JPS6019292B2 - Prostaglandin derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel prostaglandin derivatives.

That is, the present invention provides a general formula (wherein ZI is a carboxy group or a methoxycarbonyl group, Z is a hydroxyl group or a penzoyloxy group, Z3 is a hydroxymethyl group or a lower alkanoyloxymethyl group, Z4
Z5 is a lower alkyl group and Z5 is a hydrogen atom).

The compound of the present invention has the following two stereoisomers regarding carbon at the 12th position.

(1) (〇) Here, the bond extending from the 5-membered ring with a dotted line represents the Q-configuration, that is, the bond extending downward from the plane of the 5-membered ring, and the bond extending from the 5-membered ring with a thick solid line represents the B-configuration. That is, it represents a bond extending upward from the plane of the five-membered ring.

Moreover, in the compounds having the general formulas (1) and (b), stereoisomers exist depending on the arrangement of the hydroxyl group bonded to the substituent. The general formula (1) and (0
), all of these isomers are shown by a single formula, but the scope of the description of the present invention is not limited thereby. In the compounds of the present invention, protected carboxyl groups such as carboxyl groups or esters are shown, and specific examples include free carboxyl groups such as methyl esters.

Z is a hydroxyl group or a protected hydroxyl group, specifically,
Free hydroxyl group; examples include hydroxyl group protected with penzoyl. Momme is a hydroxymethyl group or a hydroxymethyl group protected by a hydroxyl group, and is a hydroxymethyl group protected by free hydroxy or a lower alkali/yl group such as acetyl, chloroacetyl, propionyl, etc.

Z4 is a lower alkyl group, specifically methyl, ethyl, bentyl, etc.

My friend is hydrogen.

Prostaglandins and their analogs are derivatives of prostanoic acid having the following structure, and the number of skeletal carbon atoms is as shown in the above formula.

The systematic name of brostanoic acid is 7-[(28-octyl)-cyclobent-IQ-yl-]hebutanoic acid.
Prostaglandins and their analogs can be named as derivatives of prostanoic acid. The compound of the general formula (1) obtained by the present invention is named with prostanoic acid as the basic skeleton (9Q. -en-1-acid 15.15
-disubstituted-w-nor-derivative, and similarly, the compound of the general formula (D) is (9o, 11o, 1 group, 1 $ or 1 station) -9, 15-dihydroxy-11-hydroxymethyl-12- Isoproster 13-eso 1 monoacid 15
-15-disubstituted-nor derivative.

For the nomenclature of prostaglandins and their derivatives, see, for example, N. A. Nelson, Journal of Medicinal Chemistry, Vol. 17, pp. 911-918 (
(1974). 12-isoprostanoic acid means a stereoisomer at the 12-position of prostanoic acid as represented by the following formula.

The compound having the general formula (1) obtained by the present invention is characterized in that the substituent at the 11th position of prostanoic acid is a hydroxymethyl group, and in addition, the carbon-carbon bonds at the 5th and 6th positions are saturated. In particular, the compound having the general formula (0) is further characterized in that all substituents bonded to the five-membered ring have a Q configuration.

From these meanings, the compounds having the general formulas (1) and (b) obtained by the present invention are novel compounds, and, as will be described later, have completely novel characteristics in terms of their production method. The general formula (
Among the compounds having 1) and (D), those in which Z is a carboxyl group can also be made into a pharmacologically acceptable salt form. Examples of pharmacologically acceptable salt forms include salts of alkali metals or alkali metals such as sodium, potassium, magnesium, and calcium;
Ammonium salt, tetramethylammonium, tetraethylammonium, benzyltrimethylammonium,
Quaternary ammonium salts such as phenyltriethylammonium, methylamine, ethylamine dimethylamiso, diethylamine, trimethylamine, triethylamine, N-methylhexylamine, cyclobentylamine, dicyclohexylamine, benzylamine, dibenzylamine, Q - salts of lower aliphatic, lower cycloaliphatic and lower araliphatic amines such as phenylethylamine, ethylenediamine, piveridine, morpholine, pyrrolidine,
Salts of dicyclic amines and their lower alkyl derivatives such as piperazine, pyridine, 1-methylpiverazine, 4-ethylmorpholine, hydrophilic salts such as monoethanolamine, ethyldiethanolamine, 2-amine-1-butanol Examples include salts of amines containing functional groups. The compounds having the general formulas (1) and (b) obtained according to the present invention exhibited significant physiological effects in animal tests and tests on excised organs.

For example, in the compound having the general formula (1), ZI is a carboxyl group, Z is a hydroxyl group, Z is a hydroxymethyl group,
However, the n-pentyl group, Z is hydrogen, and the allyl alcoholic hydroxyl group is in the S configuration (9Q, 11Q, 1 group, 1 $)
-9,15-dihydroxy-11-hydroxymethylbroster 13-en-1-acid contracted isolated guinea pig gastrogeni muscle (by the Nsagi gnue method) and also enhanced the effect of histamine on isolated guinea pig tracheal muscle contraction.
*Also, among the compounds having the general formula (0), ZI is a carboxyl group, Z is a hydroxyl group, Z3 is a hydroxymethyl group, Z is an n-pentyl group, and Z5 is hydrogen (
9o・11Q・1st group)-9・15-dihydroxy-11
-Hydroxymethyl-12-isof.

Rostar 13-en-1-acid suppressed the effect of histamine on isolated guinea pig tracheal muscle contraction, and also showed the effect of causing regression of the corpus luteum of pregnant hamsters and terminating the pregnancy state. The compound of the present invention, that is, the compound represented by the general formula (1) above, can be produced, for example, by a method as shown in the following figure.

(1) (V) (m) (machi) (W) The compound of the present invention, that is, the compound represented by the general formula (0) above, can be produced, for example, by a method as shown in the following figure.

（〇） (W) These methods will be explained in detail below.

The compound having the general formula (1) reduces the compound having the general formula (m)
is a halogen atom and Z5 is an alkyl group), and then subjected to a reaction in any order to remove a hydroxyl group-protecting group or a carboxyl group-protecting group as necessary. can get.

However, in the general formula (m), ZI to Z each have the same meaning as explained in the general formula (1).

