JP2839841B2 - Process for producing prostaglandin E1s, and synthetic intermediate thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a platelet aggregation inhibiting action,
Prostaglandin E ₁ is expected to have a vasodilator hypotensive action, etc., and is useful as a pharmaceutical.
And its synthetic intermediates.

[0002]

2. Description of the Related Art Prostaglandins have a platelet aggregation inhibitory effect, a vasodilatory hypotensive effect, a gastric acid secretion inhibitory effect,
It has various physiological actions such as smooth muscle contraction action, cytoprotection action, diuresis action, and is useful for treatment or prevention of myocardial infarction, angina, arteriosclerosis, hypertension, duodenal ulcer, labor induction, abortion, etc. Compound. Of these prostaglandin E ₁ compound represented by the following formula (VIII) is potent platelet aggregation inhibitory action, has a vasodilating effect, it has already been used in clinical. (Hereafter, compound numbering was performed in the same manner as described herein.)

[0003]

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On the other hand, 7-thiaprostaglandins E ₁ have an inhibitory action on platelet aggregation, antihypertensive action, antithrombotic action due to vasodilatory action, antiangina, antimyocardial infarction, antiatherosclerosis, and prevention of metastasis of malignant tumor Or have an antitumor effect. (JP-A-53-68753, JP-A-58-1983)
110562, JP-A-59-29661, JP-A-60-
185761 and JP-A-61-204163). It is also known that 7-thiaprostaglandins E ₁ are useful for neuropathy in diabetes (Japanese Patent Application Laid-Open No.
4-52721 gazette).

Further, enol butyrate of prostaglandin E ₁ is known as a prostaglandin E ₁ analogue (Japanese Patent Laid-Open No. 5-213862) is a stable formulated at a high temperature, prostacyclin prostaglandin E ₁ equivalent physiological activity have been shown to be expected.

Heretofore, as a method for producing such prostaglandins E ₁ , a two-component linkage type reaction has been carried out from a cyclopentenone derivative having a side chain corresponding to the α chain and an organolithioaluminate in the ω chain. Prostaglandin E ₁
It is known that species can be synthesized. [MJ Weiss et al.
J. Org. Chem. 44, 1439, (1978)] Further, as an example of a synthesis by a two-component linkage type reaction using an organolithiocuprate having an ω chain as a nucleophile, the following method is known. ing. [KG Untch et al., J. Am. Che
m. Soc. 94, 7826, (1972)], [R. Pappo, PW Colli
ns, Tetrahedron Lett. 4217, (1954)], [Kurosumi et al., Che
m. Pharm. Bull. 30, 1102, (1982)], [CK Sih,
J. Am. Chem. Soc. 97 , 865, (1975)], [ Sato et al., In JP-A 1-228933 discloses] Similarly, as the synthesis of 7-thiaprostaglandin E ₁ compound is 7- thia A two-component linked reaction of a cyclopentenone derivative having an α-chain of the type and organolithiocuprates in the ω-chain is known. [Tanaka et al., Chem. Phar
m. Bull. 33, 2359, (1985)] Further, as a method for producing enol butyrate esters of prostaglandins, Japanese Patent Application Laid-Open No. Hei 5-213682 discloses the following formula (IX).

[0007]

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Is described. According to this, for example, the hydroxyl group of 1-iodo-3-hydroxy-1-octene is protected and reacted with alkyllithium to form 1-iodo-3-hydroxy-1-octene.
After the lithioalkene is formed, it is reacted with a trialkylphosphine-copper (I) iodide complex to obtain an organolithiocuprate. Then, the organolithiocuprate is converted to a hydroxy-protected 4-hydroxy-2- (6-carbothioate). 1,4-butoxyhexyl) -2-cyclopenten-1-one
It is produced by conjugate addition and then quenching by adding butyric anhydride or butyric halide to the reaction mixture.

On the other hand, a higher copper reagent (Higher Order Cyanocu)
from the vinylstannane-type ω chain using prates)
After generating the cuprate in situ, alpha by a method of 1,4 conjugate addition to the cyclopentenone derivative having a corresponding side chain in a chain, a prostaglandin E ₁ derivative misoprostol is known to be synthesized I have. [J
ames R. Behling et al., J. Am. Chem. Soc. 110, 2641,
(1988)]. According to this document, it is possible to make 1,4 conjugate addition to unsubstituted cyclohexanone using only one of two stannyl groups of trans-1,2-bis (tri-n-butylstannyl) ethylene as cuprate. It has been shown.

A method for substituting the stannyl group of vinylstannane with iodine while maintaining the steric structure to induce iodoolefin is described in, for example, [F. Sato et al., Tetrahed.
ronLett. 28, 2033, (1987)], [GA Tolstikov et al.
Synthesis. (6), 496, (1986)].

Further, a method of adding an alkenyl halide to a carbonyl compound in a Grignard type using chromium (II) chloride (CrCl ₂ ) has been developed by Nozaki et al. [Kazuhiko Takai et al., Tetrahedron Lett. .
24, 5281, (1983)]. This method has been studied in more detail by Kishi et al., And nickel (II) chloride, palladium acetate (I
It has been shown that by adding a catalytic amount of I), the desired product can be obtained with high reproducibility and high yield. [Haolun Jin et al.
J. Am. Chem. Soc. 108, 5644, (1986)] Further, the compound represented by the above formula (VII) used in the present invention is novel and has been used for the synthesis of prostaglandins. There are no examples.

[0012]

An object of the present invention is to provide a novel method for producing enol ester derivatives of prostaglandins E ₁ or 7-thiaprostaglandins E _{1 in} a simple and high yield. To provide. Conventionally, a two-component ligation reaction is carried out using a previously synthesized ω-chain portion from the 13-position onward, and the resulting enolate anion is trapped by an acid anhydride or an acid halide, thereby obtaining an enol ester of prostaglandin E ₁ class. A derivative was being synthesized. This method is not suitable for the purpose of easily and conveniently synthesizing a large number of derivatives obtained by converting the ω-chain portion, since it usually takes four or more steps to synthesize the ω-chain portion.

[0013]

Accordingly, we have devised a method of synthesizing a common intermediate containing a ω chain up to the 14th position in advance, and finally introducing a ω chain portion containing a hydroxyl group at the 15th position and thereafter. As a result of the study, the above-mentioned reaction 1) Using one of the two stannyl groups of trans-1,2-bis (tri-n-butylstannyl) ethylene as cuprate using higher copper reagents (Higher Order Cyanocuprates) Reaction for 1,4 conjugate addition 2) Enolate anion generated after 1,4 conjugate addition is trapped by quenching by adding butyric anhydride or butyric acid halide to the reaction mixture, and enol of prostaglandin E ₁ class Reaction for synthesizing ester derivative 3) Reaction for substituting stannyl group of vinylstannane with iodine while maintaining the steric structure to induce iodoolefin 4 ) Using chromium chloride (II) (CrCl _2), found that the alkenyl halide and aldehyde by combining well the reaction of coupling, can be an ideal way enol ester derivative of prostaglandin E ₁ compound synthesis, The present invention has been reached.

