JPS6144864B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing prostaglandin derivatives. More specifically, the invention relates to the general formula [In the formula, Z ¹ is a carboxyl group or a protected carboxyl group, Z ² is a hydroxyl group or a protected hydroxyl group, Z ³ is a hydroxymethyl group or a hydroxymethyl group with a hydroxyl group protected, Z ⁴ is a hydrogen atom, an alkyl group, or Indicates a substituted alkyl group. The dotted line extending from the five-membered ring indicates a bond extending downward from the plane of the five-membered ring, that is, the α-coordination. ] A general formula characterized in that the compound represented by is treated with a carbonyl reducing agent or reacted with a Grignard reagent, and then subjected to a reaction to remove a protecting group as necessary. [In the formula, Z ¹ to ^{Z 4} have the same meanings as described above, and Z ⁵ represents a hydrogen atom or an alkyl group. This invention relates to a method for producing a prostaglandin derivative represented by the following. In addition, among the compounds of the present invention, especially compounds () in which Z ¹ is a carboxyl group, Z ² is a hydroxyl group, and Z ³ is a hydroxymethyl group, the compound () is subjected to a reaction to remove the protecting group as shown below. It can also be produced by Here, Z ¹ to ^{Z 5} have the same meanings as described above,
Z ⁶ represents a hydrogen atom or a hydroxyl group protecting group. Prostaglandins and their analogs can be named as derivatives of prostanic acid with the following structure. The method of counting the skeletal carbon atoms of prostanoic acid is as shown in the above formula. The systematic name of prostanoic acid is 7-[β-octyl]-cyclopent-1
α-yl]heptanoic acid. The compound of the general formula () obtained by the present invention is named (5Z, 9α, 11α, 13E, 15S or 15R) with prostanoic acid as the basic skeleton.
-9,15-dihydroxy-11-hydroxymethyl-12-isoprosta-5,13-diene-1-acid
It is a 15,15-disubstituted-ω-nor derivative. For nomenclature of prostaglandins and prostaglandin derivatives, see, for example, NA Nelson, Journal of Medicinal Chemistry, Vol. 17.
See Vol. 911-918 (1974). 12-isoprostanoic acid means a stereoisomer at the 12-position of prostanoic acid as represented by the following formula. The compound of the general formula () obtained by the present invention can arbitrarily refer to either the 15S form or the 15R form, and is not particularly limited to either one. The compounds having the general formulas () and () obtained by the present invention are characterized in that all substituents attached to the five-membered ring of prostanoic acid have an α configuration, and in addition, the 11th-position substitution It is characterized in that the group is a hydroxymethyl group, and from these meanings, the compounds having the general formulas () and () obtained by the present invention are structurally novel compounds, and will be described later. As mentioned above, the manufacturing method is also completely new. Some of the compounds having the general formulas () and () obtained according to the present invention also showed significant effects in pharmacological tests. Among the compounds obtained according to the present invention, those in which Z ¹ is a carboxyl group can also be made into a pharmacologically acceptable salt form. Pharmaceutically acceptable salt forms include, for example, alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium, calcium, ammonium salts, tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, phenyltriethyl. Quaternary ammonium salts such as ammonium, methylamine, ethylamine, dimethylamine, diethylamine trimethylamine,
triethylamine, N-methylhexylamine,
Salts of lower aliphatic, lower cycloaliphatic and lower araliphatic amines such as cyclobenzylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine, ethylenediamine, piperidine, morpholine, pyrrolidine,
piperazine, pyridine, 1-methylpiperazine,
Salts of heterocyclic amines and their lower alkyl derivatives such as 4-ethylmorpholine, monoethanolamine, ethyldiethanolamine, 2-
Examples include salts of amines containing hydrophilic groups such as amino-1-butanol. In the general formula of the compounds of the present invention, Z ¹ represents a carboxyl group or a protected carboxyl group such as an ester, but specifically a free carboxyl group: methyl, ethyl, n-propyl, n-butyl, isobutyl, isobutyl, etc. Substituted or unsubstituted alkyl esters such as propenyl, cyclohexylmethyl, benzyl and 2,2,2-trichloroethyl: 2
Examples include heterocyclic esters such as -tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrothienyl, and 4-methoxytetrahydropyran-4-yl. Z ² is a hydroxyl group or a protected hydroxyl group such as an acyloxy group, specifically a free hydroxyl group; a hydroxyl group protected with an alkyl group such as acetyl, chloroacetyl, propionyl, etc.; a hydroxyl group such as benzoyl, p-phenylbenzoyl, etc. Hydroxyl group protected with an aroyl group; Hydroxyl group protected with a carbon residue such as 2,2,2-trichloroethoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl; Hydroxyl group protected with a trialkylsilyl group such as trimethylsilyl; 2-tetrahydropyranyl,
2-tetrahydrothiopyranyl, 2-tetrahydrothienyl, 4-methoxytetrahydropyran-
hydroxyl group protected by a heterocyclic group such as 4-yl;
Hydroxyl groups protected with alkoxy hydrocarbon groups such as methoxymethyl, ethoxymethyl, 1-ethoxyethyl, and 1-methoxycyclohexan-1-yl: Hydroxyl groups protected with hydrocarbon groups such as methyl, ethyl, and benzyl. can give. Z ³ is a hydroxymethyl group or a hydroxymethyl group whose hydroxyl group is protected, and specifically, a free hydroxymethyl group or a hydroxymethyl group whose hydroxyl group is protected with the same protecting group as Z ² above. Z ⁴ is a hydrogen atom or an alkyl group, and the alkyl group is specifically preferably an alkyl group having 1 to 10 carbon atoms or a substituted alkyl group, such as methyl, ethyl, pentyl, and owathyl. Z ⁵ is hydrogen or an alkyl group, and the alkyl group preferably has 1 to 5 carbon atoms. In the present invention, the protecting group for the carboxyl group contained in general formula ^Z1 is one that does not substantially affect other parts of the compound when the protecting group is later removed and replaced with a hydrogen atom. If so, there is no particular limitation, and specific examples thereof are as described above. The protecting group for the hydroxyl group contained in Z ² must be one that does not affect other parts of the compound due to the removal reaction when the protecting group is subsequently removed and replaced with a hydrogen atom. There are no particular limitations,
Examples of such protecting groups include those mentioned above. As a protecting group for the hydroxyl group contained in Z ³ , the ether ring bond is cleaved under acylation conditions as described below, and then, after several steps of reaction, the general formula)
Preferably, acyl groups such as acetyl, propionyl, benzoyl, chloroacetyl, and p-phenylbenzoyl are desirable because they lead to the compound (), but they are not particularly limited. There is no particular limitation as long as it does not affect other parts of the compound when the protecting group is substantially removed later and replaced with a hydrogen atom, and such protecting groups include, for example, ^Z2 . The protecting group for hydroxyl group is arbitrarily selected from those mentioned above. The protecting group for the hydroxyl group represented by Z ⁶ must be one that does not itself undergo changes during other reactions, and when the protecting group is removed later, it will not affect other parts of the compound. There is no particular limitation as long as it is such a protecting group, and such a protecting group can be arbitrarily selected from, for example, those mentioned above as protecting groups for the hydroxyl group contained in Z ² . To explain the method of the present invention in more detail, the compound () having the general formula () is reduced with a carbonyl reducing agent or treated with a Grignard reagent, and then, if necessary, a hydroxyl protecting group or It can be obtained by subjecting the carboxyl group to a reaction for removing the protecting group in any order.
