JPH07324081A - Production of dihalogenated prostacyclins - Google Patents

Abstract

PURPOSE:To efficiently and readily obtain the compounds excellent in suppressing actions, etc., on blood agglutination from a readily available raw material in a short step by carrying out the addition reaction of an organometallic compound with specific dihalogenated lactones, dehydrating the resultant product and, as necessary, deprotecting the dehydrated compound. CONSTITUTION:This method for producing dihalogenated prostacyclins of formula III [A is ethy(ny)lene or vinylene; R<1> is a (substituted)1-10C alkyl, a (substituted)1-10C alkenyl, a (substituted)1-10C alkynyl, a (substituted)3-8C cycloalkyl, a (substituted)aralkyl or a (substituted)aryloxy; R<2> and R<4> are each H or a protecting group; X<1> and X<2> are each a halogen] is to carry out the addition reaction of a compound of formula I (R<12> and R<14> are each a protecting group) with a compound of formula II [Q is a (substituted)1-10C alkyl, a (substituted)1-10C alkenyl, a (substituted)1-10C alkynyl, a (substituted)3-8C cycloalkyl, a (substituted)aralkyl or a (substituted)aryl; M is a metallic atom; L is a ligand, (m) is 1-8; (n) is 0-10], dehydrating the reactional product and, as necessary, deprotecting the resultant compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a dihalogenated prostacyclin, a novel intermediate used therein, and a method for producing the same.

[0002]

2. Description of the Related Art Natural prostacyclin (PGI)
₂ ) is a local hormone that has strong physiological activities in vivo, such as platelet aggregation inhibitory activity, vasodilatory activity, and cytoprotective activity, and is an important factor that regulates various cell functions in vivo.

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

To date, attempts have been made to introduce a halogen atom into the structure of prostacyclin in order to synthesize chemically stable prostacyclin derivatives. Such a prostacyclin derivative has a halogen atom at position 7 of the prostacyclin skeleton (position corresponding to position 7 of natural PGI ₂ ; hereinafter, the carbon atom position number refers to the position corresponding to natural PGI ₂ ). A method for producing the possessed prostacyclins has been reported (Tokusho Sho 56-
501319, JP 57-165382, JP 57-171988, and JP 61-9.
1136, JP-A-62-482, JP-A-5
No. 9184, Japanese Patent Publication No. 314030, Japanese Patent Publication No. 3-47272, and Japanese Patent Publication No. 1-24147). However, all of these production methods have drawbacks in that the reaction is difficult to control because they use harsh reaction conditions and they are not general methods. Therefore, it has been strongly desired to develop a practical method for producing a prostacyclin derivative having a halogen atom at the 7-position of the prostacyclin skeleton.

Further, in US Pat. No. 4,317,906 and Japanese Patent Publication No. 56-501319, difluoroprostacyclins having two fluorine atoms respectively at the 7-position and the 10-position of a prostacyclin skeleton, and their derivatives are disclosed. Manufacturing methods are described. In all of these production methods, the corresponding difluoroprostaglandin F ₂ is used as a raw material to produce difluoroprostacyclin by a cyclization reaction. However, the synthesis of difluoroprostaglandin F ₂ as a raw material has a drawback that it requires many steps, is very difficult, and is complicated.

In addition, in particular, the cyclization reaction of the prostaglandin F ₂ having two electron-withdrawing fluorine atoms at the 7-position of the prostacyclin skeleton is the same as the cyclization reaction of the natural prostaglandin F ₂ In contrast, there is a problem that the reactivity is remarkably low, the reaction takes a long time, the reaction yield is low, and the like, which is a practically difficult production method. That is, the cyclization reaction between the 6-position and the 9-position of the prostaglandin F ₂ having two fluorine atoms at the 7-position causes the natural prostaglandin F ₂ or two fluorine atoms at the 10-position. Compared to the cyclization reaction between the 6th and 9th positions of the prostaglandin F ₂ having, the reactivity is remarkably low due to the electron withdrawing property of the fluorine atom, and therefore the corresponding difluoroprostacyclin is not substantially obtained. .

[0007]

The present invention has been made to solve the above drawbacks and problems. The present inventors have found a method for producing a dihalogenated prostacyclin having two halogen atoms at the 7-position without undergoing a cyclization reaction of prostaglandin F ₂ . Further, they have found an intermediate useful for the production and a production method thereof. The present invention provides a halogen atom 2 at the 7-position of the prostacyclin skeleton.
The following inventions relate to a method for producing a 7,7-dihalogenated prostacyclin having 1 group, two intermediates useful for the production, and one intermediate thereof.

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

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 give the general formula. A method for producing a dihalogenated lactone represented by (1a).

A method 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.

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 give the general formula. A method for producing a monohalogenated lactone represented by (7).

Dihalogenated lactones represented by the general formula (1b).

[0013]

[Chemical 15]

[0014]

[Chemical 16]

[0015]

[Chemical 17]

[0016]

[Chemical 18]

[0017]

[Chemical 19]

[0018]

[Chemical 20]

[0019]

[Chemical 21]

[0020]

[Chemical formula 22]

[0021]

[Chemical formula 23]

[0022]

[Chemical formula 24]

(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 An alkenyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or An unsubstituted aryl group,

R ^{1 is a} substituted or unsubstituted C ^{1 to} C 10
Alkyl group, 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 cycloalkyl group having 3 to 8 carbon atoms, substituted or non-substituted A substituted aralkyl group, or a substituted or unsubstituted aryloxy group,

R ² , R ⁴ , and R ⁵ are each independently a hydrogen atom or a protecting group, R ^{6 is a} lower alkyl group, R ¹² ,
R ^14: each independently, protecting group, X ^1, X ^2: each independently, a halogen atom, Y: a halogen atom is X ¹ or X ^2,

M is a metal atom, L is a ligand, m is an integer of 1 to 8 and n is an integer of 0 to 10. )

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 thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group and a hexyl group. Further, 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,
Suitable examples thereof include vinyl group, allyl group, 1-propenyl group, isopropenyl group, 3-butenyl group, 3-pentenyl group, 4-hexenyl group and the like. Unless otherwise specified, the "alkynyl group" is preferably a lower alkynyl group, more preferably a linear or branched alkynyl group having 2 to 6 carbon atoms and one unsaturated group, and a suitable example thereof is , 1-propynyl group, 2-propynyl group, isopropynyl group, 3-butynyl group, 3-
Examples thereof include a pentynyl group and a 4-hexynyl group.

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

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

The "protecting group" is a group for temporarily protecting a reactive functional group such as a hydroxyl group, a carboxyl group and a formyl group, and has the general formula (1b), (2),
In the intermediates for producing the final object such as (4) and (5), it is necessary that the functional groups are protected in most cases, except for the functional group which is reacted next. For example, the protecting group for the hydroxyl group includes a triorganosilyl group, an acyl group, an alkyl group, an alkoxyalkyl group, an aralkyl group and the like.

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

Q in the present invention is natural PGI
Organic groups corresponding to the α chain of ₂ and organic groups corresponding to the α chain of various PGI ₂ are preferable. As such an organic group, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 1 to 10 carbon atoms, an alkynyl group having 1 to 10 carbon atoms, and 3 carbon atoms in the ring.
There are ~ 8 cycloalkyl groups, aryl groups such as phenyl groups, and these groups with various substituents. The substituent may be a cycloalkyl group or an aryl group, for example, a cycloalkyl group-substituted alkyl group, a cycloalkyl group-substituted alkenyl group, an aryl group-substituted alkenyl group, or the like. Further, it may be an organic group in which a carbon atom of the chain organic group is substituted with an oxygen atom or a sulfur atom, or an organic group having a ring such as a cycloalkylene group or an arylene group between the chain organic groups.

In addition to the above-mentioned substituents, the substituent 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 a terminal carboxyl group or other polar substituent or an organic group that can be converted into a polar substituent. 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 convertible into those groups, and particularly preferably a group convertible into a carboxyl group and a carboxyl group. . Particularly preferred Q is an organic group having Z, which is a polar substituent represented by -BZ described later or a group which can be converted into a polar substituent.

Q is a compound represented by the general formula (3), except that the compound represented by the general formula (3) is the final target compound (that is, a dihalogenated prostacyclin having physiological activity). Q having a group capable of being converted into a carboxyl group at the terminal is preferable so that it is inactive in the reactions up to. That is, Q in the organometallic compound represented by the general formula (2) is preferably Q having a group capable of converting to a carboxyl group at the terminal. After synthesizing the compound represented by the general formula (3),
This Q is converted into Q having a terminal carboxyl group. As described below, when Q is a group represented by -BZ,
Z in the organometallic compound represented by the general formula (2) is preferably a group which can be similarly converted into a polar substituent,
After reaching the compound represented by the general formula (3), this Z is converted into a polar substituent, particularly a carboxyl group.

