JPH0798796B2 - Method for producing isocarbacyclines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Field of Industrial Application> The present invention relates to a novel method for producing isocarbacyclines.

More specifically, the present invention relates to 9 (O) in which the oxygen atom at the 6- and 9-positions of prostaglandin I ₁ is substituted with a methine group (-HC =).
It relates to a synthetic intermediate of ^-methano- Δ ^{6 (9α) -prostaglandin} I ₁ ^{(isocarbacycline)} , and per se relates to a method for producing a novel isocarbacycline derivative.

<Prior Art> Prostaglandins are local hormones that are mainly produced in the inner wall of blood vessels of arteries in the living body, and are important factors that regulate cellular functions of the living body by their strong physiological activities such as platelet aggregation inhibitory activity and vasodilatory activity. Attempts have been made to use this product directly as a medicine [Clinical Pharmacology of Prostacyclin, Raven.
Press, NY, 1981].

However, since natural prostacyclin has an enol ether bond which is very easily hydrolyzed in the molecule, it is easily inactivated under neutral or acidic conditions, and it cannot be said to be a preferable compound as a drug because of its chemical instability. Therefore, a chemically stable synthetic prostacyclin derivative having physiological activity similar to that of natural prostacyclin has been intensively studied both inside and outside.

Among them, a derivative obtained by substituting the oxygen atom at the 6- and 9-positions of prostacyclin with a methylene group, that is, 9 (O) -methanoprostacyclin (carbacycline) is known as a prostacyclin that sufficiently satisfies chemical stability. [Prostacyclin, JRVane an
d S. Bergstrom, Eds. Raven Press, NY p31-41] Expected as a drug. However, the biological activity of this 6,9 (O) -methanoprostacyclin is weaker than that of natural prostacyclin, and its action selectivity cannot be said to be specific, so that it cannot be said to be a preferable compound.

In recent years, isocarbacycline, one of the double bond isomers of carbacycline, namely 9 (O) -methano-
^{△ 6 (9α)} - prostaglandin I ₁ class is found to exhibit the strongest inhibiting platelet aggregation action among the homologues, application as medicines has decreased as expected [Ikegami et al Tetrahedron Letters (Tetrahedron Let
t.), 24, 3493 ( 1983), JP-59-137445 JP].

Regarding the production of such 9 (O) -methano-Δ ^{6 (9α) -prostaglandin} I ₁ (isocarbacycline), the following are known.

(1) Ikegami et al., Tetrahedro Letters
n Letters), 24 , 3493 (1983) and Chemistry Letters, 1984 , 1069: (2) Ikegami et al., Tetrahedro Letters
n Letters), 24, 3497 (1983): (3) Ikegami et al., Journal of the Chemical Mesoscience, Chemical Communication (J. Che
m.Soc., Chemical Communi-cations), 1984 , 1602: (4) Shibasaki et al., Tetrahedro Letters
n Letters), 25, 5087 (1984): (5) Shibasaki et al., Tetrahedro Letters
n hetters), 25 , 1067 (1984): (6) Kojima et al., Chemical and Pharmacy Bulletin (Chem.Pharm.Bull), 32 , 2866 (198).
Four): (7) Kojima et al., JP 60-28943 A: Of these seven methods, method (1) and method (5) are
PGE ₂ is used as a starting material, leads to a key intermediate through several steps, and then the desired isocarbacycline is obtained through several steps, which is not an industrial process.

In addition, both the method (2) and the method (3) require a multi-step process from expensive corey lactone to obtain the corresponding starting material and key intermediate, and the total yield is not high.
There is a drawback that it is not always an industrially advantageous method. In addition, in the method (6) and the method (7), the final product was
This is an unfavorable method as a manufacturing method intended to be a medicinal product because it can be obtained only in the dl form.

Finally, method (4) not only allows the starting material to be readily obtained from the optically active (R) -4-hydroxy-2-cyclopentenone by our method (see Japanese Patent Application Laid-Open No. 2000-242242).
57-155116), a method in which the starting material can be derived into a key intermediate without any industrial problems. However, in the process from the key intermediate to the final isocarbacyclines, due to various difficulties such as the use of organomercury compounds, loss of regiospecificity, and incorporation of inseparable by-products. The total yield is low, and there is a major drawback that it cannot be a practical or industrial manufacturing method.

The present inventors have focused on various points described above, 9 (O) - methanol ^- △ ^{6 (9α)} - prostaglandin I ₁ compounds (isocarbacyclin acids) and intensive studies with a result to find out a process for their preparation the The invention has been reached.

According to the present invention, the following formula [I] There is provided a process for producing a novel isocarbacycline which is a compound represented by the formula (1), an enantiomer thereof, or a mixture thereof in any ratio.

In the above formula [I], R ¹ represents a hydrogen atom or a C ₁ -C ₄ alkyl group or alkenyl group. Examples of the C _{1 to} C ₄ alkyl group for R ¹ include a methyl group, an ethyl group, a propyl group, and a butyl group, and examples of the alkenyl group include a 2-propene group and a 3-butene group. Of these, a methyl group and a 2-propene group are preferable.

In the above formula [I], R ² and R ³ are the same or different and each represents a hydrogen atom, a tri (C ₁ -C ₇ ) hydrocarbon silyl group or a group forming an acetal bond with the oxygen atom of the hydroxyl group.

Examples of the tri (C ₁ -C ₇ ) hydrocarbon silyl group include tri (C ₁ -C ₄ ) alkylsilyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, and t-butyldimethylsilyl group; a diphenyl (C ₁ -C ₄ ) alkylsilyl group such as t / butyldiphenylsilyl group;
Preferred examples include a di (C ₁ -C ₄ ) alkylphenyl group such as a dimethylphenyl group; or a tribenzylsilyl group. Among these, birds (C ₁
To C ₄ ) alkylsilyl group, phenyl (C _{1 to} C ₄ ) alkylsilyl group, and phenyldi (C _{1 to} C ₄ ) alkylsilyl group are preferable, and t-butyldimethylsilyl group and trimethylsilyl group are particularly preferable.

The group forming an acetal bond with the oxygen atom of the hydroxyl group includes, for example, methoxymethyl group, 1-ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy-2 group.
-Propyl group, (2-methoxyethoxy) methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-
Tetrahydrofuranyl group, or 6,6-dimethyl-3-
Mention may be made of the oxa-2-oxobicyclo [3.1.0] hex-4-yl group. 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2
-Ethoxy-2-propyl group, (2-methoxyethoxy) methyl group, 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hex-4-yl group are particularly preferable. Of these, a 2-tetrahydropyranyl group is particularly preferable.

It is to be understood that these silyl groups and the groups forming an acetal bond are protecting groups for hydroxyl groups. These protecting groups can be easily removed in the final product stage under mildly acidic to neutral conditions to give free hydroxyl groups useful as drugs.

In the above formula [I], R ⁴ represents a hydrogen atom, a methyl group or a vinyl group.

In the above formula [I], R ⁵ is a linear or branched C ₃ -C ₈ alkyl group which may contain an oxygen atom; a substituted or unsubstituted phenyl group; a substituted or unsubstituted phenoxy group; Or an unsubstituted C ₃ -C ₁₀ cycloalkyl group; or a C ₁ -C ₆ flucoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group or an optionally substituted C ₃ -C ₁₀ represents a straight or branched C _{1 to} C ₅ alkyl group substituted with a cycloalkyl group. In addition, when the group which may be substituted here is substituted, it is shown as a reference example.

The unsubstituted straight or branched chain C ₃ -C ₈ alkyl group which may be interrupted by an oxygen atom includes propyl group, butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2- Methyl-2-hexyl group, 2-methylbutyl group, 2-
A methylpentyl group, a 2-methylhexyl group and a 2,2-dimethylhexyl group are preferred.

Examples of the substituent of the substituted phenyl group, the substituted phenoxy group, and the C _{3 to} C ₁₀ substituted cycloalkyl group include a halogen atom and a protected hydroxyl group (eg, silyloxy group, C ₁ to
C, such as ₆ alkoxy group), such as C ₁ -C ₄ alkyl group. Examples of the C _{3 to} C ₁₀ cycloalkyl group include, for example,
Examples thereof include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, a cyclooctyl group and a cyclodecyl group.
Of these, a cyclopentyl group and a cyclohexyl group are preferable.

C ₁ -C ₆ alkoxy group, optionally substituted phenyl group, optionally substituted phenoxy group, or optionally substituted C ₃ -C ₁₀ straight chain or branched chain In the branched chain C ₁ -C ₅ alkyl group,
The C ₁ -C ₆ alkoxy group such as methoxy group, ethoxy group, propyloxy group, isopropyloxy group, a butoxy group, t-butoxy group, and hexyloxy group. Examples of the substituent of the optionally substituted phenyl group, the optionally substituted phenoxy group, or the optionally substituted C _{3 to} C ₁₀ cycloalkyl group and the C _{3 to} C ₁₀ cycloalkyl group are the above-mentioned examples. Can be the same as. Examples of the straight chain or branched chain C _{1 to} C ₅ alkyl group include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t
Examples thereof include a butyl group and a pentyl group. Examples of R ⁵ include butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-methyl-2-hexyl group, 2
-Methylbutyl group, 2-methylpentyl group, cyclopentyl group, cyclohexyl group, phenyl group, phenoxy group,
Cyclopentylmethyl group, cyclohexylmethyl group and the like can be mentioned as preferable ones. In addition, the substituent may be bonded to any position thereof.

