JP2004256547A - Method for producing dihalogenated prostacyclins - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing dihalogenated prostacyclins having two halogens at the 7-position, to provide a compound useful as an intermediate for synthesizing the same, and to provide a method for producing the compound. <P>SOLUTION: The method for producing the dihalogenated prostacyclins comprises subjecting dihalogenated lactones expressed by general formula (1b) (A is vinylene or the like; R<SP>1</SP>is an organic group, such as an alkyl, which corresponds to the ω chain part of the prostacyclins; X<SP>1</SP>and X<SP>2</SP>are each a halogen, such as fluorine; and R<SP>12</SP>and R<SP>14</SP>are each a protecting group for hydroxy) to addition reaction with an organometallic compound having an organic group corresponding to the α chain of the prostacyclins, and then dehydrating the addition reaction product, so that the organic group corresponding to the α chain is introduced. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

The present invention also relates to a novel dihalogenated prostacyclins.

Natural prostacyclin (PGI ₂ ) is a local hormone having a strong physiological activity in vivo, for example, platelet aggregation inhibitory activity, vasodilator activity, cytoprotective action, etc., and regulates various cell functions in vivo. It is an important factor.

However, since natural PGI ₂ has a vinyl ether bond that is very easily decomposed in the molecule, it has a property of being easily deactivated under neutral or acidic conditions. For example, the half-life in an aqueous solution at pH 7.48 is only 10.5 minutes. For this reason, when a prostacyclin compound is to be used as a pharmaceutical product, there is a problem that the application range is limited because the compound is chemically unstable. Therefore, development of a prostacyclin derivative having the same physiological activity as that of the natural type and chemically stable has been studied.

To date, attempts have been made to introduce halogen atoms into the structure of prostacyclin in order to synthesize chemically stable prostacyclin derivatives. As such a prostacyclin derivative, a halogen atom is placed at the 7th position of the prostacyclin skeleton (position corresponding to the 7th position of the natural PGI ₂ ; hereinafter, the position number of the carbon atom refers to the corresponding position of the natural PGI ₂ ). A method for producing prostacyclins has been reported (Japanese Patent Publication No. 56-501319, Japanese Patent Publication No. 57-165382, Japanese Patent Publication No. 57-171988, Japanese Patent Publication No. 61-91136, Japanese Patent Publication No. 61-91136). JP-A-62-482, JP-A-5-9184, JP-B-3-14030, JP-B-3-47272, JP-B-1-24147). However, these production methods all have harsh reaction conditions, so that it is difficult to control the reaction and there is a disadvantage that the method is not general. Therefore, development of a practical method for producing a prostacyclin derivative having a halogen atom at the 7-position of the prostacyclin skeleton has been strongly desired.

In addition, USP 4,317,906 and JP-A-56-501319 disclose difluoroprostacyclins having two fluorine atoms at the 7th and 10th positions of the prostacyclin skeleton, and methods for producing the same. Has been described. In any of these production methods, the corresponding difluoroprostaglandin F ₂ is used as a raw material, and difluoroprostacyclin is produced by a cyclization reaction.

However, the synthesis of the raw material difluoroprostaglandin F ₂ requires a number of steps, and is very difficult and complicated.
In addition, the cyclization reaction of prostaglandin F ₂ having two electron-withdrawing fluorine atoms at the 7-position of the prostacyclin skeleton is significantly different from the cyclization reaction of natural prostaglandin F _2. There are problems such as low reactivity, long reaction time, low reaction yield, and the like, which is a practically difficult production method. That is, the cyclization reaction between the 6-position and 9-position of prostaglandin F ₂ having two fluorine atoms at the 7-position is performed by adding two fluorine atoms at the natural prostaglandin F ₂ or 10-position. Compared with the cyclization reaction between the 6th and 9th positions of the prostaglandin F ₂ possessed, the electron withdrawing property of the fluorine atom is remarkably low, and therefore the corresponding difluoroprostacyclin is not substantially obtained. .

The present invention has been made to solve the above drawbacks and problems. The present inventors have found a method for producing dihalogenated prostacyclins having two halogen atoms at the 7-position without undergoing a cyclization reaction of prostaglandins F ₂ . In addition, the inventors have found intermediates useful for the production and production methods thereof. The present invention is the following invention relates to 7,7-dihalogenated prostacyclins having two halogen atoms at the 7-position of prostacyclin skeleton.

The present invention relates to dihalogenated prostacyclins represented by the general formula (3). The dihalogenated prostacyclin represented by the general formula (3) of the present invention is obtained by adding an organometallic compound represented by the general formula (2) to the dihalogenated lactone represented by the general formula (1b). dehydrating Te, and can then optionally produced Ri by the deprotection.

The dihalogenated lactones represented by the general formula (1b) are compounds in which R ² and R ^{4 in} the general formula (1a) are both protective groups. The compound represented by the general formula (1a) is obtained by converting the compound represented by the general formula (4) into the compound represented by the general formula (5) and reacting with the compound represented by the general formula (6). after, it can be produced Ri due to be reduced. Or the general formula monohalogenated lactones represented by (7) dihalide lactones represented by O Ri formula in reacting halogenated (1a) can be produced. Monohalogenated lactones represented by the general formula (7) are represented by the general formula (6) by converting the compound represented by the general formula (8) into a compound represented by the general formula (9). after reacted with compounds, it can be prepared Ri by the reducing.

(However, in the general formulas (1a) to (9),
A: ethylene group, vinylene group, or ethynylene group,
Q: substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, substituted or unsubstituted carbon A cycloalkyl group having a number of 3 to 8, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group,
R ¹ : substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, substituted or unsubstituted A cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxy group,
R ² , R ⁴ , R ⁵ : each independently a hydrogen atom or a protecting group,
R ⁶ : lower alkyl group,
R ¹² and R ¹⁴ are each independently a protecting group,
X ¹ and X ² are each independently a halogen atom,
Y: a halogen atom which is X ¹ or X ² ,
M: metal atom,
L: a ligand,
m: an integer from 1 to 8,
n: an integer from 0 to 10,
Represents. ).

  In the following description of the present specification, the “lower” organic group means 1 to 6 carbon atoms. A more preferable 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 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like. The “alkenyl group” is preferably a lower alkenyl group unless otherwise specified, and more preferably a linear or branched alkenyl group having 2 to 6 carbon atoms and one unsaturated group. Examples thereof include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 3-butenyl group, a 3-pentenyl group, and a 4-hexenyl group. The “alkynyl group” is preferably a lower alkynyl group unless otherwise specified, and more preferably a linear or branched alkynyl group having 2 to 6 carbon atoms and one unsaturated group. 1-propynyl group, 2-propynyl group, isopropynyl group, 3-butynyl group, 3-pentynyl group, 4-hexynyl group and the like.

  The “alkoxyl group” is preferably a lower alkoxyl group, more preferably a linear or branched alkoxyl group having 1 to 4 carbon atoms, and suitable examples thereof include a methoxy group, an ethoxy group, a propoxy group, Examples include butoxy group. As the “alkoxyalkyl group”, a lower alkyl group in which the alkoxyl group portion is a lower alkoxyl group is preferable, and suitable examples thereof include 2-methoxyethyl group, 3-methoxypropyl group, 2-ethoxyethyl group and the like. Can be mentioned.

  Furthermore, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. “Aryl group” means a monovalent aromatic hydrocarbon group which may have a substituent (for example, a lower alkyl group, a halogen atom, a lower alkoxyl group, a lower alkylamino group, etc.), preferably phenyl. Groups and derivatives thereof, for example, phenyl group, tolyl group, p-halophenyl group (for example, p-chlorophenyl group, p-bromophenyl group), alkoxyphenyl group (for example, methoxyphenyl group, ethoxyphenyl group, etc.), etc. Is mentioned. The “aralkyl group” refers to an aryl group-substituted alkyl group. Examples of the aryl group as a substituent include those described above, and the alkyl group preferably has 1 to 4 carbon atoms. Suitable examples 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, a carboxyl group, or a formyl group, and is represented by the general formulas (1b), (2), (4), (5 In the intermediate for producing the final product such as), it is often necessary that the functional group is protected except for the functional group to be reacted next. For example, examples of the hydroxyl protecting group include a triorganosilyl group, an acyl group, an alkyl group, an alkoxyalkyl group, and an aralkyl group.

A in the present invention is an ethylene group, vinylene group, or ethynylene group, preferably a vinylene group or ethynylene group, and most preferably a vinylene group similar to that corresponding to A of natural PGI ₂ .

Q in the present invention is preferably an organic group corresponding to the α chain of natural PGI ₂ or an organic group corresponding to the α chain of various PGI ₂ species. 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 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. Moreover, the organic group which substituted the carbon atom of the chain organic group by the oxygen atom or the sulfur atom, or the organic group which has rings, such as a cycloalkylene group and an arylene group, between the chain organic groups may be sufficient.

  In addition to the above-described substituents, the substituent in Q includes a halogen atom, an oxygen atom-containing substituent, a sulfur atom-containing substituent, a nitrogen atom-containing substituent, and others. Preferred Q is an organic group which can be converted into a carboxyl group or other polar substituent or polar substituent at the terminal. The polar substituent is preferably an oxygen atom-containing polar substituent (preferably a carboxyl group, a formyl group, and a hydroxyl group), and a group that can be converted into those groups, and particularly preferably a group that can be converted into a carboxyl group and a carboxyl group. . Particularly preferable Q is an organic group having Z which is a polar substituent represented by -BZ described later or a group that can be converted into a polar substituent.

  Q represents a compound represented by the general formula (3) except when the compound represented by the general formula (3) is the final target compound (that is, a dihalogenated prostacyclin having physiological activity). Q is preferably Q having a group that can be converted into a carboxyl group at the terminal so that it is inactive in the reaction. That is, Q in the organometallic compound represented by the general formula (2) is preferably Q having a group that can be converted into a carboxyl group at the terminal. After synthesizing the compound represented by the general formula (3), this Q is converted to Q having a terminal carboxyl group. As described later, when Q is a group represented by -B-Z, Z in the organometallic compound represented by the general formula (2) may be a group that can be similarly converted to a polar substituent. Preferably, after reaching the compound represented by the general formula (3), this Z is converted into a polar substituent, particularly a carboxyl group.

In the present invention, R ¹ 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 species. 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, 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. Moreover, the organic group which substituted the carbon atom of the chain organic group by the oxygen atom or the sulfur atom, or the organic group which has rings, such as a cycloalkylene group and an arylene group, between the chain organic groups may be sufficient. As the substituent for R ^1, in addition to the above-mentioned substituents, there are a halogen atom, an oxygen atom-containing substituent, a sulfur atom-containing substituent, a nitrogen atom-containing substituent, and others.

