JP2005330191A - Method for producing prostaglandin derivative, prostaglandin derivative, intermediate compound therefor and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a prostaglandin derivative, the prostaglandin derivative and an intermediate compound therefor, especially a method for producing a δ-12-prostaglandin J<SB>2</SB>derivative using a new method for chemical synthesis through the intermediate compound. <P>SOLUTION: The method for production is a method for producing the prostaglandin derivative using (1R,3R)-4-cyclopentene-1,3-diol 3-acetate (carboxylate) as a starting material. The method is composed of (A) an α-side chain introduction step of providing a malonic acid ester addition compound at the 3-position of the (1R,3R)-4-cyclopentene-1,3-diol, (B) an α-side chain extension step of affording a (1R,3R)-4-cyclopenten-1-one compound having the α-side chain of the prostaglandin derivative at the 3-position and (C) a prostaglandin derivative synthesizing step of conversion into the prostaglandin derivative. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a method for producing a prostaglandin derivative, a prostaglandin derivative, an intermediate compound thereof, and a method for producing the same. _{The present} invention relates to a method for producing ₂ derivatives.

  Prostaglandins (hereinafter also referred to as “PG”) are a group of physiologically active substances synthesized by an arachidonic acid cascade in animal tissues starting from eicosapolyenoic acid and having a local hormone action, Ten types of prostaglandins A to J are known. Since these PGs have various physiological functions such as blood pressure lowering / rising, platelet aggregation inhibition / induction, and uterine contraction, various PGs and their derivatives have been developed as drugs having various effects.

Recently, among these PG, prostaglandin J delta-12-prostaglandin is a _second derivative Grandin J ₂ (hereinafter, also referred to as "Δ ¹² -PGJ _2".) Is noted as a compound for controlling the nuclear receptor Has been. Δ ¹² -PGJ ₂ and its derivative 5-deoxydelta-12,14-prostaglandin J ₂ (hereinafter also referred to as “5-d-Δ ¹² -PGJ ₂ ”) have antiviral activity, PPAR. It is known to have various effects such as -γ receptor agonistic action, anti-inflammatory action, and cytoprotective action.

Conventionally, Δ ¹² -PGJ ₂ has been produced by treating prostaglandin D ₂ (hereinafter referred to as “PGD ₂ ”) with albumin or plasma. In this production method, Δ ¹² -PGJ ₂ is produced by a dehydration reaction of a 5-membered ring of PGD ₂ and a rearrangement reaction of a double bond (see Non-Patent Document 1 below). Attempts to produce Δ ¹² -PGJ ₂ by chemical synthesis have also been reported (see Non-Patent Documents 2 to 6 below).

F. A. Fitzpatrick et al. , J .; Biol. Chem. 1983, 258, 11713-11718. M.M. Suzuki et al. , Tetrahedron Letters, 1982, 23, 4057-4060. S. Sugiura et al. , Chem. Pharm. Bull. 1984, 32, 11, 4658-4661. K. M.M. Maxey et al. , Prostaglandins & other Lipid Mediators, 2000, 62, 15-21 J. et al. F. Brickley et al. Synlett, 2003, 1170-1174. K. M.M. Brummond et al. , Organic Letters, 2004, Vol. 6, No. 2, pages 149-152.

However, since the production method of Non-Patent Document 1 is accompanied by undesirable double bond isomerization and dehydration reactions, pure Δ ¹² -PGJ ₂ could not be obtained. In addition, in the production methods of Non-Patent Documents 2 and 3, pure Δ ¹² -PGJ ₂ cannot be obtained by a side reaction. In the production methods of Non-Patent Documents 4 and 5, the synthesis efficiency is extremely low and practical use is not possible. There was almost no sex. In the manufacturing method of the above Non-Patent Document 6, there is no versatility as a production method of the Δ ¹² -PGJ ₂ derivatives. Thus, there has been no practical method for producing a Δ ¹² -PGJ ₂ derivative.

The present invention has been made in view of the above, and includes a method for producing a prostaglandin derivative, a prostaglandin derivative, an intermediate compound thereof, and a method for producing the same, and in particular, a novel chemical synthesis method via the intermediate compound. It is an object of the present invention to provide a method for producing the delta-12-prostaglandin J ₂ derivative used.

In order to solve the above-mentioned problems, the inventors of the present invention are concerned with a chemical production method of delta-12-prostaglandin J ₂ (hereinafter also referred to as “Δ ¹² -PGJ ₂ ”), in particular, α in a 5-membered ring. As a result of diligent research on the reaction for introducing a side chain, the inventors succeeded in synthesizing an intermediate compound in which an α side chain is introduced into a 5-membered ring, which is a key for the production of Δ ¹² -PGJ _2. A method for producing a prostaglandin derivative using a novel chemical synthesis method has been found, and the present invention has been completed based on this finding.

The method for producing a prostaglandin derivative of the present invention uses a (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound as a starting material, and an α side chain at the 1-position of the 2-cyclopenten-4-one compound. A prostaglandin derivative having a ω side chain at the 5-position,
(A) In the presence of a palladium catalyst and a base, a substitution reaction between the acyloxy group at position 1 of the (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound and a malonic acid diester is performed, A partial introduction step of the α side chain to obtain a compound in which malonic acid diester is added to the 1-position of (1R, 4S) -2-cyclopenten-4-ol;
(B) The carbon chain of the compound in which malonic acid diester is added to the 1-position of the (1R, 4S) -2-cyclopenten-4-ol is extended, and the α side chain is in the 1-position (1R, 4S)- An α side chain extension step to obtain a 2-cyclopenten-4-one compound;
(C) The ω side chain is introduced at the 5-position of the (1R, 4S) -2-cyclopenten-4-one compound to construct the core structure of the prostaglandin derivative, and then converted to the prostaglandin derivative. A prostaglandin derivative synthesizing step.
In the method for producing a prostaglandin derivative of the present invention, the prostaglandin derivative is preferably a delta-12-prostaglandin J ₂ derivative.
Further, the base in the α side chain introduction step (A) of this production method is preferably any one selected from metal tert-butoxide and organolithium.

In the method for producing a prostaglandin derivative, the α side chain extending step (B) is at least:
(B1) By decarboxylation of a compound in which malonic acid diester is added to the 1-position of the (1R, 4S) -2-cyclopenten-4-ol, (1R, 4S) -2-cyclopenten-4-ol-1- A decarboxylation reaction step to obtain an acetic acid compound;
(B2) a reduction reaction step of reducing the (1R, 4S) -2-cyclopenten-4-ol-1-acetic acid compound to convert it into an aldehyde compound.

In the step (B),
(B3) (1R, 4S) -2-cyclopenten-4-ol having the α-side chain introduced with a carbon-carbon double bond at the 1-position by reacting the aldehyde compound in the step (b2) with a Wittig reagent. An introduction reaction step of a carbon-carbon double bond to obtain a compound;
(B4) A (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position is obtained by oxidizing the hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound. An oxidation reaction step.

The step (B) further includes:
(B5) Introduction of a carbon-carbon triple bond to obtain an acetylene compound having one carbon number increased by a dehydrohalogenation reaction with a strong base after the condensation reaction of the aldehyde compound in the step (b2) with carbon tetrahalide A reaction process;
(B6) a carbon chain extension reaction step of reacting the acetylene compound with a halogenated carbon compound in the presence of a base to obtain a (1R, 4S) -2-cyclopenten-4-ol compound having the α side chain at the 1-position;
(B7) A hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound is oxidized to obtain a (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position. An oxidation reaction step.
By the (b5) (b7) step, 5-deoxy - it can be produced delta-12-prostaglandin J ₂ derivatives.

The prostaglandin derivative synthesis step (C) in the production method of the prostaglandin derivative
(C1) The above-mentioned (1R) -2-cyclopenten-4-one compound obtained in the step (B) is condensed with n-octanal in which the hydroxyl group at position 3 is protected to synthesize an aldol compound. ω side chain introduction step
(C2) a double bond forming step of forming a double bond of the ω side chain by a dehydration reaction of the aldol compound;
(C3) an oxidation reaction step of obtaining a prostaglandin derivative by oxidizing the terminal alcohol of the α side chain to a carboxylic acid.

The method for producing a compound in which malonic acid diester is added to the 1-position of the (1R, 4S) -2-cyclopenten-4-ol of the present invention is a (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound. As a starting material, a substitution reaction between the 1-position acyloxy group of the (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound and a malonic acid diester is carried out in the presence of a palladium catalyst and a specific base. Features.
The specific base is preferably one selected from metal tert-butoxide and organolithium.

（式中、Ｒ¹は水酸基の保護基を表し、Ｒ²は炭素数１から３の有機基を表わす。）で示される。 The compound in which malonic acid diester is added to the 1-position of (1R, 4S) -2-cyclopenten-4-ol of the present invention is represented by the following general formula (1).

(Wherein R ¹ represents a hydroxyl-protecting group, and R ² represents an organic group having 1 to 3 carbon atoms).

The method for producing the (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position, which is an intermediate compound useful for producing the prostaglandin derivative of the present invention, is represented by the above general formula (1). (1R) -2-cyclopentene-4-ol having a α-side chain of the prostaglandin derivative at the 1-position, starting from a compound in which malonic acid diester is added to the 1-position of (1R, 4S) -2-cyclopenten-4-ol A method for producing a -4-one compound, comprising at least
(B1) By decarboxylation of a compound in which malonic acid diester is added to the 1-position of the (1R, 4S) -2-cyclopenten-4-ol, (1R, 4S) -2-cyclopenten-4-ol-1- A decarboxylation reaction step to obtain an acetic acid compound;
(B2) a reduction reaction step of reducing the (1R, 4S) -2-cyclopenten-4-ol-1-acetic acid compound to convert it into an aldehyde compound.

In the production method, (b3) the aldehyde compound in the step (b2) is reacted with a Uttig reagent, and the α side chain into which a carbon-carbon double bond is introduced is located at the 1-position (1R, 4S) — Introduction reaction step of carbon-carbon double bond to obtain 2-cyclopenten-4-ol compound;
(B4) A (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position is obtained by oxidizing the hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound. An oxidation reaction step.

The production method further includes (b5) an acetylene compound having one carbon number increased by a dehydrohalogenation reaction with a strong base after the condensation reaction of the aldehyde compound in the step (b2) with a tetrahalogenated carbon. An introduction reaction step of a carbon-carbon triple bond to obtain
(B6) a carbon chain extension reaction step of reacting the acetylene compound with a halogenated carbon compound in the presence of a base to obtain a (1R, 4S) -2-cyclopenten-4-ol compound having the α side chain at the 1-position;
(B7) A hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound is oxidized to obtain a (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position. An oxidation reaction step.

（式中、Ｘは炭素−炭素不飽和結合を表し、Ｒ³は水酸基の保護基を表わす。）で示されることを特徴とする。
前記中間化合物としては、上記一般式（２）中、Ｘが炭素−炭素二重結合であることを特徴とするプロスタグランディン誘導体のα側鎖を１位に有する（１Ｒ）−２−シクロペンテン−４−オン化合物、および上記一般式（２）中、Ｘが炭素−炭素三重結合であることを特徴とするプロスタグランディン誘導体のα側鎖を１位に有する（１Ｒ）−２−シクロペンテン−４−オン化合物を挙げることができる。 The intermediate compound useful for the production of the prostaglandin derivative of the present invention is represented by the following general formula (2)

(Wherein X represents a carbon-carbon unsaturated bond, and R ³ represents a hydroxyl-protecting group).
As the intermediate compound, (1R) -2-cyclopentene- having an α side chain of the prostaglandin derivative in the general formula (2), wherein X is a carbon-carbon double bond at the 1-position (1R) -2-cyclopentene-4 having an α-side chain at the 1-position of a 4-one compound and the general formula (2), wherein X is a carbon-carbon triple bond -ON compounds can be mentioned.

（式中、Ｒ⁴，Ｒ⁵は、独立して水素原子または炭素数１から５の有機基を表わす。）で示される５−デヒドロ−デルタ−１２−プロスタグランディンＪ₂誘導体、および下記一般式（４）

（式中、Ｒ⁴は、独立して水素原子または炭素数１から５の有機基を表わす。）で示される５−デヒドロ−デルタ−１２，１４−プロスタグランディンＪ₂誘導体を挙げることができる。 The prostaglandin derivative of the present invention is produced by the above production method.
The prostaglandin derivative of the present invention includes the following general formula (3)

(. Wherein, R ^4, R ⁵ are, independently represent a hydrogen atom or an organic group having 1 to 5 carbon) in shown is 5-dehydro - delta-12-prostaglandin J ₂ derivatives the following general, Formula (4)

Can be exemplified delta -12,14- prostaglandin J ₂ derivatives - which (wherein, R ⁴ are independently a hydrogen atom or an organic group having 1 to 5 carbon.) 5-dehydro represented by .