In the above formula [I], n represents 0 or 1.

Ar represents a substituted or unsubstituted phenyl group, and examples of the substituent include those mentioned above, but a phenyl group and a p-tolyl group are preferable. The substituted phenol group is shown as a reference example.

In the compound represented by the above formula [I], the bicyclo [3.3.0] octane ring itself and its bicyclo [3.3.0]
Stereoisomers exist due to an asymmetric environment in which the carbon bonded to the substituent bonded to the octane ring (the carbon substituted with the hydroxyl group on the ω chain) exists, but in the present invention, any stereoisomer is present. The body is also included, and a mixture of stereoisomers in any proportion thereof may be used. Among these, the compound having the three-dimensional structure represented by the formula is most preferred.

3, which is represented by the above formula [I] provided in the present invention,
Specific preferred examples of the 6,7-trisubstituted bicyclo [3.3.0] -2-octenes include the compounds shown below.

(1) (1 S , 5 S , 6 S , 7 R ) -3- (4-carbomethoxy-2,2-bisphenylsulfonylbutyl) -6-
[(E, 3 S) -3- hydroxy-1-octenyl] -7
- hydroxy bicyclo [3.3.0] -2-octene (2) (1 S, 5 S, 6 S, 7 R) -3- (4- carbomethoxy-2,2-bis-phenylalanine sulfonyl butyl) -6-
[(E, 3 S) -3- hydroxy-1-nonenyl] -7
Hydroxy bicyclo [3.3.0] -2-octene (3) (1 S, 5 S, 6 S, 7 R) -3- (4- carbomethoxy-2,2-bis-phenylalanine sulfonyl butyl) -6-
[(E, 3 S) -3- hydroxy-4-methyl-1-octenyl] -7-hydroxy bicyclo [3.3.0] -2-octene (4) (1 S, 5 S, 6 S, 7 R) -3- (4-carbomethoxy-2,2-bisphenylsulfonylbutyl) -6-
[(E, 3 S) -3- hydroxy-4,4-dimethyl-1-
Octenyl] -7-hydroxybicyclo [3.3.0] -2
- octene (5) (1 S, 5 S, 6 S, 7 R) -3- (4- carbomethoxy-2,2-bis-phenylalanine sulfonyl butyl) -6-
[(E, 3 S) -3- hydroxy-5-methyl-1-octenyl] -7-hydroxy bicyclo [3.3.0] -2-octene (6) (1 S, 5 S, 6 S, 7 R) -3- (4-carbomethoxy-2,2-bisphenylsulfonylbutyl) -6-
[(E, 3 S) -3- hydroxy-5-methyl-1-nonenyl] -7-hydroxy bicyclo [3.3.0] -2-octene (7) (6) 6 - [(E, 3 S, 5 S ) ………] body (8) 6-[( E , 3 S , 5 S ) ………… body (9) (1 S , 5 S , 6 S , 7 R ) -3 -(4-carbomethoxy-2,2-bisphenylsulfonylbutyl) -6-
[(E, 3 S) -3- hydroxy-3- Shirokupenchiru -
1-propenyl] -7-hydroxybicyclo [3.3.0]
2- octene (10) (1 S, 5 S, 6 S, 7 R) -3- (4- carbomethoxy-2,2-bis-phenylalanine sulfonyl butyl) -6-
[(E, 3 S) -3- hydroxy-3- Shirokuhekishiru -
1-propenyl] -7-hydroxybicyclo [3.3.0]
2- octene (11) (1 S, 5 S, 6 S, 7 R) -3- (4- carbomethoxy-2,2-bis-phenylalanine sulfonyl butyl) -6-
[(E, 3 S) -3- hydroxy-3- Shirokuhekishiru -
1-butenyl] -7-hydroxybicyclo [3.3.0]-
2- octene (12) (1 S, 5 S, 6 S, 7 R) -3- (4- carbomethoxy-2,2-bis-phenylalanine sulfonyl butyl) -6-
[(E, 3 S) -3- hydroxy-5-phenoxy-1-
Bentenyl] -7-hydroxybicyclo [3.3.0] -2
- octene (13) (1 S, 5 S, 6 S, 7 R) -3- (4- carbomethoxy-2,2-bis-phenylalanine sulfonyl butyl) -6-
[(E, 3 S) -3- hydroxy-5-ethoxy-1-pentenyl] -7-hydroxy-bicyclo [3.3.0] -2-
Octene (14) (1 S, 5 S, 6 S, 7 R) -3- (4- carbomethoxy-2,2-bis-phenylalanine sulfonyl butyl) -6-
[(E, 4 S) -4- hydroxy-4-methyl-1-octenyl] -7-hydroxy bicyclo [3.3.0] -2-octene (15) (1 S, 5 S, 6 S, 7 R) -3- (4-carbomethoxy-2,2-bisphenylsulfonylbutyl) -6-
[(E, 4 R) -4- hydroxy-4-methyl-1-octenyl] -7-hydroxy bicyclo [3.3.0] -2-octene (16) (1 S, 5 S, 6 S, 7 R) -3- (4-carbomethoxy-2,2-bisphenylsulfonylbutyl) -6-
[(E)-3-hydroxy-4-vinyl-1-octenyl] -7-hydroxy bicyclo [3.3.0] -2-octene (17) (1 S, 5 S, 6 S, 7 R) -3- (4-carbomethoxy-2,2-bisphenylsulfonylbutyl) -6-
[( E ) -3-Hydroxy-1-heptene-7-yne-
1-yl] -7-hydroxybicyclo [3.3.0] -2-
Octene (18) (1 S, 5 S, 6 S, 7 R) -3- (4- carbomethoxy-2,2-bis-phenylalanine sulfonyl butyl) -6-
[( E ) -3-Hydroxy-1-octene-6-yne-
1-yl] -7-hydroxybicyclo [3.3.0] -2-
Octene (19) (1) to (18) 3- (4-carbomethoxy-1)
-P-trisulfonylbutyl) compound (20) A compound in which the methyl ester of (1) to (19) is a carboxylic acid (21) A compound in which the methyl ester of (1) to (19) is an allyl ester (22) ( Compounds in which the 7-position hydroxyl group of 1) to (21) and the hydroxyl group on the 6-position substituent are protected by t-butyldimethylsilyl group (23) Substitution of 7-position and 6-position of (1)-(21) A compound in which the hydroxyl group on the group is protected by a 2-tetrahydropyranyl group (24) (1) to (23) enantiomers of the compounds (25) (1) to (13) Stereoisomers of asymmetric carbons substituted with hydroxyl groups on the 6-, 7- and 6-position substituents. The novel isocarbacyclines represented by the above formula [I] are represented by the following formula [II] The compound represented by the formula
I-a] 3,6,7-trisubstituted bicyclo (3.3.7), which is a compound represented by the formula (1), its enantiomer, or a mixture thereof in any proportion.
0] -2-octenes in the presence of a palladium compound,
It can be obtained by reacting in a position-specific manner, and by carrying out a deprotection reaction and a hydrolysis reaction as necessary.

Similarly, the novel isocarbacycline represented by the above formula [I] is represented by the following formula [II] [In the formula, R ¹¹ and Ar are the same as defined above. ] The compound represented by the formula
-A] 3-methylene-2,6,7-trisubstituted bicyclo [3.3.0] -octane, which is a compound represented by the formula, its enantiomer, or a mixture thereof in any proportion, is reacted site-specifically in the presence of a palladium compound. And a deprotection reaction or a hydrolysis reaction, if necessary.

The present invention has the formula [III-b] 3,6,7-trisubstituted bicyclo [3.3.
0] -2-octenes are represented by the above formula [II] [In the formula, Ar and R ¹¹ are as described above. ] In the presence of a compound represented by and a palladium compound,
It is intended to provide a method for producing the isocarbacyclines of the above formula [I] by reacting in a position-specific manner and, if necessary, performing a deprotection reaction and a hydrolysis reaction.

Furthermore, the present invention further provides a compound of formula [IV-b] 3-methylene-2,6,7-trisubstituted bicyclo [3.3.0] -octanes, which are compounds represented by the formula (1), enantiomers thereof, or a mixture thereof in any proportion, are represented by the above formula (II). A method for producing an isocarbacycline of the above formula [I] by reacting a compound with a palladium compound in a position-specific manner, and optionally performing a deprotection reaction and a hydrolysis reaction. It is provided.

In the bisarylsulfonyl compound represented by the above formula [II] which is a raw material of the present invention, R ¹¹ represents a C _{1 to} C ₄ alkyl group or alkenyl group. As the group, the same group as the alkyl group or alkenyl group exemplified as R ^{1 in the} above formula [I] can be mentioned as a preferable group, but a methyl group is particularly preferable.

In the above formula [II], Ar represents a substituted or unsubstituted phenyl group. Examples of such a group include the same groups as those exemplified as Ar in the above formula [I], but a phenyl group and a p-tolyl group are particularly preferable.

