JPH08217772A - Production of difluoro-substituted vinyl ethers - Google Patents

Abstract

PURPOSE: To obtain the subject compounds useful as a medicine or an agrochemical or its intermediate, especially an important intermediate, etc., for difluoroprostaglandins in high yield by reacting difluorolactones with specific phosphoranes. CONSTITUTION: Difluorolactones of formula I [R<1> to R<4> are each H, a halogen, a (protected)hydroxyl group, a (protected)amino, a (protected)carboxyl, a (substituted)1-20C monovalent hydrocarbon, etc.; (n) is an integer of 0-10] are reacted with phosphoranes of formula II [R<5> is a monovalent organic group; R<6> is a (substituted)1-20C hydrocarbon] to readily afford the objective difluoro- substituted vinyl ethers of formula III useful as a medicine or an agrochemical or its intermediate, especially an important intermediate for difluoroprostaglandins or a raw material, etc., for polymers, etc., in high reactional yield.

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 a difluoro-substituted vinyl ether which is useful as an important intermediate for difluoroprostaglandins, particularly an intermediate for medicines and agricultural chemicals.

[0002]

2. Description of the Related Art Fluorine-containing vinyl ethers are important compounds as raw materials for medical and agricultural chemicals or their intermediates, or polymers. Among them, vinyl ethers containing two fluorine atoms are enzyme inhibitors or their intermediates (P.
Bay et al., “Selective Fluorination” (American Chemical Society), edited by JT Welch, p105), and an intermediate of difluoroprostaglandin I ₂ class (Table 56-501319). The prostaglandins I ₂ are also called prostacyclins and are abbreviated as PGI ₂ .

However, few methods are known for selectively producing vinyl ethers containing two fluorine atoms at desired positions. As a method for producing difluoro-substituted vinyl ethers, the method described in the above-mentioned publication is known, but an electron-withdrawing fluorine atom is added to the α-position of the olefin.
Unlike the case where there is no fluorine atom, the cyclization reaction of alcohols with olefins has extremely low reactivity, and there are problems that the reaction takes a long time and the reaction yield is low. There is a problem that it is a different manufacturing method.

JP Begue is an example of producing vinyl ether by a Wittig type reaction with fluorinated carboxylic acids.
Et al., J. Org. Chem., 57, 3807 (1992), which only describes the reaction of perfluorocarboxylic acid or perfluorochlorocarboxylic acid ester or acid anhydride. Witt for difluorocarboxylics such as carboxylic esters and difluorolactones
No example of producing a difluoroalkyl-substituted vinyl ether by an ig-type reaction has been known.

Up to now, as a practical method for producing difluoroalkyl-substituted vinyl ethers, Japanese Patent Application No. 6-20450 and Japanese Patent Application No. 6-80 developed by the present inventors have been practically used.
No. 641 and the development of a new practical production method for difluoro-substituted vinyl ethers has been strongly desired.

[0006]

The present invention provides a novel method for directly converting difluorolactones to difluoro-substituted vinyl ethers, which solves the above problems.

[0007]

The present inventors have found a practical production method for efficiently producing difluoro-substituted vinyl ethers. The present invention is a pesticide or an intermediate thereof,
In particular, the following invention relates to a method for producing difluoro-substituted vinyl ethers useful as important intermediates for difluoroprostaglandins.

A difluoro-substituted vinyl ether represented by the following formula (3), characterized in that a phosphorane represented by the following formula (2) is allowed to act on a difluorolactone represented by the following formula (1). Production method.

[0009]

[Chemical 6]

[Chemical 7]

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

(B) Any two selected from n R ¹ , n R ² , R ³ and R ⁴ may be bonded to each other and have 10 or less carbon atoms 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,
It represents a protected carboxyl group or a monovalent hydrocarbon group having 20 or less carbon atoms, which may have a substituent.

N represents an integer of 0-10. R ⁵ represents a monovalent organic group. R ⁶ represents a hydrocarbon group having 20 or less carbon atoms which may have a substituent. ]

The difluorolactone represented by the formula (1) is preferably a difluorolactone represented by the following formula (4), and the difluoro-substituted vinyl ether represented by the formula (3) is represented by the following formula (5): The difluoro-substituted vinyl ethers represented by are preferred. The difluoro-substituted vinyl ethers represented by the formula (5) are useful as important intermediates for difluoroprostaglandins, especially difluoroprostacyclins. In some cases, the difluoro-substituted vinyl ethers represented by formula (5) represent difluoroprostacyclines.

[0014]

[Chemical 9]

[Chemical 10]

[Wherein R ⁷ 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 alkynyl group having 14 or less carbon atoms which may be present. R ⁸ represents a hydrogen atom or a protecting group. ]

R ⁷ in the difluorolactones represented by the formula (4) and the difluoro-substituted vinyl ethers represented by the formula (5) is an organic group which can be easily converted into a so-called ω chain or ω chain of prostacyclins. , Or a group in which such an organic group can be easily introduced is preferable. R ⁷ is preferably an organic group represented by —A—CH (OR ¹⁰ ) —R ⁹ which is a preferable ω chain to a protected ω chain.

