JP3195002B2 - New prostaglandin derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to novel prostaglandin I ₂ derivatives. In particular, the present invention is a cycloalkylene group is inserted into the α side chain, and the natural PGI ₂ 7
Position the corresponding halogen atom to a carbon atom, especially prostaglandin I ₂ such that the fluorine atom is bonded, as well as to esters or salts thereof prostaglandin I ₂ class. Hereinafter, including the prostaglandin I ₂ such that collectively these prostaglandin I ₂ derivative. Furthermore, the present invention relates to a medicament containing these prostaglandin I ₂ derivatives as active ingredients. Hereinafter, prostaglandin may be abbreviated as PG.

[0002]

_2. Description of the Related Art Natural PGI ₂ is a local hormone produced in vivo mainly on the inner wall of arterial blood vessels, and has a strong physiological activity, for example, a platelet aggregation inhibitory activity.
It is an important factor that regulates the cell function of living organisms by vasodilatory activity, etc., and attempts have been made to use this directly as a pharmaceutical (PJ Lewis, J.O.
Grady (PJLewis, JOGrady) et al.
Pharmacology of Prostacy
clin), Raven Press, NY, 1981).

[0003]

However, natural PGI
₂ has a very easily hydrolyzed vinyl ether bond in the molecule, and thus is easily deactivated under neutral or acidic conditions, and is not a preferable compound because of its chemical instability as a pharmaceutical.

[0004] For this reason, synthetically stable synthetic PGI ₂ derivatives having the same physiological activity as natural PGI ₂ have been intensively studied inside and outside the country. Among them, examples of introducing a fluorine atom into various sites have been reported ("Journal of the Society of Organic Synthesis", Vol. 42, 794 (1984)).
Fluoro PGI ₂ derivatives have also been reported (JP-A-57-1).
71988, JP-A-60-243079). Also,
The ω side chain for increased efficacy enhancement and stability, PGI ₂ derivative obtained by introducing a cycloalkyl group have also been reported (JP 59-163365 discloses the like).

[0005] However, PGI ₂ compound or its derivative obtained by introducing a cycloalkylene group in α-side chains there is no example is reported.

[0006]

The present inventors SUMMARY OF THE INVENTION introduces a cycloalkylene group in α-side chain of PGI _2, and the natural 7
By introducing a halogen atom to the carbon atom corresponding to the position, a strong platelet aggregation inhibitory effect, anti-anginal effect is obtained,
Moreover, stability was found to be higher due. The halogen atom is preferably a fluorine atom, and the number is preferably one.

The present invention provides the following prostaglandin I ₂
Derivatives, and about the use as a pharmaceutical.

A prostaglandin I ₂ having a structure in which a halogen atom is bonded to the carbon atom corresponding to the 7-position of the natural prostaglandin I ₂ and a cycloalkylene group is inserted into the α-chain, esters thereof, And prostaglandin I ₂ derivatives selected from salts thereof.

A prostaglandin I ₂ derivative represented by the following formula [I]:

[0010]

Embedded image

[0011] However, R ^1: a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, an alkenyl group, an Rukiniru group or a substituted or unsubstituted 5-6 membered cycloalkyl group ring,, R ^2: a hydrogen atom An alkyl group having 1 to 10 carbon atoms or a cation, R ³ and R ^{4 are the} same or different and are a hydrogen atom or a protective group, X ¹ and X ² are one of a hydrogen atom and the other is a fluorine or chlorine atom, k , L , m , n: each represents an integer of 0 to 6, and
0 ≦ k + n ≦ 4, 1 ≦ l + m ≦ 6.

A platelet aggregation inhibitor or an antianginal agent comprising the above-mentioned prostaglandin I ₂ derivative as an active ingredient.

In the PGI _{2 of the} present invention, the natural PG
₂ of the α chain corresponding to the trimethylene group at positions 2 to 4 of I 2
Hydrocarbon moiety of valence is either cycloalkylene group having 3 to 8 carbon atoms, a methylene group Moshiku on at least one of the bonds of the cycloalkylene group bonded dimethylene group
And a divalent hydrocarbon group.

The cycloalkylene group includes cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3
-Cyclopentylene group, 1,2-cyclohexylene group,
A 1,3-cyclohexylene group and a 1,4-cyclohexylene group are preferred.

The hydrocarbon group corresponding to the n-pentyl group at positions 16 to 20 of natural PGI ₂ comprises various monovalent organic groups. Examples of the organic group include an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, and a substituted aryl group, and an alkyl group, a cycloalkyl-substituted alkyl group, and a cycloalkyl group are preferable. Particularly, preferably a linear or branched alkyl group having 5-9 carbon atoms. Preferred PGI ₂ such present invention,
PGI ₂ compounds represented by the formula [I] (where R ² is a hydrogen atom).

The PGI _{2 of the} present invention represented by the general formula [I]
In the derivative, R ¹ is a substituted or unsubstituted C 1
10 alkyl group, an alkenyl group, an Rukiniru group or a substituted or unsubstituted 5-6 membered cycloalkyl group ring. An alkyl group having 1 to 10 carbon atoms, an alkenyl group,
Alkynyl groups include methyl, ethyl, n-propyl,
Iso-propyl, n- butyl, n- pentyl, n- hexyl, 1,1-dimethylpentyl, 2-methylhexyl,
Preferred is 1-methyl-3-pentenyl, 1-methyl-3-hexenyl, 1-methyl-3-pentynyl, or 1-methyl-3-hexynyl. Particularly preferred are alkyl groups having 5 to 9 carbon atoms, and among them, n-pentyl, n-hexyl, 2-methylhexyl, 1,1-
A dimethylpentyl group is preferred.

[0017] The cycloalkyl group of 5 to 6-membered ring substituted or unsubstituted cyclopentyl group, or, for example, methyl, ethyl, propyl, butyl, pentyl, phenoxy, trifluoromethyl Moshiku trifluoromethyl phenoxy group in a cyclohexyl group substituted Moshiku cyclopentyl group.

R ² represents a hydrogen atom , an alkyl group having 1 to 10 carbon atoms , or a cation. As the alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n- propyl, iso-propyl, n- butyl, s- butyl, t- butyl, n- pentyl, n- hexyl, n- heptyl, n-
Examples thereof include linear or branched alkyl groups such as octyl, n-nonyl and n-decyl. Of these, a methyl group and an ethyl group are preferred.

Examples of the cation include NH ₄ ⁺ , tetramethylammonium, monomethylammonium, dimethylammonium, trimethylammonium, benzylammonium, phenethylammonium, morpholinium cation, monoethanolammonium, tris cation and piperidinium cation. Ammonium cation: Alkali metal cation such as Na ⁺ , K ⁺ : 1/2
Examples thereof include divalent or trivalent metal cations such as Ca ²⁺ , 1 / 2Mg ²⁺ , 1 / 2Zn ²⁺ , and 1 / 3Al ³⁺ . Particularly preferred R ² is a methyl group or a sodium ion (Na ⁺ ) .

R ³ and R ⁴ represent the same or different hydrogen atoms or protecting groups. Various protecting groups can be adopted as the protecting group. For example, an alkyl group, an aryl group or an aralkyl group, or the three linked silyl group, an alkanoyl group,
Examples include a tetrahydropyranyl group, a tetrahydrofuranyl group, a benzoyl group, and a methoxyethoxy group. Preferably, three alkyl groups are the same or different trialkylsilyl groups, and among them, at least one alkyl group is particularly preferably an alkyl group having 2 or more carbon atoms.
Specifically, for example, a dimethyl-t-butylsilyl group,
Examples thereof include a triethylsilyl group and a diphenyl-t-butyl group, and a dimethyl-t-butylsilyl group is particularly preferable.

[0021] X ^1, X ^2, one is a hydrogen atom and the other canvas <br/> Tsu atom or a chlorine atom, a fluorine atom is particularly preferred. Particularly preferably when X ¹ is fluorine atom, X ² is a hydrogen atom.

K , l , m and n each represent an integer of 0 to 6, and 1 ≦ l + m ≦ 6 and 0 ≦ k + n ≦ 4.

1 and m each represent a number related to the number of rings of the cycloalkyl group and the position of a bond. Chi Sunawa, l + m + 2
Is the number of carbon atoms constituting the ring of the cycloalkylene group. The smaller numerical value of l and m represents the position of the bond of the cycloalkylene group. For example, when the smaller one of l and m is 0, a 1,2-cycloalkylene group is used.
When the smaller one is 1, it represents a 1,3-cycloalkylene group.

K and n represent the number of methylene groups bonded to the bond of the cycloalkylene group. Both k and n may be 0.

L and m are 0, 1, 2,AlsoIs 3
Is preferred. In particular, l + m is preferably 1 to 4.Sand
The cycloalkylene group is a cyclopropylene group to a cycloalkyl group.
Rohexylene groups are preferred. k and n are each 0,
1,AlsoIs preferably 2, in which case k + n is preferably 0 to 2.
Good. Particularly preferably, k + n is 0.AlsoIs 1.

[0026] further to k + n is preferably smaller as the number of carbon atoms constituting the ring of the cycloalkylene group is increased. Chi Sunawa, l + m + 2 is 3 when 0 ≦ k + n ≦
2, when l + m + 2 is 4, 0 ≦ k + n ≦ 1, l + m + 2
Is preferably 5 to 6, it is preferable that k + n = 0.

Further in addition, the length of the carbon chain corresponding to the trimethylene group at the 2-position and 4-position of naturally occurring PGI _2, Chi words,
Each of k + l + n + 2 and k + m + n + 2 is preferably 6 or less. In particular, the smaller one of k + 1 + n + 2 and k + m + n + 2 is preferably 2 to 4, and the larger one is 3 to 5.

The compound of the present invention represented by the general formula [I] has from 6 to 10 asymmetric carbon atoms in its structure, and therefore has various stereoisomers. Includes all stereoisomers, optical isomers and mixtures thereof.

The PGI ₂ derivative of the present invention can be synthesized by various methods. The feature of the PGI ₂ derivative of the present invention is that it has a structure in which a cycloalkylene group is inserted into the α chain, and can be synthesized using a known method for synthesizing 7-halo PGI ₂ except for this point. In addition, general PG
Application of the I ₂ synthesis method is also possible.

[0030] One of the synthetic methods, as described later, the corresponding 7-halo PGF ₂ alpha and 7-halo-5,6-dehydro-PGF ₂ α (5, 6, 7 in the native This is a method of synthesizing by cyclization at the corresponding position (the same applies to the following description) (see the flow sheet in FIGS. 1 and 2 and the description thereof). There is also a method of synthesizing using Corey lactone as a starting material. Furthermore, it can be synthesized by synthesizing PGI ₂ having a structure in which a cycloalkylene group is inserted into the α chain, and then halogenating the 7-position.

When synthesizing the PGI ₂ derivative of the present invention using Corey lactone as a starting material, it is customary to introduce an ω chain first and then introduce an α chain. However, the α-chain may be introduced first. The introduction of halogen atoms is
The introduction of the two chains can be performed in any order. The synthesis method using Corey lactone as a starting material includes a method in which a halogen atom is introduced before introducing both the α chain and the ω chain and then the remaining chain is introduced, and a method in which the halogen atom is introduced after introducing the α chain and the ω chain. there is a method of introducing a (7-halo-PGF ₂ α and 7-halo-5,6-dehydro-PGF ₂ how to via the α). The former method, and a method which does not pass through the method and it is through the 7-halo PGF ₂ alpha.

Hereinafter, (1) to (3) will be briefly described as examples of a method of introducing an α chain after first introducing an ω chain using Corey lactone as a starting material. The case where the halogen atom is a fluorine atom will be described.

(1) The Corey lactone with an ω chain is fluorinated to synthesize the corresponding fluoroketone. Fluorination is a method in which a hydroxyl group is first introduced into a carbon atom at a position where a fluorine atom is to be introduced, and a fluorine atom is introduced with a fluorinating agent such as dimethylaminosulfur trifluoride.The lactone is converted to an enolate and reacted with XeF ₂ . There are methods.

Next, an α chain is introduced into the fluoroketone.
The basic reaction of introducing an α-chain into a lactone by direct methyleneation is known (T. Okazoe, K. Takai, K. Oshima, K. Utimoto,
J. Org. Chem., 52, 4410, 1987), this method can be applied. Further, fluorolactone is reduced to fluorohemiacetal, and α chain is introduced by Wittig reaction to synthesize compound [VII] (7-fluoro PGF ₂ α) described later. Can be synthesized. For the Wittig reaction, for example, EJCorey, NMWeinshenker, TKSchaaf, W. Huber,
See J. Am. Chem. Soc., 91, 5675, 1969.

(2) The Corey lactone with an ω chain is reduced to lactol, then an α chain is introduced by a Wittig reaction, and then a hydroxyl group is introduced at the 7-position to synthesize the compound [VII] described below. Thereafter, the target compound can be synthesized from compound [VII] as described below.

(3) Cyclopentanecarbaldehyde is synthesized from Corey lactone with ω chain (cyclopentanones with ω chain can also be used as a starting material), and reacted with acetylide to be α-chain to react with 7- synthesizing hydroxy-5,6-dehydro-PGF ₂ alpha. Thereafter, the compound is fluorinated (refer to the fluorination of the flow sheet in FIGS. 1 and 2) to obtain the compound [IV] (7-fluoro-5,6-dehydroPGF ₂ α) described later, Can be synthesized.

Hereinafter, 7-halo PGF ₂ α and 7-halo-
Synthetic method via 5,6-dehydroPGF ₂ α, and 7-halo PGF without Corey lactone as starting material
Will be described in detail _{2 α} and 7-halo-5,6-dehydro-PGF _{2 α} synthesis method. In the description, 7
The halogen atom at the position is a fluorine atom.

The compound of the present invention represented by the general formula [I] is produced by the method shown in the flow sheet shown in FIGS. 1 and 2 (the final product in this flow sheet is represented by the formula [I ']). Compound). FIG. 1 is a flow sheet (part 1) until the synthesis of the compound represented by the formula [IV],
FIG. 2 shows the synthesis of the compound represented by the formula [IV] and the formula [I ′]
5 is a flow sheet (No. 2) up to the compound represented by.