The other starting material for this reaction is the arylacyloxy compound of the above formula [III-a] or [IV-a] and [II
In the carbonate compound represented by Ib] or [IV-b], R ²¹ and R ³¹ are the same or different and form an acetal bond with the oxygen atom of the tri (C ₁ -C ₇ ) hydrocarbon silyl group or hydroxyl group. Represents a group. As the group forming an acetal bond with the oxygen atom of the tri (C ₁ -C ₇ ) hydrocarbon silyl group or the hydroxyl group, the same groups as those exemplified for R ² or R ³ in the formula [I] are preferable. I can give you.

In the above formula [III-a], [IV-a], [III-b] or [IV-b], R ⁴ represents a hydrogen atom, a methyl group or a vinyl group, and R ⁵ is interrupted by an oxygen atom. Optionally linear or branched C ₃ -C ₉ alkyl group; substituted or unsubstituted phenyl group; substituted or unsubstituted phenyl group; substituted or unsubstituted phenoxy group; substituted or unsubstituted C ₃ ~ C ₁₀ cycloalkyl group; or C _{1 to} C ₈ alkoxy group, optionally substituted phenyl group, straight chain or branched chain C substituted with optionally substituted C _{3 to} C ₁₀ cycloalkyl group _It is preferably a C ₁ -C ₅ alkyl group, all of which are the same as those exemplified for R ⁵ in the above formula [I].

Formula [III-a], [IV-a], [III-b] or [IV-
In b], n represents 0 or 1.

R ⁶ in the formula [III-a] or [IV-a] represents a C _{1 to} C ₆ hydrocarbon group, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a butyl group and a pentyl group. However, a methyl group is preferable.

R ⁷ in the formula [III-b] or [IV-b] represents a C _{1 to} C ₄ hydrocarbon group, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and a butyl group. However, a methyl group is preferred.

3,6,7 represented by the formulas [III-a] and [III-b]
-Trisubstituted bicyclo [3.3.0] -2-octenes are described in, for example, Shibasaki et al .; Tetrahedron Letters.
Letters), 25 , 5087 (1984) or similar method, but the manufacturing process is briefly introduced as shown in the following process diagram. That is, Manufacturing process.

On the other hand, 3-methylene-2,6,7-trisubstituted bicyclo [3.3.0] -octanes represented by the formula [IV-a] or [IV-b] are disclosed in, for example, the above-mentioned reference (tetrahedron).・ Letters, 25 , 5087 (1984)) and known methods using 6,7-disubstituted-3-hydroxymethylbicyclo [3.3.0] -2-octenes as starting materials, which are produced by a method similar thereto. Obtained by the synthetic route (route A) or by the cyclization reaction (route B) of the acetylene derivative obtained by starting the optically active 4-hydroxy-2-cyclopentenone presented in the present invention. . The reaction route is briefly shown below.

The final step acylation reaction is carried out by reacting an acid chloride such as R ⁶ COCl (R ⁶ is as defined above) or an acid anhydride such as (R ⁶ CO) ₂ O with an allyl alcohol in the presence of a base. can get. On the other hand, the carbonation reaction is ClCOOR ⁷
It can be obtained by reacting a chloroformic acid derivative such as [R ⁷ is the same as defined above] with an allyl alcohol derivative in the presence of a base. As the base, organic bases such as pyridine, triethylamine and diisopropylethylamine are preferably used. Thus, an alkoxy compound of [III-a] or [IV-a] or a carbonate compound of [III-b] or [IV-b] is obtained.

The synthesis of the acyloxy compound represented by the above formula [III-a] or [IV-a] to the 4,4-bisarylsulfonylisocarbacyclines represented by the above formula [I] is represented by the above formula [II]. The bisarylsulfonyl compound is treated with a base to react with an acyloxy compound represented by the above formula [III-a] or [IV-a] in the presence of palladium.

The bisarylsulfonyl compound represented by the above formula [II] is used in an amount of 0.5 to 30 equivalents, preferably 1 to 5 equivalents, relative to the acyloxy compound represented by the above formula [III-a] or [IV-a]. The base for treating the bisarylsulfonyl compound may be an organic alkali metal or an alkali metal hydride such as n-butyllithium, s.
ec-butyl lithium, t-butyl lithium, phenyl lithium, methyl lithium, naphthyl lithium, trityl lithium, lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, etc. are used, Preferably sodium hydride is used. The amount of the base used is 0.5 to 30 equivalents, preferably 1 to 10 equivalents based on the bisarylsulfonyl compound represented by the above formula [II], but it is 1 equivalent in principle.
The reaction temperature of the salt formation reaction is -100 ° C to 100 ° C, preferably -78 ° C to 2 ° C, and the reaction time is 5 minutes to 50 hours, preferably 10 minutes to 2 hours. The reaction is carried out in an organic solvent. As the solvent, ether solvents such as ether, tetrahydrofuran and dioxane, hydrocarbon solvents such as n-hexane and benzene, and other DMF,
DMSO or the like is used, but tetrahydrofuran is preferably used.

The reaction mixture thus obtained is added with the arylacyloxy compound represented by the above formula [III-a] or [IV-a] without isolation of the alkali metal salt of the bisarylsulfonyl compound. Then, the reaction can proceed. This reaction is carried out in the presence of palladium, and examples of the palladium compound include Tetrahedron Vol.
42, No. 16, pp. 4361 to 4401, 1986; Accounts of Chemical
Research Vol.13, No.11, pp385 to 393,1980; and “Org
anic Synthesis with Pallaldium Compounds "J. Tsuji, S
Various palladium complexes described in pringer-Verlag (1980) can be used. Preferably tetrakis (triphenylphosphine) paradiu (O), bis [bis (1,2-diphenylphosphino) -ethane] palladium) O, bis [bis (1.3-diphenylphosphine) -propane] palladium ( O) is used, but is not limited thereto. The amount used is the above formula [III-a] or [IV
-A] to the acetate compound represented by 0.001 ~
It is 1 equivalent, preferably 0.01 to 0.2 equivalent. The reaction temperature is -30 ° C to 200 ° C, preferably 0 ° C to 100 ° C, and the reaction time is 10 minutes to 100 hours, preferably 1 hour to 2 hours.
4 hours. The reaction is carried out in an organic solvent, but the same solvent as in the previous salt formation reaction may be used.

The synthesis of the carbonate represented by the above formula [III-b] or [IV-b] into the 4,4-bisarylsulfonylisocarbacyclines represented by the above formula [I] is represented by the above formula [II]. The bisarylsulfonyl compound was prepared by reacting the compound of the above formula [III-b] or [I
V-b] and reacting with a carbonate.

The bisarylsulfonyl compound represented by the above formula [II] is used in an amount of 0.5 to 30 equivalents, preferably 1 to 5 equivalents, relative to the carbonates represented by the above formula [III-b] or [IV-b]. This reaction is carried out in the presence of a palladium complex, and the above-mentioned palladium compounds are preferably used.

The amount used is 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalent, based on the carbonate compound represented by the above formula [III-b] or [IV-b]. Reaction temperature is -30 ℃ to 200
C., preferably 0.degree. C. to 100.degree. C., and the reaction time is 10 minutes to 100 hours, preferably 0.5 hour to 24 hours. As the solvent, ether solvents such as ether, tetrahydrofuran and dioxane, hydrocarbon solvents such as n-hexane and benzene, DMF, DMSO and the like can be used, but tetrahydrofuran is preferably used.

In particular, the advantages of the reaction using a carbonate such as [III-b] or [IV-b] are as follows: 1) Decarboxylation with Pa (O) is involved, so the reaction proceeds irreversibly and the reaction conditions are mild.

2) Alkyloxy anions (eg Me
O ) Is generated, which is methyl-4,4'-bisphenyls.
Extraction of hydrogen from lephonyl butanoateTherefore, a base (for example, Na
The reaction may proceed without the addition of H).

The reaction liquid thus obtained may be post-treated in accordance with a commonly used method. For example, if necessary, the organic mixture obtained by adding a poorly soluble organic solvent to water such as hexane, pentane, ethyl ether, ethyl acetate, etc. is washed with saline, etc., and dried with anhydrous magnesium sulfate, anhydrous sodium sulfate, etc. After drying with an agent, the organic solvent is removed under reduced pressure to obtain a crude product. The crude product can be purified by a purification means such as column chromatography, thin layer chromatography, liquid chromatography, etc., if desired.

Then, the obtained product is optionally subjected to a deprotection reaction and hydrolysis, and the reaction proceeds in a position-specific manner to finally obtain a novel isocarbacycline represented by the above formula [I]. To be

Removal of the protective group of the hydroxyl group, when the protective group is a group forming an acetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, using a pyridinium salt of p-toluenesulfonic acid or a cation exchange resin as a catalyst, And, for example, water, tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile and the like are used as a reaction solvent, and the treatment is usually carried out at a temperature range of −78 ° C. to + 30 ° C. for about 10 minutes to 3 days. The protecting group is tri (C ₁ -C ₇ ).
In the case of a hydrocarbon silyl group, for example, acetic acid, tetrabutylammonium fluoride, cesium fluoride,
The protecting group is removed by treatment in the reaction solvent as described above at the same temperature and for the same time in the presence of hydrogen fluoride water or pyridine-hydrogen fluoride.