[0017] [However, in ^{-A-CH (OR 10) -R} 9, A represents a vinylene group, ethynylene group or an ethylene group. R ⁹ has 1 carbon atom which may have a substituent.
0 or less alkyl group, alkenyl group or alkynyl group, optionally substituted 3- to 8-membered ring cycloalkyl group, optionally substituted aryl group, or optionally substituted Represents an optionally substituted aralkyl group.
R ¹⁰ represents a hydrogen atom or a protecting group. ]

Another preferred R ⁷ is a group represented by —CH ₂ OR ¹¹ which facilitates introduction of the above ω chain to a protected ω chain (provided that R ¹¹ represents a hydrogen atom or a protective group). ).

Also, R ⁶ introduced by the method of the present invention
R ⁶ is preferably as follows: ═CH ₂ —R ⁶ having it is a so-called α chain of prostacyclins to a protected α chain. Such R ⁶ is preferably a substituted alkyl group having 3 to 5 carbon atoms and having a carboxyl group or a carboxyl group-related group at the terminal.

The present invention will be described in more detail below. In the following description of the present specification, the organic group is “lower”
Means 1 to 6 carbon atoms. A more preferred lower organic group is an organic group having 1 to 4 carbon atoms. "Alkyl group"
May be linear or branched, and a lower alkyl group is preferred 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 suitable examples thereof are ,
1-propynyl group, 2-propynyl group, 3-butynyl group, 3-pentynyl group, 4-hexynyl group and the like can be mentioned.

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, an ethoxy group, Examples include propoxy group and butoxy group. As the "alkoxyalkyl group", a lower alkyl group whose alkoxy group part is a lower alkoxy group is preferable, and suitable examples thereof include
Methoxyethyl group, 3-methoxypropyl group, 2-ethoxyethyl group and the like can be mentioned.

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 the aryl group as a substituent may be any of those mentioned above, and 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, an amino group and a carboxyl group, and is, for example, a final target substance (eg difluoroprostacyclin). , A step of synthesizing an intermediate in which the functional group is considered to have no possibility of causing an undesirable side reaction in the subsequent reaction, and a step of synthesizing an intermediate in which the functional group is converted in the next reaction, Up to protecting its functional groups. In the production method of the present invention, it is preferable that reactive functional groups such as a hydroxyl group, an amino group and a carboxyl group are protected, unless otherwise specified.

As the hydroxyl-protecting group, a known or well-known protecting group used as a hydroxyl-protecting group can be adopted. Examples of the hydroxyl-protecting group include a triorganosilyl group, an acyl group, a cyclic ether group, and an optionally substituted alkyl group or aralkyl group.
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.

As a specific protective group for hydroxyl group, for example, a triorganosilyl group is preferably t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triethylsilyl group, triphenylsilyl group, triisopropylsilyl group, or the like. . 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 amino-protecting group, known or well-known protecting groups used as amino-protecting groups can be adopted. Examples of the amino group-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 trifluoro group. An acetyl group and the like are preferable. The alkoxycarbonyl group is preferably a t-butoxycarbonyl group, a benzyloxycarbonyl group or the like, and the alkyl group, the alkenyl group or the alkynyl group is a methoxymethyl group, an allyl group, a benzyl group, a trityl group or a nuclear-substituted methoxybenzyl group. Is preferred. 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. 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 carboxyl group-protecting group, a known or well-known protecting group used as a carboxyl group-protecting group can be employed. As the protected carboxyl group, an ester type carboxyl group protected by an alkyl group or the like or a carboxylic acid equivalent such as orthoester or tetrazole can be adopted. As the carboxylic acid residue of the ester type protecting group, an alkyl group, an alkenyl group, an aralkyl group, a triorganosilyl group and the like are preferable. Examples of the alkyl group, alkenyl group and aralkyl group include lower alkyl groups such as methyl group, ethyl group, propyl group, butyl group and t-butyl group, methoxymethyl group, allyl group, benzyl group, trityl group and methoxybenzyl group. Are preferred. 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 difluorolactones in the present invention are
General difluorolactones are widely used. N in Formulas (1) and (3) represents an integer of 0 to 10. That is, the difluorolactone ring forms a 4- to 14-membered ring. Particularly, difluorolactones having a 5- to 8-membered ring [n is 1 to 4] are preferable. This difluorolactone may have other condensed or non-condensed rings (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. An aliphatic ring is particularly preferable as this ring.
The difluorolactone represented by the formula (4) is one of the difluorolactones having one condensed aliphatic ring.

[0030] formula (1), (3), 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. The carbon number of the monovalent hydrocarbon group is the number of carbon atoms not containing a substituent. As shown in the formula, each of R ¹ and R ² exists in n number, and when n is 2 or more, a plurality of R ¹ may be different from each other (the same applies to R ² ).