That is, the present invention relates to the following formula (I)

[0015]

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[In the formula, P represents a C1-C6 linear or branched alkyl group or a phenyl group. And trans-1,2-bis (trialkylstannyl) ethylene or trans-1,2-bis (triphenylstannyl) ethylene, and CuQ wherein Q is a halogen atom, a cyano group, Represents a phenylthio group, a 1-pentynyl group, or a 1-hexynyl group. And an organocopper reagent prepared from a C1 to C4 linear or branched alkyllithium compound, and a compound represented by the following formula (II):

[0017]

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Wherein A represents a divalent sulfur atom (—S—) or a methylene group (—CH 2 —), and R ¹ represents tri (C
1~C7 a hydrocarbon) silyl group or a hydroxyl group forming an acetal bond with the oxygen atom of the,, R ² is
A C1-C10 linear or branched alkyl group;
A C2-C10 linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C
Cycloalkyl group 3～C10, a substituted or unsubstituted phenyl (C1 -C2) alkyl group, notation ---
Represents a single bond or a double bond. After reaction with a 2-substituted-2-cyclopentenone represented by the formula (I), an enantiomer thereof, or a mixture thereof in an arbitrary ratio, further comprises: (R ³ CO) ₂ O ³ is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, or Represents a substituted or unsubstituted phenyl (C1 to C2) alkyl group. Or R ³ COCl wherein R ³ is the same as defined above. With the following formula (III)

[0019]

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[Wherein, A, R ¹ , R ² , R ³ , P, and the notation --- are the same as defined above. ], And further converting this compound to X ₂ [wherein
X represents an iodine atom or a bromine atom. And a halogen molecule represented by the following formula (IV)

[0021]

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[Wherein A, R ¹ , R ² , R ³ , X, and the notation --- are the same as defined above. To the haloolefin compound represented by the formula (V):

[0023]

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Wherein R ⁴ is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a C2-C10 linear or branched alkynyl group, Or an unsubstituted phenyl group or a substituted or unsubstituted C3 to C10 cycloalkyl group, and the above alkyl group, alkenyl group and alkynyl group are (C1 to C5 alkoxy group, substituted or unsubstituted phenyl group) Group, a substituted or unsubstituted phenoxy group, or a C3-C10 cycloalkyl group). Aldehydes represented by NiCl ₂ or Pd using CrCl ₂
The following formula (VI) characterized in that the reaction is carried out with / without using (OAc) ₂ as a catalyst.

[0025]

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[In the formula, A, R ¹ , R ² , R ³ , R ⁴ and the notation ----- are the same as defined above. Is a preparation of prostaglandin E ₁ compound represented by.

The transformer-1, 2 represented by the above formula (I)
In -bis (trialkylstannyl) ethylene or trans-1,2-bis (triphenylstannyl) ethylene, P represents a C1-C6 linear or branched alkyl group or a phenyl group. Preferred examples of the C1-C6 linear or branched alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group and a t-butyl group. And among them, trans-1,2- which is an n-butyl group
Bis (tri-n-butylstannyl) ethylene is most preferred.

In the above formula CuQ, Q represents a halogen atom, a cyano group, a phenylthio group, a 1-pentynyl group, or a 1-pentynyl group.
Represents a hexynyl group. Among them, Q is preferably a cyano group. C1-C4 linear or branched alkyllithium compounds include, for example, n-butyllithium,
t-butyllithium and the like.
The organocopper reagent is prepared using 0-3.0 mole times. In particular, using CuCN, a higher copper reagent (Higher Order Cyano)
When preparing cuprates, it is desirable to use 1.8 to 2.2 mole times. On the other hand, 0.3 to 0.6 mole times, preferably 0.5 mole times of the alkyllithium compound is reacted with the bisstannyl ethylene to form a monolithium form, and then CuQ is added to 0.5 to 2.5 mole times. 0 mole times, preferably 1.0 to 1.0.
An organic copper reagent can be prepared and used by reacting 3 mole times. Usually, the temperature range of about -100 ° C to 50 ° C, particularly preferably about -78 ° C to 30 ° C, is adopted as the organocopper reagent. The reaction time varies depending on the reaction temperature, but is usually -78 ° C to 30 ° C
It is sufficient if the reaction is carried out for about 2 hours.

The first step of the production method of the present invention comprises the above-mentioned organolithium compound, CuQ (Q is the same as defined above), and trans-1,2-bis (trialkylstannyl)
An organocopper compound prepared from ethylene or trans-1,2-bis (triphenylstannyl) ethylene is converted to a 2-substituted-2-cycloalkyl compound represented by the above formula (II) in the presence of an aprotic inert organic solvent. The reaction is performed by reacting pentenones and then reacting with an acid anhydride or an acid chloride.

The method of synthesizing the compound represented by the formula (II) is described, for example, in Tanaka et al., Chem. Pharm.Bull.33,2
356-2385 (1985).

In the above formula (II), A represents a divalent sulfur atom (—S—) or a methylene group (—CH ₂ —).
Preferably, A is a divalent sulfur atom (-S-).

In the above formula (II), R ¹ is tri (C1
-C7 hydrocarbon) represents a silyl group or a group that forms an acetal bond with an oxygen atom of a hydroxyl group. Preferred examples of the tri (C1 to C7 hydrocarbon) silyl group include tri (C1 to C4 alkyl) such as trimethylsilyl, triethylsilyl and t-butyldimethylsilyl.
Examples thereof include a diphenyl (C1-C4) alkylsilyl group such as a silyl group, a t-butyldiphenylsilyl group, and a tribenzylsilyl group. Preferred examples of the group that forms an acetal bond with the oxygen atom of the hydroxyl group include a methoxymethyl group, a 1-ethoxyethyl group, a 2-methoxy-2-propyl group, a 2-ethoxy-2-propyl group,
(2-methoxyethoxy) methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hex- 4-yl group and the like. Among these, a t-butyldimethylsilyl group is particularly preferred as R ¹ .

In the above formula (II), R ² represents C1 to C1
0 linear or branched alkyl group, C2-C10
A linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3-C10
And a substituted or unsubstituted phenyl (C1-C2) alkyl group. Such C1 to C10
Preferred examples of the linear or branched alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, Examples include a neopentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. Preferred examples of the C2-C10 linear or branched alkenyl group include a vinyl group,
Allyl, 3-butenyl, 2-butenyl, 4-pentenyl, 2-pentenyl, prenyl (3-methyl-2-butenyl), 2,4-hexadienyl, 2,
Examples include a 6-octadienyl group, a neryl group, a geranyl group, a citronellyl group, a farnesyl group, and an arachidyl group. Preferred examples of the substituent of the substituted or unsubstituted phenyl group include a halogen atom, a hydroxyl group, a C2 to C7 acyloxy group, a C1 to C4 alkyl group which may be substituted with a halogen atom, and a halogen atom. An optionally substituted C1-C4 alkoxy group,
Examples thereof include a nitrile group, a carboxyl group, and a (C1-C6) alkoxycarbonyl group. Preferred examples of the substituted or unsubstituted C3-C10 cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, a cyclooctyl group, a cyclodexyl group, and the like. Further, as the substituted or unsubstituted phenyl (C1-C2) alkyl group, the phenyl group may be substituted with the same substituent as described above, or an unsubstituted benzyl group, α
-Phenethyl group and β-phenethyl group. Among them, R ² is preferably a C1-C10 linear or branched alkyl group, and particularly preferably a methyl group.