In carrying out the process of the present invention, the reaction is carried out in the presence or absence of a solvent using a cyclic agent or a Grignard reagent expressed as Z ⁵ Mgx (Z ⁵ is an alkyl group,
This is preferably achieved by using a C ₁ -C ₅ alkyl group, x is a halogen. The reducing agent used is not particularly limited as long as it converts a carbonyl group into a hydroxyl group, and examples include sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, and tri-tert hydride. Metal hydride compounds such as -ptoxylithium aluminum, trimethoxylithium aluminum hydride, and sodium cyanoborohydride are preferably used. The Grignard reagent (Z ⁵ Mgx) used is preferably an alkylmagnesium halide having 1 to 5 carbon atoms prepared by the reaction of metallic magnesium and an alkyl halide in ether or tetrahydrofuran. The reaction is carried out in the presence or absence of a solvent, but in order for the reaction to proceed smoothly, it is preferable to use a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction. For example, in the case of a reduction reaction, inert organic solvents such as alcohols such as methanol, ethanol, and isopropanol, and ethers such as tetrahydrofuran and dioxane are used, and in the case of a Grignard reaction,
Inert solvents such as ethers and ethers such as tetrahydrofuran are preferably used. Although there are no particular limitations on the reaction temperature, a relatively low temperature is desirable in order to suppress side reactions, and the reaction is usually preferably carried out at -20°C to room temperature. The reaction time varies mainly depending on the reaction temperature and the type of reaction reagent used, but is usually from 1 minute to 1 hour. After completion of the treatment, the target compound is collected from the reaction mixture in a conventional manner. For example, after the reaction is complete, an organic acid such as formic acid, acetic acid, oxalic acid, or tartaric acid is added to the reaction mixture to decompose the excess reducing agent or Grignard reagent, and then an organic solvent is added to perform extraction and the extract is washed with water. It is obtained by distilling off the solvent from the extract after drying. The obtained target compound can be further purified, if necessary, using conventional methods such as column chromatography, thin layer chromatography, etc. Among the compounds having the general formula () obtained in this way, those having hydroxyl or carboxyl protecting groups can be subjected to a reaction to remove those protecting groups, if necessary. The conditions for the reaction for removing a hydroxyl protecting group differ depending on the type of protecting group. When the protecting group for the hydroxyl group is, for example, an acyl group such as acetyl, chloroacetyl, propionyl, benzoyl, or p-phenylbenzoyl, or a carbonate residue such as 2,2,2-trichloroethoxycarbonyl, ethoxycarbonyl, or benzyloxycarbonyl, This is easily accomplished by contacting with a salt or base. Acids or bases used include, for example, mineral acids such as hydrochloric acid, hydrochloric acid and sulfuric acid, alkali metal and alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide: calcium carbonate; Alkali metal and alkaline earth metal carbonates such as potassium carbonate and calcium carbonate are preferably used. Usually, it is suitably carried out under basic conditions. The reaction is carried out in the presence or absence of a solvent, but in order to carry out the reaction smoothly, it is preferable to use a solvent, and the solvent used is not particularly limited as long as it does not participate in the reaction, for example, Water; Alcohols such as methanol and ethanol;
Ethers such as tetrahydrofuran and dioxane, or aqueous organic solvents that are mixtures of these organic solvents and water are preferably used. There is no particular limitation on the reaction temperature, and the reaction is carried out at room temperature or the reflux temperature of the solvent. When the hydroxyl protecting group is, for example, a trialkylsilyl group such as trimethylsilyl, protection is easily achieved by contacting with water or water containing an acid. When using water containing acids, the acids contained are particularly limited to organic acids such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, and malonic acid; mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid. It can be used without The reaction is carried out in the presence or absence of a solvent. Other solvents are usually not necessary if an excess of water is used. When using other solvents, organic solvents that are easily miscible with water, such as ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol, are preferably used. There is no particular limitation on the reaction temperature, but it is usually suitably carried out at room temperature. A hydroxyl protecting group is a heterocyclic group such as 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrothienyl, 4-methoxytetrahydropyran-4-yl;
In the case of alkoxy hydrocarbon groups such as methoxymethyl, ethoxymethyl, 1-ethoxyethyl, and 1-methoxycyclohexan-1-yl, this is easily achieved by contacting with an acid. Examples of acids used include formic acid, acetic acid, propionic acid,
Organic acids such as butyric acid, oxalic acid, malonic acid; hydrochloric acid,
Mineral acids such as hydrobromic acid and sulfuric acid are preferably used. The reaction is carried out in the presence or absence of a solvent, but it is preferable to use a solvent in order to carry out the reaction smoothly, and the solvent used is not particularly limited as long as it does not participate in the reaction, such as water. Alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and aqueous organic solvents of these organic solvents and water are preferably used. The reaction temperature is not particularly limited, and the reaction is carried out at room temperature to the reflux temperature of the solvent, and is particularly preferably carried out at room temperature. When the protecting group for the hydroxyl group is a hydrocarbon group such as methyl, ethyl, or benzyl, this can be easily achieved by contacting it with a boron halide compound such as boron trichloride or boron tribromide. The reaction is carried out in the presence or absence of a solvent, but it is preferable to use a solvent in order to carry out the reaction smoothly, and the solvent used is not particularly limited as long as it does not participate in the reaction, such as dichloromethane. , chloroform and other halogenated hydrocarbons are preferably used. The reaction temperature is not particularly limited, but in order to suppress side reactions, it is desirable to carry out the reaction at a relatively low temperature, and the reaction is preferably carried out at -30°C to room temperature. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an appropriate organic solvent to the reaction mixture after completion of the reaction, performing extraction, and distilling off the solvent from the extract. The obtained target compound can be further purified, if necessary, using conventional methods such as column chromatography, thin layer chromatography, etc. Next, in the reaction for removing the protecting group of the carboxyl group, the removal conditions differ depending on the type of protecting group. For example, the protecting group for carboxyl group is methyl,
In the case of hydrocarbon groups such as ethyl, n-propyl, n-butyl, isobutyl, isopropyl, n-octyl, 2-ethylhexyl, 2-propenyl, cyclohexylmethyl, benzyl, this is achieved by contacting with acids or bases. Ru. The acids or bases used are those commonly used for hydrolyzing esters without particular limitation, such as mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, or sodium hydroxide, potassium hydroxide, and water. Alkali metal and alkaline earth metal hydroxides such as barium oxide; alkali metal and alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, and calcium carbonate are preferably used. Usually, it is suitably carried out under basic conditions. The reaction is carried out in the presence or absence of a solvent, but in order to make the reaction proceed smoothly, it is preferable to use a solvent, and the solvent to be used is not particularly limited as long as it does not participate in the reaction. For example, a mixed solvent with water or an alcohol such as methanol or ethanol, or an ether such as tetrahydrofuran or dioxane is preferably used. There is no particular limitation on the reaction temperature, and the reaction is carried out at room temperature or the reflux temperature of the solvent. When the carboxyl protecting group is an alkyl halide such as 2,2,2-trichloroethyl, this is achieved by contacting with zinc and acetic acid. The reaction is carried out in the presence or absence of a solvent, but in order to make the reaction proceed smoothly, it is preferable to use a solvent, and the solvent used is not particularly limited as long as it does not participate in the reaction, such as Water; ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; or a mixed solvent of these organic solvents and water are preferably used. The reaction temperature is not particularly limited and is usually suitably carried out at room temperature. For example, the carboxyl group protecting group is 2