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
Below, 1-2 are particularly preferable. 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 linear to branched unsaturated hydrocarbon groups such as a 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.

As the cycloalkyl group having 3 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms and a cycloalkyl group substituted with lower alkyl are preferable, and an unsubstituted cyclopentyl group, an unsubstituted cyclohexyl group, and a carbon number of 1 to 1 are particularly preferable. 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 alkoxy 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 Base,
o-methoxyphenyl group, o-ethoxyphenyl group, o
-Nitrophenyl group and the like are preferable.

A protected hydroxyl group, a 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. Above "1 carbon number
The number of carbon atoms in the “divalent hydrocarbon group of 0 or less” refers to the number of carbon atoms constituting the ring.

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. R like this
There may be two or more rings formed by ^{1 to} R ⁴ .

The divalent hydrocarbon group having 10 or less carbon atoms, which is 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 number of carbon atoms forming the ring of the divalent hydrocarbon group is 6 or less, and preferably 2 to 4. The saturated hydrocarbon group is an alkylene group, and the unsaturated hydrocarbon group is an alkenylene group or an alkynylene group.

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 difluorolactone represented by the formula (1) in the present invention, the lactone represented by the formula (4) is most preferable. The difluorolactone represented by the formula (4) has the formula (1) in which n is 1, R ¹ and R ^{4 are}
Are hydrogen atoms, R ² and R ³ are bonded to each other to form a trimethylene group, and R ⁷ and OR ⁸ are bonded to the trimethylene group.
Is a compound having a structure in which the following substituents are bonded and which has the specific configuration shown in formula (4). This formula (4)
The difluorolactones represented by the formula have the same skeleton as the prostacyclins, and are described in, for example, JP-A-56-50131.
It can be produced by the method described in Japanese Patent Application No. 6-20450, Japanese Patent Application No. 6-80641, Japanese Patent Application No. 6-283857 and the like. Particularly, a difluorolactone represented by the formula (4) is produced by fluorinating a lactone having the same structure as that represented by the formula (4) except that two fluorine atoms are hydrogen atoms. It is preferable.

R ⁷ in equations (4) and (5) is
An organic group corresponding to the ω chain of natural prostacyclin, an organic group corresponding to the ω chain of various prostacyclins, 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. The carbon number of this hydrocarbon group means the number not containing a substituent. Specifically, it has an alkyl group having 1 to 14 carbon atoms which may have a substituent, an alkenyl group having 2 to 14 carbon atoms which may have a substituent, or has a substituent. And an alkynyl group having 2 to 14 carbon atoms is also preferable. Particularly preferred is a hydrocarbon group having a protected hydroxyl group. Further, it may have a substituent such as a cycloalkyl group or an aryl group. Most preferred R ⁷ is -A-CH
A group represented by group and -CH ₂ OR ¹¹ represented by (OR ¹⁰⁾ -R ^9.

A in --A--CH (OR ¹⁰ )-R ⁹
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 prostacyclin. R ⁹ is a part of an alkyl group, an alkenyl group, or an alkynyl group having a substituent OR ¹⁰ , or represents a substituent such as a cycloalkyl group or an aryl group.

R ⁹ is preferably an organic group corresponding to the ω chain portion of natural prostacyclin or an organic group corresponding to the ω chain portion of various prostacyclins. 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, a cycloalkyl group having 3 to 8 carbon atoms in a ring, and a phenyl group. There are aryloxy groups with aryl groups, and these groups with 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 ⁹ includes a halogen atom, an oxygen atom-containing substituent, a sulfur atom-containing substituent, a nitrogen atom-containing substituent, and others.

R ⁹ 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 ⁹ 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.

In the case of a substituted or unsubstituted aralkyl group, R ⁹ is 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 ⁹ 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 ⁹ 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 ⁸ , R ¹⁰ and R ¹¹ are each a protecting 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
⁸ and R ¹⁰ are preferably triorganosilyl groups, cyclic ether groups and acyl groups. R ¹¹ is preferably a triorganosilyl group, a cyclic ether group or an acyl group, but is preferably one having a reactivity different from that of other protecting groups (such as R ⁸ which is a protecting group).

The above-mentioned hydroxyl-protecting groups can be converted into hydroxyl groups by a conventional method. For example, “New Experimental Chemistry Course 14 Synthesis and Reactions of Organic Compounds (I), (II),
(V) ”(Maruzen),“ Protective Groups in Organic Synthesis ”(TW Greene, J.Wi.
It can be easily converted into a hydroxyl group by the method described in the textbooks by Lee et al.