In the above formula (II), the notation --- represents a single bond or a double bond. Among these, the case where the notation --- represents a single bond is preferable.

The above formulas (R ³ CO) ₂ O and R ³ COC
In the formula, R ³ is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3-C10 Represents a cycloalkyl group or a substituted or unsubstituted phenyl (C1 to C2) alkyl group. Preferred examples of the C1-C10 linear or branched alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a t-butyl group and a pentyl group. , Isopentyl group, neopentyl group, hexyl group, heptyl group,
Examples include an octyl group, a nonyl group, and a decyl group. C
Preferred examples of 1 to C10 linear or branched alkenyl groups include vinyl, allyl, 3-butenyl, 2-butenyl, 4-pentenyl, 2-pentenyl, prenyl (3-methyl) -2-butenyl group),
Examples include a 2,4-hexadienyl group, a 2,6-octadienyl group, a neryl group, a geranyl group, a citronellyl group, a farnesyl group, and an arachidyl group. Preferred examples of the substituent of the substituted or unsubstituted phenyl group include a halogen atom, a hydroxyl group, a C2 to C7 acyloxy group, and a C1 which may be substituted with a halogen atom.
-C6 linear or branched alkyl group, C1-C6 linear or branched alkoxy group optionally substituted with halogen atom, nitrile group, carboxyl group, (C1-C6) alkoxycarbonyl group, etc. No. Preferred examples of the substituted or unsubstituted C3-C10 cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, a cyclooctyl group, a cyclodexyl group, and the like. Further, as the substituted or unsubstituted phenyl (C1-C2) alkyl group, the phenyl group may be substituted with the same substituent as described above, or an unsubstituted benzyl group, α-phenethyl group, β-phenethyl group Is mentioned. Among them, R ³ is preferably a C1-C10 linear or branched alkyl group, and particularly preferably a propyl group.

In the method of the present invention, together with the organic copper compound,
Trivalent organic phosphorus compounds, for example, trialkyl phosphine (for example, triethyl phosphine, tributyl phosphine, etc.), trialkyl phosphite (for example, trimethyl phosphite, triethyl phosphite, triisobutyl phosphite, tri-n-butyl phosphite, etc.) ), Hexamethylphosphorustriamide, triphenylphosphine, or the like may cause the conjugate addition reaction to proceed smoothly. Especially tributylphosphine,
Hexamethylphosphorus triamide is preferably used.

The 2-substituted-2-cyclopentenone represented by the above formula (II) and the organocopper compound undergo a stoichiometric equimolar reaction. The reaction is carried out using an organic copper compound in an amount of 0.5 to 5.0 times, preferably 0.8 to 2.0 times, particularly preferably 1.0 to 1.7 times, 1 mole of the cyclopentenone.

The reaction temperature of the conjugate addition reaction between the 2-substituted-2-cyclopentenones and the organocopper compound is in the range of -100 ° C to 50 ° C, particularly preferably about -78 ° C to 0 ° C. The reaction time depends on the reaction temperature, but is usually
A reaction at -20 ° C for about 1 hour is sufficient.

A reaction intermediate obtained by a conjugate addition reaction of a 2-substituted-2-cyclopentenone with an organocopper compound and an acid anhydride or an acid chloride are stoichiometrically equimolar. The reaction is usually performed such that the amount of the acid anhydride or acid chloride is excessive. That is, 2-
For 1 mol of organothio-2-cyclopentenone,
The reaction is carried out using 1.0 to 10.0 moles, preferably 2.0 to 5.0 moles, of the acid anhydride or acid chloride.

The reaction temperature of the reaction between the reaction intermediate obtained by the conjugate addition reaction of the 2-substituted-2-cyclopentenones and the organic copper compound with an acid anhydride or an acid chloride is -30 ° C.
A temperature of 50 ° C, particularly preferably about -20 ° C to 30 ° C, is employed. The reaction time varies depending on the reaction temperature, but is usually from 0 ° C to
A reaction at 20 ° C for about 15 minutes is sufficient.

The reaction is performed in the presence of an organic solvent. An inert aprotic organic solvent that is liquid at the reaction temperature and does not react with the reaction reagent is used.

Examples of such aprotic inert organic solvents include saturated hydrocarbons such as pentane, hexane, heptane and cyclohexane, benzene, toluene and the like.
Aromatic hydrocarbons such as xylene, diethyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ether solvents such as diethylene glycol dimethyl ether, other, hexamethylphosphoric amide (HMP), N, N-dimethylformamide (DMF), N,
A so-called aprotic polar solvent such as N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), sulfolane, N-methylpyrrolidone and the like can be mentioned, and it can be used as a mixed solvent of two or more kinds. Further, as the aprotic inert organic solvent, the inert solvent used for producing the organic copper compound can be used as it is. That is, in this case, the reaction may be performed by adding a 2-substituted-2-cyclopentenone to the reaction system in which the organocopper compound has been produced. The amount of the organic solvent used may be an amount sufficient to allow the reaction to proceed smoothly, and usually 1 to 100 times, preferably 2 to 20 times the volume of the raw material is used.

The trivalent organophosphorus compound can be present during the preparation of the organocopper compound described above, and the reaction can be carried out by adding a 2-substituted-2-cyclopentenone to the system. .

Thus, a compound represented by the above formula (III), that is, a vinylstannane compound in which the hydroxyl group at position 11 is protected and the carboxylic acid at position 1 is esterified is obtained. Since the production method of the present invention uses a reaction that proceeds stereospecifically, the starting material having the configuration represented by the above formula (II) has the configuration represented by the above formula (III) A compound is obtained, and an enantiomer of the above formula (III) is obtained from an enantiomer of the above formula (II).

After the reaction, the obtained product is separated and purified from the reaction solution by a usual means. For example, extraction, washing, chromatography or a combination thereof is performed.

The second step of the production method of the present invention is a vinylstannane compound represented by the above formula (III) and obtained by protecting the hydroxyl group at the 11-position and esterifying the carboxylic acid at the 1-position. Is a halogen molecule represented by X ₂
The reaction is carried out at 0.5 to 1.5 mole times, preferably 1.0 mole time, in the presence of a solvent, and the reaction is carried out to obtain a haloolefin represented by the above formula (IV). In this production method, X in X ₂ and formula (IV) represents an iodine atom or a bromine atom. Among them, X is most preferably an iodine atom. As a solvent for this reaction, for example, pentane, hexane, heptane, saturated hydrocarbons such as cyclohexane, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ether solvents such as, hexamethylphosphoric amide (HMP), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), sulfolane, N-methylpyrrolidone So-called aprotic polar solvents, such as
Alternatively, alcohol solvents such as methanol, ethanol, and isopropyl alcohol, ketone solvents such as acetone and methyl ethyl ketone, and halogen solvents such as methylene chloride and chloroform can be used. Is also possible. The amount of the organic solvent used may be an amount sufficient for the reaction to proceed smoothly, and is usually 1 to 100 times the volume of the raw material, preferably 2 to 100 times.
Twenty times the capacity is used. After the reaction, the obtained product is separated and purified from the reaction solution by usual means. For example, extraction, washing, chromatography or a combination thereof is performed.