In the case of heterocyclic groups such as -tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrothienyl, 4-methoxytetrahydropyran-4-yl, this is achieved by contacting with an acid. Preferred acids used include organic acids such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, and malonic acid; mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid. The reaction is carried out in the presence or absence of a solvent, but it is preferable to use a solvent in order to carry out the reaction smoothly, and the solvent used is not particularly limited as long as it does not participate in the reaction. For example, water; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; and mixed solvents of these organic solvents and water are preferably used. The reaction temperature is not particularly limited, and the reaction is carried out at room temperature to the reflux temperature of the solvent, and is preferably carried out at room temperature. After the reaction is completed, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reaction is completed, a suitable organic solvent is added to the reaction mixture, extraction is performed, and the solvent is distilled off from the extract. The obtained target compound can be further purified, if necessary, by conventional methods such as column chromatography or thin layer chromatography. The compound having the general formula () used as a raw material compound in carrying out the method of the present invention is a new compound, and can be produced, for example, by the following method, but of course it is not limited to these. It's not a thing. The compound having the general formula () used as a raw material compound in carrying out the method of the present invention is:
If Z ⁶ means a hydrogen atom, the general formula ()
However, when Z ⁶ represents a hydroxyl-protecting group, it is a novel compound. The method for deriving compound () from compound () is a reaction to remove a protecting group, and the method is exactly the same as the method previously explained in the method for deriving compound () from compound (). In addition, the starting material () is a new compound,
For example, it can be produced from a compound having the general formula () as follows. In the above formula, the meanings of Z ¹ to ^{Z 6} are the same as described above. A represents a protected carbonyl group. The protecting group for the carbonyl group is not particularly limited as long as it does not undergo any change in the seventh step, that is, the step of oxidizing alcohol to aldehyde. Examples of the carbonyl group protected with such a protecting group include methylene, etc. Alkylene dioxy groups such as dioxy and ethylene dioxy; dialkoxy groups such as dimethoxy and diethoxy; alkyne dithio groups such as ethylene dithio and trimethylene dithio; and oximes. It is not particularly limited to the base. Z ⁷ represents a hydroxyl protecting group. The protecting group for the hydroxyl group represented by Z ⁷ is one that does not change in the subsequent 4th, 5th, and 12th steps, and that does not affect other parts of the compound in the step of removing the protecting group. Although there is no particular limitation as long as it does not give the following, a protecting group is desirably selected that can be preferentially removed in distinction from the hydroxyl group-protecting groups contained in Z ² and Z ³ . Examples of such protecting groups include chloroacetyl group, 2,2,2-
These include, but are not limited to, trichloroethoxycarbonyl groups. Here, A also represents an oxygen atom only if Z ⁴ represents an alkyl group. When A represents an oxygen atom, the fifth and tenth steps, that is, the step of protecting the carbonyl group and the step of removing the protecting group of the carbonyl group, can be omitted. In this case, both an aldehyde and a ketone will be present in the eighth step, ie, the Witteig reaction described below, but since the Witteig reaction occurs preferentially to the aldehyde, the compound represented by the general formula () is mainly produced. The compound having the general formula () used here as a raw material compound is a known compound, and its synthesis method is described, for example, by Fujise, Maruyama, Uda, Ohara, Kurosawa, Nippon Kagaku Zasshi Vol. 82, pp. 367-372 (1961 Year)
It is described in. The steps from the first step to the 16th step will be briefly explained below. The first step is a reaction that protects the alcohol,
The protecting group contained in Z ² is selected from one that does not change during the subsequent steps. The second step is an aldol condensation analogous reaction,
general formula This can be achieved by using a compound having the formula and a Lewis acid such as titanium tetrachloride, tin tetrachloride, aluminum trichloride, or boron trifluoride etherate as a reaction reagent. Here, Z ⁵ represents an acyl group such as acetyl or propionyl; an alkyl group such as methyl or ethyl; or a trialkylsilyl group such as trimethylsilyl. The reaction using titanium tetrachloride is described, for example, in Mukaiyama, Izawa, and Saigo, Chemistry Letters, (1974), pp. 323-326. The third step is a reaction for protecting the hydroxyl group, and the protecting group for the hydroxyl group is selected from the protecting group described above for ^Z7 . The fourth step is to place the compound () in the presence of an acid.

This can be easily achieved by heating with a carboxylic acid anhydride represented by the formula. Therefore, in this case, Z ³ represents a hydroxymethyl group protected by forming an ester with a carboxylic acid RCOOH. In common practice, heating in acetic anhydride in the presence of P-toluenesulfonic acid is sufficient to accomplish the purpose. The fifth step is a reaction for protecting the carbonyl group, and the protecting group for the carbonyl group is selected from those described above for A, and the target is achieved by a generally known reaction. The sixth step is a reaction to remove the hydroxyl protecting group ^Z7 . When Z ⁷ represents a chloroacetyl group,
It can be removed by gentle heating with thiourea or 2-amino-thioethanol. When Z ⁷ represents a 2,2,2-trichloroethoxycarbonyl group, it can be removed by treatment with zinc powder. The seventh step is a reaction in which a hydroxyl group is oxidized to an aldehyde, and the oxidizing agent is not particularly limited as long as it does not affect other parts of the compound, and known oxidizing agents are preferably used. _{The eighth} step is a Witteitz reaction, in _{which the above} -mentioned A compound having general formula (XII) is obtained. The ninth step is a reaction for protecting a carboxyl group, and any protecting group for the carboxyl group may be used without particular limitation as long as it does not change in the subsequent steps. The 10th step is a reaction for removing the protecting group of the carbonyl group, and known removal conditions depending on the protecting group represented by A are preferably used. The 11th step is the step of reducing the α/β unsaturated carbonyl group to convert it into allyl alcohol, and the reducing agent can be used without any particular restrictions as long as it does not change other parts of the compound. As such a reducing agent, for example, a known one such as zinc borohydride is preferably used. The twelfth step is a reaction to protect the hydroxyl group, and the protecting group for the hydroxyl group is one that does not undergo any change during the subsequent reaction steps, and is subsequently used in other parts of the compound during the reaction to remove the protecting group. Any material that does not have any adverse effects may be suitably used. The 13th step is a reaction in which the protective group Z ⁷ of the hydroxyl group is removed and replaced with a hydrogen atom, and is the same reaction as described above for the 6th step. The 14th step is a step of oxidizing the hydroxyl group and converting it into an aldehyde, and is the same as the aforementioned 7th step. The 15th step is a Witteig reaction and is the same as the above-mentioned 8th step. The 16th step is a step of protecting the carboxyl group, which is the same as the above-mentioned 9th step, but it is then subjected to a reaction for removing each protecting group by the method described in claim 2. In this case, the 16th step can be omitted, and in that case, it is obvious that in the compound having the general formula (), Z ¹
means a carboxyl group. After the completion of the reaction, the target compound of each step is collected from the reaction mixture by a conventional method, and if necessary, the target compound obtained is subjected to a conventional method such as column chromatography, thin layer chromatography, or a high-performance liquid chromatography method. Further purification can be achieved by means such as chromatography. Next, the method of the present invention will be explained in more detail with reference to Examples and Reference Examples, but the scope of the present invention is of course not limited by these. The following abbreviations were used. mp: touch point (end correction) TLC: thin layer chromatography (unless otherwise specified, Merck's silica gel thin layer plate ART 5715 is used) IR: infrared absorption spectrum mass: mass spectrum nmr: nuclear magnetic resonance absorption spectrum (Proton, measured at 100MHZ) ¹³ C-nmr: Carbon-13 nuclear magnetic resonance absorption spectrum [α] _D : Light intensity Only the main peaks of the IR data are listed. For mass data, only the parent peak or its corresponding peak is listed. Example 1 (5Z・9α・11α・13E・15S)-9・15-dihydroxy-11-hydroxymethyl-12-isoprosta-5・13-diene-1-acid and (5Z・9α・11α・13E・15R) −9・15
-dihydroxy-11-hydroxymethyl-12-
Prostar-5,13-diene-1-acid (5Z・9α・11α・13E)-11-acetyl oxymethyl-9-hydroxy-15-oxo-12-
Dissolve 150 mg of isoprostate-5.13-diene-1-acid methyl ester in 8 ml of methanol, cool it in an ice-water bath, and add 40 mg of sodium borohydride while stirring. After 1 hour, 6 ml of 1N aqueous potassium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. Add a saturated aqueous solution of oxalic acid dropwise to adjust the reaction solution to pH
-3 and distill off most of the methanol under reduced pressure using a water jet pump, and remove the remaining aqueous layer with 100% ethyl acetate.