  The medicament of the present invention is characterized by containing the above prostaglandin derivative as an active ingredient.

Method for producing a prostaglandin derivative of the present invention is the first practical chemical method for producing Δ ¹² -PGJ ₂ derivatives, medicaments containing Δ ¹² -PGJ ₂ derivatives of various, various derivatives as an active ingredient Can be provided.

Hereinafter, embodiments of the present invention will be described.
[Method for producing prostaglandin derivative]
The method for producing a prostaglandin derivative of the present invention uses a (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound as a starting material, and an α side chain at the 1-position of the 2-cyclopenten-4-one compound. A prostaglandin derivative having a ω side chain at the 5-position,
(A) In the presence of a palladium catalyst and a base, a substitution reaction between the acyloxy group at position 1 of the (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound and a malonic acid diester is performed, A partial introduction step of the α side chain to obtain a compound in which malonic acid diester is added to the 1-position of (1R, 4S) -2-cyclopenten-4-ol;
(B) The carbon chain of the compound in which malonic acid diester is added to the 1-position of the (1R, 4S) -2-cyclopenten-4-ol is extended, and the α side chain is in the 1-position (1R, 4S)- An α side chain extension step to obtain a 2-cyclopenten-4-one compound;
(C) The ω side chain is introduced at the 5-position of the (1R, 4S) -2-cyclopenten-4-one compound to construct the core structure of the prostaglandin derivative, and then converted to the prostaglandin derivative. A prostaglandin derivative synthesizing step.

The production method of the prostaglandin derivative of the present invention is shown by the following reaction scheme. That is, the acyloxy group of the (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound represented by the general formula (5) is represented by the general formula (1) by the step (A) (1R, 4S) -2-cyclopenten-4-ol is converted into a compound in which malonic acid diester is added to the 1-position (hereinafter referred to as “malonic acid diester adduct”), and then, by step (B), prostaglandy It is converted to a (1R) -2-cyclopenten-4-one compound represented by the general formula (2), which is an intermediate compound that is a key for the production of a thione derivative. Furthermore, this intermediate compound (2) can be converted by the step (C) to obtain the desired prostaglandin derivative.
In the method for producing a prostaglandin derivative of the present invention shown by the following reaction scheme, practical chemical production of Δ ¹² -PGJ ₂ becomes possible for the first time via a key intermediate compound (2). In addition, this production method can provide various Δ ¹² -PGJ ₂ derivatives.

In the method for producing a prostaglandin derivative of the present invention, the prostaglandin derivative is preferably a Δ ¹² -PGJ ₂ derivative. Examples of Δ ¹² -PGJ ₂ derivatives include 15-deoxy-Δ ^12,14 -PGJ ₂ derivatives, 5-dehydro-Δ ¹² -PGJ ₂ derivatives, 5-dehydro-15-deoxy-Δ ^12,14 -PGJ ₂ derivatives, and the like. And derivatives thereof.

  The step (A) in the method for producing a prostaglandin derivative of the present invention comprises the step (A, 4S) -1-acyloxy-2-cyclopenten-4-ol compound acyloxy group and malonic acid diester in the presence of a palladium catalyst and a base. This is a step of introducing a part of the α side chain to obtain a malonic acid diester addition compound at the 1-position of (1R, 4S) -2-cyclopenten-4-ol.

The starting material of the step (A) is a (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound represented by the general formula (5). In this compound (5), the hydroxyl group at the 4-position may be a free hydroxyl group (in the above general formula, R ¹ is a hydrogen atom) or a hydroxyl group protected by a protective group. A hydroxyl group protected by a protecting group is preferred from the viewpoint of reaction yield.
The protecting group is not particularly limited as long as it is a protecting group for an alcoholic hydroxyl group and can be deprotected under selective conditions in which the protecting group for the primary alcohol hydroxyl group is not deprotected. Examples of such protecting groups include tert-butyldimethylsilyl group (hereinafter also referred to as “TBS”), tert-butyldiphenylsilyl group, triethylsilyl group, triisopropylsilyl group, triphenylsilyl group, α-ethoxyethyl. Group, tetrahydropyranyl group and the like. Of these protecting groups, a tert-butyldimethylsilyl group (TBS) is preferred.

In the (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound (5), the acyloxy group at the 1-position is particularly preferably any one that is eliminated from the 1-position carbon and substituted with a malonic acid diester. It is not limited. In these acyloxy groups, R ⁶ in the general formula (5) is preferably a lower alkyl group such as a methyl group, an ethyl group, or a propyl group, and more preferably a methyl group.

The substitution reaction in the step (A) occurs in the presence of a palladium catalyst and a base when the active methylene of the malonic acid diester attacks the carbon atom at the 1-position to which the acyloxy group of the cyclopentenone ring is bonded. As this palladium catalyst, a wide range of palladium catalysts such as tetrakis (triphenylphosphine) palladium and bis (triphenylphosphine) palladium chloride can be used.
The base is preferably a metal tert-butoxide or an organolithium compound, not a metal hydride such as sodium hydride conventionally used. As the metal tert-butoxide, potassium tert-butoxide is preferable, and as the organic lithium compound, lithium diisopropylamide is preferable.
As malonic acid diesters, malonic acid diesters having various lower alkyl groups can be used without particular limitation, and examples thereof include dimethyl malonate, diethyl malonate, dipropyl malonate, di-tert-butyl malonate, and malon. Examples include rutile-tert-butyl acid. Among these, dimethyl malonate is preferable from the viewpoint of reactivity and price.

The malonic acid diester addition compound at the 1-position of (1R, 4S) -2-cyclopenten-4-ol, which is a result of the step (A), is represented by the general formula (1). R ¹ in the general formula (1) depends on the starting material, R ² depends on the malonic acid diester used in the step (A), and various (1R, 4S) -2-cyclopentene-4- A malonic ester addition compound at the 1-position of all can be obtained.

Step (B) in the method for producing a prostaglandin derivative of the present invention includes a malonic acid diester addition compound (1) of the (1R, 4S) -2-cyclopenten-4-ol obtained in step (A). ) To extend the α side chain to obtain a (1R) -2-cyclopenten-4-one compound having the α side chain of the prostaglandin derivative represented by the above general formula (2) at the 1-position. It is a process to do.
As the step of extending the α side chain, various steps combining known chemical reactions can be used. Among these steps, for example, the following step is preferable as a step for efficiently obtaining a (1R) -2-cyclopenten-4-one compound.

That is, the step (B) includes at least
(B1) By decarboxylation of a compound in which malonic acid diester is added to the 1-position of the (1R, 4S) -2-cyclopenten-4-ol, (1R, 4S) -2-cyclopenten-4-ol-1- A decarboxylation reaction step to obtain an acetic acid compound;
(B2) A reduction reaction step of reducing the (1R, 4S) -2-cyclopenten-4-ol-1-acetic acid compound into an aldehyde compound.

In the step (B),
(B3) (1R, 4S) -2-cyclopenten-4-ol having the α side chain introduced with a carbon-carbon double bond at the 1-position by reacting the aldehyde compound in the step (b2) with a Uttig reagent. An introduction reaction step of a carbon-carbon double bond to obtain a compound;
(B4) A (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position is obtained by oxidizing the hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound. An oxidation reaction step.
By the steps (b1) to (b4), a (1R, 4S) -2-cyclopenten-4-ol compound in which X in the general formula (2) is a carbon-carbon double bond can be obtained. This compound can be used as a useful intermediate compound for Δ ¹² -PGJ ₂ derivatives and 15-deoxy-Δ ^12,14 -PGJ ₂ derivatives having a double bond at the 5-position of the α side chain.

The step (B) further includes:
(B5) Introduction of a carbon-carbon triple bond to obtain an acetylene compound having one carbon number increased by a dehydrohalogenation reaction with a strong base after the condensation reaction of the aldehyde compound in the step (b2) with carbon tetrahalide A reaction process;
(B6) a carbon chain extension reaction step of reacting the acetylene compound with a halogenated carbon compound in the presence of a base to obtain a (1R, 4S) -2-cyclopenten-4-ol compound having the α side chain at the 1-position;
(B7) A hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound is oxidized to obtain a (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position. An oxidation reaction step.
(1R, 4S) -2-cyclopenten-4-ol compound in which X in the general formula (2) is a carbon-carbon triple bond by the steps (b1), (b2), (b5) to (b7). Can be obtained. This compound can be used as a useful intermediate compound of a 5-dehydro-Δ ¹² -PGJ ₂ derivative having a triple bond at the α-position 5 position and a 5-dehydro-15-deoxy-Δ ^12,14 -PGJ ₂ derivative. .

The said process as an example of a process (B) can be shown with the following reaction scheme. That is, the 1-position malonic acid diester addition compound (1) of (1R, 4S) -2-cyclopenten-4-ol is converted into an aldehyde compound represented by the following general formula (6) by the steps (b1) and (b2). Next, the aldehyde compound can be converted into a precursor compound of (1R) -2-cyclopenten-4-one compound represented by the following general formula (7) by the step (b3).
The precursor compound (7) of the (1R) -2-cyclopenten-4-one compound can be led to the target (1R) -2-cyclopenten-4-one compound (2) by deprotection.

In step (C) in the method for producing a prostaglandin derivative of the present invention, the ω side chain of the prostaglandin derivative is introduced into the 5-position of the (1R) -2-cyclopenten-4-one compound, This is a step of synthesizing a prostaglandin derivative that is converted into the prostaglandin derivative after the core structure of the thiol derivative is constructed.
As a process for synthesizing this prostaglandin derivative, various processes combining known chemical reactions can be used. Among these steps, for example, the following step is preferable as a step for efficiently synthesizing a prostaglandin derivative.

That is, the step (C)
(C1) The above-mentioned (1R) -2-cyclopenten-4-one compound obtained in the step (B) is condensed with n-octanal in which the hydroxyl group at position 3 is protected to synthesize an aldol compound. ω side chain introduction step
(C2) a double bond forming step of forming a double bond of the ω side chain by a dehydration reaction of the aldol compound;
(C3) An oxidation reaction step of obtaining a prostaglandin derivative by oxidizing the terminal alcohol of the α side chain to a carboxylic acid.

  The said process as an example of a process (C) can be shown with the following reaction scheme. That is, (1R) -2-cyclopenten-4-one compound (2) is converted into an aldol compound represented by the following general formula (9) by the step (c1). Next, the aldol compound is converted into a compound having a 12-position double bond represented by the following general formula (10) by the step (c2), and further the prostaglandin derivative (13) by the step (c3). Can be obtained.

[Prostaglandin derivatives]
The prostaglandin derivative of the present invention is characterized by being produced by the above method for producing a prostaglandin derivative.
Examples of the prostaglandin derivative of the present invention include various prostaglandin derivatives. Of these, Δ ¹² -PGJ ₂ derivatives are preferable. Examples of Δ ¹² -PGJ ₂ derivatives include 15-deoxy-Δ ^12,14 -PGJ ₂ derivatives, 5-dehydro-Δ ¹² -PGJ ₂ derivatives, 5-dehydro-15-deoxy-Δ ^12,14 -PGJ ₂ derivatives, and the like. And derivatives thereof.
These Δ ¹² -PGJ ₂ derivatives are compounds that regulate nuclear receptors, and Δ ¹² -PGJ ₂ and its derivatives 5-deoxydelta-12,14-prostaglandin J ₂ (hereinafter referred to as “5- d-delta ¹² also referred to as -PGJ ₂ ".) has antiviral activity, PPAR-gamma receptor agonist activity, anti-inflammatory action, various effects such as cytoprotection. Therefore, these Δ ¹² -PGJ ₂ derivatives are expected to be used as active ingredients of pharmaceuticals.

As the Δ ¹² -PGJ ₂ derivative, or Δ ¹² -PGJ ₂ represented by the following general formula (14), derivatives thereof such as 15-epi -Δ ¹² -PGJ _2, 14- methyl -Δ ¹² -PGJ _2, Examples thereof include 16-methyl-Δ ¹² -PGJ ₂ and 20-nor-Δ ¹² -PGJ ₂ .

The 15-The deoxy -Δ ^12,14 -PGJ ₂ derivative, and 15-deoxy--Δ ^12,14 -PGJ ₂ represented by the following general formula (15), derivatives thereof such as 15-epi -Δ ¹² -PGJ ₂ , 16-methyl-Δ ¹² -PGJ ₂ , 20-nor-15-deoxy-Δ ¹² -PGJ _{2 and the} like.

The 5- The dehydro -Δ ¹² -PGJ ₂ derivative, or 5-dehydro -Δ ¹² -PGJ ₂ represented by the following general formula (16), derivatives thereof such as 15-epi -Δ ¹² -PGJ _2, 14- Examples include methyl-Δ ¹² -PGJ ₂ , 16-methyl-Δ ¹² -PGJ ₂ , and 20-nor-Δ ¹² -PGJ ₂ .