R ¹ in the present invention is natural PG
An organic group corresponding to the ω chain portion of I ₂ or an organic group corresponding to the ω chain portion of various PGI ₂ 's is preferable. As such an organic group, an alkyl group having 1 to 10 carbon atoms, or 1 to 1 carbon atoms
There are 0 alkenyl groups, C 1-10 alkynyl groups, ring C 3-8 cycloalkyl groups, aryloxy groups with aryls such as phenyl groups, and these groups with various substituents. The substituent may be a cycloalkyl group or an aryl group, for example,
It may be a cycloalkyl group-substituted alkyl group, a cycloalkyl group-substituted alkenyl group, an aryl group-substituted alkenyl group, or the like. Further, it may be an organic group in which a carbon atom of the chain organic group is substituted with an oxygen atom or a sulfur atom, or an organic group having a ring such as a cycloalkylene group or an arylene group between the chain organic groups. In addition to the above-mentioned substituents, the substituent for R ¹ includes 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, and 3 to 8 carbon atoms.
8 are alkynyl groups, especially 5 to 6 linear groups thereof and their monomethyl or dimethyl substituents. Specific examples of these groups include n-propyl group and n
-Butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-decyl group, 1-methylpentyl group, 1,1-dimethylpentyl group, 1-methylhexyl group, 2 -Methylpentyl group, 2-methylhexyl group, 3-pentenyl group, 1-methyl-3-pentenyl group, 1-methyl-3-hexenyl group, 1,1-dimethyl-3-pentenyl group, 1,1-dimethyl -3-hexenyl group, 2-methyl-3-pentenyl group, 2-methyl-3
-Hexenyl group, 3-pentynyl group, 1-methyl-3-
Pentynyl group, 1-methyl-3-hexynyl group, 2-methyl-3-pentynyl group, 2-methyl-3-hexynyl group, 1,1-dimethyl-3-pentynyl group, 1,1-dimethyl-3-hexynyl group Groups and the like. Of these, an n-pentyl group, a 2-methylhexyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group and a 1,1-dimethyl-3-hexynyl group are preferable.

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

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

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

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

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, a dihalogenated compound having a physiological activity). Except in the case of prostacyclins), each is preferably a protective group. Also 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 deprotected to obtain the final target compound. In another 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) means a compound represented by the general formula (1a) in which R ² and R ⁴ are both protective groups. This protecting group, R
² and R ⁴ are represented by R ¹² and R ¹⁴ , respectively. Therefore,
For example, in the invention relating to the process for producing the compound represented by the general formula (1a), the compound represented by the general formula (1a) in which R ² and R ⁴ are both protective groups (that is, the compound represented by the general formula (1b) When the compound represented by the formula (3) is obtained, it can be used as it is as a starting material for producing 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 producing the compound represented by the general 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 give 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 protective group in the case where R ² , R ⁴ and R ⁵ are each a protective group (hydroxyl protective group) and the protective group represented by R ¹² and R ¹⁴ are not particularly limited, A known or known protecting group used as a protecting group can be adopted. 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 adopted depending on the purpose. This is because, for example, when it is necessary to selectively deprotect only one protecting group of a compound having two protecting groups, it is preferable to use protecting groups having different reactivities. Specifically, for example, R 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 (in the case where the other protecting group is a triorganosilyl group, a reaction different from that). Those having properties) 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 at least one selected from a lower alkyl group and an aryl group. A triorganosilyl group having 3 groups is preferable. Specifically, for example, t-butyldimethylsilyl group, t-
A butyldiphenylsilyl group, a triethylsilyl group, a triphenylsilyl group, a triisopropylsilyl group and the like are preferable.

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

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

R ⁶ is a lower alkyl group, for example,
There are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group and the like, and a methyl group and an ethyl group are 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 particularly preferably a fluorine atom. Y
Similarly, a fluorine atom or a chlorine atom is preferable, and a fluorine atom is particularly preferable.

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 and the type of ligand, m is an integer of 1 to 8, and n is 0.
It is an integer of -10. m is preferably 1 to 4, particularly 1 to 2, n is 0 to 4, particularly 0 to 2, m + n is 1 to
3 is preferable. Q is the above-mentioned Q, especially -B described later.
It is preferably -Z.

Examples of the metal atom M include metals such as lithium, sodium, potassium, magnesium, calcium, boron, aluminum and silicon, and zinc, copper, iron, titanium, zirconium, manganese, tin, cobalt, nickel, cerium and samarium. And other transition metals. Of these, lithium, sodium, magnesium, boron, aluminum, zinc and copper are preferable. Particularly preferred M are lithium, magnesium, aluminum and zinc.

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

The dihalogenated prostacyclin represented by the general formula (3) of the present invention can be produced by adding the dihalogenated lactone represented by the general formula (1b) to the organometallic compound represented by the general formula (2). It is carried out by subjecting a compound to an addition reaction and dehydration. This is a so-called α chain part introduction reaction. Since the introduction of the α-chain portion by this reaction is a method which does not go through the synthesis of prostaglandin F ₂ having a fluorine atom or the cyclization reaction between the 6-position and the 9-position thereof as in the above-mentioned conventional example, the 7-position Even if there are two fluorine atoms in the reaction, the reaction is easy.

To carry out this reaction, a compound of the general formula (1a)
11 and 15 of the dihalogenated lactone represented by
The hydroxyl group at position usually needs to be protected with a protective group.
If free hydroxyl groups are present at these positions, it becomes difficult to produce by-products or to proceed the reaction. Therefore, for example, when the dihalogenated lactone obtained by the method for producing the 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, the dihalogenated lactone represented by the general formula (1b) is used as a starting material in this production method. The dihalogenated lactone represented by the general formula (1b) is a novel compound.

In the addition reaction of the dihalogenated lactone represented by the general formula (1b) and the organometallic compound represented by the general formula (2), the organometallic compound represented by the general formula (2) The amount used is usually 0.1 to 10 equivalents, and preferably 0.5 to 3 equivalents, based on the dihalogenated lactone of the general formula (1b). The reaction temperature is -150.
To + 100 ° C is preferable, and particularly -100 to + 40 ° C.
Is good.

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

Further, the dihalogenated lactone of the general formula (1b) is subjected to an addition reaction with the organometallic compound of the general formula (2) and then dehydrated to give the compound of the general formula (3) (R ² and R ⁴ can be any protective group).

In the dehydration reaction, various dehydrating agents are used. As the dehydrating agent, those described in the literatures such as “New Experimental Chemistry Course, 14, Synthesis and Reaction of Organic Compound (I)” (Maruzen) are used. Examples thereof include acid catalysts, base catalysts, halogenating agents, sulfonation agents, esterification agents, acid anhydrides, alumina, silica, ion exchange resins and the like. Specifically, sulfonation agents 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. Imide, iodine, sulfur dioxide, phosphorus pentoxide,
A dehydrating agent such as dicyclohexylcarbodiimide, an acid catalyst such as p-toluenesulfonic acid, pyridinium-p-toluenesulfonate, sulfuric acid, and the like are preferable.

In this dehydration reaction, the amount of the dehydrating agent is usually 0.1 to 10 with respect to 1 equivalent of the general formula (1b).
Equivalent, preferably 1-5 equivalent. When the base is used in combination, the amount of the base is usually preferably about 0.1 to 10 equivalents per 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 include triethylamine, diisopropylethylamine, tributylamine, pyridine, collidine, lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3]. .0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, and other amines, and sodium acetate, potassium carbonate, sodium methoxide, and other bases may be used in combination. Particularly preferably, a sulfonating agent such as methanesulfonyl chloride or toluenesulfonyl chloride as a dehydrating agent, and triethylamine, diisopropylethylamine, tributylamine, pyridine, collidine, lutidine, 1,8-diazabicyclo [5.4.0].
Undec-7-ene, 1,5-diazabicyclo [4.
3.0] Nona-5-ene, 1,4-diazabicyclo [2.2.2] octane and the like amines are preferably used in combination.

The compound represented by the general formula (3) obtained by the above addition reaction and dehydration reaction is, if desired, deprotection or conversion reaction to carboxylic acid by oxidation, deprotection of hydroxyl group, hydrolysis of ester. Alternatively, it can be converted into another compound having a different Q structure by subjecting it to a salt forming reaction of a carboxylic acid. For example, Q is a carboxyl group, a formyl group, a protected formyl group, a hydroxyl group,
Alternatively, when it has a protected hydroxyl group, it can be converted to Q having a carboxyl group by a general functional group conversion reaction such as deprotection, hydrolysis, or oxidation reaction.
Usually, Q having a polar group other than a carboxyl group is converted to Q having a carboxyl group together with deprotection of R ² and R ⁴ which are protecting groups. This deprotection and conversion to a carboxyl group may be carried out simultaneously, or one of them may be carried out first.