Extract in several batches using ml. The ethyl acetate layers were combined, washed with a small amount of brine, dried over magnesium sulfate, and the solvent was distilled off to obtain 157 mg of an oily substance. This was subjected to column chromatography using 9 g of silica gel-60 manufactured by Merck.
Elute with chloroform containing 15% and take 23 fractions of 25 ml each. By concentrating fractions No. 8 to No. 12, pure (5Z, 9α, 11α, 13E, 15R)-9, 15-dihydroxy-11-hydroxymethyl-12-isoprosta-5. 76.6 mg of 13-diene-1 acid was obtained.
By collecting and concentrating fractions No. 16 to No. 23, pure (5Z/9
α・11α・13E・15S)-9・15-dihydroxy-
11-hydroxymethyl-12-isoprosta-5.
38.6 mg of 13-diene-1-acid was obtained. By collecting and concentrating fractions No. 13 to No. 155, 25.7 mg of a mixture of the above two types of compounds was obtained as an oily substance. Confirmed by the following analytical means. (However, for 15S and 15R, the one with the smaller Rf value in TLC was assumed to be the 15S form.) TLC (Ethyl acetate expansion twice) 15S form Rf = 0.20 15R form Rf = 0.29 tlc (Benzene: Dioxane: Acetic acid 20: 10:1) 15S form Rf = 0.35 15R form Rf = 0.45 tlc (ethyl acetate: acetic acid 100:1) 15S form Rf = 0.14 15R form Rf = 0.24 ir (liquid film) ν = cm ^-1 15S form: 3400, 2920 , 2850, 1710, 970 15R body: 3400, 2920, 2850, 1710, 970 [α] ²³ _D ; 15S body: +17.1° (C = 1.11 CHCl ₃ ) 15R body: +47.5° (C = 1.07 CHCl ₃ ) nmr (CDCl ₃ ) σPPm (from TMS) 15S body 0.87 (t, 3H) 1.05-2.5 (C, 20H) 2.6-2.9 (m, 1H) 3.59 (d, 2H) 4.0-4.3 (m, 2H) 4.96 (S, 4H) 5.2 ~ 6.1 (m 4H) 15R body 0.87 (t, 3H) 1.0 ~ 2.5 (C, 20H) 2.5 ~ 2.9 (m, 1H) 3.56 (d, 2H) 4.0 ~ 4.3 (m, 2H) ) 4.96 (S, 4H) 5.2-6.0 (m 4H) Example 2 (5Z・9α・11α・13E)-9-acetyloxy-11-acetyloxymethyl-15-hydroxy-12-isoprosta-5・13- diene-1-acid-methyl ester (5Z・9α・11α・13E)-9-acetyloxy-11-acetyloxymethyl-15-oxo-12
-Isobroster-5,13-diene-1-acid methyl ester (210 mg) was dissolved in 10 ml of alcohol, and while stirring at room temperature, 60 mg of sodium borohydride was dissolved.
Add little by little. After stirring for 30 minutes, the alcohol was removed under reduced pressure, and 20 ml of a saturated aqueous solution of sodium hydrogen tartrate was added to the residue, followed by extraction five times with 40 ml of ethyl acetate. The ethyl acetate extracts were combined, washed with a small amount of sodium bicarbonate solution and a small amount of brine, dried over sodium sulfate, and ethyl acetate was distilled off to obtain 205 mg of an oily substance. This product was obtained from the following analysis data and the results of Example 3 shown below (5Z/9).
It is presumed to be α·11α·13E)-9-acetyloxy-11-acetyloxymethyl-15-hydroxy-12-isobroster-5·13-diene-1-acid-methyl ester. tlc (cyclohexane: ethyl acetate 1:1) Rf = 0.25 0.3 iv (liquid film) νcm ^-1 3450, 2930, 2850, 1735, 970 Example 3 (5Z・9α・11α・13E・15S) −9・15− Dihydroxy-11-hydroxymethyl-12-isoprosta-5,13-diene-1-acid The oily substance obtained in Example 2, namely (5Z・9α・11
α・13E)-9-acetyloxy-11-acetyloxymethyl-15-hydroxy-12-isoprosta-5・13-diene-1-acid methyl ester
Dissolve 205 mg of the 15S and 15R mixture in 20 ml of methanol, add 20 ml of 1N aqueous potassium hydroxide solution, and stir at room temperature for 1.5 hours. After distilling off most of the methanol under reduced pressure,
Add a saturated aqueous solution of oxalic acid to the remaining aqueous solution to adjust the pH.
After adjusting to 2-3, extract 5 times with 50 ml of ethyl acetate. Combine the ethyl acetate extracts and dilute with a small amount of saline solution.
After washing twice, it was dried over magnesium sulfate and concentrated under reduced pressure to obtain 170 mg of an oily substance.
This product was subjected to preparative thin layer chromatography using two thin silica gel plates (20 cm x 20 cm) prepared with a thickness of 2 mm, and developed with ethyl acetate containing 1% acetic acid. The silica gel layer with Rf in the range of 0.15 to 0.25 is scraped off, extracted with methanol, filtered to remove the silica gel, and then concentrated. Dissolve the concentrate in 60 ml of ethyl acetate and dilute with water containing acetic acid.
