JPS632972A - Novel prostaglandin e1 derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R is H or lower alkyl; R1 is 5-7C alkyl; broken line is alpha steric configuration of bond between stoms, wedge line is beta steric configuration of bond between stoms and wavy line is alpha of beta steric configuration of bond between atoms or mixture thereof) and a salt thereof. EXAMPLE:(11S, 13E, 15S)-11, 15-dihydroxy-10, 10-dimethylo-9-oxoprost-13-en-1-oic acid methyl ester. USE:Useful for treatment for human diseases as a drug effective for improving cerebral blood flow, peripheral circulation. peripheral blood circulation disorder, etc. PREPARATION:A compound shown by formula III (R' is lower alkyl; R2 is OH-protecting group) obtained by using 5,5-dimethyl-4-hydroxy-2-cyclopentenone shown by formula II as a raw material is deprotected and then hydrolyzed or hydrolyzed and deprotected to give a compound shown by formula I wherein R is H.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the Groustaglanson E.
1 derivative and its manufacturing method. A. Prostaglandin El derivatives and their usefulness in the prevention or treatment of diseases for pharmaceutical scientists.

It has an inversion that is extremely important from a medical and pharmaceutical perspective.

More specifically, the present invention relates to the following formula (I), where R represents a hydrogen atom or a lower alkyl group, % RI represents a C5 to C1 alkyl group, and the broken line (----- 1) indicates that the bond between atoms is in the alpha configuration, wedge line (4) indicates that the bond between atoms is in the beta configuration, and the wave # t' −
> indicates that the bond between the atoms is either alpha or beta configuration, or a mixture thereof In the above formula (I), a novel prostaglanson E derivative represented by The carbon atoms at the 8th, 11th, 12th and 15th positions are optically active carbon atoms, provided that 1
The case where the carbon atom at the 5th position is not optically active is also included.

Prostagranone (PG) is a compound that is biosynthesized in vivo from arachidonic acid, and is known to be a physiologically active substance that exhibits various important physiological effects in minute amounts.

Furthermore, PG is a derivative of gulostanic acid having the structure of the following formula, and depending on the structure of its 5-membered ring, for example, E, Fα, A, B,
It is also well known that it is classified into various types such as C and D [for example, "Monthly Yakuji JVrLZ.

22,! +1 (19801:l.

For example, PGE is a compound represented by the following structural formula and is named (11α, 13E, 15S)-11,15-dihydroxy-9-oxo-prost-13-en-1-oic acid (CHEMICAL A
BSTRACTS-VOl, 95.1981-CHE
M, 5UBSTA-NCE INDEX 5921
C, S).

f-1 In the above structural formula, the bond indicated by a broken line (--------) has an alpha configuration, meaning that the substituent is bonded downward in this plane. Also, a bond indicated by a wedge line (-1) indicates a beta configuration, that is, a substituent is bonded upward in this plane.

Furthermore, the physiologically active effects of these PGs, for example, the circulatory system,
It has been reported that it affects almost all tissues of the body including the respiratory system, digestive system, urinary system, reproductive system, and central nervous system [for example, "Monthly Pharmaceutical Affairs" Vol.
22.49 (1980)).

Conventionally, some of the natural p'a, such as PGEt(lE
, PGEt, PGE, etc. have already been put into practical use as pharmaceuticals.

However, natural PGs generally have rapid substitution, are often chemically unstable, have side effects, and have the disadvantage that their physiologically active effects are not necessarily specific.

In recent years, attempts have been made to develop non-natural PGs that do not have the above-mentioned drawbacks of natural PGs and have superior specific properties.

The present inventors have conducted development research on such non-natural PG. As a result, we succeeded in synthesizing PGE, derivatives, and pharmaceutically acceptable salts thereof, which have not been described in the literature, represented by the formula (I), and compared them with natural PGE. The compound and its salts are chemically stable;
It was discovered that it has a more selective and excellent bioactive effect.

Therefore, an object of the present invention is to provide novel optically active prostaglanson E, its derivatives, and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a method for producing the novel prostaglanson E, its derivatives, and pharmaceutically acceptable salts thereof.

The above objects and many other objects and advantages of the present invention will become more apparent from the following description.

In the compound of formula (1) of the present invention, R8 represents a C3 to C7 alkyl group, such as a lupentyl group, a ruhexyl group, a ruhebutyl group, and the like. R represents a hydrogen atom or a lower alkyl group, such as a methyl group or an ethyl group. In the compound of formula (I), when R is a hydrogen atom, it can be in the form of a pharmaceutically acceptable salt thereof, and examples of such salts include Nα salt, X salt, ammonium salt, It can include quaternary ammonium salts derived from amines.

The nuclear formula (I) compounds include compounds of the following formula (I)-1 where R is a hydrogen atom and compounds of the following formula (IL2) where R is a low-grained alkyl group R'.

However, in the formula, R8, broken line (-------), wedge line (
-1, wave, and line (□) have the same meaning as above.

However, in the formula, R' represents a lower alkyl group, R1, the broken line (
−−−−−−−), wedge line (-) and wavy line rehe~φ~
) has the same meaning as above.

Further, the compound of formula ('I) of the present invention includes, for example, a compound represented by the following formula.

Rust line (4) has the same meaning as described above for formula CI).

However, in the formula, R, R, the broken line (----) and the wedge line (4) have the same meanings as described above for formula (I).

Among the compounds of formula II) of the present invention, the compound represented by the above formula (1)-2 in which R is a lower alkyl group R' is the compound represented by the following formula (n
) However, in the formula, R1 represents a lower alkyl group, and R3 is CIl
, R, represents an alkyl group, R1 represents a protecting group for the hydroxyl group, and the broken line (------) in the formula represents the alpha configuration of the bond between atoms, and the wedge line (
4) indicates that the bond between the atoms is in the beta configuration, and the wavy line (-- to ~) indicates that the bond between the atoms is in either the alpha or beta configuration, or a mixture thereof. It can be obtained by subjecting the compound represented by the following to a deprotecting group reaction. The resulting compound represented by the formula (Ii2) can be obtained by subjecting it to a hydrolysis reaction -1,4- reaction to form a compound represented by the formula (I)-1 [where R is a hydrogen atom] can be easily converted into a compound].

Furthermore, instead of the above embodiment in which the compound of formula (II) is subjected to a hydrolysis reaction after the deprotection reaction to obtain the compound of formula (I)-1, the compound of formula (n) is subjected to a hydrolysis reaction. A compound of formula +I)-1 can also be obtained by subjecting the compound to a deprotecting group reaction after the reaction.

The compound of the present invention represented by formula (I) can be produced, for example, as follows.

[Xm) CXII'l [XI]CIV”
l HOR.

Cm'1 (I)-2 (I)-1 L-EPh represents L-ephedrine, R1 represents a hydroxyl group protecting group, and R,, R4 and R3 represent a hydrogen atom or R7.

In the above embodiment, the compound of formula [X■] is JP-A-58-
It can be manufactured by using the manufacturing method described in No. 044318.

The compound of formula (X■) can be produced by reacting the compound of formula [X■] with phthalic anhydride. It is usually preferable to use pyridine as the reaction solvent.
The reaction can be carried out, for example, at about 120 to 150°C for a reaction time of about 24 hours.

By subjecting the thus obtained compound of formula [X■] to optical resolution using L-ephedrine as an optical resolution reagent, a compound of formula [:XVI] can be produced.

