JPH0455422B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to novel isocarbacyclines and a method for producing the same. More specifically, 9(0)-methano-△ ^{6(9〓 )} -prostaglandin ₁ in which the oxygen atom at position 6.9 of prostaglandin ₁ is substituted with a methylene group (-HC=)
It is a synthetic intermediate of (isocarbacycline),
The present invention also relates to novel isocarbacycline derivatives and methods for their production. <Prior art> Prostaglandin is a local hormone produced mainly on the inner wall of arteries in living bodies.
Its strong physiological activities include platelet aggregation inhibitory activity,
Prostacyclin is an important factor that regulates cell functions in the living body through its vasodilatory activity, etc., and attempts are being made to provide it directly as a drug [Clinical Pharmacology of Prostacyclin]
Raven Press, NY, 1981]. However, natural prostacyclin has an enol ether bond in its molecule that is highly susceptible to hydrolysis, so it is easily deactivated under neutral or acidic conditions.
As a drug, it is not a desirable compound due to its chemical instability. For this reason, chemically stable synthetic prostacyclin derivatives that have physiological activities similar to natural prostacyclin have been intensively investigated at home and abroad. Among them, derivatives in which the oxygen atoms at the 6 and 9 positions of prostacyclin are substituted with methylene groups, that is, 9
(0)-Methanoprostacyclin (carbacyclin) is known as a prostacyclin with sufficient chemical stability [Prostacyclin, JRVane and S.
Bergstrom, Eds.Raven Press, NYpp31−41
Reference] It is expected to be used as a medicine. However, the biological activity of this 6,9(0)-methanoprostacyclin is weaker than that of natural prostacyclin.
Moreover, its selectivity of action cannot be said to be specific, and it cannot necessarily be said that it is a preferable compound. In recent years, isocarbacycline, a type of double bond isomer of carbacycline, i.e. 9
It has been discovered that (0)-methano-△ ^{6(9〓 )} -prostaglandin ₁ exhibits the strongest platelet aggregation inhibitory effect among these congeners, and its application as a pharmaceutical has been anticipated [ Ikegami et al. Tetrahedron Lett., 24 , 3493
(1983), Japanese Unexamined Patent Publication No. 137445/1983]. Conventionally, the following methods are known for producing 9(0)-methano- ^{Δ6(9〓 )} -prostaglandin ₁ (isocarbacycline). (1) Ikegami et al., Tetrahedron Letters., 24 , 3493 (1983) and Chemistry Letters.
Letters), 1984 , 1069: (2) Ikegami et al., Tetrahedron Letters, 24, 3497 (1983): (3) Ikegami et al., Journal of the Chemical
J.Chem.Soc., Chemical
Communications), 1984 , 1602: (4) Shibasaki et al., Tetrahedron Letters, 25, 5087 (1984): (5) Shibasaki et al., Tetrahedron letters, 25 , 1067 (1984): (6) Kojima et al. Chemical and Pharmaceutical Bulletin (Chem.Pharm.Bull),
32, 2866 (1984): (7) Kojima et al. JP-A No. 60-28943: Among these seven methods, method (1) and method (5) are
This process uses PGE ₂ as a starting material, leads to a key intermediate through several steps, and obtains the target isocarbacycline through several more steps, so it cannot be described as an industrial manufacturing method. In addition, both methods (2) and (3) require a multi-step process from expensive Corey lactone to obtain the corresponding starting materials and key intermediates, the total yield is not high, and they are not necessarily suitable for industrial use. The disadvantage is that it is not a financially advantageous method. Furthermore, method (6) and method
In method (7), the final product can only be obtained in the dl form, and is therefore not preferred as a manufacturing method intended for pharmaceutical production. Finally, in method (4), the starting material is optically active R-4-hydroxy-2-
Not only can it be easily obtained from cyclopentenone (Japanese Unexamined Patent Publication No. 57-155116), it can also be produced from the starting material into a key intermediate without any industrial problems. However, in the process from key intermediates to the final isocarbacyclines, there are many difficulties such as the use of organic mercury compounds, loss of regiospecificity, and contamination by non-separable by-products. There is a major drawback in that the total yield is low and it cannot be used as a practical or industrial production method. <Object of the invention> The present inventors have focused on the above-mentioned points and have developed 9(0)-