The desired (5Z, 9α, 11α, 13E, 65 mg of 15S)-9,15-dihydroxy-11-hydroxymethyl-12-isoprosta-5,13-diene-1-acid was obtained. This was confirmed by the following analytical data. tlc (ethyl acetate containing 1% acetic acid) Rf = 0.14 iv (liquid film) νcm ^-1 3400, 2920, 2850, 1710, 970 nmr (CDCl ₃ ) δPPm (from TMS) 0.87 (t, 3H) 1.05 to 2.5 (C , 20H) 2.6~2.9 (m, 1H) 3.59 (d, 2H) 4.0~4.3 (m, 2H) 4.96 (S, 4H) 5.2~6.1 (m 4H) Example 4 (5Z・9α・11α・13E・15R)-9,15-dihydroxy-11-hydroxymethyl-12-isoprosta-5,13-diene-1-acid In the preparative thin layer chromatography of Example 3, the silica gel layer with Rf ranging from 0.25 to 0.3 is scraped off, extracted with methanol, the silica gel is filtered off, and then concentrated. The concentrate was dissolved in 60 ml of ethyl acetate, washed three times with a small amount of water containing acetic acid, and once with a small amount of brine, dried over magnesium sulfate, and then the ethyl acetate was distilled off. (5Z・9α・11α・13E・
15R)-9,15-dihydroxy-11-hydroxymethyl-12-isoprosta-5,13-diene-1
-35 mg of acid were obtained. This was confirmed using the following analytical data. tlc (ethyl acetate containing 1% acetic acid) Rf = 0.24 ir (liquid film) νcm ^-1 3400, 2920, 2850, 1710, 970 Example 5 (5Z・9α・11α・13E・)-9・15-dihydroxy-11 -Hydroxymethyl-15-methyl-12
-isoprosta-5,13-diene-1-acid (5Z・9α・11α・13E)-9-acetyloxy-11-acetyloxymethyl-15-oxo-12
164 mg of -isoprosta-5.13-diene-1-acid methyl ester are dissolved in 16 ml of ether and stirred in a dry ice-acetone bath. To this was added 2 ml (excess) of an ether solution (0.75 M) of methylmagnesium iodide, and the temperature was gradually raised while stirring was continued. After the temperature reached room temperature, stirring was continued for another hour, and while cooling and stirring in an ice-water bath, a small amount of saturated sodium hydrogen tartrate solution was added to decompose the excess Grignard reagent, and then the ether was distilled off under reduced pressure. do. To the remaining reaction mixture, 10 ml of methanol was added, followed by 10 ml of 1N potassium hydroxide solution, and after stirring at room temperature for 2 hours, most of the methanol was distilled off under gentle vacuum, and tartaric acid was added to the remaining aqueous solution. Carefully add saturated aqueous sodium hydrogen solution to bring the pH to 3.5-4.0. This aqueous layer was extracted five times with 50 ml of ethyl acetate, the extracts were combined, washed once with a small amount of brine, dried over sodium sulfate, and the solvent was distilled off to obtain an oily layer. 140 mg of crude product was obtained. Silica gel thin layer plate (20 cm) prepared from this material with a thickness of 2 mm
20cm) and developed twice with ethyl acetate containing 1% acetic acid. The silica gel layer with Rf from 0.25 to 0.32 was scraped off, extracted with methanol, and treated in the same manner as described above in Examples 3 and 4 to obtain the target compound containing mainly the 15S form (5Z, 9α, 11α・
13E)-9,15-dihydroxy-11-hydroxymethyl-15-methyl-12-isoprosta-5,13
54 mg of -diene-1-acid were obtained. By scraping off the silica gel layer with Rf from 0.32 to 0.4 and extracting with methanol, and performing the same treatment, the target compound (5Z・9α・11α・13E)-9・15 containing mainly the 15R form was obtained. 36 mg of -dihydroxy-11-hydroxymethyl-15-methyl-12-isoprosta-5,13-diene-1-acid were obtained. (However, the determination of 15S and 15R bodies is determined by TLC.
The one with the smaller Rf value was assumed to be a 15S body. ) This was confirmed by the following analytical data. tlc (ethyl acetate: acetic acid 99:1 15S form Rf = 0.25 15R form Rf = 2.7 ir (liquid film) νcm ^-1 3450, 2930, 2850, 1710, 970 nmr (CDCl ₃ ) δPPm (from TMS) 0.88 (t 3H ) 1.05 to 2.8 (C 21H) (excluding 1.27S3H) 1.27 (S 3H) 3.57 (m 2H) 4.0 to 4.3 (m 1H) 4.9 (S 4H) 5.2・6.1 (m 4H) (IR, nmr are 15S bodies , 15R body) Example 6 (5Z・9α・11α・13E)-20-ethyl-9・15
-dihydroxy-11-hydroxymethyl-12-
Isoprosta-5,13-diene-1-acid (5Z・9α・11α・13E)-9-acetyloxy-
11-acetyloxymethyl-20-ethyl-15-oxo-12-isoprosta-5,13-diene-1-
Dissolve 115 mg of acid methyl ester in 10 ml of alcohol, add 50 mg of sodium borohydride little by little while stirring in an ice-water bath, and continue stirring for 2 hours. After removing alcohol under reduced pressure, add 10 ml of methanol and 10 ml of 1N potassium hydroxide aqueous solution to the residue.
ml and stir at room temperature for 1.5 hours. After distilling off most of the methanol under gentle vacuum, a saturated aqueous solution of oxalic acid is carefully added to the remaining aqueous solution to bring the pH to 3. Extracted 6 times with 40 ml of ethyl acetate,
The extracts were combined, washed once with a small amount of brine, dried over magnesium sulfate, and the solvent was distilled off to obtain 105 mg of an oily crude product. This was subjected to column chromatography using 7 g of silica gel, eluted with chloroform containing 5 to 10% methanol, and 20 fractions of 25 ml were taken.
By collecting and concentrating fractions No. 5 to No. 14, the target compound (5Z, 9α, 11
α・13E)-20-Ethyl-9・15-dihydroxy-11-hydroxymethyl-12-isobroster
5,13-diene-1-acid (mixture of 15S, 15R)
72mg was obtained. This was confirmed from the following analytical data. tlc (benzene: dioxane: acetic acid 20:10:1) Rf=0.4 (15S, 15R mixture) Rf=0.47 ir (liquid film) νcm ^-1 3450, 2920, 2850, 1710, 970 nmr (CDCl ₃ ) δPPm (TMS ) 0.87 (tm 3H) 1.0~2.9 (m 25H) 3.57 (m 2H) 4.0~4.3 (m 2H) 5.0 (S 4H) 5.2~6.1 (m 4H) Reference example 1 (5Z・9α・11α・13E) -9-acetyloxy-11-acetyloxymethyl-15-oxo-12
-isoprosta-5,13-diene-1-acid methyl ester The crude product obtained in Reference Example 3, namely (5Z・9α・11
α・13E)-11-acetyloxymethyl-15・15
-50 ml of a mixture of about 0.7 g of ethylenedioxy-9-hydroxy-12-isoprosta-5,13-diene-1 acid methyl ester and its 9-acetylated product.
50 mg of P-toluenesulfonic acid hydrate was added thereto, and the mixture was stirred at room temperature for 2 hours. After removing the acetone under reduced pressure, the remaining
ml of ethyl acetate, the ethyl acetate solution was washed with a small amount of saturated sodium bicarbonate solution, followed by a small amount of brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily crude product. 0.7g was obtained. This was subjected to column chromatography using 35 g of silica gel, developed and eluted with cyclohexane containing ethyl acetate (20-30%), and 5 fractions of 100 ml were taken, followed by 24 fractions of 30 ml.
By collecting and concentrating fractions No. 3 to No. 11, the desired compound (5Z, 9α, 11α,
13E) -9-acetyloxy-11-acetyloxymethyl-15-oxo-12-isoprosta-5.