It is preferable to use acetonitrile or isozolopanol as the separation solvent.

For example, the compound of formula [X] and approximately equimolar amount of L-ephedrine are heated and dissolved in acetonitrile, and then allowed to cool to precipitate salt crystals. This salt crystal contains unnecessary thea stereomers and has low optical purity. Therefore, by repeating the recrystallization operation of this salt crystal with acetonitrile several times, for example, four times, it is possible to produce a compound of formula (XVt) with high optical purity.

For example, the formula [
The compound of formula [XVI] can be converted into the compound of formula [X■] by subjecting it to a reaction that eliminates t-ephedrine (7). According to that embodiment, after dissolving the compound of formula [:XVI) in a solvent such as methylene chloride, 2
Extract t-ephedrine as the hydrochloride salt using N-hydrochloric acid. - Since the compound of formula [X'l] is dissolved in the square methylene solution, it can be extracted as the Nα salt of the compound of formula [XV] using saturated sodium bicarbonate water. By neutralizing the extract with hydrochloric acid, the compound of formula (: .

The compound of formula [XV] which can be obtained as described above can be subjected to Michael addition reaction with nitromethane and a base to obtain the compound of formula [:XIV]. This reaction is carried out in a reaction solvent such as ethanol with the formula [:XV].
The reaction can be carried out by adding a compound, nitromethane, and tetramethylguanison, and subjecting the reaction to, for example, about 20 to about 30° C. for about 20 hours. The compound of formula [XIV] can be obtained as a mixture of cis and trans isomers.

For example, the formula [XIV
A compound of the formula [X■] can be produced by subjecting the compound of the formula [X■] to a hydrolysis reaction. This reaction is expressed by the formula [XIV:]
dissolving the compound in a reaction solvent such as methanol,
For example, 2N caustic soda may be added and the mixture may be heated under reflux for about 5 hours. After the reaction, it is made acidic by adding, for example, 1N-hydrochloric acid, and then extracted using, for example, ethyl acetate, and the solvent is distilled off to obtain a mixture of cis and trans isomers of the compound of formula [Xm]. .

This can be subjected to a separation and purification operation using, for example, column chromatography (for example, silica dal, for example, luhexane:ethyl acetate-2:1) to obtain a compound (trans isomer) of formula [XIN].

For example, the compound of formula [XIII] obtained as described above is subjected to an ethylene acetalization reaction to form a compound of formula [XI[
) can be produced. This reaction can be carried out by adding a compound of formula 1'XIII), ethylene glycol, and noratoluenesulfonic acid monohydrate to benzene as a reaction solvent, and heating and refluxing the mixture for about 21 hours using, for example, a Dganstar water removal device. can be obtained, and a compound of formula [X■] can be obtained. If necessary, it can be subjected to a separation and purification operation, for example, by column chromatography.

For example, the formula [”X
A compound of formula [XI] can be obtained by subjecting the compound of formula I[) to a reduction reaction with, for example, titanium trichloride. This reaction is carried out by dissolving a compound of formula [XI[:l] in methanol as a reaction solvent, cooling to, for example, about -20°C, and adding and dissolving, for example, sodium methoxide.
Next, a titanium trichloride-ammonium acetate aqueous solution is added and reacted at, for example, about -20°C to about 0°C, thereby producing a compound of formula [XI]. The compound of formula [IX) can be obtained by converting the compound of formula [XI] which can be obtained as described above to formula
using a phosphonate of the formula (wherein R is as defined above) and a base such as sodium hydride, sodium methoxide, sodium ethoxide, etc.
References, J. Am.

ch-Soc, 9Q, 3247 ([6B) and J, Am, Chgm, Cot, 83.1733 (
It can be produced by reacting using or applying the method described in (1961).

As a reaction solvent, THF (tetrahydrofuran),
DME (1,2-dimethoxyethane), ethers such as dioxane, methylene chloride, etc. can be preferably used.

The reaction can be carried out at a temperature of, for example, about -20 to about 70°C and a reaction time of, for example, about 1 to about 10 hours.

The ethylene groups at positions 13 and 14 produced in this reaction are preferentially of the trans type.

The compound of Wenmu [x] is in the literature, J, AnL.

ch-m, 5ot19Q, 3247 (1968) and J
, Ar1L, Cham, Soc,, B B, 56
It can be produced by using or applying the method described in 54 (1966).

The compound of the formula [■] can be obtained by subjecting the compound of the formula [■], which can be obtained as described above, to a reduction reaction, for example, by reacting a reducing agent in an appropriate reaction solvent to convert a ketone group into a hydroxyl group. It can be manufactured by attaching.

Examples of reducing agents include hydrides of metals such as boron and aluminum. Specific examples of such reducing agents include sodium borohydride, lithium borohydride, potassium borohydride, and borohydride. Zinc, stium cyanoborohydride, sodium trimethoxyboronate, potassium triisopropoxyborohydride, potassium tri-jt6-butylborohydride, lithium-5ac-butylborohydride, tetralupyl cyanoborohydride - Ammonium (in the above cases, it is also preferable to use cerous chloride with addition), lithium aluminum hydride, diisobutyl aluminum hydride, lithium trimethoxyaluminum hydride, lithium triethoxyaluminum hydride, tgrt-butyloxyaluminum-lithium,
Sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, other aluminum isopropoxides, Reference J.

Am, Chgm, SoC, 94, 8616 (1972
), J, Am,, Chgrn, SOe,.

101.5845 (1979), J. Org.

Examples include the reducing agent for the ketone group described in Chsm, 44.1363 (1979). In addition, all reducing agents capable of selectively reducing only ketone groups to hydroxyl groups can be appropriately selected and used.

Examples of reaction solvents include water, methanol, ethanol,
Alcohols such as n-f lovanol, inpropar/-al, ethyl ether, dioxane, DME, T//F,
Ethers such as diglyme, DMF (N, N-dimethylformamide), DMSO (dimethyl sulfoxide), H
Examples include MPA (hexamethylphosphoramide).

The reaction can be carried out, for example, at a temperature of about -1801 to around room temperature, for example, for about 1 to 10 hours.

The above reduction to convert the ketone group of the compound of formula [TX) into a hydroxyl group usually does not proceed stereoselectively, and in the resulting compound of formula [■], the absolute value of the hydroxyl group of '2 R and S coordination isomers are produced, and a mixture of these isomers is usually obtained. Furthermore, when a stereoselective reducing agent is used, the production ratio of these isomers can be greatly biased toward one side.

The compound of formula [■] thus obtained is obtained as a mixture of two isomeric epimers, but this can be easily separated into each isomer by separation and purification operations such as silica glu column chromatography. is possible.

The compound of the formula [■] can be produced, for example, by subjecting the compound of the formula [■], which can be obtained as described above, to a deacetal reaction. This deacetal reaction can be carried out by a conventional method, for example, by adding a compound of the formula [■] to an appropriate inorganic or organic This can be carried out by adding an acid such as hydrochloric acid, sulfuric acid, acetic acid, monochloroacetic acid, etc., and subjecting it to a reaction at a temperature of, for example, about 1°C to about 70°C for about 1 to about 24 hours.

Furthermore, the compound of formula [V] (R2) can be produced by forming a hydroxyl group.