The chain R ¹ is an alkyl group having 3 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, or an alkynyl group having 3 to 8 carbon atoms, and particularly these linear groups having 5 to 6 carbon atoms and The monomethyl or dimethyl substitution product. Specific examples of these groups include n-propyl group, 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-hexini Group, and the like. Among these, n-pentyl group, 2-methylhexyl group, 1-methyl-3-pentynyl group, 1-methyl-3-hexynyl group, and 1,1-dimethyl-3-hexynyl group are preferable.

R ¹ which is a substituted or unsubstituted cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms and a lower cycloalkyl-substituted cycloalkyl group, particularly an unsubstituted cyclopentyl group, an unsubstituted cyclohexyl group, or a carbon number of 1 A cyclopentyl group substituted with a ˜4 alkyl group and a cyclohexyl group substituted with a C 1-4 alkyl group are preferred.

As R ¹ which is a substituted or unsubstituted aralkyl group, an aralkyl group containing a benzene ring, a furan ring, a thiophene ring, a naphthalene ring or the like substituted with a halogen atom, a halogenated alkyl group, an alkoxy group, a hydroxyl group, or the like preferable. As for carbon number of the alkyl part (namely, alkylene group) of an aralkyl group, 1-4 are preferable. A particularly preferred aralkyl group is a C 1-2 alkyl group having a phenyl group.

As R ¹ which is a substituted or unsubstituted aryloxy group, an aryloxy group containing a benzene ring, a furan ring, a thiophene ring, a naphthalene ring or the like substituted with a halogen atom, a halogenated alkyl group, an alkoxy group, a hydroxyl group, or the like preferable. A particularly preferred aryloxy group is a phenoxy group.

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

R ² , R ⁴ and R ⁵ are each independently a hydrogen atom or a protecting group, and the compound represented by the general formula (3) is the final target compound (ie, dihalogenated prostacyclins having physiological activity). It is preferable that all are protective groups except the case where it is. Even in the compound represented by the general formula (3), R ² and R ⁴ are usually protecting groups at the beginning of the synthesis, and then are deprotected to obtain the final target compound. Further, in a certain synthesis method, a compound represented by the general formula (1a) or (7) in which R ² is a hydrogen atom is obtained (see the synthesis method described later).

In the present invention, the compound represented by the general formula (1b) refers to a compound represented by the general formula (1a) in which R ² and R ⁴ are both protecting groups. The protecting groups R ² and R ⁴ are represented by R ¹² and R ¹⁴ , respectively. Thus, for example the general formula general Oite R ² and R ⁴ to the preparation of the compounds represented by (1a) is either a protecting group formula (1a) compound represented by (i.e., formula (1b) Can be used as it is as a starting material for the production of the compound represented by the general formula (3). In some cases, the protective group may be converted and then used as a starting material for the production of the compound represented by formula (3). Of course, when a compound represented by the general formula (1a) in which at least one of R ² and R ⁴ is a hydrogen atom is obtained, the hydroxyl group is protected to form a compound represented by the general formula (1b). It is converted and used as a starting material for producing the compound represented by the general formula (3).

The protecting group when R ² , R ⁴ and R ⁵ are each a protecting group (a protecting group for a hydroxyl group) and the protecting group represented by R ¹² and R ¹⁴ are not particularly limited, Any known or well-known protecting group used can be employed. These protecting groups may be the same or different. Examples of the protecting group include a triorganosilyl group, an acyl group, an alkyl group, an aralkyl group, and a cyclic ether group. These protecting groups are employed depending on the purpose. 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 reactivity. Specifically, for example, R ² and R ⁵ are preferably a triorganosilyl group or an acyl group, and R ⁴ is a cyclic ether group or a triorganosilyl group (if the other protecting group is a triorganosilyl group, a different reaction from that) Are preferred).

  The triorganosilyl group is a group in which three organic groups such as an alkyl group, an aryl group, an aralkyl group, and an alkoxyl group are bonded to a silicon atom, and particularly includes at least one group selected from a lower alkyl group and an aryl group. Three triorganosilyl groups are preferred. 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 or a benzoyl group, and the cyclic ether group is preferably a tetrahydropyranyl group or a tetrahydrofuranyl group. Examples of the alkyl group or aralkyl group which may have a substituent include alkoxyalkyl groups such as methoxymethyl group, 1-ethoxyethyl group, 2-methoxyethoxymethyl group, benzyl group, methoxybenzyl group, and trityl group. There are groups.

  The hydroxyl-protecting group as described above can be converted to a hydroxyl group by a conventional method. For example, “New Experimental Chemistry Lecture 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 to a hydroxyl group by the method described in the book such as

R ⁶ is a lower alkyl group, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group or a t-butyl group, and a methyl group or an ethyl group is particularly preferable.

In the present invention, X ¹ and X ² are each independently a halogen atom, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom. Similarly, Y is preferably a fluorine atom or a chlorine atom, and particularly preferably a fluorine atom.

  In the organometallic compound represented by the general formula (2), M represents a metal atom, and L represents a ligand to the metal. m and n are integers determined by the type of metal atom or the type of ligand, m is an integer of 1 to 8, and n is an integer of 0 to 10. m is preferably from 1 to 4, particularly preferably from 1 to 2, n is preferably from 0 to 4, particularly preferably from 0 to 2, and m + n is preferably from 1 to 3. Q is the above-described Q, and is particularly preferably -BZ described later.

  Metal atoms M include lithium, sodium, potassium, magnesium, calcium, boron, aluminum, silicon and other metals, and transitions such as zinc, copper, iron, titanium, zirconium, manganese, tin, cobalt, nickel, cerium, samarium, etc. A metal is mentioned. Of these, lithium, sodium, magnesium, boron, aluminum, zinc, and copper are preferable. Particularly preferred M is lithium, magnesium, aluminum, and zinc.

  The ligand L to the metal is not particularly limited, and various ligands can be used. A ligand containing a halogen atom such as chlorine, bromine, iodine or fluorine, or a hetero element such as sulfur or phosphorus, an alkyl An organic ligand such as a group, an aryl group, an alkenyl group, or an alkynyl group is preferred. Particularly preferred L is chlorine, bromine, a lower alkyl group (particularly an alkyl group having 1 to 4 carbon atoms), and a phenyl group.

In the production of the dihalogenated prostacyclin represented by the general formula (3) of the present invention, the organometallic compound represented by the general formula (2) is added to the dihalogenated lactone represented by the general formula (1b). This is done by reacting and dehydrating. This is a so-called α chain partial introduction reaction. The introduction of the α chain portion by this reaction is a method that does not involve the synthesis of prostaglandin F ₂ having a fluorine atom or the cyclization reaction between the 6-position and 9-position as in the conventional example. The reaction is easy even if two fluorine atoms are present.

  In order to perform this reaction, the hydroxyl groups at the 11th and 15th positions of the dihalogenated lactones represented by the general formula (1a) usually need to be protected with a protecting group. When a free hydroxyl group is present at these positions, a by-product is generated or the reaction is difficult to proceed. Therefore, for example, when the dihalogenated lactone obtained by the method for producing a dihalogenated lactone represented by the general formula (1) described later has a free hydroxyl group, it is necessary to protect the free hydroxyl group prior to this reaction. There is. That is, as described above, in this production method, a dihalogenated lactone represented by the general formula (1b) is used as a starting material. The dihalogenated lactone represented by the general formula (1b) is a novel compound.

  In the addition reaction between the dihalogenated lactone represented by the general formula (1b) and the organometallic compound represented by the general formula (2), the amount of the organometallic compound represented by the general formula (2) is as follows. The dihalogenated lactone of the general formula (1b) is usually 0.1 to 10 equivalents, preferably 0.5 to 3 equivalents. The reaction temperature is preferably about −150 to + 100 ° C., particularly preferably −100 to + 40 ° C.

  The above addition reaction can be usually carried out in the presence of a solvent. As the reaction solvent, an ether solvent, a hydrocarbon solvent, a polar solvent, or a mixed solvent thereof is preferable. Examples of ether solvents include diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diglyme, t-butyl methyl ether, and hydrocarbon solvents include hexane, toluene, benzene, pentane, xylene, petroleum ether, and the like. Examples of polar solvents include dimethyl sulfoxide, hexamethylphosphoramide (HMPA), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (DMPU), 1,3-dimethyl-2- Examples include imidazolidinone (DMI), N, N, N ′, N′-tetramethylethylenediamine (TMEDA), and the like.

Furthermore, the addition of the organometallic compound of the general formula (2) to the dihalogenated lactones of the general formula (1b), followed by dehydration, whereby the compounds represented by the general formula (3) (R ² and R ⁴ are In either case, a protecting group) can be synthesized.

  Various dehydrating agents are used in the dehydration reaction. As the dehydrating agent, those described in books such as “New Experimental Chemistry Course, 14, Synthesis and Reaction of Organic Compounds (I)” (Maruzen) are used. Examples include acid catalysts, base catalysts, halogenation reagents, sulfonation reagents, esterification reagents, acid anhydrides, alumina, silica, and ion exchange resins. Specifically, sulfonation reagents such as methanesulfonyl chloride and toluenesulfonyl chloride, phosphoryl chloride, thionyl chloride, oxalyl chloride, acetyl chloride, acetyl bromide, acetic anhydride, phthalic anhydride, phosphorus tribromide, N-bromosuccinic acid Preferable are dehydrating agents such as imide, iodine, sulfur dioxide, phosphorus pentoxide, and dicyclohexylcarbodiimide, and acid catalysts such as p-toluenesulfonic acid, pyridinium-p-toluenesulfonate, and sulfuric acid.

  In this dehydration reaction, the amount of the dehydrating agent is usually 0.1 to 10 equivalents, preferably 1 to 5 equivalents per 1 equivalent of the general formula (1b). When the base is used in combination, the amount of the base is usually preferably about 0.1 to 10 equivalents per 1 equivalent of the dehydrating agent. The reaction temperature of the dehydration reaction is usually about −80 to + 100 ° C., and the reaction time is preferably about 10 minutes to 10 hours.

  These dehydrating agents are triethylamine, diisopropylethylamine, tributylamine, pyridine, collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0]. You may use together with bases, such as amines, such as non-5-ene and 1, 4- diazabicyclo [2.2.2] octane, sodium acetate, potassium carbonate, sodium methoxide. Particularly preferably, as a dehydrating agent, a sulfonation reagent such as methanesulfonyl chloride and toluenesulfonyl chloride, and triethylamine, diisopropylethylamine, tributylamine, pyridine, collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7 An amine such as -ene, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane is preferably used in combination.