0.235 g of 13-diene-1-acid methyl ester was obtained as an oil. This was confirmed by the following analytical data. tlc (benzene: ethyl acetate 6:4) Rf = 0.24 tlc (cyclohexane: ethyl acetate 8:23 times development) Rf = 0.24 [α] ²⁴ _D = +14° (C = 0.86 chloroform) ir (liquid film) νcm ^-1 2925, 2850, 1740, 1670, 1620 nmr (CDCl ₃ ) δPPm (from TMS) 0.89 (t 3H) 1.1~2.7 (C 20H) (excluding 2.01S, 2.09S) 2.01 (S 3H) 2.09 (S 3H) 2.7~3.1 (m 1H) 3.65 (S 3H) 3.8~4.1 (m 2H) 5.1~5.5 (m 3H) 6.1 (d 1H) 6.89 (dd 1H) Reference example 2 (5Z・9α・11α・13E)−11 -acetyloxymethyl-9-hydroxy-15-oxo-12-isoprosta-5,13-diene-1-acid methyl ester In column chromatography of Reference Example 1
By collecting and concentrating fractions No. 12 to No. 29, the target compound (5Z/9
α・11α・13E)-11-acetyloxymethyl-
0.282 g of 9-hydroxy-15-oxo-12-isoprosta-5,13-diene-1-acid methyl ester was obtained as an oily substance. This was confirmed by the following analytical data. tlc (benzene: ethyl acetate 6:4) Rf = 0.57 tlc (cyclohexane: ethyl acetate 8: 23 times development) Rf = 0.24 [α] ²⁴ _D = +20° (C = 2.14 chloroform) ir (liquid film) νcm ^-1 3500, 2925, 2850, 1740, 1660, 1620 nmr (CDCl ₃ ) δPPm (from TMS) 0.89 (t 3H) 1.1-2.7 (C 21H) (excluding 2.01 S3H) 2.01 (S 3H) 2.7-3.0 (m 1H) ) 3.65 (S 3H) 4.0 (m 2H) 4.36 (m 1H) 5.4 (m 2H) 6.01 (d 1H) 7.5 (dd 1H) Reference example 3 (5Z・9α・11α・13E) -11-acetyloxymethyl- 15,15-ethylenedioxy-9-hydroxy-12-isoprosta-5,13-diene-
1-acid methyl ester and (5Z・9α・11α・13E)-9-acetyloxy-11-acetyloxymethyl-15・15
-ethylenedioxy-12-isoprosta-5.
13-diene-1-acid methyl ester The crude product obtained in Reference Example 4 (5Z・9α・11
α・13E)-15・15-ethylenedioxy-9-hydroxy-11-hydroxymethyl-12-isoprosta-5・13-diene-1-acid methyl ester
Dissolve 0.7 g in 6 ml of acetic anhydride, and add 2 ml of pyridine while stirring in an ice-water bath.
After stirring for 1 hour, acetic anhydride and pyridine were removed under reduced pressure to obtain 0.7 g of an oily substance. This product was immediately used as a raw material for Reference Example 1. tlc (benzene:ethyl acetate 6:4) Rf=0.38 (9-hydroxy form) Rf=0.56 (9-acetyloxy form) ir (liquid film) νcm ^-1 3400, 2925, 2850, 1730 Reference example 4 (5Z・9α・11α・13E)-15・15-ethylenedioxy-9-hydroxy-11-hydroxymethyl-12-isoprosta-5・13-diene-1-
acid methyl ester (5Z・9α・11α・13E)-15・15-ethylenedioxy-9-hydroxy-11-hydroxymethyl-12-isoprosta-5・13-diene-1-acid
Dissolve 0.70 g in 70 ml of diethyl ether, and add an excess of a solution of diazomethane in diethyl ether. Immediately remove excess diazomethane and diethyl ether under reduced pressure to obtain the desired (5Z・9α・11α・13E)-15・15-ethylenedioxy-9-hydroxy-11-hydroxymethyl-
0.71 g of 12-isoprosta-5.13-diene-1-acid methyl ester was obtained as an oil. This product was immediately used as a raw material for Reference Example 3. tlc (ethyl acetate) Rf=0.47 ir (liquid film) νcm ^-1 3400, 2930, 2850, 1740 Reference example 5 (5Z・9α・11α・13E)-15・15-ethylenedioxy-9-hydroxy-11- Hydroxymethyl-12-isoprosta-5,13-diene-1-
acid 4-Carbohydroxybutyltriphenylphosphonium bromide dried at 90°C under reduced pressure for 1 hour.
Dissolve 4.43 g (10 mmol) in 9 ml of dry dimethyl sulfoxide. While stirring this at room temperature, 9 ml of a dimethyl sulfoxide solution (2.09M) of sodium methylsulfinyl carbanide is added to obtain a reddish-orange phosphorane solution. This was added to (3aS・4S・5R・6aS)-hexahydro-4-[(E)-3.3-ethylenedioxy-1-
Add a solution of 0.66 g (2 mmol) of dimethyl sulfoxide (octenyl)-2-hydroxymethyl-2H-cyclopenda[b]furan in dimethyl sulfoxide (10 ml) and let the mixture cool at room temperature.
Stir for 1.5 hours. Dimethyl sulfoxide is removed in a high vacuum and 60 ml of cold water is added to the residue. After the aqueous layer is extracted four times with 50 ml of ethyl acetate:ether (1:1) mixed solvent, about 4 g of sodium hydrogen tartrate is added to the aqueous layer to adjust the pH to about 4. Extraction was performed 6 times with 60 ml of ether, the ether extracts were combined, washed with a small amount of brine, dried over sodium sulfate, and the desired crude product (5Z/9α) was obtained by distilling off the ether.・11α・13E)-15・15-ethylenedioxy-9-hydroxy-11-hydroxymethyl-
12-isoprosta-5・13-diene-1-acid 0.7
g was obtained as an oil. This product was used as the raw material for Reference Example 4 without any particular purification. tlc (acetic acid) Rf=0.15 Reference example 6 (3aS・4S・5R・6aS)-hexahydro-4-
[(E)-3,3-ethylenedioxy-1-octenyl]-2-hydroxy-5-hydroxymethyl-2H-cyclopenda[b]furan (1S・2R・3R・4R)-4-acetyloxymethyl-1-benzoyloxy-3 obtained in Reference Example 7
-[(E)-3,3-ethylenedioxy-1-octenyl]-2-formylmethyl-cyclopentane
A mixture of 0.95 g, 50 ml of methanol, and 50 ml of 1N aqueous potassium hydroxide solution is stirred at room temperature. 3.5
After some time, most of the methanol was distilled off under gentle vacuum, and the remaining aqueous layer was saturated with salt and then ethyl acetate.
Extract 5 times with 100ml. The ethyl acetate extracts were combined, washed with a small amount of brine, dried over sodium sulfate, and the solvent was distilled off to give a colorless semi-solid product (3aS, 4S,
0.66 g of 5R.6aS)-hexahydro-4-[(E)-3.3-ethylenedioxy-1-octenyl]-2-hydroxy-5-hydroxymethyl-2H-cyclopenda[b]furan was obtained. tlc (acetic acid) Rf=0.25 ir (KBr) νcm ^-1 3400, 2950, 2924, 2850, 1020 Reference example 7 (1S・2R・3R・4R)-4-acetyloxymethyl-1-benzoyloxy-3- [(E)-3・3
-ethylenedioxy-1-octenyl]-2-
Formylmethyl-cyclopentane Celite thoroughly dried at 150℃ under reduced pressure - 545 18
g and chromic acid 2-pyridine complex (Collins reagent) 9
Example 8 was obtained by stirring a mixture of g and 90 ml of dried and purified methylene chloride at -5° to 0° C. in an argon atmosphere. (1S・2R・3R・4R) −4−
Acetyloxymethyl-1-benzoyloxy-
A solution of 1.08 g of 3-[(E)-3.3-ethylenedioxy-1-octenyl]-2-(2-hydroxyethyl-cyclopentane in methylene chloride (15 ml)) is added in one portion and stirred for 15 minutes. Thereafter, 18 g of finely ground sodium hydrogen sulfate was added and stirred for an additional 10 minutes.The reaction mixture was filtered through a glass filter lined with Celite-545 and thoroughly washed with methylene chloride.