Here, examples of the protecting group for the carboxyl group contained in Z include methyl. There are no particular limitations on the protecting group for the hydroxyl group contained in Z, as long as it does not affect other parts of the compound by a removal reaction when the protecting group is later removed and replaced with a hydrogen atom. An example of such a protecting group is a benzoyl group. Z3
As will be described later, the hydroxyl group incorporated in is preferably a lower alkanoyl group such as acetyl, propionyl, or chloroacetyl, since the ether ring bond is cleaved depending on the acylation conditions to yield the compound of general formula (m). It is. Further, 2 is three lower alkyl groups, and Z is hydrogen. According to the method of the present invention, the compound having the general formula (B) can be prepared by reducing the compound having the general formula (N) or treating it with a Grignard reagent, and then optionally converting the compound to a hydroxyl-protecting group or a carboxyl group. It can be obtained by subjecting the group to a reaction for removing the protecting group in any order.

However, in the general formula (N), Z to Z4 are each the same rhombus as described above in the general formula (0). Further, the compound having the general formula (m) can be obtained by isomerizing the compound having the general formula (N) by treating it under acidic conditions.

However, in the general formulas (m) and (W), the meanings of ZI to Z are as described above, and the content as a protecting group for a hydroxyl group or a carboxyl group is also as already exemplified. A compound having general formula (W) can be obtained by treating a compound having general formula (V) under acylation conditions.

However, in the general formula (V), Z, Z2 and Z4 have the same meanings as described above, and the direction of the heterocyclic bond is defined by the direction of the bond to hydrogen drawn by the thick solid line. That is, in the case of general formula (V), 5 containing an ether bond
The member ring is bent downward from the cyclobentane ring. A compound having general formula (V) can be obtained by catalytic hydrogenation of a compound having general formula (W).

However, in the general formula (W), the meanings and bonding directions of Z1, Z2 and 2 are the same as described above. Next, the method of the present invention will be explained in more detail.

In obtaining the compound (1) from the compound (m), the reaction is accomplished using a reducing agent or Grignard reagent in the presence or absence of a solvent. The reducing agent used is not particularly limited as long as it converts a carbonyl group into a hydroxyl group, and examples thereof include sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, trihydride Metal hydride compounds such as lithium aluminum hydride, lithium aluminum hydride, and sodium cyanoborohydride are preferably used. The Grignard reagent used is preferably an alkylmagnesium halide prepared by reacting metal magnesium with an alkyl halide in an ether or tetrahydrofuran represented by ZMgX. 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, 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 the Grignard reaction, ethers such as ethers and ethers such as tetrahydrofuran are used. Inert solvents are preferably used. Although there is no particular limitation 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 qo 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 the reaction is completed, the target compound is collected from the reaction mixture according to a conventional method. 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, then an organic solvent is added to perform extraction, and the extract is washed with water and dried. After that, the solvent is distilled off from the extract.The obtained target compound can be further purified if necessary using conventional methods such as column chromatography and thin layer chromatography. Among the compounds having the general formula (1) obtained in this way, those having a protecting group for a hydroxyl group or a carboxyl group can be subjected to a reaction to remove those protecting groups, if necessary. The conditions for removing the protecting group differ depending on the type of protecting group.For example, if the protecting group for the hydroxyl group is an acyl group such as acetyl, chloroacetyl, propionyl, benzoyl, p-phenylbenzoyl, etc. This is easily achieved by contacting with an acid or base. Examples of acids or bases used include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydroxide,
Alkali metal and alkali metal hydroxides such as potassium hydroxide and calcium hydroxide; sodium carbonate,
Alkali metal and alkali 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 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 aqueous organic solvents that are mixtures of these organic solvents and water are preferably used. The reaction temperature is not particularly limited and is carried out at room temperature to the reflux temperature of the solvent. 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 to perform extraction, and the solvent is distilled off from the extract. The obtained target compound can be further purified if necessary using conventional methods such as column chromatography and thin layer chromatography.
Next, the reaction step for removing the carboxyl group protecting group is achieved by contacting it with an acid or base if the carboxyl group protecting group is a hydrocarbon group such as methyl, and the removal conditions vary depending on the type of the protecting group. be done.

The acids or bases used are those that are commonly used to hydrolyze esters, and are used without particular limitation, such as hydrochloric acid, hydrobromic acid, sulfuric acid, or hydrochloric acid, sodium hydroxide, potassium hydroxide, hydroxide, etc. Hydroxides of alkali and alkali metals such as barium: sodium carbonate,
Carbonates of alkaline metals and alkaline metals 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 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 necessarily participate in the reaction, for example, Water or a mixed solvent of water and an alcohol such as methanol or ethanol or an ether such as tetrahydrofuran or dioxane is preferably used. The reaction temperature is not particularly limited and is carried out at room temperature to the reflux temperature of the solvent. 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, an appropriate organic solvent is added to the reaction mixture to perform extraction, and the solvent is removed 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 reaction for obtaining the compound 0) from the compound (N) is exactly the same as the method described above for obtaining the compound having the general formula (1) from the compound having the general formula (m). That is, the reaction may be carried out using (W) instead of (m). The general formula (
The compound having m) can be obtained by treating the compound having the above general formula (W) under acidic conditions.

In practicing the method of the invention, the reaction is accomplished by contacting with an acid in the presence or absence of a solvent. Acids used include formic acid, acetic acid, propionic acid,
Organic acids such as butyric acid, schonic acid, and malonic acid; Organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; Mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, singly or in combination. Although not particularly limited, a combination of an organic acid and an organic sulfonic acid is particularly preferably used. The reaction is carried out in the presence or absence of a solvent, and the solvent used is not particularly limited as long as it does not participate in the reaction. When an organic acid is used as the acid, the reaction proceeds smoothly even without the coexistence of other solvents, and desirably, the reaction proceeds particularly preferably with a combination of acetic acid and p-toluenesulfonic acid. There is no particular limitation on the reaction temperature, and the reaction is usually suitably carried out at room temperature to the reflux temperature of the solvent or liquid organic acid. The reaction time mainly depends on the reaction temperature and the type of acid used, but it is usually several hours.
For example, the completion of the reaction can be determined by analytical means such as thin layer chromatography. After the reaction is completed, the target compound is collected from the reaction mixture according to a conventional method. For example, after the reaction is complete, if a volatile organic acid is used, it is removed from the reaction mixture by source pressure distillation, then an organic solvent is added for extraction, and the extract is diluted with a weak alkaline aqueous solution, such as aqueous sodium bicarbonate solution. It is obtained by washing with a cloth, washing with water, drying, and then distilling off the solvent. The obtained target compound can be further purified if necessary by conventional methods such as column chromatography and thin layer chromatography. By treating the compound having the general formula (V) under acylation conditions, the compound having the general formula (N
) is obtained.