Examples of such hydroxyl protecting group R7 include tetrahydro2ranyl group, tetrahydrofuranyl group, 1-methoxyethyl group, 1-ethoxyethyl group, 1-n-butoxyethyl group, 1-inbutyloxyethyl group, 1- 1-alkoxyethyl groups such as octyloxyethyl and 1-isooctyloxyethyl groups, trimethylsilyl group, triethylsilyl group z, tgrt-butyldimethylsilyl group, luprovir dimethylsilyl group, tribenzylsilyl group, triphenylsilyl group Preferred examples include groups.

For the compound of formula [v] in which the hydroxyl protecting group Rt is a tetrahydropyranyl group, for example, the compound of formula [■] is mixed with 2,6-sohydropyran and a catalytic amount of para-toluenesulfonic acid 1 in a methylene chloride solvent. Add water salt, for example, at about -20°C to about 50°C, for example, about 15 minutes to about 1 hour.
It can be produced by subjecting it to a reaction for 20 minutes.

The protecting group R2 is a tetrahydrofuranyl group or a 1-alkoxyethyl group, such as a 1-methoxyethyl group.

1-ethoxyethyl group, 1-tb-butoxyethyl group,
Compounds containing a 1-ine butyloxyethyl group, a 1-octyloxyethyl group, a 1-ine octyloxyethyl group, etc. [v
] are also treated in the same manner with 2゜3-sohydrofuran, vinyl alkyl ethers, such as tJf vinyl methyl ether, vinyl ethyl ether, vinyl-rubutyl ether, vinyl isobutyl ether, vinyl octyl ether, vinyl isooctyl ether, etc. It can be produced by subjecting it to the reaction -30-.

Furthermore, in the compound of formula [V), the hydroxyl protecting group R1 is t
Compounds having an art-butyldimethylsilyl group are described in Document J.
,Am,Cham,SoC,,94,6190+197
By using or applying the method described in 2), the compound of formula [■] can be produced by reaction with tart-butyltmethylchlorosilane using DMF as a reaction solvent and imidazole as a base. Furthermore, in the compound of formula [V], R8 is a trimethylsilyl group, triethylsilyl group, tart-butyldimethylsilyl group, luglovirsomethylsilyl group, tribenzylsilyl group, triphenylsilyl group, etc. Compound 1 [v] They can also be produced in the same manner by reacting with trimethylchlorosilane, triethylchlorosilane, tart-butyltmethylchlorosilane, lupropyldimethylchlorosilane, trihensylchlorosilane, and triphenylchlorosilane, respectively.

For example, the formula [v] that can be obtained in the manner described above
A reaction in which a compound of formula f[) can be produced by reacting a compound of formula [■] with a compound of formula [■] (in the formula, R' represents a lower alkyl group) is a reaction that produces a compound of formula [v]. in an inert solvent, e.g. THF, DME, etc., with a base, e.g. lithium dialkylamide, e.g.
This can be carried out by subjecting it to a reaction at 70" to about -10 DEG C. for, for example, about 60 to about 120 minutes to produce the erulate of the compound of formula [v].

The lithium dialkylamides used in this case are various dialkylamines, such as diethylamine, diisopropylamine, piperidine, hexamethyldisilazane, di-
Louptylamine, Shiitubu.

thylamine, so-propylamine, N-ethyl-propylamine, N-ethyl-isopropylamine,
N-tea-butyl-loupropylamine, N-ethyl-loupropylamine or N-ethyl-1-butylamine etc. and various organic lithium compounds such as methyllithium or loopyllithium in an inert solvent such as THF or DAZE. It can be prepared by using a reaction solvent in a conventional manner, for example, by reacting at about -70'' to about -10°C for about 30 to about 90 minutes.

Then, the formula [V)) that can be obtained as described above
The compound of formula [IV] is produced by adding the compound of formula [VI) to a solution of the compound of formula [IV] and subjecting the compound to a reaction at, for example, about -60 to about -50°C for about 30 to about 90 minutes. can do.

In this case, the compound of formula [Vf] is about 1 to 1 of the compound of formula [v]
Preferably, about two equivalents are used.

After the reaction is completed, the product is extracted using an organic solvent and the solvent is distilled off, and the resulting residue is extracted using a conventional method such as silica glu,
Compound [IV] was separated and purified by column chromatography using ethyl acetate-hexane system.
can be obtained.

For the compound of formula [VI], sentence 9SYNTHE-51
, 5, 19B5.942, using ε-caprolactone as a starting material.

When the compound of formula [IV] is produced from the compound of formula [■], if the protecting group R is a protecting group that is easily eliminated, the protecting group R1 of the compound of formula [■] is partially or completely eliminated. Compounds may be formed. When such a compound is produced, it is preferable to subject the hydroxyl group to the above-mentioned reaction again with a protecting group R1 to protect it and proceed to the next step. At this time, the 7-position hydroxyl group is also protected at the same time.

For example, it can be obtained as described above. A formula that can be done [■]
The compound (7? and R4 represent R1, and R3 represents a hydrogen atom) can be converted to the compound of formula [■] by subjecting it to an elimination reaction.

The reaction can be carried out by reacting a compound of chain formula [IV] with a base such as pyridine, 4-tmethylaminopyridine, etc. and methanesulfonyl chloride in an inert solvent such as methylene chloride. As the reaction conditions, for example, conditions such as about 5 hours at room temperature can be exemplified.

Compound of formula [rV] (R,, R4 and R,1 are both R
1), for example, DBNx, 5-soazabicyclo+4.3.0)-5-nonene, or It'rDBU(
It can be converted to the compound of formula [■] by reacting with 1,8-177fl:'/rio(5,4,0)-7-undecene. The reaction can be carried out in an inert solvent such as benzene, for example, at about 60° for about 6 hours.

The compound of formula [II] can be produced by subjecting the thus obtained compound of formula [■] to a reduction reaction.

The reaction may be carried out using, for example, tri-butyltin hydride as a reducing agent and di-tert-butyltin hydride as a catalyst.
This can be carried out by reacting the compound of formula [■] in the presence of 2-oxide. Examples of reaction conditions include conditions such as, for example, at 70 to about 120°C for about 1 to about 5 hours.

Among the compounds of formula [■] of the present invention, the compound of formula [I)-2 can be produced by removing the protecting group of the compound of formula [1, II) obtained in this way] by a conventional method. can do.

For example, a compound of formula [II), provided that the protecting group R2 is a tetrahydropyranyl group, a tetrahydrofuranyl group, 1
- In the case of a compound of the formula [■] representing an alkoxyethyl group, a trimethylsilyl group, or a triethylsilyl group, in a solvent such as a lower alcohol such as methanol or ethanol, or a water-containing organic solvent, such as a T II F-water system,
For example, the protective group is removed by adding an acid such as hydrochloric acid, sulfuric acid, paratoluenesulfonic acid, acetic acid, oxalic acid, etc. and subjecting it to a reaction at, for example, about 0 to about 50°C for about 1 to about 24 hours. You can let go.

Further, the compound of formula [II) provided that in the formula, the protecting group R1 is tg
In the case of compounds of formula CII) representing an rt-butylzmethylsilyl group, a lupropylzmethylsilyl group, a tripentylsilyl group, a triphenylsilyl group, Documents J, Am,
CharrL, Soc, 94.6190 (19
By using or applying the method described in 72), the protecting group can be removed by reaction with nato-9-n-butylammonium fluoride in a reaction solvent such as THF. .

In the formula [I] obtained in 1 to 1, by subjecting the compound represented by (:l-2 to a hydrolysis reaction, the formula [I)-1
Compounds of can be produced.