However, the formulas [II] to [II] shown in FIGS.
[VI], and each of the compounds represented by the formula [I ']
The symbols have the following meanings. R¹ ,k,l,m,n: R in the formula [I]¹ ,k,
l,m,Same as n. R^{twenty one}:1-10 carbon atomsAn alkyl group. R³¹ ,R⁴¹: Same or differentAndTrimethylsilyl group
Other protecting groups. R^Five : R other than trimethylsilyl group³¹ ,R⁴¹Different from
Protection group.

[0040] Sunawa Chi, a compound of the formula [II] to the applicant
[III] by the method described in JP-A-61-10551.
], Fluorination (compound [IV]), deprotection (compound [V]), cyclization (compound [VI]), deprotection,
The compound represented by the above formula [I '] can be produced by performing hydrolysis, salt formation, and the like as desired.

In the above formula [III], R ⁵ is a tri (C ₁ -C ₇ ) hydrocarbon silyl group other than a trimethylsilyl group;
Or a group which forms an acetal bond with the oxygen atom of a hydroxyl group. As the tri (C ₁ -C ₇ ) hydrocarbon silyl group, a triethylsilyl group is particularly preferred. The group forming an acetal bond together with the oxygen atom of the hydroxyl group is 2
-Tetrahydropyranyl and 2-tetrahydrofuranyl groups are particularly preferred.

R ³¹ and R ⁴¹ represent R other than a trimethylsilyl group.
It is a protecting group different from ⁵ and is preferably a tri (C ₁ -C ₇ ) hydrocarbon silyl group. Tri (C ₁ -C ₇₎ birds such hydrocarbons as the silyl group t- butyldimethylsilyl group (C
₁ -C ₄₎ alkylsilyl group, t-diphenyl and butyl diphenyl silyl group (C _{1 ~C 4)} such as an alkyl silyl group, or a tribenzylsilyl group is not preferable. R ³¹ , R ⁴¹
Is particularly preferably a t-butyldimethylsilyl group.

The fluorination of the compound [III] can be carried out by a known method (JP-A-60-32718 , JP-A-59-227888). That is, 1,1,2-trichloro-1,2,2-, by an aminosulfur trifluoride fluorinating agent such as piperidinosulfur trifluoride and diethylaminosulfur trifluoride.
It can be preferably carried out in a fluorinated hydrocarbon solvent such as trifluoroethane and trichlorofluoromethane.

The compounds of the formula [IV] by reaction with fluorinating agents are obtained, which compound is converted to a compound of formula [V] by a known deprotection reactions. Examples of the deprotecting agent include acetic acid, p-toluenesulfonic acid, and pyridinium p-
Toluenesulfonate, cation exchange resin and the like as a catalyst, for example, water, methanol, ethanol, or water,
It is preferably carried out by using tetrahydrofuran (hereinafter, also referred to as THF) coexisting with methanol, ethanol, or the like, ethyl ether, dioxane, acetone, acetonitrile, or the like as a reaction solvent. Reaction temperature is usually -78 ° C
It is carried out in a temperature range of up to + 50 ° C. for about 10 minutes to 3 days.

The compound of the formula [V] is converted to a compound of the formula [V] by a cyclization reaction.
[I]. This cyclization reaction can basically use a known method, for example, J. Amer.
c., vol. 104, pp. 5842-5844 (1982). Chi words, allowed cyclized by mercuric trifluoroacetate, then it is possible to carry out the cyclization reaction by hydrogenation in the hydrogenation agent. JP-A-62-120
It can also be carried out according to the method described in JP-A-377. Chi words, allowed cyclized by phenylselenenylsuccinate chloride, then it is possible to perform the cyclization reaction by performing the elimination of phenylselenenylsuccinate group using a reducing agent such as tributyltin hydride.

The cyclization can also be carried out according to the method described in US Pat. No. 4,612,380. Sunawa <br/> Chi, a known method (Tetrahedron Letters, 25, pp. 1383-13
The compound of the formula [V] is hydrogenated according to page 86 (1984)) to give a compound represented by the following formula [VII] (provided that R ¹ , R
² , R ³ , R ²¹ , R ³¹ , R ⁴¹ , k , l , m , and n are the same as defined above), and cyclized with N-iodosuccinimide or iodine. 8-diazabicyclo [5.4.0] window down des Cats 7- et emissions by using a base such as by performing elimination of hydrogen iodide may be carried out cyclization reaction.

[0047]

Embedded image

The thus obtained compound of the formula [VI] may be subjected to a deprotection reaction and / or a hydrolysis reaction and / or an esterification reaction and / or a salt formation reaction, if necessary, to obtain the prostaglandin of the present invention. An I ₂ derivative [I ′] can be obtained. Removal of the hydroxyl-protecting group (deprotection reaction) is performed using tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid, hydrogen fluoride /
Although a fluorine-based reagent such as pyridine can be used, tetrabutylammonium fluoride is particularly preferred. As the reaction solvent, tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile and the like can be used, and usually-
It is preferably carried out by performing the treatment in a temperature range of 78 ° C. to + 50 ° C. for about 10 minutes to 3 days.

The hydrolysis reaction of the 1-position of the ester group by conventional methods, such as sodium hydroxide, potassium, aqueous solution or water calcium hydroxide - alcohol mixture solution, or sodium methoxide, potassium methoxide, alcohol containing sodium ethoxide - water mixture, cut with implementation by allowed to hydrolysis. Further, for example, the treatment is performed by using an enzyme such as lipase in water or a solvent containing water in a temperature range of -10 ° C to + 60 ° C for about 10 minutes to 24 hours. Workup and purification after the reaction of the hydrolysis is carried out in the usual manner after neutralization with dilute hydrochloric acid, acids such as oxalic acid.

The compound to which the carboxyl group formed by the above hydrolysis reaction is bonded is then subjected to a salt formation reaction, if necessary, to give a corresponding carboxylate. The salt formation reaction is known per se, and a carboxylic acid is neutralized with a base compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, or the like in an equivalent amount, or ammonia, trimethylamine, monoethanolamine, morpholine, or the like by an ordinary method. It is performed by reacting. Carboxylates can also be obtained directly by hydrolysis of the esters.

The hydroxyl group is esterified by a usual method of reacting an acid anhydride, an acid halide or the like in the presence of a base, that is, by reacting acetic anhydride, acetyl chloride, benzoyl chloride or the like in the presence of a base such as pyridine or triethylamine. Easily achieved (New Laboratory Chemistry Course 14-II,
1002-1027, edited by The Chemical Society of Japan, Maruzen Co., Ltd.).

[0052] Departure material synthesis of compounds of the formula [II] is but is not particularly limited, for example, FIGS. 3 and 4
Can be synthesized by two methods shown in the flow sheet (No. 1 and No. 2) described in (1).

In the formulas of FIGS. 3 and 4, M is an organic metal (copper, nickel, zirconium, zinc, aluminum)
Represents a species, R ¹ , R ²¹ , R ³¹ , R ⁴¹ and k , l , m ,
n has the same meaning as in formula [II].

Here, the flow sheet shown in FIG. 3 (No. 1)
The method described in the literature (Tetrahedron Letters, vol. 23,
4057 (1982)). Further, in the method of the flow sheet (No. 2) shown in FIG. 4, a method of adding an alkenyl metal reactant to enones by 1,4-addition and capturing with a trimethylsilyl group is known (J. Am. Chem. Soc., 97).
Vol. 107 (1975)), and the obtained silyl ether can be prepared by a known method (J. Am. Chem. Soc., Vol. 95, 3310 (1973)).
I].

The aldehyde represented by the formula [VIII] used herein is a novel compound. The method of synthesizing this compound is not particularly limited, but for example, it is synthesized by the method shown in the flow sheets (Nos. 1 to 5) shown in FIGS.

However, the flow sheet of FIG. 5 (part 1)
Is a flow sheet when k and n are 0 in the formula [VIII]. The flow sheet (No. 2) in FIG. 6 is a flow sheet when k is 0 and n is 1 in the formula [VIII]. The flow sheet (No. 3) in FIG.
5 is a flow sheet when k is 2, l is 1, m and n are 0. The flow sheet (No. 4) in FIG. 8 is a flow sheet when k and l are 1, and m and n are 0 in the formula [VIII]. The flow sheet (No. 5) in FIG. 9 shows that in Formula [VIII], k and n are 0, 1 is 1,
7 is a flow sheet when m is 2.

The compound [I] of the present invention and a salt thereof have a strong platelet aggregation inhibitory action and an antianginal action, and have low toxicity, so that thrombosis, angina, myocardial infarction, arteriosclerosis, etc. It is effective for prevention and treatment of

The pharmacological test results of the compound of the present invention are as follows.

Platelet Aggregation Inhibiting Action Citrated blood was obtained from a guinea pig (Hartley strain) by heart blood sampling. This blood was centrifuged at 120 G for 10 minutes, and the platelet-rich plasma in the supernatant was separated. Platelet aggregation is measured by a bone turbidimetric method (GVR bone: Nature,
Volume 194, page 927, 1962), using an aggregometer.

In the in vitro experiment, the test compound was added to the platelet-rich plasma and incubated for 10 minutes, and then adenosine diphosphate (1 μM) was added to induce platelet aggregation. The degree of aggregation was represented by the maximum change rate (maximum aggregation rate) of the light transmittance within 5 minutes after the addition of adenosine diphosphate, and the results were shown at a 50% inhibitory concentration.

In the ex vivo experiment, the test compound was dissolved in ethanol, and the solution was dissolved in 0.5% tragacanth solution or 1%
It was orally administered suspended in β- cyclo dextrin solution.
Thirty minutes after administration, platelet-rich plasma was prepared from blood obtained by cardiac blood sampling, and platelet aggregation was measured in the same manner as in vitro. The results are shown in Table 1.

In Table 1 and each of the following tables, the abbreviations of the compounds and solvents are as follows. The following compound F (natural prostaglandin I ₂ ) was used as a compound for comparison.

Compound A: 2,3 synthesized in Example 1
-Methylene-7α-fluoro-17,20-dimethyl P
GI ₂ sodium salt. Compound B-b; (1S ^* , 3S ^* ) synthesized in Example 3.
Highly polar substance of -2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester. Compound C: (1S ^* , 3R ^* ) synthesized in Example 4.
-2,4-Ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester. Compound Da; 2,4-methylene- synthesized in Example 7
Low-polarity substance among 7α-fluoro-17,20-dimethyl PGI ₂ methyl ester. Compound D-b; 2,4-methylene- synthesized in Example 7
Highly polar substance among 7α-fluoro-17,20-dimethyl PGI ₂ methyl ester. Compound Ea; 2,4-methylene- synthesized in Example 7
Low polar compound of the 7α- fluoro -17,20- dimethyl PGI ₂ sodium salt. Compound E-b; 2,4-methylene-synthesized in Example 7
High polar compound of the 7α- fluoro -17,20- dimethyl PGI ₂ sodium salt. Compound F; natural PGI ₂ . Solvent X: 0.5% tragacanth solution. The solvent Y; 1% beta-cyclo dextrin solution.

[0064]

[Table 1]

As shown in Table 1, the compounds of the present invention
Has strong platelet aggregation inhibitory activity.

Antianginal effect (suppressive effect of vasopressin-induced ST depression) Vasopressin (0.2 IU / k) from femoral vein of male rat (Donryu strain) anesthetized with pentobarbital
g), and 5 minutes at 30 second intervals for 5 minutes after administration.
The electrocardiogram was recorded for 2 seconds, and the degree of ST depression on the electrocardiogram (average of 5 beats) was calculated. Test compound was dissolved in ethanol intravenous vasopressin load 2 minutes before, or after dissolved in ethanol 0.5% tragacanth solution or suspended in 1% beta-cyclo dextrin solution was orally administered to vasopressin load 30 minutes ago .

The test compound administration group and the untreated control group (5
Example) Two-way analysis of variance was performed for ST
It was determined whether the test compound had an effect of inhibiting ST depression. The results are shown in Table 2.

[0068]

[Table 2]

As shown in Table 2, the compounds of the present invention have strong antianginal activity.

Acute toxicity One group of five ddy male mice (body weight: 25 to 32 g)
Then, a predetermined dose of the test compound dissolved in a small amount of ethanol and then diluted with a 1% aqueous solution of β-cyclodextrin was orally administered, and death was observed for 7 days after the administration. Table 3 shows the dose and the number of dead animals in 5 animals.

[0071]

[Table 3]

As shown in Table 3, the compounds of the present invention
Very low toxicity.

The compounds of the present invention can be administered orally, or subcutaneously,
It is administered parenterally, such as intramuscular, intravenous, transdermal, and rectal. Examples of the dosage form for oral administration include solid preparations such as tablets, granules, powders and capsules, and liquid preparations such as emulsions, solutions, suspensions, syrups and elixirs.

For tablet form, for example, excipients such as lactose, starch, crystalline cellulose, polyvinylpyrrolidone; binders such as carboxymethylcellulose, methylcellulose; disintegration such as sodium alginate, sodium hydrogencarbonate, sodium lauryl sulfate; It can be formed by an ordinary method using an agent or the like. Similarly, granules and powders can be formed by an ordinary method using the above-mentioned excipients and the like.

Capsules can be obtained, for example, by dissolving the compound of the present invention in a vegetable oil such as coconut oil and filling a gelatin soft capsule with a solution obtained.

[0076] Formulations for parenteral administration include sterile aqueous Moshiku non-aqueous solutions, suspensions or Chichinigozai, solid preparation sterile for use in solvent for injection sterile immediately before use Is mentioned. In addition, suppositories for rectal administration,
Pessaries for vaginal administration;

The compounds of the present invention, alpha, can also be used to formulated brought form a β or γ- shea click <br/> b cyclodextrin or methylated cyclodextrin such as inclusion compounds.

[0078] The dosage of the compounds of the present invention is usually a 0.0001~1.0mg / kg per day, intramuscularly, 0.0001~0.3mg / k is subcutaneous or intravenous administration
g , for oral administration, 0.0001 to 1.0 mg / kg is preferred. However, the dosage a patient age, weight, extent of symptoms, kind of disease, differs by number of administrations, but is not limited thereto.

[0079]

EXAMPLES Reference Example below, examples will be described in detail further the present invention by way of Formulation Examples, the present invention is not limited to these examples. Reference Examples 6, 11, 14, 1
7, 24, 31, 38, and 40 are those represented by the formula [VIII]
It is an Example about the aldehyde represented by these.