As the 5-dehydro-15-deoxy -Δ ^12,14 -PGJ ₂ derivative, or 5-dehydro-15-deoxy -Δ ^12,14 -PGJ ₂ represented by the following general formula (17), derivatives thereof such as Examples thereof include 15-epi-Δ ¹² -PGJ ₂ , 16-methyl-Δ ¹² -PGJ ₂ , and 20-nor-15-deoxy-Δ ¹² -PGJ ₂ .

[Method for Producing Malonic Acid Diester Addition Compound (1) at Position 1 of (1R, 4S) -2-Cyclopenten-4-ol]
The method for producing a malonic acid diester addition compound at the 1-position of (1R, 4S) -2-cyclopenten-4-ol, which is an intermediate compound of the prostaglandin derivative of the present invention, comprises (1R, 4S) -1-acyloxy-2. -Substitution of acyloxy group and malonic acid diester of (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound in the presence of a palladium catalyst and a specific base, starting from cyclopenten-4-ol compound It is characterized by performing a reaction.

Production of malonic acid diester addition compound at position 1 of the (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol as described in the step (A) in the production method of the prostaglandin derivative of the present invention The starting material in the process is a (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound represented by the above general formula (5). In this compound (5), the hydroxyl group at the 4-position may be a free hydroxyl group (in the above general formula, R ¹ is a hydrogen atom) or a hydroxyl group protected by a protective group. A hydroxyl group protected by a protecting group is preferred from the viewpoint of reaction yield.
The protecting group is not particularly limited as long as it is a protecting group for an alcoholic hydroxyl group and can be deprotected under selective conditions in which the protecting group for the primary alcohol hydroxyl group is not deprotected. Examples of such protecting groups include tert-butyldimethylsilyl group (TBS), tert-butyldiphenylsilyl group, triethylsilyl group, triisopropylsilyl group, triphenylsilyl group, α-ethoxyethyl group, tetrahydropyranyl group, etc. Can be mentioned. Of these protecting groups, a tert-butyldimethylsilyl group (TBS) is preferred.

As described above, in the (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound (5), the 1-position acyloxy group is eliminated from the 1-position carbon and exchanged with a malonic acid diester. If it is a thing, it will not specifically limit. In these acyloxy groups, R ⁶ in the general formula (5) is preferably a lower alkyl group such as a methyl group, an ethyl group, or a propyl group, and more preferably a methyl group.

In the presence of a palladium catalyst and a base, the exchange reaction occurs when the active methylene of malonic acid diester attacks the carbon atom at the 1-position to which the acyloxy group of the cyclopentenone ring is bonded. As this palladium catalyst, a wide range of palladium catalysts such as tetrakis (triphenylphosphine) palladium and bis (triphenylphosphine) palladium chloride can be used.
The base is preferably a metal tert-butoxide or an organolithium compound, not a metal hydride such as sodium hydride conventionally used. As the metal tert-butoxide, potassium tert-butoxide is preferable, and as the organic lithium compound, lithium diisopropylamide is preferable.
As malonic acid diesters, malonic acid diesters having various lower alkyl groups can be used without particular limitation, and examples thereof include dimethyl malonate, diethyl malonate, dipropyl malonate, di-tert-butyl malonate, and malon. Examples include rutile-tert-butyl acid. Among these, dimethyl malonate is preferable from the viewpoint of reactivity and price.

The 1-position malonic ester addition compound of (1R, 4S) -2-cyclopenten-4-ol, which is a result of the step (A), is represented by the general formula (1). R ¹ in the general formula (1) depends on the starting material, R ² depends on the malonic acid diester used in the step (A), and various (1R, 4S) -2-cyclopentene-4- An all-position 1-malonate addition compound can be obtained.

  The method for producing a malonic acid diester addition compound at the 1-position of (1R, 4S) -2-cyclopenten-4-ol according to the present invention uses the target malonic acid by using potassium tert-butoxide or lithium diisopropylamide as a base. Since the diester addition compound (1) can be obtained in high yield, it is not only useful as a method for producing an intermediate compound of a prostaglandin derivative, but also extremely useful as a method for introducing a side chain into a general cyclopentene ring. It is.

[1-position malonic ester addition compound of (1R, 4S) -2-cyclopenten-4-ol (1)]
The intermediate compound of the prostaglandin derivative of the present invention is a malonic acid diester addition compound at the 1-position of (1R, 4S) -2-cyclopenten-4-ol represented by the general formula (1).
In general formula (1), R ¹ represents a hydroxyl-protecting group, and R ² represents an organic group having 1 to 3 carbon atoms. R ¹ is a protecting group for an alcoholic hydroxyl group, and is not particularly limited as long as it is a protecting group that can be deprotected under selective conditions where the primary alcohol hydroxyl protecting group is not deprotected. Examples of such protecting groups include tert-butyldimethylsilyl group (TBS), tert-butyldiphenylsilyl group, triethylsilyl group, triisopropylsilyl group, triphenylsilyl group, α-ethoxyethyl group, tetrahydropyranyl group, etc. Can be mentioned. Of these protecting groups, a tert-butyldimethylsilyl group (TBS) is preferred.
R ² is a lower alkyl group such as methyl, ethyl, propyl, tert-butyl and the like, and among these alkyl groups, a methyl group is preferable from the viewpoint of price.

  The 1-position malonic acid diester addition compound (1) of (1R, 4S) -2-cyclopenten-4-ol of the present invention is not only useful as an intermediate compound of a prostaglandin derivative, but also a general cyclopentene ring. It is also extremely useful as an intermediate compound having a side chain introduced therein.

[Production Method of (1R) -2-Cyclopenten-4-one Compound (2)]
The method for producing the (1R) -2-cyclopenten-4-one compound represented by the above general formula (2), which is an intermediate compound of the prostaglandin derivative of the present invention, is shown in the aforementioned method for producing a prostaglandin derivative. As at least,
(B1) By decarboxylation of a compound in which malonic acid diester is added to the 1-position of the (1R, 4S) -2-cyclopenten-4-ol, (1R, 4S) -2-cyclopenten-4-ol-1- A decarboxylation reaction step to obtain an acetic acid compound;
(B2) a reduction reaction step of reducing the (1R, 4S) -2-cyclopenten-4-ol-1-acetic acid compound to convert it into an aldehyde compound.

In the production method, (b3) the aldehyde compound in the step (b2) is reacted with a Uttig reagent, and the α side chain into which a carbon-carbon double bond is introduced is located at the 1-position (1R, 4S) — Introduction reaction step of carbon-carbon double bond to obtain 2-cyclopenten-4-ol compound;
(B4) A (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position is obtained by oxidizing the hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound. An oxidation reaction step.

The production method further includes (b5) an acetylene compound having one carbon number increased by a dehydrohalogenation reaction with a strong base after the condensation reaction of the aldehyde compound in the step (b2) with a tetrahalogenated carbon. An introduction reaction step of a carbon-carbon triple bond to obtain
(B6) a carbon chain extension reaction step of reacting the acetylene compound with a halogenated carbon compound in the presence of a base to obtain a (1R, 4S) -2-cyclopenten-4-ol compound having the α side chain at the 1-position;
(B7) A hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound is oxidized to obtain a (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position. An oxidation reaction step.

  The (1R) -2-cyclopenten-4-one compound (2) obtained by the above production method is extremely useful as an intermediate compound of a prostaglandin derivative, as will be described later.

[(1R) -2-cyclopenten-4-one compound (2)]
A useful intermediate compound for producing the prostaglandin derivative of the present invention is a (1R) -2-cyclopenten-4-one compound having the α side chain of the prostaglandin derivative represented by the general formula (2) at the 1-position. It is characterized by that.
In the method for producing a prostaglandin derivative of the present invention, Δ ¹² -PGJ ₂ can be practically chemically produced for the first time via this key intermediate compound (2). Can provide various Δ ¹² -PGJ ₂ derivatives.
In the general formula (2), X represents a carbon-carbon unsaturated bond, and R ³ represents a hydroxyl-protecting group. R ³ is an alcoholic hydroxyl protecting group, and is not particularly limited as long as it is a protecting group that can be deprotected under selective conditions in which the secondary alcohol hydroxyl protecting group is not deprotected. Examples of such a protecting group include a paramethoxybenzyl group (hereinafter also referred to as “PMB”), a tert-butyldimethylsilyl group, and the like. Of these protecting groups, a paramethoxybenzyl group (PMB) is preferable.

  The intermediate compound is a (1R) -2-cyclopenten-4-one compound having an α side chain at the 1-position of a prostaglandin derivative in which X is a carbon-carbon double bond in the general formula (2). Alternatively, it may be a (1R) -2-cyclopenten-4-one compound having an α side chain at the 1-position of a prostaglandin derivative in which X is a carbon-carbon triple bond. These (1R) -2-cyclopenten-4-one compounds (18) and (19) are shown below. Preferred examples of such (1R) -2-cyclopenten-4-one compounds (18) and (19) include compounds (28) and (33) in which the hydroxyl group described later is protected with a paramethoxybenzyl group (PMB). Can be mentioned.

The medicament of the present invention is characterized by containing the above prostaglandin derivative as an active ingredient.
As described above, the above prostaglandin derivatives have various physiological activities. Among these, Δ ¹² -PGJ ₂ derivative is a compound that regulates a nuclear receptor, and Δ ¹² -PGJ ₂ and its derivative 5-deoxydelta-12,14-prostaglandin J ₂ (hereinafter, referred to as “deoxy delta J”) “5-d-Δ ¹² -PGJ ₂ ”) has various actions such as antiviral action, PPAR-γ receptor agonist action, anti-inflammatory action, and cytoprotective action. Therefore, these Δ ¹² -PGJ ₂ derivatives are expected to be used as active pharmaceutical ingredients.

  Hereinafter, the present invention will be described in more detail based on examples. In addition, this invention is not limited to the following Example.

<Example 1> Synthesis of 1-position malonic acid dimethyl ester addition compound (22) of (1R, 4S) -1-tert-butyldimethylsilyloxy-2-cyclopenten-4-ol (1R, 4S) of the present invention Among the 1-position malonic acid diester addition compound (1) of 2-cyclopenten-4-ol, R ¹ = tert-butyldimethylsilyl (TBS), R ² = CH ₃ is represented by the following chemical formula (22) The compound was synthesized according to the following scheme.

(1R, 4S) -4-[(tert-Butyldimethylsilyl) oxy] -2-cyclopenten-1-yl acetate (21)
(1R, 4S) -2-cyclopenten-1-yl acetate which is a 5-membered ring monoacetate [produced by asymmetric hydrolysis of the corresponding diacetate using porcine pancreatic esterase. ] (20) To a solution of 1.52 g (10.7 mmol) of dimethylformamide (DMF) in 22 mL of tert-butyldimethylsilyl chloride (t-BuMe ₂ SiCl) [manufactured by Tokyo Chemical Industry Co., Ltd.] 2.42 g (16.04 mmol) And reacted at room temperature for 2 hours. Saturated aqueous sodium bicarbonate and hexane were added to stop the reaction, and the mixture was stirred vigorously. The hexane layer was separated and the aqueous layer was extracted with hexane. The extracts were collected together, dried, concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography to give (1R, 4S) -4-[(tert-butyldimethylsilyl) oxy] -2- 2.58 g of cyclopenten-1-yl acetate (21) was obtained (yield: 94%). The results of NMR analysis were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.08 (s, 3H), 0.09 (s, 3H), 0.89 (s, 9H), 1.60 (dt, J = 14.5 Hz) , 2H), 2.04 (s, 3H), 2.80 (dt, J = 14, 7.5 Hz, 1H), 4.66-4.75 (m, 1H), 5.42-5.50. (M, 1H), 5.88 (dt, J = 6, 1.5 Hz, 1H), 5.97 (dt, J = 6, 1.5 Hz, 1H).

Dimethyl (1R, 4S) -4-[(tert-butyldimethylsilyl) oxy] -2-cyclopenten-1-yl malonate (22)
Potassium tert-butoxide (t-BuOK) [Merck Japan Co., Ltd.] 2.19 g (19.5 mmol) of tetrahydrofuran (THF) suspension in 18 mL of dimethyl malonate [Tokyo Kasei Co., Ltd.] 2.46 mL (21. 4 mmol) was added and stirred for 30 minutes. Thereafter, Pd (PPh ₃ ) ₄ [prepared by reducing hydrazine of palladium chloride PdCl ₂ in the presence of triphenylphosphine. 564 mg (0.49 mmol) and 2.50 g (9.76 mmol) of compound (23) dissolved in 2 mL of THF were added, and the mixture was heated to 55 ° C. and reacted for 3 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added. The organic layer was separated and the aqueous layer was extracted with hexane. The extracts were collected together and dried, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 2.98 g of a malonate adduct (22) (yield: 93%). The results of NMR analysis were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.06 (s, 6H), 0.88 (s, 9H), 1.40 (ddd, J = 14, 11, 5 Hz, 1H), 2.44 (Dt, J = 14, 7 Hz, 1H), 3.15-3.26 (m, 1H), 3.37 (d, J = 10 Hz, 1H), 3.74 (s, 6H), 4.77 -4.84 (m, 1H), 5.80 (s, 2H).