Thus, a compound represented by the formula (IV), that is, an alkenyl halide in which the hydroxyl group at the 11-position is protected and the carboxylic acid at the 1-position is esterified is obtained. Since the production method of the present invention uses a reaction that proceeds while maintaining the configuration, the starting material having the configuration represented by the above formula (III) is converted from the starting material having the configuration represented by the above formula (IV). Is obtained, and from the enantiomer of the above formula (III), the enantiomer of the above formula (IV) is obtained.

The third step of the production method of the present invention is as follows.
The obtained alkenyl halide represented by the above formula (IV)
With respect to the aldehyde represented by the above formula (V),
rCl _TwoUsing NiCl_TwoOr Pd (OAc)_Two
Under the conditions of using / or not using as catalyst a Grignard type
By the addition reaction, 1 represented by the following formula (VI)
The hydroxyl group at position 1 is protected and the carboxylic acid at position 1 is
Tells Prostaglandin E₁Kind of enol es
This is performed by leading to a tell derivative.

In the present production method, the formula (V) and the formula (V
R ⁴ in I) is a linear or branched alkyl group of C1 -C10, straight-chain or branched alkenyl group of C2 -C10, linear or branched alkynyl group C2 -C10, substituted or unsubstituted Represents a substituted or unsubstituted C3-C10 cycloalkyl group, and the alkyl group, alkenyl group, and alkynyl group each represent a (C1-C5 alkoxy group, a substituted or unsubstituted phenyl group, (A substituted or unsubstituted phenoxy group or a C3-C10 cycloalkyl group).

Preferred examples of the C1-C10 linear or branched alkyl group include a methyl group, an ethyl group,
Propyl group, iso-propyl group, butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, 1-methyl-1-butyl group, 2-methylhexyl group, 2-hexyl group, 1-dimethylpentyl group,
Examples include a 2,2-dimethylpentyl group. C2-C
Preferred examples of the 10 linear or branched alkenyl groups include vinyl, allyl, 3-butenyl, and 2
-Butenyl group, 4-pentenyl group, 2-pentenyl group,
Prenyl group (3-methyl-2-butenyl group), 2,4-
Examples include a hexadienyl group, a 2,6-octadienyl group, a neryl group, a geranyl group, a citronellyl group, a farnesyl group, and an arachidyl group.

Preferred examples of the C2-C10 linear or branched alkynyl group include an ethynyl group, a 2-propynyl group, a 4-pentynyl group, a 1-pentynyl group,
-Pentynyl group, 3-pentynyl group, 2-ethyl-3-
Pentynyl group, 3-hexynyl group, 2-methyl-3-hexynyl group, 1-octynyl group, 2-decynyl group, 1-
And a methyl-3-hexynyl group. As the substituent of the substituted or unsubstituted phenyl group, those exemplified as the substituent of the substituted phenyl group in R ³ can be preferably mentioned. Preferred examples of the substituted or unsubstituted C3-C10 cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a cyclodecyl group.

(C1-C5 alkoxy group, substituted or unsubstituted phenyl group, substituted or unsubstituted phenoxy group, or C3-C10 cycloalkyl group) In the alkyl group, alkenyl group and alkynyl group, C as a substituent
Examples of the 1 to C5 alkoxy group include a methoxy group,
Examples include ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, hexyloxy and the like. In the case where a phenyl group or a phenoxy group as a substituent is substituted, the substituent for the phenyl group in R ³ is preferably used as it is. Also, C3 to C as substituents
As the cycloalkyl group of 10, those in R ³ and R ² described above are directly preferred. These substituents may be bonded at any position. Preferred examples of the substituted alkyl group, alkenyl group and alkynyl group include a 2-phenylethyl group,
Phenylbutyl group, 2-phenoxybutyl group, 1,1-
Examples include a dimethyl-4-phenylbutyl group, a 1-methyl-5-phenyl-3-pentynyl group, a 3-ethoxypropyl group, and the like.

The coupling reaction between the alkenyl halide and the aldehyde in the present production method is carried out using chromium (II) chloride (Cr
Cl ₂ ) is used at a molar ratio of 1.0 to 10.0, preferably about 5.0. Furthermore, NiCl ₂ or Pd (OA
c) It is desirable to use 0.01 to 1 mol% of ₂ as a catalyst. Hexamethylphosphoric amide (HMP), N, N-dimethylformamide (DM
F) So-called aprotic polar solvents such as N, N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), sulfolane, and N-methylpyrrolidone are good, and they can be used as a mixed solvent of two or more kinds. . Among them, N, N-dimethylacetamide (DMA) and dimethylsulfoxide (DMSO) are preferred. The amount of the organic solvent used may be an amount sufficient to allow the reaction to proceed smoothly, and is usually 1 to 100 times the volume of the raw material, preferably 2 to 20 times.
Double volume is used. The reaction temperature of the present coupling reaction is from -30 ° C to 50 ° C, particularly preferably from -20 ° C to 30 ° C. The reaction time varies depending on the reaction temperature, but it is usually sufficient to react at 0 ° C to 30 ° C for about 3 hours.
After the reaction, the obtained product is separated and purified from the reaction solution by usual means. For example, extraction, washing, chromatography or a combination thereof is performed.

Thus, a compound represented by the above formula (VI), that is, a prostaglandin E ₁ in which the hydroxyl group at the 11-position is protected and the carboxylic acid at the 1-position is esterified is obtained.

The compound represented by the formula (VI) can be subjected to deprotection, hydrolysis, or a salt formation reaction, if necessary.

The removal of the protecting group R ^{1 for} the hydroxyl group may be carried out, for example, by using acetic acid, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin as a catalyst when the protecting group forms an acetal bond with the oxygen atom of the hydroxyl group. For example,
It is preferably carried out by using water, tetrahydrofuran, dioxane, acetone, acetonitrile or the like as a reaction solvent. The reaction is usually carried out in a temperature range of -78 ° C to 50 ° C for 10 minutes to 3 minutes.
It takes place for about a day. When the protecting group is a tri (C1 -C7 hydrocarbon) silyl group, for example, acetic acid, tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid, hydrogen fluoride-pyridine and the like are used as catalysts. It is carried out in a reaction solvent at a similar temperature for a similar time.

The removal of the protecting group R ^{2 for} the carboxyl group at the 1-position, ie, the hydrolysis of the ester, is carried out using an enzyme such as lipase or esterase in water or a solvent containing water at -10 ° C. to 60 ° C. The temperature range is about 10 minutes to 24 hours. However, since the enol ester at the 9-position is also hydrolyzed under these conditions, the progress of the reaction is frequently checked, and when the enol ester at the 9-position is hydrolyzed, protection of the carboxy group at the 1-position is performed. It is better to stop the reaction without waiting for complete removal of the group (R ² ) so that the desired prostaglandins E ₁ are obtained.

Alternatively, the compound having a carboxyl group obtained by the hydrolysis reaction as described above may be further subjected to a salt formation reaction, if necessary, to obtain a corresponding carboxylate. In the salt formation reaction, potassium hydroxide, sodium hydroxide, almost equivalent to the carboxylic acid,
The reaction is carried out by subjecting a basic compound such as sodium carbonate, or ammonia, trimethylamine, monoethanolamine or morpholine to a neutralization reaction in a usual manner.