In carrying out the process of the invention, the reaction is accomplished by using an acylating agent in the presence or absence of a solvent. The acylating agent to be used is not particularly limited, and includes acid anhydrides such as anhydrous E acid and propionic anhydride, acetyl chloride, and propionic anhydride.
Acid halides such as chloride, benzoyl chloride, etc. are preferably used, and these are usually combined with a base such as pyridine triethylamine, or p-tatoluenesulfonic acid,
The reaction is achieved by a combination with an acid such as an organic sulfonic acid such as benzenesulfonic acid, and a combination of an acid anhydride and p-toluenesulfonic acid is particularly preferably used. The reaction is carried out in the presence or absence of a solvent, and the solvent used is not particularly limited as long as it is not involved in this reaction, but when using an acid anhydride, the reaction may be carried out in the absence of a solvent. will proceed smoothly. The reaction temperature is not particularly limited, and is carried out at room temperature to the reflux temperature of the solvent or acid anhydride, but is particularly preferably carried out at 50°C to 10°C.

The reaction time varies mainly depending on the reaction temperature and the type of acylating agent used, but is usually from several minutes to several hours. Completion of the reaction can be determined by analytical means such as thin layer chromatography. After completion of the reaction, the target compound is recovered from the reaction mixture by conventional means. For example, after the reaction is complete, excess acylating agent is removed by vacuum distillation, extraction is performed by adding an organic solvent, washing with a weak alkaline aqueous solution such as aqueous sodium bicarbonate, washing with water, drying, and then Obtained by removing the solvent.
The obtained target compound can be further purified, if necessary, by conventional methods such as column chromatography and thin layer chromatography. When the desired final compound is a compound having the above general formula (1) and a compound having the above general formula (m) as a raw material is required, the compound (N) obtained in this reaction can be subjected to the next reaction (W→blood) without any particular purification, and this is rather preferable. This is because this reaction produces the compound having the general formula (W) as well as the compound having the general formula (W).
) in which the conjugated ketone is enolated,
The acylation product of the conjugated polymer is produced as a by-product, and this compound is converted into the compound having the general formula (m) in the same way as the compound having the general formula (N) in the next reaction. It is. A compound having the general formula (V) can be obtained by catalytically hydrogenating the compound having the general formula (W).

In carrying out the process of the invention, conventional catalytic hydrogenation catalysts are used. The catalytic hydrogenation catalyst used is not particularly limited, and includes heterogeneous catalysts such as palladium-carbon, platinum-carbon, palladium black, Raney nickel, etc., or organometallic complexes such as chlorotris(triphenylphosphine)rhodium, etc. Homogeneous catalysts and the like are preferably used. 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 is not involved in this reaction, such as Alcohols such as methanol and ethanol; Ethers such as diethyl ether, dioxane, tetrahydrofuran, and diglyme; Hydrocarbons such as penzene, toluene, and cyclohexane; Esters such as ethyl acetate; Organic carboxylic acids such as acetic acid and propionic acid; Dialkylformamides such as chillformamide are preferably used. The reaction may be carried out under normal pressure or elevated pressure, and is conveniently carried out by contacting with hydrogen. 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 0°C to room temperature. The reaction time is usually several minutes to several hours, and the completion of the reaction can be determined by the amount of hydrogen absorbed or analytical means such as thin layer chromatography. After completion of the reaction, the target compound is recovered from the reaction mixture by conventional means. For example, after the reaction is complete,
It is obtained by filtrating the reaction mixture through a filtrate or the like and removing the solvent from the filtrate. The obtained target compound can be purified, if necessary, by conventional methods such as column chromatography and thin layer chromatography. The compound having the general formula (Kawa) used as a raw material compound in carrying out the method of the present invention is a novel compound, and can be produced, for example, by the following method.

(W) (Wind) (K) (X) (Red) (Dish) Sixth Step (Xm) In the above formula, the meanings of Z, Z and Z are the same as those 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 fourth step, that is, the step of oxidizing alcohol to aldehyde. Examples of the carbonyl group protected with such a protecting group include methylene dihydride, etc. Examples include alkylene dioxy groups such as oxy and ethylene dioxy; dialkoxy groups such as dimethoxy and diethoxy; alkylene dithio groups such as ethylene dithio and trimethylene dithio; oxime, etc.; It is not limited. Here, A also represents an oxygen atom only if Z represents an alkyl group. When A represents an oxygen atom, the third and seventh 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 aldehyde and ketone will be present in the fifth step, ie, the Wittig reaction described below, but since the Wittig reaction preferentially occurs with aldide, the compound represented by the general formula (skin) is mainly produced. The compound having the general formula (skin) used here as a raw material compound is a known compound, and its synthesis method is described in Fujise, Maruyama, Uda, Ohara, Kurosawa, Nippon Kagaku Zasshi Vol. 82, pp. 367-372 ( There is a method described in (1961). The steps from the first step to the seventh step will be explained below.

The first step is a reaction to protect the alcohol, and the protecting group contained in Z2 is selected from one that does not change during the subsequent steps. The second step is an aldol condensation-like reaction, which is achieved by using a compound having the general formula (XN) and a Lewis acid such as titanium tetrachloride, tin tetrachloride, aluminum trichloride, or boron trifluoride etherate as a reaction reagent. Ru.

Here, x indicates 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 Hitsuji), pages 323-326. The third step is a reaction for protecting the carbonyl group, and a protecting group for the L carbonyl group is selected so that it does not change in the subsequent fourth step.

The fourth step is a reaction in which alcohol is oxidized and rubbed with aldehyde, and the oxidizing agent is not particularly limited as long as it does not affect other parts of the compound, but usually chromic acid-pyridine (Collins reagent) is used. is preferably used.

The fifth step is a Wittig reaction in which the phosphonium isodide represented by the formula 9 (C6day5)8P--CH(CH2)3COONa is reacted with a compound having the general formula (phantom). A compound having pongee) is obtained.

The sixth step is a reaction for protecting carboxylic acid, and the protecting group for carboxylic acid is selected from a group that does not undergo any change in the subsequent steps.

The seventh step is a reaction to remove the protective group of the carbonyl group.

Here, the sixth step and the seventh step can also be performed in reverse order. That is, it is also possible to carry out a reaction to remove the protecting group of the carbonyl group first, and then carry out a reaction to protect the carboxylic acid. 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 processed by a conventional method such as column chromatography, thin layer chromatography, or preparative high performance liquid chromatography. It can be further purified by 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.