The present invention was achieved as a result of intensive research to discover methanol- ^{Δ6(9〓 )} -prostaglandin ₁ (isocarbacyclines) and a method for producing the same. <Structure and effects of the invention> That is, in the present invention, the following formula [] [In the formula, R ¹ represents a hydrogen atom or a C ₁ to _{C 4} alkyl group or alkenyl group; R ² and R ³ are the same or different, and are a hydrogen atom, a tri(C ₁ to _{C 7} ) hydrocarbon silyl group, or represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group: R ⁴ represents a hydrogen atom, methyl group, or vinyl group: R ⁵ represents a straight or branched chain C ₃ to C that may contain an oxygen atom ₉ Alkyl group, alkenyl group or alkynyl group; phenyl group optionally substituted with a halogen atom, C ₁ - C ₆ alkoxy group or C ₁ - C ₄ alkyl group; halogen atom, C ₁ -
Phenoxy group optionally substituted with a C ₆ alkoxy group or a C ₁ to C ₄ alkyl group; a phenoxy group optionally substituted with a halogen atom, a C ₁ to _{C 6} alkoxy group, or a C ₁ to C ₄ alkyl group Good _C3 - _C10 cycloalkyl group; or () _C1 - _C6 alkoxy group,
() Halogen atom, C ₁ to C ₆ alkoxy group, or
A phenyl group optionally substituted with a C ₁ to C ₄ alkyl group, () a halogen atom, a C ₁ to _{C 6} alkoxy group, or a phenoxy group optionally substituted with a C ₁ to C ₄ alkyl group, or () Straight chain or branched C ₁ that is substituted with a halogen atom, a C ₃ to _{C 10} cycloalkyl group which may be substituted with a C ₁ to C ₆ alkoxy group, or a C ₁ to C ₄ alkyl group
- represents a _C5 alkyl group: n represents 0 or 1: Ar represents a phenyl group which may be substituted with a _C1 - _C4 alkyl group. ] A novel isocarbacycline which is a compound represented by the above, its enantiomer, or a mixture thereof in any proportion, and a method for producing the same. In the above formula [], R ¹ is a hydrogen atom or C ₁ ~
Represents a _C4 alkyl group or alkenyl group.
The C ₁ to _{C 4} alkyl group of R ¹ includes a methyl group, an ethyl group, a propyl group, a butyl group, etc.
Examples of the alkenyl group include a 2-propene group and a 3-butene group, and among these, a methyl group and a 2-propene group are preferred. In the above formula [], R ² and R ³ are the same or different and represent a group that forms an acetal bond with a hydrogen atom, a tri(C ₁ -C ₇ ) hydrocarbon silyl group, or an oxygen atom of a hydroxyl group. As a tri(C ₁ - C ₇ ) hydrocarbon silyl group,
For example, tri(C1 _- C4)alkylsilyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, and t-butyldimethylsilyl; diphenyl(C1- _C4 ) such as _t -butyldiphenylsilyl; Preferred examples include a _C4 ) alkylsilyl group; a di( _C1 - _C4 )alkylphenyl group such as a dimethylphenyl group; and a tribenzylsilyl group. Among these, tri(C ₁ - C ₄ ) alkylsilyl group,
Diphenyl( _C1 - _C4 )alkylsilyl group and phenyldi( _C1 - _C4 )alkylsilyl group are preferred,
Among them, t-butyldimethylsilyl group and trimethylsilyl group are particularly preferred. Groups that form an acetal bond with the oxygen atom of a hydroxyl group include, for example, a methoxymethyl group, a 1-ethoxyethyl group, and a 2-methoxy-2-
Propyl group, 2-ethoxy-propyl group, (2-
methoxyethoxy)methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, or 6,6-dimethyl-
Mention may be made of the 3-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,
Particularly preferred is the 6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hex-4-yl group. Among them, 2-tetrabidropyranyl group is particularly preferred. It is to be understood that these silyl groups and groups forming acetal bonds are hydroxyl protecting groups. These protecting groups can be easily removed in the final product stage under mildly acidic to neutral conditions to form free hydroxyl groups useful as pharmaceuticals. In the above formula [], R ⁴ represents a hydrogen atom, a methyl group, or a vinyl group. In the above formula [], R ⁵ is a linear or branched C ₃ to C ₉ alkyl group, alkenyl group, or alkynyl group that may contain an oxygen atom; a halogen atom, a C ₁ to _{C 6} alkoxy group, or _C1 ～ _C4