Chemical methods and enzymatic methods can be used for this hydrolysis reaction of ester groups.

When using a chemical hydrolysis reaction, preferred examples of the reaction solvent include alcohols-water systems such as methanol and ethanol, and examples of the base include ammonia, lithium hydroxide, sodium hydroxide, and potassium hydroxide. , a caustic alkali such as calcium hydroxide, or sodium carbonate, potassium carbonate, etc. can be used.

The reaction is carried out, for example, at a temperature of about 0.6 to about 40°C, for example, about 4 to about 9°C.
It can be carried out under conditions such as 6 hours.

After the reaction is completed, the reaction is neutralized with dilute hydrochloric acid, extracted with an organic solvent such as ethyl acetate, the organic solvent is distilled off, and the resulting residue is subjected to a separation and purification operation using, for example, silica gel column chromatography. It can be manufactured by attaching it.

Furthermore, when a hydrolysis reaction using an enzyme is used as an alternative method, examples of the enzyme used include esterase, lipase, and the like. The origins of these enzymes do not matter.

For example, when using esterase, the compound of formula CI)-2 and, for example, pig liver esterase are stirred in a phosphate buffer solution at around pH 3, and the mixture is stirred at, for example, about 20" to about 30° C. for about 12 to about 56 hours. It can be subjected to a hydrolysis reaction such as

For example, when using lipase, McLl at around pH 7
For example, Cttnd, id, a cylinrLrttcg with a compound of formula [I)-2 in a buffer of vairbg.
The lipase produced by culturing a strain belonging to A is stirred, for example, at about 20" to about 50°C, for example, about 10 to about 50".
This can be carried out by subjecting it to a hydrolysis reaction over a period of time.

In any case, it is also preferable to add a small amount of an organic solvent such as acetone to the buffer solution.

After the reaction is completed, the desired product can be obtained by performing separation and purification operations in the same manner as described above using an organic solvent such as ethyl acetate.

In the formula [1, the compound of formula CIE-1 is also. After carrying out the hydrolysis reaction first in the same manner as in the above embodiment,
It can also be produced by subjecting it to a deprotecting group reaction in the same manner as described above.

Formula [I] in which R is a hydrogen atom in the compound of the present invention formula CI)
-1 The method for producing pharmaceutically acceptable salts of compound is the formula [I]
It can be produced by neutralizing the compound of 1 using an equivalent amount of metal hydroxide, ammonia, primary amine, tertiary amine, tertiary amine, etc. by a conventional method, and then subjecting it to, for example, freeze-drying. .

Each intermediate compound from the compound of formula [X■] to the compound of formula CI) may be subjected to, for example, column chromatography, if desired.

It can be separated and purified by subjecting it to separation and purification operations such as high performance liquid chromatography and thin layer chromatography.

Examples Example 1 4-+2-carboxybenzoyloxy)
-5,5-Methyl-2-cyclobentenone 5.5-Methyl-4-hydroxy-2-cyclobentenone 10. OL 16.4 F of phthalic anhydride was added to a solution of 50 fnl of pyridine, and the mixture was heated under reflux for 24 hours. After cooling, 50 d of 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with 50ml of saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give a brown oil.
I got an F. This was subjected to chromatography (Silica Glu, Wako Glu 21, Chloroform: Methanol).
:13 to obtain an oily substance of the title compound, 19.5I! I got it. Yield 91.1%.

NMR (CDOL, -TMS) δ: 1.12 (51
% Ri1.51 (3F% JP) 5, b7-6, oo (IH, m) 6.27-6.47 (11% m) 7:2O-C27 (5F% m) 10.72 (IH, #) Example 2 l-ephedrine salt of (4S)-4-(2-carboxybenzoyloxy)-5,5-dimethyl-2-cyclobentenone 4-(2-carboxybenzoyloxy)-55-dimethyl-2 -cyclobentenone 80.40 g, 4l- L-ephedrine 4a2g acetonyl) IJle 640
After heating and dissolving the mixture in mt, it was allowed to stand overnight at room temperature.

The precipitated crystals were collected in a furnace and dried under vacuum at about 50°C for 4 hours to obtain 60.0 g of divided salt crystals. Yield 46.
7%, [α:l”, +27.4” (CO,97,
methanol).

This salt crystal 60. (), P acetonitrile 6 D
[Salt crystal 32.4.9 was obtained by recrystallization from 1 ml.

Yield 54.0%, [α)%”+63.0° (CD, 9
8, methanol).

This salt crystal 32.4. Add 7 to 32 more acetonitrile
The salt crystals 21.40' and 9 were obtained by recrystallization from 0.0 g. Yield 66.0%, (: α]”D + 80-0
@(C0181, methanol). This salt crystal 21.40
．． F was further recrystallized from acetonitrile 21011+/ to obtain 16.9 g of salt crystals. Yield 79.0%,
I:α)j”+sa4° (CO, 95, methanol).

This salt crystal 16.901/ is further added to acetonitrile 17
11.59 g of salt crystals were obtained by recrystallization from 0-.

Yield 6a6%. [α')”; +92.5° (
CO,97, methanol). rn7) 142-144℃
.

Example 3 (4,5)-4-(2-carboxybenzoyloxy)-5,5-dumethyl-2-cyclobentenone (4S)-4-(2-carboxybenzoyloxy)-
2.0II of the 2-ephedrine salt of 5,5-dimethyl-2-cyclobentenone was dissolved in 100 g of methylene chloride.
Extracted 5 times with 20-N-hydrochloric acid. Next, the methylene chloride solution was extracted five times with 50 tllt of saturated sodium bicarbonate solution. The obtained aqueous sodium bicarbonate solution was neutralized with hydrochloric acid, and then extracted with methylene chloride. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain the title compound extract 1.
20, p t[7'c. Yield 96.0%, [α]v+1
6752° (C1,10, methylene chloride).

Example 4 (!1.5)-3-(2-carboxybenzoyloxy)-2,2-tmethyl-4-nitromethylcyclopentanone 0ON (4S)-4-(2-carboxybenzoyloxy)-
2,2-dimethyl-4-nitromethyl-2-cyfrobentenone 2.49.9. Tetramethylguanidine 1.25.9. in a solution of ethanol 15. Nitromethane 3.61
1! was added and stirred at 20 to 28°C for 20 hours. The mixture was then made acidic by adding 50% of 1N hydrochloric acid, and then extracted with ethyl acetate.

The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off to give the title compound as an oily substance.
f! I got it.

NMR (CDC-TMS) δ: 1.10, 1.17.1.23+677% JP)2.
0 0 - 3.9 0 (3#:F 77L
)4.27-5.85 (5H% m) 7.25-C50 (4H% m) 10.75 (IH% JP) Example 5 (58,4S)-5-hydroxy-2,
2-Dimethyl-4-nitromethylcyclopentanone BS)-3-(2-carboxybenzoyloxy)-2
,2-dimethyl-4-nitromethylcyclointanone 3
．． 28 I! was dissolved in methanol so*, then 2N
-Caustic soda 15- was added and heated under reflux for 5 hours.

After cooling, the mixture was made acidic by adding 50% of 1N hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain an oily substance 3.81.9. This was separated and purified by column chromatography (silica glu, hexane: ethyl acetate - 2:1).