Reference Example 1 Synthesis of ethyl 2-bromomethylcyclopropanecarboxylate Ethyl (2-formyl) cyclopropanecarboxylate (14.2 g, 0.10 mol) was dissolved in methanol (200 ml).
After cooling to 0 ° C., sodium borohydride (3.8 g, 0.10 mol) was added, and the mixture was stirred for 20 minutes. After evaporating the solvent, saturated saline was added and the mixture was extracted with chloroform. After drying and concentration, silica gel column chromatography (hexane: ethyl acetate =
2: 1) to give (2-hydroxymethyl) cyclopropanecarboxylic acid ethyl ester (14.3 g, yield 99%).

(2-Hydroxymethyl) cyclopropanecarboxylic acid ethyl ester (14.3 g, 0.1 mol) was dissolved in N, N-dimethylformamide (150 ml), and triphenylphosphine (25.9 g, 0.1 mol) was added at room temperature. And stirred for 10 minutes. After cooling to −20 ° C., bromine (15.8 g, 0.1 mol) was added dropwise over 10 minutes. After 1 hour, the reaction mixture was added to a saturated aqueous solution of sodium hydrogen carbonate and extracted with ether. After drying and concentration, purification was performed by column chromatography (hexane: ethyl acetate = 5: 1) to obtain ethyl (2-bromomethyl) cyclopropanecarboxylate (15.3 g, yield 74%).

¹ H- NMR (CDCl ₃ ) δ 0.9-1.0 (m, 1H), 1.27 (t,
J = 7.6Hz, 3H), 1.3-1.5 (m, 1H), 1.6-1.7 (m, 1H), 1.8-2.0 (m,
1H), 3.3-3.4 (m, 2H), 4.25 (q, J = 7.6Hz, 2H).

Reference Example 2 Synthesis of 2-bromomethylcyclopropylmethanol (2-bromomethyl) cyclopropanecarboxylic acid ethyl ester (15.3 g, 74 mmol) was dissolved in ether (50 ml), and lithium aluminum hydride ( 2.8 g, 74 mmol) of ether (1
50 ml) and stirred at room temperature for 1 hour. 2N-
Hydrochloric acid was added, extracted with ether, dried and concentrated. Column chromatography purification provided (2-bromomethyl) cyclopropylmethanol (6.7 g, 55% yield).

¹ H-NMR (CDCl ₃ ) δ 0.6-0.7 (m, 1H), 0.7-0.8
(m, 1H), 1.0-1.2 (m, 2H), 1.7-1.8 (m, 1H), 3.2-3.6 (m, 4H).

Reference Example 3 Synthesis of 2-bromomethylcyclopropylmethyl t-butyldimethylsilyl ether (2-bromomethyl) cyclopropylmethanol (6.7 g,
41 mmol) was dissolved in N, N-dimethylformamide (80 ml), imidazole (6.8 g, 0.1 mol) and t-butyldimethylsilyl chloride (9.0 g, 60 mmol) were added at 0 ° C., and the mixture was stirred for 1 hour. Water was added, the mixture was extracted with ether, dried and concentrated, and purified by silica gel column chromatography to obtain (2-bromomethyl) cyclopropylmethyl t-butyldimethylsilyl ether (10.5 g, yield 92%).

¹ H-NMR (CDCl ₃ ) δ 0.08 (s, 6H), 0.5-0.6 (m,
1H), 0.7-0.8 (m, 1H), 0.92 (s, 9H), 1.0-1.1 (m, 1H), 1.2-1.3
(m, 1H), 3.3-3.4 (m, 2H), 3.56 (d, J = 5.6Hz, 2H).

Reference Example 4 2- (4-tetrahydropyraniloxy-2-butynyl)
Synthesis of cyclopropylmethyl t-butyldimethylsilyl ether Propargyl alcohol tetrahydropyranyl ether
(5.6 g, 40 mmol) was dissolved in THF (80 ml) and cooled to -78 ° C. n-butyl lithium (27 ml, factor = 1.48,
After 40 minutes, the temperature was raised to 0 ° C. After 10 minutes, hexamethylphosphate triamide (hereinafter referred to as HMPT)
(14.3 g, 80 mmol), and (2-bromomethyl) cyclopropylmethyl t-butyldimethylsilyl ether was added thereto.
(11.2 g, 40 mmol) in THF (20 ml) was added, and the mixture was stirred at 0 ° C. for 1 hour and at room temperature for 3 hours. Add water, extract with ether,
After drying and concentration, purification by silica gel column chromatography
2- (4-tetrahydropyraniloxy-2-butynyl)
Cyclopropylmethyl t-butyldimethylsilyl ether (5.8 g, yield 43%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00 (s, 6H), 0.4-0.5 (m,
1H), 0.8-1.0 (m, 3H), 0.86 (s, 9H), 1.4-1.9 (m, 6H), 2.2-2.3
(m, 2H), 3.4-3.5 (m, 3H), 3.8-3.9 (m, 1H), 4.15 (d, J = 14Hz, 1
H), 4.23 (d, J = 14Hz, 1H), 4.7-4.8 (m, 1H).

Reference Example 5 Synthesis of 2- (4-hydroxy-2-butynyl) cyclopropanecarboxylic acid methyl ester 2- (4-tetrahydropyraniloxy-2-butynyl)
Cyclopropylmethyl t-butyldimethylsilyl ether (5.8 g, 17.2 mmol) was dissolved in THF (50 ml), and tetrabutylammonium fluoride (factor = 1.0
, A THF solution (33 ml, 33 mmol)) at 0 ° C. and stirred for 1 hour. By column chromatography purification, 2- (4-tetrahydropyranyloxy-2-butynyl) cyclopropylmethanol (4.3 g) was obtained.

2- (4-tetrahydropyraniloxy-2)
-Butynyl) cyclopropylmethanol (4.3 g) was dissolved in acetone (30 ml) and oxidized to cyclopropanecarboxylic acid with Jones reagent at 0 ° C.

The crude product was dissolved in ether (50 ml) and methylesterified with diazomethane. The reaction solution was concentrated, and the crude product was dissolved in ethanol (30 ml), and pyridinium p-
Add toluenesulfonate (0.5 g) and heat to 50 ° C.
Stir for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride . After drying over magnesium sulfate and concentration, the residue was purified by silica gel column chromatography.
(4-Hydroxy-2-butynyl) cyclopropanecarboxylic acid methyl ester (0.7 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.9-1.0 (m, 1H), 1.1-1.3
(m, 1H), 1.5-1.7 (m, 1H), 1.8-1.9 (m, 1H), 2.4-2.5 (m, 2H),
3.64 (s, 3H), 4.22 (s, 2H).

[0093] <Reference Example 6> 2- (4-oxo-2-butynyl) Synthesis of cyclopropanecarboxylic acid methyl ester O hexa Rirukurorido (0.78 g, 6.2 mmol) in methylene chloride (1
2 ml) and cooled to -40 ° C. A solution of dimethyl sulfoxide (1.0 g, 12.3 mmol) in methylene chloride (4 ml) was added dropwise over 10 minutes. After 15 minutes, a solution of methyl 2- (4-hydroxy-2-butynyl) cyclopropanecarboxylate (0.70 g, 4.1 mmol ) in methylene chloride (5 ml) was added dropwise over 15 minutes. After 40 minutes, triethylamine (2.5
g, 25 mmol) and the temperature was raised to 0 ° C. Add water and add chloride
Extracted with tylene , the crude product was roughly separated by silica gel column chromatography, and 2- (4-oxo-2-butynyl) cyclopropanecarboxylic acid methyl ester (0.32 g)
I got

Reference Example 7 2- (2-hydroxyethyl) cyclopropylmethyl t
Synthesis of -butyldimethylsilyl ether 2-vinylcyclopropylmethyl t-butyldimethylsilyl ether (17.1 g, 81 mmol) was dissolved in THF (100 ml) and cooled to 0 ° C. A borane-dimethylsulfide complex (2.5 g, 33 mmol) was added thereto, and the mixture was stirred for 1 hour. Ethanol (38 ml), 3N-sodium hydroxide (38 ml) and 30% hydrogen peroxide (18.2 ml) were added, and the mixture was stirred for 30 minutes. Saturated saline was added, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, concentrating and purifying by silica gel column chromatography,
(2-Hydroxyethyl) cyclopropylmethyl t-butyldimethylsilyl ether (15.0 g, yield 81%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00 (s, 3H), 0.05 (s, 3
H), 0.3-0.4 (m, 2H), 0.5-0.6 (m, 1H), 0.91 (s, 9H), 0.9-1.0
(m, 1H), 1.1-1.2 (m, 1H), 1.81 (dq, J = 14.0,4.7Hz, 1H), 3.03
(dt, J = 9.4,10.3Hz, 1H), 3.71 (d, J = 4.2Hz, 1H), 3.75 (d, J =
4.2Hz, 1H), 3.94 (dd, J = 10.3,5.1Hz, 1H).

Reference Example 8 Synthesis of 2- (5-tetrahydropyraniloxy-3-pentynyl) cyclopropylmethyl t-butyldimethylsilyl ether 2- (2-hydroxyethyl) cyclopropylmethyl t
-Butyldimethylsilyl ether (15.0 g, 65 mmol) was added to N,
Dissolve in N-dimethylformamide (120 ml), add triphenylphosphine (17.3 g, 66 mmol) at room temperature, and after 20 minutes
It was cooled to -20 ℃ to. Bromine (10.5 g, 66 mmol) was added over 5 minutes, and the temperature was gradually raised to 0 ° C. The mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ether. Drying over magnesium sulfate and purification by silica gel column chromatography gave 2-
(2-Bromoethyl) cyclopropylmethyl t-butyldimethylsilyl ether (2.7 g) was obtained.

A solution of propargyl alcohol tetrahydropyranyl ether (1.44 g, 10.3 mmol) in THF (15 ml) was
After cooling to 78 ° C., n-butyllithium (factor = 1.
5, 6.9 ml, 10.3 mmol) was added, and after 15 minutes, the temperature was raised to 0 ° C. HMPT (3.76 ml, 21 mmol) was added thereto, and the mixture was stirred for 15 minutes. 2- (2-bromoethyl) cyclopropylmethyl t-butyldimethylsilyl ether (2.73 g, 10.3 mmol)
Was added and stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. The crude product was purified by silica gel column chromatography to obtain 2- (5-tetrahydropyranyloxy-3-pentynyl) cyclopropylmethyl t-butyldimethylsilyl ether (3 g).

¹ H-NMR (CDCl ₃ ) δ 0.00 (s, 6H), 0.2-0.3 (m,
1H), 0.3-0.4 (m, 1H), 0.6-0.7 (m, 1H), 0.7-0.8 (m, 1H), 0.87
(s, 9H), 1.4-1.9 (m, 8H), 2.2-2.3 (m, 2H), 3.4-3.5 (m, 3H),
3.7-3.9 (m, 1H), 4.14 (d, J = 14.0Hz, 1H), 4.26 (d, J = 14.0Hz,
1H), 5.76 (t, J = 3.7Hz, 1H).

Reference Example 9 Synthesis of 2- (5-tetrahydropyranyloxy-3-pentynyl) cyclopropylmethanol 2- (5-tetrahydropyranyloxy-3-pentynyl) cyclopropylmethyl t-butyldimethylsilyl ether (3 g) , 10 mmol) was dissolved in THF (10 ml), and tetrabutylammonium fluoride (factor = 1.0, 12 ml,
12 mmol) at 0 ° C. and stirred for 30 minutes. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 2- (5-tetrahydropyranyloxy-3-pentynyl) cyclopropanemethanol (1.2 g).

¹ H-NMR (CDCl ₃ ) δ 0.2-0.4 (m, 2H), 0.6-0.8
(m, 1H), 0.88 (t, J = 7.5Hz, 1H), 1.1-1.9 (m, 8H), 2.2-2.4 (m,
2H), 3.3-3.6 (m, 3H), 3.7-3.9 (m, 1H), 4.14 (d, J = 15Hz, 1H),
4.27 (d, J = 15Hz, 1H), 4.76 (s, 1H).

Reference Example 10 Synthesis of 2- (5-hydroxy-3-pentynyl) cyclopropanecarboxylic acid methyl ester The alcohol (0.70 g, 2.9 mmol) synthesized in Reference Example 9 was chlorinated.
The residue was dissolved in methylene (30 ml), pyridinium chlorochromate (0.90 g) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered through celite and concentrated to give the aldehyde (0.62 g).

In the above aldehyde (0.62 g), silver nitrate (2 g) dissolved in water (4 ml) and sodium hydroxide (0.93 g)
Was dissolved in water (4 ml), a mixture was added at 0 ° C., and the mixture was stirred for 5 minutes. The mixture was filtered through celite and adjusted to pH 7 with concentrated hydrochloric acid. After the solvent was distilled off, the residue was dissolved in ether (3 ml), and a diazomethane-ether solution was added to perform methyl esterification. Methyl ester by silica gel column chromatography purification
(0.46 g) was obtained.

The above methyl ester (0.45 g, 1.5 mmol) was dissolved in ethanol (30 ml), and pyridinium p-toluenesulfonate (80 mg, 0.3 mmol) was added, followed by stirring at 60 ° C. for 2 hours. The title compound (0.31 g) was obtained by silica gel column chromatography purification.

¹ H-NMR (CDCl ₃ ) δ 0.8-2.0 (m, 6H), 2.3-2.5
(m, 3H), 3.68 (s, 3H), 4.25 (s, 2H).

[0105] <Reference Example 11> 2- (5-oxo-3-pentynyl) Synthesis of cyclopropanecarboxylic acid methyl ester O hexa Rirukurorido (0.40 g, 3.1 mmol) in methylene chloride (6
ml) and cooled to -40 ° C. A solution of dimethyl sulfoxide (0.52 g, 6.2 mmol) in methylene chloride (2 ml) was added thereto over 5 minutes, and the mixture was stirred for 20 minutes. 2-
(5-hydroxy-3-pentynyl) cyclopropanecarboxylic acid methyl ester 0.37 g (2 mmol) of salt methylene (5
ml), and stirred for 30 minutes, and triethylamine (1.7 ml, 12 mmol) was added. After the temperature was raised to 0 ° C., saturated saline was added, and the mixture was extracted with methylene chloride . The extract was dried over magnesium sulfate and purified by silica gel column chromatography to give the title compound (0.35 g, yield 96%).