In the method of the present invention, when a racemic mixture is used as a starting material, the intermediate in the course of the synthesis proceeds stereospecifically through a synthetic route as a mixture of the compound shown in the scheme and its enantiomer. If the compound represented by the formula (II) is optically active, each stereoisomer can be isolated as a pure product by separation at an appropriate stage.

In the compounds represented by the above formulas (III), (IV) and (VI), the configuration relating to the mode of attachment of the substituent on the cyclopentene ring is determined by the configuration derived from the natural prostaglandin E _1. Due to the configuration, this compound is a particularly useful stereoisomer, but its enantiomers, or mixtures thereof in any proportion, can also be used as starting materials in the process according to the invention. Also R
^{Since the} carbon to which ⁴ is bonded is an asymmetric carbon, there are two types of stereoisomers. According to the present invention, any of the stereoisomers or a mixture of any ratio thereof can be obtained. Can be. The two kinds of stereoisomers derived from the asymmetric carbon to which R ^{4 in the} formula (VI) is bonded can be obtained by using the optically active compound represented by the formula (II) as a starting material. At the stage where the protecting group at the 11-position of the formula (VI) is removed, usually, each of them can be easily isolated as a pure product by a method such as silica gel chromatography.

Further, the present invention provides a compound represented by the following formula (VII):

[0062]

Embedded image

[Wherein A, R ¹ , R ² , R ³ and the notation
--- is the same as defined above, Y is a halogen atom,
Or a group represented by (wherein, P is a is as previously defined) in -SnP ₃ represents a. ], And a synthetic intermediate of prostaglandin E ₁ class.

Here, A, R¹, R^Two, R^Three, Notation−−
−, And P are preferably specific examples of the above formula (I)
The corresponding preferred examples in formula (VI) are given as such
Can be Preferred examples of Y include iodine source
Or -Sn (n-Bu) _ThreeTri-n-but represented by
A tilstanyl group.

[0065] Specific preferred examples of prostaglandin E ₁ compound produced in the present invention method may include the following compounds. The compounds mentioned here have two types of isomers derived from the asymmetric carbon at the 15-position, and any of these isomers or a mixture thereof in any ratio is included.

[0066]

Embedded image

[0067]

Embedded image

The prostaglandin E _{1 of the} present invention
Preferred specific examples of such synthetic intermediates include the following compounds.

[0069]

Embedded image

[0070]

According to the present invention, the prostaglandin E ₁
High yield in a simple classes or 7-thiaprostaglandin enol ester derivative of E ₁ such new manufacturing method is provided. In addition, in this method, since the ω-chain portion after the 15th position is introduced last, it is possible to flexibly convert the ω-chain portion to synthesize a new compound, and thus to create a new derivative having new pharmacological properties. It is thought to contribute to.

[0071]

【Example】

Example 1 Synthesis of Compound 9 1.88 g of CuCN was placed in a 300 mL two-necked flask, dried under reduced pressure while heating with a heat gun, and then the system was replaced with argon. 35 mL of dry tetrahydrofuran was added thereto, and the mixture was stirred well to form a suspension. The suspension was cooled to 0 ° C.
37.0 mL of methyl lithium (1.25 mol / L) was added with stirring, and the temperature was raised to room temperature. Further there, transformer-
35 mL of a dry tetrahydrofuran solution of 1,2-bis (tri-n-butylstannyl) ethylene was added, and the mixture was stirred at room temperature for another 1.5 hours to produce a copper reagent. The obtained copper reagent was cooled to −78 ° C., and 30 mL of a dry tetrahydrofuran solution of 5.60 g of (4R) -t-butyldimethylsiloxy-2- (5-methoxycarbonylpentylthio) -2-cyclopenten-1-one was added. It was dropped. The reaction solution was heated to -35 ° C over 1 hour and stirred for 30 minutes. 8.60 mL of butyric anhydride was further added to the reaction solution, and the mixture was stirred for 3 hours while raising the reaction temperature to room temperature.
The reaction solution was poured into a mixture (9: 1) of 300 mL of a saturated ammonium sulfate aqueous solution and concentrated aqueous ammonia to terminate the reaction. After separating the mixture, the aqueous layer was separated from ether (150 mL × 3).
), The extract and the organic layer were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (3 to 5% ethyl acetate / hexane) to give pure target compound 9.
10.46 g (yield 92%) was obtained.

Compound 9 1H-NMR (270 MHz, δppm, CDC
l ₃ ) 0.00 (s, 6H), 0.84 (s, 9H), 0.85 (t, 9H, J = 7.0
Hz), 0.97 (t, 3H, J = 7.4 Hz), 1.18-1.75
(m, 26 H), 2.26 (t, 2H, J = 7.5 Hz), 2.39 (t,
2H, J = 7.5 Hz), 2.4-2.7 (m, 3 H), 2.81 (dd,
1H, J = 16.5 Hz, 6.5 Hz), 3.13-3.2 (m, 1 H),
3.63 (s, 3H), 4.1-4.2 (m, 1 H), 5.80 (dd, 1H,
J = 18.8 Hz, 8.2 Hz), 6.09 (d, 1H, J = 18.8 Hz)

Example 2 Synthesis of Compound 10 A vinylstannyl compound 9 was added to a 300 mL eggplant flask in 8.
74 g was added, and 90 mL of ether was added and dissolved. 2.92 g of iodine was added to this solution, and the mixture was stirred and reacted at room temperature for 1 hour. Saturated aqueous sodium thiosulfate solution 50 mL
Then, the mixture was decolorized and extracted with 250 mL of ether. The ether layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 10.45 g of a yellow oil. This was purified by silica gel column chromatography (5% ethyl acetate / hexane) to obtain 6.44 g of pure target compound 10 (yield 94%).

Compound 10 1H-NMR (270 MHz, δppm, CDCl ₃ ) 0.05 (s, 6H), 0.87 (s, 9H), 1.00 (t, 3H, J = 7.4)
Hz), 1.2-1.75 (m, 8 H), 2.31 (t, 2H, J = 7.3
Hz), 2.42 (t, 2H, J = 7.4 Hz), 2.4 -2.7 (m,
3 H), 2.84 (dd, 1H, J = 16.5 Hz, 6.9 Hz), 3.1-
3.15 (m, 1H), 3.67 (s, 3H), 4.05-4.15 (m, 1
H), 6.28 (d, 1H, J = 14.5 Hz) 6.45 (dd, 1H, J
= 14.5 Hz, 8.3 Hz)

Example 3 Synthesis of Compound 1 307 mg of chromium (II) chloride and 0.3 mg of nickel chloride were placed in a 30 mL two-necked flask, dried under reduced pressure while heating with a heat gun, and then the system was replaced with argon. DMF dry there
3.0 mL was added and the mixture was stirred well to form a suspension. Under stirring at room temperature, 298 mg of Compound 10 and 2.0 mL of DMF solution of 136 mg of phenoxyacetaldehyde were added to this suspension with a syringe. After stirring at room temperature for another 1 hour, 70 mL of water was added to terminate the reaction. After liquid separation of the mixture, the aqueous layer was extracted with ether (50 mL × 3). The extract and the organic layer were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the resulting yellow oil was purified by silica gel column chromatography (15% ethyl acetate / hexane) to give the desired compound 1 as a diastereomeric mixture.
183 mg (yield: 60%) of a compound in which the hydroxyl group at the 11-position was protected by a t-butyldimethylsilyl group was obtained.