<Example 2> Synthesis of (1R) -4-cyclopenten-1-one compound (21) Among the (1R) -2-cyclopenten-4-one compound (18) of the present invention, R ¹ = PMB. A compound represented by the following chemical formula (28) was synthesized according to the following scheme.

Methyl (1R, 4S) -4-[(tert-butyldimethylsilyl) oxy] -2-cyclopenten-1-yl acetate (23)
2.8 g (8.52 mmol) of malonate adduct (22), potassium iodide (KI) [manufactured by Yanagishima Pharmaceutical Co., Ltd.] 11.32 g (68.2 mmol), 1,3-dimethyl-2-imidazolidinone (DMI) ) [Tokyo Chemical Industry Co., Ltd.] A mixture of 30 mL and 3 mL of water was reacted for 10 hours while heating to 130 ° C. After returning to room temperature, water and hexane were added, and the mixture was vigorously stirred. The two layers were separated, and the aqueous layer was extracted four times with hexane. The extracts were collected together, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel chromatography to obtain 2.05 g of the acetate derivative (23) (yield: 89%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ³¹ _D : -19 (c 0.56, CHCl ₃ );
IR (neat): 1742, 1252, 1085, 836, 776 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.07 (s, 6H), 0.89 (s, 9H), 1.30 (ddd, J = 13, 6, 5 Hz, 1H), 2.38 (Dd, J = 16, 8 Hz, 1H), 2.46 (dt, J = 13, 7.5 Hz, 1H), 2.48 (dd, J = 16, 7 Hz, 1H), 2.86-3. 00 (m, 1H), 3.68 (s, 3H), 4.78-4.86 (m, 1H), 5.74 (dt, J = 6, 2 Hz, 1H), 5.80 (dt, J = 6, 2 Hz, 1 H).

(1R, 4S) -4-[(tert-Butyldimethylsilyl) oxy] -2-cyclopenten-1-yl ethanal (24)
A solution of 1.8 g (6.65 mmol) of the acetate derivative (23) in 26 mL of dichloromethane was cooled to 70 ° C. Hexane solution was added slowly. This was poured into a mixed solution of water and ether after 45 minutes. Further, 2.8 g (66.7 mmol) of sodium fluoride (NaF) [manufactured by Yoneyama Pharmaceutical Co., Ltd.] was added, stirred for 30 minutes, and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography to obtain 1.42 g of aldehyde (24) (yield: 89%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
_{^{[Α] 30 D: -23 (}} c0.38, CHCl 3);
IR (neat): 1726, 836, 775 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.05 (s, 6H), 0.87 (s, 9H), 1.29 (ddd, J = 13, 6, 5 Hz, 1H), 2.41 -2.68 (m, 3H), 2.92-3.04 (m, 1H), 4.78-4.85 (m, 1H), 5.71-5.80 (m, 2H), 9 .79 (s, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.44, −4.42, 18.3, 26.1, 38.1, 40.9, 50.6, 77.2, 135.0, 135.4, 201.6.

Wittig compound (26)
Using 5-paramethoxybenzyl bromide (PMB) oxypentane bromide prepared from 1,5-dibromopentane [manufactured by Tokyo Chemical Industry Co., Ltd.], 5-paramethoxybenzyl bromide (PMB) oxypentylphosphonium bromide (25 ) Prepared.
A suspension of 2.05 g (2.49 mmol) of 5-paramethoxybenzyl bromide (PMB) oxypentylphosphonium (25) and 25 mL of THF was cooled to 0 ° C., and NaN (TMS) ₂ [manufactured by Aldrich Japan Co., Ltd.] ] 5.0 mL (1M, 5.0 mmol) of THF solution was slowly added dropwise. The ice bath was removed and stirred for 30 minutes, followed by cooling to -70 ° C. In this, 0.6 g (2.49 mmol) of aldehyde (24) was added, and it stirred at -70 degreeC for 1 hour. Then, it returned to room temperature over 2 hours, and also stirred for 10 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added. The organic layer was separated and the aqueous layer was extracted with hexane. The organic layers were collected together and dried, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 0.90 g of a Wittig compound (26) (yield: 84%). The results of NMR analysis and infrared analysis were as follows.
IR (neat): 1612, 1513, 1249 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.07 (s, 6H), 0.89 (s, 9H), 1.22-1.32 (m, 1H), 1.35-1.48 (M, 2H), 1.54-1.66 (m, 2H), 1.98-2.25 (m, 4H), 2.36 (dt, J = 13, 7 Hz, 1H), 2.46. -2.58 (m, 1H), 3.43 (t, J = 7 Hz, 2H), 3.78 (s, 3H), 4.42 (s, 2H), 4.78-4.86 (m , 1H), 5.33-5.46 (m, 2H), 5.70 (dt, J = 6, 2 Hz, 1H), 5.78 (dt, J = 6, 2 Hz, 1H), 6.87. (D, J = 8 Hz, 2H), 7.26 (d, J = 9 Hz, 2H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.34, −4.31, 18.4, 26.2, 26.5, 27.3, 29.6, 34.0, 40.8, 44.5, 55.4, 70.1, 72.6, 77.7, 113.8, 128.1, 139.2, 130.54, 130.75, 134.1, 136.7, 159. 0.

Alcohol compound (27)
In a THF solution of 1.21 g (2.8 mmol) of Wittig compound (26) in a THF solution of tetrabutylammonium fluoride (Bu ₄ NF) [manufactured by Tokyo Chemical Industry Co., Ltd.] 3.36 mL (1M, 3.36 mmol) Was added. The mixture was stirred at room temperature for 5 hours, and a saturated aqueous ammonium chloride solution and ethyl acetate were added to stop the reaction. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel chromatography to obtain 835 mg of the alcohol compound (27) (yield: 95%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁶ _D : +51 (c0.51, CHCl ₃ );
IR (neat): 3409, 1613, 1513, 1247 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.27 (dt, J = 14.5 Hz, 1H), 1.36-1.48 (m, 2H), 1.55-1.68 (m, 2H), 1.93 (brs, 1H), 1.98-2.25 (m, 4H), 2.43 (dt, J = 14, 8 Hz, 1H), 2.56-2.68 (m, 1H), 3.43 (t, J = 6 Hz, 2H), 3.79 (s, 3H), 4.42 (s, 2H), 4.71-4.82 (m, 1H), 5.30 -5.52 (m, 2H), 5.74-5.81 (m, 1H), 5.82-5.88 (m, 1H), 6.87 (d, J = 9 Hz, 2H), 7 .26 (d, J = 9 Hz, 2H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 26.3, 27.2, 29.4, 33.7, 39.8, 44.5, 55.3, 70.0, 72.5, 77. 2, 113.7, 127.6, 129.2, 130.6, 131.1, 133.4, 138.1, 159.0.

(1R) -4-cyclopenten-1-one compound (28)
A 20 mL solution of dichloromethane containing 765 mg (3.55 mmol) of pyridinium chlorochromate (hereinafter also referred to as “PCC”) was cooled to 0 ° C., and 3 mL of a dichloromethane solution of 750 mg (2.37 mmol) of the alcohol compound (27) was added thereto. Was added dropwise. After completion of dropping, the mixture was stirred for 3 hours and diluted with ether. The resulting mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 690 mg of (1R) -4-cyclopenten-1-one compound (21) (yield: 93%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁹ _D : +106 (c 0.39, CHCl ₃ );
IR (neat): 1711, 1612, 1586, 1512, 1247 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.36 to 1.49 (m, 2H), 1.54 to 1.67 (m, 2H), 1.95 to 2.08 (m, 3H) 2.12-2.34 (m, 2H), 2.50 (dd, J = 19, 6 Hz, 1H), 2.93-3.03 (m, 1H), 3.43 (t, J = 6 Hz, 2H), 3.79 (s, 3H), 4.42 (s, 3H), 5.28-5.40 (m, 1H), 5.43-5.56 (m, 1H), 6 .15 (dd, J = 6, 2 Hz, 1H), 6.87 (d, J = 9 Hz, 2H), 7.26 (d, J = 9 Hz, 2H), 7.61 (dd, J = 6 2Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 26.3, 27.2, 29.5, 32.0, 40.6, 41.5, 55.3, 69.9, 72.6, 113. 7, 125.7, 129.2, 130.6, 132.4, 134.0, 159.0, 167.9, 209.6.

<Example 3> Synthesis of (1R) -2-cyclopenten-4-one compound (22) Among (1R) -2-cyclopenten-4-one compound (19), R ¹ = PMB The compound represented by 33) was synthesized according to the following scheme.

Dibromide compound (29)
Triphenylphosphine (PPh ₃ ) [manufactured by Wako Pure Chemical Industries, Ltd.] 36 mL of a solution of 4.36 g (16.64 mmol) in dichloromethane was ice-cooled, and carbon tetrabromide (CBr ₄ ) [manufactured by Tokyo Chemical Industry Co., Ltd.] ] 2.76 g (8.32 mmol) was added in small portions. After 10 minutes, 5 mL of a dichloromethane solution of 1.0 g (4.16 mmol) of (1R, 4S) -4-[(tert-butyldimethylsilyl) oxy] -2-cyclopenten-1-yl ethanal (24) was slowly added dropwise. . After stirring for 30 minutes, hexane was added, and the resulting insoluble material was removed by Celite filtration. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain 1.25 g of the dibromide compound (29) (yield: 76%). The results of NMR analysis and infrared analysis were as follows.
IR (neat): 3058, 1256, 1086, 836, 775 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.08 (s, 6H), 0.89 (s, 9H), 1.31 (dt, J = 13.5 Hz, 1H), 2.08-2 .32 (m, 2H), 2.39 (dt, J = 13, 8 Hz, 1H), 2.66 (quantet, J = 7 Hz, 1H), 4.78-4.85 (m, 1H), 5 .75 (s, 2H), 6.45 (t, J = 7 Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.3, 18.4, 26.1, 39.2, 40.3, 42.8, 77.3, 89.3, 135.1, 135 .5, 137.0.

Acetylene compound (30)
30 mL of a THF solution of 1.15 g (2.90 mmol) of the dibromide (29) was cooled to −78 ° C., and n-butyllithium (n-BuLi) [self-prepared. ] A hexane solution of 3.2 mL (2.25 M, 7.25 mmol) was added dropwise. It was kept at −78 ° C. for 30 minutes and then immersed in an ice bath. The mixture was further reacted for 30 minutes and poured into a saturated aqueous ammonium chloride solution. The product was extracted several times with hexane, and the collected extract was dried and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel chromatography to obtain 605 mg of an acetylene compound (30) (yield: 88%). The results of NMR analysis and infrared analysis were as follows.
IR (neat): 3313, 1256, 1079, 836, 775 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.08 (s, 6H), 0.90 (s, 9H), 1.37 (ddd, J = 13, 6, 5 Hz, 1H), 1.96 (T, J = 2.5 Hz, 1H), 2.26 (d, J = 2.5 Hz, 1H), 2.28 (d, J = 2.5 Hz, 1H), 2.44 (dt, J = 13, 8 Hz, 1 H), 2.66-2.78 (m, 1 H), 4.79-4.87 (m, 1 H), 5.76 (dt, J = 6, 2 Hz, 1 H), 5. 87 (dt, J = 6, 2 Hz).

4-Bromobutanol PMB ether (31)
50% sodium hydride (NaH) [manufactured by Yoneyama Pharmaceutical Co., Ltd.] 1.22 g (25.44 mmol) was added 82 mL of THF and cooled to 0 ° C., and paramethoxybenzyl alcohol (hereinafter “PMB-OH”) (Abbreviated.) 2.64 mL (21.2 mmol) [manufactured by Tokyo Chemical Industry Co., Ltd.] was slowly added dropwise. The ice bath was removed, and the mixture was stirred for 30 minutes, after which 5.0 mL (42.4 mmol) of 1,4-dibromobutane [manufactured by Tokyo Chemical Industry Co., Ltd.] was added. After 12 hours, it was poured into a saturated aqueous ammonium chloride solution and the product was extracted several times with hexane. The extracts were collected together, dried and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography to obtain 4.75 g of 4-bromobutanol PMB ether (31) (yield: 82%). The NMR analysis results were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70-1.80 (m, 2H), 1.90-2.02 (m, 2H), 3.43 (t, J = 7 Hz, 1H) 3.47 (t, J = 6 Hz, 1H), 3.89 (s, 3H), 4.42 (s, 2H), 6.88 (d, J = 9 Hz, 2H), 7.25 (d , J = 9 Hz, 2H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 28.5, 29.9, 33.9, 55.4, 69.0, 72.7, 113.8, 129.2, 130.5, 159. 1.