If desired, the compound represented by the general formula (3) obtained by the above addition reaction and dehydration reaction may be converted to a carboxylic acid by deprotection or oxidation, deprotection of a hydroxyl group, hydrolysis of an ester, or By subjecting it to a carboxylic acid salt formation reaction, it can be converted to another compound having a different Q structure. For example, when Q has a carboxyl group-related group, formyl group, protected formyl group, hydroxyl group, or protected hydroxyl group, a general functional group conversion reaction such as deprotection, hydrolysis, or oxidation reaction, etc. Can be converted to Q having a carboxyl group. Normally, Q having a polar group other than a carboxyl group is converted to Q having a carboxyl group, together with deprotection of protecting groups R ² and R ⁴ . This deprotection and conversion to a carboxyl group may be performed simultaneously, or one of them may be performed in sequence.

  As described above, Q is preferably a monovalent organic group represented by -BZ. Z is a polar group or a group that can be converted into a polar group (for example, a protected polar group), and B is a divalent organic group. Z is preferably a carboxyl group, a group that can be converted into a carboxyl group (hereinafter referred to as an analogous group of a carboxyl group), a formyl group, a protected formyl group, a hydroxyl group, a protected hydroxyl group, or the like. In particular, Z may be an analogous group of a carboxyl group, except when it is the final target compound in the compound represented by the general formula (3) (that is, a dihalogenated prostacyclin having physiological activity). preferable. In the final target compound, it is most preferable that Z is a carboxyl group or a salt group thereof. Usually, Z is a carboxyl group after synthesizing a compound represented by the general formula (3) in which Z is an analogous group of a carboxyl group. Is converted to a group, and if necessary, converted to a salt of a carboxyl group. Further, when Z is a formyl group, a protected formyl group, a hydroxyl group, a protected hydroxyl group or the like, it is preferable that Z is finally converted into a carboxyl group.

  When Z is a protected formyl group, various protecting groups can be used as the protecting group, but protecting groups such as acetals and thioacetals are preferred. In the case where Z is a protected hydroxyl group, various protecting groups can be used as the protecting group, and the hydroxyl protecting groups described above are suitable.

  In the case where Z is a carboxyl group-related group, the carboxyl group-related groups include a carboxyl group neutralized with a base, an esterified carboxyl group, an orthoesterified carboxyl group, an amidated carboxyl group, Examples thereof include a carboxyl group protected with tetrazole or nitrile. Preferred carboxyl group analogs are esterified carboxyl groups, orthoesterified carboxyl groups, and carboxyl groups protected with tetrazoles. As the esterified carboxyl group, a carboxyl group esterified with a lower alkanol, particularly an alkoxycarbonyl group in which the alkyl portion is an alkyl group having 1 to 4 carbon atoms is preferable. The orthoesterified carboxyl group is preferably an orthoester with a lower alkanol or an orthoester with an alkanetriol. Examples of alkanetriol include trimethylolethane, trimethylolpropane, glycerin and the like. Tetrazole is preferably 1H-tetrazole or 2H-tetrazole.

  Z is particularly preferably an esterified or orthoesterified carboxyl group that is stable in the synthesis reaction of the general formula (3) and is an analog of a carboxyl group that can be easily converted into a carboxyl group after completion of the reaction. preferable. When Z is an esterified or orthoesterified carboxyl group, this is represented by Z '.

  Z as described above other than the carboxyl group and its salt can be converted to a carboxyl group by a general functional group conversion reaction such as deprotection, hydrolysis, oxidation reaction and the like. As described above, these transformations are described in “New Experimental Science Course, 14, Synthesis and Reaction of Organic Compounds (I), (II), (V), Maruzen”, “Protective Groups in Organic, Synthesis, TW. This method can be carried out by the method described in a book written by Green, J. Wiley & Sons.

  B is a residue obtained by removing Z from the above Q, and a lower alkylene group including a lower alkylene group, a lower cycloalkylene group, and a lower cycloalkylene group (the alkylene group may be present on both sides of the cycloalkylene group) , A lower alkylene group containing an ether bond or a thioether bond, or a phenylene group is preferred. In particular, one intermediate of an alkylene group having 3 to 5 carbon atoms, a cycloalkylene group having 3 to 6 carbon atoms, an alkylene group having 1 to 4 carbon atoms including a cycloalkylene group having 3 to 6 carbon atoms, an ether bond or a thioether bond. Are preferably an alkylene group having 2 to 4 carbon atoms and an m-phenylene group. Most preferred B is a linear alkylene group having 3 to 5 carbon atoms.

Specific examples of B include the following. Trimethylene group, tetramethylene group, pentamethylene group, cyclopropylene group, 1,2-cyclobutylene group, 1,3-cyclobutylene group, 1,2-cyclopentylene group, 1,3-cyclopentylene group, 1 , 3-cyclohexylene group, one having a methylene group bonded to one of these cycloalkylene groups, —CH ₂ OCH ₂ —, —CH ₂ SCH ₂ —, — (CH ₂ ) ₃ OCH ₂ —, — (CH ₂ ) ₃ SCH ₂ —, m-phenylene group.

The compound represented by the general formula (1a) is a chemically stable compound. Specific examples of the compound represented by the general formula (1a) include, but are not limited to, the following compounds. Among them, a compound in which R ² and R ⁴ are both protecting groups is a compound represented by the general formula (1b). In addition, the following compounds include those various stereoisomers, optical isomers, and mixtures thereof.

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -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- (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-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-hydroxy-4,4-dimethyl-E-1-nonen-6-ynyl) -bicyclo [ 3.3.0] octane-3-one,
(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-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-{(3S) -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- (2-phenylethyl) -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-5-methyl-1-nonynyl} -bicyclo [3.3. 0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6- (3-hydroxy-4-methyl-1,6-octadiynyl) -bicyclo [3.3.0] Octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6- (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- (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-{(3S) -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, 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-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-5-methyl-nonanyl} -bicyclo [3.3.0] Octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-tert-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) -3-tert-butyldimethylsiloxy-5-methyl- E-1-nonenyl} -bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-triethylsiloxy-6-{(3S) -3-tert-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) -3-tert-butyldimethylsiloxy-5-methyl-E-1-nonenyl}- Bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-benzoyloxy-6-{(3S) -3-tert-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -Bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (4-phenylbenzoyloxy) -6-{(3S) -3-tert-butyldimethylsiloxy-5-methyl-E -1-nonenyl} -bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-benzyloxy-6-{(3S) -3-tert-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -Bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-methoxyethoxy) -6-{(3S) -3-tert-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) -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) -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) -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-{(3S) -3-acetoxy-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) -3-benzoyloxy-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) -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-{(3S) -3-acetoxy-5-methyl-E-1-nonenyl} -bicyclo [3. 3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (4-methoxybenzoyloxy) -6-{(3S) -3-acetoxy-5-methyl-E-1-nonenyl } -Bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-benzoyloxy-6-{(3S) -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- (3-t-butyldimethylsiloxy-4-methyl-E-1-octene-6 -Inyl) -bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-tert-butyldimethylsiloxy-6- (3-hydroxy-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- {3- (2-tetrahydropyranyloxy) -4-methyl-E-1- Octene-6-ynyl} -bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-tert-butyldimethylsiloxy-6- (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- (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- {3- (2-tetrahydropyranyloxy) -4-methyl-E -1-octene-6-ynyl} -bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-acetoxyxy-6- {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-tert-butyldimethylsiloxy-6- (3-tert-butyldimethylsiloxy-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- (3-tert-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- (3-tert-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-acetoxy-6- (3-tert-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- (4-methoxybenzoyloxy) -6- (3-tert-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-benzoyloxy-6- (3-tert-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- {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- (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- (2-tetrahydropyranyloxy) -6- (3-acetoxy-4-methyl-E-1-nonene-6 Inyl) -bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (3-benzoyloxy-4-methyl-E-1-nonene-6 -Inyl) -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-hydroxy-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-acetoxy-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- (benzoyloxy) -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-{(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-{(3S) -3-cyclopentyl-3-hydroxy-E-1- Propenyl} bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranoyloxy) -6-{(3S) -3-cyclopentyl-3-acetoxy-E-1- Propenyl} bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranoyloxy) -6-{(3S) -3-cyclopentyl-3-benzoyloxy-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, 7R) -2-oxa-4,4-difluoro-7-acetoxy-6-{(3S) -3-tert-butyldimethylsiloxy-E-1-octenyl} bicyclo [3.3 .0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-benzoyloxy-6-{(3S) -3-tert-butyldimethylsiloxy-E-1-octenyl} bicyclo [3. 3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-tert-butyldimethylsiloxy-E-1-octenyl} bicyclo [3.3 .0] octane-3-one,
(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-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3-acetoxy-E-1-octenyl} bicyclo [ 3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3-benzoyloxy-E-1-octenyl} bicyclo [3.3.0] Octane-3-one.

  Specific examples of the organic metal represented by the general formula (2) include, but are not limited to, the following compounds.

4- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) butyllithium,
4- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) butyl magnesium bromide,
4- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) butylmagnesium chloride,
4- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) butyldiethylaluminum,
Di {4- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) butyl} zinc,
6- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) hexyl lithium;
6- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) hexyl magnesium bromide,
6- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) hexyl magnesium chloride,
6- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) hexyl diethylaluminum,
Di {6- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) hexyl} zinc,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclobutyl} methyllithium,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclobutyl} methyl magnesium bromide,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclobutyl} methyldiethylaluminum,
Di [{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclobutyl} methyl] zinc,
2- {2- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclobutyl} ethyllithium,
2- {2- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclobutyl} ethyl magnesium bromide,
2- {2- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclobutyl} ethyl diethylaluminum,
Di [2- {2- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclobutyl} ethyl] zinc,
2- {2- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclopropyl} ethyllithium,
2- {2- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclopropyl} ethyl magnesium bromide,
2- {2- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclopropyl} ethyldiethylaluminum,
Di [2- {2- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclopropyl} ethyl] zinc,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclopentyl} methyl magnesium bromide,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclopentyl} methyldiethylaluminum,
Di [{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclopentyl} methyl] zinc,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclohexyl} methyllithium,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclohexyl} methyl magnesium bromide,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclohexyl} methyldiethylaluminum,
Di [{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclohexyl} methyl] zinc,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) phenyl} methyllithium,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) phenyl} methyl magnesium bromide,
{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) phenyl} methyldiethylaluminum,
Di [{3- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) phenyl} methyl] zinc,
4-pentenylmagnesium bromide,
4-pentenylmagnesium chloride,
4-pentenyl lithium,
5- (triethylsiloxy) pentyllithium,
5- (triethylsiloxy) pentylmagnesium bromide,
5- (t-butyldimethylsiloxy) pentyl lithium,
5- (t-butyldimethylsiloxy) pentylmagnesium bromide,
5- (trimethylsiloxy) pentyl lithium,
5- (trimethylsiloxy) pentylmagnesium bromide,
5- (2-tetrahydropyranyloxy) pentyl lithium,
5- (2-tetrahydropyranyloxy) pentylmagnesium bromide,
3- (triethylsiloxy) propyllithium,
3- (triethylsiloxy) propyl magnesium bromide,
4- (1,3-dioxan-2-yl) butyllithium,
4- (1,3-dioxan-2-yl) butylmagnesium bromide,
n-butyllithium,
n-butylmagnesium bromide,
3-butynyl lithium,
3-butynyl magnesium bromide,
4-chlorobutylmagnesium bromide.