In the examples, the following abbreviations were used. mp
: Melting point (uncorrected) tic: Thin layer chromatography (unless otherwise specified, silica gel thin layer plate art manufactured by Merck & Co.)
5715) ir: infrared absorption spectrum mass: mass spectrum nmr: nuclear magnetic resonance absorption spectrum (proton measured at 100 MHz) 13C-nmr: carbon-13 rhombic magnetic resonance absorption spectrum [Q].

: Only the main peaks are described for the optical rotation ir data.

For mass data, only the parent peak or the peak corresponding to it is described. Example 1 9o・11Q・1st group)-11-acetyloxymethyl-9-benzoyloxy-15-hydroxy-proster
13-ene-1-acid ester (9o・11Q・1
Group) -11-acetyloxymethyl-9-benzoyloxy-15-oxoproster-13-en-1 Dissolve 9 of river acid ester ester 191 in 20M methyl alcohol, cool the solution to 0°C and sprinkle it with a rope. while adding 9 parts of 13 parts of sodium borohydride.

After 10 minutes, add 2 parts of a saturated solution of sodium hydrogen tartrate to destroy excess sodium borohydride, and
Make the reaction solution slightly acidic.

After removing the methyl alcohol under reduced pressure, the residue was extracted over 150 ml of ethyl acetate, the ethyl acetate extract was washed with a small amount of brine, dried over sodium sulfate, and the solvent was distilled off to obtain the desired product. (9Q.11o・1st group) -
197 mo of 11-acetyloxymethyl-9-benzoyloxy-15-hydroxy-prostar 13-en-1 monoacid ester was obtained. This one is an IS body and 1
It is a mixture of spheres and contains some other impurities. Purification of the target compound and separation of the 1$ body and 1 porridge body were performed using thin layer chromatography. That is, the product obtained above was mixed with cyclohexane:acetate 7:2 by using two thin silica gel plates (20 layers x 2 squares) with a thickness of 2 layers.
It can be separated and purified by developing it three times with a mixed solvent of 3. A thin layer with an Rf value ranging from 0.23 to 0.29 was scraped off and extracted with 200 ml of ethyl acetate to remove the ethyl acetate.
o・1 paper・01$)-11-acetyloxymethyl-9
-Benzoyloxy-15-Hydroxy Broster 1
3-ene-1 monoacid ester ester 76.5% was obtained.

A thin layer with an Rf value in the range of 0.31 to 0.37 was scraped off and extracted with 200 units of ethyl acetate, and ethyl acetate was removed to form one sphere (9o, 11Q, 1 unit, 1 sphere) - 11-acetyloxymethyl-9-penzoyloxy-15-hydroxy-proster 13-en-1-acid tertyl ester p 81.6 was obtained. The target compound 1$ body and 1 sphere were confirmed by the following analytical method 0. UC:
Cyclohexane ethyl myacetate 6:4) 1$ body: Rf=
0.231 stamp body: Rf=0.28 ir (liquid film) enemy-1 35 1$ body: 345029202850173517
1516009707151 Sphere: 350029202
850173517151600970715QD 40 1$ body: [Q] Customer = 150.70 (C = 1.53
methanol) 1 unit: [Q] 2 = 133.4o (C
= 1.632 m/r) mmr (CDc12) 6 willow (from TMS) 1$ body: 0.90 (t 3H) 1.0~2.5 (C 2 group) (1.90 S excluding thin ) 1,90 (S thin) 3.57 (S thin) 3.7~43 (C navy blue) 5.3~5.6 (C original) 7.3~7.6 (m thin) 7.9~ 8.1 (m) 1 translation: 0.90 (t mother H) 1.0~2.6 (C 2nd group) (1.90 excluding S thin) 1.90 (S aim) 3.58 (S Coarse) 3.7~4.3 (C Fine) Z5
2-5.7 (C thin) 7.3-7.6 (m wide) 7.9-8.1 (m wide) Example 2 (9Q・11o・1 group・1$) -9・15- dihydro 2
xy-11-hydroxymethyl-prostar-13-en-1 acid obtained in Example 1 (9Q, 11Q, 1 batch, 1 $) -
11-acetyloxymethyl-9-penzoyloxy-
A mixture of 76.5 parts of 15-hydroxy-prostyl-13-en-1-acid ester, 3 parts of methanol, and 3 parts of 1N aqueous potassium hydroxide solution was incubated at room temperature for 1 hour.

A small amount of saturated aqueous oxalic acid solution is added to bring the reaction mixture to pH 3, most of the methyl alcohol is removed under reduced pressure, and the remaining aqueous layer is extracted with ethyl acetate. The ethyl acetate extract was washed with a small amount of saturated saline, dried over sodium sulfate, and the ethyl acetate was distilled off.
A pale yellow semi-solid material with an o of 0 is obtained. Silica gel-6
Column chromatography was performed using 0.4 molar column, eluted with a solvent containing 2% to 20% methyl alcohol in chloroform, and 25 fractions of 20% were taken.
By collecting and concentrating the fractions from the 11th to the 22nd, pure target compound (9Q, 11Q, 1 group, 1 $) -9,15-dihydroxy-11-hydroxymethyl-prostar-13-ene-1-acid 39 I got it.

By combining and concentrating the 9th, 1st, and 2nd order fractions, the target compound containing a small amount of impurities (9Q, 11Q, 1 unit, 1$) -9,15-dihydroxy-11- Hydroxymethyl prostar 13-eso-
9 of 1-acid 14 was obtained.

The target compound was confirmed by the following analysis method.

OC: (benzene: dioxane: acetic acid 20:10:・
) Rf=0.30 uC: (methylene chloride:methanol 5:1) Rf=0
．． 20mP: 64-68pm ○ [Q] Color 4-50 = 128.30 (C = ○-865
Methanol)-r: (KBr)R-2 340029201705965 nmr: (CDc13) 6 legs (from TMS) 0.87
(t network) 1.0-2.5 (C 2 beats) 3.57 (m ga) 3.9-43 (m ga) 5.46 (m ga) 7.0 (S 4H) 13C-nmr ( CDC13) 6 legs (TMS to low field) 177.674 134.087 133.418
72.62363.52252.05647. clothes 74
5.13937.070(X) 33.73331.6
0929.061 28.454 27.423 26
．． 513 25.118 24.45022.5691
3.954 Example 3 (9o, 11Q, 1 group, 1 ball) -9,15-dihydroxy-11-hydroxymethyl-prostar 13-en-1-acid Obtained in Example 1 (9Q, 11Q, 1 group, 1 skin) −
A mixture of 11-acetyloxymethyl-9-benzoyloxy-15-hydroxy-prosyl-13-ene-1monoacid methyl ester, 3 parts of methyl alcohol, and 3 parts of 1N aqueous sodium hydroxide solution was heated to room temperature. The light frame will be on for 17 hours.