Alcohol compound (33)
6 mL of THF solution of 180 mg (0.761 mmol) of acetylene compound (30) was cooled to −78 ° C., and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidine (hereinafter referred to as “DMPU”). It is also referred to as “.” (Manufactured by Tokyo Chemical Industry Co., Ltd.) 1.5 mL of n-BuLi and 4-bromobutanol PMB ether (31) in 0.76 mL (1.9 M, 0.913 mmol) in hexane were added dropwise. The reaction was continued for 1 hour at −78 ° C., 5 hours at 0 ° C., and returned to room temperature for 5 hours. The reaction was stopped by adding saturated aqueous ammonium chloride and hexane. The organic layer was separated and the aqueous layer was extracted twice with hexane. The extracts were collected together, dried and concentrated under reduced pressure, and the resulting crude product was passed through a short silica gel column to obtain the ether compound (32).
Desilylation of the synthesized acetylene compound (30) using 8 mL of THF and 1.14 mL of Bu ₄ NF [manufactured by Tokyo Chemical Industry Co., Ltd.] (1M in THF, 1.14 mmol) according to the deprotection of TBS ether (27) And then purified by silica gel column chromatography to obtain 193 mg of the alcohol compound (33) (yield from the acetylene (30): 81%, 2 steps). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁸ _D : +50 (c 0.31, CHCl ₃ );
IR (neat): 3420, 1612, 1513, 1248 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (dt, J = 14.4 Hz, 1H) 1.50-1.75 (m, 4H), 1.89-1.97 (m, 1H) ), 2.12-2.22 (m, 2H), 2.28-2.36 (m, 2H), 2.45 (dt, J = 14, 8 Hz, 1H), 2.74-2.84. (M, 1H), 3.44 (t, J = 6 Hz, 2H), 3.80 (s, 3H), 4.42 (s, 2H), 4.73 (brs, 1H), 5.83 (Dd, J = 6, 2 Hz, 1H), 5.88 (dt, J = 6, 2 Hz, 1H), 6.87 (d, J = 9 Hz, 2H), 7.26 (d, J = 8 Hz, 2H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 18.6, 25.1, 25.9, 29.0, 39.1, 43.5, 55.3, 69.6, 72.6, 76. 9, 79.2, 81.7, 113.7, 129.2, 130.6, 134.3, 137.0, 159.0.

Enone compound (34)
According to the oxidation of the alcohol form (33), 190 mg (0.604 mmol) of the alcohol form (32) was dissolved in 6 mL of dichloromethane, and 195 mg (0.905 mmol) of pyridinium chlorochromate (PCC) [manufactured by Tokyo Chemical Industry Co., Ltd.] was used. The reaction was carried out for 1 hour. The same post-treatment was performed, and purification by silica gel column chromatography gave 177 mg of the enone compound (33) (yield: 94%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
: [Α] ²⁸ _D : +107 (c 0.62, CHCl ₃ );
IR (neat): 1714, 1612, 1512, 1247 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.50-1.72 (m, 4H), 2.08-2.21 (m, 3H), 2.34-2.44 (m, 2H) 2.52 (dd, J = 19, 7 Hz, 1H), 3.06-3.16 (m, 1H), 3.45 (t, J = 6 Hz, 2), 3.80 (s, 3H) 4.43 (s, 2H), 6.20 (dd, J = 6, 2Hz, 1H), 6.87 (d, J = 8Hz, 2H), 7.26 (d, J = 8Hz, 2H) , 7.63 (dd, J = 6, 3 Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 18.6, 24.0, 25.8, 29.0, 40.2, 40.6, 55.4, 69.6, 72.6, 76. 4, 82.4, 113.7, 129.2, 130.6, 134.6, 159.0, 166.7, 209.2.

Example 4 Synthesis of Delta 12-Prostaglandin J ₂ (Δ ¹² -PGJ ₂ ) (14) 3-TBSoxy-octanal (39) used as a raw material for the ω chain of Δ ¹² -PGJ ₂ synthesis is represented by the following scheme. Was synthesized.

Epoxy alcohol compound (35)
Titanium tetraisopropoxide Ti (i-PrO) ₄ [manufactured by Junsei Co., Ltd.] 0.69 mL (2.33 mmol), L-(+)-diisopropyl tartrate L-(+)-DIPT [manufactured by Tokyo Chemical Industry Co., Ltd. ] 0.59 mL (2.78 mmol) and 4A molecular sieve [manufactured by Aldrich Japan Co., Ltd.] in the presence of 600 mg, 1.2 g (9.36 mmol) of 2-heptenol (34) [manufactured by Tokyo Chemical Industry Co., Ltd.] are tert-butyl. Hydroperoxide (hereinafter also referred to as “TBHP”) [prepared in-house. ] Asymmetric epoxidation using 2.3 mL (5.71 M in dichloromethane, 2.78 mmol) (−20 ° C., 9 hours). After usual post-treatment, purification by silica gel chromatography and recrystallization gave 1.11 g of an epoxy alcohol compound (35) (yield: 82%). The results of NMR analysis and polarization degree analysis were as follows.
[Α] ²⁴ _D : -43 (c0.45, CHCl ₃ );
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 (t, J = 7 Hz, 3H), 1.24 to 1.66 (m, 8H), 1.73 (br t, J = 6 Hz, 1H ), 2.90-3.00 (m, 2H), 3.58-3.70 (m, 1H), 3.87-3.97 (m, 1H).
Literature value [α] ²⁵ _D : -42.7 (c4.7, CHCl ₃ ); Gao, R.A. M.M. Hanson, J .; M.M. Klunder, S.M. Y. Ko, H .; Masamune, K.M. B. Sharpless, J. et al. Am. Chem. Soc. 1987, 109, 5765-5780.

(S) -1,3-octanediol (36)
Epoxy alcohol compound (35) 150 mg (1.04 mmol) in THF 4 mL solution dihydro-bis (2-methoxyethoxy) sodium aluminate (Red-Al) [Wako Pure Chemical Industries, Ltd.] 0.65 mL (2.1 mmol) Thereafter, the mixture was reacted for 10 hours. The reaction solution was poured into a mixture containing 0.4 mL (22 mmol) of water, 10 mL of ether Et ₂ O, and 350 mg (8.3 mmol) of sodium fluoride (NaF) [manufactured by Yoneyama Pharmaceutical Co., Ltd.] and vigorously for 30 minutes. After stirring, the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography to obtain 134 mg of 1,3-octanediol (36) (yield: 88%). The results of NMR analysis and infrared analysis were as follows.
IR (neat): 3350, 1055 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.88 (t, J = 7 Hz, 3H), 1.22-1.54 (m, 8H), 1.58-1.78 (m, 2H) 2.61 (brs, 1H), 2.70 (brs, 1H), 3.76-3.94 (m, 3H).

(S) -1,3-[(tert-butyldimethylsilyl) oxy] octane (37)
In a solution of 1.70 g (11.6 mmol) of (S) -1,3-octanediol (36) in 22 mL of dimethylformamide (DMF), 3.16 g (46.4 mmol) of imidazole [manufactured by Tokyo Chemical Industry Co., Ltd.] tert-butyldimethylsilyl chloride (TBSCl) (5.25 g, 34.8 mmol) was added thereto, and silylation was performed over 3 hours. The post-treatment and purification were performed in the same manner as in the synthesis of the 5-membered silyl ether (21) to obtain 3.64 g of a disilyl compound (37) (yield: 94%). The results of NMR analysis were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.04 (s, 12H), 0.88 (s, 9H), 0.89 (s, 9H), 0.86-0.90 (m, 3H) ), 1.20-1.48 (m, 9H), 1.64 (q, J = 6 Hz, 1H), 3.62-3.73 (m, 2H), 3.79 (quintet, J = 6 Hz) , 1H).

(S) -3-[(tert-Butyldimethylsilyl) oxy] octan-1-ol (38)
380 mg (1.14 mmol) of the disilyl compound (37) was dissolved in 6 mL of ethanol and 6 mL of dichloromethane, and pyrididium paratoluenesulfonic acid (hereinafter also referred to as “PPTS”) [manufactured by Tokyo Chemical Industry Co., Ltd.] 342 mg ( 1.36 mmol) was added and allowed to react for 14 hours at room temperature. Saturated aqueous ammonium chloride was added to quench the reaction, and the product was extracted twice with ethyl acetate. The organic layers were combined and concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography to obtain 226 mg of the monoalcohol compound (38) (yield: 76%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁷ _D : +18 (c 0.62, CHCl ₃ );
IR (neat): 3350, 1255, 1058, 836, 774 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (br s, 9H), 0.85-0.91 (m, 3H), 1.20-1.36 (m, 6H), 1.45-1.56 (m, 2H), 1.57-1.70 (m, 1H), 1.74-1.87 ( m, 1H), 2.55 (brs, 1H), 3.65-3.76 (m, 1H), 3.77-3.95 (m, 2H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.5, −4.2, 14.2, 18.2, 22.8, 25.2, 26.0, 32.1, 36.9, 37.8, 60.4, 72.1.

(S) -3-[(tert-Butyldimethylsilyl) oxy] octanal (39)
1.95 g (9.05 mmol) of PCC [manufactured by Tokyo Chemical Industry Co., Ltd.] was added to a solution of 1.18 g (4.53 mmol) of the monoalcohol compound (38) in 45 mL of dichloromethane, and the mixture was vigorously stirred for 3 hours and then diluted with ether. . The same post-treatment and purification as when enone (28) was synthesized gave 1.10 g of aldehyde compound (39) (yield: 94%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁷ _D : +6.7 (c0.21, CHCl ₃ );
IR (neat): 1713, 1256, 1095, 836, 776 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.05 (s, 3H), 0.07 (s, 3H), 0.87 (br s, 9H), 0.84-0.92 (m, 3H), 1.18-1.40 (m, 6H), 1.45 to 1.60 (m, 2H), 2.51 (dd, J = 6, 2 Hz, 2H), 4.17 (quintet, J = 6 Hz, 1H), 9.81 (t, J = 2 Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.5, −4.2, 14.2, 18.2, 22.8, 25.0, 25.9, 31.9, 38.0, 51.0, 68.4, 202.3.
The enantiomer of aldehyde (39) is known in the literature and has been synthesized by another route. [Α] ²⁴ _D : -5.0 (c1.0, CHCl ₃ ); Kiyooka, M .; A. Hena, J. et al. Org. Chem. 1999, 64, 5511-5523.

Delta 12-prostaglandin J ₂ (Δ ¹² -PGJ ₂ ) (14) was synthesized according to the following scheme.

Dienone Compound (43)
According to a conventional method, diisopropylamine (i-Pr) ₂ NH [manufactured by Tokyo Chemical Industry Co., Ltd.] 0.15 mL (1.07 mmol), THF 4 mL, n-BuLi (1.90 M in hexane, 0.37 mL) to lithium diisopropylamide ( Hereinafter, a THF solution of “LDA”) was prepared and cooled to −78 ° C. Into this, 2 mL of a THF solution of 109 mg (0.347 mmol) of the enone compound (28) was dropped, and after 20 minutes, 1 mL of a THF solution of 108 mg (0.418 mmol) of the aldehyde compound (39) was added. The mixture was stirred for 30 minutes and then poured into a mixed solution of saturated aqueous ammonium chloride and ether. After 15 minutes, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The extracts were combined into one, dried and concentrated. The obtained crude aldol product (40) was a 1: 3 mixture of syn and anti isomers, but was not separated and used for the next reaction through a short silica gel column with ethyl acetate.
The crude aldol product (40) thus obtained and 0.24 mL (1.72 mmol) of triethylamine (Et ₃ N) were dissolved in 3.5 mL of dichloromethane and cooled to 0 ° C. To this, 0.053 mL (0.685 mmol) of mesyl chloride (MsCl) [manufactured by Tokyo Chemical Industry Co., Ltd.] was added dropwise and reacted for 45 minutes. Saturated aqueous sodium bicarbonate was added to stop the reaction, and the product was extracted twice with ethyl acetate. The extracts were combined into one, dried and concentrated. The obtained mesylate compound (41) was passed through a short silica gel column and used for the next reaction.
Alumina [IC Biomedicals Co., Ltd.] Into 353 mg of dichloromethane / suspension 5 mL, a 2 mL solution of mesylate compound (41) in dichloromethane was added dropwise. The mixture was stirred for 10 hours at room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography to obtain 114 mg of the dienone compound (42) (yield from the enone compound (28): 59%, 3 steps). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁶ _D : +96 (c0.43, CHCl ₃ );
IR (neat): 1705, 1657, 1513, 1249 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.04 (s, 3H), 0.05 (s, 3H), 0.80-0.96 (m, 12H), 1.20-1.64 (M, 12H), 2.00 (q, J = 7 Hz, 2H), 2.17 (dt, J = 15, 9 Hz, 1H), 2.39-2.46 (m, 2H), 2.55 -2.67 (m, 1H), 3.43 (t, J = 7 Hz, 3H), 3.80 (s, 3H), 3.78-3.88 (m, 1H), 4.42 (s , 2H), 5.28-5.40 (m, 1H), 5.42-5.56 (m, 1H), 6.32 (dd, J = 6, 1.5 Hz, 1H), 6.60. (T, J = 8 Hz, 1H), 6.87 (d, J = 8 Hz, 2H), 7.25 (d, J = 8 Hz, 2H), 7.49 (dd, J = 6, 2 Hz, 1H) ;
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.4, −4.2, 14.2, 18.3, 22.8, 25.1, 26.0, 26.4, 27.3 29.6, 30.7, 32.1, 37.4, 37.5, 43.6, 55.4, 70.0, 71.6, 72.6, 113.6, 125.1, 129. 2, 130.7, 132.45, 132.51, 134.8, 138.7, 159.0, 161.5, 196.2, 132.4, 132.6, 134.8, 138.7, 161.5, 196.2.