Hydrolysis of esters is carried out by a conventional method, that is, lithium hydroxide, sodium hydroxide or water in a solvent containing water.
Potassium hydroxide and -40 ° C to 100 ° C, preferably 0 ° C to 50
It is carried out by reacting in the temperature range of ℃ for 10 minutes to 24 hours.

Thus, the compound represented by the above formula [I] having an isocarbacycline skeleton is produced.

Route B described above as a process for preparing 3-methylene-2,6,7-3-substituted bicyclo [3.3.0] -octanes of formula [IV-a]
This method is described in detail below since the synthetic steps after the cyclization reaction of propargyl cyclopentanes are industrially important.

The following formula [V] The compound represented by and its enantiomer or a mixture of propargyl cyclopentanes in any proportion thereof are cyclized by a reducing agent using a metal species, and optionally deprotected by a deprotection reaction, Formula [VI] A 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octane which is a compound represented by the formula (1) and its enantiomer or a mixture thereof in any proportion is produced.

Examples of the metal species of the reducing agent used in the cyclization reaction include alkali metals such as lithium sodium and potassium, and sodium and lithium are particularly preferable. In addition, examples of the metal species of the reducing agent include alkaline earth metals such as calcium and magnesium. The amount of the alkali metal or alkaline earth metal used is 1.0 to 20.0 times mol, preferably 1.2 to 10.0 times mol, for 1 mol of the propargylcyclopentane represented by the formula [V].

Such an alkali metal or alkaline earth metal reducing agent is used for the cyclization reaction as an anion radical solution. As the solvent of the anion radical solution, naphthalene, 1- (N, N-dimethylamino) -naphthalene or 4,
Ether-based solvents such as diethyl ether, tetrahydrofuran, and dimethoxyethane, which contain 4'-di-t-butylbiphenyl in an equimolar amount or more with an alkali metal or an alkaline earth metal, or liquid ammonia are preferable, and among them, naphthalene is preferable. Alternatively, tetrahydrofuran containing 4,4'-di-t-butylbiphenyl is most preferred. The amount used may be an amount sufficient for the reaction to proceed smoothly, and is usually 1 to 100 times, preferably 2 to 20 times the volume of the starting compound.

The reaction temperature is -100 ° C to 100 ° C, preferably -78 ° C to 50 ° C.
Particularly preferably, a temperature range of about -78 ° C to 0 ° C is adopted. The reaction time varies depending on the reaction temperature, but is usually -78 ° C.
The reaction is complete within a few hours at ~ 0 ° C.

Zinc is also preferably used as a metal species used as a reducing agent. The cyclization reaction with zinc is usually carried out in the coexistence of trimethylchlorosilane and a base. The amount of such zinc used is 1 to 50 times mol, preferably 10 to 30 times mol, per mol of the propargyl cyclopentane represented by the formula [V]. Further, zinc activated by hydrochloric acid, copper, silver, mercury, etc. is used. Trimethylchlorosilane is used in an amount of 1 to 20 times, preferably 5 to 10 times the molar amount of the compound represented by the formula [V]. As the base, 2,6-lutidine is preferably used. The base is used in an amount of 1 to 10 times, preferably 1 to 5 times the mol of the compound represented by the formula [V].

As a solvent for the cyclization reaction, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane and the like are preferable, and tetrahydrofuran is most preferable. The amount used may be an amount sufficient for the reaction to proceed smoothly, and is usually 1 to 100 times the volume of the starting compound, preferably 2 to 20 times the volume.

The reaction temperature is 0 ° C to 100 ° C, preferably 20 ° C to 80 ° C. Although the reaction time varies depending on the reaction temperature, the reaction is usually completed within 30 minutes to 24 hours at 20 ° C to 80 ° C.

The product thus obtained can be taken out from the reaction system as a crude product by carrying out quenching with saturated aqueous ammonium chloride, extraction and the like. If desired, the crude product can be purified by purification means such as column chromatography, thin layer chromatography, liquid chromatography, recrystallization and the like.

The product thus obtained by the cyclization reaction using zinc has the following formula And the enantiomer thereof or a mixture thereof in any proportion.

The thus produced 6,7-disubstituted-3-methylene-
As a method for hydrolyzing 2-trimethylsilyl ether at the 2-position of 2-trimethylsilyloxybicyclo [3.3.0] octane to a 2-hydroxy compound, a usual trimethylsilyl ether cleaving reagent such as tetrabutylammonium fluoride (solvent tetrahydrofuran) is used. , p-toluenesulfonic acid (solvent methanol), potassium carbonate (solvent methanol), citric acid (solvent methanol), p-toluenesulfonic acid-pyridine (solvent methanol) and the like. That is, the target compound can be converted by performing a reaction similar to the deprotection reaction described below.

Propargyl cyclopentanes represented by the formula [V] and 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octanes at the 7-position and 6-position 3'position (or 4'-position) When () is a protected hydroxyl group, it can be converted to a free hydroxyl group by deprotecting it if necessary.

When the protective group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, a pyridinium salt of p-toluenesulfonic acid or a cation exchange resin is used as a catalyst to remove the protective group of the hydroxyl group. , Tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile and the like are preferably used as a reaction solvent. The reaction is usually performed in the temperature range of -78 ° C to + 30 ° C for about 10 minutes to 3 days. When the protecting group is a tri (C ₁ -C ₇ ) hydrocarbon silyl group, for example, in the presence of acetic acid, tetrabutylammonium fluoride, cesium fluoride, hydrogen fluoride, pyridine-hydrogen fluoride, It is carried out in a reaction solvent as described above at similar temperatures and for similar times.

Further, in the compounds represented by the above formulas [V] and [VI], the cyclopentane ring and the bicyclo [3.3.0] octane ring itself and the carbons to which the substituents bonded to these rings are bonded are asymmetric. Although stereoisomers exist due to the environment, the present invention includes any stereoisomer and any mixture of these stereoisomers may be used. Further, the compound represented by the formula represents all of these stereoisomers and a mixture of these isomers at an arbitrary ratio, and the compound having the stereostructure represented by the formula is most preferred.

Thus, in the method of the present invention for obtaining the isocarbacyclines represented by the above formula [I], (1) industrially easily available starting materials are used.

(2) The skeleton synthesis of the method of the present invention proceeds regiospecifically, resulting in a high yield.

It has advantages such as Further, the novel isocarbacyclines represented by the above formula [I] obtained in the present invention are expected to have isocarbacyclin-like activity per se, such as platelet aggregation inhibitory action, vasodilatory action, antihypertensive action and cytoprotective action. It is also a useful compound as an intermediate for synthesizing isocarbacycline, which is promising as a drug.

That is, the compound represented by the above formula [I], its enantiomer,
Alternatively, the 4,4-bis (arylsulfonyl) isocarbacyclines, which are a mixture of them at any ratio, should be reacted with a reducing agent and, if necessary, subjected to deprotection reaction and / or hydrolysis reaction. The following formula [VI
I] The compound can be converted into 9 (O) -methanoprostacyclin which is a compound represented by the formula (1), an enantiomer thereof, or a mixture of them in a ratio.

This desulfonation reaction is achieved by reacting the compound of the above formula [I] with an alkali metal amalgam as a reducing agent. This reaction is basically the Trost (Tr
ost) et al., Tetrahedron Lets
t.), 3477 (1976). That is, as the alkali metal amalgam, sodium amalgam is preferably used, and one having a sodium content of 1 to 20%, preferably 2 to 10% is particularly preferably used. The amount of sodium used is 5-500 mol times, preferably 50-500 mol times, per mol of 5-arylsulfonylisocarbacyclines represented by the above formula [I]. The reaction temperature is -78 ° C to 100 ° C, preferably -40 ° C to 30 ° C.
The reaction time varies depending on the reaction temperature. For example, at -10 ° C, it is sufficient to carry out the reaction for about 4 hours. In this reaction, 1 to 10 molar amount of disodium phosphate is allowed to coexist.

Such a reaction is carried out in an organic medium. Such organic media include hexane, benzene, toluene, ether, tetrahydrofuran, dimethoxyethane, dioxane, N, N
-Dimethylformamide, methanol, ethanol and the like are used, but methanol is preferably used. The amount used may be an amount that allows the reaction to proceed smoothly, and is usually 1.0 to 100 volumes with respect to the volume of the reaction substance, preferably
Use 5.0 to 50 volumes.

The reaction liquid thus obtained may be post-treated in accordance with a commonly used method. For example, a mixture obtained by adding a poorly soluble organic solvent to water such as hexane, pentane, petroleum ether, ethyl ether, ethyl acetate, etc. is washed with saline, etc., if necessary, and anhydrous magnesium sulfate, anhydrous sodium sulfate is used. After drying with a drying agent such as anhydrous calcium chloride, the organic medium is removed under reduced pressure to obtain a crude product. The crude product can be purified by a purification means such as column chromatography, thin layer chromatography, liquid chromatography, etc., if desired.