The title compound (trans form) 800Ilv was obtained. Yield 47.1% C(X)V-11a 8
@(C1,2, methanol), 71L7) 99-10
7℃.

This crystal was recrystallized from methylene chloride [α] ￥-12
7.5 @ (C1,01, Meta/-R),? l1p10
Crystals 40019 were obtained at 7-10&5°C.

NMR (CDC13-TMS) δ: 1.05 (5H% I) 1.15<5H% JP) 1.75-3.50 (4H, m, OH included)! L8
2 (1H, rid, J=1r3.6Hz) 4.20-5.07 (277%?1L) Separately, d-(5S,4R)-5-hydroxy-2,2-dimethyl-4-di Tromethylcyclopentanone crystal 40
I got 0■. Yield 23.6%. [%-'V" 52.
8” I C1,0, methanol), mp50-60
℃.

NMR (CDCts-TMS) δ: 1.07+3H% JP) 1.14 (3H, J) 1.73-3.67 (4H%m, OH included) 4.1
2 (1g%t, J=4Hz)4.30-5.30
(2H%71L) Example 6 (55,45)-5
-Hydroxy-(55,,aS)-s-hydroxy-2
,2-methyl-4-nitromethylcyclopentanone 1
15.06J? , ethylene glycol j2.48J7.
Paratoluenesulfonic acid monohydrate 0.54g, benzene 1
The solution of 80- was heated to reflux with stirring for 21 hours using a Dtαn-5 tarlc water removal device. After cooling, the reaction solution was diluted with 130 m/s of saturated saline solution, 80 w/s of saturated sodium bicarbonate solution,
Washing was carried out in the order of 80°C of saturated saline. The aqueous layers were combined and further extracted with ethyl acetate. After all the organic layers were combined and dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain 19.21 g of a yellow oil. The crystal 1Zqsg of the title compound was obtained by the separation and purification operation according to 1). Yield: 96.
4%. [α) t,,a+ 4.2@(C1,00,
methanol), rILp 28-30°C.

NMR (CDC1, -TMS) δ: 0.96+6H% 1.3Cl-3,05 (411%m, including OH)
3.28-3.85 <211%7FL) 3.93(4
g%JP) 3.40-4.25 (IH%m) Example 7 (55,4R)-4-formyl-3-hydroxy-2,2-dimethylcyclohentanone Ethylene acetal HOCll0 Titanium trichloride-ammonium acetate Preparation of aqueous solutions.

(under nitrogen flow) 149.40 g of ammonium acetate,
Water 570m7! BOml of concentrated ammonia water was added to the aqueous solution to adjust the pH to 9.15. Then, 191.34 liters of a 25% titanium trichloride aqueous solution was added. Furthermore, concentrated ammonia water 1
5- was added to adjust the pH to 5A2.

(35,4S)-1-hydroxy- under argon flow
2,2-Tmethyl-4-ditromethylcyclopentanone 17.93 g of ethylene acetal was dissolved in 14 g of methanol.
0- and cooled to about -20°C. Next, 5.151I of sodium methoxide was added and dissolved. Next, the previously prepared titanium trichloride-ammonium acetate aqueous solution was added dropwise at -20 to 0°C for 20 minutes, and then further heated to -8 to 0°C.
The mixture was stirred for 80 minutes.

The reaction solution was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate solution. After adding common salt to the obtained washing liquid, the solvent was distilled off to obtain 13.51 g of the title compound as an oil. Yield 8.
10%.

NMR (CDCL, -TMS) δ: 0.70-1.10 +6H, 71L) 1.20-2.
36 (2H%m) 2.40-510 (1H, rIL) 595 (4H,,?) 3.70-4.12 (1H,m) 9.72-9.91+IH%? 7L) Example 8 (3,S,4S)-3-hydroxy-2
, 2-methyl-4-[IE)-1 50- 5-oxo-1-octenylcocyclopentanone ethylene acetal Anhydrous tetrahydrofuran 180- is added to sodium methoxide 1409 under an argon stream, and then Damedel 2-
A solution of oxoheptyl phosphonate 13.911 anhydrous tet-2hydrofuran 80- was added dropwise at -7 to -4°C over 27 minutes, and the mixture was further stirred at -5 to -2°C for 50 minutes. Then (55,4R)-4-formyl-5-hydroxy-
A solution of 10.51 ml of 2,2-dimethylcyclopentanone ethylene acecool and 80 ml of anhydrous tetrahydrofuran was
After dropping for 23 minutes at 5 to -5°C, further drop to -3 to 1
The mixture was stirred at 5°CK for 90 minutes. Next, after adding 2.7 units of acetic acid, 500 m7 of saturated brine was added! was added and separated.

The aqueous layer was extracted with methylene chloride. All the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain 25.51 of a yellow oil. Column Chromadogsifii (Silica Dal, Merck 7)
754.1200m, Rouhexane:Ethyl acetate-5:
2), 156 g of an oily product of the title compound was obtained. Yield 47.4%. Cα)',:
-q, 9° (C2,00, chloroform).

NMRIDCZ, -TMS) δ: 0.90-2.90 (21H, m) 565 (1H% 2% J=7Hz) 3.90 (4H, #) 610 (1H%d, 7=16Hz)6. 83+IH
%d, d% J=16.7H2) Example 9 (38,4,5)-4-(E)-(,3
S)-3-Hydroxy-1-octenyl-3-hydro-2,2-methylcyclopentanone ethylene acetal "] Lithium aluminum hydride 1,02 under argon stream
．． Add anhydrous ether 65- to 1F, then (55,
4S), 5-hydroxy-2,2-tmethyl-4-[(
E)-5-oxo-1-octenylcocyclopentanone ethylene acetal 7,21! .

Anhydrous ether 40m/! The solution was added dropwise at -70 to -66°C over 70 minutes. Further, the mixture was subsequently stirred at -70 to -68°C for 2 hours.

Next, methanol was added to decompose excess lithium aluminum hydride, and then 120% of water was added and filtered. The filtration residue was washed with 200% of ether [separated into 7 layers]. The aqueous layer was extracted with ether, all the ether layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain an oily substance 6.6011. This column chromatography (Silica Dal, Merck 7734.70
After separation and purification using 0-1 methylene chloride:ethyl acetate (5:1 to 3:2), the title compound was obtained as an oily substance (3.0%).
Obtained 0g. Yield 41.4%. [α]i, O-42m (
C2,01, chloroform) 6 NMR (CDCL, -TMS): [170-2,66 (20H, m) 517-566 (contains 5ff% 凰, OH) 5B! +-
4,25(sH,?FL) 5.65 (2H%m) Separately as an epimer (5S, 4S-4C(E)-1J
? ) 2.74 g of an oily product of i-hydroxy-1-octenyl]-3-hydroxy-2,2-dimethylcyclopentanone ethylene acecool was obtained. Revenue'? i67. B
%, [α]942' (C2,01, chloroform).

NMR (CDCL, -TMS) δ: [1,67-3, []0 (21H%m)s, 56-3
．． 66 (IH%m) 3.85-4.17t 6N%m, including OH)5
．． 65 (2H, m) Example 10 (35,4,5)-4-C(El(5
5)-5-hydroxy-1-octenyl-5-hydroxy-2,2-dimethylcyclopentanone OH <55.4S)-4-C(E)-(3S)-5-hydroxy-1-octenyl-6-hydroxy -2,2-y
Methyl cyclopentanone ethylene acetal 3. OOg
, add 7.66% of 1N hydrochloric acid to a solution of 85% of acetone under ice cooling.
ml was added and stirred at room temperature for 4 hours. Then, 75 fnt of saturated brine was added and extracted with ether. After washing the extract with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off to give an oily product of 3.0! I got j. This was subjected to column chromatography (Silicadal, Merck 7734
．． 500-, hexane:ethyl acetate-4=5) to separate and purify the crystals of the title compound, 2.451
I got it. Yield 95.0%. mp5o-35℃.