Reference Example 12 Synthesis of (1S ^* , 3S ^* )-3- (3-tetrahydropyraniloxy-1-propynyl) cyclopentanecarboxylic acid methyl ester Preparation of borane-dimethylsulfide complex (1.92 ml, 20.2 mmol) THF (18.3 ml) was added at 0 ° C. 2,3-dimethyl-2-butene 1M in THF (20.2 ml, 20.2 mmol) and the mixture was stirred at the same temperature. After 2 hours, the reaction was cooled to -25 ° C and
-Cyclopentenecarboxylic acid methyl ester (2.55 g, 20.
(2 mmol) in THF (20 ml) was added dropwise, and the mixture was stirred at the same temperature. After 1.5 hours, methanol (1.64 ml) was added dropwise, the reaction temperature was raised to 0 ° C., and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure,
After drying, it was dissolved in THF (20 ml).

Separately, a 1.5 M hexane solution of n-butyllithium (13.7 ml, 20.2 mmol) was added to a solution of propargyl tetrahydropyranyl ether (2.83 g, 20.2 mmol) in THF (20 ml).
0.6 mmol) at 0 ° C. and stir for 1 hour. This solution was added dropwise to the above solution of THF (10 ml) at 0 ° C. After this,
The reaction solution was cooled to −78 ° C., and a solution of iodine (5.13 g, 20.2 mmol) in THF (10 ml) was added dropwise.
Stirred for hours. 2N-sodium hydroxide aqueous solution (12.1m
l), 30% aqueous hydrogen peroxide (2.83 ml) was added dropwise, stirred for 5 minutes, diluted with ethyl acetate (150 ml), and washed with saturated aqueous sodium thiosulfate (150 ml) and saturated saline (150 ml). . The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.56 g, 47.6%).

¹ H-NMR (CDCl ₃ ) δ 1.50-2.10 (m, 12H), 2.80
-3.02 (m, 2H), 3.48-3.60 (m, 1H), 3.67 (s, 3H), 3.80-3.92
(m, 1H), 4.18 (d, J = 15Hz, 1H), 4.30 (d, J = 15Hz, 1H), 4.70-4.
80 (m, 1H).

Reference Example 13 Synthesis of (1S ^* , 3S ^* )-3- (3-hydroxy-1-propynyl) cyclopentanecarboxylic acid methyl ester The carboxylic acid methyl ester synthesized in Reference Example 12 (1.0 g,
3.75 mmol) was dissolved in methanol (4 ml), and pyridinium p-toluenesulfonate (100 mg, 0.4 mmol) was added.
The mixture was stirred at C for 1 hour and 30 minutes. The reaction solution was concentrated under reduced pressure, purified by silica gel column chromatography, and the title compound (532 mg, 78.0
%).

¹ H-NMR (CDCl ₃ ) δ 1.60-2.10 (m, 6H), 2.80-
3.02 (m, 2H), 3.68 (s, 3H), 4.24 (s, 2H).

Reference Example 14 Synthesis of (1S ^* , 3S ^* )-3- (3-oxo-1-propynyl) cyclopentanecarboxylic acid methyl ester The compound (1.95 g, 10.7 mmol) synthesized in Reference Example 13 was obtained. And the title compound (1.31 g, 67.7 g) was obtained in the same manner as in Reference Example 6.
%).

¹ H-NMR (CDCl ₃ ) δ 1.80-2.35 (m, 6H), 2.95
3.10 (m, 2H), 3.69 (s, 3H), 9.19 (s, 1H).

Reference Example 15 Synthesis of (1S ^* , 3R ^* )-3- (3-tetrahydropyraniloxy-1-propynyl) cyclopentanecarboxylic acid methyl ester THF of diisopropylamine (16.6 ml, 118.4 mmol) in 250 ml
ml) solution at 0 ° C. was added with a 1.5 M hexane solution of n-butyllithium (71.0 ml, 106.6 mmol) and stirred for 15 minutes. After the reaction solution was cooled to -70 ° C, a THF (60 ml) solution of the compound (15.8 g, 59.2 mmol) synthesized in Reference Example 12 was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. The reaction solution was poured into a saturated aqueous solution of ammonium chloride (300 ml) and extracted with ether (150 ml × 2). After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 4: 1) to give the title compound (2.34 g, 8.76 mmol, The yield was 14.8%) and the raw material was recovered (8.53 g, 54.0% yield).

¹ H-NMR (CDCl ₃ ) δ 1.50-2.38 (m, 12H), 2.60
-2.84 (m, 2H), 3.48,3.60 (m, 1H), 3.68 (s, 3H), 3.80-3.92
(m, 1H), 4.19 (d, J = 15Hz, 1H), 4.30 (d, J = 15Hz, 1H), 4.75-4.
85 (m, 1H).

Reference Example 16 Synthesis of (1S ^* , 3R ^* )-3- (3-hydroxy-1-propynyl) cyclopentanecarboxylic acid methyl ester The compound (2.34 g, 8.76 mmol) synthesized in Reference Example 15 was obtained. Use
In the same manner as in Reference Example 13, the title compound (1.41 g, 7.75 mmol,
Yield 88.5%).

¹ H-NMR (CDCl ₃ ) δ 1.72-2.35 (m, 6H), 2.62-
2.90 (m, 2H), 3.69 (s, 3H), 4.25 (s, 2H).

Reference Example 17 Synthesis of (1S ^* , 3R ^* )-3- (3-oxo-1-propynyl) cyclopentanecarboxylic acid methyl ester The compound (1.41 g, 7.75 mmol) synthesized in Reference Example 16 was obtained. And using the title compound (1.08 g, 6.05 mmol) in the same manner as in Reference Example 6.
1, yield 77.4%).

¹ H-NMR (CDCl ₃ ) δ 1.80-2.42 (m, 6H), 2.75
2.95 (m, 2H), 3.70 (s, 3H), 9.19 (s, 1H).

Reference Example 18 Synthesis of 4- (t-butyldimethylsiloxymethyl) -1-cyclohexanecarbaldehyde 1,4-Cyclohexanedimethanol (72.1 g) was added to N, N
-Dissolved in dimethylformamide (500 ml), imidazole (68.1 g) and t-butyldimethylsilyl chloride (75.4
g) was added and stirred at room temperature for 14 hours. The mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with ether, and dried. Purification by silica gel column chromatography, and monosilyl ether (7
2.5 g).

[0120] Then, methylene chloride Oki Sa Rirukurorido (18.5ml) (480ml) was added dimethyl sulfoxide (30.1ml)
Was added at -78 ° C. After stirring for 5 minutes, a solution of the above monosilyl ether (50 g) in methylene chloride (190 ml) was added at -78 ° C, and the mixture was further stirred for 30 minutes. After dropwise addition of triethylamine (135 ml) at -78 ° C, the temperature was gradually raised to room temperature. The mixture was poured into 1 liter of water, and the aqueous layer was extracted with methylene chloride. The extracts were combined, washed with saline, dried and concentrated, and then purified by column chromatography to give the title compound.
(49 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.84-0.85 (m, 9H), 3.37
(m, 2H), 9.58 (s, 1H).

Reference Example 19 Synthesis of 4- (2,2-dibromovinyl) -1-cyclohexanemethanol t-butyldimethylsilyl ether A solution of the aldehyde (57.6 g) synthesized in Reference Example 18 in methylene chloride (600 ml) was prepared. At 0 ° C., triphenylphosphine (118
g), a mixture of carbon tetrabromide (81.9 g) and methylene chloride (200 ml) was added. After stirring for 1 hour, the mixture was added to a saturated aqueous solution of sodium hydrogen carbonate and extracted with ether. The extract was washed with saline, dried and purified by column chromatography to give the title compound (67.
6g).

¹ H-NMR (CDCl ₃ ) δ 0.86 (s, 9H), 3.4 (m, 2H).

Reference Example 20 Synthesis of 4- (3-tetrahydropyranyloxy-1-propynyl) cyclohexanemethanol t-butyldimethylsilyl ether THF of dibromide (62 g) synthesized in Reference Example 19 (500 g) was used.
l) 1.5M hexane solution of n-butyllithium in the solution
(207 ml), and the mixture was cooled to -78 ° C, paraformaldehyde (9.34 g) was added, and the mixture was stirred at -20 ° C for 12 hours and at room temperature for 2 hours, and then poured into a saturated aqueous solution of sodium hydrogen carbonate.
Extracted with ether. The extract was washed with brine, dried and concentrated. The residue was dissolved in methylene chloride (310 ml),
-Dihydropyran (15.7 ml) and p-toluenesulfonic acid
(2.97 g) was added and the mixture was stirred at room temperature for 14 hours. Pour into saturated aqueous sodium bicarbonate, extract with methylene chloride, dry,
After concentration, the residue was purified by column chromatography to obtain the title compound (31.6 g).

¹ H-NMR (CDCl ₃ ) δ 0.86 (s, 9H), 3.37 (m, 2
H), 4.79 (m, 1H).

Reference Example 21 Synthesis of 4- (3-tetrahydropyranyloxy-1-propynyl) -1-cyclohexanemethanol THF of silyl ether (31.6 g) synthesized in Reference Example 20
To the (170 ml) solution was added a 1 M solution of tetrabutylammonium fluoride in THF (94.8 ml) at 0 ° C., and the mixture was stirred at room temperature for 14 hours, concentrated, and purified by column chromatography to give the title compound (21.3 g).

¹ H-NMR (CDCl ₃ ) δ 4.81 (m, 1H).

[0128] in methylene chloride (165 ml) solution of <Reference Example 22> 4- (3-tetrahydropyranyloxy-1-propynyl) -1-cyclohexanecarbaldehyde Oki Sa Rirukurorido (6.38Ml), dimethyl sulfoxide (10.38 ml) methylene chloride
(35 ml) solution was added dropwise at -78 ° C. After stirring for 10 minutes, a solution of the alcohol (16.78 g) synthesized in Reference Example 21 in methylene chloride (65 ml) was added dropwise at -78 ° C, and the mixture was stirred for 30 minutes. Triethylamine (46.3 ml) was added dropwise at -78 ° C, the temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 30 minutes. After pouring into water and extracting with methylene chloride, the extract is washed with brine, dried, concentrated, and purified by column chromatography to give the title compound.
(16.0 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 4.80 (m, 1H), 9.63 (m, 1
H).

Reference Example 23 Synthesis of methyl 4- (3-hydroxy-1-propynyl) -1-cyclohexanecarboxylate Silver nitrate (22.7
g) (45 ml) and an aqueous solution (45 ml) of sodium hydroxide (10.5 g) were added with the aldehyde (16.0 g) synthesized in Reference Example 22 at 0 ° C., and the mixture was stirred at 0 ° C. for 15 minutes. The reaction mixture was filtered through celite, washed with hot water, and allowed to cool. After acidification with hydrochloric acid, ether extraction, the extract was dried,
Concentrated. The residue was dissolved in ether (120 ml), and diazomethane (0.5 M ether solution, 13 ml) was added dropwise at 0 ° C.

The reaction solution was concentrated, and the residue was ethanol (100 m
l) and dissolved in pyridinium p-toluenesulfonate
(0.89 g), and the mixture was stirred at 40 ° C for 30 minutes and at 55 ° C for 3.5 hours. The mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate, extracted with chloroform, dried and concentrated, and then purified by column chromatography to obtain the title compound (7.42 g).

¹ H-NMR (CDCl ₃ ) δ 1.3-2.4 (m, 10H), 3.67
(m, 3H), 4.25 (m, 2H). IR (CDCl ₃ ) 3600, 3460, 2220, 1720 cm ^-1 .

[0133] <Reference Example 24> 4- (3-oxo-1-propynyl) cyclohexane methylene chloride-carboxylic acid methyl ester Synthesis Oki Sa Rirukurorido (3.63 ml) in methylene chloride (95 ml) solution of dimethyl sulfoxide (5.91Ml) (19ml)
The solution was added at −78 ° C., and the mixture was stirred for 5 minutes.
Methylene chloride (38 ml) of the alcohol (7.02 g) synthesized in Step 3
The solution was added dropwise at -78 ° C and stirred for 30 minutes. Triethylamine (26.4 ml) was added at −78 ° C., the temperature was raised to room temperature, and 30
Stirred for minutes. The mixture was poured into water and extracted with methylene chloride. The extract was washed with brine, dried, concentrated, and purified by column chromatography to give the title compound (5.2 g).

¹ H-NMR (CDCl ₃ ) δ 1.4-2.5 (m, 10H), 3.68
(m, 3H), 9.19 (m, 1H).

[0135] [Example 1] 2,3-methylene -7α- fluoro -17,20- dimethyl PGI ₂ sodium salt

Example 1-1 5,6-dehydro-2,3-methylene-7-hydroxy-17,20-dimethyl PGE ₂ methyl ester 1
Synthesis of 1,15-bis (t-butyldimethyl) silyl ether t-butyllithium (factor = 1.5, pentane solution, 2.7 ml, 4.0 mmol) was added to ether (5 ml) at -78 ° C. (1E, 3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-1-iodo-1-nonene (0.79
g, 2.0 mmol) was dissolved in ether (5 ml) and added dropwise over 10 minutes. After stirring at −78 ° C. for 2 hours, pentyl copper
(0.26 g, 2.0 mmol) and HMPT (0.65 g, 4.0 mmol) were dissolved in ether (10 ml) and added dropwise over 15 minutes.

After 1.5 hours, (4R) -4-t-butyldimethylsiloxy-2-cyclopentenone (0.40 g, 1.9 mm
ol) in ether (10 ml) was added thereto, and after 20 minutes,-
The temperature was raised to 40 ° C. Further, 2- (4-oxo-
A solution of 2-butynyl) cyclopropanecarboxylic acid methyl ester (0.32 g, 2.0 mmol) in ether (10 ml) was added dropwise over 15 minutes. After stirring at -40 ° C for 1 hour, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. Purify by silica gel column chromatography to give the title compound (0.66 g, 53% yield)
I got

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.6-
1.0 (m, 27H), 1.0-1.5 (m, 9H), 2.2-2.9 (m, 9H), 3.65 (s, 3H),
4.0-4.2 (m, 2H), 5.5-5.7 (m, 2H).