The difluoro-substituted vinyl ethers represented by the above formula (3) are obtained by reacting the difluorolactones represented by the formula (1) with phospholanes represented by the formula (2) which is a Wittig type reactant. It can be manufactured by squeezing. Wi
Regarding the ttig type reaction, for example, “New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compound (I)” (Maruzen), “4th
Edition Experimental Chemistry Course 19 Organic Synthesis I, Hydrocarbons / Halogen Compounds "(Maruzen), etc., as well as phospholanes and their manufacturing methods.

In the production method of the present invention, difluoro-substituted vinyl ethers having the Z-type stereochemistry as represented by the above general formula (3) are given priority over isomers having the E-type stereochemistry. Can be selectively manufactured.

In the phosphorane represented by the formula (2), R ⁵ represents a monovalent organic group, and the carbon atom at the terminal of the organic group is bonded to the phosphorus atom. The three R ^{5 s} may be different from each other, but usually they are the same organic group. R
⁵ is preferably an aryl group which may have a substituent, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or a dialkylamino group. Examples of these organic groups include the following organic groups, and among them, a phenyl group and a lower alkyl group are particularly preferable.

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 Group, o-methoxyphenyl group, o-ethoxyphenyl group, o-nitrophenyl group and the like are preferable, and phenyl group and tolyl group are particularly preferable.

The alkyl group which may have a substituent is preferably an alkyl group having 20 or less carbon atoms, such as methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group and n- A linear alkyl group such as a hexyl group, an n-heptyl group and an n-octyl group, a branched alkyl group such as an isopropyl group, an isobutyl group, a t-butyl group and a neopentyl group are preferable.

The substituted or unsubstituted aralkyl group is preferably an aralkyl group containing a halogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a benzene ring substituted with a hydroxyl group, or a naphthalene ring. The alkyl moiety of the aralkyl group (that is, the alkylene group) preferably has 1 to 4 carbon atoms. A particularly preferred aralkyl group is a C1-C2 alkyl group having a phenyl group. As the dialkylamino group, a dialkylamino group having an alkyl group having 1 to 6 carbon atoms is preferable, and a dimethylamino group, a diethylamino group and a dibutylamino group are preferable.

R ⁶ has 2 carbon atoms which may have a substituent.
It represents a monovalent hydrocarbon group having 0 or less, and a wide range of hydrocarbon groups having 20 or less carbon atoms and not particularly limited are used. For example, a monovalent aliphatic hydrocarbon group having 20 or less carbon atoms, which may have a substituent, and 2 carbon atoms, which may have a substituent.
There are 0 or less monovalent aromatic hydrocarbon groups.

When R ⁶ is a monovalent aliphatic hydrocarbon group having 20 or less carbon atoms, it is a linear or branched or cyclic saturated or unsaturated hydrocarbon group, and when it is an unsaturated hydrocarbon group, it is unsaturated. Saturated group (carbon-carbon double bond or triple bond)
Is preferably 4 or less, and particularly preferably 1 or 2. The monovalent aliphatic hydrocarbon group preferably has 10 or less carbon atoms.

Examples of the monovalent aliphatic hydrocarbon group having 20 or less carbon atoms include methyl group, ethyl group, n-propyl group and n-
Butyl group, n-pentyl group, n-hexyl group, n-heptyl group, 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
-Straight chain saturated hydrocarbon group such as eicosyl group, isopropyl group, isobutyl group, t-butyl group, neopentyl group, 1-methylpentyl group, 1,1-dimethylpentyl group, 1-methylhexyl group, 2-methyl Pentyl group, 2
-Branched saturated hydrocarbon group such as 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,
Linear to branched unsaturated hydrocarbon group such as 1,1-dimethyl-3-hexynyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, etc. And saturated or unsaturated cyclic hydrocarbon groups.

R ⁶ has 20 carbon atoms which may have a substituent.
In the case of the following aromatic hydrocarbon groups, phenyl group, naphthyl group and derivatives thereof are preferable.

Examples of the substituent bonded to the above monovalent hydrocarbon group include a cycloalkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aryl group, a halogen atom, a hydroxyl group, a protected hydroxyl group and an amino group. Group, protected amino group, carboxyl group, protected carboxyl group, formyl group, protected formyl group, alkoxy group, alkylthio group, thiocarboxyl group, sulfo group, sulfino group, sulfeno group, carbamoyl group, nitro group , A cyano group, an oxime group, an alkoxyme group, an azide group, a substituent such as a trialkylsilyl group, and a substituent containing a heterocycle such as a furanyl group, a pyridyl group, an imidazoyl group, an indolyl group, and a piperidyl group. However, a plurality of these may be substituted at the same time.

R ⁶ is preferably a linear C 2-7 hydrocarbon group having a carboxyl group, a salt of a carboxyl group or a protected carboxyl group at the terminal, and an ether bond is attached to the carbon chain. Alternatively, it may have a thioether bond. Most preferred are the 3-carboxypropyl group, which is a group corresponding to the α chain portion of natural prostacyclin, and a group in which the carboxyl group is salt or protected.