As described above, Q is preferably a monovalent organic group represented by -BZ. Z is a polar group or a group convertible to a polar group (for example, a protected polar group),
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 a carboxyl group), a formyl group, a protected formyl group, a hydroxyl group, a protected hydroxyl group, or the like. In particular,
Z is preferably a carboxyl group-related group except for the final target compound (that is, a dihalogenated prostacyclin having physiological activity) in the compound represented by the general formula (3). In the final target compound, Z is most preferably a carboxyl group or a salt group thereof, and usually Z is a compound represented by the general formula (3) in which Z is a carboxyl group-related group.
Is converted to a carboxyl group and, if necessary, then 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, etc., it is preferable that Z is finally converted to a carboxyl group.

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

When Z is a carboxyl group, the carboxyl group may be a base-neutralized carboxyl group, an esterified carboxyl group, an orthoesterified carboxyl group, or an amidated group. Examples thereof include a carboxyl group and a carboxyl group protected with tetrazole or nitrile. Preferred carboxyl group analogs are esterified carboxyl groups, orthoesterified carboxyl groups, and tetrazole protected carboxyl groups. The esterified carboxyl group is preferably a carboxyl group esterified with a lower alkanol, particularly an alkoxycarbonyl group whose alkyl moiety is an alkyl group having 1 to 4 carbon atoms. The orthoesterified carboxyl group is preferably an orthoester with a lower alkanol or an orthoester with an alkanetriol. Examples of the alkanetriol include trimethylolethane, trimethylolpropane and glycerin. The tetrazole is preferably 1H-tetrazole or 2H-tetrazole.

Z is an esterified or orthoesterified carboxyl which is stable in the synthesis reaction of the general formula (3) and which is a related group of a carboxyl group which can be easily converted into a carboxyl group after the reaction. Groups are particularly preferred. 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 is a general functional group conversion reaction, for example, deprotection,
It can be converted to a carboxyl group by hydrolysis, oxidation reaction and the like. As described above, these conversions are carried out according to "New Experimental Science Course, 1
4. Synthesis and reaction of organic compounds (I), (II), (V),
Maruzen, "Protective Groups in Organic, Synthesis, TW Green, J. Wi.
It can be carried out by a method described in a textbook such as “ley & Sons”.

B is a residue obtained by removing the above Z from Q and is a lower alkylene group, a lower cycloalkylene group, or a lower alkylene group including a lower cycloalkylene group (the alkylene groups are 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,
Contains 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 in the middle. An alkylene group having 2 to 4 carbon atoms and an m-phenylene group are preferable. Most preferable 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
- those cyclohexylene group, a methylene group to one of bonds of these cycloalkylene groups bonded, -CH ₂ O
_{CH 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. The following compounds may be mentioned as specific examples of the compound represented by the general formula (1a).
It is not limited to these. A compound in which R ² and R ⁴ are both protective groups is a compound represented by the general formula (1b). The following compounds include various stereoisomers, optical isomers, and mixtures thereof.

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

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

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (4-phenylbenzoyloxy) -6-{(3S) -3-t-butyldimethylsiloxy-5- Methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one, (1S, 5R, 6
R, 7R) -2-oxa-4,4-difluoro-7-benzyloxy-6-{(3S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3. 3.0] Octane-3-one, (1S, 5R,
6R, 7R) -2-Oxa-4,4-difluoro-7-
(2-Methoxyethoxy) -6-{(3S) -3-t-
Butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy)-
6-{(3S) -3-hydroxy-5-methyl-E-1
-Nonenyl} -bicyclo [3.3.0] octane-3-
ON, (1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (2-tetrahydropyranyloxy) -6-{(3S) -3- (2-tetrahydropyranyloxy) -5-methyl-E-1-nonenyl} -bicyclo [3.3. 0] octan-3-one,

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

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

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6- (3-t
-Butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl) -bicyclo [3.3.0] octane-
3-one, (1S, 5R, 6R, 7R) -2-oxa-
4,4-Difluoro-7- (2-tetrahydropyranyloxy) -6- (3-t-butyldimethylsiloxy-4
-Methyl-E-1-nonen-6-ynyl) -bicyclo [3.3.0] octane-3-one, (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-acetoxy-6- (3-t-butyldimethylsiloxy-4)
-Methyl-E-1-nonen-6-ynyl) -bicyclo [3.3.0] octane-3-one, (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-
(4-Methoxybenzoyloxy) -6- (3-t-butyldimethylsiloxy-4-methyl-E-1-nonene-
6-ynyl) -bicyclo [3.3.0] octane-3-
ON, (1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-benzoyloxy-6- (3-t
-Butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl) -bicyclo [3.3.0] octane-
3-on,

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- {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-ynyl) -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-ynyl) -bicyclo [3.3.0] octane-3-
ON, (1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (2-tetrahydropyranyloxy) -6- (3-benzoyloxy-4-methyl-E-
1-nonene-6-ynyl) -bicyclo [3.3.0] octane-3-one, (1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-cyclopentyl-3-
t-butyldimethylsiloxy-E-1-propenyl} bicyclo [3.3.0] octane-3-one,

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

(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-{(3
S) -3-t-Butyldimethylsiloxy-E-1-octenyl} bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy)-
6-{(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 organometal 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) butyl magnesium chloride, 4- (4-methyl-2,6,6) 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) hexyllithium, 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} methylmagnesium bromide, {3- (4-methyl-2,6,7-trio) Xabicyclo [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} ethylmagnesium bromide, 2-
{2- (4-Methyl-2,6,7-trioxabicyclo [2.2.2] octanyl) cyclobutyl} ethyldiethylaluminum, 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} ethylmagnesium 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} methylmagnesium 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} methylmagnesium 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} methylmagnesium 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-pentenyl magnesium bromide, 4
-Pentenyl magnesium chloride, 4-pentenyl lithium, 5- (triethylsiloxy) pentyllithium, 5- (triethylsiloxy) pentylmagnesium bromide, 5- (t-butyldimethylsiloxy) pentyllithium, 5- (t-butyldimethylsiloxy) Pentyl magnesium bromide, 5- (trimethylsiloxy) pentyllithium, 5- (trimethylsiloxy) pentylmagnesium bromide, 5- (2-tetrahydropyranyloxy) pentyllithium, 5- (2-tetrahydropyranyloxy) pentylmagnesium bromide, 3- (triethylsiloxy) propyl lithium, 3
-(Triethylsiloxy) propyl magnesium bromide, 4- (1,3-dioxan-2-yl) butyl lithium, 4- (1,3-dioxan-2-yl) butyl magnesium bromide, n-butyl lithium, n-butyl Magnesium bromide, 3-butynyl lithium, 3-butynyl magnesium bromide, 4-chlorobutyl magnesium bromide.

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

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

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

As the cation which is the counter ion of the carboxyl group, for example, NH ₄ ⁺ , tetramethylammonium, monomethylammonium, dimethylammonium,
Trimethylammonium, benzylammonium, phenethylammonium, morpholium cation, monoethanolammonium, tris cation, ammonium cation such as piperidinium cation, alkali metal cation such as Na ⁺ and K ⁺ , 1 / 2Ca ²⁺ , 1 / 2M
Examples thereof include g ²⁺ , 1 / 2Zn ²⁺ and 1 / 3Al ³⁺ . Of these, sodium ion and potassium ion are particularly preferable.

[0093] Usually PGI ₂ compound having a high physiological activity,
It is a compound having a free carboxyl group at the end of the α chain or a compound in which the carboxyl group is a neutralized salt. Also in the compound represented by the general formula (3) in the present invention, the final target compound is a compound having such a free carboxyl group or a compound in which the carboxyl group is a neutralized salt. preferable. However, the final target compound in the present invention is not limited to these compounds as long as it is a compound having physiological activity. The final target compound in the present invention is a compound which does not have (or has low) physiological activity per se, which is called a prodrug, and which is converted into a compound having physiological activity in vivo. It may be. An example of such a compound is a compound in which the terminal carboxyl group of the α chain is esterified.

Specific examples of the compound represented by formula (3) are shown below, but the invention is not limited thereto. In particular, Q is −
Compounds that are BZ are preferred.