On the other hand, as described above, from the formula [I] to the formula [VI
The desulfonation reaction to [I] is a method of using magnesium metal instead of alkali metal amalgam [basically
AC Brown, et. Al., J. Org. Chem., 50 , 1749 (1985)]. In this case, the post-treatment of the reaction solution may be performed in the same manner as the above case.

In the method of the present invention, the product obtained here is further subjected to a deprotection reaction and a hydrolysis reaction, if necessary, to finally obtain the compound represented by the above formula [VII], its enantiomer, or a compound thereof. Isocarbacyclines, which are mixtures in any proportion, are produced.

Specific examples of R ^{12 when it} is a C ₁ -C ₄ alkyl group or alkenyl group are the same as those exemplified for R ¹ in the above formula [I].

Specific examples when R ²² and R ³² are a hydroxyl-protecting group are the same as those exemplified for R ² and R ³ in the above formula [I].

When the protective group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, a pyridinium salt of p-toluenesulfonic acid or a cation exchange resin is used as a catalyst to remove the protective group of the hydroxyl group. , Tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile and the like are preferably used as a reaction solvent. The reaction is usually performed in the temperature range of -78 ° C to + 30 ° C for about 10 minutes to 3 days. When the protecting group is a tri (C ₁ -C ₇ ) hydrocarbon silyl group, for example, in the presence of acetic acid, tetrabutylammonium fluoride, cesium fluoride, hydrogen fluoride water, pyridine-hydrogen fluoride, It is carried out in a reaction solvent as described above at similar temperatures and for similar times.

Thus, using the arylsulfonylisocarbacyclines represented by the above formula [I] as a starting material, the isocarbacyclines represented by the above formula [II] can be obtained by the method of the present invention.

<Examples> Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto. still,
Examples and Reference Examples in -OZ represents -OSi · ^t BuMe ₂ (t- butyl-dimethyl-silyloxy group), -OZ 'is -OSiM
represents e ₃ (trimethylsilyloxy group).

<Production of 4,4-bis (phenylsulfonyl) isocarbacyclines> Reference Example 1 Methyl-4,4-bis (phenylsulfonyl) butanoate 59 mg (1.05 mmol) in 0.8 ml THF solution was added to a solution of NaH (6
6.2 mg (0.15 mmol) of 0% in oil) was added at 0 ° C. and stirred for 1 hour. Here, the acetate body represented by the above formula (1)
68 mg (0.12 mmol) of 0.8 ml THF solution was added, and then bis [bis (1,2-diphenylphosphino) ethane] palladium (O) 6.3 mg (0.007 mmol) was added, and the mixture was added at room temperature for 3 hours at 60 ° C. Stir for 4 hours. After the reaction, the reaction was terminated with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 →
10: 1), 64 mg (59%) of 4,4-bis (phenylsulfonyl) isocarbacycline-11,15-bis (t-butyldimethylsilyl) ether methyl ester (2).
%), And 23 mg (34%) of recovered acetate was obtained.

IR (cm ⁻¹ , neat); 2950,2860,1740,1580,1460,1440,1330,1310,1255,1140 NMR (δppm, CDCl ₃ ): 0.9 (s + m, 21H), 1.2 to 2.4 (m, 14H ), 2.6 to 3.1 (m, 7H), 3.7 (s, 3H), 3.75 (m, 1H), 4.05 (m, 1H), 5.4 (m, 2H), 5.55 (m, 1H), 7.1 to 8.0 ( m, 10H) Reference example 2 87 mg (0.10 mmol) of disilyl compound (2) was dissolved in 2 ml of dry tetrahydrofuran (2 ml), and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) was added to 47
0 μl (0.47 mmol) was added, and the mixture was stirred at room temperature for 10 hours. Water was added and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The product was subjected to silica gel column chromatography (ethyl acetate, 2% methanol) to obtain 51 mg (79%) of desilylated product (3).

NMR (δ ppm, CDCl ₃ ); 0.9 (m, 3H), 1.2 to 2.4 (m, 14H), 2.6 to 31 (m, 7H), 3.65 (s, 3H), 3.65 to 4.05 (m, 2H), 5.4 (M, 2H), 5.55 (m, 1H), 7.1 to 8.0 (m, 10H) Reference example 3 In a 1 ml THF solution of 84 mg (0.22 mmol) of methyl-4,4-bis (phenylsulfonyl) butanoate (4) treated with 8.8 mg (60% in oil, 0.22 mmol) of NaH under a nitrogen stream, represented by the above formula (5). Acetate 116mg (0.2mmol) 1mlT
The HF solution was added, then 13 mg (0.011 mmol) of tetrakistriphenylphosphine palladium (O) was added, and the mixture was stirred at 60 ° C for 7 hours. After the reaction, the reaction was terminated with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 10: 1) to give 17 ( S ), 20-dimethyl-4,4-bis (phenylsulfonyl) isocarbacycline dihexane. 128 mg (71%) of silyl ether and methyl ester compound (5) were obtained.

NMR (δ ppm, CDCl ₃ ); 0.9 (s + m, 21H), 1.0 to 2.4 (m, 18H), 2.6 to 3.1 (m, 7H), 3.65 (s, 3H), 3.7 to 4.1 (m, 2H), 5.3 ~ 5.6 (m, 3H), 7.1 ~ 8.0 (m, 10H) Reference example 4 To a solution of methyl-4,4-bis (phenylsulfonyl) butanoate (6) 65 mg (0.17 mmol) treated with NaH 6.8 mg (60% in oil, 0.17 mmol) under a nitrogen stream in 1 ml THF, the above formula (7) was used. Acetate represented by 78mg (0.15mmol) 1m
lTHF solution, then bis [bis (1.2-diphenylphosphino) ethane] palladium (O) 7.2 mg (0.008 mmol)
Was added and the mixture was stirred at 80 ° C. for 10 hours. On the way, the above-mentioned palladium (O) 7.2 mg (0.008 mmol) was added at 5 hours.
After the reaction, the reaction was terminated with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 20: 1 → 10: 1) to obtain 92 mg (73%) of the product (7).

NMR (δppm, CDCl ₃ ): 0.9 (s + m, 12H), 1.1-2.4 (m, 14H), 1.1 (s, 3H), 2.6-3.1 (m, 7H), 3.65 (s, 3H), 3.8 (m , 1H), 5.3 to 5.6 (m, 3H), 7.1 to 8.0 (m, 10H) Reference example 5 To a solution of methyl-4,4-bis (phenylsulfonyl) butanoate (8) 84 mg (0.22 mmol) treated with NaH 9 mg (0.23 mmol, 60% in oil) in 1 ml THF in a nitrogen stream, the above formula (9) was used. Acetate body represented 110 mg (0.2 mmol)
1 ml DMF solution was added, and then bis [bis (1,2-diphenylphosphino) ethane] palladium (O) 9 mg (0.01 m
mol) was added and the mixture was stirred at 60 ° C. for 5 hours. After the reaction, the reaction was terminated with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 20: 1 → 10: 1) to obtain 113 mg (65) of the product (9).
%) Was obtained.

NMR (δ ppm, CDCl ₃ ): 0.9 (s, 18H), 1.0 to 2.4 (m, 15H), 2.6 to 3.0 (m, 7H), 3.70 (s, 3H), 3.6 to 4.1 (m, 2H), 5.3 ~ 5.6 (m, 3H), 7.1 ~ 8.0 (m, 10H) Reference example 6 4,4-bis (phenylsulfonyl) isocarbacycline methyl ester (3) 48 mg (0.075 mmol) in tetrahydrofuran (3 ml), methanol (1.5 ml), water (1 ml)
Dissolved in a mixed solvent of lithium hydroxide hydrate 60
mg was added and the mixture was stirred at room temperature for 20 hours. After adding ammonium chloride aqueous solution, the solvent was distilled off under reduced pressure and acidified with diluted hydrochloric acid (pH
After 3-4), it was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried (MgSO ₄ ) and concentrated to give a crude product. This product was purified by column chromatography (hexane: acetic acid = 1: 4), and the carboxylic acid (1
0) 40 mg (85%) was obtained.

NMR (δppm, CDCl ₃ ): 0.9 (m, 3H), 1.2 to 2.4 (m, 14H), 2.6 to 3.1 (m, 7H), 3.6 to 4.1 (m, 2H), 5.4 (m, 2H), 5.6 (M, 1H), 7.1-8.0 (m, 10H) Reference example 7 To a 0.8 ml THF solution of 57 mg (0.15 mmol) of methyl-4,4-bis (phenylsulfonyl) butanoate (11) treated with 6 mg (60% in oil, 0.15 mmol) of NaH under a nitrogen stream, represented by the above formula (). 70 mg (0.13 mmol) of acetate
0.8 ml THF solution was added, and then bis [bis (1,2-diphenylphosphino) ethane] palladium (O) 6.3 mg (0.0
07 mmol) was added. The reaction mixture was stirred at 70 ° C. for 15 hours. After the reaction, terminate the reaction with saturated ammonium chloride aqueous solution,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 20: 1 → 5: 1) to obtain 89 mg (79%) of the product (12).