  After the dihalogenated prostacyclin represented by the general formula (3) is produced, as described above, the protecting group is dehydrated and Q is usually converted. In particular, when Q has a group that can be a carboxyl group, the group is converted to a carboxyl group, and in some cases, the carboxyl group is further converted to a salt thereof.

  When Q in the general formula (3) has an ester group (particularly when Q is -BZ and Z is an analogous group of a carboxyl group having an ester group or an orthoester group), a hydrolysis reaction is performed. As a result, dihalogenated prostacyclins in which Q has a carboxyl group can be obtained. The hydrolysis reaction is usually carried out by using sodium hydroxide, potassium hydroxide, calcium hydroxide or the like as a base in an aqueous solution, a solvent such as ethanol, methanol, dioxane, tetrahydrofuran, dimethoxyethane, or a mixture thereof. This can be carried out by alkaline hydrolysis in a solvent. It can also be hydrolyzed using an enzyme such as esterase or lipase. Dihalogenated prostacyclins that are free carboxylic acids can be obtained by neutralization and extraction with an organic solvent such as ether, chloroform, dichloromethane, or ethyl acetate.

  Furthermore, when Q of General formula (3) has a carboxyl group, it can be set as the salt of carboxylic acid. The salt of the carboxylic acid can be easily obtained by concentrating the above ester hydrolysis solution as it is or by adding a desired base to the free carboxylic acid solution.

Examples of the cation that is a counter ion of the carboxyl group include NH ₄ ⁺ , tetramethylammonium, monomethylammonium, dimethylammonium, trimethylammonium, benzylammonium, phenethylammonium, morpholium cation, monoethanolammonium, triscation, and piperidinium. Examples thereof include ammonium cations such as nium cations, alkali metal cations such as Na ⁺ and K ⁺ , 1 / 2Ca ²⁺ , 1 / 2Mg ²⁺ , 1 / 2Zn ²⁺ , and 1 / 3Al ³⁺ . Of these, sodium ion and potassium ion are particularly preferable.

Usually, PGI ₂ having high physiological activity is a compound having a free carboxyl group at the end of the α chain or a compound in which the carboxyl group is neutralized. In the compound represented by the general formula (3) in the present invention, the final target compound may be a compound having such a free carboxyl group or a compound in which the carboxyl group is neutralized. preferable. However, as long as the compound has physiological activity, the final target compound in the present invention is not limited to these compounds. In addition, the final target compound in the present invention is a compound that does not have (or has low) physiological activity by itself, such as a prodrug, and changes into a compound having physiological activity in vivo. There may be. An example of such a compound is a compound in which the carboxyl group at the end of the α chain is esterified.

  Although the specific example of a compound represented by General formula (3) is given below, it is not limited to these. In particular, a compound in which Q is -BZ is preferable.

5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S, 5S) -3-hydroxy-5-methyl-E-1-nonenyl} Methyl bicyclo [3.3.0] octane-3-ylidene] pentanoate,
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-4,4-dimethyl-E-1-octenyl} Methyl bicyclo [3.3.0] octane-3-ylidene] pentanoate,
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-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 -Propenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoic acid methyl ester,
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-4-methyl-E-1-nonene-6 Inyl} bicyclo [3.3.0] octane-3-ylidene] pentanoic acid methyl ester,
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] methyl pentanoate,
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S, 5S) -3-hydroxy-5-methyl-1-noninyl} 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-1-octynyl} 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-1-propynyl} 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} 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-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-hydroxy-4-methyl-1,6-nonanediynyl} bicyclo [ 3.3.0] octane-3-ylidene] methyl pentanoate,
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] methyl pentanoate,
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] methyl pentanoate,
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] 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 Inyl} 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-noninyl} 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 -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-hydroxy-4-methyl-E-1-nonene-6 Inyl} bicyclo [3.3.0] octane-3-ylidene] pentanoic acid sodium,
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] sodium 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.

Compounds represented by a general formula (1) is not limited to dihalogenated prostacyclins expressed by the above general formula (3) is an important intermediate capable of inducing the variety of dihalogenated prostacyclins. For example, Taroshima et al. “Prostaglandins and related bioactive substances” (Kodansha Scientific) and SMRoberts et al. “New Synthetic Routes to Prostaglandins and Tromboxanes” (Academic Press) It can be converted to dihalogenated prostacyclins with a chain moiety introduced.

Dihalogenated lactones represented by the general formula (1a) can be produced by various methods. For example, the dihalogenated lactones can be produced by the method described in JP-A-56-501319. However, the present inventor has found a method for producing this dihalogenated lactone which is advantageous over this method. The method starts from 7-monohalogenated lactones having no ω chain moiety (—A—CH (OR ² ) —R ¹ ), and (a) fluorinated 7,7-dihalogenated lactones and (B) a method of introducing a ω chain portion into a 7-monohalogenated lactone having a ω chain and then fluorinating the 7-position to form a dihalide. The starting mono-halogenated lactones having no ω chain moiety are basically known compounds.

In the method (a), the fluorination process to produce 7,7-dihalogenated lactones and their products are novel. These are described in the prior patent application relating to the inventor's invention. Way of (a) is involved in the process for preparing dihalide lactones represented by the general formula (1a) by introducing the ω-chain moiety to the 7,7-dihalogenated lactones, are the inventions . That is, “the compound represented by the general formula (4) is converted into the compound represented by the general formula (5), reacted with the compound represented by the general formula (6), and then reduced. “Method for producing dihalogenated lactone represented by (1a)”.

Way of (b) above, the method of preparing a 7- to monohalogenated lactone to introduce ω-chain moiety having a ω chain 7 monohalogenated lactones, and resulting with a ω chain 7- There are two methods for producing dihalogenated lactones represented by the general formula (1a) by fluorinating monohalogenated lactones. That is, the former is “by converting the compound represented by the general formula (8) into the compound represented by the general formula (9), reacting with the compound represented by the general formula (6), and then reducing the compound. “The production method of monohalogenated lactones represented by the general formula (7)”, the latter “general formula (1a) obtained by halogenating the monohalogenated lactones represented by the general formula (7)” Is a process for producing dihalogenated lactones represented by

  In the above two methods (a) and (b), the reaction for introducing the ω chain portion is basically the same reaction, although the reaction itself is different, although there is a difference between the starting material and the product. Hereinafter, this reaction is referred to as ω chain introduction reaction. Similarly, the fluorination reaction is basically the same reaction when the reaction itself is viewed. Hereinafter, this reaction is referred to as a fluorination reaction. These two reactions will be described below, but these will be described at once as they are common to the two methods (a) and (b). The fluorination reaction in the above method (a) is an invention related to the patent application of the prior application and is not particularly explained, but the starting compound is a compound represented by the above general formula (8), and the product Since is a compound represented by the above general formula (4), its production method by fluorination reaction is substantially explained below.

The ω chain introduction reaction is a reaction for converting —CH ₂ OR ⁵ into —A—CH (OR ² ) —R ¹ in the compound represented by the general formula (4) or the compound represented by the general formula (8). is there. This reaction consists of three steps: a reaction for changing —CH ₂ OR ⁵ to —CH (═O), a reaction with the compound represented by the general formula (6), and a reduction reaction.

The ω chain introduction reaction can be performed according to the Wittig-Horner-Emmons reaction, which is a known reaction. That is, when R ⁵ is a hydrogen atom, it is oxidized as it is to obtain a compound represented by the general formula (5/9) [a compound represented by the general formula (5) or a general formula (9) And then reacting with the compound represented by the general formula (6) to introduce the ω chain, and reducing the resulting unsaturated ketone, the general formula (1a / 7) It is possible to synthesize a compound in which A of the represented compound [meaning the compound represented by the general formula (1a) or the compound represented by the general formula (7)] is a vinylene group. On the other hand, when R ⁵ is a protecting group, it can be similarly carried out by selectively deprotecting R ⁵ and converting it to a hydrogen atom.

The deprotection reaction of R ⁵ will differ depending on the structure of R ^5, it can be applied methods and conditions known deprotection reactions. For example, when R ⁴ is a tetrahydropyranyl group or an acetyl group and R ⁵ is a t-butyldimethylsilyl group, only R ⁵ is selectively used by using tetrabutylammonium fluoride or HF-pyridine. The deprotection method can be applied.

Furthermore, the reaction for synthesizing the compound represented by the general formula (5/9) by oxidizing R ⁵ is usually performed in the presence of dimethyl sulfoxide, trifluoroacetic acid, pyridine, dicyclohexylcarbodiimide, and the like. It is good to stir at +50 degreeC, Preferably, it is 0- + 25 degreeC. In general, the reaction between the compound represented by the general formula (5/9) and the compound represented by the general formula (6) is preferably carried out in the presence of sodium hydride and dimethoxyethane. The reaction temperature is usually −50 to + 50 ° C., preferably 0 to + 50 ° C.

  Further, the compound represented by the general formula (1a / 7) is obtained by reducing the unsaturated ketone produced by the reaction between the compound represented by the general formula (5/9) and the compound represented by the general formula (6). In general, the reaction for synthesizing is preferably carried out in methanol in the presence of sodium borohydride and cerium trichloride. The reaction temperature is −100 to + 50 ° C., preferably −80 to + 10 ° C.

  In addition, when A in the compound represented by the general formula (1a / 7) is an ethylene group, the compound represented by the general formula (5/9) and the compound represented by the general formula (6) The method of reducing the unsaturated ketone produced in the reaction of using a metal hydride such as lithium aluminum hydride, the method of hydrogenation, or a copper hydride reagent, for example, hydrogenated (tributyltin) copper lithium, or hydrogenated It can synthesize | combine by reducing after making it into a saturated ketone using the method of 1, 4-reduction reaction using a copper triphenylphosphine complex etc.

  Furthermore, when A of the compound represented by the general formula (1a / 7) is an ethynylene group, the compound represented by the general formula (5/9) and the compound represented by the general formula (6) In the reaction, it can be synthesized by the presence of a halogenating agent such as N-bromosuccinimide and N-chlorosuccinimide and further treatment with a strong base such as potassium t-butoxide.