[α) Hl-7t6@< C1, [ ] 2, chloroform).

NMR (CDC1, -TMS) δ: 0.70-3.00 <20g% m) 3.43-3.87 <2H, m% including OH) 3.8
7-4.30 (including 2H, m, OH) 4.55-4
．． 76 (2N%m) Example 11 (3S, +5)-4-[(E)-(5R
)-5-hydroxy-1-octenyl)]-]5-hydroxy 2,2-tmethylcyclopentanone+35,4S)-4-CCE)-+3R)-3-hydroxy-1-octenyl-5-hydroxy2. 2-sol
Tylcyclopentanone ethylene acetal 2.74F,
Add 7.0 f of 1N hydrochloric acid to a solution of 78 td of acetone under water cooling.
nl was added and stirred at room temperature for 4 hours. Then, 70 tons of saturated brine was added and extracted with ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain oil 2.6011. This was subjected to column chromatography (Silicadal, Merck 7734
．． 50〇-, 2.181 crystals of the title compound were subjected to separation and purification operations using roohexane:ethyl acetate (4:5).
I got it. Yield 93.5%. Exhibit 7) 60-61.5℃.

[α]l'-85,9'' + C1,0, chloroform).

NMR (CDCL, -TMS) δ: 0.70-2.86 <20g%? 7L) 3.07-550 (1#%hz%0H) 3.47-5.90 (2H,
(55,45)-4-CIE)-(5
5)-5-trimethylsilyloxy-1-octenyl)-3-trimethylsilyloxy-2,2 monozomethylcyclobentanone O8t (CHs)s (5S,4S)-4-11:1)-(5S)-! i me hydroxy-1-octenyl-3-hydroxy-2,2
- 2.45 g of dimethylcyclopentanone.

3.26 g of imidazole and 3.64 WL1. 1
After 0 minutes of addition, the mixture was stirred at room temperature for 5 hours. Then, 80 g of ice water was added and extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to give an oily product with a concentration of 5.80%. I got an F. This was subjected to column chromatography (Silicadal, Merck 7754.500-,
Separation and purification using hexane:ethyl acetate (50:1 to 20:1) yielded an oily substance of the title compound (3.25%).
I got 1.

Yield 84.8%. [α]v-57.9° (C1,0
2. Chloroform).

NMR (CDCI, -TH5) δ: o, 12<qHls) 0.15 (9H% #) 0.87-2.90 <20S%Tan) 567 (1#%d% J=7.5Hz)3 .93-
4.30 (IH%m> 5.50-5.67 (2H%WL) Example 1s (sS, 4S)-+-C(E)-+3
7? )-3-)dimethylsilyloxy-1-octenyl]-3-trimethylsilyloxy-2,2-dimethylcycloentanone 05i (CH,).

(55,45)-4-CIE)-<5R)-5-hydroxy-1-octenyl-5-hydroxy-2,2-tmethylcyclopentanone 2.18 g, imidazole 2.
To a solution of 92 g and 5 Bwl of DMF was added dropwise 3.26 g of trimethyl crotrezirane under water over 5 minutes, and the mixture was stirred at room temperature for 5 hours. Then, 70 g of ice water was added and extracted with ether. After washing the extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain an oily substance 4.50.9. Column chromatography (silica r/I)
/%Merck 7764.400m/, n-hexane:ethyl acetate-50=1 to 20:1) to obtain 2.9411 of the title compound as an oil. Yield 86.1%. Cα: ]ri'-71,6" (C1
,0,ri.

Roholm).

NMR (CDC1, -TH5) δ; Q, 10 (9H% I) α15 (9H% #) 0.80-2.80 (20S% milk)! 1.65 (I H%d, J = 75Hz) 3.9
7-4.27 (IJ7.7jL) 5.47-5.63
(2H, FIL) Example 14 (11S, 13S
, 15S)-11,15-bis(trimethylsilyloxy)-7-hydroxy-10,10-dimethyl-9-oxtbrost-15-ene-1-oicandmethyl ester 05i (CHs).

Under an argon stream, 2.12 m/2.12 m of 10% loop tillithium hexane solution was added to a solution of anhydrous tetrahydrone 15- and soisoprobylamine 0.46- to -63 to -60
The mixture was added dropwise at ℃ for 10 minutes. Subsequently, the mixture was stirred at -60 to -30°C for 70 minutes. Then (3S,45)-4-CIE
)-<55)-5-trimethylsilyloxy-1-octenyl]-5-trimethylsilyloxy-2,2-dimethylcyclopentanone 1.20.9, anhydrous tetrahydrone 2-5- solution at -65 to -62 After the dropwise addition at 15 minutes at ℃, the mixture was further stirred for 88 minutes at -60 to -30 ℃.

then methyl 7-oxhegutanoate) 0.57.9
．． A solution of anhydrous tetrahydrofuran 5- from -60 to -58
After dropping for 5 minutes at ℃, it was further added at about -40℃ for 60 minutes.
The mixture was stirred for a minute. The reaction solution was diluted with a cooled saturated ammonium chloride aqueous solution 6
The mixture was poured into a mixture of 0- and ether 60-, and the liquid was separated. The aqueous layer was extracted with ethyl acetate. All the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain 2.10 g of an oily substance. This was subjected to column chromatography (Silicadal, Merck 7754.
200-, Ruhexane:ethyl acetate-15:2) to separate and purify the title compound as an oil.
I got g. Yield 93.1%.

[α)”7-19.5” (C1, o, methanol)
.

NMR (CDCZ, +TMS) 0.13 (18g%S) 0.812.50 (3077, rL) 2.98 (I
H, d, 0H) xhbo-31,83 (4H, m) 4.00-4.25 (IH, m) 5.45-5.67 (2, Zr%m) Example 15
(11S, 1iE, 15R)-11-trimethylsilyloxy-7,15-dihydroxy-10゜10-methyl-9-oxycarboxylate-15-ene-1-oic acid methyl ester under an argon stream, anhydrous tetrahydrofuran 4040
t/, after dissolving 1.09 t/d of diisopropylamine -
The mixture was stirred at 60 to -25°C for 77 minutes.

Then (sS, 4R)-4-C(E)-tl? )-3
A solution of 2.94 g of -trimethylsilyloxy-1-octenyl-3-trimethylsilyloxy-2,2-dimethylcyclopentanone and 20 g of anhydrous tetrahydrofuran was added at -65 to -60'0. ．． After the dropwise addition took 15 minutes, the mixture was further stirred at -60 to -20°C for 80 minutes. Next, a solution of 1.28 g of methyl 7-oxheptanoate and 10-g of anhydrous tetrahydrofuran was added dropwise at -63 to -60°C over 10 minutes, and the mixture was further stirred at about -40°C for 90 minutes. Extracted with a sieve. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off to give an oily product.
Got 80#. This was subjected to separation and purification operations by column chromatography (Silicadal, Merck, 7754.60〇-, luhexane:ethyl acetate-4=3) to obtain 2.74 g of the title compound as an oil. Yield 76.6%
. FJ) 50-45°C.