[0139] <Example 1-2> 5,6-dehydro-2,3-methylene-7-trimethylsiloxy -17,20- dimethyl PGF ₂ alpha methyl ester 11,15- bis (t-butyldimethyl) silyl 9 Synthesis of triethylsilyl ether The alcohol (0.40 g, 0.62 mmol) synthesized in Example 1-1 was used.
Dissolved in methylene chloride (5 ml) and cooled to 0 ° C. Pyridine (0.50 ml, 6.2 mmol) and chlorotrimethylsilane (0.20 ml, 1.55 mmol) were added thereto for post-treatment. The crude product was dissolved in methanol (6ml) and cooled to -30 ° C. To this was added sodium borohydride (78 mg, 2.1 mmol) and 40
For a minute. A post-treatment was performed by adding a saturated aqueous solution of ammonium chloride.

The crude product was dissolved in pyridine (5 ml).
Cooled to 2 ° C. Here chlorotriethylsilane (0.22m
1,1.3 mmol) and stirred at 0 ° C. for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added, extracted with hexane, dried,
After concentration, purify by silica gel column chromatography to obtain the title compound.
(0.32 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.5-
0.7 (m, 6H), 0.7-1.0 (m, 36H), 1.1-1.6 (m, 9H), 1.9-2.7 (m, 7
H), 3.63 (s, 3H), 3.8-4.2 (m, 3H), 4.5-4.7 (m, 1H), 5.4-5.6
(m, 2H).

[0142] <Example 1-3> 5,6-dehydro-2,3-methylene -7β- fluoro -17,20- dimethyl PGF ₂ alpha methyl ester 1
Synthesis of 1,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether The trimethylsilyl ether synthesized in Example 1-2 (0.3
2g, 0.39 mmol) with 1,1,2-trichloro-1,2,2-
Dissolved in trifluoroethane (8 ml) and cooled to 0 ° C.
Piperidinosulfur trifluoride (0.062ml, 0.47mmo
l) was added and the mixture was stirred at room temperature for 5.5 hours. Triethylamine was added, and a saturated aqueous potassium carbonate solution was added. The title compound (0.21 g) was obtained by silica gel column chromatography purification.

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.5-
0.7 (m, 6H), 0.7-1.0 (m, 36H), 1.1-1.6 (m, 9H), 1.9-2.7 (m, 7
H), 3.63 (s, 3H), 3.85 (q, J = 6.5Hz, 1H), 4.1-4.2 (m, 1H), 4.2
-4.3 (m, 1H), 5.35 (dd, J = 48,7.5Hz, 1H), 5.4-5.5 (m, 2H). 19 F-NMR (CDCl 3, CCl 3 F reference) -170.0ppm (m) .

[0144] <Example 1-4> 5,6-dehydro-2,3-methylene -7β- fluoro -17,20- dimethyl PGF ₂ alpha methyl ester 1
Synthesis of 1,15-bis (t-butyldimethyl) silyl ether Triethylsilyl ether synthesized in Example 1-3 (0.2
1 g, 0.27 mmol) was dissolved in ethanol (5 ml), pyridinium p-toluenesulfonate (7 mg, 0.027 mmol) was added at 0 ° C, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride . After drying and concentration, the title compound (9
5 mg).

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.8-
1.0 (m, 36H), 1.0-2.0 (m, 13H), 2.4-2.6 (m, 2H), 3.12 (dd, J =
8.4, 11.2Hz, 1H), 3.62 (s, 3H), 4.0-4.2 (m, 2H), 4.2-4.4 (m,
1H), 5.2-5.5 (m, 3H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -169.3 ppm (dm, J = 47.1 Hz).

[0146] <Example 1-5> 2,3 methylene -7β- fluoro -17,20- dimethyl PGF ₂ alpha methyl ester 11,15- bis (t
Synthesis of (-butyldimethyl) silyl ether Examples 1-4
(95mg, 0.15mmol) with benzene (2.5ml)
And cyclohexane (2.5 ml), and cyclohexene (0.15 ml, 1.5 mmol) and a Lindlar catalyst (20 mg) were added. The mixture was hydrogenated at 0 ° C. for 1.5 hours to obtain the title compound .

¹ H-NMR (CDCl ₃ ) δ 0.0-0.1 (m, 12H), 0.6-1.
0 (m, 27H), 1.0-2.4 (m, 16H), 3.70 (s, 3H), 4.0-4.2 (m, 2H),
4.3-4.4 (m, 1H), 5.2- 5.7 (m, 5H). 19 F-NMR (CDCl 3, CCl 3 F reference) -167.0ppm (d, J = 48Hz ).

Example 1-6 2,3-Methylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester 11,15-bis (t-
Synthesis of butyldimethyl) silyl ether The compound (100 mg, 0.15 mmol) synthesized in Example 1-5 was dissolved in acetonitrile (4 ml), and N-iodosuccinimide was dissolved.
(0.49 g, 2.2 mmol) was added and the mixture was stirred at 40 ° C. for 24 hours.
A 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with methylene chloride . The organic layer was dried and concentrated, and purified by silica gel chromatography to give a cyclized form (83 mg).

[0149] The cyclized compound of (83 mg) was dissolved in toluene (5 ml), 1,8-diazabicyclo [5.4.0] window down des Cats -
7-d down the (0.15 ml) was added and stirred for 18 hours at 110 ° C.. Saturated saline was added, and the mixture was extracted with ether. The organic layer was dried and concentrated, and purified by silica gel column chromatography to obtain the title compound (14 mg).

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.7-
1.0 (m, 27H), 1.0-1.8 (m, 12H), 2.0-2.2 (m, 1H, H-4), 2.3-2.
4 (m, 1H, H-10), 2.4-2.6 (m, 1H, H-8), 2.7-2.8 (m, 1H, H-12),
3.62 (s, 3H), 3.8-3.9 (m, 1H, H-11), 4.1-4.2 (m, 1H, H-15),
4.5-4.6 (m, 2H, H-5, H-9), 5.32 (dd, J = 53,7.5Hz, 1H), 5.4-
5.6 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -184.0 ppm (d, J = 53 Hz, 0.5
F), - 184.2 ppm (d, J = 51.7Hz, 0.5F).

<Example 1-7> Synthesis of 2,3-methylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester The t-butyldimethylsilyl ether compound (13 mg) synthesized in Example 1-6 was prepared. Dissolve in THF (1 ml) and add tetrabutylammonium fluoride (factor = 1, THF solution,
0.16 ml, 0.16 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium sulfate solution was added, and the mixture was extracted with ethyl acetate. After drying and concentrating the organic layer, florisil (florisi
l) Purification by column chromatography gave the title compound (9 mg).

¹ H-NMR (CDCl ₃ ) δ 0.7-1.0 (m, 9H), 1.0-1.9
(m, 11H), 2.4-2.8 (m, 5H), 3.60 (s, 3H), 3.85 (q, J = 7.5Hz, 1
H), 4.10 (q, J = 6.5Hz, 1H), 4.5-4.6 (m, 2H), 5.35 (dm, 1H), 5.
5-5.6 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -186.0 ppm (d, J = 55.0 Hz, 0.
5F),-188.0ppm (d, J = 55.5Hz, 0.5F).

[0153] <Example 1-8> 2,3 methylene -7α- fluoro -17,20- synthesized methyl ester in Example 1-7 dimethyl PGI ₂ sodium salt (9 mg) in ethanol (0.30 ml) Dissolved in 0.1N sodium hydroxide
(0.28 ml) was added and the mixture was stirred at 25 ° C. for 36 hours. Concentration and drying gave the title compound.

[0154] [Example 2] 4-homo-2,3-methylene -7α- fluoro -17,20- dimethyl PGI ₂ sodium salt

<Example 2-1> 5,6-Dehydro-4-homo-2,3-methylene-7-
Synthesis of hydroxy-17,20-dimethyl PGE ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether t-butyllithium (factor = 1.5, pentane solution, 2.7 ml, 4.0 mmol) was added to ether (5 ml). , At -78 ° C. (1E, 3S, 5S) -3-t-butyldimethylsiloxy-5-methyl-1-iodo-1-nonene (0.79
g, 2.0 mmol) was dissolved in ether (5 ml) and added dropwise over 10 minutes. After stirring at −78 ° C. for 2 hours, pentyl copper
(0.26 g, 2.0 mmol) and HMPT (0.65 g, 4.0 mmol) were dissolved in ether (10 ml) and added dropwise over 15 minutes.

After 1.5 hours, (4R) -4-t-butyldimethylsiloxy-2-cyclopentenone (0.40 g, 1.9 m
mol) of ether (10 ml) was added thereto, and after 20 minutes,-
The temperature was raised to 40 ° C. Further, 2- (5-oxo-
A solution of 3-pentynyl) cyclopropanecarboxylic acid methyl ester (0.35 g, 2.0 mmol) in ether (10 ml) was added dropwise over 15 minutes. After stirring at -40 ° C for 1 hour, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. Purify by silica gel column chromatography to give the title compound (0.66 g, yield 53
%).

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.6-
1.0 (m, 27H), 1.0-1.5 (m, 11H), 2.1-2.4 (m, 7H), 2.6-2.8 (m,
2H), 3.62 (s, 3H), 4.0-4.2 (m, 2H), 5.5-5.6 (m, 2H).

<Example 2-2> 5,6-Dehydro-4-homo-2,3-methylene-7-
Trimethylsiloxy -17,20- dimethyl PGF ₂ alpha
Synthesis of methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the alcohol (0.66 g, 1.0 mmol) synthesized in Example 2-1 in the same manner as in Example 1-2, the title compound ( 0.59g)
I got

Example 2-3 5,6-dehydro-4-homo-2,3-methylene-7β
Synthesis of -Fluoro-17,20-dimethyl PGF ₂ α-methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Trimethylsilyl ether synthesized in Example 2-2 (0.5
(9 g, 0.70 mmol) and fluorinated in the same manner as in Example 1-3 to obtain the title compound (0.39 g).

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.5-
0.6 (m, 6H), 0.7-1.0 (m, 36H), 1.1-1.6 (m, 11H), 1.8-2.4 (m,
6H), 2.6-2.7 (m, 1H), 3.63 (s, 3H), 3.86 (q, J = 6.5Hz, 1H), 4.
1-4.2 (m, 1H), 4.2-4.3 (m, 1H), 5.32 (dd, J = 49,7.5Hz, 1H),
5.4-5.6 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -169.6 ppm (m).

<Example 2-4> 5,6-Dehydro-4-homo-2,3-methylene-7β
Synthesis of -Fluoro-17,20-dimethyl PGF ₂ α-methyl ester 11,15-bis (t-butyldimethyl) silyl ether Triethylsilyl ether synthesized in Example 2-3 (0.3
The title compound (0.24 g) was obtained in the same manner as in Example 1-4 using 9 g (0.50 mmol).

Example 2-5 4-Homo-2,3-methylene-7β-fluoro-17,
20-dimethyl PGF ₂ α methyl ester 11,15
Synthesis of -bis (t-butyldimethyl) silyl ether Using the compound (0.24 g) synthesized in Example 2-4, the title compound (0.21 g) was obtained in the same manner as in Example 1-5.

¹ H-NMR (CDCl ₃ ) δ 0.0-0.1 (m, 12H), 0.6-1.
0 (m, 27H), 1.0-2.4 (m, 18H), 3.65 (s, 3H), 4.0-4.2 (m, 2H),
4.3-4.4 (m, 1H), 5.2-5.7 (m, 5H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -167.2 ppm (dm, J = 47.9 Hz).

Example 2-6 4-Homo-2,3-methylene-7α-fluoro-17,
20-dimethyl PGI ₂ methyl ester 11,15-
Synthesis of bis (t-butyldimethyl) silyl ether Using the compound (0.21 g, 0.35 mmol) synthesized in Example 2-5, the title compound (34 mg) was obtained in the same manner as in Example 1-6.

¹ H-NMR (CDCl ₃ ) δ -0.1-0.1 (m, 12H), 0.6-
1.0 (m, 27H), 1.0-1.8 (m, 13H), 2.0-2.2 (m, 2H), 2.3-2.4 (m,
1H), 2.4-2.6 (s, 1H), 2.7-2.8 (m, 1H), 3.62 (s, 3H), 3.80 (q,
J = 7.5Hz, 1H), 4.1-4.2 (m, 1H), 4.5-4.6 (m, 2H), 5.28 (dd, J =
56,7.5Hz, 1H), 5.4-5.6 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.6ppm (d, J = 56Hz).

Example 2-7 4-Homo-2,3-methylene-7α-fluoro-17,
Synthesis of 20-dimethyl PGI ₂ methyl ester Using the silyl ether compound (34 mg) synthesized in Example 2-6, the title compound (24 mg) was obtained in the same manner as in Example 1-7.

¹ H-NMR (CDCl ₃ ) δ 0.7-1.0 (m, 6H), 0.87 (d,
J = 6.3Hz, 3H), 1.0-1.9 (m, 13H), 2.4-3.0 (m, 5H), 3.66 (s, 1.
5H), 3.67 (s, 1.5H), 3.8-3.9 (m, 1H), 4.1-4.2 (m, 1H), 4.5-
4.7 (m, 1H), 5.40 (d, J = 55Hz, 1H), 5.56 (d, J = 4.1Hz, 1H). 19 F-NMR (CDCl 3, CCl 3 F reference) -187.0ppm (d, J = 57.0Hz, 0.
5F),-187.3ppm (d, J = 54.7Hz, 0.5F).

Example 2-8 4-Homo-2,3-methylene-7α-fluoro-17,
20-synthesized methyl ester in Example 2-7 dimethyl PGI ₂ sodium salt (24mg, 0.06mmo
l) was dissolved in ethanol (0.73 ml), 0.1 N sodium hydroxide (0.68 ml) was added, and the mixture was stirred at 25 ° C for 48 hours. Concentration and drying gave the title compound.

[Embodiment 3] (1S ^* , 3S ^* )-2, 4
-Ethylene-7α-fluoro-17,20-dimethyl P
GI ₂ methyl ester and sodium salt

Example 3-1 (1S ^* , 3S ^* )-2,4-ethylene-5,6-dehydro-7-hydroxy-17,20-dimethyl PGE ₂
Synthesis of methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the aldehyde (1.36 g, 7.56 mmol) synthesized in Reference Example 14, the title compound (3.07 g) was obtained in the same manner as in Example 1-1. g,
Yield 67.2%).

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.80
-1.00 (m, 24H), 3.69 (s, 3H), 4.15-4.25 (m, 2H), 5.54-5.70
(m, 2H).