The fluorination reaction can be produced by halogenating a monohalogenated lactone represented by the general formula (7). The compound represented by the general formula (7) is a monohalogenated dihalogenated lactone represented by the corresponding general formula (1a). As a method for producing a dihalogenated lactones represented by the general formula (1a) a compound represented by the general formula (7) brought halogenated, but are not limited to, electrophilic in the presence of a metallic catalyst A method of reacting with a halogenating agent is preferred.

  Examples of the metal catalyst include an organometallic catalyst, a salt of halogen and metal, and the like. Examples of the metal include metals such as boron, aluminum, magnesium, calcium, and silicon, and transition metals such as zinc, titanium, zirconium, manganese, iron, copper, cobalt, nickel, cerium, and samarium. As specific metal catalysts, boron trifluoride etherate, aluminum chloride, dialkylaluminum chloride, alkylaluminum dichloride, zinc halide, titanium halide, zirconium halide, magnesium halide, iron halide and the like are preferable. The amount of the metal catalyst is usually about 0.01 to 10 parts by weight, preferably about 0.1 to 3 parts by weight with respect to 1 part by weight of the compound represented by the general formula (7).

  As the electrophilic halogenating agent, various electrophilic fluorinating agents, electrophilic chlorinating agents, electrophilic brominating agents, electrophilic iodinating agents and the like are used. Examples of the electrophilic fluorinating agent include fluoroxytrifluoromethane, perchloryl fluoride, acetyl hypofluorite, N-fluorosulfonamides, N-fluorosulfonimides, xenon fluoride, fluorine gas, and the like. Examples of the electrophilic chlorinating agent include carbon tetrachloride, N-chlorosuccinimide, and chlorine. Examples of the electrophilic brominating agent include carbon tetrabromide, N-bromosuccinimide, bromine, and the like. Examples of the agent include N-iodosuccinimide and iodine. Of these, electrophilic fluorinating agents such as perchloryl fluoride, acetyl hypofluorite, N-fluorosulfonamides and N-fluorosulfonimides are preferably used. The amount of the electrophilic halogenating agent is usually about 0.5 to 10 parts by weight, preferably about 1 to 5 parts by weight with respect to 1 part by weight of the compound represented by the general formula (4). .

  The halogenation reaction is preferably carried out in an inert solvent under basic conditions. As the base, alkali metals such as lithium, sodium and potassium, amides of ammonia and secondary amines, alkali metal hydrides, alkali metal organic compounds and the like are used. Specifically, 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, n-butyllithium, s-butyllithium, t-butyl Lithium etc. are mentioned. The amount of the base is usually 0.5 to 20 parts by weight, preferably 1 to 10 parts by weight with respect to 1 part by weight of the compound represented by the general formula (7).

  As the inert solvent, an ether solvent, a hydrocarbon solvent, a polar solvent, or a mixed solvent thereof is preferable. Specific examples of these solvents include the aforementioned ether solvents, hydrocarbon solvents, and polar solvents. The amount of the inert solvent is usually about 5 to 1000 parts by weight, preferably 10 to 100 parts by weight with respect to 1 part by weight of the compound represented by the general formula (7). The reaction temperature of the halogenation reaction is usually about −150 to + 50 ° C., preferably −80 to + 30 ° C.

  Specific examples of the compound represented by the general formula (4) include the following compounds, but are not limited thereto. The following compounds include those various stereoisomers, optical isomers, and mixtures thereof. Moreover, as a compound represented by General formula (8), the compound whose Y is a fluorine atom is preferable, As a specific example, there exists a monofluoro compound corresponding to a compound below.

(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-dichloro-7-hydroxy-6-hydroxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-dibromo-7-hydroxy-6-hydroxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-diiodo-7-hydroxy-6-hydroxymethyl-bicyclo [3.3.0] octan-3-one.

  Examples of the above-mentioned derivatives in which the hydroxyl group of the dihalogenated lactone is protected include (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-hydroxy. Taking the case of methyl-bicyclo [3.3.0] octane-3-one as an example, the following compounds may be mentioned.

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] Octane-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 -On,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (triphenylsiloxy) methyl-bicyclo [3.3.0] octane- 3-on,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (triisopropylsiloxy) methyl-bicyclo [3.3.0] octane- 3-on,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (4-phenylbenzoyloxy) methyl-bicyclo [3.3.0] Octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (tetrahydropyranyloxy) methyl-bicyclo [3.3.0] octane -3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-benzyloxymethyl-bicyclo [3.3.0] octan-3-one ,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (methoxybenzyloxy) methyl-bicyclo [3.3.0] octane- 3-on,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-trityloxymethyl-bicyclo [3.3.0] octane-3-one ,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (methoxymethoxy) methyl-bicyclo [3.3.0] octane-3 -On,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (2-methoxyethoxymethoxy) methyl-bicyclo [3.3.0] Octane-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, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (t-butyldimethylsiloxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3 -On,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (t-butyldiphenylsiloxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3 -On,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (triethylsiloxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (triphenylsiloxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one ,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (triisopropylsiloxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one ,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (acetoxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (benzoyloxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (4-phenylbenzoyloxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3 -On,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (tetrahydrofuranyloxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one ,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (benzyloxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (methoxybenzyloxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one ,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (trityloxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (methoxymethoxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-methoxyethoxymethoxy) -6-tert-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3 -On,
(1S, 5R, 6R, 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- (acetoxy) -6-triethylsiloxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (acetoxy) -6-benzoyloxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (benzoyloxy) -6-benzoyloxymethyl-bicyclo [3.3.0] octane-3-one.

  Specific examples of the compound represented by the general formula (6) include the following compounds, but are not limited thereto.

(4S) -4-methyl-2-oxooctanylphosphonate dimethyl,
(4S) -4-methyl-2-oxooctanylphosphonate diethyl,
Dimethyl 2-oxoheptanylphosphonate,
Diethyl 2-oxoheptanylphosphonate,
Dimethyl 2-oxo-2-cyclopentylethylphosphonate,
Diethyl 2-oxo-2-cyclopentylethylphosphonate,
Dimethyl 3-methyl-2-oxo-5-octynylphosphonate,
Diethyl 3-methyl-2-oxo-5-octynylphosphonate,
(3S) -3-methyl-2-oxo-5-octynylphosphonate dimethyl,
(3S) -3-methyl-2-oxo-5-octynylphosphonic acid diethyl ester,
Dimethyl 3-methyl-2-oxo-5-heptynylphosphonate,
Diethyl 3-methyl-2-oxo-5-heptynylphosphonate,
(3S) -3-methyl-2-oxo-5-heptynylphosphonate dimethyl,
(3S) -3-methyl-2-oxo-5-heptynylphosphonic acid diethyl ester,
Dimethyl 3,3-dimethyl-2-oxo-5-octynylphosphonate,
Diethyl 3,3-dimethyl-2-oxo-5-octynylphosphonate,
Dimethyl 2-oxo-2-cyclohexylethylphosphonate,
Diethyl 2-oxo-2-cyclohexylethylphosphonate.

  Furthermore, the compound represented by the general formula (7) is preferably a compound in which Y is a fluorine atom, and specific examples thereof include specific examples of the dihalogenated lactones represented by the general formula (1a). There are monohalides corresponding to these compounds.

Any of the production methods in the present invention is an excellent method that does not require severe reaction conditions, a long-time reaction, and does not require any special reaction reagent or reaction apparatus. Therefore, the production method in the present invention is versatile and is an extremely excellent method applicable to the synthesis of many derivatives.

  Hereinafter, the present invention will be specifically described with reference to Examples and Reference Examples. However, the present invention is not limited to these examples.

[Reference Example 1]
Synthesis of 1- (4-iodobutyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane
In the same manner as described in EJCorey et al., Tetrahedron Letters, 24,5571 (1983), it was synthesized as follows.
To a solution of 4.21 g of 3-methyl-3-hydroxymethyloxetane in methylene chloride (20 ml), 5 ml of pyridine and 12.2 g of 5-iodopentanoic acid chloride were added at 0 ° C. and stirred for 2 hours. After pouring into sodium bicarbonate water and extracting with dichloromethane, the residue was 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 dichloromethane (20 ml), 0.62 ml of boron trifluoride etherate was added at -15 ° C, and the mixture was stirred at -15 ° C for 4 hours, at 0 ° C for 2 hours, and at room temperature for 1 hour. After adding 2.79 ml of triethylamine 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), 3.17 (t, J = 7.2 Hz, 2H), 3.89 (s, 6H).

[Reference Example 2]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane- Synthesis of 3-one After adding 19.1 ml of n-butyllithium (1.56 M, hexane solution) at −78 ° C. to a solution of hexamethyldisilazane (6.84 ml) in tetrahydrofuran (hereinafter referred to as THF) (90 ml). A lithium hexamethyldisilazide solution was prepared by stirring for 30 minutes. To this solution was added (1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane- A solution of 3-one 10 g in THF (20 ml) was added dropwise at −78 ° C. and stirred for 60 minutes. Next, a solution of 9.37 g of N-fluorobenzenesulfonimide in THF (40 ml) was added at -78 ° C. After stirring at -78 ° C for 60 minutes, the temperature was raised, and the mixture was stirred at room temperature for 30 minutes. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 8 to 1: 4) gave 9.46 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.05 (m, 6H), 0.88 (m, 9H), 1.4-1.8 (m, 6H), 2.0-3.1 (m, 4H), 3.4-5.3 (m , 8H).
¹⁹ F-NMR (CDCl ₃ , ppm): -179 (m).

[Reference Example 3]
Synthesis of (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octane-3-one Reference (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo synthesized in Example 2 [3.3 0.0] Octan-3-one 8.01 g in THF (100 ml) was ice-cooled, 10 ml of HF-pyridine was added, and the mixture was stirred at room temperature for 1 hour. After diluting with ethyl acetate, saturated aqueous sodium hydrogen carbonate was slowly added, and the mixture was extracted with ethyl acetate. The extract was concentrated by drying and purified by silica gel column chromatography (dichloromethane: methanol = 10: 1) to give 4.92 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3-3.1 (m, 10H), 3.4-5.3 (m, 8H).
¹⁹ F-NMR (CDCl ₃ , ppm): -179 (m).

[Reference Example 4]
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] Synthesis of Octane-3-one (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy)-synthesized in Reference Example 2 on 136 mg (1 mmol) of anhydrous zinc chloride A solution of 194 mg of 6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-one in THF (3 ml) was added at room temperature and cooled to −78 ° C., then lithium diisopropylamide (1M, 1 ml of THF solution) was added and stirred for 20 minutes. To this solution, 236 mg (0.75 mmol) of N-fluorobenzenesulfonamide was added at −78 ° C. and stirred for 1.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and purified by silica gel column chromatography to give 126 mg of the title compound.

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 ⁺ ).