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-
Methyl ylidene] pentanoate, 5-[(1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-4,4-
Dimethyl-E-1-octenyl} bicyclo [3.3.
0] octane-3-ylidene] methyl pentanoate, 5-
[(1S, 5R, 6R, 7R) -2-oxa-4,4-
Difluoro-7-hydroxy-6-{(3S) -3-hydroxy-E-1-octenyl} bicyclo [3.3.
0] octane-3-ylidene] methyl pentanoate, 5-
[(1S, 5R, 6R, 7R) -2-oxa-4,4-
Difluoro-7-hydroxy-6-{(3S) -3-cyclopentyl-3-hydroxy-E-1-propenyl}
Methyl bicyclo [3.3.0] octane-3-ylidene] 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-
Methyl {(3S) -3- (2-phenylethyl) -3-hydroxy-E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate, 5-[(1
S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3-hydroxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [ 3.3.0] Methyl octane-3-ylidene] pentanoate, 5-[(1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6- (3-
Hydroxy-4-methyl-E-1-octene-6-ynyl) bicyclo [3.3.0] octane-3-ylidene]
Methyl pentanate,

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S, 5S) -3-Hydroxy-5-methyl-1-
Methyl nonynyl} 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-1-octynyl} bicyclo [3.3.0] octane-3- Methylidene] 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
-Propinyl} bicyclo [3.3.0] octane-3-
Methyl ylidene] pentanoate, 5-[(1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-hydroxy-6-{(3S) -3- (2-phenylethyl) -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-{(3
S) -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-
Methyl (3-hydroxy-4-methyl-1,6-octanediynyl) bicyclo [3.3.0] octane-3-ylidene] pentanoate, 5-[(1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7-hydroxy-6- (3-hydroxy-4,4-dimethyl-1,6
Methyl -octanediynyl) bicyclo [3.3.0] octane-3-ylidene] pentanoate, 5-[(1S, 5
R, 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-{(3
S) -3-Cyclopentyl-3-hydroxy-E-1-
Propenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoic acid, 5-[(1S, 5R, 6R, 7
R) -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, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-hydroxy-6-{(3S) -3- (2-phenylethyl) -3-hydroxy-E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoic acid,

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

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
{(3S) -3-Hydroxy-4,4-dimethyl-1-
Octynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoic acid, 5-[(1S, 5R, 6R, 7
R) -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-[(1
S, 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, 7
R) -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, 7
R) -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, 6
R, 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, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-Hydroxy-6-{(3S) -3-hydroxy-E
-1-octenyl} bicyclo [3.3.0] octane-
Sodium 3-ylidene] 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-
Sodium 3-ylidene] 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-
Sodium nonene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate,

5-[(1S, 5R, 6R, 7R) -2-
Oxa-4,4-difluoro-7-hydroxy-6-
(3-Hydroxy-4-methyl-E-1-octene-6
-Inyl) bicyclo [3.3.0] octane-3-ylidene] sodium pentanoate, 5-[(1S, 5R, 6
R, 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.

The compound represented by the general formula (1) of the present invention is not limited to the dihalogenated prostacyclin represented by the above general formula (3), but is an important compound capable of being induced into various dihalogenated prostacyclins. It is an intermediate.
For example, Takero Terashima and others "Prostaglandins and related physiologically active substances" (Kodansha Scientific) and SMRobe
rts et al., `` New Synthetic Routes to Prostaglandins and
Tromboxanes "(Academic Press) and the like can be converted into dihalogenated prostacyclins into which various α-chain moieties have been introduced by a method described in a textbook.

The dihalogenated lactone 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 production method of this dihalogenated lactone which is more advantageous than this method. The method does not have a ω chain moiety ^{(-A-CH (OR 2)} -R 1) 7
-Starting from a monohalogenated lactone, (a) a method of fluorinating 7,7-dihalogenated lactone and then introducing an ω chain portion, (b) introducing an ω chain portion and having an ω chain 7 -A method in which a monohalogenated lactone is formed and then the 7-position is fluorinated to form a dihalide. The 7-monohalogenated lactones which do not have the ω chain portion as the starting compound are basically known compounds.

The process of fluorinating 7,7-dihalogenated lactones in the above method (a) and its products are novel. These are described in the prior patent application relating to the present invention. The present invention relating to the method (a) relates to a method for producing a dihalogenated lactone represented by the general formula (1a) by introducing an ω chain portion into the 7,7-dihalogenated lactone.
It is the above-mentioned invention. That is, “a compound represented by the general formula (4) is converted into a compound represented by the general formula (5),
It is a process for producing a dihalogenated lactone represented by the general formula (1a) by reacting with a compound represented by the general formula (6) and then reducing the compound.

The present invention relating to the above method (b) includes 7
A method for producing a 7-monohalogenated lactone having an ω chain by introducing an ω chain portion into the monohalogenated lactone, and fluorinating the obtained 7-monohalogenated lactone having an ω chain. And a method for producing a dihalogenated lactone represented by the formula (1a). That is, in the former, "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. A method for producing a monohalogenated lactone represented by the general formula (7), the latter being a general formula (1a) obtained by subjecting a monohalogenated lactone represented by the general formula (7) to a halogenation reaction. Is a method for producing a dihalogenated lactone ".

In the above two methods (a) and (b), ω
The reaction of introducing the chain portion is basically the same reaction, although there is a difference between the starting material and the product, if the reaction itself is seen. Hereinafter, this reaction is referred to as an ω chain introduction reaction. Similarly, the above fluorination reaction is basically the same reaction if the reaction itself is seen. Hereinafter, this reaction is referred to as a fluorination reaction. Below these 2
Two reactions will be explained, but they will be explained at once as being common to the two methods (a) and (b). In addition,
The fluorination reaction in the above method (a) is an invention relating to the patent application of the earlier application and will not be particularly described, but the starting compound is the compound represented by the above general formula (8),
Since the product is a compound represented by the above general formula (4), its production method by the fluorination reaction is substantially explained below.

The ω chain introduction reaction is carried out in the compound represented by the general formula (4) or the compound represented by the general formula (8).
It is a reaction for converting CH ₂ OR ⁵ to —A—CH (OR ² ) —R ¹ . This reaction is a -CH ₂ OR ⁵ -CH (=
O), a reaction with the compound represented by the general formula (6), and a reduction reaction.

The ω chain introduction reaction is a known reaction, Wit
It can be carried out according to the tig-Horner-Emmons reaction. That is, when R ⁵ is a hydrogen atom, the compound represented by the general formula (5/9) [the compound represented by the general formula (5) or the general formula (9) is oxidized by being oxidized as it is. A compound represented by the general formula (1a / 7) by reacting with a compound represented by the general formula (6) to introduce an ω chain, and reducing the resulting unsaturated ketone. A compound of the formula [meaning a compound represented by the general formula (1a) or a compound represented by the general formula (7)] in which A is a vinylene group can be synthesized.
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 into a hydrogen atom.

[0114] 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, by using tetrabutylammonium fluoride, HF-pyridine or the like, only R ⁵ is selectively selected. The deprotection method can be applied.

Further, R ⁵ is oxidized to give a compound of the general formula (5/9)
The reaction for synthesizing the compound represented by is usually -50 in the presence of dimethyl sulfoxide, trifluoroacetic acid, pyridine, dicyclohexylcarbodiimide and the like.
It is good to stir at ˜ + 50 ° C., preferably 0˜ + 25 ° C. The reaction between the compound represented by the general formula (5/9) and the compound represented by the general formula (6) is usually 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 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) is reduced to be represented by the general formula (1a / 7). The reaction for synthesizing the compound described is usually and preferably carried out in methanol in the presence of sodium borohydride and cerium trichloride. Reaction temperature is -100 to +50
C., preferably -80 to + 10.degree.

Further, when A of the compound represented by the general formula (1a / 7) is an ethylene group, the compound represented by the general formula (5
/ 9) and an unsaturated ketone formed by the reaction of the compound represented by the general formula (6) with a metal hydride such as lithium aluminum hydride, a method of hydrogenating Or a copper hydride reactant such as lithium copper (tributyltin) hydride, or a method of conducting a 1,4-reduction reaction with a copper triphenylphosphine hydride complex to give a saturated ketone, followed by reduction. , Can be synthesized.

Further, 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 general formula (6) are shown. In the reaction of a compound of N-bromosuccinimide, N
-In the presence of a halogenating agent such as chlorosuccinimide,
Moreover, it can be synthesized by further treating with a strong base such as potassium-t-butoxide.

The fluorination reaction can be produced by subjecting the monohalogenated lactone represented by the general formula (7) to a halogenation reaction. The compound represented by the general formula (7) is a monohalogenated product of the corresponding dihalogenated lactone represented by the general formula (1a). The method for producing the dihalogenated lactone represented by the general formula (1a) by halogenating the compound represented by the general formula (7) is not particularly limited, but in the present invention, in the presence of a metal catalyst. Particularly preferred is a method of reacting with an electrophilic halogenating agent.

