4-5.2 (m, 6
H), 6.2-6.8 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , ppm): -179 (m).

[Reference Example 6] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 5
S) -3-Hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of sodium pentanoate.

5-[(1S, 5R, synthesized in Reference Example 5
6R, 7R) -2-Oxa-4,4-difluoro-7-
Hydroxy-6-{(3S, 5S) -3-hydroxy-
5-Methyl-E-1-nonenyl} bicyclo [3.3.
0] octane-3-ylidene] methyl pentanoate 139
To 39 mg of ethanol (8 ml) solution was added 0.1N sodium hydroxide (3.39 ml), and the mixture was stirred at room temperature for 14 hours.
Concentration under reduced pressure gave 125 mg of the title compound. ¹ H-NMR (D ₂ O) δ (ppm): 0.8-2.9 (m, 25H), 3.7-4.3 (m, 2H),
4.5-5.0 (m, 2H), 5.5-5.7 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm):-84 (dd, J = 17,250Hz),-117 (d, J = 250H
z).

Example 5 (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy)-
Synthesis of 6-{(3S, 5S) -3- (2-Tetrahydropyranyloxy) -5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one.

(1S, 5R, 6R, 7R) -2-Oxa-7- (2-tetrahydropyranyloxy) -6-
Using 232 mg of {(3S, 5S) -3- (2-tetrahydropyranyloxy) -5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one,
In the same manner as in Example 1, 143 mg of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.90 (m, 6H), 1.0-
2.3 (m, 23H), 2.95-3.25 (m, 2H), 3.45 (m, 2H), 3.80 (m, 2H),
4.15 (m, 2H), 4.60 (m, 2H), 5.15-5.65 (m, 3H). ¹⁹ F-NMR (CDCl ₃ , ppm): -92.9 (dd, J = 26,279Hz), -93.1 (dd, J
= 26,279Hz), -115 (d, J = 279Hz), -116 (d, J = 279Hz).

Example 6 (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-
{(3S, 5S) -3-t-butyldimethylsiloxy-
5-Methyl-E-1-nonenyl} -bicyclo [3.3.
0] Octane-3-one synthesis.

(1S, 5R, 6R, 7R) -2-Oxa-7-t-butyldimethylsiloxy-6-{(3S, 5
S) -3-t-Butyldimethylsiloxy-5-methyl-
Using 854 mg (1.62 mmol) of E-1-nonenyl} -bicyclo [3.3.0] octane-3-one,
In the same manner as in Example 1, 513 mg of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.84
-0.88 (m, 24H), 1.0-1.5 (m, 9H), 2.1-2.2 (m, 2H), 2.9-3.1
(m, 2H), 4.0-4.2 (m, 2H), 5.15 (m, 1H), 5.36 (dd, J = 7.7,15.3
Hz, 1H), 5.54 (dd, J = 6.3,15.3Hz, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm):-92 (dd, J = 26,282Hz),-114 (d, J = 282
Hz).

Reference Example 7 (1S, 5R, 6R, 7R) -2-Oxa-3- {4-
(4-methyl-2,6,7-trioxabicyclo [2.
2.2] Octanyl) butylidene} -4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S,
Synthesis of 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane.

1- (4-iodobutyl) -4-methyl-
A solution of 1.13 g of 2,6,7-trioxabicyclo [2.2.2] octane in anhydrous ether (30 ml) was added to -78.
The mixture was cooled to ° C, 5.07 ml of t-butyllithium (1.48M, pentane solution) was added, and the mixture was stirred at -78 ° C for 2 hours. This was synthesized in Example 6 (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-t
-Butyldimethylsiloxy-6-{(3S, 5S) -3
-T-Butyldimethylsiloxy-5-methyl-E-1-
An ether solution (10 ml) of 1.75 g of nonenyl} bicyclo [3.3.0] octane-3-one was added at -78 ° C, and then the mixture was stirred at -78 ° C for 1 hour and at -60 ° C for 1 hour. It was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with saturated brine and then concentrated under reduced pressure. Methylene chloride (10 ml) was added to the residue, triethylamine (2.6 ml) and methanesulfonyl chloride (0.72 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hr. It was poured into aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
30-1: 10) to obtain 1.83 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.02-0.05 (m, 12
H), 0.80-0.89 (m, 27H), 1.2-2.5 (m, 19H), 3.84 (m, 1H), 3.88
(s, 6H), 4.13 (m, 1H), 4.7-4.9 (m, 2H), 5.53 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , ppm): -83 (d, J = 251Hz), -115 (d, J = 250Hz)
.