The pH of the reaction mixture was adjusted to 3 by adding a saturated aqueous solution of oxalic acid, most of the methyl alcohol was removed under reduced pressure, and the remaining aqueous layer was extracted with ethyl acetate. After washing the ethyl acetate extract with a small amount of saturated saline,
Drying over sodium sulfate and distilling off the ethyl acetate yields a semi-solid pale yellow material of 90.8. Acidic silica gel (Silic AR-CC4 manufactured by Mallinckrodt)
) Column chromatography was performed using 7 days of use, and 14 fractions were taken from the top 30 eluted with a mixed solvent of cyclohexane-ethyl acetate (1:1). 4th to 11th
By collecting and concentrating the fractions up to the 1st fraction, the pure target compound (9Q, 11Q, 1 group, 1 station) - 9, 1
9 of 46.2 of 5-dihydroxy-11-hydroxymethyl prostar 13-en-1-acid was obtained. The target compound was confirmed by the following analytical method.

tic: (benzene: dioxane: acetic acid 20:10:
・) Rf=0.40 -r: (KBr) Rehada-1 340029201700965 nmr: (CDc13) 6 Yanagi (from TMS) 0.87
(t) 1.0-2.5 (C2 group) 3.57 (m) 3.9-4.3 (m) 5.46 (m2H) 7 (S4H) Example 4 ( 9Q・11o・1 paper）Sunday 9・15-Dihydroxy 1
1-Hydroxymethyl-12-isoprosta-13-eso-1 monoacid (9-11Q-1 group)-11-acetyloxymethyl-9-penzoyloxy-15-oxo1
Dissolve 336 mos of 2-isoprost-13-en-1-acid methylester in 30% alcohol and add 30% of sodium borohydride.

After incubating at room temperature for 2 hours, the alcohol was distilled off under reduced pressure, and then 10% of methyl alcohol and 10% of a 6% aqueous solution of sodium hydroxide were added, and the mixture was incubated at room temperature for 2 hours.
000 oil bath for 1 hour while heating. After removing most of the methyl alcohol under reduced pressure with a water jet pump, the remaining aqueous layer is adjusted to pH 2 with an aqueous oxalic acid borate solution. The aqueous layer was extracted in several portions with 170 ml of ethyl acetate, and the ethyl acetate extracts were combined and washed with a small amount of brine, dried over sodium sulfate, and the solvent was distilled off to obtain the desired crude product. 9Q/11o/1st group) -9/15-
Approximately 0.5 units of dihydroxy-11-hydroxymethyl-12-isoprost-13-ene-1 monoacid (containing impurities) was obtained. This was subjected to column chromatography using acidic silica gel (Silic AR-CC4 manufactured by Mallinckrodt) for 20 minutes, and 27 fractions of 30' were eluted with a mixed solvent of cyclohexane and ethyl acetate (1:1). Pure fractions (9Q, 11Q.
B.E. 1$) 85% of 19,15-dihydroxy-11-hydroxymethyl-12-isoprost-13-en-1 monoacid was obtained.

However, in this case, the arrangement of the 19-stand hydroxyl group was set as 1$ because it has a high pharmacological activity. By collecting and concentrating the fractions from the 17th to the 2nd order, pure (9Q, 11o, 1 spot, 1 station)-9,15-dihydroxy-11-hydroxymethyl-12-isoprosta-
13-ene-1 monoacid 13 of 9 was obtained.

By collecting and concentrating the 11th to 16th fractions, a mixture of the above two compounds, 36.5:9, was obtained.

Confirmed by the following analytical means.

tic (benzene: dioxane: acetic acid 20:10:・
)1 dollar body Rf=0.35 1 station body Rf=0.25 mP 1 dollar body 78-81°C 1 stamp body Did not crystallize.

QD 1$ Body [Q] Color 3 = 11 (C = 1.68 Chloroform) 1 Station Body [Q] Color 3 = 190 (C = 0.43 Chloroform) 1r: Skin-1 1$ Body: 3470292028501710 Spot 01 Sphere: 34502 Rudder 028501710 Job 0 nmr (CDc
13) 1$ body: 0.90 (t 9H) 1.0~3.0 (C 2 beats) 3.58 (d ga) 3.9~44 (m ga) Z5.
18 (S 4H) 5.5-59 (m) 1 arc body: 0.90 (t thin) 1.0-3.0 (C 2 arc) 3.58 (d) J3
．． 9-4,4 (m is) 5.2 (S 4H) 5.5-59 (m is) Reference example 1 (9Q, 11Q, 1st group) -11-acetyloxymethyl-9-penzoyloxy-15- oxo prostar
13-en-1-acid ester (9Q.11Q.1
Group) -11-acetyloxymethyl-9-penzoyloxy-15-oxo-12-isoproster 13-en-1 monoacid Dissolve 9 part of methylester 640 in 100' of acetic acid, and add 500 part of P-toluenesulfonic acid to this. In addition, heat it in a 110 qo oil bath while roasting it.

After 9 hours, after removing the acetic acid under reduced pressure, the remaining oil is purified by column chromatography using 120 hours of silica gel.

The pure target compound (9Q, 11Q, 1st group) is obtained by performing cinnabar melting using methylene chloride as a solvent, collecting 100' fractions in bottles, and collecting and concentrating the 17th and 18th fractions. -11-acetyloxymethyl-9-penzoyloxy-15-oxobroster 13-ene-1-acid ester ester 204 skin c was obtained. In addition, by collecting and concentrating the fractions from the 14th to the 1st eye and the fraction from the 1st to the 21st, 9 of 206 target compounds containing some impurities were obtained. The target compound was confirmed by the following analytical method.