a phenyl group which may be substituted with an alkyl group; a halogen atom, a _C1 -C6 alkoxy group or a _C1 - _C6 alkoxy group;
Phenoxy group optionally substituted with a _C4 alkyl group; C3- _C10 cycloalkyl group optionally substituted with a halogen atom, a _C1 - _C6 alkoxy group, or a _{C1 -C4 alkyl} group ; or ()C ₁ ~
C ₆ alkoxy group, () halogen atom, phenyl group optionally substituted with a C ₁ to C ₆ alkoxy group or C ₁ to _{C 4} alkyl group, () halogen atom,
A phenoxy group or () halogen atom, which may be substituted with a C ₁ - C ₆ alkoxy group or a C ₁ - C ₄ alkyl group, a C ₁ - _{C 6} alkoxy group or a C ₁ - _{C 4} alkyl group May be replaced
It represents a straight-chain or branched C1- _C5 alkyl group substituted with a _{C3 - C10} cycloalkyl group. Examples of the straight chain or branched C ₃ -C ₉ alkyl group, alkenyl group or alkynyl group which may contain an oxygen atom include 2-methoxyethyl group, 2-methoxyethyl group,
-Ethoxyethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-rutyl-2-hexyl group, 2-methylbutyl group, 2-methylpentyl group, 2-methylhexyl group , 2,2-dimethylhexyl group, 4-hexyn-1-yl group, 4-hexyn-2-yl group, 3-pentyn-1-yl group, 4-heptyn-
2-yl group, 5-heptene-2,6-dimethyl-
Examples include 1-yl group. Butyl group, pentyl group, hexyl group, heptyl group, 2-
hexyl group, 2-methyl-2-hexyl group, 2-
Methylbutyl group, 2-methylpentyl group, 4-hexyn-1-yl group, 4-hexyn-2-yl group, 3-pentyn-1-yl group, 4-peptin-
2-yl group, 5-heptene-2,6-dimethyl-
A 1-yl group is preferred. Substituted phenyl group, substituted phenoxy group, and _C3
As substituents for the ~ _C10 substituted cycloalkyl group,
For example, halogen atoms, protected hydroxyl groups (e.g. silyloxy groups, C ₁ - _{C 6} alkoxy groups, etc.), C ₁
~ _C4 alkyl group, etc. Examples of the _C3 to _C10 cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, a cycloheptyl group, a cyclooctyl group, and a cyclodecyl group. Among these, cyclopentyl group and cyclohexyl group are preferred. A linear or branched chain substituted with a C ₁ to C ₆ alkoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C ₃ to _{C 10} cycloalkyl group. In the branched chain _C1 - _C5 alkyl group, examples of the _C1 - _C6 alkoxy group include a methoxy group, an ethoxy group,
Examples include propyloxy group, isopropyloxy group, butoxy group, t-butoxy group, hexyloxy group, and the like. The substituents 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 include the above-mentioned examples. The same thing can be mentioned. Examples of straight-chain or branched _C1 - _C5 alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,
Examples include sec-butyl group, t-butyl group, and pentyl group. Such R ⁵ includes butyl group, pentyl group, hexyl group, peptyl group, 2
-hexyl group, 2-methyl-2-hexyl group, 2
-Methylbutyl group, 2-methylpentyl group, cyclopentyl group, cyclohexyl group, phenyl group,
Preferred examples include a phenoxy group, a cycumopentylmethyl group, and a cyclohexylmethyl group. Note that the substituent may be bonded to any position thereof. In the above formula [], n represents 0 or 1. Ar represents a substituted or unsubstituted phenyl group, and examples of the substituent include those mentioned above, preferably phenyl group, p-tolyl group, etc. In addition, in the compound represented by the above formula [], the carbon to which the bicyclo[3.3.0]octane ring itself and the substituent bonded to the bicyclo[3.3.0]octane ring; the hydroxyl group on the ω chain are Although stereoisomers exist due to the asymmetric environment of the substituted carbon, the present invention includes any stereoisomers, and mixtures of these stereoisomers in arbitrary proportions are also acceptable. Among these, compounds having the steric structure represented by the formula are most preferred. 3,6,7-trisubstituted bicyclo[3.3.0]-2 represented by the above formula [] provided in the present invention
Specific examples of preferred -octenes include the compounds shown below. (1) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-1-
octenyl]-7-hydroxybicyclo[3.3.0]-2-octene(2) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6- [(E,3S)-3-hydroxy-1-