Example 3-2 (1S ^* , 3S ^* )-2,4-Ethylene-5,6-dehydro-7-trimethylsiloxy-17,20-dimethyl PGF ₂ α-methyl ester 11,15-bis Synthesis of (t-butyldimethyl) silyl ether Using the compound (3.07 g, 4.62 mmol) synthesized in Example 3-1 and in the same manner as in Example 1-2, the title compound (2.77 g, yield 70.5). %).

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 21H), 0.50
-0.70 (m, 6H), 0.80-1.00 (m, 30H), 3.68 (s, 3H), 4.15-4.25
(m, 2H), 5.50-5.70 (m, 2H).

Example 3-3 (1S ^* , 3S ^* )-2,4-ethylene-5,6-dehydro-7β-fluoro-17,20-dimethyl PGF ₂
Synthesis of α-methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound synthesized in Example 3-2 (2.77 g, 3.26 mmol), the same as in Example 1-3 The title compound (2.15 g, yield 84.9%) was obtained by the operation.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.50
-0.70 (m, 6H), 0.80-1.00 (m, 30H), 3.68 (s, 3H), 4.15-4.25
(m, 2H), 5.40-5.70 (m, 3H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -169.0 ppm (m).

Example 3-4 (1S ^* , 3S ^* )-2,4-ethylene-5,6-dehydro-7β-fluoro-17,20-dimethyl PGF ₂
Synthesis of α-methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the compound synthesized in Example 3-3 (2.15 g, 2.77 mmol), the title was obtained in the same manner as in Example 1-4. The compound (1.13 g , yield 61.5%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.80
-1.00 (m, 24H), 3.68 (s, 3H), 4.08-4.24 (m, 2H), 5.28-5.56
(m, 3H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F) -169.0 ppm (m).

Example 3-5 (1S ^* , 3S ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester 1
Synthesis of 1,15-bis (t-butyldimethyl) silyl ether The same operation as in Examples 1-5 and 1-6 using the compound (1.13 g, 1.70 mmol) synthesized in Example 3-4. To give the title compound. Low polarity (127 mg, 11.2% yield), high polarity (67 mg, 5.9% yield).

Low polar substance ¹ H-NMR (CDCl ₃ ) δ 0.00-0.10 (m, 12H), 0.80-0.90 (m, 24
H), 3.63 (s, 3H), 5.26 (dd, J = 56,9Hz, 1H), 5.50-5.55 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -183.4 ppm (dd, J = 56, 9 Hz).

Highly polar substance ¹ H-NMR (CDCl ₃ ) δ 0.02 (s, 12H), 0.84-0.88 (m, 24H), 3.65
(s, 3H), 5.26 ( dd, J = 56,9Hz, 1H), 5.50-5.55 (m, 2H). 19 F-NMR (CDCl 3, CCl 3 F reference) -183.0ppm (dd, J = 56 , 9Hz).

Example 3-6 Synthesis of (1S ^* , 3S ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI _2- methyl ester Among the compounds synthesized in Example 3-5 Low polar substance (127mg,
0.19 mmol) to obtain a low-polar compound (58 mg, yield 70.2%) of the title compound in the same manner as in Example 1-7. Example 3
Highly polar compound (67 mg, 0.10 mmol) among the compounds synthesized in -5
Was used to obtain a highly polar title compound (33 mg, yield 75.1%) in the same manner as in Example 1-7.

Low polar substance ¹ H-NMR (CDCl ₃ ) δ 0.80-0.95 (m, 6H), 3.67 (s, 3H), 3.80-
3.95 (m, 1H), 4.10-4.20 (m, 1H), 4.55-4.65 (m, 2H), 5.35 (d
d, J = 56,9Hz, 1H) , 5.50-5.60 (m, 2H). 19 F-NMR (CDCl 3, CCl 3 F reference) 185.6ppm (dd, J = 56,9Hz ).

Highly polar substance ¹ H-NMR (CDCl ₃ ) δ 0.80-0.95 (m, 6H), 6.67 (s, 3H), 3.80-
3.95 (m, 1H), 4.10-4.20 (m, 1H), 4.50-4.65 (m, 2H), 5.35 (d
d, J = 56,9Hz, 1H) , 5.55-5.60 (m, 2H). 19 F-NMR (CDCl 3, CCl 3 F reference) -184.9ppm (dd, J = 56,9Hz ).

[0184] <Example ^{3-7> (1S *, 3S *} ) of 2,4-ethylene -7α- fluoro -17,20- compound synthesized in Synthesis Example 3-6-dimethyl PGI ₂ sodium salt Using a low-polar substance (96 mg) and the same operation as in Example 1-8, a low-polar substance (83 mg) of the title compound was obtained. A highly polar compound (69 mg) of the title compound was obtained in the same manner as in Example 1-8 using the highly polar compound (87 mg) among the compounds synthesized in Example 3-6.

[0185] less polar product _{^{1 H-NMR (CD 3 OD}} ) δ 0.92-1.05 (m, 6H), 3.90-4.00 (m, 1H),
4.12-4.25 (m, 1H), 4.58-4.72 (m, 2H), 5.45 (dd, J = 64,8.4H
z, 1H), 5.56-5.80 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -186.0 ppm (d, 64 Hz).

Highly polar substance ¹ H-NMR (CD ₃ OD) δ 0.90-1.05 (m, 6H), 3.88-4.02 (m, 1H),
4.14-4.24 (m, 1H), 4.58-4.70 (m, 2H), 5.45 (dd, J = 64,8.4H
z, 1H), 5.55-5.80 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -185.4 ppm (d, 64 Hz).

[Embodiment 4] (1S ^* , 3S ^* )-2, 4
-Ethylene-7α-fluoro-17,20-dimethyl P
GI ₂ methyl ester

<Example 4-1> (1S ^* , 3R ^* )-2,4-ethylene-5,6-dehydro-7-hydroxy-17,20-dimethyl PGE ₂
Synthesis of methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using aldehyde (1.09 g, 6.05 mmol) synthesized in Reference Example 17, the title compound (2.28) was obtained in the same manner as in Example 1-1. g,
Yield 62.2%).

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.80
-1.00 (m, 24H), 3.67 (s, 3H), 4.16-4.30 (m, 2H), 5.50-5.70
(m, 2H).

<Example 4-2> (1S ^* , 3R ^* )-2,4-ethylene-5,6-dehydro-7-trimethylsiloxy-17,20-dimethyl PGF ₂ α methyl ester 11,15-bis Synthesis of (t-butyldimethyl) silyl ether Using the compound (2.28 g, 3.42 mmol) synthesized in Example 4-1 and in the same manner as in Example 1-2, the title compound (1.98 g, yield 68.1). %).

¹ H-NMR (CDCl ₃ ) δ 0.00-0.10 (m, 21H), 0.50
-0.65 (m, 6H), 0.28-1.00 (m, 30H), 3.67 (s, 3H), 5.40-5.60
(m, 2H).

Example 4-3 (1S ^* , 3R ^* )-2,4-Ethylene-5,6-dehydro-7β-fluoro-17,20-dimethyl PGF ₂
Synthesis of α-methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.98 g, 2.33 mmol) synthesized in Example 4-2, the same as in Example 1-3 The title compound (1.55 g, yield 85.4%) was obtained by the operation.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.10 (m, 12H), 0.50
-0.70 (m, 6H), 0.80-1.00 (m, 30H), 3.68 (s, 3H), 5.20-5.60
(m, 3H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -169.8 ppm (m).

Example 4-4 (1S ^* , 3R ^* )-2,4-Ethylene-5,6-dehydro-7β-fluoro-17,20-dimethyl PGF ₂
Synthesis of α-methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the compound synthesized in Example 4-3 (1.55 g, 1.99 mmol), the title was obtained in the same manner as in Example 1-4. Compound (845mg,
Yield 64.0%).

¹ H-NMR (CDCl ₃ ) δ 0.00-0.15 (m, 12H), 0.85
-0.95 (m, 24H), 3.68 (s, 3H), 4.10-4.20 (m, 2H), 5.30-5.55
(m, 3H). ¹⁹ F-NMR (based on CDCl ₃ and CCl ₃ F) -169.0 ppm (dd, J = 56, 9 Hz).

Example 4-5 (1S ^* , 3R ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester 1
Synthesis of 1,15-bis (t-butyldimethyl) silyl ether Using the compound synthesized in Example 4-4 (845 mg, 1.27 mmol), the same procedure as in Example 1-5 was performed, followed by Example 1-6. The title compound (205 mg, yield 24.3%) was obtained by the operation.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.80
-0.95 (m, 24H), 3.67 (s, 3H), 5.30 (dd, J = 56Hz, 1H), 5.55-5.
60 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.4 ppm (dd, J = 56,9H
z),-182.8ppm (dd, J = 56,9Hz).

Example 4-6 Synthesis of (1S ^* , 3R ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI _2- methyl ester The compound synthesized in Example 4-5 (205 mg) , 0.31 mmol) to give the title compound (118 mg, yield 87.5%) in the same manner as in Example 1-7.

¹ H-NMR (CDCl ₃ ) δ 0.85-1.00 (m, 6H), 3.67
(s, 3H), 3.85-3.95 (m, 1H), 4.15-4.25 (m, 1H), 4.55-4.65
(m, 1H), 5.38 ( dd, J = 56,9Hz, 1H), 5.55-5.65 (m, 2H). 19 F-NMR (CDCl 3, CCl 3 F reference) -184.5ppm (dd, J = 56 , 9Hz),
-185.1ppm (dd, J = 56,9Hz).

Example 5 2,4-Ethylene-3α-homo-7α-fluoro-17,20-dimethyl PGI _2- methyl ester

Example 5-1 2,4-Ethylene-3α-homo-5,6-dehydro-7
Synthesis of -hydroxy-17,20-dimethyl PGE ₂ methyl ester 11,15-bis (t-butyldimethyl) silyl ether Example 1-1 using the aldehyde (3.68 g, 19.9 mmol) synthesized in Reference Example 24. In the same manner as above, the title compound (5.41
g, yield 44%).

Example 5-2 2,4-Ethylene-3α-homo-5,6-dehydro-7
- trimethylsiloxy -17,20- dimethyl PGF ₂
Synthesis of α-methyl ester 11,15-bis (t-butyldimethyl) silyl ether Using the compound synthesized in Example 5-1 (5.41 g, 7.99 mmol), the title was obtained in the same manner as in Example 1-2. Compound (4.39 g,
Yield 64%).

¹ H-NMR (CDCl ₃ ) δ 3.67 (s, 3H), 5.4-5.7 (m,
2H).

Example 5-3 2,4-Ethylene-3α-homo-5,6-dehydro-7
Synthesis of β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether The compound (4.39 g, 5.07 mmol) synthesized in Example 5-2 was obtained. Using the same procedures as in Example 1-3, the title compound (2.60 g,
Yield 65%).

Example 5-4 2,4-Ethylene-3α-homo-5,6-dehydro-7
Synthesis of β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl ether Example using compound (2.60 g, 3.27 mmol) synthesized in Example 5-3 In the same manner as in 1-4, the title compound (1.31 g,
Yield 59%).

¹ H-NMR (CDCl ₃ ) δ 3.67 (m, 3H), 5.45 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -168.4 ppm (m), -169.1 ppm
(m).

Example 5-5 2,4-Ethylene-3α-homo-7α-fluoro-1
7,20-dimethyl PGI ₂ methyl ester 11,1
Synthesis of 5-bis (t-butyldimethyl) silyl ether Using the compound (1.31 g, 1.92 mmol) synthesized in Example 5-4, the same operation as in Example 1-5, and then in Example 1-6. , Two isomers of the title compound (low polarity (115 mg, yield
8.8%) and a highly polar substance (102 mg, yield 7.8%).

Low polar substance ¹ H-NMR (CDCl ₃ ) δ 3.67 (s, 3H), 5.54 (m, 1H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.2 ppm (m).

Highly polar substance ¹ H-NMR (CDCl ₃ ) δ 3.66 (s, 3 H), 5.3 (m, 1 H), 5.54 (m, 1 H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F)- 182.7 ppm (m).

<Example 5-6> 2,4-Ethylene-3α-homo-7α-fluoro-1
Synthesis of 7,20-dimethyl PGI ₂ methyl ester Among the compounds synthesized in Example 5-5, a low-polar compound (115 mg,
0.17 mmol) to obtain a low-polar compound (57 mg, yield: 75%) of the title compound in the same manner as in Example 1-7. Example 5-
A highly polar compound (62 mg, yield: 91%) of the title compound was obtained by the same operation as in Example 1-7 using a highly polar compound (102 mg, 0.15 mmol) among the compounds synthesized in 5.

Low polar substance ¹ H-NMR (CDCl ₃ ) δ 0.8-2.8 (m, 29H), 3.68 (s, 3H), 3.90 (m,
1H), 4.18 (m, 1H ), 4.64 (m, 2H), 5.37 (m, 1H), 5.59 (m, 2H). 19 F-NMR (CDCl 3, CCl 3 F reference) -184.5ppm (m) .

Highly polar substance ¹ H-NMR (CDCl ₃ ) δ 0.8-2.8 (m, 29H), 3.66 (s, 3H), 3.90 (m,
1H), 4.15 (m, 1H), 4.4-4.7 (m, 2H), 5.38 (m, 1H), 5.58 (m, 2
H). ¹⁹ F-NMR (based on CDCl ₃ , CCl ₃ F) -184.8 ppm (m).

Reference Example 25 Synthesis of 3- (t-butyldimethylsiloxymethyl) cyclohexanecarbaldehyde Using 1,3-cyclohexanedimethanol (48 g),
The title compound (31 g) was obtained in the same manner as in Reference Example 18.

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 6H), 0.7-0.9
(m, 9H), 1.0-2.4 (m, 8H), 3.4-3.6 (m, 2H), 9.6 (s, 1H).

Reference Example 26 Synthesis of 3- (2,2-dibromovinyl) cyclohexanemethanol t-butyldimethylsilyl ether Reference Example 1 was made using the compound (14 g) synthesized in Reference Example 25.
By the same procedure as in 9, the title compound (16 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 6H), 0.7-0.9
(m, 9H), 1.2-1.8 (m, 8H), 3.3-3.5 (m, 2H), 6.2 (m, 1H).