[Example 1]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6-{(5S) -3-oxo-5-methyl-E-1-nonenyl} Synthesis of -bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy) synthesized in Reference Example 3 To a solution of -6-hydroxymethyl-bicyclo [3.3.0] octane-3-one 300 mg in benzene (10 ml), 89 μl of pyridine, 930 μl of dimethyl sulfoxide, 12.6 μl of trifluoroacetic acid, and 677 mg of dicyclohexylcarbodiimide were added. Stir for hours. Insoluble matter was filtered, and the filtrate was washed with water and concentrated to obtain the corresponding crude aldehyde. 116 mg of sodium hydride was added to a dimethoxyethane (30 ml) solution of 735 mg of dimethyl (4S) -4-methyl-2-oxooctanylphosphonate and stirred for 10 minutes. To this solution, a solution of the above aldehyde crude dimethoxyethane (10 ml) was added at 0 ° C., stirred at room temperature for 30 minutes, poured into brine and extracted with ethyl acetate. After drying and concentration, purification by silica gel column chromatography gave 270 mg of the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-3.0 (m, 25H), 3.4-5.2 (m, 6H), 6.2-6.8 (m, 2H).
¹⁹ F-NMR (CDCl ₃ , ppm): -179 (m).

[Example 2]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl } Synthesis of Bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7- (2-tetrahydroplanyloxy) synthesized in Example 1 ) -6-{(5S) -3-oxo-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one in a solution of 61 mg in methanol (5 ml) and cerium chloride 7 water 52 mg of a Japanese product and 8 mg of sodium borohydride were added at −40 ° C., and the mixture was stirred at −40 ° C. for 10 minutes and at 0 ° C. for 10 minutes. After concentration, the residue was dissolved in methanol (3 ml), 2 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 1 hour. After distilling off methanol, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added for extraction. The extract was dried and concentrated, the residue in dimethylformamide 3 ml, imidazole 34 mg, and stirred at room temperature for 2 hours added t- butyldimethylsilyl chloride 61 mg. The mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was concentrated after drying and purified by silica gel column chromatography to give 70 mg of the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.86 (m, 24H), 1.0-4.2 (m, 15H), 4.9-5.7 (m, 4H).
¹⁹ F-NMR (CDCl ₃ , ppm): -177 (dd, 30.2, 52.7 Hz).
Mass spectrum: 542 (M ⁺ ).

[Example 3]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-tert-butyldimethylsiloxy-6-{(3S) -3-tert-butyldimethylsiloxy-E-1-octenyl} bicyclo [3 .3.0] Synthesis of octan-3-one (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3. 3.0] The title compound was synthesized in the same manner as in Examples 1 and 2 using octan-3-one and dimethyl 2-oxoheptanylsulfonate.

[Example 4]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1 -Synthesis of nonenyl} -bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-7-t-butyldimethylsiloxy-6-{(3S, 5S)- 3-t-Butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one 524 mg in THF (2 ml) was added lithium diisopropylamide in THF (1M, 1.1 ml) at −78 ° C. and stirred for 30 minutes. After evaporating the solvent under reduced pressure, THF (3 ml) was added for dissolution, and the mixture was added to an acetyl hypofluorite solution (2 mmol) at -78 ° C. The mixture was poured into a 10% aqueous sodium thiosulfate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10) gave 125 mg of the title compound as a mixture of isomers.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.86 (m, 24H), 1.0-4.2 (m, 15H), 4.9-5.7 (m, 4H).
¹⁹ F-NMR (CDCl ₃ , ppm): -177 (dd, 30.2, 52.7 Hz), -203 (d, 48.8 Hz).
Mass spectrum: 542 (M ⁺ ).

[Example 5]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1 -Nonenyl} -bicyclo [3.3.0] octane-3-one synthesis Hexamethyldisilazane (51 μl, 0.242 mmol) in THF (1 ml) at −78 ° C. with n-butyllithium (1.56 M Hexane solution) 0.14 ml was added and stirred for 30 minutes to prepare a lithium hexamethyldisilazide solution. To this solution was added (1S, 5R, 6R, 7R) -2-oxa-7-t-butyldimethylsiloxy-6-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1. -Nonenyl} -bicyclo [3.3.0] octane-3-one 105 mg in THF (2 ml) was added dropwise at -78 ° C and stirred for 30 minutes. Next, 76.2 mg of N-fluorobenzenesulfonimide was added at -78 ° C. The mixture was stirred at −78 ° C. for 15 minutes, 0 ° C. for 30 minutes and room temperature for 30 minutes, then poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10) gave 40 mg of the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.86 (m, 24H), 1.0-4.2 (m, 15H), 4.9-5.7 (m, 4H).
¹⁹ F-NMR (CDCl ₃ , ppm): -177 (dd, 30.2, 52.7 Hz), -203 (d, 48.8 Hz).
Mass spectrum: 542 (M ⁺ ).

[Example 6]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3-tert-butyldimethylsiloxy-4-methyl-1- Synthesis of octene-6-ynyl} -bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6- { (3S) -3-tert-butyldimethylsiloxy-4-methyl-1-octen-6-ynyl} -bicyclo [3.3.0] octan-3-one was used in the same manner as in Example 5 above. 127 mg of the title compound were obtained.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 6H), 0.88 (m, 12H), 1.0-4.5 (m, 21H), 5.0-5.7 (m, 4H).
¹⁹ F-NMR (CDCl ₃ , ppm): -177 (dd, 30.1, 52.8 Hz), -178 (dd, 30.2, 52.7 Hz), -203 (m).
Mass spectrum: 494 (M ⁺ ).

[Example 7]
(1S, 5R, 6R, 7R) -2-oxa-4-bromo-7- (2-tetrahydropyranyl) -6-{(3S) -3-tert-butyldimethylsiloxy-5-methyl-1-nonenyl } Synthesis of Bicyclo [3.3.0] octane-3-one To a solution of hexamethyldisilazane (146 μl, 0.694 mmol) in THF (1 ml) at −78 ° C., n-butyllithium (1.56 M, hexane) Solution) 0.41 ml was added and stirred for 30 minutes to prepare a lithium hexamethyldisilazide solution. To this solution was added (1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyl) -6-{(3S) -3-tert-butyldimethylsiloxy-5-methyl-1-nonenyl. } -Bicyclo [3.3.0] octane-3-one 285 mg of THF solution (1 ml) was added dropwise at −78 ° C. and stirred for 30 minutes. Next, a solution of 230 mg of carbon tetrabromide in THF (1 ml) was added at -78 ° C. After stirring at −78 ° C. for 1 hour, the mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 20-1: 5) gave 291 mg of the title compound.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 6H), 0.87 (m, 15H), 1.2-1.9 (m, 15H), 2.0-4.6 (m, 10H), 5.16 (m, 1H ), 5.58 (m, 2H).
Mass spectrum: 573 (M ⁺ ).

[Example 8]
(1S, 5R, 6R, 7R) -2-oxa-4-bromo-7- (2-tetrahydropyranyloxy) -6-{(3S) -3-tert-butyldimethylsiloxy-4-methyl-1- Synthesis of octene-6-ynyl} -bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6- { (3S) -3-tert-butyldimethylsiloxy-4-methyl-1-octen-6-ynyl} -bicyclo [3.3.0] octan-3-one 277 mg was used in the same manner as in Example 7 above. 284 mg of the title compound were obtained.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 6H), 0.88 (m, 12H), 1.0-1.8 (m, 12H), 2.0-4.5 (m, 10H), 5.13 (m, 1H ), 5.57 (m, 2H).
Mass spectrum: 555 (M ⁺ ).

[Example 9]
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-tert-butyldimethylsiloxy-6-{(3S, 5S) -3-tert-butyldimethylsiloxy-5-methyl-E Synthesis of -1-nonenyl} -bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyl synthesized in Example 4 Dimethylsiloxy-6-{(3S, 5S) -3-tert-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one 524 mg in THF (2 ml After adding 0.22 g (1.6 mmol) of anhydrous zinc chloride to room temperature, a THF solution (1 M, 1.1 ml) of lithium diisopropylamide was added at −78 ° C. and stirred for 20 minutes. After evaporating the solvent under reduced pressure, THF (3 ml) was added for dissolution, and the mixture was added to an acetyl hypofluorite solution (2 mmol) at -78 ° C. The mixture was poured into a 10% aqueous sodium thiosulfate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10) gave 105 mg of the title compound.

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, 15.3Hz, 1H), 5.54 (dd, J = 6.3, 15.3Hz, 1H).
¹⁹ F-NMR (CDCl ₃ , ppm): -92 (dd, J = 26, 282 Hz), -114 (d, J = 282 Hz).
Mass spectrum: 560 (M ⁺ ).

[Example 10]
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-tert-butyldimethylsiloxy-6-{(3S, 5S) -3-tert-butyldimethylsiloxy-5-methyl-E Synthesis of -1-nonenyl} -bicyclo [3.3.0] octane-3-one To a solution of diisopropylamine (1.23 ml, 8.9 mmol) in THF (14 ml) at −78 ° C. with n-butyllithium (1 (.66M, hexane solution) was added, followed by stirring for 30 minutes to prepare a lithium diisopropylamide solution. In a separate container, 1.47 g (10.8 mmol) of anhydrous zinc chloride was weighed and synthesized in Example 2 (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethyl. 3.57 g of siloxy-6-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one (6. 76 mmol) in THF (20 ml) was added. The solution was cooled to −78 ° C., and the above lithium diisopropylamide solution was added dropwise at −78 ° C. and stirred for 20 minutes. Next, 2.56 g (8.1 mmol) of N-fluorobenzenesulfonimide was added at −78 ° C. After stirring at −78 ° C. for 60 minutes and at room temperature for 30 minutes, the mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. Purification by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10) gave 2.90 g of the title compound.

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, 15.3Hz, 1H), 5.54 (dd, J = 6.3, 15.3Hz, 1H).
¹⁹ F-NMR (CDCl ₃ , ppm): -92 (dd, J = 26,282 Hz), -114 (d, J = 282 Hz).
Mass spectrum: 560 (M ⁺ ).

[Example 11]
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-4-methyl-E-1 Synthesis of -octene-6-ynyl} -bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6 -{(3S) -3-tert-butyldimethylsiloxy-4-methyl-E-1-octen-6-ynyl} -bicyclo [3.3.0] octane-3-one In the same manner, 147 mg of the title compound was obtained.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.86 (m, 18H), 1.1-4.5 (m, 15H), 5.0-5.7 (m, 3H).
¹⁹ F-NMR (CDCl ₃ , ppm): -93 (m), -114 (m).
Mass spectrum: 542 (M ⁺ ).

[Example 12]
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-4-methyl-E-1 -Nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one synthesis (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6 Example 10 with 226 mg of-{(3S) -3-tert-butyldimethylsiloxy-4-methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one Similarly, 152 mg of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.03-0.06 (m, 12H), 0.85-0.88 (m, 18H), 1.0-4.6 (m, 17H), 5.1-5.7 (m, 3H).
¹⁹ F-NMR (CDCl ₃ , ppm): -92 (m), -114 (m).
Mass spectrum: 556 (M ⁺ ).