The filtrate was combined with the washing solution, concentrated, dissolved in 300 ml of ether, and filtered again to remove most of the chromium compound precipitate.By concentrating the ether solution, an oily product (1S/2R・3R・4R)-4-acetyloxymethyl-1-benzoyloxy-3
-[(E)-3,3-ethylenedioxy-1-octenyl]-2-formylmethyl-cyclopentane
0.95g was obtained. tlc (benzene: ethyl acetate 8:2) Rf=0.33 ir (liquid film) νcm ^-1 2930, 2850, 2720, 1735, 1720, 1600, 715 Reference example 8 (1S・2R・3R・4R)-4-acetyl Oxymethyl-1-benzoyloxy-3-[(E)-3.3
-ethylenedioxy-1-octenyl]-2-
(2-hydroxyethyl)-cyclopentane (1S・2R・3R・4R)-4-acetyloxymethyl-1-benzoyloxy-2-(2-chloroacetyloxyethyl)-3-[(E)-3,3-ethylenedioxy-1-octenyl ]Cyclopentane
Dissolve 1.183g in 120ml of alcohol, add 167mg of thiourea and 185mg of sodium bicarbonate.
Stir in a 70°C oil bath. After 24 hours, the alcohol was removed from the mixture, the residue was dissolved in 400 ml of ether, and the ether solution was diluted with a small amount of saturated sodium bicarbonate solution.
The crude product (1S・2R・3R・4R)-4-acetyloxymethyl-1-benzoyloxy −3− [(E)−
3,3-ethylenedioxy-1-octenyl]-
2-(2-hydroxyethyl)-cyclopentane
1.08g was obtained as an oil. tlc (benzene: ethyl acetate 8:2) Rf=0.17 ir (liquid film) νcm ^-1 3500, 2940, 2860, 1740, 1720, 1600, 715 Reference example 9 (1S・2R・3R・4R)-4-acetyl Oxymethyl-1-benzoyloxy-2-(2-chloroacetyloxyethyl)-3-[(E)-3,3-ethylenedioxy-1-octenyl]-cyclopentane (1S・2R・3R・4R)-4-acetyloxymethyl-1-benzoyloxy-2-(2-chloroacetyloxyethyl)-3-[(E)-3,3-ethylenedioxo-1-octenyl ] - 1.804 g of cyclopentane, 100 ml of benzene, 6 ml of ethylene glycol, and 20 mg of P-toluenesulfonic acid monohydrate
The mixture is heated and brought to reflux while being dehydrated using a thread equipped with a water separator. After 24 hours, the benzene solution was washed three times each with a small amount of sodium bicarbonate solution and a small amount of brine, dried over sodium sulfate, and the benzene was distilled off to obtain 1.96 g of an oily crude product. By column chromatography using 70g of silica gel, the pure target product (1S, 2R, 3R, 4R) was obtained by developing and eluating with benzene containing ethyl acetate (5-10%), collecting and concentrating the corresponding fractions.
-4-acetyloxymethyl-1-benzoyloxy-2-(2-chloroacetyloxyethyl)-
1.2 g of 3-[(E)-3.3-ethylenedioxy-1-octenyl]-cyclopentane were obtained as an oil. This was confirmed by the following analytical data. tlc (benzene: ethyl acetate 8:2) Rf = 0.44 ir (liquid film) νcm ^-1 2940, 2850, 1760, 1740, 1720, 1600, 715 [α] ²⁶ _D = +24° (C = 2.34 methanol) nmr ( CDCl ₄ ) δPPm (from TMS) 0.87 (t3H) 1.1~3.0 (C15H) (excluding 1.95S3H) 1.95 (S3H) 3.6~4.0 (m2H) (excluding 3.93S2H) 3.93 (S2H) 4.14 (t 2H) 5.42 (d 1H) 5.55 (m 1H) 6.0 (dd 1H) 7.3-7.6 (m 3H) 7.9-8.1 (m 2H) Reference example 10 (1S・2R・3R・4R)-4-acetyloxy Methyl-1-benzoyloxy-2-(2-chloroacetyloxyethyl)-3-[(E)-3-oxo-1-octenyl]cyclopentane (1R・3aR・5S・6R・6aR) -hexahydro-
5-benzoyloxy-6-(2-chloroacetyloxyethyl)-1-(2-oxo-hebutyl)
-1H-cyclopentane[C]furan 5.9g and P-
Add 1g of toluenesulfonic acid monohydrate to 120% of acetic anhydride.
ml and stir this solution in a 70°C oil bath.
After 2.5 hours, the acetic anhydride was distilled off under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate, washed twice with a small amount of sodium bicarbonate water and three times with a small amount of brine, dried over magnesium sulfate, and concentrated. 6.48 g of crude product was obtained. This was subjected to column chromatography using 300 g of silica gel, containing ethyl acetate (20
%) Elute with cyclohexane and take 20 fractions of 200 ml each. By collecting and concentrating fractions No. 8 to No. 14, the pure target compound (1S, 2R, 3R, 4R)-4-acetyloxymethyl-1-benzoyloxy-2-(2-
4.179 g of chloroacetyloxyethyl)-3-[(E)-3-oxo-1-octenyl]-cyclopentane
was obtained as an oil. This was confirmed by the following analytical data. tlc (benzene: ethyl acetate 8:2) Rf=0.37 ir (liquid film) νcm ^-1 2950, 2925, 2850, 1760, 1740, 1720, 1670,
1625, 1600, 715 [α] ²³ _D = +17° (C = 1.06 chloroform) [α] ²³ _D = +22.6° (C = 1.06 methanol) nmr (CDCl ₃ ) δPPm (from TMS) 0.87 (t 3H) 1.1~3.1 (C 13H (excluding 1.99S3H and 2.54t2H) 1.99 (S 3H) 2.54 (t 2H) 3.8~4.3 (m 2H) (excluding 3.99S2H and 4.18t2H) 3.99 (S 2H) 4.18 (t 2H) ) 5.57 (m 1H) 6.19 (d 1H) 7.03 (dd 1H) 7.3-7.7 (m 3H) 7.9-8.2 (m 2H) Reference example 11 (1S・2R・3R・4R)-4-acetyloxymethyl-1 -Benzoyloxy-2-(2-chloroacetyloxyethyl)-3-[(E)-3-oxo-1-octenyl]-cyclopentane (1S・2R・3R・4R)-4 obtained in Reference Example 9 -acetyloxymethyl-1-benzoyloxy-2
-(2-chloroacetyloxyethyl)-3-[(E)
-3,3-ethylenedioxy-1-octenyl]
- 5 mg of cyclopentane, 1 ml of acetone and P-
A mixture of 1 mg of toluenesulfonic acid hydrate was stirred at room temperature for 2 hours, and the acetone was removed under reduced pressure. The residue was dissolved in 10 ml of ethyl acetate, washed with a small amount of aqueous sodium bicarbonate, dried over magnesium sulfate, and then the solvent was removed. By distilling off, the indicated compound (1S, 2R, 3R,
4R)-4-acetyloxymethyl-1-benzoyloxy-2-(2-chloroacetyloxyethyl)-3-[(E)-3-oxo-1-octenyl]-
4 mg of cyclopentane was obtained. This was confirmed using the following analytical data. tlc (benzene: ethyl acetate 8:2) Rf=0.37 ir (liquid film) νcm ^-1 2950, 2925, 2850, 1760, 1740, 1720, 1670,
1625, 1600, 715 Reference example 12 (1R・3aR・5S・6R・6aR)-hexahydro-5
-benzoyloxy-6-(2-chloroacetyloxyethyl)-1-(2-oxo-hebutyl)-1H-cyclopenta[C]furan (1R・3aR・5S・6R・6aR) -hexahydro-
0.30 g (0.77 mmol) of 5-benzoyloxy-6-(2-hydroxyethyl)-1-(2-oxo-hebutyl)-1H-cyclopenta[C]furan and 0.102 g (0.9 mmol) of chloroacetyl chloride.