NMR (δppm, CDCl ₃ ); 0.9 (s + m, 12H), 1.1-2.4 (m, 14H), 2.6-3.1 (m, 7H), 3.65 (s, 3H), 3.8 (m, 1H), 4.7-5.6 (M, 6H), 7.1 to 8.0 (m, 10H) Reference Examples 8 to 10 In the same manner as in Reference Example 7, the following compounds were prepared from the corresponding acetate form and methyl-4,4-bis (phenylsulfonyl) butanoate. Was synthesized.

Reference example 8 NMR (δppm, CDCl ₃ ); 0.9 (s + m, 21H), 1.0 to 2.4 (m, 16H), 1.13 (s, 6H), 3.65 (s, 3H), 3.7 to 4.1 (m, 2H), 5.3 to 5.6 (M, 3H), 7.1 to 8.0 (m, 10H) Reference example 9 NMR (δ ppm, CDCl ₃ ); 0.9 (s, 18H), 1.0 to 2.4 (m, 17H), 2.6 to 3.0 (m, 7H), 3.70 (s, 3H), 3.6 to 4.1 (m, 2H), 5.3 ~ 5.6 (m, 3H), 7.1 ~ 8.0 (m, 10H) Reference example 10 NMR (δ ppm, CDCl ₃ ); 0.9 (s + m, 21H), 1.0 to 2.4 (m, 18H), 2.6 to 3.1 (m, 7H), 3.65 (s, 3H), 3.7 to 4.1 (m, 2H), 5.3 ~ 5.6 (m, 3H), 7.1 ~ 8.0 (m, 10H) Example 1 73 mg (0.13 mmol) of methylcarbonyldioxy compound (16) and 57 mg (0.15 mmol) of methyl-4,4-bis (phenylsulfonyl) butanoate and bis [bis (1,2-diphenylphosphino) -ethane] Palladium (O) 5.8mg (0.0
A solution of 065 mmol) in 1 ml THF was stirred at 50 ° C. for 4 hours under a nitrogen stream. After the reaction, the reaction was terminated with an aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 10: 1) to give 4,4-
Bis (phenylsulfonyl) isocarbacycline-1
76 mg (68%) of 1,15-bis (t-butyldimethylsilyl) ether methyl ester (2) was obtained.

IR (cm ⁻¹ , neat); 2950,2860,1740,1580,1460,1440,1330,1310,1255,1140 NMR (δppm, CDCl ₃ ); 0.9 (s + m, 21H), 1.2 to 2.4 (m, 14H ), 2.6 to 3.1 (m, 7H), 3.7 (s, 3H), 3.75 (m, 1H), 4.05 (m, 1H), 5.4 (m, 2H), 5.55 (m, 1H), 7.1 to 8.0 ( m, 10H) Reference example 11 Methyl-4,4-bis (phenylsulfonyl) butanoate (17) 400 mg (1.05 mmol) in 2 ml THF solution was added N 2 under nitrogen stream.
44 mg (1.1 mmol) of aH (60% in oil) was added at 0 ° C. and stirred for 1 hour. To this, a solution of 450 mg (0.82 mmol) of the acetate compound represented by the above formula (1) in 2 ml of THF was added, and then bis [bis (1,2-diphenylphosphino) -ethane] was added.
80 mg (0.09 mmol) of palladium (O) was added, and the mixture was heated to 60 ° C and stirred for 5 hours. After the reaction, the reaction was terminated with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the crude product (hexane: ethyl acetate = 20: 1 → 10: 1)
Then, 493 mg (70%) of 4,4-bis (phenylsulfonyl) isocarbacycline-11,15-bis (t-butyldimethylsilyl) ether methyl ester (2) was obtained.

IR (cm ⁻¹ , neat); 2950,2860,1740,1580,1460,1440,1330,1310,1255,1140 NMR (δppm, CDCl ₃ ); 0.9 (s + m, 21H), 1.2 to 2.4 (m, 14H ), 2.6 to 3.1 (m, 7H), 3.7 (s, 3H), 3.75 (m, 1H), 4.05 (m, 1H), 5.4 (m, 2H), 5.55 (m, 1H), 7.1 to 8.0 ( m, 10H) Example 2 Allyl alcohol represented by the above formula (18) 225 mg (0.4
4 mmol) in 2 ml of methylene chloride was cooled to 0 ° C. and about 160 μl (2 mmol) of pyridine was added, followed by methyl chloroformate.
78 μl (1 mmol) was added, and the mixture was stirred as it was for 1 hour and then at room temperature for 2 hours. The reaction was terminated with water and extracted with ether. The organic layer was washed with an aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain 246 mg (98%) of methoxycarbonyloxy compound (19).

IR (cm ⁻¹ , neat); 2950,2860,1755,1460,1440,1360,1260,1120 NMR (δppm, CDCl ₃ ); 0.85 (s, 9H), 0.9 (s, 9H), 0.8-1.0 ( m, 3H), 1.0 to 1.8 (m, 8H), 1.8 to 2.5 (m, 6H), 3.0 (m, 1H), 3.8 (s, 3H), 3.7 to 4.2 (m, 2H), 4.7 (br. s, 2H), 5.5 (m, 2H), 5.7 (br.s, 1H) Then obtained methoxycarbonyloxy compound (19) 340m
g (0.6 mmol), methyl-4,4-bis (phenylsulfonyl) butanoate 298 mg (0.78 mmol) and bis [bis (1,2-diphenylphosphino) ethane] palladium (O) 45 mg (0.05 mmol) A THF (4 ml) solution of the above mixture was stirred at 50 ° C. for 6 hours under a nitrogen stream. After the reaction, the reaction was terminated with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate.
The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1).
→ 10: 1), 157 mg (30%) of 4,4-bis (phenylsulfonyl) isocarbacycline-11,15-bis (t-butyldimethylsilyl) ether methyl ester (2)
%)Obtained.

IR (cm ⁻¹ , neat); 2950,2860,1740,1580,1460,1440,1330,1310,1255,1140 NMR (δppm, CDCl ₃ ); 0.9 (s + m, 21H), 1.2 to 2.4 (m, 14H ), 2.6 to 3.1 (m, 7H), 3.7 (s, 3H), 3.75 (m, 1H), 4.05 (m, 1H), 5.4 (m, 2H), 5.55 (m, 1H), 7.1 to 8.0 ( m, 10H) Examples 3 to 10 In the same manner as in Example 13, the reaction proceeds in the same manner even with a compound having a protecting group different from the protecting group for water oxygen (t-butyldimethylsilyl group) of the compound in Example 2. did. Examples of protecting groups are shown in Table 1.

<Cyclization Reaction of Acetylene Aldehydes> Reference Example 12 15 mg of metallic lithium and 266 mg of naphthalene are added to 7 ml of tetrahydrofuran and stirred at room temperature for 2 hours to prepare a dark green anion radical solution. This is cooled to -50 ° C, and a solution of (20) 50 mg in tetrahydrofuran 3 ml is added thereto. After 5 minutes, a saturated aqueous solution of ammonium chloride was added to quench the reaction, extraction with ethyl acetate was performed, and the organic phase was washed with a saturated saline solution, dried with magnesium sulfate, and then the solvent was concentrated under reduced pressure to obtain 346 mg of a crude product. This was eluted by silica gel column chromatography with a mixed solvent of hexane-ethyl acetate 9: 1 to obtain (21) 34 mg. Yield 67%. This (21) consists of the following [(21) α] 14 mg and [(21) β] 20 mg.

Spectral data 0.8 to 1.0 (21H, m), 3.5 to 4.2 (4H, br), 4.91 (1H, brs), 5.01 (1H, brs), 5.43 (2H, m) Rf value (silica gel thin layer chromatography, developing solvent n- Hexane-ethyl acetate 4: 1) [(21) α] 0.43, [(21) β] 0.30 Reference Example 13 Metallic lithium 15 mg and 4,4′-di-t-butylbiphenyl 5
53 mg and 5 ml of tetrahydrofuran were stirred at 0 ° C for 18 hours,
A dark green anion radical solution is prepared. -50
Cool to ℃ (20) and add a solution of 50.6 mg of tetrahydrofuran in 3 ml of tetrahydrofuran. After 5 minutes, after quenching and purification in the same manner as in Reference Example 1, (21) 30 mg ([(21) α] 11 mg, [(21) β] 19 m
g) was obtained. Yield 59%.

Reference Example 14 14 mg of sodium metal, 85 mg of naphthalene, and 2 ml of tetrahydrofuran are stirred at room temperature for 2.5 hours to prepare an anion radical solution. After cooling this to -70 ° C, a solution of 51 mg of (20) in 1.2 ml of tetrahydrofuran was added. After stirring at -70 ° C for 1 hour, the mixture was quenched with saturated aqueous ammonium chloride solution, post-treated and purified in the same manner as in Reference Example 1 to give (21) 25 mg ([(21) α].
7 mg, [(21) β] 18 mg) were obtained. Yield 42%.