[Reference Example 8] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-t-butyldimethylsiloxy-6
-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.
3.0] Synthesis of octane-3-ylidene] methyl pentanoate.

Synthesized in Reference Example 7 (1S, 5R, 6R,
7R) -2-oxa-3- {4- (4-methyl-2,
6,7-Trioxabicyclo [2.2.2] octanyl) butylidene} -4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S, 5S) -3-t-
Butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane To a solution of 1.83 g of 1,2-dimethoxyethane (25 ml), 10% was added.
Add 2.5 ml of aqueous sodium hydrogen sulfate solution at 0 ° C and
Stir for 0 minutes. Pour into sodium bicarbonate water and extract with ethyl acetate,
The residue obtained by concentrating the extract under reduced pressure was added with 25 m of methanol.
1, 680 mg of potassium carbonate were added, and the mixture was stirred at room temperature for 2 hours. Pour into aqueous sodium hydrogen carbonate, and mix with ethyl acetate-hexane (1:
1), the extract was concentrated under reduced pressure, and subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 1).
30-1: 10) to obtain 981 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.03-0.11 (m, 12
H), 0.85-0.89 (m, 24H), 1.1-2.6 (m, 19H), 3.67 (s, 3H), 3.8-
4.2 (m, 2H), 4.7-4.9 (m, 2H), 5.4-5.6 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , ppm):-83 (dd, J = 14,251Hz),-115 (d, J = 251
Hz). Mass spectrum: 659 (M ⁺⁺ 1).

Reference Example 9 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 5
Synthesis of S) -3-Hydroxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-ylidene] pentanoate.

5-[(1S, 5R, synthesized in Reference Example 8
6R, 7R) -2-Oxa-4,4-difluoro-7-
t-Butyldimethylsiloxy-6-{(3S, 5S)-
3-t-butyldimethylsiloxy-5-methyl-E-1
-Nonenyl} -bicyclo [3.3.0] octane-3-
Ilidene] methyl pentanoate 976 mg THF (15
(4.5 ml) tetrabutylammonium fluoride (1 M, THF solution) was added to the solution, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the title compound (470 mg)
I got

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-2.7 (m, 25H),
3.67 (s, 3H), 3.9-4.3 (m, 2H), 4.7-4.9 (m, 2H), 5.5-5.7 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , ppm):-84 (dd, J = 17,248Hz),-117 (d, J = 248)
Hz). Mass spectrum: 431 (M ⁺⁺ 1).

[Reference Example 10] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 5
Synthesis of S) -3-hydroxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-ylidene] pentanoate sodium.

5-[(1S, 5R, synthesized in Reference Example 9
6R, 7R) -2-Oxa-4,4-difluoro-7-
Hydroxy-6-{(3S, 5S) -3-hydroxy-
5-Methyl-E-1-nonenyl} -bicyclo [3.3.
0] octane-3-ylidene] methyl pentanoate 139
To an ethanol (8 ml) solution (mg) was added 3.39 ml of 0.1N sodium hydroxide and the mixture was stirred at room temperature for 14 hours.
Concentration under reduced pressure gave 125 mg of the title compound.