The phosphorane represented by the formula (2) can be synthesized from the corresponding phosphonium salt by a known method. For example, it can be produced by reacting the following quaternary phosphonium salt (X ⁻ is an anion such as a halogen ion) with a base in an inert solvent. _{^{[R 5 3 -P-CH 2}} -R 6] + X -

Regarding the method for producing phospholanes from phosphonium salts, "New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (I)" (Maruzen), "4th Edition Experimental Chemistry Course 19 Organic Synthesis I, Carbonization" The method described in the document such as "Hydrogen / halogen compound" (Maruzen) can be adopted.

The difluorolactone represented by the formula (1) is reacted with the phospholane represented by the formula (2) which is a Wittig type reaction agent to form the difluoro-substituted vinyl ether represented by the formula (3). As the production method, in the present invention, the phospholane represented by the general formula (2) is produced from the corresponding phosphonium salt in the presence of a base in an inert solvent, and the phospholane is directly isolated without isolation. A method of reacting with a lactone is usually used.

The amount of the phosphorane represented by the general formula (2) to be used is appropriately about 0.1 to 20 equivalents relative to 1 equivalent of the difluorolactone represented by the formula (1).
1 to 10 equivalents are preferred. The amount of the base is usually 0.1 to 20 equivalents per 1 equivalent of the difluorolactone represented by the formula (1), and 1 to 10 is appropriate.
Equivalent weights are preferred. 0.1 for quaternary phosphonium salts
An equivalent amount or more, particularly an equivalent amount or more is preferable.

The above Wittig type reaction is preferably carried out under basic conditions and further carried out in an inert solvent. The reaction temperature is usually about -150 to + 200 ° C, and preferably -80 to + 100 ° C.

The types of preferred bases vary depending on the acidity of α-hydrogen of the phosphonium salt as a raw material for the phosphorane, the stability of the phosphorane formed, and the like, but the following bases are listed. Two or more kinds of these bases can be used.

Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, diazabicyclononene, diazabicycloundecene, potassium t - butoxide (t-BuOK), lithium amide, sodium amide (NaNH _2), potassium amide, lithium diisopropylamide, lithium diethylamide, lithium dicyclohexyl amide, lithium isopropyl cyclohexyl amide, lithium 2,2,
6,6-tetramethylpiperidine, lithium hexamethyldisilazide, sodium diethylamide, sodium hexamethyldisilazide _{(NaN (SiMe 3) 2)} ,
Potassium-3-aminopropylamide, potassium hexamethyldisilazide (KN (SiMe ₃ ) ₂ ), lithium hydride, sodium hydride, potassium hydride, sodium dimcyl, n-butyllithium (n-BuLi), s
-Butyllithium, t-butyllithium, methyllithium, phenyllithium, lithium naphthalenide, lithium biphenylide, trityl sodium.

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 is usually about 5 to 1000 parts by weight, preferably 10 to 100 parts by weight, based on 1 part by weight of the difluorolactone represented by the formula (1).

Examples of ether solvents include diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2.
-Dimethoxyethane, diglyme, t-butyl methyl ether and the like, hydrocarbon solvents include hexane, toluene, benzene, pentane, xylene, petroleum ether,
Pentane or the like is used as a polar solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, 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), nitromethane, etc., and water, alcoholic solvents such as methanol, ethanol, Preferred are t-butanol, t-amyl alcohol and the like.

The compound represented by the formula (5) in the present invention is an important intermediate which can induce various difluoroprostacyclins. For example, R ⁷ is —CH ₂ O
This —CH ₂ OR ¹¹ of the difluoro-substituted vinyl ether represented by the formula (5), which is the group represented by R ¹¹ , is converted into various ω
Can be converted into a chain. A group represented by ^{-A-CH (OR 10) -R} 9 is a preferred example of ω-chain. The method for introducing the ω chain into so-called corey lactones is basically known, and the corresponding formula (5) can be obtained using this basically known method.
The ω chain can be introduced into the difluoro-substituted vinyl ether represented by Further, for example, Japanese Patent Application No. 6-8 of the present inventors
The ω chain can also be introduced by the method described in, for example, 0641, 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.

Further, the compound represented by the formula (5) in the present invention represents difluoroprostacyclin and difluoroprostacyclin having a protected functional group. For example, a compound in which R ⁷ is a group represented by —A—CH (OH) —R ⁹ and R ⁶ is an alkyl group having a carboxy group at the terminal (particularly 3-carboxypropyl group) is a typical difluoro group. Prostacyclins. Difluoroprostacyclins with protected functional groups,
The protecting group can be easily deprotected and converted into the final target product.

The compound represented by the formula (3) and the formula (5)
Specific examples of the compound represented by the following include the following compounds, but the target compound of the present invention is not limited thereto. The following compounds include various stereoisomers, optical isomers, and mixtures thereof.