UC (cyclohexane: ethyl acetate 8:2, developed twice) Rf = 0.26 [Q] customer = 165.6o (C = 1.128 methanol) ir (liquid film) - 129202850174017
15 167016301600715 mmr (Cc14) 6 legs (from TMS) 0.92 (t cone) 1.1 to 2.6 (C 2 Hu) (1.86S excluding thin)
1.86 (S ga) 3.56 (S ancestor) 4.01 (m ga) 5.46 (m IH) 6.12 (d IH) 6.58 (dd IH) 7.3~7.5 ( m is) 7.9 ~ 8.1 (m is) 13C-nmr (CDc14) 6 legs (TMS to low field) 199.186 173.218 170.122
164.967 146.945132.447 1
30. Porridge 5 129.714 128.807 (X)1
27.895 (next) 76.02166.43451.
14550.417 (next) 42.34840.649
35.371 33.79431.36629.24
328.75827,544 (Friend) 24,69323
．． 78322. Paper 720.62813.893 reference example
2 (9Q, 11Q, Group 1) -11-acetyloxymethyl-9-benzoyloxy-15-oxo-12-isoproster 13-en-1-acid (9Q,
1) -9-benzoyloxy-15-oxo 12
-iso-13.11Q-epoxymethanoph.

Dissolve 1.5 parts of rostane-1 monoacid, 1.5 parts of ester and 1.5 parts of P-toluenesulfonic acid in 75' of acetic anhydride,
Heat this mixture in an oil bath for 70 minutes while stirring.
After 90 minutes, acetic anhydride was removed under reduced pressure, the residue was dissolved in 170% ethyl acetate, and the ethyl acetate solution was washed with a small amount of sodium bicarbonate aqueous solution, then washed with a small amount of brine, and then dried over sodium sulfate. Then, the solvent was distilled off to obtain 1.61 g of an oily substance.

This oily substance was subjected to column chromatography using silica gel 150% and 5% to 20% ethyl acetate.
% of cyclohexane, and 100' fractions were collected sequentially. By collecting and concentrating the fractions from the 42nd to the 5th order, the pure target compound (9Q, 11o, 1st group)-11-day acetyloxymethyl-J9-benzoyloxy--15-oxo-12-isoproster-13-ere was obtained. 1.032 of tertyl-1-acid ester was obtained.

By collecting and concentrating the fractions from the 37th to the 41st, a mixture of the target compound and the compound in which the conjugated ketone of the target compound is genolized and acetylated is obtained.
．． I got 4 sides.

The target compound was confirmed from the following analytical data.

OC (cyclohexane:ethyl acetate 8:2 developed twice) Rf=0.23
2 [Q] Customer + 27-30 (C = 1-994 methanol) IR (liquid film) and skin - 12920285017
351710 167016251600715 nmr (Cc14) 6 traces (from TMS) 0.90 (t 9H) 1.1-3.0 (C 2 seedlings) (1. except for group S 9 days) 1.93 (S spot) 3. 57 (S thin) 3.94 (d ga) 550 (m IH) 6. Female (d IH) 7.03 (ddIH) 73-7.6 (m thin) 7.9-81 (m) 13C-nmr (C ratio 13) 6 breasts (TMS to low field) 1 job. 885 173.218 169.879 1
65.025 154.119143.062 132
．． 326129.593128.807 (winter) 127.
957 (2C) 75.

899 me. 85751.14549.0 spot 48.051
41.620 40.043 35.856 33.
794 31.36629.122 28.819 2
7.423 25.967 24.693 23.84
422. Class 720. Total 913.833 Reference Example 3 (9o.11o・1 group) -11-acetyloxymethyl-9-benzoyloxy-15-oxo Broster 1
3-ene-1-acid methyl ester In the column chromatography of Example 6, fractions from 3rd to 41st were collected and concentrated, and 0.4% of the mixture was obtained.
57.4 females are subjected to reaction conditions similar to those described in Example 5.

That is, 7 is dissolved in acetic acid, 65 and 9 of P-toluenesulfonic acid are added thereto, and the mixture is heated in an oil bath at 11°C. After 4 hours, the acetic acid was removed under reduced pressure, and the residue was dissolved in 30% of ethyl acetate, washed with a small amount of saturated aqueous sodium bicarbonate solution, followed by a small amount of brine, dried over sodium sulfate, and dissolved in ethyl acetate. By distilling off, an oil of 49.5% is obtained.

A thin silica gel plate prepared to the thickness of 2 sails (
Developed with a mixed solvent of cyclohexane and ethyl acetate (8:2) using a 8:2 x 8:2 solution, scraped off the corresponding band, extracted with ethyl acetate, filtered off the silica gel, and removed the ethyl acetate. As a result, 30 females of the pure target compound (9Q, 11Q, 1 group)-11-acetyloxymethyl-9-benzoyloxy-15-oxoprostar 13-en-1 monoacetyl ester were obtained. This was confirmed from the following analytical data. UC (cyclohexane:ethyl acetate 8:2 2 times development) Rf=0.26 ir (liquid film) -1 2920285017401715 167016301600715 mmr (Cc14) hexapod (from TMS) o. 92 (t 3H) 1.1~2.6 (C 2 arc) (1.86 S 3 days excluded) 1.86 (S criminal) 3.56 (S thin) 4.01 (m ga) 5. 46 (m IH) 6.12 (d IH) 6.58 (ddIH) 7.3~7.6 (m thin) 7.9~8.1 (m wide) Reference example 4 (9o/1 field) - 9-penzoyloxy-15-oxo-12-iso-13.11Q-epoxymethanoprostane-1-acid ester (Z.9Q.1 dose) -9-penzoyloxy-15-oxo-12-iso-13.1
A mixture of 2.59 g of 1Q-epoxymethanoprosyl-5-ene-1-acid ester, 300 g of chlorotritriphenylsulfosphin rhodium, 50 g of alcohol, and 50 g of benzene was contacted with 1 atm of hydrogen. Burn the topetsu for 3 hours while keeping it warm.

Alcohol and benzene were removed under reduced pressure, and the residue was dissolved in a mixed solvent of diethyl ether and n-bentane (1:1) 200%
The extract was filtered and the solvent was distilled off to obtain a 2.7M9 oily substance. This was subjected to column chromatography using 100% silica gel, and the portion eluted with methylene chloride was collected and concentrated to obtain the pure target compound (9Q・1)-9-benzoyloxy-15-oxo-12-iso -13・1
2.17 ml of 1Q-epoxymethanoprostane-1 monoacid ester was obtained. The target compound was confirmed from the following analytical data.