¹ H-NMR (D ₂ O) δ (ppm): 0.8-2.9 (m, 25H), 3.7
-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.5-5.7 (m, 2H). ¹⁹ F-NMR (D ₂ O, ppm):-84 (dd, J = 17,250Hz),-117 (d, J = 250H
z).

[0157]

INDUSTRIAL APPLICABILITY The method of the present invention produces corresponding difluorolactones from lactones without requiring severe reaction conditions or long reaction times, and without requiring special reaction reagents or reaction equipment. This is an excellent method. Furthermore, the lactones used as raw materials are readily available compounds,
Since the synthesized difluorolactones are versatile intermediates, they can be applied to the synthesis of many derivatives.

Particularly, as shown in Reference Examples, the synthesized difluorolactones are useful as an intermediate for the synthesis of difluoro PGI ₂ having two fluorine atoms at the 7-position of the prostacyclin skeleton, It is an intermediate that is more chemically stable than the intermediate and can efficiently synthesize difluoro PGI ₂ compounds.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 309/30 311/20 311/94 313/00 407/12 307 C07F 7/18 S // ( C07D 407/12 307: 935 309: 12)

Claims (6)

[Claims] (1) A lactone represented by the following formula (1) is fluorinated by acting an electrophilic fluorinating agent under basic conditions and in the presence of a metal compound reactant. A method for producing a difluorolactone represented by (2). Embedded image Embedded image [Wherein R ¹ , R ² , R ³ , and R ⁴ are the same or different, and (a) individually represent a hydrogen atom, a halogen atom, a protected hydroxyl group, a protected amino group, a protected carboxyl group, or Represents a monovalent hydrocarbon group having 20 or less carbon atoms, which may have a substituent, or (b) is selected from n R ¹ , n R ² , R ³ and R ^4. And any two of them represent a divalent hydrocarbon group having 10 or less carbon atoms which may be bonded to each other and have a substituent, and other R ^{1 to} R ⁴ are individually a hydrogen atom or a halogen atom. An atom, a protected hydroxyl group, a protected amino group, a protected carboxyl group, or a monovalent hydrocarbon group having 20 or less carbon atoms, which may have a substituent, and n is 0 to 10 Represents an integer. ] 2. A lactone represented by the formula (1) is a lactone represented by the following formula (3), and a difluorolactone represented by the formula (2) is represented by the following formula (4). The method according to claim 1, which is a difluorolactone. Embedded image [Chemical 4] [However, R ⁵ has 1 carbon atom which may have a substituent.
Represents an alkyl group having 4 or less, an alkenyl group having 14 or less carbon atoms which may have a substituent, or an alkynyl group having 14 or less carbon atoms which may have a substituent, and R ⁶ represents a hydrogen atom or Represents a protecting group. ] 3. The process according to claim 2, wherein R ⁵ is a group represented by —A—CH (OR ⁸ ) —R ⁷ . [However, A represents a vinylene group, an ethynylene group, or an ethylene group, and R
⁷ represents an alkyl group having 10 or less carbon atoms, which may have a substituent, an alkenyl group or an alkynyl group, a cycloalkyl group having a 3- to 8-membered ring which may have a substituent, and a substituent. Represents an optionally substituted aryl group or an optionally substituted aralkyl group, and R ⁸ represents a hydrogen atom or a protecting group. ] 4. The method according to claim _{2, wherein} R ⁵ is a group represented by —CH ₂ OR ⁹ (wherein R ⁹ represents a hydrogen atom or a protecting group). 5. A metal compound reactant is B, Mg, Al, C.
a, Ti, V, Mn, Fe, Co, Ni, Cu, Zn,
Zr, Sn, Ba, Hf, W, La, Ce, and Sm
A metal compound containing a metal species selected from the group consisting of:
1. A manufacturing method of 1, which is selected from 6. The method according to claim 1, wherein the electrophilic fluorinating agent is N-fluorosulfonimides or N-fluorosulfonamide.