NMR (CDCL, THE) δ: o, 15t9H, #) 0.85-2.85 (51g%m) 5.25 (11?1.A#, □H) 556-585 (4H%7FL) 4.00-4.18 (IH%7)L) 5.45-5.
67 (2J7%m) Example 16 (11S, 11E, 15R)-7,1
1,15-)Su(trimethylsilyloxy)-10,↑0-dimethyl-9-oxtubrost-13- Nin-1-oic acidomethyl ester O5i (CHs)m (11S, 15E, 15J?)-11-) Limethyl Silyloxy-7,15-sohydroxy 10゜10-dimethyl-9-oxytubrost-15-ene-1-oic acid methyl ester 2.10 g, imidazole 1.48
g.DMF! 1B- in a solution of 1.66 tnl. of trimethylchlorosilane under water. was added and stirred at room temperature for 16 hours.Then, the reaction solution was poured into 100ml of ice water and extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to form an oily product at 4.50F.
I got l. This was subjected to column chromatography (Silica Dal, Merck 7754.200rn!, Rouhexane:
Separation and purification using ethyl acetate (25:1 to 1:1) gave 2.54 g of the title compound as an oil. Yield 9
3.0%.

NMRlCDC1,-TMS) δ: 0.11 (2'777, j) 0.83-2.96 <29H, m) 3.47-3.73 (477%m) 4.00-4.20 + IH , m) 5.40-5.60 (2H%ml Example 17 (11S, 13E, 15S) -11,1
5-bis(trimethylsilyloxy)-10,10-trimethyl-9-oxoglostaph.

15-diene-1-oic acid domethyl ester 05i(CH,).

+11S, 15E, 15S)-11,15-bis(trimethylsilyloxy)-7-hydroxy-10.10
-Dimethyl-9-ocitubrost-13-en-1-oic acidomethyl ester 1,561! , 4-Jime'
IF-le 7 minopirimison 1.70! % methylene chloride 1
0.54-methanesulfonyl chloride was added to the solution of 5r,/ under water cooling, and the mixture was stirred at room temperature for 2 hours. Pour the reaction solution into ice water for 6 oz! , and extracted with methylene chloride. After washing the extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain an oily substance 2.80.9. This was subjected to column chromatography (silica gel, Merck 7754
,250-, rubexane:ethyl acetate-25=1-1
゜: 7 of the title compound was subjected to separation and purification operations etc. according to 1).
0.84.9 of H-form oil was obtained. Yield 55.6%.

[α) r+ 17.6@((1'1.o, chloroform).

/VM// (CI)C13-TMS) δ:0.10(
9B,,r) o, 13(9H,z) 0.83-2.46 (28J ?7L) 3.15-3
．． 4011H%m) 3.65 (!, I1.I) 3.96-4.25 + IHlm) 5.50-5.67 (2H, m) 6.55-6.83 (IH, m) Separate title An oily product of 0.22.9 of the 7Z form of the compound was obtained.

Yield 14.6%. [α]', j-35.1@ ((1'
1.0°chloroform).

N, MR (CDCL, -TMS) δ: 0.14+18
H% I) 0.85-3.53 (2H1%m) 5.50-5.73 (4H,m) 4.00-4.26 + IH%m) 5.00-6.00 <5H% 7+1) Example 18
C11S, 15E, 15R)-11,15-bis(trimethylsilyloxy)-10,10-dimethyl-9-oxobrostaph.

13-diene-1-oic acidomethyl ester 05i(CH,)s +11S,1iE,11)-7,11,j5-tri(trimethylsilyloxy)-10,10-tumethyl-9-
Okitsubrost-13-en-1-oic and methyl ester 2.54 g, 1.8-diazabicyclo+5.
4.0)-7-undecene 1.8-, benzene 25tn
1. The solution was stirred at 60' for 5 hours.

The reaction solution was poured into 100ml of ice water and extracted with ethyl acetate.

After washing the extract with water and drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 2.20 g of an oil. Column chromatograph 4-(silica glu, Merck 7754)
．． 250fnt, n-hexane:ethyl acetate-25
:1 to 10:1) to obtain 0.89 F of the 7E form of the title compound as an oil. Yield: 40.
8%. [α]υ+14.6° (C1,03, chloroform).

NMRI CDC1,-TMS) δ: 1.10 (18th, J) αB6-2.30 (28H, 77L) 5.07-5.
55 (1H%77L) 3.63 (377%,?) 4.00-4.25 (177, 7K) 5.5 (]-5
, 63<2H, m) 6.55-6.96 (1H, m) Separately, 0.78 g of an oily substance of the 7Z form of the title compound was obtained.

Yield 35.8%. [α) yl-+14.1 L cl
ol, chloroform).

NJfl? (CI) CL, -THE) δ: 0.10
(9H, s) 0.13 (9H, s) 0.83-3.00 (28H, m) 3.50-3.76 (411, m) 4.00-4.
27 (111% m) 5.30-5.66 t 21
f, m)s,ya-6,C6<1H,m) Real M1 example 19 [11,5,13Ei5S)-11
Quacid methyl ester0Si(CH,)3 (11S, 13E, 15S)-11,15-bis(trimethylsilyloxy)-10,10-tumethyl-9-oxozoroster 7.16-thien-1-oic acid methyl ester 1.11 g of tri-butyltin hydride 12+n/, and tert-butyltin oxide 12On+9 were mixed and stirred at an external temperature of 110° C. for 1 hour. After cooling the reaction solution, column chromatography (
Silica cell, Merck 7734.250m1. Separation and purification using n-hexane:ethyl acetate (1:0 to 10:1) gave 1.02.9 of the title compound as an oil. Yield 91.6%. CC1) '1,7-26.9°
(C1, [l, chloroform).

NMR (CDC1, -TMS) δ: o, 12 (1811, ri 0.83-2.43 (31H, m,) 3, 60-3.
s 5 (477, m) 4.00-4.35 (1/
7S77L)5.43-5.60 C211,m) Example 20 (11S, 13E, 15R)-11,
15-bis(trimethylsilyloxy)-10,10-tumethyl-9-oxobros l--13-en-1-oic acid methyl ester O5t ((?IIs)t+11.5.13E,15R)-11 ,15-bis(trimethylsilyloxy)-10,10-dimethyl-9-
Oxobrostaph, 13-tzen-1-oic acid methyl ester j, 80. 19.6 ml of +7° tri-butyltin hydride and 196 ml of so-teri-butyl peroxide were mixed and stirred at an external temperature of 110° C. for 1 hour. After cooling the reaction solution, column chromatography (silica case, Merck 7754.220 mA, a
-Hexane:ethyl acetate-0 to 15:1) to separate and purify the title compound as an oily substance, 1.3 D.
I got a 9. Yield 72.0%. [α1'D'-17,4°
IC1.01, chloroform).

NAfR (CDCt3-TMS) δ: 0.13
(I B11. ε) 0, 86-2.53 (318% yy+, )3.5
0-3.76 +4H, m) 4.00-4.26 < 1H, m) 5.07-5.60 +2H, m) Example 21 (11S, 16E, 15S) -11,1
5-dihydroxy 10. 10-trimethyl-9-oxogerost-13-ene-1-oic acidomethyl ester II +11S, 13E, 15.5)-11,15-bis(trimethylsilyloxy)-10,10-trimethyl-9-
1.38. f, methanol 14tn! 0.32 p-toluenesulfonic acid monohydrate was added to a solution of , under water cooling.
g was added thereto, and the mixture was stirred at room temperature for 2 hours.