nonenyl]-7-hydroxybicyclo[3.3.0]
-2-octene(3) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-4 −
Methyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene(4) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl )-6-[(E,3S)-3-hydroxy-4,
4-dimethyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene(5) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenyl sulfonylbutyl)-6-[(E,3S)-3-hydroxy-5-
Methyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene(6) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl )-6-[(E,3S)-3-hydroxy-5-
Methyl-1-nonenyl]-7-hydroxybicyclo[3.3.0]-2-octene (7) (6) 6-[(E,3S,5S)...] form (8) (6) 6- [(E, 3S, 5S)...] body (9) (1S, 5S, 6S, 7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E, 3S)-3-hydroxy-3-
cyclopentyl-1-propenyl]-7-hydroxybicyclo[3.3.0]-2-octene(10) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl )-6-[(E,3S)-3-hydroxy-3-
cyclohexyl-1-propenyl]-7-hydroxybicyclo[3.3.0]-2-octene(11) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl )-6-[(E,3S)-3-hydroxy-3-
cyclohexyl-1-butenyl]-7-hydroxybicyclo[3.3.0]-2-octene(12) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl )-6-[(E,3S)-3-hydroxy-5-
phenoxy-1-pentenyl]-7-hydroxybicyclo[3.3.0]-2-octene(13) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl )-6-[(E,3S)-3-hydroxy-5-
ethoxy-1-pentenyl]-7-hydroxybicyclo[3.3.0]-2-octene(14) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl )-6-[(E,4S)-4-hydroxy-4-
Methyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene(15) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl )-6-[(E,4R)-4-hydroxy-4-
Methyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene(16) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl )-6-[(E)-4-hydroxy-4-vinyl-1-octenyl]-7-hydroxybicyclo[3.3.0]-2-octene(17) (1S,5S,6S,7R)-3- (4-Carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E)-3-hydroxy-1-hepten-7-yn-1-yl]-7-hydroxybicyclo[3.3.0] -2-octene(18) (1S,5S,6S,7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-6-[(E)-3-hydroxy-1-octene -6-yn-1-yl]-7-hydroxybicyclo[3.3.0]-2-octene (19) (1) to (18) 3-(4-carbomethoxy-1-
p-trisulfonylbutyl) compound (20) Compound (21) in which the methyl ester of (1) to (19) is a carboxylic acid Compound (22) (1) in which the methyl ester of (1) to (19) is an allyl ester ) to (21) in which the 7-position hydroxyl group and the 6-position hydroxyl group on the substituent are protected with a t-butyldimethylsilyl group. (23) A compound in which the hydroxyl groups on the 7- and 6-position substituents of (1) to (21) are protected with a 2-tetrahydropyranyl group. (24) Enantiomers of the compounds (1) to (23). (25) 1st, 5th, 6th, and 7th positions of compounds (1) to (23)
Examples include stereoisomers of asymmetric carbon atoms substituted with hydroxyl groups on the substituents at the position and the 6th position, but are not limited thereto. The new isocarbacyclines represented by the above formula [] are the following formula [] [In the formula, R ¹¹ represents a C ₁ to C ₄ alkyl group or alkenyl group, and Ar is the same as defined above. ] The compound represented by is treated with a base, and then the following formula [] [However, in the formula, R ²¹ and R ³¹ are the same or different and represent a tri(C ₁ to _{C 7} ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group: R ⁴ , R ⁵ and n is the same as the above definition. ] In the presence of a palladium compound, 3,6,7-trisubstituted bicyclo[3.3.0]-2-octenes, which are the compound represented by the formula, its enantiomer, or a mixture thereof in any proportion, are subjected to regiospecific treatment. react to,
It can be obtained by performing a deprotection reaction and a hydrolysis reaction as necessary. Similarly, the novel isocarbacycline represented by the above formula [] is the following formula [] [In the formula, R ¹¹ and Ar are the same as defined above. ] A compound represented by the following formula [] is treated with a base, and then the following formula [] [In the formula, R ²¹ , R ³¹ , R ⁴ , R ⁵ and n are the same as defined above. ] 3-methylene- which is a compound represented by, its enantiomer, or a mixture thereof in any proportion