5-[(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-
Ylidene] methyl pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4,4-dimethyl-E-1-octenyl} bicyclo [3.3.0] octane-3-ylidene]
Methyl pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-E-1-octenyl} bicyclo [3.
3.0] Octane-3-ylidene] methyl pentanoate.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S) -3-Cyclopentyl-3-hydroxy-E
-1-propenyl} bicyclo [3.3.0] octane-
3-Ylidene] methyl pentanoate. 5-[(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-ylidene]
Methyl pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-(2-Phenylethyl) -3-hydroxy-E-1-
Methyl propenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S) -3-Hydroxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-
3-Ylidene] methyl pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
Methyl 4-difluoro-7-hydroxy-6- (3-hydroxy-4-methyl-E-1-octen-6-ynyl) bicyclo [3.3.0] octane-3-ylidene] pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 5
S) -3-Hydroxy-5-methyl-1-nonynyl} bicyclo [3.3.0] octane-3-ylidene] methyl pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
Methyl -hydroxy-4,4-dimethyl-1-octynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S) -3-Cyclopentyl-3-hydroxy-1
-Propinyl} bicyclo [3.3.0] octane-3-
Ylidene] methyl pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Cyclohexyl-3-hydroxy-1-propynyl}
Methyl bicyclo [3.3.0] octane-3-ylidene] pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
Methyl-(2-phenylethyl) -3-hydroxy-1-propynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S) -3-Hydroxy-4-methyl-1,6-nonanediynyl} bicyclo [3.3.0] octane-3-
Ylidene] methyl pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
Methyl 4-difluoro-7-hydroxy-6- (3-hydroxy-4-methyl-1,6-octanediynyl) bicyclo [3.3.0] octane-3-ylidene] pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
Methyl 4-difluoro-7-hydroxy-6- (3-hydroxy-4,4-dimethyl-1,6-octanediynyl) bicyclo [3.3.0] octane-3-ylidene] pentanoate. 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]
Pentanoic acid.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S) -3-Hydroxy-4,4-dimethyl-E-
1-octenyl} bicyclo [3.3.0] octane-3
-Ylidene] pentanoic acid. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-E-1-octenyl} bicyclo [3.
3.0] Octane-3-ylidene] pentanoic acid. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Cyclopentyl-3-hydroxy-E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene]
Pentanoic acid. 5-[(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-ylidene]
Pentanoic acid.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S) -3- (2-phenylethyl) -3-hydroxy-E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoic acid. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene]
Pentanoic acid. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6- (3-hydroxy-4-methyl-E-1-octen-6-ynyl) bicyclo [3.3.0] octane-3-ylidene] pentanoic acid. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-Difluoro-7-hydroxy-6- (3-hydroxy-4,4-dimethyl-E-1-octene-6-ynyl) bicyclo [3.3.0] octane-3-ylidene]
Pentanoic acid.

5-[(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-ylidene] pentanoic acid. 5-[(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-ylidene] pentanoic acid. 5-[(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-ylidene] pentanoic acid. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Cyclohexyl-3-hydroxy-1-propynyl}
Bicyclo [3.3.0] octane-3-ylidene] pentanoic acid.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S) -3- (2-Phenylethyl) -3-hydroxy-1-propynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoic acid. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4-methyl-1,6-nonanediynyl}
Bicyclo [3.3.0] octane-3-ylidene] pentanoic acid. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6- (3-hydroxy-4-methyl-1,6-octanediynyl) bicyclo [3.3.0] octane-3-ylidene] pentanoic acid. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6- (3-hydroxy-4,4-dimethyl-1,6-octanediynyl) bicyclo [3.3.0] octane-3-ylidene] pentanoic acid.

5-[(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-
Ylidene] sodium pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4,4-dimethyl-E-1-octenyl} bicyclo [3.3.0] octane-3-ylidene]
Sodium pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-E-1-octenyl} bicyclo [3.
3.0] Octane-3-ylidene] sodium pentanoate.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S) -3-Cyclopentyl-3-hydroxy-E
-1-propenyl} bicyclo [3.3.0] octane-
3-ylidene] sodium pentanoate. 5-[(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-ylidene]
Sodium pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-(2-Phenylethyl) -3-hydroxy-E-1-
Sodium propenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S) -3-Hydroxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-
3-ylidene] sodium pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
Sodium 4-difluoro-7-hydroxy-6- (3-hydroxy-4-methyl-E-1-octen-6-ynyl) bicyclo [3.3.0] octane-3-ylidene] pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-Difluoro-7-hydroxy-6- (3-hydroxy-4,4-dimethyl-E-1-octene-6-ynyl) bicyclo [3.3.0] octane-3-ylidene]
Sodium pentanoate.