mol) in 10 ml of dry ether, and while cooling and stirring in an ice water bath, add 0.071 g (0.9 ml) of pyridine.
mol). After 1 hour, diluted with 70 ml of ether, washed the ether solution with water, aqueous sodium bicarbonate, 1N hydrochloric acid, and aqueous sodium bicarbonate in order, dried over magnesium sulfate, and distilled off the ether to form a colorless oil. Thing is
0.312g was obtained. According to the following analytical data, (1R・3aR・5S・6R・6aR)-hexahydro-5-benzoyloxy-6-(2-chloroacetyloxyethyl)-1-(2-oxo-hebutyl) It was confirmed that it was -1H-cyclopenta[C]furan. tlc (cyclohexane: ethyl acetate 6:4) Rf = 0.35 [α] ²³ _D = +51.7° (C = 1.16 methanol) ir (liquid film) νcm ^-1 2950, 2860, 1760, 1710, 1600, 1270, 713 nmr (CDCl ₃ ) δPPm (from TMS) 0.91 (t 3H) 1.1 ~ 3.1 (C 17H) 3.3 ~ 3.7 (m 1H) 3.94 (S 2H) 3.9 ~ 4.3 (m 1H) 4.19 (t 2H) 4.58 (m 1H) ) 5.50 (m 1H) 7.3-7.6 (m 3H) 7.9-8.1 (m 2H) Reference example 13 (1R・3aR・5S・6R・6aR)-hexahydro-5
-benzoyloxy-6-(2-hydroxyethyl)-1-(2-oxo-hebutyl)-1H-cyclopenta[C]furan 2-acetoxy-1-heptene 6.357g (40.7
m mol) was dissolved in 80 ml of purified methylene chloride, and this solution was cooled to 0°C to 5°C in an argon atmosphere, and while stirring, 63.8 ml (40.7 m mol) of a methylene chloride solution of titanium tetrachloride (0.64 M) was added thereto. Add slowly and dropwise. Add 10.15 g of 6-epi-tetrahydroanhydroaucubigenin benzoate to the resulting pale yellow mixture while stirring.
(37.05m mol) in methylene chloride solution (50
ml) slowly and dropwise. After the dropwise addition was completed, stirring was continued for 30 minutes at 0°C to 5°C, and 200 ml of cooled saturated sodium bicarbonate solution was added to the resulting colored reaction solution to decompose the titanium complex. After separating the methylene chloride layer, water was added. The layer was extracted 5 times with 400 ml of ethyl acetate,
Combine the organic layers and wash once with 200ml of baking soda water.
After drying over magnesium sulfate and concentration, 15.27 g of an oily crude product was obtained. Subjected to column chromatography using 300 g of silica gel, developed and eluted with methylene chloride containing 5 to 20% ethyl acetate, and
Collect 21 ml fractions. By collecting and concentrating fractions No. 7 to No. 13, a pure product as a colorless oil is produced8.82
g (22.7 mmol) was obtained. Fraction No. 6 and fractions No. 14 to 21 were collected and concentrated to yield 0.96 g of product containing a small amount of impurities. This product is expressed as (1R, 3aR, 5S, 6R,
6aR)-hexahydro-5-benzoyloxy-
It was confirmed that it was 6-(2-hydroxyethyl)-1-(2-oxo-hebutyl)-1H-cyclopenta[C]furan. tlc (cyclohexane: ethyl acetate 6:4) Rf = 0.1 tlc (methylene chloride: ethyl acetate 10:1) Rf = 0.2 [α] ²⁵ _D = +68.6° (C = 1.101 methanol) ir (liquid film) νcm ^{- 1} 3450, 2940, 2850, 1713, 1600, 1275, 1110,
1070, 1025, 712 mass M ⁺ = 388 nmr (CDCl ₃ ) δPPm (from TMS) 0.88 (t 3H) 1.1 ~ 3.1 (C 18H) 3.4 ~ 4.4 (C 4H) 4.64 (m 1H) 5.57 (m 1H) 7.3 ~7.6 (m3H) 7.9~8.2 (m2H) ¹³ C−nmr ( _CDCl3 ) δPPm (low field from TMS) 209.538 166.333 133.129 130.270 129.687 (2C) 128.648 (2C) 79.008 77.188 7 4.719 61.465 52.953 48.665 43.597 43.402 42.947 37.425 31.381 28.653 23.195 22.415 13.904 Example 14 6-epi-tetrahydroanhydroaucubigenin benzoate 7.27 g (42.8 mmol) of 6-epi-tetrahydroanhydroaucubigenin is dissolved in 20 ml of pyridine, and 7.6 g (54 mmol) of benzoyl chloride is added dropwise to the solution while stirring and cooling in an ice-water bath. After dropping, return to room temperature, stir for another 2 hours, dilute with 500 ml of ether, water, 1N hydrochloric acid,
Wash sequentially with water, saturated sodium bicarbonate solution, and saturated saline solution. The ether solution was dried over sodium sulfate and concentrated to yield 12.46 g of crude product as an oil. The product was purified by column chromatography using 500 g of silica gel and developed and eluted with a mixed solvent of benzene and ethyl acetate to obtain 10.18 g of colorless crystals. According to the following analysis data 6
-Epi-tetrahydroanhydroaucubigenin benzoate. mP 60-61℃ tlc (methylene chloride) Rf = 0.75 [α] ²⁵ _D = +32.7゜ (C = 1.04 methanol) ir (KBr) νcm ^-1 2940, 2850, 1710, 1285, 1120, 1055, 710 mass M ⁺ = 274 nmr (CDCl ₃ ) δPPm (from TMS) 1.6-3.0 (C 7H) 3.3-3.6 (m 1H) 3.6-4.2 (C 3H) 5.27 (d 1H 5CPS) 5.45 (m 1H) 7.3-7.7 ( m 3H) 7.9-8.2 (m 2H) ¹³ C−nmr (CDCl ₃ ) δPPm (from TMS) 166.073 133.067 13.337 129.620 (2C) 128.518 (2C) 100.771 79.202 71.731 59.646 41.6 48 40.088 36.125 (2C) 21.831

Claims (1)

[Claims] 1. General formula [In the formula, Z ¹ is a carboxyl group or a protected carboxyl group, Z ² is a hydroxyl group or a protected hydroxyl group, Z ³ is a hydroxymethyl group or a hydroxymethyl group with a hydroxyl group protected, Z ⁴ is a hydrogen atom, an alkyl group, or Indicates a substituted alkyl group. The dotted line extending from the five-membered ring indicates a bond extending downward from the plane of the five-membered ring, that is, the α-coordination. ] A general formula characterized in that the compound represented by is treated with a carbonyl reducing agent or reacted with a Grignard reagent, and then subjected to a reaction to remove a protecting group as necessary. [In the formula, Z ¹ to ^{Z 4} have the same meanings as described above, and Z ⁵ represents a hydrogen atom or an alkyl group. ] A method for producing a prostaglandin derivative represented by