UC (cyclohexane:ethyl acetate 6:4) Rf=0
．． 43 raw material Rf = 0.43 OC (silica gel coated with silver nitrate) (benzene: ethyl acetate 10:1 developed twice) Rf =
0.50 Raw material Rf = 0.36 [Q] Customer = 153.9o (C = 1.446 methanol) jr (liquid film) and skin - 129202850173517
10 1600715 nmr (Cc14) 6 legs (from TMS) 0.92 (t ancestor) 1.1-3.1 (C 27H) 3 spots (S thin) 3.3-3.7 (m IH) (3. 58S Excluding ancestor) 3.8-4.2 (m IH) 4.6 (m IH) 5.49 (m IH) 73-7,6 (m ga) 7.9-8,1 (m ga) 13C-nmr (C ratio 13) 6 legs (TMS to low field) 2 females. 165 173.225 165.336
132. Bush 129.778128. Satoshi 6 (X) 1
27.957 (book) 78.44875.414 74
．． 382 52.662 51.206 48.537
46.17043.319 (next) 37.070 3
3.794 31.24529.24328.8192
8.394 25・54224.69323.1152
2.38713.893 Reference example 5 (9o, 1 spot)-9-penzoyloxy-15-oxo-12-iso-13,11Q-epoxymethanoprostane-1-acid (string, 9Q, 1 station)-9-penzoyloxy 15-oxo-12-iso 13,11Q-epoxymethanopropyro-5-ene-1 monoacid 124-pan-c was dissolved in 20 grams of this ethyl acetate, and palladium-carbon (5
%) Add 9 of 77 catalysts.

After 3 hours of contact with hydrogen at 1 atm, the catalyst was removed by filtration, and ethyl acetate was distilled off.
24 target compounds (9Q, primary)-9-penzoyloxy-15-oxo-12-iso-13.11Q-epoxymethanoprostane-1 monoacid were obtained.

This was confirmed by the following analysis data.

tic (silica gel coated with silver nitrate) Benzene:ethyl acetate 10:1 developed twice) Rf=0
．． 50 raw material Rf = 0.36 tic (cyclohexane: ethyl acetate 6:4) Rf =
0.43 Raw material Rf = 0.43 ir (liquid film) Shihada-1 2920285017351710 1600715 *mmr (Cc14) 6 Willow (from TMS) 0.92 (
t 9H) 1.1-3.1 (C 27H) 3,58 (S fine) 3.57-3.7 (m IH) (3.58S excluding lees) 3.8-4.2 (m IH ) 4.6 (m IH) 5.49 (m IH) 7,3~7.6 (m) 7.9~8.1 (m 2H) Reference Example 6 In a 50 mm two-necked flask replaced with argon. Add 2.96 mmol (6.6 mmol) of 4-carbohydroxy-nmbutyltriphenylphosphonium bromide, and add 15 ml of dry degassed DMSO to dissolve.

Then, DMSO solution (2.03H) of 4.94' (10.02 mmol) is added to produce a red phosphorane solution.

This was dissolved on top of DMS05 (Su3oR, Shu, S,
6oR)-hexahydro-5-benzoyloxy-4-formylmethyl-3-(2-oxoheptyl)-IH-cyclobenta[C]furan (1.29 mmol) (3.34 mmol) was added, and after heating to room temperature for 2 hours, Decompression (5×10
-6 legs Hg) to remove DMSO. 100 ice water in the remaining ditch
Add and dissolve the above, then add the neutral compound to
Extract and remove 50 [×3]. The aqueous layer was adjusted to pH 2-3 with an aqueous oxalic acid solution, and then extracted with acetic acid (50' x 5). When the combined ethyl acetate solution was concentrated, the crude (Z)-7-[(Spot, 3QR, Calm, $, 6QR)-hexahydro-5-benzoyloxy-3-(2-oxoheptyl)IH-cyclobenta[C [Mount Fran 4-Ile]
-5-heptenoic acid is obtained. This crude product was dissolved in 30 parts of a 1:2 mixed solvent of methylene chloride and ether, and an ether solution of diazomethane was added until the generation of nitrogen gas stopped.The progress of the reaction was monitored by thin layer silica gel chromatography (developing solvent: cyclohexane :aceti=6:4). The oil obtained by removing the solvent under reduced pressure was purified by column chromatography (silica gel 100%, distilled using benzene:ethyl acetate = 8:2) to give 930
9 (57%) of pure (Z)-7-[(interpretation・3oR・
4R.$.6oR)-hexahydro-5-benzoyloxy-3-(2-oxoheptyl)-IH-cyclobenta[C]furan-4-yl]-15-heptenoic acid methyl ester was obtained. The structure of this compound was confirmed by the data shown below. Infrared spectrum (liquid film method): 1735
Arc-1, 1715 ka-1, 1270 skin-1, 1250 skin-1, 710 skin-INMR (CDc13, 10 sacrum 3)
:0.9 skin (t, 3H), 1.10-2.94 (m, 2
9H), 3.52 (dd, IH), 4.10 (t, IH
), 3.62 (S, group), 4.72 (m, IH), 5.
36 (m, 2H), 5.46 (m, IH), 7.52 (
m, thin), 8.04 (m, ga) [Q] D: 164.53
(CHd3・CI.046 evening/10th month) Crude (Z)-7-[(Station・3QR.4R.$・6qR
)-hexahydro-5-penzoyloxy-3-(2-
Oxoheptyl)-IH-cyclobenta[C]furan-4-yl]-15-heptenoic acid was purified by column chromatography, and its structure was confirmed from the following data.

Infrared spectrum (liquid film method): 1715 skin-1, 1278
Skin-1.713 skin-INMR (CDc13, 10 skin 4 days 3): 0.90 legs (T, thin), 2.90 (m, IH),
1.15-2.75 feet (m, 2), 3.50 (dd,
IH), 4.10 (t, IH), 4.70 (m, IH)
, 5.38 (m, general), 5.48 (m, IH), 7.5
2*(m, thin), 8.06(m, 2H), 8.40(b
road S, IH) Reference example 74-carbohydroxy-1-n-butyltriphenylphosphonium bromide 5.
36 mmol (12.1 mmol) in anhydrous deoxygenated D
Dissolve in MS020' and purge the system with argon.

Then, while worshiping the candles, DMS of NaCH2SCH3↓
O solution (1.95M) 9.3 skin (18.15 mmol)
A red phosphorane solution is produced.