1H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 3H), 0.05 (s, 1.5H), 0.06 (s, 1.5H),
0.88 (s, 4.5H), 0.89 (s, 4.5H), 1.00 (t, 3H, J =
7.4 Hz), 1.2-1.8 (m, 8 H), 2.29 (t, 2H, J =
6.5 Hz), 2.43 (t, 2H, J = 7.3 Hz), 2.4-2.7
(m, 1H), 2.80- 2.95 (m, 1H), 3.2 (br, 1H), 3.6
6 (s, 3H), 3.89 (dd, 1H, J = 9.4 Hz, 7.5 Hz), 4.0
1 (dd, 1H, J = 9.4 Hz, 3.4 Hz), 4.15-4.25 (m, 1
H), 4.5-4.6 (m, 1 H), 5.79 (d-like, 2H, J =
4.5 Hz), 6.85-7.00 (m, 3 H), 7.25-7.33 (m,
2H) 1.5 mL of acetonitrile and pyridine in a Teflon test tube
0.4 mL was added and cooled on ice. HF-pyridine solution there
0.4 mL was added. Under ice cooling, a solution of 172 mg of the protected t-butyldimethylsilyl solution in 0.4 mL of pyridine and 1.5 mL of acetonitrile were added to the solution, and the mixture was stirred for 15 hours while removing the ice bath and returning to room temperature. The reaction solution was mixed with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate (1: 1) 5
Poured into 0 mL. After separating the organic layer, the aqueous layer was re-extracted with ethyl acetate (30 mL). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and silica gel column chromatography (ethyl acetate: hexane =
1: 1), and 49 mg of a colorless oily substance (yield: 37%) of the isomer which was eluted earlier and the later isomer was eluted by chromatography of Compound 1.
And 56 mg (40% yield).

Isomer 1H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, 3H, J = 7.4 Hz), 1.2-1.8 (m, 8H), which is previously eluted by chromatography of compound 1
2.29 (t, 2H, J = 7.4Hz), 2.44 (t, 2H, J = 7.3
Hz), 2.5-2.75 (m, 3 H), 2.97 (ddd, 1H, J = 1
6.5 Hz, 6.6 Hz, 1.3 Hz), 3.26 (m, 1H), 3.66
(s, 3H), 3.89 (dd, 1H, J = 9.6 Hz, 7.3 Hz), 4.0
1 (dd, 1H, J = 9.6 Hz, 3.6 Hz), 4.13- 4.23 (m, 1
H), 5.81 (d-like, 2H, J = 4.0Hz), 6.88 -7.00
(m, 3 H), 7.22-7.35 (m, 2 H) Isomer 1H-NMR (270 MHz, δppm, CDCl ₃ ) 1.00 (t, 3H, J = 7.6 Hz) ), 1.3-1.8 (m, 8 H),
2.28 (t, 2H, J = 7.3Hz), 2.43 (t, 2H, J = 7.3Hz)
Hz), 2.45-2.72 (m, 3 H), 2.7 (br-s, 1H), 2.
94 (ddd, 1H, J = 16.5 Hz, 6.9 Hz, 1.3 Hz), 3.25
(m, 1H), 3.66 (s, 3H), 3.90 (dd, 1H, J = 9.6 Hz,
7.2 Hz), 4.00 (dd, 1H, J = 9.6 Hz, 3.6 Hz),
4.15-4.25 (m, 1 H), 4.5-4.6 (m, 1 H), 5.78-
5.81 (m, 2 H), 6.88 -7.00 (m, 3 H), 7.22-7.35
(m, 2 H)

Example 4 Synthesis of Compound 2 307 mg of chromium (II) chloride and 0.3 mg of nickel chloride were placed in a 30 mL two-neck flask, dried under reduced pressure while heating with a heat gun, and then the system was replaced with argon. DMF dry there
3.0 mL was added and the mixture was stirred well to form a suspension. Under stirring at room temperature, 2.0 mL of a DMF solution of 298 mg of Compound 10 and 162 mg of 5-phenylvaleraldehyde was added to this suspension with a syringe. After stirring at room temperature for another 3 hours, 70 mL of water was added to terminate the reaction. After separating the mixture, the aqueous layer was extracted with ether (50 mL × 3). The extract and the organic layer were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained yellow oil was purified by silica gel column chromatography (15% ethyl acetate / hexane) to give the desired compound 2 as a diastereomeric mixture.
263 mg (yield 83%) of a compound in which the hydroxyl group at the 11-position was protected with a t-butyldimethylsilyl group was obtained.

1H-NMR (270 MHz, δppm, CDCl ₃ ) 0.03 (s, 3H), 0.04 (s, 3H), 0.87 (s, 9H), 1.00
(t, 3H, J = 7.3 Hz), 1.2-1.8 (m, 14H), 2.29
(t, 2H, J = 7.3 Hz), 2.42 (t, 2H, J = 7.5 Hz),
2.4-2.65 (m, 5H), 2.86 (dd, 1H, J = 16.0 Hz,
7.1 Hz), 3.1- 3.15 (m, 1H), 3.66 (s, 3H), 4.02
-4.15 (m, 2 H), 5.52 (ddd, 1H, J = 15.5 Hz, 8.
6 Hz, 2.6 Hz), 5.67 (dd, 1H, J = 15.5 Hz, 6.1
Hz), 7.1-7.3 (m, 5 H) 2 mL of acetonitrile and 0.5 pyridine in a Teflon test tube
mL was added and cooled on ice. There HF-pyridine solution 0.5 m
L was added. Under ice-cooling, a solution of the above protected t-butyldimethylsilyl compound (243 mg) in pyridine (0.5 mL) and acetonitrile (2 mL) were added to the solution, and the mixture was stirred for 15 hours while removing the ice bath and returning to room temperature. The reaction solution was poured into 50 mL of a mixed solution (1: 1) of ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate. After separating the organic layer, the aqueous layer was re-extracted with ethyl acetate (30 mL). The organic layers are combined, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) and eluted first by the chromatography of compound 2. The isomer and the later-eluted isomer were obtained as colorless oily substances 70 mg (36% yield) and 73 mg (37% yield, respectively).
%)Obtained.