[Example 13]
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-tert-butyldimethylsiloxy-6-{(3S) -3-tert-butyldimethylsiloxy-5-methyl-E-1 -Nonenyl} -bicyclo [3.3.0] octane-3-one Synthesis (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2- The t-butyldimethylsilyl group of tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-one was deprotected in the same manner as in Reference Example 3. Obtained (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (hydroxymethyl) -bicyclo [3.3.0] octane- 3-one and (4S) -4- The title compound was synthesized in the same manner as in Examples 1 and 2 using dimethyl methyl-2-oxooctanylphosphonate.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.84-0.88 (m, 24H), 1.0-1.5 (m, 9H), 2.1-3.1 (m, 4H), 4.0-4.3 (m, 2H), 5.0-5.7 (m, 3H).
¹⁹ F-NMR (CDCl ₃ , ppm): -92 (m), -114 (m).
Mass spectrum: 560 (M ⁺ ).

[Example 14]
(1S, 5R, 6R, 7R) -2-oxa-3- {4- (4-methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) butylidene} -4,4-difluoro Synthesis of -7-t-butyldimethylsiloxy-6-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane 1- ( 4-Iodobutyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane 1.13 g in anhydrous ether (30 ml) was cooled to −78 ° C. and t-butyllithium (1 .48M, pentane solution) was added and stirred at −78 ° C. for 2 hours. To this, (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S, 5S) -3-t- synthesized in Example 10 was added. Butyldimethylsiloxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-one 1.75 g of an ether solution (10 ml) was added at −78 ° C., then 1 at −78 ° C. The mixture was stirred at -60 ° C for 1 hour. The mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. To the residue was added 10 ml of dichloromethane, 2.6 ml of triethylamine and 0.72 ml of methanesulfonyl chloride were added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. The mixture was poured into aqueous sodium bicarbonate 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 give 1.83 g of the title compound. .

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.02-0.05 (m, 12H), 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 = 251 Hz), -115 (d, J = 250 Hz).

[Example 15]
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S, 5S) -3-t-butyldimethylsiloxy-5- Synthesis of methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate (1S, 5R, 6R, 7R) -2-oxa-3- {synthesized in Example 14 4- (4-Methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) butylidene} -4,4-difluoro-7-tert-butyldimethylsiloxy-6-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane in a solution of 1.83 g of dimethoxyethane (25 ml) was added 2.5 ml of 10% aqueous sodium hydrogensulfate solution. At 0 ℃ Added and stirred for 30 minutes. The mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure, and 25 ml of methanol and 680 mg of potassium carbonate were added to the residue, followed by stirring at room temperature for 2 hours. The mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate-hexane (1: 1). The extract was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1:10). 981 mg of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.03-0.11 (m, 12H), 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, 251 Hz), -115 (d, J = 251 Hz).
Mass spectrum: 659 (M ⁺ +1).

[Example 16]
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S, 5S) -3-hydroxy-5-methyl-E-1-nonenyl} Synthesis of methyl bicyclo [3.3.0] octane-3-ylidene] pentanoate 5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- synthesized in Example 15 t-Butyldimethylsiloxy-6-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene] methyl pentanoate To a solution of 976 mg of THF (15 ml), 4.5 ml of tetrabutylammonium fluoride (1M, THF solution) was added and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 470 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, 2H).
¹⁹ F-NMR (CDCl ₃ , ppm): -84 (dd, J = 17, 248 Hz), -117 (d, J = 248 Hz).
Mass spectrum: 431 (M ⁺ +1).

[Example 17]
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S, 5S) -3-hydroxy-5-methyl-E-1-nonenyl} Synthesis of sodium bicyclo [3.3.0] octane-3-ylidene] pentanoate 5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- synthesized in Example 16 Hydroxy-6-{(3S, 5S) -3-hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene] methyl pentanoate 139 mg ethanol (8 ml) To the solution, 3.39 ml of 0.1N sodium hydroxide was added and 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, 250 Hz), -117 (d, J = 250 Hz).

[Example 18]
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-E-1-octenyl} bicyclo [3.3. Synthesis of methyl 0! Octane-3-ylidene] pentanoate (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-tert-butyldimethylsiloxy-6-{(3S) -3- t-Butyldimethylsiloxy-E-1-octenyl} bicyclo [3.3.0] octane-3-one and 1- (4-iodobutyl) -4-methyl-2,6,7-trioxabicyclo [2. 2.2] The title compound was synthesized in the same manner as in Examples 14 to 16 using octane.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.9-2.7 (m, 21H), 3.67 (s, 3H), 3.9-4.3 (m, 2H), 4.7-4.9 (m, 2H), 5.5-5.7 (m, 2H).
¹⁹ F-NMR (CDCl ₃ , ppm): -84 (dd, J = 16, 249 Hz), -117 (d, J = 249 Hz).
Mass spectrum: 403 (M ⁺ +1).

[Example 19]
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-E-1-octenyl} bicyclo [3.3. Synthesis of 0] octane-3-ylidene] pentanoic acid sodium 5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(synthesized in Example 18 The title compound was synthesized in the same manner as in Example 17 using 3S) -3-hydroxy-E-1-octenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoic acid methyl ester.
¹ H-NMR (D ₂ O) δ (ppm): 0.8-2.9 (m, 21H), 3.7-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.4-5.7 (m, 2H).
¹⁹ F-NMR (D ₂ O, ppm): -84 (dd, J = 17, 250 Hz), -117 (d, J = 250 Hz).

[Example 20]
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] Synthesis of methyl octane-3-ylidene] pentanoate (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-tert-butyldimethylsiloxy-6-{(3S ) -3-cyclopentyl-3-t-butyldimethylsiloxy-E-1-propenyl} bicyclo [3.3.0] octane-3-one and 1- (4-iodobutyl) -4-methyl-2,6 The title compound was synthesized in the same manner as in Examples 14 to 16 using 7-trioxabicyclo [2.2.2] octane.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.1-2.7 (m, 19H), 3.67 (s, 3H), 3.8-4.3 (m, 2H), 4.7-4.9 (m, 2H), 5.4-5.7 (m, 2H).
¹⁹ F-NMR (CDCl ₃ , ppm): -84 (dd, J = 17, 250 Hz), -117 (d, J = 250 Hz).
Mass spectrum: 401 (M ⁺ +1).

[Example 21]
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] Synthesis of sodium octane-3-ylidene] pentanoate 5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy- synthesized in Example 20 6-{(3S) -3-Cyclopentyl-3-hydroxy-E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoic acid methyl ester by a method similar to that in Example 17, The title compound was synthesized.
¹ H-NMR (D ₂ O) δ (ppm): 1.0-2.9 (m, 19H), 3.7-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.4-5.7 (m, 2H).
¹⁹ F-NMR (D ₂ O, ppm): -84 (dd, J = 17, 250 Hz), -117 (d, J = 250 Hz).

[Example 22]
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-4-methyl-E-1-nonene-6 Inyl} bicyclo [3.3.0] octane-3-ylidene] methyl pentanoate (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- obtained in Example 12 t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-4-methyl-E-1-nonen-6-ynyl} bicyclo [3.3.0] octane-3-one and 1 The title compound was synthesized in the same manner as in Examples 14 to 16 using-(4-iodobutyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.8-2.8 (m, 21H), 3.67 (s, 3H), 3.9-4.3 (m, 2H), 4.4-4.7 (m, 2H), 5.4-5.7 (m, 2H).
¹⁹ F-NMR (CDCl ₃ , ppm): -84 (m), -117 (m).
Mass spectrum: 427 (M ⁺ +1).

[Example 23]
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-4-methyl-E-1-nonene-6 Synthesis of sodium inyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate 5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-synthesized in Example 22 Implementation with methyl 7-hydroxy-6-{(3S) -3-hydroxy-4-methyl-E-1-nonen-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate The title compound was synthesized in the same manner as in Example 17.
¹ H-NMR (D ₂ O) δ (ppm): 0.7-2.8 (m, 21H), 3.7-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.3-5.7 (m, 2H).
¹⁹ F-NMR (D ₂ O, ppm): -84 (m), -117 (m). .
[Example 24]
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-4-methyl-E-1-octene-6 Inyl} bicyclo [3.3.0] octane-3-ylidene] methyl pentanoate (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6 Examples 14-16 using-{(3S) -3-tert-butyldimethylsiloxy-4-methyl-E-1-octen-6-ynyl} -bicyclo [3.3.0] octane-3-one The title compound was synthesized by the same method as described above.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.9-2.8 (m, 19H), 3.67 (s, 3H), 3.9-4.3 (m, 2H), 4.5-4.7 (m, 2H), 5.5-5.7 (m, 2H).
¹⁹ F-NMR (CDCl ₃ , ppm): -84 (m), -117 (m).
Mass spectrum: 413 (M ⁺ +1).

[Example 25]
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-4-methyl-E-1-octene-6 Synthesis of sodium inyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate 5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-synthesized in Example 24 Implementation with methyl 7-hydroxy-6-{(3S) -3-hydroxy-4-methyl-E-1-octene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate The title compound was synthesized in the same manner as in Example 17.

¹ H-NMR (D ₂ O) δ (ppm): 0.7-2.8 (m, 19H), 3.7-4.3 (m, 2H), 4.5-5.0 (m, 2H), 5.3-5.7 (m, 2H).
¹⁹ F-NMR (D ₂ O, ppm): -84 (m), -117 (m).

[Example 26]
5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3S) -hydroxy-4-methyl-1,6-nonadiynyl} bicyclo [3. 3.0] Synthesis of methyl octane-3-ylidene] pentanoate (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-tert-butyldimethylsiloxy-6-{(3S)- t-butyldimethylsiloxy-4-methyl-1,6-1-nonadiynyl} bicyclo [3.3.0] octan-3-one and 1- (4-iodobutyl) -4-methyl-2,6,7- The title compound was synthesized in the same manner as in Examples 14 to 16 using trioxabicyclo [2.2.2] octane.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.9-2.8 (m, 21H), 3.67 (s, 3H), 3.9-4.7 (m, 4H).
¹⁹ F-NMR (CDCl ₃ , ppm): -84 (m), -117 (m).
Mass spectrum: 425 (M ⁺ +1).

[Example 27]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-E-1-octenyl} -bicyclo [ 3.3.0] Synthesis of octan-3-one (1S, 5R, 6R, 7R) -2-oxa-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy- The title compound was synthesized in the same manner as in Example 5 using E-1-octenyl} -bicyclo [3.3.0] octane-3-one.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.88 (m, 18H), 1.0-4.5 (m, 17H), 4.8-5.7 (m, 4H).
¹⁹ F-NMR (CDCl ₃ , ppm): -178 (dd, 30.1, 52.9 Hz).