5-[(1S, 5R, 6R, 7R) -2-
Methyl oxa-4,4-difluoro-6- (t-butyldimethylsiloxymethyl) -7- (2-tetrahydropyranyloxy) bicyclo [3.3.0] octane-3-ylidene] pentanoate. 7-[(1S, 5R, 6R, 7R) -2-oxa-4,
Methyl 4-difluoro-6- (t-butyldimethylsiloxymethyl) -7- (2-tetrahydropyranyloxy) bicyclo [3.3.0] octane-3-ylidene] heptanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-6- (t-butyldimethylsiloxymethyl) -7- (2-tetrahydropyranyloxy) bicyclo [3.3.0] octane-3-ylidene] pentanoic acid. 7-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-6- (t-butyldimethylsiloxymethyl) -7- (2-tetrahydropyranyloxy) bicyclo [3.3.0] octane-3-ylidene] heptanoic acid.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S, 5S) -3- (2-tetrahydropyranyloxy) -5-methyl-E-1-
Methyl nonenyl} -bicyclo [3.3.0] octane-3-ylidene] pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (t-butyldimethylsiloxymethyl) -6-{(3S, 5S) -3- (t-butyldimethylsiloxymethyl) -5-methyl-E-1-nonenyl} bicyclo [3.3 .0] Octane-3-ylidene]
Methyl pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3- (2-tetrahydropyranyloxy) -4,4-dimethyl-E-1-octenyl}
Methyl bicyclo [3.3.0] octane-3-ylidene] pentanoate.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3- (2-tetrahydropyranyloxy) -E-1-octenyl} bicyclo [3.3.0] ] Octane-3-ylidene] methyl pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3-cyclopentyl-3- (2
-Tetrahydropyranyloxy) -E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene]
Methyl pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3-cyclohexyl-3- (2
-Tetrahydropyranyloxy) -E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene]
Methyl pentanoate.

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3- (2-phenylethyl) -3- (2-tetrahydropyranyloxy)
Methyl -E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate. 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3- (2-tetrahydropyranyloxy) -4-methyl-E-1-nonene-6-ynyl} bicyclo [3 .3.0] Octane-3-ylidene]
Methyl pentanoate.

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 3 show examples of synthesizing raw material difluorolactones, and Reference Examples 4 to 5 show examples of synthesizing unprotected difluoroprostacyclines by deprotecting the compounds synthesized in Examples.

[0095]

【Example】

[Reference Example 1] (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3 .3.0] Octane-3-one synthesis.

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 ⁺ ).

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

(1S, 5R, 6R, 7R) -2-Oxa-7- (2-tetrahydropyranyloxy) -6-
Using (g) {(3S, 5S) -3- (2-tetrahydropyranyloxy) -5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one 1.7 g, reference example In the same manner as in 1, 0.93 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.89 (m, 6H), 1.1-2.3 (m, 25H), 3.
0-3.2 (m, 1H), 3.5 (m, 2H), 3.7-3.9 (m, 2H), 4.1-4.2 (m, 2H),
4.6-4.7 (m, 2H), 5.2-5.6 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , ppm): -93 (m), -115 (m).

[Reference Example 3] Synthesis of (1S, 5R) -2-oxa-4,4-difluoro-bicyclo [3.3.0] oct-6-en-3-one.

55 mg of the title compound was obtained in the same manner as in Reference Example 1 using 62 mg of (1S, 5R) -2-oxa-bicyclo [3.3.0] oct-6-en-3-one. 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).

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

180 mg of (4-carboxybutyl) triphenylphosphonium bromide in anhydrous THF (2 ml)
1.0M sodium hexamethyldisilazide T in solution
0.81 ml of HF solution was added and the mixture was heated under reflux for 1 hour and synthesized in Reference Example 2 (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy). -6-{(3S, 5S) -3- (2-Tetrahydropyranyloxy) -5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one 1
31 mg of anhydrous THF solution was added at room temperature and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate was added, the mixture was extracted with ethyl acetate-hexane (1: 1), the extract was concentrated under reduced pressure, and the obtained residue was benzene-methanol (4: 1) (2.5: 1).
ml), 1.3 ml of 10% trimethylsilyldiazomethane (hexane solution) was added, and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added until nitrogen disappeared, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate-hexane, 1: 7) to obtain 87 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-2.8 (m, 37H),
3.4-3.5 (m, 2H), 3.67 (s, 3H), 3.8-4.3 (m, 4H), 4.6-4.9 (m, 4
H), 5.3-5.7 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , ppm): -83 to -84 (m), -115 to -117 (m).

Using the same starting materials as above, the base was changed to synthesize the title compound. The type of base used and the yield of the title compound are shown in Table 1. In Table 1, “NaNH ₂ + (Me
₃ Si) ₂ NH ”means NaNH ₂ and (Me ₃ Si) ₂ NH
Is a reaction mixture in which NaN (SiMe ₃ ) ₂ is considered to be produced.

[0106]

[Table 1]

[Embodiment 2] 5-[(1S, 5R, 6R,
7R) -2-oxa-4,4-difluoro-7- (2-
Tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) -bicyclo [3.3.0] octane-3
-Ilidene] Synthesis of methyl pentanoate.