Alcohol compound (43)
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (hereinafter also referred to as “DDQ”) in a 3.6 mL solution of iced dienone compound (42) in dichloromethane [manufactured by Tokyo Chemical Industry Co., Ltd.] ] 66 mg (0.29 mmol) was added and stirred for 45 minutes. The resulting reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 77 mg of the alcohol compound (43) (yield: 91%). The results of NMR analysis and infrared analysis were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.04 (s, 3H), 0.05 (s, 3H), 0.80 (brs, 12H), 1.2-1.7 (m, 12H), 1.95-2.30 (m, 3H), 2.39-2.46 (m, 2H), 2.55-2.67 (m, 1H), 3.43 (m, 1H) 3.65 (t, J = 7 Hz, 2H), 3.78-3.90 (m, 1H), 5.28-5.40 (m, 1H), 5.42-5.56 (m, 1H), 6.32 (dd, J = 6, 1.5 Hz, 1H), 6.60 (t, J = 8 Hz, 1H), 7.49 (dd, J = 6, 2 Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.4, −4.2, 14.2, 18.3, 22.8, 25.1, 25.9, 26.0, 27.3 30.8, 32.1, 32.5, 37.5, 43.6, 62.8, 71.7, 125.3, 132.4, 132.6, 134.8, 138.7, 161. 5, 196.2.

Aldehyde compound (44)
45 mg (0.104 mmol) of the alcohol form (43) was dissolved in 1 mL of dichloromethane, cooled to 0 ° C., and then 45 mg (0.209 mmol) of PCC [manufactured by Tokyo Chemical Industry Co., Ltd.] was slowly added. After removing the ice bath and stirring for 2.5 hours, the post-treatment was performed in the same manner as when the enone compound (28) was synthesized, and 42 mg of the aldehyde compound (44) was isolated (yield: 94%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁹ _D : +57 (c 0.14, CHCl ₃ );
IR (neat): 1709, 1649, 836, 775 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.04 (s, 3H), 0.05 (s, 3H), 0.87 (s, 9H), 0.83-0.91 (m, 3H) ), 1.16-1.52 (m, 8H), 1.60-1.76 (m, 2H), 2.04 (q, J = 7 Hz, 2H), 2.12-2.26 (m) , 1H), 2.30-2.54 (m, 4H), 2.56-2.68 (m, 1H), 3.40-3.52 (m, 1H), 3.78-3.90. (M, 1H), 5.30-5.53 (m, 2H), 6.33 (dd, J = 6, 2 Hz, 1H), 6.60 (t, J = 8 Hz, 1H), 7.48. (Dd, J = 6, 2.5 Hz, 1H), 9.76 (t, J = 1.5 Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.4, −4.2, 14.2, 18.3, 22.0, 22.8, 25.1, 26.0, 26.8, 30.7, 32.1, 37.4, 37.5, 43.40, 43.44, 71.6, 126.2, 131.2, 132.7, 135.0, 138.5, 161. 2, 196.1, 201.9.

Carboxylic acid compound (45)
The pH of 3.6 was added to 1.3 mL of a tert-butanol solution of 42 mg (0.097 mmol) of the aldehyde compound (44) and 0.103 mL (0.97 mmol) of 2-methyl-2-butene [manufactured by Tokyo Chemical Industry Co., Ltd.]. 0.61 mL of phosphate buffer and 0.5 mL of NaClO ₂ [manufactured by Yoneyama Pharmaceutical Co., Ltd.] (purity 80%, 17 mg, 0.15 mmol) were added. After reacting for 3 hours, the low boiling point component was removed by connecting to a vacuum pump. The remaining oily substance was diluted in phosphate buffer (pH 3.6) and extracted several times with ethyl acetate. The collected extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography to obtain 39 mg of the carboxylic acid compound (45) (yield: 89%). The results of NMR analysis and infrared analysis were as follows.
IR (neat): 3229, 1699, 1652, 1252, 836, 775 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.05 (s, 6H), 0.84-0.92 (m, 12H), 1.18-1.52 (m, 8H), 1.69 (Quintet, J = 7 Hz, 2H), 2.00-2.22 (m, 3H), 2.34 (t, J = 7 Hz, 2H), 2.40-2.48 (m, 2H), 2 .60-2.70 (m, 1H), 3.41-3.50 (m, 1H), 3.84 (q, J = 6 Hz, 1H), 5.32-5.56 (m, 2H) 6.33 (dd, J = 6, 1 Hz, 1H), 6.60 (t, J = 8 Hz, 1H), 7.50 (dd, J = 6, 2 Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.4, −4.2, 14.2, 18.3, 22.8, 24.6, 25.1, 26.0, 26.8, 30.7, 32.0, 33.3, 37.4, 37.5, 43.6, 71.8, 126.2, 131.3, 132.7, 134.9, 138.6, 161. 5, 178.1, 196.3.

Δ ¹² -PGJ ₂ (14)
55% hydrogen fluoride (HF) and acetonitrile (MeCN) were mixed at a ratio of 1:19, and 0.2 mL of this solution was added to 9 mg (0.02 mmol) of the carboxylic acid compound (45) cooled to 0 ° C. After 15 minutes, the mixture was poured into saturated brine, and the product was extracted three times with ethyl acetate. The collected extract was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography to obtain 6.2 mg of Δ ¹² -PGJ ₂ (14) (yield: 92%). The results of NMR analysis and infrared analysis were as follows.
IR (neat): 3409, 1699, 1653 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.88 (tJ = 7 Hz, 3H), 1.20-1.80 (m, 10H), 2.06-2.18 (m, 3H), 2 26-2.63 (m, 4H), 2.66-2.78 (m, 1H), 3.42-3.54 (m, 1H), 3.78-3.92 (m, 1H) 5.20-5.80 (br s, 2H), 6.35 (dd, J = 6, 2 Hz, 1H), 6.59 (t, J = 8 Hz, 1H), 7.56 (dd, J = 6, 2 Hz, 1 H).

Example 5 15-Deoxy-Δ ¹² -PGJ ₂ (15) was synthesized according to the following scheme.

Aldol compound (48)
The aldol compound (47) was synthesized according to the synthesis method of the aldol compound (40). Briefly, a THF solution of LDA was prepared by adding (i-Pr) ₂ NH (Tokyo Chemical Industry Co., Ltd.) 0.145 mL (1.03 mmol), THF 6 mL, and n-BuLi 0.44 mL (1.90 M in hexane, 0. 84 mmol), and 2 mL of a THF solution of 130 mg (0.413 mmol) of the enone compound (28) was added thereto. Subsequently, 2 mL of a THF solution of 0.074 mL (0.47 mmol) of (E) -2-octanal (46) [manufactured by Tokyo Chemical Industry Co., Ltd.] was added dropwise. The aldol compound (47) thus produced was a 1: 3 mixture of syn and anti isomers, but was not separated and used for the next reaction through a short silica gel column with ethyl acetate.

Dienone Compound (48)
A 4 mL solution of the aldol compound (47) in dichloromethane was cooled to −15 ° C., and 0.29 mL (2.1 mmol) of triethylamine (Et ₃ N) and mesyl chloride (MsCl) [manufactured by Tokyo Chemical Industry Co., Ltd.] 0.064 mL (0 .83 mmol) was added. After 45 minutes, saturated aqueous sodium hydrogen carbonate was added to stop the reaction, and the product was extracted twice with ethyl acetate. The extracts were combined, dried and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to isolate 121 mg of the dienone compound (48) (yield from the enone compound (28): 69%). , 2 steps). The results of NMR analysis and infrared analysis were as follows.
IR (neat): 1685, 1631, 1512, 1248 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.82 (t, J = 7 Hz, 3H), 1.1-1.6 (m, 10H), 1.93 (q, J = 7 Hz, 2H) 2.10-2.28 (m, 3H), 2.51 (dt, J = 14, 6 Hz, 1H), 3.35 (t, J = 6 Hz, 2H), 3.44-3.53 ( m, 1H), 3.73 (s, 3H), 4.35 (s, 2H), 5.20-5.32 (m, 1H), 5.34-5.46 (m, 1H), 6.08-6.32 (m, 3H), 6.80 (d, J = 8 Hz, 2H), 6.87 (d, J = 11 Hz, 1H), 7.18 (d, J = 8 Hz, 2H) ), 7.39 (dd, J = 6, 2 Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 14.2, 22.6, 26.4, 27.3, 28.6, 29.6, 31.0, 31.5, 33.6, 43. 7, 55.4, 70.0, 72.6, 113.8, 125.1, 125.7, 129.2, 130.6, 131.7, 132.5, 135.1, 135.2. 146.7, 159.0, 160.7, 197.2.

Alcohol compound (49)
According to the deprotection of the PMB ether compound (42), 53 mg of the dienone compound (48) was added using 43 mg (0.19 mmol) of DDQ [manufactured by Tokyo Chemical Industry Co., Ltd.] in a mixed solvent consisting of 1.2 mL of dichloromethane and 0.1 mL of water. 0.125 mmol) was deprotected at 0 ° C. for 45 minutes. The product was purified by silica gel column chromatography to synthesize 35 mg of the alcohol compound (49) (yield: 93%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁵ _D : +178 (c 0.36, CHCl ₃ );
IR (neat): 3421, 1685, 1629, 1207 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.88 (t, J = 7 Hz, 3H), 1.1-1.7 (m, 11H), 2.10 (q, J = 7 Hz, 2H) 2.14-2.38 (m, 3H), 2.52-2.66 (m, 1H), 3.50-3.70 (m, 3H), 5.25-5.60 (m, 2H), 6.16-6.40 (m, 3H), 6.94 (d, J = 11 Hz, 1H), 7.48 (dd, J = 6, 2 Hz, 1H).

Aldehyde compound (50)
According to the synthesis method of the aldehyde compound (44) from the alcohol compound (43), 35 mg (0.116 mmol) of the alcohol compound (49) is dissolved in 1 mL of dichloromethane, and 37 mg (0.17 mmol) of PCC [manufactured by Tokyo Chemical Industry Co., Ltd.] is used. The oxidation reaction was performed for 2.5 hours. The product was purified by silica gel column chromatography to synthesize 32 mg of aldehyde compound (50) (yield: 92%). The results of NMR analysis and infrared analysis were as follows.
IR (neat): 1727, 1695, 1632, 1206 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.89 (t, J = 7 Hz, 3H), 1.20-1.72 (m, 8H), 2.02 (q, J = 7 Hz, 2H) 2.16-2.44 (m, 5H), 2.52-2.64 (m, 1H), 3.54-3.62 (m, 1H), 5.28-5.52 (m, 2H), 6.14-6.40 (m, 3H), 6.94 (d, J = 11 Hz, 1H), 7.45 (dd, J = 6, 3 Hz, 1H), 9.75 (s, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 14.2, 22.0, 22.7, 26.8, 28.7, 30.9, 31.6, 33.6, 43.4, 43. 6, 125.6, 126.1, 131.3, 131.6, 135.0, 135.3, 146.9, 160.4, 197.1, 202.0.