Reference Example 27 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclohexanemethanol t-butyldimethylsilyl ether Reference Example 2 was made using the compound (16 g) synthesized in Reference Example 26.
By the same operation as in Example 0, the title compound (11.6 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 6H), 0.8-0.9
(m, 9H), 1.2-2.3 (m, 14H), 3.3-3.4 (m, 2H), 3.4-3.6 (m, 1H),
3.8-3.9 (m, 1H), 4.1-4.3 (m, 2H), 4.8-4.9 (m, 1H).

Reference Example 28 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclohexanemethanol The compound (11.6 g) synthesized in Reference Example 27 was used in the same manner as in Reference Example 21. The title compound (7.8 g) was obtained.

Reference Example 29 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclohexanecarbaldehyde Using the compound (7.8 g) synthesized in Reference Example 28, Reference Example 2 was carried out.
By the same operation as in 2, the title compound (6.0 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.2-2.4 (m, 14H), 3.4-3.
6 (m, 1H), 3.8-3.9 (m, 1H), 4.2-4.4 (m, 2H), 4.8-4.9 (m, 1H),
9.6 (m, 1H).

Reference Example 30 Synthesis of 3- (3-hydroxy-1-propynyl) cyclohexanecarboxylic acid methyl ester Reference Example 23 was performed using the compound (9 g) synthesized in Reference Example 29.
By the same procedure as in the above, the title compound (3.8 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.2-2.4 (m, 8H), 3.7 (s, 3
H), 4.2-4.3 (m, 2H).

Reference Example 31 Synthesis of methyl ester of 3- (3-oxo-1-propynyl) cyclohexanecarboxylic acid Reference Example 2 was made using the compound (3.8 g) synthesized in Reference Example 30.
By the same operation as in 4, the title compound (3.1 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.2-2.6 (m, 8H), 3.7 (s, 3
H), 9.2 (m, 1H).

Example 6 2,4-propylene-7α-
Fluoro-17,20-dimethyl PGI _2- methyl ester

Example 6-1 2,4-propylene-5,6-dehydro-7-hydroxy-17,20-dimethyl PGE ₂ methyl ester 1
Synthesis of 1,15-bis (t-butyldimethyl) silyl ether Using the aldehyde (0.92 g) synthesized in Reference Example 31, the title compound (1.50 g) was obtained in the same manner as in Example 1-1. .

Example 6-2 2,4-propylene-5,6-dehydro-7-trimethylsiloxy-17,20-dimethyl PGF ₂ α-methyl ester 11,15-bis (t-butyldimethyl) silyl 9 -Synthesis of triethylsilyl ether Using the compound (1.50 g) synthesized in Example 6-1 and in the same manner as in Example 1-2, the title compound (1.47 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 21H), 0.50
-0.70 (m, 6H), 0.80-1.00 (m, 33H), 3.58 (s, 3H), 3.98-4.15
(m, 2H), 5.32-5.60 (m, 2H).

[0230] <Example 6-3> 2,4-propylene-5,6-dehydro -7β- fluoro -17,20- dimethyl PGF ₂ alpha methyl ester
Synthesis of 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.47 g) synthesized in Example 6-2, the title compound was obtained in the same manner as in Example 1-3. (0.90 g) was obtained.

¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -169.5 ppm
(m).

[0232] <Example 6-4> 2,4-propylene-5,6-dehydro -7β- fluoro -17,20- dimethyl PGF ₂ alpha methyl ester
Synthesis of 11,15-bis (t-butyldimethyl) silyl ether Using the compound (0.90 g) synthesized in Example 6-3, the title compound (488 mg) was obtained in the same manner as in Example 1-4. I got

¹ H-NMR (CDCl ₃ ) δ 0.00-0.12 (m, 12H), 0.80
-1.00 (m, 24H), 3.61 (s, 3H), 4.00-4.18 (m, 2H), 5.22-5.54
(m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -168.6 ppm (m).

Example 6-5 2,4-propylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester 11,15-bis (t
Synthesis of -butyldimethyl) silyl ether Using the compound (488 mg) synthesized in Example 6-4, the same procedures as in Example 1-5 and Example 1-6 were carried out to obtain two title compounds. Isomers (low polar (53 mg) and high polar (4
8 mg)).

Low polar substance ¹ H-NMR (CDCl ₃ ) δ 0.00-0.20 (m, 12H), 0.80-0.90 (m, 24
H), 3.59 (s, 3H), 5.22 (dd, J = 57.9,9Hz, 1H), 5.42-5.48 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.9 ppm (dd, J = 60, 10H
z).

Highly polar substance ¹ H-NMR (CDCl ₃ ) δ 0.00-0.15 (m, 12H), 0.78-0.90 (m, 24
H), 3.61 (s, 3H), 5.22 (dd, J = 60,9Hz, 1H), 5.42-5.48 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.4 ppm (dd, J = 60, 10H
z).

<Example 6-6> Synthesis of 2,4-propylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester Among the compounds synthesized in Example 6-5, a low-polar compound (53 mg) was used. In the same manner as in Example 1-7, a low-polar substance (27 mg) of the title compound was obtained. A highly polar compound (25 mg) of the title compound was obtained in the same manner as in Example 1-7 using the highly polar compound (48 mg) among the compounds synthesized in Example 6-5.

Low polar substance ¹ H-NMR (CDCl ₃ ) δ 0.88-0.96 (m, 6H), 3.65 (s, 3H), 3.82-
4.00 (m, 1H), 4.16-4.24 (m, 1H), 4.46-4.52 (m, 1H), 4.60-4.
70 (m, 1H), 5.38 (dd, J = 57,9Hz, 1H), 5.56-5.64 (m, 2H). 19 F-NMR (CDCl 3, CCl 3 F reference) -184.8ppm (dm, J = 57Hz),-18
6.8 ppm (dm, J = 57 Hz).

Highly polar substance ¹ H-NMR (CDCl ₃ ) δ 0.88-0.92 (m, 6H), 3.65 (s, 3H), 3.82-
4.00 (m, 1H), 4.16-4.24 (m, 1H), 4.46-4.52 (m, 1H), 4.60-4.
70 (m, 1H), 5.38 (dd, J = 58,10Hz, 1H), 5.58-5.62 (m, 2H). 19 F-NMR (CDCl 3, CCl 3 F reference) -184.2ppm (dm, J = 58Hz),-18
4.4ppm (dm, J = 58Hz).

Reference Example 32 Synthesis of 3- (t-butyldimethylsiloxymethyl) cyclobutanecarbaldehyde Using 1,3-cyclobutanedimethanol (4.11 g),
By the same procedure as in Reference Example 18, the title compound (3.61 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.07-0.13 (m, 6H), 0.96
(s, 9H), 1.98-2.60 (m, 5H), 2.98-3.15 (m, 1H), 3.51 (d, J = 5.
4Hz, 0.5H), 3.61 (d, J = 5.4Hz, 0.5H), 9.67 (d, J = 3.2Hz, 0.5
H), 9.79 (d, J = 3.2Hz, 0.5H).

Reference Example 33 Synthesis of 3- (2,2-dibromovinyl) cyclobutanemethanol t-butyldimethylsilyl ether The same operation as in Reference Example 19 was performed using the compound (3.61 g) synthesized in Reference Example 32. Thus, the title compound (5.35 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.04 (s, 3H), 0.06 (s, 3
H), 0.90 (s, 9H), 1.80-2.50 (m, 5H), 2.90-3.20 (m, 1H), 3.50
(d, J = 5.1Hz, 0.5H), 3.62 (d, J = 5.1Hz, 0.5H), 6.44 (d, J = 8.4
(Hz, 0.5H).

Reference Example 34 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclobutanemethanol t-butyldimethylsilyl ether Reference Example 20 was performed using the compound (5.35 g) synthesized in Reference Example 33. By the same procedure as in, the title compound (3.82 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.04 (s, 3H), 0.07 (s, 3
H), 0.90 (s, 9H), 1.42-2.60 (m, 11H), 2.80-3.10 (m, 1H), 3.4
8-3.60 (m, 3H), 3.78-3.94 (m, 1H), 4.15-4.38 (m, 2H), 4.78-
3.84 (m, 1H).

Reference Example 35 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclobutanemethanol Using the compound (3.82 g) synthesized in Reference Example 34, the same procedure as in Reference Example 21 was carried out. The title compound (2.07 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.40-2.65 (m, 11H), 2.85
-3.18 (m, 1H), 3.50-3.70 (m, 3H), 3.78-3.90 (m, 1H), 4.15-
4.38 (m, 2H), 4.75-5.05 (m, 1H).

Reference Example 36 Synthesis of 3- (3-tetrahydropyranyloxy-1-propynyl) cyclobutanecarbaldehyde Using the compound synthesized in Reference Example 35 (2.07 g), the same procedure as in Reference Example 22 was carried out. The title compound (1.96 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.40-1.90 (m, 6H), 2.18-
2.55 (m, 4H), 2.95-3.18 (m, 2H), 3.46-3.60 (m, 1H), 3.73-3.
90 (m, 1H), 4.12-4.36 (m, 2H), 4.76 (m, 1H), 9.65 (d, 2.2Hz,
0.5H), 9.77 (d, 2.2Hz, 0.5H).

Reference Example 37 Synthesis of methyl 3- (3-hydroxy-1-propynyl) cyclobutanecarboxylate Compound synthesized in Reference Example 36
(1.96 g) and the title compound (1.24 g) was obtained in the same manner as in Reference Example 23.

¹ H-NMR (CDCl ₃ ) δ 2.25-2.26 (m, 4H), 2.90-
3.10 (m, 1H), 3.12-3.28 (m, 1H), 3.68 (s, 1.5H), 3.70 (s, 1.5
H), 4.27 (m, 1H).

<Reference Example 38> Synthesis of methyl 3- (3-oxo-1-propynyl) cyclobutanecarboxylate Using the compound (1.24 g) synthesized in Reference Example 37, the same procedure as in Reference Example 24 was carried out to obtain a target. The title compound (803 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ 2.36-2.53 (m, 2H), 2.60-
2.75 (m, 2H), 3.20-3.45 (m, 2H), 3.70 (s, 3H), 9.21 (s, 1H).

Example 7 Methyl ester of 2,4-methylene-7α-fluoro-17,20-dimethyl PGI ₂ and sodium salt

Example 7-1 2,4-Methylene-5,6-dehydro-7-hydroxy-17,20-dimethyl PGE ₂ methyl ester 1
Synthesis of 1,15-bis (t-butyldimethyl) silyl ether The title compound (1.60 g) was obtained in the same manner as in Example 1-1 using the compound (803 mg) synthesized in Reference Example 38. .

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 12H), 0.80-0.9
5 (m, 24H), 3.66 (m, 3H), 5.50-5.70 (m, 2H).

Example 7-2 2,4-Methylene-5,6-dehydro-7-trimethylsiloxy-17,20-dimethyl PGF ₂ α-methyl ester 11,15-bis (t-butyldimethyl) silyl 9 -Synthesis of triethylsilyl ether The title compound (1.54 g) was obtained in the same manner as in Example 1-2, using the compound (1.60 g) synthesized in Example 7-1.

¹ H-NMR (CDCl ₃ ) δ 0-0.2 (m, 12H), 0.45-1.0
0 (m, 48H), 3.73 (m, 3H), 3.82-3.95 (m, 1H), 4.10-4.25 (m, 2
H), 4.55-4.80 (m, 2H), 5.40-5.70 (m, 2H).

[0259] <Example 7-3> 2,4-methylene-5,6-dehydro -7β- fluoro -17,20- dimethyl PGF ₂ alpha methyl ester 1
Synthesis of 1,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.54 g) synthesized in Example 7-2, the title compound was obtained in the same manner as in Example 1-3. (1.17 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0-0.20 (m, 12H), 0.50-1.
0 (m, 33H), 3.73 (s, 1.5H), 3.75 (s, 1.5H), 3.85-3.95 (m, 1
H), 4.10-4.20 (m, 1H), 4.21-4.35 (m, 1H), 5.35 (dm, J = 46.6H
z, 1H), 5.50 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -170.1 ppm (m).

[0261] <Example 7-4> 2,4-methylene-5,6-dehydro -7β- fluoro -17,20- dimethyl PGF ₂ alpha methyl ester 1
Synthesis of 1,15-bis (t-butyldimethyl) silyl ether Using the compound (1.17 g) synthesized in Example 7-3, the title compound (717 mg) was obtained in the same manner as in Example 1-4. Obtained.

¹ H-NMR (CDCl ₃ ) δ 0-0.15 (m, 12H), 0.75-0.
95 (m, 24H), 3.71 (s, 1.5H), 3.73 (s, 1.5H), 4.08-4.20 (m, 2
H), 4.30-4.41 (m, 1H), 5.40-5.50 (m, 2H), 5.47 (dm, J = 46.6H
z, 1H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -168.2 ppm (m).

Example 7-5 2,4-Methylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester 11,15-bis (t-
Synthesis of (butyldimethyl) silyl ether Using the compound (717 mg) synthesized in Example 7-4, the title compound (251 mg) was obtained in the same manner as in Example 1-5 and then in Example 1-6. Was.

¹ H-NMR (CDCl ₃ ) δ 0-0.10 (m, 12H), 0.75-0.
95 (m, 24H), 3.66 (s, 1.5H), 3.69 (s, 1.5H), 3.75-3.90 (m, 1
H), 4.10-4.20 (m, 1H), 4.48-4.80 (m, 2H), 5.30 (dm, J = 56.5H
z, 1H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -183.8 ppm (dd, J = 5
6.5,7.5Hz),-184.2ppm (dd, J = 56.5,7.5Hz).

<Example 7-6> Synthesis of 2,4-methylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester Example 1 was performed using the compound (251 mg) synthesized in Example 7-5. By a similar operation to -7, the title compound (132 mg) was obtained.
Further, the obtained compound (132 mg) was subjected to high performance liquid chromatography (silica, hexane: ethanol = 96:
Using 4), the two isomers were separated, and the low-polarity compound (55
mg) and a highly polar substance (67 mg).

Low polar ¹ H-NMR ((CD ₃ ) ₂ CO) δ 0.80-0.90 (m, 6H), 3.55-3.60 (m, 1
H), 3.60 (s, 3H), 3.80-3.95 (m, 1H), 4.05-4.15 (m, 2H), 4.55
-4.68 (m, 2H), 5.41 (dd, J = 60,8.3Hz, 1H), 5.50-5.71 (m, 2
H). ¹⁹ F-NMR (based on (CD ₃ ) ₂ CO, CCl ₃ F) -184.8 ppm (dd, J = 60,
8.1Hz).