Next, while cooling with water, 5% aqueous sodium bicarbonate solution was added, followed by 40 g of saturated brine. Extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain 1.10 g of an oil. This was subjected to column chromatography (silica gel, Merck 773
4.200+++/.

The title compound was subjected to separation and purification operations using K (1 to 5:5) (hexane:ethyl acetate-1=1 to 5:5) to obtain 0.83F of the title compound as a crystal. Yield 82.0%. WLp5B-59°C. C(1)
', 7-27.4° (C1,02, chloroform)
.

NMR (CDCL, -TMS) δ: [1,7(]-2,50131H%m) 3.08 (IJ
7. h#, 0H) 3.45-3.7515H, including rn%OH) 3.9
5-4.20 (14%ff1) 5.52-5.65
(2H% 1 Example 22 (115, 13E, 157?)-11
,15-dihydroxy-10,10-dimethyl-9-oxogerost-13-en-1-eutsacidomethylethyl(11S,15E,15,5)-11,15-bis(trimethylsilyloxy)-10, 10-methyl-9-
Okitsubrost-13-ene-1-oic acid methyl ester 1.54F was added to a solution of 13.5 methanol and 0.5111 p-toluenesulfonic acid monohydrate under water cooling.
was added and stirred at room temperature for 2 hours.

Next, under water cooling, 2 ml of 5% sodium chloride solution and 2 ml of water were added, and 50% of saturated brine solution was added, followed by extraction with methylene chloride. The extract was washed with saturated brine solution, dried over anhydrous magnesium sulfate, and then the solvent was removed. Distillation gave 1.09 g of oil. This was subjected to column chromatography (silica gel, Melf 7
34.220m, ruohexane:ethyl acetate-1:1)
The oily substance of the title compound was obtained by separation and purification operations such as 0.
85, f was obtained. Yield 86.5%. (:α)”,”−
41j° (C1,01, chloroform).

NMR (CDCL3-TMS) δ: a80-2.55 <54H, m, including OH) 3.5
0-3.70+4J7. Tan) 4.05-4.25 (IH, m) 5.60-5.80 + 2H,77L) Example 25
(11S, 1iE, 15S)-11,15-dihydroxy-10°, 10-dimethyl-9-oxitubrost-15-en-1-oic acid 0H +115.13E, 15.5)-11,15-dihydroxy-10, 10-dimethyl-9-okitubrost-1
5-en-1-oic acid methyl ester 0.54
．． 9. Acetone 3.7, 0.1M p-If 8!
A mixture of 37 units of J acid buffer and 53 units of Sigma's Pork Liver Air 4-Zero was stirred at room temperature for 23 hours.

The reaction solution was adjusted to pH 4 with dilute hydrochloric acid to 7, saturated with ammonium sulfate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium acetate, and then the solvent was distilled off to obtain 0.54 g of crude crystals. This was recrystallized from ether:petroleum ether+2:1) to obtain crystals 245■ of the title compound. Yield 74.7%.

mP1r]3-106°C0Cα)", 5-2t4°
(C1,02, methanol).

NMR (CDC13-TMS) δ: 0.80-2.65 (51H, m) 3.60 (I II%d-%J=9.5H2) 2.9
5-3.20 (IH% fi) 5.50-5.70 (2H% m) 5.70-i
s, 20 ("rH%h s%OH, C00II) Example 24 (11S, 13E, 1sR) -11,15
-dihydroxy-10,10-tumethyl-9-ocitubrost-13-ene-1-oic acid H (11S, 13E, 15R)-11,15-dihydroxy-10.10-tumethyl-9-ocitubrost-1
3-en-1-oic acid methyl ester 0.35
．． 9. Acetone 3.8m/, 0.1 & p II 81
J acid buffer 38m7! A mixture of 672 units of pig liver esterase from Shiguya was stirred at room temperature for 24 hours. The reaction solution was adjusted to pH 4 with diluted hydrochloric acid, saturated with ammonium sulfate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give an oily substance 4.
I got 00■.

This was subjected to column chromatography (silica glu, Merck 7734.40m/ethyl acetate:methylene chloride-2:
The oily substance 200'9 of the title compound was obtained by the separation and purification operations described in 1). Yield 59.2%.

[α] Terry 5.7' (C1,02, chloroform).

NMR (CDCt, -TMS) δ: 0.75-2.60 (21H,77L)i65 (I
H%tL%J = 6Hz)4.00-4.30(I
H%77L) 5.30-5.90 (Including 5H%m%OH, C0OH) Procedural Amendment August 1, 1985

Claims (1)

[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ However, in the formula, R represents a hydrogen atom or a lower alkyl group, R_1 represents a C_5 to C_7 alkyl group, and In the formula, the dashed line (------) indicates that the bond between atoms is in the alpha configuration, the wedge line (■) indicates that the bond between atoms is in the beta configuration, and the wavy line (■ ) indicates that the bond between atoms is in either alpha or beta configuration, or a mixture thereof; and pharmaceutically acceptable salts thereof. 2. The following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ However, in the formula, R, R_1, broken lines (------) and wedge lines (■) have the same meaning as described above for formula (I), The prostanglandin E_1 derivative according to claim 1 and its pharmaceutically acceptable salts. 3. The following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ However, in the formula, R, R_1, broken lines (------) and wedge lines (■) have the same meaning as described above for formula (I). The prostaglandin E_1 derivative according to claim 1 and its pharmaceutically acceptable salts. 4. Formula (II) below ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ However, in the formula, R^1 represents a lower alkyl group, represents a hydroxyl group protecting group, and the broken line in the formula (---- −) indicates that the bond between atoms is in the alpha configuration, a wedge line (■) indicates that the bond between atoms is in the beta configuration, and a wavy line (■) indicates that the bond between atoms is in the alpha or beta configuration. A compound represented by the following, which indicates either one of the three-dimensional configurations or a mixture thereof, is subjected to a hydrolysis reaction after a deprotection reaction, or after a hydrolysis reaction, a compound represented by the following is subjected to a deprotection reaction. There is the following formula (I)-1▲mathematical formula, chemical formula, table, etc.▼However, in the formula, R_1, broken line (---), wedge line (■), and wavy line (■) are Production of a novel prostaglandin E_1 derivative represented by the same meaning as above and its pharmaceutically acceptable salts. 5. Formula (I)-2 below ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ However, in the formula, R' represents a lower alkyl group, [R_1 is C
Indicates an alkyl group of _5 to C_7, and the broken line (
−−−−−−−) indicates that the bond between atoms is in the alpha configuration, a wedge line (■) indicates that the bond between atoms is in the beta configuration, and a wavy line (■) indicates that the bond between atoms is in the beta configuration. The following formula (I)-1 ▲ is characterized by subjecting to a hydrolysis reaction a compound represented by the following, in which the bond is in either the alpha or beta configuration, or a mixture thereof: There are mathematical formulas, chemical formulas, tables, etc. ▼ However, in the formula, R_1, destruction (------), wedge line (■), and wavy line (■) have the same meanings as above, and a new prostagrange E_1 derivative represented by and a method for producing pharmaceutically acceptable salts thereof.