15-deoxy-Δ ^12,14 -PGJ ₂ (15)
According to the oxidation reaction of the aldehyde compound (44), 32 mg (0.106 mmol) of the aldehyde compound (50) was dissolved in a mixed solvent consisting of 1.4 mL of tert-butanol and 0.66 mL of pH 3.6 phosphate buffer, 2-methyl-2-butene [manufactured by Tokyo Chemical Industry Co., Ltd.] 0.11 mL (1.04 mmol) and NaClO ₂ [manufactured by Yoneyama Pharmaceutical Co., Ltd.] (purity: 80%, 18 mg, 0.16 mmol) 0.53 mL aqueous solution Was added. The mixture was reacted at room temperature for 3 hours and purified by silica gel column chromatography. 15-deoxy-Δ
^12,14- PGJ ₂ (15) 31 mg was synthesized (yield: 92%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows. By ¹ H-NMR measured at 500 MHz, the olefin at positions 14 and 15 could be identified as trans.
[Α] ²⁶ _D : +193 (c 0.17, CHCl ₃ );
IR (neat): 3303, 1707, 1628, 1209 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.89 (t, J = 7 Hz, 3H), 1.20-1.54 (m, 6H), 1.67 (quintet, J = 7 Hz, 2H) , 2.05 (q, J = 7 Hz, 2H), 2.16-2.40 (m, 5H), 2.54-2.66 (m, 1H), 3.54-3.62 (m, 1H), 5.28-5.56 (m, 2H), 6.16-6.42 (m, 3H), 6.96 (d, J = 11 Hz, 1H), 7.47 (dd, J = 6, 2 Hz, 1 H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 14.2, 22.6, 24.6, 26.7, 28.6, 30.9, 31.6, 33.4, 33.6, 43. 6, 125.6, 126.1, 131.3, 131.9, 135.0, 135.3, 147.0, 160.7, 178.5, 197.5;
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 0.89 (t, J = 7 Hz, 3H), 1.22-1.36 (m, 4H), 1.39-1.49 (m, 2H) 1.62-1.72 (m, 2H), 2.04 (q, J = 7 Hz, 2H), 2.18-2.37 (m, 5H), 2.56-2.62 (m, 1H), 3.56-3.61 (m, 1H), 5.33-5.40 (m, 1H), 5.42-5.49 (m, 1H), 6.23 (dt, J = 15, 7 Hz, 1 H), 6.31 (ddt, J = 15, 11, 1 Hz, 1 H), 6.36 (dd, J = 6, 2 Hz, 1 H), 6.95 (d, J = 11 Hz, 1 H) ), 7.47 (ddd, J = 6, 2.5, 1 Hz, 1H).

Example 6 5-dehydro-Δ ¹² -PGJ ₂ (16) was synthesized according to the following scheme.

Aldol compound (51)
The aldol compound (51) was synthesized according to the synthesis method of the aldol compound (40). Briefly, a THF solution of LDA was (i-Pr) ₂ NH (manufactured by Tokyo Chemical Industry Co., Ltd.) 0.23 mL (1.64 mmol), THF 9 mL, and n-BuLi 0.67 mL, (1.90 M in hexane, 1 27 mL), 2 mL of a THF solution of 200 mg (0.64 mmol) of enone (15) was added thereto, followed by dropwise addition of 1 mL of a THF solution of 199 mg (0.770 mmol) of the aldehyde compound (39). The aldol compound (51) thus produced was a 1: 3 mixture of syn and anti isomers, but was not separated and used for the next reaction through a short silica gel column with ethyl acetate.

Dienone Compound (53)
The same operation as when the aldol compound (40) was converted to the dienone (42) was performed on the aldol compound (51) to synthesize the dienone compound (53). Briefly, a solution of aldol (52) in dichloromethane (6.5 mL) was cooled to 0 ° C., and MsCl [manufactured by Tokyo Chemical Industry Co., Ltd.] was added in the presence of 0.45 mL (3.23 mmol) of triethylamine (Et ₃ N). 10 mL (1.29 mmol) was reacted to synthesize the mesylate compound (52). Subsequently, the mesylate compound (52) was dissolved in 7 mL of dichloromethane, and 496 mg of alumina [manufactured by IC Biomedicals Co., Ltd.] was added. The mixture was reacted at room temperature for 10 hours, and the product was purified by silica gel column chromatography to isolate 151 mg of the dienone compound (53) (yield from the enone compound (33): 43%, 3 steps). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁸ _D : +98 (c 0.38, CHCl ₃ );
IR (neat): 1708, 1662, 1246, 1091 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 0.84-0.92 (m, 3H) ), 1.16-1.74 (m, 12H), 2.10-2.28 (m, 3H), 2.35-2.44 (m, 2H), 2.70-2.82 (m) , 1H), 3.45 (t, J = 6 Hz, 2H), 3.48-3.58 (m, 1H), 3.80 (s, 3H), 3.70-3.92 (m, 1H) ), 4.42 (s, 2H), 6.37 (dd, J = 6, 1.5 Hz, 1H), 6.61 (t, J = 8 Hz, 1H), 6.87 (d, J = 8 Hz) , 2H), 7.26 (d, J = 8 Hz, 2H), 7.65 (dd, J = 6, 2 Hz, 1H).

Alcohol compound (54)
According to the deprotection of the PMB ether compound (42), DDQ (manufactured by Tokyo Chemical Industry Co., Ltd.) 63 mg (0.28 mmol) was used in a mixed solvent consisting of 2 mL of dichloromethane and 0.1 mL of water, and 102 mg (0. 184 mmol) was deprotected at 0 ° C. over 45 minutes. The product was purified by silica gel column chromatography to synthesize 73 mg of the alcohol compound (54) (yield: 92%).
[Α] ²⁹ _D : +158 (c 0.61, CHCl ₃ );
IR (neat): 3441, 1703, 1653 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.03 (s, 3H), 0.04 (s, 3H), 0.86 (s, 9H), 0.82 to 0.90 (m, 3H) ), 1.12-1.68 (m, 12H), 1.87 (brs, 1H), 2.10-2.20 (m, 2H), 2.28-2.48 (m, 3H) , 2.72 (ddt, J = 17, 4, 2 Hz, 1H), 3.50-3.68 (m, 3H), 3.82 (quintet, J = 6 Hz, 1H), 6.39 (dd, J = 6, 2 Hz, 1H), 6.61 (t, J = 8 Hz, 1H), 6.59 (dd, J = 6, 2 Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.4. -4.2, 14.2, 18.2, 18.6, 22.8, 22.9, 25.1, 25.2, 26.0, 31.9, 32.0, 37.3, 37 4, 42.8, 62.5, 71.5, 76.3, 82.9, 133.1, 135.4, 137.8, 160.9, 196.2.

Aldehyde compound (55)
According to the synthesis method of the aldehyde compound (44) from the alcohol compound (43), 20 mg (0.046 mmol) of the alcohol compound (54) is dissolved in 1 mL of dichloromethane, and 15 mg (0.069 mmol) of PCC [manufactured by Tokyo Chemical Industry Co., Ltd.] is used. Then, oxidation reaction was performed for 2 hours. The product was purified by silica gel column chromatography to synthesize 18 mg of the aldehyde compound (55) (yield: 90%). The results of NMR analysis and infrared analysis were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 0.84-0.92 (m, 3H) ), 1.16-1.50 (m, 8H), 1.72-1.84 (m, 2H), 2.16-2.62 (m, 7H), 2.68-2.82 (m) , 1H), 3.50-3.60 (m, 1H), 3.83 (quantet, J = 6 Hz, 1H), 6.39 (dd, J = 6, 2 Hz, 1H), 6.61 (t , J = 8 Hz, 1H), 7.60 (dd, J = 6, 2 Hz, 1H), 9.79 (t, J = 1.5 Hz);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: −4.4, −4.1, 14.2, 18.26, 18.32, 21.5, 22.8, 23.0, 25.1 26.0, 32.1, 37.4, 37.5, 42.7, 42.9, 71.6, 77.4, 81.8, 133.1, 135.4, 137.8, 160. 6, 195.7, 201.7.

Carboxylic acid compound (56)
According to the oxidation reaction of the aldehyde compound (44), 18 mg (0.042 mmol) of the aldehyde compound (55) is mixed with 0.55 mL of tert-butanol [manufactured by Tokyo Chemical Industry Co., Ltd.] and 0.26 mL of phosphate buffer solution of pH 3.6. Dissolved in a solvent, 0.11 mL (1.04 mmol) of 2-methyl-2-butene [manufactured by Tokyo Chemical Industry Co., Ltd.] and 0.21 mL of NaClO ₂ (purity: 80%, 18 mg, 0.16 mmol) aqueous solution were added. added. The reaction was carried out at room temperature for 3 hours, and the resulting crude product was purified by silica gel column chromatography to synthesize 17.5 mg of the carboxylic acid compound (56) (yield: 91%). The results of NMR analysis and infrared analysis were as follows.
IR (neat) 3253, 1707, 1653, 813, 775 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 0.84-0.92 (m, 3H) ), 1.16-1.54 (m, 8H), 1.79 (quintet, J = 7 Hz, 2H), 2.12-2.60 (m, 7H), 2.70-2.84 (m , 1H), 3.52-3.62 (m, 1H), 3.84 (quintet, J = 6 Hz, 1H), 4.4-5.6 (brs, 1H), 6.41 (dd, J = 6, 2 Hz, 1H), 6.62 (t, J = 8 Hz, 1H), 7.63 (dd, J = 6, 2 Hz, 1H).

5-dehydro-Δ ¹² -PGJ ₂ (16)
According to the deprotection of the TBS ether compound (45), 0.4 mL of a 1:19 mixed solution of 55% HF and MeCN was added to 17 mg (0.039 mmol) of the carboxylic acid compound (56) and reacted at 0 ° C. for 15 minutes. . The obtained crude product was purified by silica gel column chromatography to synthesize 12 mg of 5-dehydro-Δ ¹² -PGJ ₂ (16) (yield: 95%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁶ _D : +199 (c 0.14, CHCl ₃ );
IR (neat): 3417, 1699, 1652 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.89 (t, J = 7 Hz, 3H), 1.20-1.60 (m, 8H), 1.77 (quintet, J = 7 Hz, 2H) , 2.16-2.28 (m, 2H), 2.38-2.56 (m, 5H), 2.68-2.82 (m, 1H), 3.56-3.64 (m, 1H), 3.83 (quintet, J = 6 Hz, 1H), 6.43 (dd, J = 6, 2 Hz, 1H), 6.66 (t, J = 8 Hz, 1H), 7.59 (dd, J = 6, 2 Hz, 1 H).

Example 7 5-dehydro-15-deoxy-Δ ^12,14 -PGJ ₂ (17) was synthesized according to the following scheme.

Aldol compound (57)
The aldol compound (57) was synthesized according to the synthesis method of the aldol compound (40). Briefly, a solution of LDA in THF (i-Pr) ₂ NH [manufactured by Tokyo Chemical Industry Co., Ltd.] 0.113 mL (0.81 mmol), THF 6 mL, and n-BuLi 0.34 mL (1.90 M in hexane, 0. 646 mL), and 1 mL of a THF solution of 101 mg (0.323 mmol) of the enone compound (33) was added thereto. Subsequently, 0.058 mL (0.388 mmol) of (E) -2-octenal (46) was added dropwise. The aldol compound (57) thus produced was a 1: 3 mixture of syn and anti isomers, but was not separated and used for the next reaction through a short silica gel column with ethyl acetate.

Dienone Compound (59)
A 3 mL dichloromethane solution of the aldol compound (57) was cooled to −15 ° C., and 0.23 mL (1.62 mmol) of triethylamine (Et ₃ N) and 0.05 mL (0.65 mmol) of MsCl [manufactured by Tokyo Chemical Industry Co., Ltd.] were added. added. After 45 minutes, saturated aqueous sodium hydrogen carbonate was added to stop the reaction, and the product was extracted twice with ethyl acetate. The extracts were combined, dried and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to isolate 96 mg of the dienone compound (59) (yield from the enone compound (33): 71%). , 2 steps). The results of NMR analysis were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 (t, J = 7 Hz, 3H), 1.22-1.75 (m, 10H), 2.10-2.28 (m, 5H) 2.70-2.82 (m, 1H), 3.46 (t, J = 6 Hz, 2H), 3.58-3.67 (m, 1H), 3.80 (s, 3H), 4 .43 (s, 2H), 6.16-6.35 (m, 2H), 6.40 (dd, J = 7, 1.5 Hz, 1H), 6.88 (d, J = 8 Hz, 2H) 6.95 (d, J = 11 Hz, 1H), 7.26 (d, J = 8 Hz, 2H), 7.64 (dd, J = 6, 2 Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 14.2, 18.7, 22.6, 23.6, 25.8, 28.7, 29.1, 31.6, 33.6, 43. 2, 55.4, 69.7, 72.7, 77.2, 82.9, 113.8, 125.4, 129.2, 130.7, 132.0, 134.3, 135.6, 147.3, 159.1, 160.2, 196.8.