Reference Example 15 Under a nitrogen gas atmosphere, a flask containing 28 mg of metallic sodium was cooled to −70 ° C., and about 7 ml of liquid ammonia was taken and concentrated with stirring. At −45 ° C., a solution of 51 mg of (20) in 3.5 ml of tetrahydrofuran was added thereto, and the mixture was stirred for 50 minutes as it was. After this, 432 mg of sodium benzoate was added, and the mixture was stirred at room temperature for 20 minutes to vaporize ammonia. After adding water and extracting twice with ether, the organic phase was washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous ammonium chloride and brine in that order, dried over magnesium sulfate and concentrated under reduced pressure to give 48 mg of a crude product. . By silica gel column chromatography, n-hexane-ethyl acetate
Elution with a mixed solvent of 97.5: 2.5 yielded 10 mg of (21) (only [(21) β]). Yield 20%.

Reference example 16 The zinc dust is stirred in 10% hydrochloric acid for 5 minutes. The supernatant was removed by decantation, washed with water (1 time), acetone (3 times), ether (2 times), and then dried and activated in vacuum for 2 hours. (20) To 53 mg, add 138 mg of this zinc dust and further add 1 ml of a tetrahydrofuran solution containing 68 mg of trimethylchlorosilane. Further, 32 mg of 2,6-lutidine was added and the mixture was heated under reflux for 4 hours. The solid and liquid are separated by decantation, and 10 ml of diethyl ether is added to the liquid side. The organic layer was washed successively with saturated aqueous potassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate and brine, dried over magnesium sulfate and the solvent removed under reduced pressure. The thus obtained crude product containing (22) is dissolved in 3 ml of methanol, a little pyridine of p-toluenesulfonate is added, and the mixture is stirred at room temperature for 10 minutes. Saturated aqueous sodium hydrogen carbonate was added thereto, methanol was concentrated under reduced pressure, and then extracted with ether. The organic phase was washed with brine, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The crude product was eluted by silica gel column chromatography using a mixed solvent of n-hexane-ethyl acetate 19: 1 to obtain (11.8 mg) of (21). Yield 23%.

Reference Example 17 Zinc dust was stirred with 3% hydrochloric acid for 1 minute. This wash is repeated 4 times. After washing 5 times with distilled water, 2% with a 2% copper sulfate solution
Wash twice, then distilled water (5 times), absolute ethanol (4 times
Then, the mixture was washed with (4 times) and diethyl ether (5 times) in that order, passed through a glass filter under a nitrogen gas stream, and dried under reduced pressure for 4 hours for activation.

(20) To 53 mg, a solution of 138 mg of this zinc dust and 68 mg of trimethylchlorosilane in 1 ml of tetrahydrofuran, 2,6-lutidine 3
2 mg was added and the mixture was heated under reflux for 4 hours.

The same post-treatment, desilylation and purification as in Reference Example 5 were carried out to obtain 16 mg of (21). Yield 31%.

Reference Example 18 350 mg of zinc dust was stirred with 10% hydrochloric acid for 4 minutes, and the supernatant was removed by decantation. After washing with acetone and ether in this order, 12 ml of silver acetate in 1.7 ml of boiling acetic acid suspension was added and stirred for 1 minute. After removing the supernatant with a syringe, acetic acid 1 ml, ether 2 m
l (3 times), 2 ml of methanol, 2 ml of ether (4 times) and 2 ml of tetrahydrofuran (4 times) in that order, and then dried for 3 hours under vacuum to activate.

(20) To 53 mg, a solution of 138 mg of this zinc dust and 68 mg of trimethylchlorosilane in 1 ml of tetrahydrofuran, 2,6-lutidine 3
2 mg was added and the mixture was heated under reflux for 4 hours. The same post-treatment, desilylation and purification as in Reference Example 5 were carried out to obtain 18 mg of (21).
Yield 34%.

Reference Example 19 4.12 g of zinc powder was stirred with 10% hydrochloric acid for 2 minutes, and the supernatant was removed. After washing with 5 ml of distilled water four times, second chloride
A solution of 0.8 g of mercury in 5 ml of boiling water was added and stirred for 10 minutes. After removing the supernatant, 5 ml of distilled water and 5 ml of ethanol (7
Washing was carried out in the order of 5 ml of ether (7 times). Activated zinc was prepared by vacuum drying for 3 hours.

(20) To 53 mg, a solution of 138 mg of this zinc dust and 68 mg of trimethylchlorosilane in 1 ml of tetrahydrofuran, 2,6-lutidine 3
2 mg was added and the mixture was heated under reflux for 4 hours. The same post-treatment, desilylation and purification as in Reference Example 5 were carried out to obtain 17 mg of (21).
Yield 32%.

Reference example 20 5.05 ml of pyridine was dissolved in 50 ml of methylene chloride, 3.12 g of chromium trioxide was added, and the mixture was stirred at room temperature for 20 minutes. Here (2
3) A solution of 1.30 g of methylene chloride in 3 ml was added, and the mixture was stirred at room temperature for 15 minutes. 150 ml of ether was added, and the solid was removed by suction through Celite. The organic phase was washed with saturated aqueous potassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate and brine (twice) in this order. After drying over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 1.32 g of a crude product. This was purified by silica gel column chromatography to obtain 1.01 g of (21) in the elution part of n-hexane-ethyl acetate (19: 1). Yield 77%.

NMR spectrum data of (21) 0.88 (21H), 2.87 (1H, m), 3.7 to 4.3 (2H, m), 5.43 (2H, m), 9.97 (1H, d, J = 3Hz) Reference Example 21 Lithium mineral oil display spargon (content 25
%; Containing 1% of sodium) 15.3 g (552 mmol) of tetrahydrofuran was added, and 70.3 g (550 mmol) of naphthalene was added under ice-cooling and nitrogen atmosphere. The mixture was stirred under ice cooling for 2 hours to prepare a dark green anion radical solution. Acetylene aldehyde (21) 25.1 g (50 mmol) and t-butanol 1
8.7 ml (320 mmol) was dissolved in 120 ml of tetrahydrofuran, cooled to -70 ° C, and then added to the above anion radical solution cooled to -70 ° C. After stirring at −70 ° C. for 15 minutes, 50 g of ammonium chloride was added, and ethanol was added until the dark green anion radical disappeared. After adding 900 ml of saturated aqueous ammonium chloride solution, extract with ethyl acetate (2 x 700
ml). After washing the combined organic layers twice with saturated saline,
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to give 5.34 g (21% yield) of [(21) α] and hexane-ethyl acetate in the eluent of hexane-ethyl acetate = 19: 1. = 12.95 g (yield 51%) of [(21) β] was obtained in the 9: 1 eluate.

Spectral data 0.8 to 1.0 (21H), 3.86 (1H, q, J = 6Hz), 4.05 (1H, br), 4.38 (1H, bt, J = 8Hz), 4.96 (1H, brs), 5.08 (1H, brs), 5.45 (2H, m) IR (liquid film) 3350,3080,1662,1255,1115,1002,968,935,835,772cm ^-1 MS 508 (M ⁺ ), 491 (M-17), 451 (M-57) 0.8 to 1.0 (21H), 3.77 (1H, m), 4.05 (1H, br), 4.15 (1H, brs), 4.95 (1H, brs), 5.07 (1H, brs), 5.46 (2H, m) IR ( Liquid film) 3350,3080,1662,1255,1115,1002,968,937,835,772cm ^-1 MS 508 (M ⁺ ), 491 (M-17), 451 (M-57) <Synthesis of isocarbacycline from carbonate> Reference Example 22 (1 S, 5 S, 6 S, 7 R) -2- hydroxy-3-methylene-6 - [(E, 3 S) -3- t- butyldimethylsilyloxy-1-octenyl] -7-t- Butyldimethylsilyloxybicyclo [3.3.0] octane (21) 400 mg (0.79
mmol) in methylene chloride solution (4 ml) under nitrogen stream at -20 ° C
To the mixture, about 250 μl (about 4 equivalents) of pyridine was added, then 122 μl (1.6 mmol) of methyl chloroformate was added, and the mixture was stirred for 1 hour as it was, and then stirred at 0 ° C. for 30 minutes. The reaction was terminated with water and extracted with ethyl acetate. The organic layer was washed with an aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 15: 1), and 2
-377 mg (85%) of methylcarbonyldioxy compound (16) was obtained.

IR (cm ^-1 , neat); 2950,2860,1750,1460,1440,1360,1260,1120 NMR (δppm, CDCl ₃ ); 0.85 (s, 9H), 0.87 (s, 9H), 0.8-2.6 ( m, 18H), 3.75 (m, 1H), 3.8 (s, 3H), 4.07 (m, 1H), 5.0 (s, 1H), 5.15 (s, 1H), 5.3 (s, 1H), 5.5 (m , 1H) Reference Example 23 According to Reference Example 21, Compounds with different values were synthesized.

Reference Example 24 According to Reference Example 22, the formula [IV-b] Compounds with different values were synthesized.

Example 11 According to Example 1, a compound of formula [I] Compounds with different values were synthesized.

<Synthesis of Isocarbacycline by Desulfonation Reaction> Example 12 4,4-bis (phenylsulfonyl) isocarbacycline methyl ester-11,15 (t-butyldimethylsilyl) ether (2) 62 mg (0.071 mmol) in anhydrous methanol (1.5 ml) was added to a solution of anhydrous phosphoric acid under a nitrogen stream. 2 sodium 4
1 mg (0.29 mmol) was added and it cooled at -30 degreeC. 600 mg of sodium amalgam (6% in Hg) was added thereto, and the mixture was stirred for 2 hours. Further, 200 mg of sodium amalgam was added and stirred for 3 hours. The reaction was quenched with aqueous ammonium chloride solution and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 50: 1 → 10: 1) to obtain 36 mg (86) of isocarbacycline methyl ester-11,15-bis (t-butyldimethylsilyl) ether. %)
Got As for this product, the TLC and the spectrum data of the separately synthesized standard product were in agreement.