Isomer 1H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, 3H, J = 7.3 Hz), 1.2-1.85 (m, 14H), which is previously eluted by chromatography of compound 2
2.30 (t, 2H, J = 7.4 Hz), 2.43 (t, 2H, J =
7.3 Hz), 2.45-2.75 (m, 5 H), 2.94 (ddd, 1H, J
= 16 Hz, 6.2 Hz, 1.3 Hz), 3.21 (d-like, 1H, J =
7.5 Hz), 3.66 (s, 3H), 4.1-4.2 (m, 2 H), 5.5
4 (dd, 1H, J = 15.5 Hz, 7.8 Hz), 5.70 (dd, 1H, J
= 15.5 Hz, 6.6 Hz), 7.1-7.35 (m, 5 H)

Isomer 1H-NMR (270 MHz, δppm, CDCl ₃ ) 1.01 (t, 3H, J = 7.4 Hz), 1.2-1.8 (m, 14 H), which is later eluted by chromatography of compound 2
1.85 (br, 1H,), 2.30 (t, 2H, J = 7.2 Hz),
2.43 (t, 2H, J = 7.4 Hz), 2.4-2.7 (m, 5H),
2.92 (ddd, 1H, J = 16.5 Hz, 6.6 Hz, 1.3 Hz), 3.2
0 (d-like, 1H, J = 7.5 Hz), 3.66 (s, 3H), 4.1-
4.2 (m, 2 H), 5.55 (dd, 1H, J = 15.5 Hz, 7.9 Hz),
5.68 (dd, 1H, J = 15.5 Hz, 6.4 Hz), 7.1-7.35
(m, 5 H)

Example 5 Synthesis of Compound 3 A 30 mL two-necked flask was charged with 246 mg of chromium (II) chloride and 0.3 mg of nickel chloride, dried under reduced pressure while heating with a heat gun, and then the system was replaced with argon. DMF dry there
2.0 mL was added and the mixture was stirred well to form a suspension. Under stirring at room temperature, 239 mg of Compound 10 and 3.0 mL of a DMF solution of 69 mg of isovaleraldehyde were added to this suspension with a syringe. After stirring at room temperature for further 17 hours, 50 mL of water was added to terminate the reaction. After separating the mixture, the aqueous layer was extracted with ether (50 mL × 3). The extract and the organic layer were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained yellow oil was purified by silica gel column chromatography (15% ethyl acetate / hexane), and the 11-hydroxyl group of the target compound 3 was protected with a t-butyldimethylsilyl group as a diastereomer mixture. 127 mg (57% yield) of the compound were obtained.

1H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 6H), 0.88 (s, 9H), 0.7-1.0 (m, 9H),
1.1-1.8 (m, 11 H), 2.30 (t, 2H, J = 7.3 Hz),
2.42 (t, 2H, J = 7.2 Hz), 2.3-2.7 (m, 3H),
2.84 (dd, 1H, J = 16.0 Hz, 7.1 Hz), 3.05-3.15
(m, 1H), 3.65 (s, 3H), 4.0-4.2 (m, 2 H), 5.57
(ddd, 1H, J = 16 Hz, 8.6 Hz, 2.6Hz), 5.67 (d
(d, 1H, J = 16 Hz, 6.5 Hz) 1.5 mL of acetonitrile and pyridine in a Teflon test tube
0.4 mL was added and cooled on ice. HF-pyridine solution there
0.4 mL was added. Under ice cooling, the t-butyldimethylsilyl protected 123 mg in pyridine 0.4 mL solution was added to the solution,
And 1.5 mL of acetonitrile, and the mixture was stirred for 15 hours while removing the ice bath and returning to room temperature. The reaction solution was mixed with ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate (1: 1).
Poured into 0 mL. After separating the organic layer, the aqueous layer was re-extracted with ethyl acetate (30 mL). After the organic layers were combined and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and silica gel column chromatography (ethyl acetate: hexane =
Purification by 1: 1) was carried out to obtain 34 mg (yield: 35%) of the isomer which was eluted earlier and the later-eluted isomer under the chromatography conditions of Compound 3 as a colorless oily substance.
And 37 mg (38% yield).

Isomer 1H-NMR (270 MHz, δppm, CDCl ₃ ) 0.92 (dd, 6H, J = 6.6 Hz, 2.3 Hz), 1.01 (t, 3H, J)
= 7.4 Hz), 1.2-1.8 (m, 11 H), 2.31 (t, 2H,
J = 7.4 Hz), 2.44 (t, 2H, J = 7.2 Hz), 2.5-
2.75 (m, 3 H), 2.97 (ddd, 1H, J = 16.5 Hz, 6.5 H
z, 1.3 Hz), 3.21 (d-like, 1H, J = 7 Hz), 3.67
(s, 3H), 4.1-4.25 (m, 2 H), 5.58 (dd, 1H, J = 1
5.6 Hz, 7.9 Hz), 5.72 (dd, 1H, J = 15.6 Hz, 6.1
Hz)

Isomer 1H-NMR (270 MHz, δppm, CDCl ₃ ) 0.92 (dd, 6H, J = 6.6 Hz, 2.3 Hz), 1.01 (t, 3H, J)
= 7.3 Hz), 1.2-1.8 (m, 11 H), 2.31 (t, 2H,
J = 7.4 Hz), 2.43 (t, 2H, J = 7.2 Hz), 2.5-
2.75 (m, 3 H), 2.94 (ddd, 1H, J = 16.6 Hz, 6.9 H
z, 1.3 Hz), 3.21 (d-like, 1H, J = 7 Hz), 3.67
(s, 3H), 4.1-4.25 (m, 2 H), 5.57 (dd, 1H, J = 1
5.6 Hz, 7.7 Hz), 5.68 (dd, 1H, J = 15.6 Hz, 6.3
Hz)

Example 6 Synthesis of Compound 4 246 mg of chromium (II) chloride and 0.3 mg of nickel chloride were placed in a 30 mL two-necked flask, dried under reduced pressure while heating with a heat gun, and the system was replaced with argon. DMF dry there
2.0 mL was added and the mixture was stirred well to form a suspension. Under stirring at room temperature, 2.0 mL of a DMF solution of 200 mg of Compound 10 and 126 mg of cyclohexylacetaldehyde was added to the suspension with a syringe. After stirring at room temperature for another 3.5 hours, water 5
The reaction was terminated by adding 0 mL. After separating the mixture,
The aqueous layer was extracted with ether (50 mL × 3), and the extract and the organic layer were combined, washed with saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the resulting yellow oil was purified by silica gel column chromatography (15% ethyl acetate /
Hexane) to give 145 mg (yield 71%) of a compound in which the hydroxyl group at the 11-position of the target compound 4 was protected with a t-butyldimethylsilyl group as a diastereomeric mixture.

1H-NMR (270 MHz, δppm, CDCl ₃ ) 0.04 (s, 6H), 0.87 (s, 9H), 0.8-1.0 (m, 2H),
1.00 (t, 3H, J = 7.4Hz), 1.1-1.8 (m, 19H),
2.30 (t, 2H, J = 7.4 Hz), 2.42 (t, 2H, J = 7.5H
z), 2.4-2.7 (m, 3H), 2.8-2.95 (m, 1H), 3.
1-3.2 (m, 1H), 3.66 (s, 3H), 4.2-4.25 (m, 2
H), 5.53 (dd, 1H, J = 15.5 Hz, 8.6 Hz), 5.66
(ddd, 1H, J = 15.5 Hz, 6.3 Hz, 2.0 Hz) 1.5 mL of acetonitrile and pyridine are placed in a Teflon test tube.
0.4 mL was added and cooled on ice. HF-pyridine solution there
0.4 mL was added. Under ice cooling, a solution of the above protected t-butyldimethylsilyl compound (140 mg) in pyridine (0.4 mL) and acetonitrile (1.5 mL) were added to the solution, and the mixture was stirred for 15 hours while removing the ice bath and returning to room temperature. The reaction solution was mixed with a mixture of ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate (1:
1) Poured into 50 mL. After separating the organic layer, the aqueous layer was re-extracted with ethyl acetate (30 mL). After the combined organic layers were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1), and eluted first by the chromatography of compound 4. 44 mg each of the isomer and the later-eluted isomer as a colorless oil (40% yield)
And 48 mg (43% yield).