Examples of the metal catalyst include organic metal catalysts and salts of halogen and metal. 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 a specific metal catalyst, 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 0.01 to 10 parts by weight, preferably 0.1 to 3 parts by weight, relative 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 fluorooxytrifluoromethane, perchloryl fluoride, acetylhypofluorite, N-fluorosulfonamides, N-fluorosulfonimides, xenon fluoride, and fluorine gas. As an electrophilic chlorinating agent, carbon tetrachloride,
N-chlorosuccinimide, chlorine, etc., as the electrophilic brominating agent, carbon tetrabromide, N-bromosuccinimide,
Examples of the electrophilic iodinating agent such as bromine 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 0.5 to 1 with respect to 1 part by weight of the compound represented by the general formula (4).
The amount is about 0 parts by weight, preferably about 1 to 5 parts by weight.

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

The inert solvent is preferably an ether solvent, a hydrocarbon solvent, a polar solvent, or a mixed solvent thereof. Specific examples of these solvents include the ether solvents, hydrocarbon solvents and polar solvents described above. The amount of the inert solvent is usually about 5 to 1000 parts by weight, preferably 10 to 100 parts by weight, relative to 1 part by weight of the compound represented by the general formula (7). The reaction temperature of the above halogenation reaction is usually -150 to +5.
It is about 0 ° C., preferably −80 to + 30 ° C.

Specific examples of the compound represented by the general formula (4) include, but are not limited to, the following compounds. The following compounds include various stereoisomers, optical isomers, and mixtures thereof. Further, the compound represented by the general formula (8) is preferably a compound in which Y is a fluorine atom, and specific examples thereof include monofluoro compounds corresponding to the following compounds.

(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, 6
R, 7R) -2-oxa-4,4-diiodo-7-hydroxy-6-hydroxymethyl-bicyclo [3.3.
0] Octane-3-one.

As the above-mentioned derivative of the dihalogenated lactone in which the hydroxyl group is protected, for example, dihalogenated lactone is (1S, 5R, 6R, 7R) -2-oxa-
Taking the case of 4,4-difluoro-7-hydroxy-6-hydroxymethyl-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, 7
R) -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-on,
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy)-
6- (triethylsiloxy) methyl-bicyclo [3.
3.0] Octane-3-one, (1S, 5R, 6R, 7
R) -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-one, (1S, 5
R, 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] octan-3-one, (1
S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6-
Benzyloxymethyl-bicyclo [3.3.0] octane-3-one, (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6 -(Methoxybenzyloxy) methyl-bicyclo [3.3.0] octane-3-one, (1
S, 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-one,

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy) -6- (2-methoxyethoxymethoxy) methyl-bicyclo [3.3 .0] octan-3-one,
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-tetrahydropyranyloxy)-
6-acetoxymethyl-bicyclo [3.3.0] octane-3-one, (1S, 5R, 6R, 7R) -2-oxa-4,4-difluoro-7-hydroxy-6-t-butyldimethylsiloxy. Methyl-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] octan-3-one,

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (t-butyldiphenylsiloxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] Octane-3-one, (1S, 5
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7- (triethylsiloxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3
-On, (1S, 5R, 6R, 7R) -2-oxa-
4,4-difluoro-7- (triphenylsiloxy)-
6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one, (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-
(Triisopropylsiloxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-
3-one, (1S, 5R, 6R, 7R) -2-oxa-
4,4-Difluoro-7- (acetoxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0]
Octan-3-on,

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (benzoyloxy) -6
-T-butyldimethylsiloxymethyl-bicyclo [3.
3.0] Octane-3-one, (1S, 5R, 6R, 7
R) -2-Oxa-4,4-difluoro-7- (4-phenylbenzoyloxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-
ON, (1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (tetrahydrofuranyloxy)
-6-t-Butyldimethylsiloxymethyl-bicyclo [3.3.0] octan-3-one, (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-
(Benzyloxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one,

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (methoxybenzyloxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane- 3-on, (1S, 5R,
6R, 7R) -2-Oxa-4,4-difluoro-7-
(Trityloxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one,
(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (methoxymethoxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3-one, (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7- (2-methoxyethoxymethoxy) -6-t-butyldimethylsiloxymethyl-bicyclo [3.3.0] octane-3 -On, (1
S, 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-
ON, (1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7- (acetoxy) -6-triethylsiloxymethyl-bicyclo [3.3.0] octane-3
-On, (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, but are not limited to, the following compounds.

Dimethyl (4S) -4-methyl-2-oxooctanylphosphonate, (4S) -4-methyl-2-
Diethyl oxooctanylphosphonate, dimethyl 2-oxoheptanylphosphonate, diethyl 2-oxoheptanylphosphonate, dimethyl 2-oxo-2-cyclopentylethylphosphonate, diethyl 2-oxo-2-cyclopentylethylphosphonate, 3 -Methyl-2-oxo-5-octynylphosphonate dimethyl, 3-methyl-2
Diethyl oxo-5-octynylphosphonate,

(3S) -3-methyl-2-oxo-5-
Dimethyl octynylphosphonate, diethyl (3S) -3-methyl-2-oxo-5-octynylphosphonate, 3
-Dimethyl-2-methyl-2-oxo-5-heptynylphosphonate, diethyl 3-methyl-2-oxo-5-heptynylphosphonate, (3S) -3-methyl-2-oxo-5
-Dimethyl heptynylphosphonate, diethyl (3S) -3-methyl-2-oxo-5-heptynylphosphonate,
Dimethyl 3,3-dimethyl-2-oxo-5-octynylphosphonate, Diethyl 3,3-dimethyl-2-oxo-5-octynylphosphonate, Dimethyl 2-oxo-2-cyclohexylethylphosphonate, 2- Oxo-2-
Diethyl 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 the dihalogenated lactones represented by the general formula (1a). There are monohalogenates corresponding to the compounds given as examples.

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

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

[0140]

【Example】

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

EJCorey et al., Tetrahedron Letters, 24,5571 (1983), and the synthesis was carried out in the same manner as described below.

A solution of 4.21 g of 3-methyl-3-hydroxymethyloxetane in methylene chloride (20 ml) was added with 5 ml of pyridine and 12.2 of 5-iodopentanoic acid chloride.
g was added at 0 ° C. and the mixture was stirred for 2 hours. The mixture was poured into aqueous sodium hydrogen carbonate, extracted with dichloromethane, and then purified by silica gel column chromatography to obtain 13.0 g of the corresponding ester.
This ester 6.24 g of anhydrous dichloromethane (20 m
l) To the solution was added boron trifluoride etherate (0.62 ml) at -15 ° C, and the mixture was stirred at -15 ° C for 4 hours, 0 ° C for 2 hours, and room temperature for 1 hour. Triethylamine 2.79
After adding ml at 0 ° C., the reaction mixture was concentrated and purified by silica gel column chromatography to give the title compound (5.42).
g was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.80 (s, 3H), 1.5-
1.9 (m, 6H), 3.17 (t, J = 7.2Hz, 2H), 3.89 (s, 6H).

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

Hexamethyldisilazane (6.84 ml)
Tetrahydrofuran (hereinafter referred to as THF) (90 m
l) The solution was added with n-butyllithium (1.56
M, hexane solution) (19.1 ml) was added and stirred for 30 minutes to prepare a lithium hexamethyldisilazide solution. To this solution, (1S, 5R, 6R, 7R) -2-oxa-7- (2-tetrahydropyranyloxy) -6-
(T-Butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-one 10 g of THF (2
0 ml) solution was added dropwise at −78 ° C. and stirred for 60 minutes.
Next, 9.37 g of N-fluorobenzenesulfonimide
THF solution (40 ml) was added at -78 ° C. -78
After stirring at 60 ° C for 60 minutes, the temperature was raised, and after stirring at room temperature for 30 minutes, 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: 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 (1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] Octane-3
-On synthesis

Synthesized in Reference Example 2 (1S, 5R, 6R,
7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3
A solution of -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 added slowly, and the mixture was extracted with ethyl acetate. After drying and concentrating the extract,
Purify by silica gel column chromatography (dichloromethane: methanol = 10: 1) to give the title compound 4.
92 g were obtained.