Synthesized in Reference Example 1 (1S, 5R, 6R,
7R) -2-oxa-4,4-difluoro-7- (2-
The title compound was synthesized in the same manner as in Example 1 using tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-one. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.06 (m, 6H), 0.89 (m, 9H), 1.2-2.
7 (m, 15H), 3.09 (m, 1H), 3.4-3.9 (m, 4H), 3.69 (s, 3H), 4.1
(m, 1H), 4.64 (m, 1H), 4.7-4.8 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , ppm): -84 (m), -117 (m).

[Embodiment 3] 5-[(1S, 5R) -2-
Oxa-4,4-difluoro-bicyclo [3.3.0]
Synthesis of Methyl Oct-6-ene-3-ylidene] pentanoate.

(1S, 5R) -2-synthesized in Reference Example 3
Oxa-4,4-difluoro-bicyclo [3.3.0]
The title compound was synthesized in the same manner as in Example 1 using oct-6-en-3-one. ¹ H-NMR (CDCl ₃ ) δ (ppm): 1.2-2.3 (m, 6H), 2.6-3.0 (m, 2H),
4.5-6.0 (m, 5H). ¹⁹ F-NMR (CDCl ₃ , ppm): -86 (m), -117 (m).

[Reference Example 4] 5-[(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 Synthesis of methyl-3-ylidene] pentanoate.

5-[(1S, 5R,
6R, 7R) -2-Oxa-4,4-difluoro-7-
(2-Tetrahydropyranyloxy) -6-{(3S,
5S) -3- (2-Tetrahydropyranyloxy) -5
-Methyl-E-1-nonenyl} -bicyclo [3.3.
0] Octane-3-ylidene] methyl pentanoate 350
To a solution of 10 mg of methanol in 10 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 3 hours. It was poured into aqueous sodium hydrogen carbonate, extracted with ethyl acetate, concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate-hexane, 1: 1) to obtain 223 mg of the title compound.

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 5] 5-[(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 Synthesis of sodium 3-ylidene] pentanoate.

5-[(1S, 5R, synthesized in Reference Example 4
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).

[0116]

INDUSTRIAL APPLICABILITY According to the method for producing difluoro-substituted vinyl ethers of the present invention, the reaction is easy and the reaction yield is high. This method is particularly suitable for producing difluoroprostacyclins and synthetic intermediates thereof.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 309/30 C07D 313/00 313/00 313/04 313/04 313/18 313/18 407 / 12 307 407/12 307 307/32 Z

Claims (5)

[Claims] 1. A difluoro-substituted vinyl ether represented by the following formula (3), characterized in that a phosphorane represented by the following formula (2) is allowed to act on a difluorolactone represented by the following formula (1). Manufacturing method. Embedded image Embedded image Embedded image [However, R ¹ , R ² , R ³ , and R ⁴ are the same or different and represent the following (a) or (b). (A) Individually a hydrogen atom, a halogen atom, a protected hydroxyl group, a protected amino group, a protected carboxyl group, or a monovalent hydrocarbon having 20 or less carbon atoms which may have a substituent. Represents a group. (B) a divalent divalent group having 10 or less carbon atoms which may be bonded to each other by any two selected from n R ¹ , n R ² , R ³ and R ⁴ ; Represents a hydrocarbon group, and each of the other R ^{1 to} R ⁴ individually has a hydrogen atom, a halogen atom, a protected hydroxyl group, a protected amino group, a protected carboxyl group, or a substituent. Optionally represents a monovalent hydrocarbon group having 20 or less carbon atoms. n is 0 to 1
Represents an integer of 0. R ⁵ represents a monovalent organic group. R ⁶ represents a hydrocarbon group having 20 or less carbon atoms which may have a substituent. ] 2. A difluorolactone represented by the formula (1) is a difluorolactone represented by the following formula (4), and a difluoro-substituted vinyl ether represented by the formula (3) is represented by the following formula (5). The method according to claim 1, which is a difluoro-substituted vinyl ether represented by: [Chemical 4] Embedded image [Wherein R ⁷ 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 alkynyl group having 14 or less carbon atoms. R ⁸ represents a hydrogen atom or a protecting group. ] 3. The method according to claim 2, wherein R ⁷ is a group represented by —A—CH (OR ¹⁰ ) —R ⁹ . [However, A represents a vinylene group, an ethynylene group, or an ethylene group. R ⁹ is 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,
It represents an aryl group which may have a substituent or an aralkyl group which may have a substituent. R ¹⁰ represents a hydrogen atom or a protecting group. ] 4. The method according to claim _{2, wherein} R ⁷ is a group represented by —CH ₂ OR ¹¹ (wherein R ¹¹ represents a hydrogen atom or a protecting group). 5. The process according to claim 1, 2, 3 or 4, wherein R ⁶ is a C 3-5 alkyl group substituted with a carboxyl group or a carboxyl group-related group.