Isomer 1H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 2H), 1.01 (t, 3H, J = 7.5 Hz), which is previously eluted by chromatography of compound 4.
1.1-1.85 (m, 19 H), 2.31 (t, 2H, J = 7.5 Hz),
2.44 (t, 2H, J = 7.3 Hz), 2.45-2.75 (m, 3H),
2.97 (ddd, 1H, J = 16.5 Hz, 6.6 Hz, 1.3 Hz),
3.22 (d-like, 1H, J = 7.9 Hz), 3.67 (s, 3H), 4.
1-4.3 (m, 2 H), 5.57 (dd, 1H, J = 15.5 Hz, 8.0H
z), 5.72 (dd, 1H, J = 15.5 Hz, 6.3 Hz)

Isomer 1H-NMR (270 MHz, δppm, CDCl ₃ ) 0.8-1.0 (m, 2H), 1.01 (t, 3H, J = 7.5 Hz), which is later eluted by chromatography of compound 4.
1.0-1.8 (m, 19 H), 2.31 (t, 2H, J = 7.6 Hz),
2.43 (t, 2H, J = 7.3 Hz), 2.4-2.75 (m, 3H),
2.94 (ddd, 1H, J = 16.5 Hz, 6.9 Hz, 1.3 Hz), 3.2
1 (dd, 1H, J = 8.0 Hz, 1.5 Hz), 3.67 (s, 3H),
4.15-4.3 (m, 2 H), 5.55 (dd, 1H, J = 15.5 Hz,
7.6 Hz), 5.68 (dd, 1H, J = 15.5 Hz, 6.4 Hz)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07F 7/22 C07F 7/22 GN

Claims (10)

(57) [Claims] 1. A compound represented by the following formula (I): [In the formula, P represents a C1-C6 linear or branched alkyl group or a phenyl group. And trans-1,2-bis (trialkylstannyl) ethylene or trans-1,2-bis (triphenylstannyl) ethylene represented by the formula: CuQ wherein Q is a halogen atom, a cyano group, Represents a phenylthio group, a 1-pentynyl group, or a 1-hexynyl group. And an organocopper reagent prepared from a C1-C4 linear or branched alkyllithium compound, and a compound represented by the following formula (II): [In the formula, A represents a divalent sulfur atom (—S—) or a methylene group (—CH ₂ —), and R ¹ represents an acetal bond together with a tri (C1 to C7 hydrocarbon) silyl group or an oxygen atom of a hydroxyl group. Wherein R ² is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3 To C10 cycloalkyl group, substituted or unsubstituted phenyl (C
1 to C2) represents an alkyl group, and the notation --- represents a single bond or a double bond. After reacting a 2-substituted-2-cyclopentenone represented by the formula (I), an enantiomer thereof, or a mixture thereof in an arbitrary ratio, further, (R ³ CO) ₂ O ³ is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C3-C10 cycloalkyl group, or Represents a substituted or unsubstituted phenyl (C1 to C2) alkyl group. Or R ³ COCl wherein R ³ is the same as defined above. With the following formula (III): [Wherein, A, R ¹ , R ² , R ³ , P, and the notation ----- are the same as defined above. ], And further synthesizes this compound with X ₂ [wherein X represents an iodine atom or a bromine atom. And reacting with a halogen molecule represented by the following formula (IV): [Wherein, A, R ¹ , R ² , R ³ , X, and the notation ----- are the same as defined above. And further reacts the compound with a haloolefin compound represented by the following formula (V): [Wherein R ⁴ is a C1-C10 linear or branched alkyl group, a C2-C10 linear or branched alkenyl group, a C2-C10 linear or branched alkynyl group, substituted or unsubstituted Represents a substituted or unsubstituted C3-C10 cycloalkyl group, and the alkyl group, alkenyl group, and alkynyl group each represent a (C1-C5 alkoxy group, a substituted or unsubstituted phenyl group, (A substituted or unsubstituted phenoxy group or a C3-C10 cycloalkyl group). An aldehyde compound represented by] using CrCl _2, Ni
Wherein the reaction is carried out with or without using Cl ₂ or Pd (OAc) ₂ as a catalyst.
I) ^{Wherein, A, R 1, R 2} , R 3, R 4, and notation ---
Is the same as defined above. Preparation of prostaglandin E ₁ compound represented by. 2. The method according to claim 1, wherein said formulas [II], [III], [IV], [V
In I], A is a divalent sulfur atom (-S-) preparation of prostaglandin E ₁ compound according to claim 1 is. 3. Formulas [II], [III], [IV], [V]
I] wherein R ¹ is a tri (C1 to C7 hydrocarbon) silyl group, R ² is a C1 to C10 linear or branched alkyl group, X is an iodine atom, and the notation --- represents a single bond, respectively. preparation of prostaglandin E ₁ such claim 2. 4. A method according to claim 1, wherein said formulas [II], [III], [IV], [V
In I], R ¹ is a t-butyldimethylsilyl group, R ²
But a methyl group, R ³ is C1~C6 alkyl group, prostaglandin preparation of E ₁ such claim 3, wherein each representing P is n- butyl group. 5. A compound of the following formula (VII): ^{Wherein, A, R 1, R 2} , R 3, and notation --- are as previously defined, Y is a halogen atom or -SnP,
A group represented by ₃ (where P is the same as defined above)
Represents Represented by, the synthesis intermediates of prostaglandin E ₁ compound. 6. The synthetic intermediate of prostaglandins E _{1 according to} claim 5, wherein in the formula [VII], A is a divalent sulfur atom (—S—). 7. In the above formula [VII], R ¹ is a tri (C1 to C7 hydrocarbon) silyl group, and R ² is C1 to C10
Linear or branched alkyl group, a group Y is represented by -SP _3, notation --- synthetic intermediates of prostaglandin E ₁ compound of claim 6, wherein represents a single bond each. 8. In the above formula [VII], R ¹ is a tri (C1-C7 hydrocarbon) silyl group, and R ² is C1-C10
Linear or branched alkyl group, Y is a halogen atom, notation --- synthetic intermediates of prostaglandin E ₁ compound of claim 6, wherein represents a single bond each. 9. In the above formula [VII], R ¹ is a t-butyldimethylsilyl group, R ² is a methyl group, and R ³ is C1 to C1.
The prostaglandin E according to claim 7, wherein each of the 6 alkyl groups and Y represents a group represented by -Sn (n-butyl) _3.
One kind of synthetic intermediate. 10. In the above formula [VII], R ¹ is
t- butyldimethylsilyl group, R ² is a methyl group, R ³ is C1~C6 alkyl group, the synthesis intermediates of Y is prostaglandin E ₁ compound of claim 8, wherein each representing an iodine atom.