Alcohol compound (60)
According to deprotection of the PMB ether compound (42), DDQ [manufactured by Tokyo Chemical Industry Co., Ltd.] 45 mg (0.198 mmol) in a mixed solvent composed of 1.2 mL of dichloromethane and 0.06 mL of water was used to obtain 55 mg of dienone compound (59) ( 0.131 mmol) was deprotected at 0 ° C. over 45 minutes. The product was purified by silica gel column chromatography to synthesize 34 mg of the alcohol compound (60) (yield: 90%). The results of NMR analysis were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 (t, J = 7 Hz, 3H), 1.20-1.83 (m, 10H), 2.10-2.30 (m, 5H) 2.37 (ddt, J = 16, 9, 2 Hz, 1H), 2.74 (ddt, J = 16, 4, 3 Hz, 1H), 3.64, (t, J = 7 Hz, 2H), 3 58-3.72 (m, 1H), 6.22-6.32 (m, 2H), 6.42 (dd, J = 6, 1.5 Hz, 1H), 6.72 (d, J = 11 Hz, 1 H), 7.59 (dd, J = 6, 3 Hz, 1 H).

Aldehyde compound (61)
According to the synthesis method of the aldehyde compound (44) from the alcohol compound (43), 35 mg (0.116 mmol) of the alcohol compound (60) is dissolved in 1 mL of dichloromethane, and 38 mg (0.175 mmol) of PCC [manufactured by Tokyo Chemical Industry Co., Ltd.] is used. For 2 hours. The product was purified by silica gel column chromatography to synthesize 32 mg of the aldehyde compound (61) (yield: 92%). The results of NMR analysis were as follows.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 (t, J = 7 Hz, 3H), 1.16 to 1.52 (m, 6H), 1.80 (quintet, J = 7 Hz, 2H) 2.10-2.40 (m, 5H), 2.54 (t, J = 7 Hz, 2H), 2.74 (ddt, J = 16, 4.5, 2 Hz, 1H), 3.60- 3.69 (m, 1H), 6.17-6.34 (m, 2H), 6.41 (dd, J = 6, 1.5 Hz, 1H), 6.96 (d, J = 11 Hz, 1H) ), 7.59 (dd, J = 6, 3 Hz, 1H), 9.79 (t, J = 2 Hz, 1H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 14.2, 18.3, 21.5, 22.6, 23.4, 28.6, 31.6, 33.6, 42.8, 42. 9, 77.3, 81.8, 125.3, 132.0, 134.2, 135.8, 147.4, 159.8, 196.7, 201.8.

5-Dehydro-15-deoxy-Δ ^12,14 -PGJ ₂ (17)
According to the oxidation reaction of the aldehyde compound (44), 25 mg (0.084 mmol) of the aldehyde compound (61) was mixed with 1.1 mL of tert-butanol [manufactured by Tokyo Chemical Industry Co., Ltd.] and 0.53 mL of pH 3.6 phosphate buffer. Dissolved in a solvent, 0.09 mL (0.084 mmol) of 2-methyl-2-butene [manufactured by Tokyo Chemical Industry Co., Ltd.] and NaClO ₂ [manufactured by Yoneyama Pharmaceutical Co., Ltd.] (purity: 80%, 14 mg, 0 .12 mmol) 0.42 mL of aqueous solution was added. The mixture was reacted at room temperature for 3 hours and purified by silica gel column chromatography to synthesize 24 mg of 5-dehydro-15-deoxy-Δ ^12,14 -PGJ ₂ (17) (yield: 91%). The results of NMR analysis, infrared analysis and polarization degree analysis were as follows.
[Α] ²⁷ _D : +157 (c0.22, CHCl ₃ );
IR (neat): 3100, 1699, 1630, 1209 cm ⁻¹ ;
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 (t, J = 7 Hz, 3H), 1.20-1.56 (m, 6H), 1.79 (quintet, J = 7 Hz, 2H) 2.14-2.38 (m, 5H), 2.45 (t, J = 7 Hz, 2H), 2.70-2.84 (m, 1H), 3.60-3.70 (m, 1H), 6.15-6.36 (m, 2H), 6.42 (dd, J = 6, 2 Hz, 1H), 6.96 (d, J = 11 Hz, 1H), 7.61 (dd, J = 6, 2 Hz, 1 H);
¹³ C-NMR (75 MHz, CDCl ₃ ) δ: 14.2, 18.3, 22.6, 23.4, 23.9, 28.6, 31.6, 32.8, 33.7, 43. 0, 77.4, 81.7, 125.3, 132.2, 134.2, 135.7, 147.6, 160.2, 178.1, 197.1.

As described above, the method for producing a prostaglandin derivative of the present invention is useful for a prostaglandin derivative, and particularly suitable for the production of a delta 12-prostaglandin J ₂ derivative. The expected Delta 12-prostaglandin J ₂ derivative can be provided.

Claims (21)

Starting from a (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound, the 2-cyclopenten-4-one compound has an α side chain at position 1 and an ω side chain at position 5. A method for producing a prostaglandin derivative, comprising:
(A) In the presence of a palladium catalyst and a base, a substitution reaction between the acyloxy group at position 1 of the (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound and a malonic acid diester is performed, A partial introduction step of the α side chain to obtain a compound in which malonic acid diester is added to the 1-position of (1R, 4S) -2-cyclopenten-4-ol;
(B) The carbon chain of the compound in which malonic acid diester is added to the 1-position of the (1R, 4S) -2-cyclopenten-4-ol is extended, and the α side chain is in the 1-position (1R, 4S)- An α side chain extension step to obtain a 2-cyclopenten-4-one compound;
(C) The ω side chain is introduced into the 5-position of the (1R, 4S) -2-cyclopenten-4-one compound to construct the core structure of the prostaglandin derivative, and then converted to the prostaglandin derivative. A method for producing a prostaglandin derivative comprising a step of synthesizing a prostaglandin derivative. The prostaglandin derivative, prostaglandin derivative The method according to claim 1 is a delta 12-prostaglandin J ₂ derivatives.   The method for producing a prostaglandin derivative according to claim 1 or 2, wherein the base in the partial introduction step (A) of the α side chain is one selected from metal tert-butoxide and organolithium. . The α side chain extending step (B) is at least
(B1) By decarboxylation of a compound in which malonic acid diester is added to the 1-position of the (1R, 4S) -2-cyclopenten-4-ol, (1R, 4S) -2-cyclopenten-4-ol-1- A decarboxylation reaction step to obtain an acetic acid compound;
And (b2) a reduction reaction step of reducing the (1R, 4S) -2-cyclopenten-4-ol-1-acetic acid compound to convert it into an aldehyde compound. 2. A method for producing a prostaglandin derivative according to item 1. The α side chain extending step (B) further comprises:
(B3) (1R, 4S) -2-cyclopenten-4-ol having the α-side chain introduced with a carbon-carbon double bond at the 1-position by reacting the aldehyde compound in the step (b2) with a Wittig reagent. An introduction reaction step of a carbon-carbon double bond to obtain a compound;
(B4) A (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position is obtained by oxidizing the hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound. It has an oxidation reaction process, The manufacturing method of the prostaglandin derivative of Claim 4 characterized by the above-mentioned. The α side chain extending step (B) further comprises:
(B5) Introduction of a carbon-carbon triple bond to obtain an acetylene compound having one carbon number increased by a dehydrohalogenation reaction with a strong base after the condensation reaction of the aldehyde compound in the step (b2) with carbon tetrahalide A reaction process;
(B6) a carbon chain extension reaction step of reacting the acetylene compound with a halogenated carbon compound in the presence of a base to obtain a (1R, 4S) -2-cyclopenten-4-ol compound having the α side chain at the 1-position;
(B7) A hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound is oxidized to obtain a (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position. It has an oxidation reaction process, The manufacturing method of the prostaglandin derivative of Claim 4 characterized by the above-mentioned. The prostaglandin derivative is 5-deoxy - delta-12-prostaglandin derivative The method according to claim 6 which is a prostaglandin J ₂ derivatives. The prostaglandin derivative synthesis step (C) includes:
(C1) The above-mentioned (1R) -2-cyclopenten-4-one compound obtained in the step (B) is condensed with n-octanal in which the hydroxyl group at position 3 is protected to synthesize an aldol compound. ω side chain introduction step
(C2) a double bond forming step of forming a double bond of the ω side chain by a dehydration reaction of the aldol compound;
The prostaglandin according to any one of claims 1 to 7, further comprising (c3) an oxidation reaction step of oxidizing a terminal alcohol of the α side chain to a carboxylic acid to obtain a prostaglandin derivative. A method for producing a derivative.   Starting from a (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol compound, the (1R, 4S) -1-acyloxy-2-cyclopenten-4-ol in the presence of a palladium catalyst and a specific base A method for producing a compound in which malonic acid diester is added to the 1-position of (1R, 4S) -2-cyclopenten-4-ol, wherein an exchange reaction between the 1-position acyloxy group of the compound and malonic acid diester is performed.   The malonic acid diester at the 1-position of (1R, 4S) -2-cyclopenten-4-ol according to claim 9, wherein the specific base is one selected from metal tert-butoxide and organolithium. The manufacturing method of the compound which added. The following general formula (1)

(In the formula, R ¹ represents a hydroxyl-protecting group, and R ² represents an organic group having 1 to 3 carbon atoms.) A compound to which an acid diester is added. A compound in which malonic acid diester is added to the 1-position of (1R, 4S) -2-cyclopenten-4-ol represented by the above general formula (1) is used as a starting material, and the α side chain of the prostaglandin derivative is placed in the 1-position. A method for producing a (1R) -2-cyclopenten-4-one compound having:
(B1) By decarboxylation of a compound in which malonic acid diester is added to the 1-position of the (1R, 4S) -2-cyclopenten-4-ol, (1R, 4S) -2-cyclopenten-4-ol-1- A decarboxylation reaction step to obtain an acetic acid compound;
(B2) useful for the production of a prostaglandin derivative characterized by having a reduction reaction step of reducing the (1R, 4S) -2-cyclopenten-4-ol-1-acetic acid compound to convert it to an aldehyde compound A method for producing a (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position, which is an intermediate compound. Further, (b3) (1R, 4S) -2-cyclopentene-4 having the α side chain introduced with a carbon-carbon double bond at the 1-position by reacting the aldehyde compound in the step (b2) with a Uttig reagent. An introduction reaction step of a carbon-carbon double bond to obtain an all compound,
(B4) A (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position is obtained by oxidizing the hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound. (1R) -2-cyclopenten-4-one having the α side chain at the 1-position, which is an intermediate compound useful for the production of a prostaglandin derivative according to claim 12, which comprises an oxidation reaction step Compound production method. Further, (b5) a carbon-carbon triple bond for obtaining an acetylene compound having one carbon number increased by a dehydrohalogenation reaction with a strong base after a condensation reaction of the aldehyde compound in the step (b2) with carbon tetrahalide. An introduction reaction step of
(B6) a carbon chain extension reaction step of reacting the acetylene compound with a halogenated carbon compound in the presence of a base to obtain a (1R, 4S) -2-cyclopenten-4-ol compound having the α side chain at the 1-position;
(B7) A hydroxyl group at the 4-position of the (1R, 4S) -2-cyclopenten-4-ol compound is oxidized to obtain a (1R) -2-cyclopenten-4-one compound having the α side chain at the 1-position. (1R) -2-cyclopenten-4-one having the α side chain at the 1-position, which is an intermediate compound useful for the production of a prostaglandin derivative according to claim 12, which comprises an oxidation reaction step Compound production method. The following general formula (2) useful as an intermediate compound for the production of prostaglandin derivatives

(Wherein X represents a carbon-carbon unsaturated bond, and R ³ represents a hydroxyl-protecting group.) (1R) -2-cyclopentene- 4-one compounds.   (1R) -2-cyclopentene- having the α side chain of the prostaglandin derivative according to claim 15 in position 1 in the general formula (2), wherein X is a carbon-carbon double bond. 4-one compounds.   (1R) -2-cyclopentene-4 having an α side chain in the 1-position of the prostaglandin derivative according to claim 15, wherein X in the general formula (2) is a carbon-carbon triple bond. -ON compounds.   A prostaglandin derivative produced by the method for producing a prostaglandin derivative according to any one of claims 1 to 8. The following general formula (3)

Delta-12-prostaglandin J ₂ derivatives - which (wherein, R ^4, R ⁵ represents independently a hydrogen atom, or 5 of an organic group having a carbon number of 1 to.) 5-dehydro represented by. The following general formula (4)

Delta -12,14- prostaglandin J ₂ derivatives - which (wherein, R ⁴ represents a 5 organic groups from a hydrogen atom or a C 1 -C independently.) 5-dehydro represented by.   The pharmaceutical which contains the prostaglandin derivative of any one of Claims 18-20 as an active ingredient.