Highly polar substance ¹ H-NMR ((CD ₃ ) ₂ CO) δ 0.80-0.90 (m, 6H), 3.50-3.60 (m, 2
H), 3.65 (s, 3H ), 3.80-3.98 (m, 1H), 4. 03-4.15 (m, 2H), 4.58
-4.66 (m, 1H), 4.70-4.80 (m, 1H), 5.44 (dd, J = 60,8.3Hz, 1
H), 5.50-5.70 (m, 2H ). 19 F-NMR ((CD 3) 2 CO, CCl 3 F reference) -184.8ppm (dd, J = 60 ,
(8.3Hz).

[0268] <Example 7-7> 2,4 methylene -7α- fluoro -17,20- low polarity compounds among the compounds synthesized in Example 7-6 dimethyl PGI ₂ sodium salt (158 mg)
Was dissolved in ethanol (9.1 ml), a 0.1 N aqueous sodium hydroxide solution (3.94 ml) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. After the reaction solution was concentrated under reduced pressure, the residue was treated with water (0.45 m
l) and acetonitrile (13.8 ml) was added with stirring.
The precipitated white solid was separated by filtration and dried to obtain a low-polar substance of the title compound.
(128 mg) was obtained.

A highly polar product (156 mg) of the title compound was obtained in the same manner using the highly polar product (188 mg) among the compounds synthesized in Examples 7-6.

Low Polarity ¹ H-NMR (CD ₃ OD) δ 0.94-1.05 (m, 6H), 1.18-1.85 (m, 10H),
2.03-2.19 (m, 2H), 2.33-3.20 (m, 7H), 3.86-4.00 (m, 1H), 4.
14-4.25 (m, 1H), 4.60-4.75 (m, 2H), 5.45 (dd, J = 60,8.4Hz, 1
H), 5.55-5.78 (m, 2H). ¹⁹ F-NMR (CD ₃ OD, CCl ₃ F standard) -186.2 ppm (d, J = 60 Hz).

Highly polar substance ¹ H-NMR (CD ₃ OD) δ 0.95-1.05 (m, 6H), 1.18-1.82 (m, 10H),
2.00-2.20 (m, 2H), 2.50-2.78 (m, 5H), 3.00-3.20 (m, 1H), 3.
30-3.40 (m, 1H), 3.90-4.00 (m, 1H), 4.15-4.25 (m, 1H), 4.63
-4.72 (m, 1H), 4.86-4.94 (m, 1H), 5.46 (dd, J = 60,8.4Hz, 1
H), 5.57-5.80 (m, 2H). ¹⁹ F-NMR (CD ₃ OD, CCl ₃ F standard) -186.0 ppm (d, J = 60 Hz).

Reference Example 39 Synthesis of methyl 3- (3-hydroxy-1-propynyl) cyclobutylacetate The compound (2.07 g) synthesized in Reference Example 35 was converted to methylene chloride (3
0ml), triethylamine (1.67ml) and methanesulfonyl chloride (0.79ml) were added at 0 ° C, and the mixture was stirred at room temperature for 1 hour. After adding a saturated aqueous solution of sodium hydrogen carbonate (20 ml) to the reaction solution, the organic layer was separated, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (50 ml) and water (10 ml), potassium cyanide (0.78 g) was added, and the mixture was stirred at 80 ° C for 7 hours. Water (100 ml) was added to the reaction solution, and extracted with ether (20 ml × 2). After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure.

The obtained residue was treated with water (25 ml) and ethanol (25 ml).
l), add potassium hydroxide (807 mg), and add
Stir for 5 hours. After adjusting the pH to 2 by adding concentrated sulfuric acid, the salt was saturated and extracted with methylene chloride (30 ml × 2). After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in benzene (10 ml), methanol (2 ml) and concentrated sulfuric acid (1 drop) were added, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (1.33 g).

¹ H-NMR (CDCl ₃ ) δ 1.70-1.90 (m, 1H), 1.95
2.10 (m, 1H), 2.18-2.35 (m, 1H), 2.35-2.60 (m, 3H), 2.75-3.
14 (m, 2H), 3.65 (s, 1.5H), 3.66 (s, 1.5H), 4.23-4.30 (m, 2
H).

<Reference Example 40> Synthesis of methyl 3- (3-oxo-1-propynyl) cyclobutylacetate The title compound was prepared in the same manner as in Reference Example 24 using the compound (1.33 g) synthesized in Reference Example 39. Compound (1.26 g)
I got

¹ H-NMR (CDCl ₃ ) δ 1.88-2.00 (m, 1H), 2.05-
2.20 (m, 1H), 2.35-2.75 (m, 4.5H), 2.85-3.28 (m, 1.5H), 3.6
6 (s, 3H), 9.20 (d, J = 7.3Hz, 1H).

Example 8 1α-Homo-2,3-methylene-7α-fluoro-17,20-dimethyl PGI _2- methyl ester

Example 8-1 1α-Homo-2,3-methylene-5,6-dehydro-7
-Hydroxy-17,20-dimethyl PGE ₂ methyl ester Synthesis of 11,15- (t-butyldimethyl) silyl ether The compound (840 mg) synthesized in Reference Example 40 was used in the same manner as in Example 1-1. The title compound (1.68 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ -0.1-0.15 (m, 12H), 0.75
-0.93 (m, 24H), 3.65 (s, 3H), 4.10-4.20 (m, 2H), 5.50-5.68
(m, 2H).

Example 8-2 1α-Homo-2,3-methylene-5,6-dehydro-7
- trimethylsiloxy -17,20- dimethyl PGF ₂
Synthesis of α-methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.68 g) synthesized in Example 8-1, the same operation as in Example 1-2 was performed. The title compound (1.58 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ -0.1-0.18 (m, 12H), 0.50
-0.68 (m, 6H), 0.72-1.00 (m, 33H), 3.65 (s, 3H), 3.82-4.98
(m, 1H), 4.07-4.21 (m, 2H), 4.55-4.76 (m, 2H), 5.40-5.68
(m, 2H).

Example 8-3 1α-Homo-2,3-methylene-5,6-dehydro-7
Synthesis of β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl 9-triethylsilyl ether Using the compound (1.58 g) synthesized in Example 8-2, By the same operation as in Example 1-3, the title compound (1.22 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 12H), 0.50-0.7
0 (m, 6H), 0.75-0.98 (m, 33H), 3.65 (s, 3H), 4.03-4.18 (m, 2
H), 5.30-5.60 (m, 3H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -168.4 ppm (m).

Example 8-4 1α-Homo-2,3-methylene-5,6-dehydro-7
Synthesis of β-fluoro-17,20-dimethyl PGF ₂ α methyl ester 11,15-bis (t-butyldimethyl) silyl ether Example 1 was performed using the compound (1.22 g) synthesized in Example 8-3. By the same operation as in 4, the title compound (753 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0-0.1 (m, 12H), 0.75-0.9
3 (m, 24H), 3.65 (s, 3H), 4.03-4.18 (m, 2H), 5.30-5.57 (m, 3
H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -168.1 ppm (m).

Example 8-5 1α-Homo-2,3-methylene-7α-fluoro-1
7,20-dimethyl PGI ₂ methyl ester 11,1
Synthesis of 5-bis (t-butyldimethyl) silyl ether Using the compound synthesized in Example 8-4 (753 mg), the title compound was prepared in the same manner as in Example 1-5 and then in Example 1-6. The compound (241 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0-0.15 (m, 12H), 0.70-0.
95 (m, 24H), 3.62 (s, 3H), 3.70-3.86 (m, 1H), 4.12 (m, 1H), 4.
50-4.80 (m, 2H), 5.27 (dm, J = 56.7Hz, 1H), 5.48-5.54 (m, 2
H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -182.9 ppm (m).

<Example 8-6> 1α-homo-2,3-methylene-7α-fluoro-1
Synthesis of 7,20-dimethyl PGI ₂ methyl ester The title compound (144 mg) was obtained in the same manner as in Example 1-7, using the compound (241 mg) synthesized in Example 8-5.

¹ H-NMR (CDCl ₃ ) δ 0.85-1.00 (m, 6H), 3.65
(s, 1.5H), 3.66 (s, 1.5H), 3.85-4.02 (m, 1H), 4.10-4.20 (m,
2H), 4.60-4.90 (m, 2H), 5.26 (dd, J = 60,8.4Hz, 0.5H), 5.54-
5.76 (m, 2H). ¹⁹ F-NMR (CDCl ₃ , CCl ₃ F standard) -183.7 ppm (dd, J = 60, 8.1H
z), -184.1 ppm (dd, J = 60, 8.1 Hz).

<Preparation Example 1> Gastric capsule (1S ^* , 3S ^* )-2,4-ethylene-7α-fluoro-17,20-dimethyl PGI _2- methyl ester 50
mg was dissolved in 10 ml of ethanol, mixed with 18.5 g of mannitol, dried through a 30-mesh sieve at 30 ° C. for 90 minutes, and again passed through a 30-mesh sieve.

To the powder, 200 mg of Aerosil (microfine silica) was added. Fill into 100 3 hard gelatin capsules, 0.5mg per capsule
(1S ^* , 3S ^* )-2,4-Ethylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester.

<Preparation Example 2> Injection 0.5 mg of 2,4-methylene-7α-fluoro-17,20-dimethyl PGI _2- methyl ester was added to ethanol 5
Dissolved in 1 ml, sterilized through a bacteria retention filter, and added in 0.1 ml per 1 ml volume ampules, containing 10 μg of 2,4-methylene-7α-fluoro-17,20-dimethyl PGI ₂ methyl ester per ampule. And sealed the ampule. The contents of the ampoule are diluted to 1 ml with a suitable solvent, for example, Tris-HCl buffer at pH 8.6, and used as an injection.

<Preparation Example 3> Lyophilized preparation for injection 2,4-methylene-7α-fluoro-17,20-dimethyl PGI _2- methyl ester 50 mg, α-cyclodextrin 1.6 g and distilled water 10 ml 10 mg of acid, 50 g of lactose and 800 ml of distilled water are added and dissolved, and the total volume is made up to 1 liter with distilled water. After that, the solution was sterile-filtered according to a conventional method, filled into ampoules in 1 ml portions, and freeze-dried to obtain a sealed, freeze-dried preparation for injection.

[0294]

Novel PGI ₂ derivatives of the present invention exhibits a weak toxic compound having a strong platelet aggregation inhibiting action and antianginal heart action, thrombosis, angina pectoris, myocardial infarction, such as arteriosclerosis effective in preventing and treating.

[Brief description of the drawings]

FIG. 1 is a synthetic flow sheet (1) of the compound [I ′] of the present invention.

FIG. 2 is a synthetic flow sheet of the compound [I ′] of the present invention (part 2)

FIG. 3 is a synthesis flow sheet of a starting material [II] of the compound of the present invention (part 1)

FIG. 4 is a synthesis flow sheet of a starting material [II] of the compound of the present invention (part 2)

FIG. 5: Synthetic flow sheet for aldehydes [III] (Part 1)

FIG. 6: Synthetic flow sheet for aldehydes [III] (part 2)

FIG. 7: Synthetic flow sheet for aldehydes [III] (part 3)

FIG. 8 is a synthesis flow sheet of aldehydes [III] (part 4)

FIG. 9 is a synthesis flow sheet of aldehydes [III] (part 5)

────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kazu Hosoki 1-5-20 Ueno Nishi, Toyonaka-shi, Osaka Examiner Shinichi Naito (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 307/935 A61D 31/5575 CA (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. A prostaglandin I ₂ having a structure in which a halogen atom is bonded to the carbon atom corresponding to the 7-position of natural type prostaglandin I ₂ and a cycloalkylene group is inserted in the α-chain, and esters thereof. And a salt thereof, and a prostaglandin I ₂ derivative selected from the group consisting of: 2. A natural prostaglandins fluorine atom bonded to a carbon atom corresponding to the 7-position of I _2, and the naturally occurring prostaglandin I ₂ 2-position and 4-position of the α-chain corresponding to the trimethylene group The divalent hydrocarbon group is a group selected from a cycloalkylene group having 3 to 8 carbon atoms and a divalent hydrocarbon group in which a methylene group or a dimethylene group is bonded to at least one bond of the cycloalkylene group; The prostaglandin I ₂ derivative according to claim 1, which is 3. A prostaglandin I ₂ derivative represented by the following formula [I]. Embedded image However, R ^1: a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, an alkenyl group, an alkynyl group, or a substituted or unsubstituted 5-6 membered cycloalkyl group ring,, R ^2: a hydrogen atom, a carbon number 1 Alkyl groups or cations, R ³ , R ⁴ : the same or different, a hydrogen atom or a protecting group, X ¹ , X ² : one of a hydrogen atom, the other being a fluorine atom or a chlorine atom, k, l, m , N: each represents an integer of 0 to 6, and
0 ≦ k + n ≦ 4, 1 ≦ l + m ≦ 6. (4) 2,3-methylene-7α-fluoro-1
7,20-dimethyl PGI ₂ , 4-homo-2,3-methylene-7α-fluoro-17,20-dimethyl PGI
_2, 2,4-ethylene -7α- fluoro -17,20-
Dimethyl PGI ₂ , 2,4-ethylene-3α-homo-7
α-fluoro-17,20-dimethyl PGI ₂ , 2,4
-Propylene-7α-fluoro-17,20-dimethyl PGI ₂ , 2,4-methylene-7α-fluoro-17,
20-dimethyl PGI ₂ , 1α-homo-2,3-methylene-7α-fluoro-17,20-dimethyl PGI ₂ ,
Lower alkyl esters of these PGI _2, and sodium salts or potassium salts of these PGI ₂ prostaglandin I ₂ derivative selected from. 5. A platelet aggregation inhibitor comprising the prostaglandin I ₂ derivative according to claim 1, 2, 3, or 4 as an active ingredient . 6. The process according to claim 1, 2, 3, or 4.
Antiangina pectoris containing a staglandin I ₂ derivative as an active ingredient
Agent. 7. An aldehyde represented by the following formula [VIII].
Provided that R ²¹ represents an alkyl group having 1 to 10 carbon atoms, k, l, m, and n each represent an integer of 0 to 6;
0 ≦ k + n ≦ 4, 1 ≦ l + m ≦ 6. Embedded image