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)-
Synthesis of 6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octane-3-one

136 mg (1 mmol) of anhydrous zinc chloride was synthesized in Reference Example 2 (1S, 5R, 6R, 7R) -2-
Oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6- (t-butyldimethylsiloxy) methyl-bicyclo [3.3.0] octan-3-one 194
After adding a solution of mg of THF (3 ml) at room temperature and cooling to −78 ° C., lithium diisopropylamide (1M, T
1 ml of HF solution) was added and stirred for 20 minutes. 236 mg of N-fluorobenzenesulfonamide was added to this solution.
(0.75 mmol) was added at -78 ° C, and the mixture was 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 obtain 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-
Synthesis of {(5S) -3-oxo-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one

Synthesized in Reference Example 3 (1S, 5R, 6R,
7R) -2-oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6-hydroxymethyl-bicyclo [3.3.0] octan-3-one 300 mg benzene (10 ml) solution in pyridine 89 μl , Dimethyl sulfoxide 930 μl, trifluoroacetic acid 12.6 μ
1, and 677 mg of dicyclohexylcarbodiimide were added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was filtered, and the filtrate was washed with water and concentrated to obtain the corresponding crude aldehyde product. (4
116 mg of sodium hydride was added to a solution of 735 mg of dimethyl S) -4-methyl-2-oxooctanylphosphonate in dimethoxyethane (30 ml), and the mixture was stirred for 10 minutes. To this solution was added a solution of the crude aldehyde above in dimethoxyethane (10 ml) at 0 ° C.
After stirring for 1 minute, the mixture was poured into brine and extracted with ethyl acetate.
After concentration by drying, the residue was purified by silica gel column chromatography to obtain 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} -bicyclo [3.3.0] octane-3
-On synthesis

Synthesized in Example 1 (1S, 5R, 6R,
7R) -2-oxa-4-fluoro-7- (2-tetrahydroplanyloxy) -6-{(5S) -3-oxo-5-methyl-E-1-nonenyl} -bicyclo [3.
3.0] Octane-3-one 61 mg of methanol (5
ml) solution, 52 mg of cerium chloride heptahydrate and 8 mg of sodium borohydride were added at -40 ° C, and -40 ° C.
After stirring for 10 minutes at 0 ° C. for 10 minutes, the mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After concentration, the residue was dissolved in methanol (3 ml), p-toluenesulfonic acid monohydrate (2 mg) was added, and the mixture was stirred at room temperature for 1 hr. After the methanol was distilled off, saturated aqueous sodium hydrogen carbonate and ethyl acetate were added for extraction. The extract was dried and concentrated, and dimethylformamide (3 m) was added to the residue.
1, imidazole 34 mg, and t-butyldimethylsilyl chloride 61 mg were added, and the mixture was stirred at room temperature for 2 hours. Pour into saturated aqueous sodium hydrogen carbonate, extract with ethyl acetate, dry and concentrate the extract,
Purification by silica gel column chromatography gave 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, 30.2,52.7Hz) .Mass spectrum: 542 (M ⁺ )

Example 3 (1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S)
Synthesis of -3-t-butyldimethylsiloxy-E-1-octenyl} bicyclo [3.3.0] octane-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,
Synthesis of 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one

(1S, 5R, 6R, 7R) -2-Oxa-7-t-butyldimethylsiloxy-6-{(3S, 5
S) -3-t-Butyldimethylsiloxy-5-methyl-
To a THF solution (2 ml) of E-1-nonenyl} -bicyclo [3.3.0] octane-3-one (524 mg), a solution of lithium diisopropylamide in THF (1M, 1.1
ml) was added at −78 ° C. and stirred for 30 minutes. After the solvent was distilled off under reduced pressure, THF (3 ml) was added to dissolve it, and-
Acetyl hypofluorite solution (2mmo at 78 ℃)
l). The mixture was poured into a 10% aqueous sodium thiosulfate solution and extracted with ethyl acetate. The extract was washed with saturated saline and then 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, 30.2,52.7Hz),-203 (d , 48.
8Hz). Mass spectrum: 542 (M ⁺ )

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

Hexamethyldisilazane (51 μl, 0.
242 mmol) in THF (1 ml) at -78 ° C.
N-butyllithium (1.56M, hexane solution)
After adding 0.14 ml, the mixture was stirred for 30 minutes to prepare a lithium hexamethyldisilazide solution. In this solution,
(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 1
A 05 mg THF solution (2 ml) was added dropwise at -78 ° C, and the mixture was stirred for 30 minutes. Next, 76.2 mg of N-fluorobenzenesulfonimide was added at -78 ° C. -78
After stirring at 15 ° C. for 15 minutes, 0 ° C. for 30 minutes and room temperature for 30 minutes, the mixture was 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, 30.2,52.7Hz),-203 (d , 48.
8Hz) .Mass spectrum: 542 (M ⁺ )

Example 6 (1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7- (2-tetrahydropyranyloxy) -6-
{(3S) -3-t-Butyldimethylsiloxy-4-methyl-1-octen-6-ynyl} -bicyclo [3.
3.0] Synthesis of octan-3-one

(1S, 5R, 6R, 7R) -2-Oxa-7- (2-tetrahydropyranyloxy) -6-
{(3S) -3-t-Butyldimethylsiloxy-4-methyl-1-octen-6-ynyl} -bicyclo [3.
3.0] Octane-3-one (210 mg) was used in the same manner as in Example 5 to obtain the title compound (127 mg).

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, 30.1,52.8Hz),-178 (dd , 3
0.2,52.7Hz), -203 (m). Mass spectrum: 494 (M ⁺ )

Example 7 (1S, 5R, 6R, 7R) -2-Oxa-4-bromo-7- (2-tetrahydropyranyl) -6-{(3S)
-3-t-butyldimethylsiloxy-5-methyl-1-
Synthesis of nonenyl} -bicyclo [3.3.0] octane-3-one

Hexamethyldisilazane (146 μl,
0.694 mmol) in THF (1 ml), -7
0.41 ml of n-butyllithium (1.56M, hexane solution) was added at 8 ° C., and then stirred for 30 minutes to prepare a lithium hexamethyldisilazide solution. In this solution, (1S, 5R, 6R, 7R) -2-oxa-7-
(2-Tetrahydropyranyl) -6-{(3S) -3-
t-Butyldimethylsiloxy-5-methyl-1-nonenyl} -bicyclo [3.3.0] octane-3-one 28
5 mg of THF solution (1 ml) was added dropwise at -78 ° C, and 3
Stir for 0 minutes. Next, 230 mg of carbon tetrabromide in THF
(1 ml) solution 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 to 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-t-Butyldimethylsiloxy-4-methyl-1-octen-6-ynyl} -bicyclo [3.
3.0] Synthesis of octan-3-one

(1S, 5R, 6R, 7R) -2-Oxa-7- (2-tetrahydropyranyloxy) -6-
{(3S) -3-t-Butyldimethylsiloxy-4-methyl-1-octen-6-ynyl} -bicyclo [3.
3.0] Octane-3-one (277 mg) was used in the same manner as in Example 7 to obtain the title compound (284 mg).

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-t-butyldimethylsiloxy-6-
{(3S, 5S) -3-t-butyldimethylsiloxy-
5-Methyl-E-1-nonenyl} -bicyclo [3.3.
[0] Synthesis of octan-3-one

Synthesized in Example 4 (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 524m
g THF solution (2 ml), anhydrous zinc chloride 0.22 g
(1.6 mmol) was added at room temperature, then a THF solution of lithium diisopropylamide (1M, 1.1 ml) was added at -78 ° C, and the mixture was stirred for 20 minutes. After evaporating the solvent under reduced pressure, THF (3 ml) was added and dissolved, 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 saline and then 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 = 7.7,15.3
Hz, 1H), 5.54 (dd, J = 6.3,15.3Hz, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm):-92 (dd, J = 26, 282Hz),-114 (d, J = 28
2Hz). Mass spectrum: 560 (M ⁺ )

Example 10 (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-
{(3S, 5S) -3-t-butyldimethylsiloxy-
5-Methyl-E-1-nonenyl} -bicyclo [3.3.
[0] Synthesis of octan-3-one

Diisopropylamine (1.23 ml,
8.9 mmol) in THF (14 ml), -78
N-Butyllithium (1.66M, hexane solution) at ℃
After adding 4.88 ml, the mixture was stirred for 30 minutes to prepare a lithium diisopropylamide solution. Weigh 1.47 g (10.8 mmol) of anhydrous zinc chloride into another container,
Synthesized in Example 2 (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] 3.57 g of octan-3-one (6.
A solution of 76 mmol) in THF (20 ml) was added. This solution was cooled to −78 ° C., the above lithium diisopropylamide solution was added dropwise at −78 ° C., and the mixture was stirred for 20 minutes. Next, N-fluorobenzenesulfonimide 2.5
6 g (8.1 mmol) was added at -78 ° C. -78 ° C
After stirring for 60 minutes at room temperature for 30 minutes at room temperature, the mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. Silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1: 1)
Purification in (0) 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 = 7.7,15.3
Hz, 1H), 5.54 (dd, J = 6.3,15.3Hz, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm):-92 (dd, J = 26,282Hz),-114 (d, J = 282
Hz). Mass spectrum: 560 (M ⁺ )

Example 11 (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-
Synthesis of {(3S) -3-t-butyldimethylsiloxy-4-methyl-E-1-octen-6-ynyl} -bicyclo [3.3.0] octane-3-one

(1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7-t-butyldimethylsiloxy-6
-{(3S) -3-t-butyldimethylsiloxy-4-
Using 215 mg of methyl-E-1-octen-6-ynyl} -bicyclo [3.3.0] octane-3-one,
In the same manner as in Example 10, 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-nonene-6-ynyl} -bicyclo [3.
3.0] Synthesis of octan-3-one