[Example 28]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-cyclopentyl-3-t-butyldimethylsiloxy-E-1-propenyl } Synthesis of bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-7-tert-butyldimethylsiloxy-6-{(3S) -3-cyclopentyl- The title compound was synthesized in the same manner as in Example 5 using 3-t-butyldimethylsiloxy-E-1-propenyl} -bicyclo [3.3.0] octane-3-one.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.89 (m, 18H), 1.1-4.4 (m, 15H), 4.7-5.7 (m, 4H).
¹⁹ F-NMR (CDCl ₃ , ppm): -178 (dd, 31.8, 52.3 Hz).

[Example 29]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-4-methyl-E-1-nonene Synthesis of -6-ynyl} -bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-7-t-butyldimethylsiloxy-6-{(3S)- In the same manner as in Example 5 using 3-t-butyldimethylsiloxy-4-methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one, the title compound was obtained. Was synthesized.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.03-0.06 (m, 12H), 0.85-0.88 (m, 18H), 1.0-4.6 (m, 17H), 4.9-5.7 (m, 4H).
¹⁹ F-NMR (CDCl ₃ , ppm): -178 (m).

[Example 30]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-4-methyl-E-1-octene Synthesis of -6-ynyl} -bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-7-t-butyldimethylsiloxy-6-{(3S)- In the same manner as in Example 5 using 3-t-butyldimethylsiloxy-4-methyl-E-1-octene-6-ynyl} -bicyclo [3.3.0] octane-3-one, the title compound was obtained. Was synthesized.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.86-0.88 (m, 18H), 1.0-4.6 (m, 17H), 4.9-5.7 (m, 4H).
¹⁹ F-NMR (CDCl ₃ , ppm): -179 (m).

[Example 31]
(1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-4-methyl-1,6-nonadiynyl } -Bicyclo [3.3.0] octane-3-one synthesis (1S, 5R, 6R, 7R) -2-oxa-7-t-butyldimethylsiloxy-6-{(3S) -3-t- The title compound was synthesized in the same manner as in Example 5 using butyldimethylsiloxy-4-methyl-1,6-nonadiynyl} -bicyclo [3.3.0] octane-3-one.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04-0.06 (m, 12H), 0.85-0.89 (m, 18H), 1.1-5.2 (m, 19H).
¹⁹ F-NMR (CDCl ₃ , ppm): -178 (m).

[Example 32]
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-E-1-octenyl}- Synthesis of bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-tert-butyldimethylsiloxy-6-{(3S) -3- The title compound was synthesized in the same manner as in Example 10 using t-butyldimethylsiloxy-1-octenyl} -bicyclo [3.3.0] octane-3-one.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04 (m, 12H), 0.88 (m, 18H), 1.0-4.5 (m, 17H), 4.8-5.7 (m, 3H).
¹⁹ F-NMR (CDCl ₃ , ppm): -92 (dd, 27, 280 Hz), -114 (d, 280 Hz).

[Example 33]
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-cyclopentyl-3-t-butyldimethylsiloxy-E-1 Synthesis of -propenyl} -bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S ) -3-Cyclopentyl-3-t-butyldimethylsiloxy-E-1-propenyl} -bicyclo [3.3.0] octane-3-one and the title compound was synthesized in the same manner as in Example 10. did.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.05 (m, 12H), 0.87 (m, 18H), 1.1-4.4 (m, 15H), 4.8-5.7 (m, 3H).
¹⁹ F-NMR (CDCl ₃ , ppm): -93 (dd, 26, 282 Hz), -115 (d, 282 Hz).

[Example 34]
(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-4-methyl-1,6 Synthesis of —nonadiynyl} -bicyclo [3.3.0] octane-3-one (1S, 5R, 6R, 7R) -2-oxa-4-fluoro-7-tert-butyldimethylsiloxy-6-{(3S ) -3-t-Butyldimethylsiloxy-4-methyl-1,6-nonadiynyl} -bicyclo [3.3.0] octane-3-one was used to synthesize the title compound in the same manner as in Example 10. did.
¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04-0.06 (m, 12H), 0.85-0.89 (m, 18H), 1.1-5.1 (m, 19H).
¹⁹ F-NMR (CDCl ₃ , ppm): -92 (m), -114 (m)

According to the manufacturing method of the present invention, it is a useful physiologically active substance dihalogenated prostacyclins are both can be efficiently synthesized in a short step from known compounds. Any of the synthesis methods is an excellent method that does not require severe reaction conditions, a long-time reaction, and does not require any special reaction reagent or reaction apparatus. In addition, the raw materials and the reaction intermediate are both chemically stable compounds and are easy to handle. Moreover, the compound of a raw material is also an easily available compound. Furthermore, the production method in the present invention is versatile and can be applied to the synthesis of many derivatives.

Claims (15)

The dihalogenated lactone represented by the general formula (1b) is subjected to an addition reaction with the organometallic compound represented by the general formula (2) for dehydration, and then optionally deprotected to give a general formula (3 The manufacturing method of dihalogenated prostacyclin represented by this.

(However, in the general formulas (1b), (2), (3),
A: ethylene group, vinylene group, or ethynylene group,
Q: substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, substituted or unsubstituted carbon A cycloalkyl group having a number of 3 to 8, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group,
R ¹ : substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, substituted or unsubstituted A cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxy group,
R ² and R ⁴ each independently represents a hydrogen atom or a protecting group,
R ¹² and R ¹⁴ each independently represents a protecting group,
X ¹ and X ² are each independently a halogen atom,
M: metal atom,
L: a ligand,
m: an integer from 1 to 8,
n: an integer from 0 to 10,
Represents. ) The manufacturing method of Claim 1 whose Q is group represented by -BZ.
(However,
B: C1-C6 alkylene group, C3-C6 cycloalkylene group, C3-C6 cycloalkylene group-containing alkylene group, C2-C6 alkylene group containing ether bond or thioether bond Or a phenylene group,
Z: carboxyl group, carboxyl group-related group, formyl group, protected formyl group, hydroxyl group, or protected hydroxyl group,
Represents. )   The production method according to claim 2, wherein Z is an esterified or orthoesterified carboxyl group, and B is an alkylene group having 3 to 5 carbon atoms. The production method according to claim 1, 2 or 3, wherein X ¹ and X ² are both fluorine atoms. A is a vinylene group, and R ¹ is a linear or branched alkyl group having 4 to 8 carbon atoms, a linear or branched alkenyl group having 4 to 8 carbon atoms, a linear or branched group. An alkynyl group having 4 to 8 carbon atoms, a halogen atom or a lower alkyl group which may be substituted with a cycloalkyl group having 3 to 8 carbon atoms, a halogen atom or a lower alkyl group which may be substituted with 3 to 8 carbon atoms The production method according to claim 1, which is an aralkyl group which is an alkyl group having 1 to 4 carbon atoms to which the cycloalkyl group is bonded, or a phenoxy group optionally substituted with a halogen atom or a lower alkyl group.   M is at least one metal atom selected from lithium, sodium, magnesium, boron, aluminum, zinc and copper, and L is a ligand consisting of a halogen atom, a ligand containing sulfur or phosphorus, and an alkyl group or The manufacturing method of Claim 1 which is at least 1 sort (s) of ligands chosen from the organic ligand which consists of an aryl group, m is an integer of 1-4, and n is an integer of 0-4. A dihalogenated prostacyclin represented by the general formula (3) in which R ² and R ⁴ are both protecting groups is produced using the production method according to claim 1, and then deprotected to produce R ^A method for producing a dihalogenated prostacyclin by producing a dihalogenated prostacyclin represented by the general formula (3), wherein both ² and R ⁴ are hydrogen atoms. Dihalogenated prostacyclins represented by the general formula (3) in which R ² and R ⁴ are both protecting groups and Q is a group represented by —B—Z ′ are prepared, and then R ² and R Z ′ is converted to a carboxyl group simultaneously with deprotection of ⁴ or in any order, and is represented by the general formula (3) in which R ² and R ⁴ are both hydrogen atoms and Q is —B—COOH. The production method of claim 7, wherein dihalogenated prostacyclins are produced.
(However,
B: C1-C6 alkylene group, C3-C6 cycloalkylene group, C3-C6 cycloalkylene group-containing alkylene group, C2-C6 alkylene group containing ether bond or thioether bond Or a phenylene group,
Z ′: an esterified or orthoesterified carboxyl group,
Represents. ) The compound represented by the general formula (4) is converted into the compound represented by the general formula (5), reacted with the compound represented by the general formula (6), and then reduced to the general formula (1a). The manufacturing method of dihalogenated lactone represented by these.

(However, in the general formulas (1a), (4), (5), (6),
A: ethylene group, vinylene group, or ethynylene group,
R ¹ : substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, substituted or unsubstituted A cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxy group,
R ² , R ⁴ , R ⁵ : each independently a hydrogen atom or a protecting group,
R ⁶ : lower alkyl group,
X ¹ and X ² are each independently a halogen atom,
Represents. ) The production method of claim 9, wherein X ¹ and X ² are both fluorine atoms. A process for producing a dihalogenated lactone represented by the general formula (1a) by subjecting a monohalogenated lactone represented by the general formula (7) to a halogenation reaction.

(However, in the general formulas (1a) and (7),
A: ethylene group, vinylene group, or ethynylene group,
R ¹ : substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, substituted or unsubstituted A cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxy group,
R ² and R ⁴ each independently represents a hydrogen atom or a protecting group,
X ¹ and X ² are each independently a halogen atom,
Y: a halogen atom which is X ¹ or X ² ,
Represents. ) The production method of claim 11, wherein X ¹ , X ² and Y are all fluorine atoms. The compound represented by the general formula (8) is converted into the compound represented by the general formula (9), reacted with the compound represented by the general formula (6), and then reduced to the general formula (7). The manufacturing method of monohalogenated lactone represented by these.

(However, in the general formulas (6), (7), (8), (9),
A: ethylene group, vinylene group, or ethynylene group,
R ¹ : substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, substituted or unsubstituted A cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxy group,
R ² , R ⁴ , R ⁵ : each independently a hydrogen atom or a protecting group,
R ⁶ : lower alkyl group,
Y: a halogen atom,
Represents. )   The manufacturing method of Claim 13 whose Y is a fluorine atom. Dihalogenated lactones represented by the general formula (1b).

(However, in the general formula (1b)
A: ethylene group, vinylene group, or ethynylene group,
R ¹ : substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, substituted or unsubstituted A cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxy group,
R ¹² and R ¹⁴ each independently represents a protecting group,
Represents. )