To this, (arc・3QR・4R・$・6QR)-hexahydro5-benzoyloxy-4-formylmethyl-3
-(2-oxopropyl) -IH-sic. Penyu [C]
Furan 2.0 mmol (6.05 mmol) in DMS08'
After adding the solution dissolved in DMS and incubating it at room temperature for 2 hours,
O is removed under reduced pressure. The residue was dissolved in 150 g of ice water, and then neutral compounds were extracted and removed with ether (100 g. x 4). Furthermore, the aqueous layer was adjusted to pH using an oxalic acid aqueous solution.
After adjusting to 2-3, it is extracted with acetic acid (100' x 5), and the combined ethyl acetate solution is washed with saturated brine and then dried over magnesium sulfate. When the ethyl acetate solution is concentrated, (Z)-7-[(clothes・3QR, Nagi・$・6QR)-hexahydro-5-penzoyloxy-3-(2-oxopropyl)-IH-cyclobenta[C]furan-4-
1-5-heptenoic acid was obtained. When this carboxylic acid is dissolved in 50 parts of methylene chloride and an ether solution of diazomethane in an excess of an equivalent amount is added, it immediately reacts to form a methyl ester. After removing the solvent, it was purified by column chromatography (silica gel 70T: tatsu-opening distillation with methylene chloride) to obtain pure (Z)-7-[(sphere/3QR
・Nagi・$・6QR)-hexahydro-5-benzoyloxy-3-(2-oxopropyl)-IH-cyclobenta[C]furan-4-yl]-5-heptenoic acid methyl ester 1.36 times (52%) was obtained Ta. The structure of this compound was confirmed from the following data. Infrared spectrum (liquid film method): 1735 Ka-1, 1715 Skin-1, 1270 Ka-1
・712 skin-INMR (CDc13, 10 blood 3): 2
．． 28 traces (S, 9H), 1.5-3.1 legs (m, 1 set)
, 3.6 ■ Fence (S, thin), 3.5 Plow plate (IH), 4.1
4 (IH), 4.75 (m, IH), 5.40 (m, 2
H), 5.52 (m, IH), 7.56 (m, 3H),
8, Cape (m, ga) [Q] D: 152.73 (CHC13
・Reference example of 1062/100 () 8 Place well-dried Celite 54 in a 3-necked flask with a retaining device.
5,100 hours, add 50 hours of chromic anhydride pyridine complex,
Next, 500 methylene chloride was added to the mixture.

The reaction vessel was cooled to 0°C with water-salt, and then 50% of methylene chloride was dissolved in the skin. ) Add 8.11 moles (20.9 mmol) of IH-cyclobenzofuran (20.9 mmol) all at once. After heating at 0° C. for 18 minutes, add 100 moles of well-pulverized sodium hydrogen sulfate monohydrate.

After concentrating for an additional 15 minutes, separate and wash the solid well with methylene chloride. The combined methylene chloride solution was concentrated to give 9.33 g of a brown oil. After dissolving this oil in 200 ml of ether, insoluble matter was removed by filtration, and the ether solution was then concentrated to give a light yellow oil (ball, 3 oR.4R. $.6QR).
5-benzoyloxy-4-formylmethyl-3-(2
-oxoheptyl)-IH-cyclobenta[C]furan 7.3 hours was obtained. The structure of this compound was confirmed from the data shown below. Infrared spectrum: 2750 skin-1
, 1715 pine-1, 1270-1, 1105 enemy-IN
MR (CDc13, 100N ratio): 0. total chest (t, zu)
, 1.0-3.2 (m, 17H), 3.58 (dd, I
H, J = group 3, thin 3), 4.08 (dd, IH, J = carp 3, thin 3), 4.54 (m, IH), 5.52 (m to I
H), 7.50 (m, original), 8.02 (m, general), 9.
76 (broad singlet, IH) [Q].

: +40.8 (MeOH) Molecular weight: 386 (by mass vector) Elemental analysis value (as C23 day 3 minus 5) C day calculated value 71.497.83 Actual value 71.507.85 Reference example 9 (IR・3QR・$・Clothes・6QR)-Hexahydro-5
-Penzoyloxy-6-(2-hydroxyethyl)-1. -(2-oxoheptyl)-IH-cyclobenta[C]furan 2-acetoxy-1-heptene 6.357
Dissolve (4.07 mmol) in 80% of purified methylene chloride, and cool the solution at 0°C to -5°C in an argon atmosphere.
63.8 cucumbers (40.7 mmol) of a methylene chloride solution (0.64 M) of titanium tetrachloride was added to this while cooling.
) slowly dropwise.

While stirring the resulting pale yellow mixture, add 6-
A methylene chloride solution (50 mmol) containing 10.15 mmol (37.05 mmol) of tetrahydroanhydroaucubigenin benzoate is slowly added dropwise.
After the addition was completed, the reaction was continued for 30 minutes at 00-15°C, and 200% of cooled saturated water was added to the resulting brown reaction solution to separate the methylene chloride layer that decomposed the titanium complex. Afterwards, the aqueous layer was extracted 5 times with 400ml of ethyl acetate.
The organic layers were combined, washed twice with 200 g of sodium bicarbonate solution and once with 200 g of brine, dried over magnesium sulfate, and concentrated to give 15.27 g of an oily crude product. The mixture was subjected to column chromatography using silica gel 300 gel, developed and eluted with methylene chloride containing 5 to 20% ethyl acetate, and 21 fractions of 500 were collected. N
O. From 7 to NO. Collecting and concentrating up to 13 fractions gave 8.82 g (22.7 mmol) of pure product as a colorless oil. No. 6 fraction and no. By collecting and concentrating fractions 14 to 21, a product containing a small amount of impurities, 0.
96 evenings were obtained. According to the analytical data shown below, this product is expressed as (IR・3oR・$・clothes・6QR)-hexahydro-5-penzoyloxy-6-(2-hydroxyethyl)-11-(2-oxo-heptyl)-IH - It was confirmed that it was cyclobenta[C]furan. OC(
Cyclohexane:ethyl acetate 6:4) Rf=0.1U
C (methylene chloride: ethyl acetate 10:1) Rf=0.
2 [Q] Customer = 168.6o (C = 1.110 methanol) IR (liquid film) Adversary - 13450 2940 285
01713 1600 1275 1110 1070
1025712mass M+=388 nmr (CDc13) 6 legs (from TMS) o. 88 (
t 3H) 1.1-3.1 (CI fence) 3.4-4.4 (C 4H) 4.64 (m IH) 0 5.57 (m IH) 7.3-76 (m general) 7.9~8.2 (m2H)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, Z^1 is a carboxyl group or methoxycarbonyl group, Z^2 is a hydroxyl group or benzoyloxy group, Z^3
is a hydroxymethyl group or a lower alkanoyloxymethyl group, Z^4 is a lower alkyl group, and Z^5 is a hydrogen atom).