(1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7-t-butyldimethylsiloxy-6
-{(3S) -3-t-butyldimethylsiloxy-4-
Using 226 mg of methyl-E-1-nonen-6-ynyl} -bicyclo [3.3.0] octane-3-one,
152 mg of the title compound was obtained in the same manner as in Example 10.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.03-0.06 (m, 12
H), 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-t-butyldimethylsiloxy-6-
Synthesis of {(3S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} -bicyclo [3.3.0] octane-3-one

Synthesized in Reference Example 4 (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 is used in Reference Example 3
Deprotected in the same manner as in (1S, 5R, 6R, 7
R) -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 2-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-7-t-butyldimethylsiloxy-6-{(3S,
Synthesis of 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane

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

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

[Example 15] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-t-butyldimethylsiloxy-6
-{(3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-E-1-nonenyl} bicyclo [3.3.
Synthesis of 0] octane-3-ylidene] methyl pentanoate

Synthesized in Example 14 (1S, 5R, 6
R, 7R) -2-oxa-3- {4- (4-methyl-
2,6,7-Trioxabicyclo [2.2.2] octanyl) butylidene} -4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S, 5S) -3-t
To a solution of 1.83 g of -butyldimethylsiloxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane in dimethoxyethane (25 ml) was added 2.5 ml of 10% sodium hydrogensulfate aqueous solution at 0 ° C. , Stirred for 30 minutes. The mixture was poured into aqueous sodium hydrogen carbonate, extracted with ethyl acetate, the extract was concentrated under reduced pressure, 25 ml of methanol and 680 mg of potassium carbonate were added to the residue, and the mixture was stirred at room temperature for 2 hours. Poured into aqueous sodium hydrogen carbonate, extracted with ethyl acetate-hexane (1: 1), concentrated the extract under reduced pressure, and subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 30 to 1: 1).
Purification in 10) gave 981 mg of the title compound.

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

[Example 16] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 5
S) -3-Hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of methyl pentanoate

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

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

[Example 17] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S, 5
S) -3-Hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of sodium pentanoate

5-[(1S, 5 synthesized in Example 16
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-Hydroxy-6-{(3S, 5S) -3-hydroxy-5-methyl-E-1-nonenyl} bicyclo [3.
3.0] Octane-3-ylidene] methyl pentanoate 1
To 39 mg of ethanol (8 ml) solution was added 3.39 ml of 0.1N sodium hydroxide, and the mixture was stirred at room temperature for 14 hours. Concentration under reduced pressure gave 125 mg of the title compound.

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

Example 18 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-E-1-octenyl} bicyclo [3.
3.0] Synthesis of Methyl [octane-3-ylidene] pentanoate

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-E-1- Example using octenyl} bicyclo [3.3.0] octane-3-one and 1- (4-iodobutyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane The title compound was synthesized by the same method as in 14 to 16.

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, 2
H). ¹⁹ F-NMR (CDCl ₃ , ppm): -84 (dd, J = 16,249Hz),-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.
3.0] Synthesis of sodium octane-3-ylidene] pentanoate

5-[(1S, 5 synthesized in Example 18
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-Hydroxy-6-{(3S) -3-hydroxy-E
-1-octenyl} bicyclo [3.3.0] octane-
The title compound was synthesized in the same manner as in Example 17 using methyl 3-ylidene] pentanoate.

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 = 17,250Hz),- 117 (d, J = 250H
z).

[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] octane-3-ylidene]
Synthesis of methyl pentanoate

(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 and 1- (4-iodobutyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane The title compound was synthesized in the same manner as in Examples 14 to 16.

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, 2
H). ¹⁹ F-NMR (CDCl ₃ ,, ppm): -84 (dd, J = 17,250Hz),-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] octane-3-ylidene]
Synthesis of sodium pentanoate

5-[(1S, 5 synthesized in Example 20
R, 6R, 7R) -2-Oxa-4,4-difluoro-
Same as Example 17 with methyl 7-hydroxy-6-{(3S) -3-cyclopentyl-3-hydroxy-E-1-propenyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate. The title compound was synthesized by the method described in 1.

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 = 17,250Hz),- 117 (d, J = 250H
z).

[Example 22] 5-[(1S, 5R, 6R, 7R) -2-oxa-4,
4-difluoro-7-hydroxy-6-{(3S) -3
-Hydroxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of methyl pentanoate

Obtained in Example 12 (1S, 5R, 6
R, 7R) -2-Oxa-4,4-difluoro-7-t
-Butyldimethylsiloxy-6-{(3S) -3-t-
Butyldimethylsiloxy-4-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-3-
On and 1- (4-iodobutyl) -4-methyl-2,
The title compound was synthesized in the same manner as in Examples 14 to 16 using 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, 2
H). 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-ynyl} bicyclo [3.3.0] octane-3-ylidene]
Synthesis of sodium pentanoate

5-[(1S, 5 synthesized in Example 22
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-hydroxy-6-{(3S) -3-hydroxy-4
The title compound was synthesized in the same manner as in Example 17 by using methyl-methyl-E-1-nonene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

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
Synthesis of methyl 4-hydroxy-4-methyl-E-1-octene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -3-t-butyldimethylsiloxy-4-methyl- The title compound was synthesized in the same manner as in Examples 14 to 16 using E-1-octen-6-ynyl} -bicyclo [3.3.0] octane-3-one.

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, 2
H). 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
Synthesis of sodium 4-hydroxy-4-methyl-E-1-octene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate

5-[(1S, 5 synthesized in Example 24
R, 6R, 7R) -2-Oxa-4,4-difluoro-
7-hydroxy-6-{(3S) -3-hydroxy-4
The title compound was synthesized in the same manner as in Example 17 by using methyl-methyl-E-1-octene-6-ynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate.

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,
Synthesis of methyl 4-difluoro-7-hydroxy-6-{(3S) -hydroxy-4-methyl-1,6-nonadiynyl} bicyclo [3.3.0] octane-3-ylidene] pentanoate

(1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-{(3S) -t-butyldimethylsiloxy-4
-Methyl-1,6-1-nonadiynyl} bicyclo [3.
3.0] Octane-3-one and 1- (4-iodobutyl) -4-methyl-2,6,7-trioxabicyclo [2.2.2] octane were used, similar to Examples 14-16. The title compound was synthesized by the method.

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)
Synthesis of -3-t-butyldimethylsiloxy-E-1-octenyl} -bicyclo [3.3.0] octane-3-one

(1S, 5R, 6R, 7R) -2-Oxa-7-t-butyldimethylsiloxy-6-{(3S)-
The title compound was synthesized in the same manner as in Example 5 by using 3-t-butyldimethylsiloxy-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 (d
d, 30.1, 52.9 Hz).

Example 28 (1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S)
Synthesis of 3--3-cyclopentyl-3-t-butyldimethylsiloxy-E-1-propenyl} -bicyclo [3.3.0] octane-3-one

(1S, 5R, 6R, 7R) -2-Oxa-7-t-butyldimethylsiloxy-6-{(3S)-
By using 3-cyclopentyl-3-t-butyldimethylsiloxy-E-1-propenyl} -bicyclo [3.3.0] octane-3-one in the same manner as in Example 5,
The title compound was synthesized.

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, 4
H). ¹⁹ F-NMR (CDCl ₃ , ppm): -178 (dd, 31.8,52.3Hz).

Example 29 (1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7-t-butyldimethylsiloxy-6-{(3S)
-3-t-butyldimethylsiloxy-4-methyl-E-
Synthesis of 1-Nonene-6-ynyl} -bicyclo [3.3.0] octane-3-one

(1S, 5R, 6R, 7R) -2-Oxa-7-t-butyldimethylsiloxy-6-{(3S)-
3-t-butyldimethylsiloxy-4-methyl-E-1
-Nonene-6-ynyl} -bicyclo [3.3.0] octane-3-one was prepared in the same manner as in Example 5.
The title compound was synthesized.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.03-0.06 (m, 12
H), 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-6-ynyl} -bicyclo [3.3.0]
Synthesis of octan-3-one

(1S, 5R, 6R, 7R) -2-Oxa-7-t-butyldimethylsiloxy-6-{(3S)-
3-t-butyldimethylsiloxy-4-methyl-E-1
The title compound was synthesized in the same manner as in Example 5 by using -octen-6-ynyl} -bicyclo [3.3.0] octane-3-one.