NMR (δ ppm, CDCl ₃ ): 0.9 (s + m, 21H), 1.2 to 2.5 (m, 22H), 3.0 (m, 1H), 3.7 (s, 3H), 3.7 to 4.1 (m, 2H), 5.3 (m , 1H), 5.55 (m, 2H) TLC: Rf = 0.75 (n = hexane: ethyl acetate = 4: 1) Isocarbacycline methyl ester-11,15-bis (t-butyldimethylsilyl) ether thus obtained 3
To a solution of 5 mg (0.06 mmol) in dry THF (3 ml) was added tetrabutylammoniumfluorite (1M in THF) 400 at 0 ° C.
μl (0.4 mmol) was added, 30 minutes later, the mixture was brought to room temperature and stirred for 14 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → 1: 2) to obtain 18 mg (85%) of isocarbacycline methyl ester (23). This product had the same HPLC, TLC, and spectral data as the separately synthesized standard.

NMR (δppm, CDCl ₃ ): 0.9 (m, 3H), 1.2 to 2.5 (m, 24H), 3.0 (m, 1H), 3.7 (s, 3H), 3.7 to 4.1 (m, 2H), 5.3 (m , 1H), 5.55 (m, 2H) TLC: Rf = 0.5 (n-hexane: ethyl acetate = 1: 4) HPLC: (Zorbax-SIL 2.5% ethanol-hexane 1.3 ml /
Minute) Retention time 24 minutes Reference example 25 17 ( S ), 20-Dimethyl-4,4-bis (phenylsulfonyl) isocarbacycline methyl ester-11,15 bis (t-butyldimethylsilyl) ether (5) 45 mg (0.
To a solution of 05 mmol) in anhydrous methanol (1.5 ml) was added anhydrous disodium phosphate 28 mg (0.2 mmol) under a nitrogen stream, and -30
Cooled to ° C. Sodium amalgam (6% in H
g) 600 mg was added and stirred for 6 hours.

The reaction was quenched with aqueous ammonium chloride solution and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane:
Ethyl acetate = 50: 1 → 10: 1), 17 (S), 20-dimethylisocarbacycline methyl ester-11,15-bis (t-butyldimethylsilyl) ether (24) 24 mg
(79%) was obtained. As for this product, the TLC and the spectrum data of the separately synthesized standard product were in agreement.

NMR (δ ppm, CDCl ₃ ): 0.9 (s + m, 21H), 1.0 to 2.5 (m, 26H), 3.0 (m, 1H), 3.7 (s, 3H), 3.7 to 4.1 (m, 2H), 5.3 (m , 1H), 5.55 (m, 2H) TLC: Rf = 0.75 (n-hexane: ethyl acetate = 4: 1) Reference Example 26 15-deoxy-16-methyl-16-hydroxy-4,4-bis (phenylerphonyl) isocarbacycline methyl ester-11-t-butyldimethylsilyl ether-16
In a solution of 34 mg (0.04 mmol) of trimethylsilyl ether (6) in anhydrous methanol (1 ml) under a nitrogen stream, anhydrous phosphoric acid 2
Sodium 24 mg (0.17 mmol) was added, and it cooled at -30 degreeC. 400 mg of sodium amalgam (6% in Hg) was added thereto, and the mixture was stirred for 7 hours. The reaction was quenched with aqueous ammonium chloride solution and extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 50: 1 → 10:
Subjected to 1), 15-deoxy-16-methyl-16-hydroxyisocarbacycline methyl ester-11-t-butyldimethylsilyl ether-16-trimethylsilyl ether (25) 17 mg (75%) was obtained. This product had the same TLC and spectral data as the separately prepared standard.

NMR (δ ppm, CDCl ₃ ): 0.9 (s + m, 12H), 1.1 (s, 3H), 1.2-2.5 (m, 22H), 3.0 (m, 1H), 3.65 (s, 3H), 3.8-4.0 (m , 1H), 5.3 (m, 1H), 5.55 (m, 2H) TLC: Rf = 0.75 (n-hexane: ethyl acetate = 4: 1) Reference Example 27 16,17,18,19,20-pentanor-15-cyclopentyl-4,
4-bis (phenylsulfonyl) isocarbacycline methyl ester-11,15-bis (t-butyldimethylsilyl) ether (9) 15 mg (0.059 mmol) in anhydrous methanol (1.5 ml) was added to a solution of anhydrous phosphoric acid under a nitrogen stream. 26 mg (0.25 mmol) of 2 sodium was added, and it cooled at -30 degreeC. 600 mg of sodium amalgam (6% in Hg) was added thereto, and the mixture was stirred for 5 hours. The reaction was quenched with aqueous ammonium chloride solution and extracted with ether. After washing the organic layer with saturated saline,
It was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 50: 1 → 10: 1) to give 1
6,17,18,19,20-Pentanol-15-cyclopentylisocarbacycline methyl ester-11,15-bis (t-
Obtained 25 mg (72%) of butyldimethylsilyl) ether (26). This product had the same TLC and spectral data as the separately prepared standard.

NMR (δ ppm, CDCl ₃ ): 0.9 (s, 18H), 1.0 to 2.5 (m, 23H), 3.0 (m, 1H), 3.7 (s, 3H), 3.7 to 4.1 (m, 2H), 5.3 (m , 1H), 5.55 (m, 2H) TLC: Rf = 0.75 (n-hexane: ethyl acetate = :) Reference Example 28 The disilyl compounds obtained in Reference Examples 25 to 27 were deprotected in the same manner as in Example 11. .

The NMR spectrum is shown below.

(Δppm, CDCl ₃ ) 0.9 (m, 3H), 1.0 to 2.5 (m, 28H), 0.3 (m, 1H), 3.7 (s, 3H), 3.0 to 4.1 (m, 2H), 5.3 (m, 1H ), 5.55 (m, 2H) 0.9 (m, 3H), 1.1 (s, 3H), 1.2 to 2.5 (m, 24H), 3.0 (m, 1H), 3.65 (s, 3H), 3.8 to 4.0 (m, 1H), 5.3 (m, 1H), 5.55 (m, 1H) 1.0 to 2.5 (m, 25H), 3.0 (m, 1H), 3.7 (s, 3H), 3.7 to 4.1 (m, 2H), 5.3 (m, 1H), 5.55 (m, 1H) Reference Example 29 After adding 90 ml of dry methanol to 3.31 g (0.14 gram atom) of metallic magnesium and stirring at room temperature under a nitrogen atmosphere, 11.9 g (13.6 mmol) of bissulfone compound (2) in dry methanol (180
ml) solution was added. The mixture was stirred while warming in an oil bath, and when the solvent began to reflex, the oil bath was removed, and the mixture was stirred at room temperature for 30 minutes while allowing the solvent to reflex naturally. 450 ml of saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (2 x 600 ml). The combined organic layers were washed with saturated aqueous potassium hydrogen sulfate solution (300 ml), saturated aqueous sodium hydrogen carbonate solution (300 ml) and saturated brine (300 ml), and dried over magnesium sulfate. After distilling off the solvent, the obtained crude product (8.23 g) was separated and purified by silica gel column chromatography to give hexane-ethyl acetate = 9: 1 in an eluate of 6.5.
2 g (yield 81%) of the desulphonated product (27) was obtained.

Spectral data 0.8 ~ 1.0 (21H), 2.88 (1H, m), 3.67 (3H, s), 3.74 (1H, m), 4.06 (1H, br), 5.25 (1H, brs), 5.48 (2H, m)

Front Page Continuation (72) Inventor Kiyoshi Sakauchi 4-3 Asahigaoka, Hino City, Tokyo Teijin Ltd. Biomedical Research Institute (72) Inventor Seiji Kurosumi 4-3 Asahigaoka, Hino City, Tokyo Teijin Limited Company Biomedical Research Institute (56) Reference JP-A-63-77853 (JP, A)

Claims (2)

[Claims] 1. The following formula [II] And a compound represented by the following formula [IV-b] 3-methylene-2,6,7-trisubstituted bicyclo [3.3.0] -octane, which is a compound represented by the formula, its enantiomer, or a mixture thereof at any ratio, in the presence of a palladium compound And a deprotection reaction and a hydrolysis reaction, if necessary, of the following formula [I] A process for producing an isocarbacycline, which is a compound represented by the formula (1), an enantiomer thereof, or a mixture thereof at any ratio. 2. The following formula [II] And a compound represented by the following formula [III-b] 3,6,7-trisubstituted bicyclo [3.3.
[0] -2-octenes are regiospecifically reacted in the presence of a palladium compound, and a deprotection reaction and a hydrolysis reaction are carried out as necessary, and the following formula [I] A process for producing an isocarbacycline, which is a compound represented by the formula (1), an enantiomer thereof, or a mixture thereof at any ratio.