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,
Synthesis of 6-nonadiynyl} -bicyclo [3.3.0] octane-3-one

(1S, 5R, 6R, 7R) -2-Oxa-7-t-butyldimethylsiloxy-6-{(3S)-
3-t-butyldimethylsiloxy-4-methyl-1,6
-Nonadiynyl} -bicyclo [3.3.0] octane-
The title compound was synthesized in the same manner as in Example 5 using 3-one.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04-0.06 (m, 12
H), 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} -bicyclo [3.3.0] octane-3
-On synthesis

(1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7-t-butyldimethylsiloxy-6
-{(3S) -3-t-butyldimethylsiloxy-1-
Octenyl} -bicyclo [3.3.0] octane-3-
The title compound was synthesized in the same manner as in Example 10 using ON.

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, 27,280Hz),-114 (d, 280Hz ).

Example 33 (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] Synthesis of octan-3-one

(1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7-t-butyldimethylsiloxy-6
Example 10 using-{(3S) -3-cyclopentyl-3-t-butyldimethylsiloxy-E-1-propenyl} -bicyclo [3.3.0] octane-3-one.
The title compound was synthesized by a method similar to.

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, 26,282Hz),-115 (d, 282Hz ).

Example 34 (1S, 5R, 6R, 7R) -2-Oxa-4,4-difluoro-7-t-butyldimethylsiloxy-6-
{(3S) -3-t-Butyldimethylsiloxy-4-methyl-1,6-nonadiynyl} -bicyclo [3.3.
[0] Synthesis of octan-3-one

(1S, 5R, 6R, 7R) -2-Oxa-4-fluoro-7-t-butyldimethylsiloxy-6
-{(3S) -3-t-butyldimethylsiloxy-4-
Methyl-1,6-nonadiynyl} -bicyclo [3.3.
The title compound was synthesized in the same manner as in Example 10 using [0] octane-3-one.

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.04-0.06 (m, 12
H), 0.85-0.89 (m, 18H), 1.1-5.1 (m, 19H). ¹⁹ F-NMR (CDCl ₃ , ppm):-92 (m),-114 (m).

[0254]

According to the production method of the present invention, dihalogenated prostacyclins, which are useful physiologically active substances, are
All of them can be efficiently synthesized in a shorter step than known compounds. All of the synthetic methods are excellent methods that do not require severe reaction conditions or long-term reactions, and do not require special reaction reagents or reaction equipment. Moreover, the raw material and the reaction intermediate are both chemically more stable compounds than known ones and are easy to handle. In addition, the raw material compounds are also easily available compounds. Furthermore, the production method of the present invention is versatile and can be applied to the synthesis of many derivatives.

Claims (15)

[Claims] 1. A dihalogenated lactone represented by the general formula (1b) is subjected to an addition reaction with an organometallic compound represented by the general formula (2) for dehydration, followed by optional deprotection. A method for producing a dihalogenated prostacyclin represented by the general formula (3). [Chemical 1] [Chemical 2] [Chemical 3] (However, in the general formulas (1b), (2), and (3), A: ethylene group, vinylene group, or ethynylene group, Q: substituted or unsubstituted alkyl group having 1 to 10 carbon atoms,
A substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group Or a substituted or unsubstituted aryl group, R ¹ : a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, a substituted or unsubstituted 1 carbon atom 10 alkynyl group, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryloxy group, R ^2, R ^4: independently a hydrogen atom or a protecting group, R ^12, R ^14: each independently a protecting group, X ^1, X ^2: each independently, a halogen atom, M: metal atom, L: a ligand, m: 1 to 8 of Number, n: an integer, of 0. ) 2. The production method according to claim 1, wherein Q is a group represented by -BZ. (However, B: C1-C6 alkylene group, C3-C6 cycloalkylene group, C3-C6 cycloalkylene group-containing alkylene group, ether bond or thioether bond-containing C2-6. Represents an alkylene group or a phenylene group, Z: a carboxyl group, a carboxyl group, a formyl group, a protected formyl group, a hydroxyl group, or a protected hydroxyl group.) 3. The 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. 4. X ¹ and X ² are both fluorine atoms,
The manufacturing method according to claim 1, 2 or 3. 5. A is a vinylene group, and R ¹ is a linear or branched C 4-8 alkyl group, a linear or branched C 4-8 alkenyl group, or a linear chain. Linear or branched alkynyl group having 4 to 8 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms which may be substituted with halogen atom or lower alkyl group, or substituted with halogen atom or lower alkyl group An aralkyl group which is an alkyl group having 1 to 4 carbon atoms to which a cycloalkyl group having 3 to 8 carbon atoms is bonded, or a phenoxy group which may be substituted with a halogen atom or a lower alkyl group. Manufacturing method. 6. 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 at least one kind of ligand selected from organic ligands consisting of an alkyl group or an aryl group, m is an integer of 1 to 4, and n is an integer of 0 to 4. Production method. 7. A dihalogenated prostacyclin represented by the general formula (3), wherein R ² and R ⁴ are both protecting groups, is produced by the method according to any one of claims 1 to 6, and thereafter A method for producing a dihalogenated prostacyclin by deprotecting to produce a dihalogenated prostacyclin represented by the general formula (3), wherein both R ² and R ⁴ are hydrogen atoms. 8. R ² and R ⁴ are both protecting groups and Q
Is a group represented by -B-Z ', and a dihalogenated prostacyclin represented by the general formula (3) is produced, and thereafter Z'is a carboxyl group at the same time as deprotection of R ² and R ^4. A general formula (3) in which R ² and R ⁴ are both hydrogen atoms and Q is —B—COOH.
The production method according to claim 7, wherein the dihalogenated prostacyclin represented by (However, B: C1-C6 alkylene group, C3-C6 cycloalkylene group, C3-C6 cycloalkylene group-containing alkylene group, ether bond or thioether bond-containing C2-6. Represents an alkylene group or a phenylene group, and Z ′: an esterified or orthoesterified carboxyl group. 9. A compound represented by the general formula (4) is converted to a compound represented by the general formula (5), reacted with the compound represented by the general formula (6), and then reduced. A method for producing a dihalogenated lactone represented by the general formula (1a). [Chemical 4] [Chemical 5] [Chemical 6] [Chemical 7] (However, in the general formulas (1a), (4), (5), and (6), A is an ethylene group, a vinylene group, or an ethynylene group, and R ^{1 is a} substituted or unsubstituted alkyl group having 1 to 10 carbon atoms. , A substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted alkyl group Alkyl group, or substituted or unsubstituted aryloxy group, R ² , R ⁴ , and R ⁵ are each independently a hydrogen atom or a protecting group, R ^{6 is a} lower alkyl group, X ¹ and X ² are each independently, Represents a halogen atom.) 10. The production method according to claim 9, wherein both X ¹ and X ² are fluorine atoms. 11. A method 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. [Chemical 8] [Chemical 9] (However, in the general formulas (1a) and (7), A: ethylene group, vinylene group, or ethynylene group, R ¹ : a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, a substituted or unsubstituted carbon number 1 to 10 alkenyl group, substituted or unsubstituted C 1 to C 10 alkynyl group, substituted or unsubstituted C 3 to C 8 cycloalkyl group, substituted or unsubstituted aralkyl group, or substituted or non-substituted Substituted aryloxy groups, R ² and R ⁴ each independently represent a hydrogen atom or a protective group, X ¹ and X ² : each independently a halogen atom, and Y: a halogen atom which is X ¹ or X ² . ) 12. The method according to claim 11, wherein X ¹ , X ² and Y are all fluorine atoms. 13. A compound represented by the general formula (8) is converted into a compound represented by the general formula (9), reacted with the compound represented by the general formula (6), and then reduced. A method for producing a monohalogenated lactone represented by the general formula (7). [Chemical 10] [Chemical 11] [Chemical 12] [Chemical 13] (However, in the general formulas (6), (7), (8), and (9), A: ethylene group, vinylene group, or ethynylene group, R ¹ : a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms , A substituted or unsubstituted alkenyl group having 1 to 10 carbon atoms, a substituted or unsubstituted alkynyl group having 1 to 10 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted or unsubstituted alkyl group (Alkyl group, or substituted or unsubstituted aryloxy group, R ² , R ⁴ , and R ⁵ each independently represent a hydrogen atom or a protecting group, R ⁶ : a lower alkyl group, and Y: a halogen atom.) 14. The method according to claim 13, wherein Y is a fluorine atom. 15. A dihalogenated lactone represented by the general formula (1b). [Chemical 14] (However, in the general formula (1b), A: ethylene group, vinylene group, or ethynylene group, R ¹ : a substituted or unsubstituted C 1-10 alkyl group, a substituted or unsubstituted C 1-10 group Alkenyl group, substituted or unsubstituted C1-10 alkynyl group, substituted or unsubstituted C3-8 cycloalkyl group, substituted or unsubstituted aralkyl group, or substituted or unsubstituted aryloxy Group, R ¹² and R ¹⁴ are each independently a protective group.)