It can be obtained by reacting 2,6,7-trisubstituted bicyclo[3.3.0]-octanes in a position-specific manner in the presence of a palladium compound, and further carrying out a deprotection reaction and a hydrolysis reaction as necessary. In the bisarylsulfonyl compound represented by the above formula [], which is a raw material for this reaction, R ¹¹ is C ₁
~ _C4 alkyl group or alkenyl group. As such a group, the same group as the alkyl group or alkenyl group exemplified as R ¹ in the above formula [] can be mentioned as a preferable group, but
Particularly preferred is a methyl group. In the above formula [], Ar represents a substituted or unsubstituted phenyl group. Examples of such a group include the same groups as those exemplified as Ar in the formula [] above, with phenyl group and p-tolyl group being particularly preferred. In the allyl acetate represented by the above formula [] or [], which is the other raw material for this reaction, R ²¹ and R ³¹ are the same or different, and the oxygen of the tri(C ₁ - _{C 7} ) hydrocarbon silyl group or hydroxyl group Represents a group that forms an acetal bond with an atom. As the group that forms an acetal bond with the oxygen atom of the tri(C ₁ -C ₇ ) hydrocarbon silyl group or hydroxyl group, the same groups as exemplified for R ² or R ³ in the above formula [] are preferred. be able to. In the above formula [] or [], R ⁴ represents a hydrogen atom, a methyl group, or a vinyl group, and R ⁵
is a linear or branched C ₃ -C ₉ alkyl group which may contain an oxygen atom; halogen atom, C ₁ -C ₆
a phenyl group optionally substituted with an alkoxy group or a C ₁ to C ₄ alkyl group; a halogen atom,
a phenoxy group optionally substituted with a _C1 - _C6 alkoxy group or a _C1 - _C4 alkyl group; a phenoxy group optionally substituted with a halogen atom, a _C1 - _C6 alkoxy group, or a _C1 - _C4 alkyl group; an optionally _C3 - _C10 cycloalkyl group; or () a _C1 - _C6 alkoxy group;
() Halogen atom, C ₁ to C ₆ alkoxy group, or
A phenyl group optionally substituted with a _C1 - _C4 alkyl group, () a halogen atom, a _C1 - _C6 alkoxy group, or a phenoxy group optionally substituted with a _C1 - _C4 alkyl group, or () Straight chain or branched chain C 1 substituted with a C ₃ - _{C 10} cycloalkyl group optionally substituted with a halogen atom, a C _{1 -C 6} alkoxy group, or a C ₁ -C ₄ alkyl group
˜C ₅ alkyl group, preferably the same as those exemplified for R ⁵ in formula [] above. In the group [] or [], n is 0 or 1
represents. The 3,6,7-trisubstituted-bicyclo[3.3.0]-2-octenes represented by the formula [] are described, for example, in Shibasaki et al., Tetrahedron Letters, 25 , 5087 (1984). It is manufactured in the same manner as described above, and the manufacturing process is briefly introduced as shown in the following process diagram. That is, This is the manufacturing process. 3-methylene-2, represented by the formula []
6,7-trisubstituted bicyclo[3.3.0]-octanes are produced by two methods separately proposed by the present inventors. That is, it is produced by the method described in the above cited document (Tetrahedron Letters, 25 , 5087 (1984)) and a method analogous thereto. 6,
Synthetic route starting from 7-disubstituted-3-hydroxymethylbicyclo[3.3.0]-2-octenes (route A) or optically active 4-hydroxy-2-cyclopentenone as starting material. It is obtained by a cyclization reaction (route B) of an acetylene derivative obtained by The reaction route is briefly shown below. The reaction of leading the acetate represented by the above formula [] or [] to the 4,4-bisarylsulfonylisocarbacycline represented by the above formula [] is performed by treating the bisarylsulfonyl compound represented by the above formula [] with a base. This reaction is carried out by reacting the obtained product with an acetate represented by the above formula [] or [] in the presence of palladium. The bisarylsulfonyl compound represented by the above formula [] is a bisaryl sulfonyl compound represented by the above formula [] or []
0.5 to 30 equivalents to the acetates represented by
Preferably 1 to 5 equivalents are used. The base used in the reaction with the bisarylsulfonyl compound is an organic alkali metal or an alkali metal hydride, such as n-butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, methyllithium, naphthyllithium, Trityllithium, lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, etc. are used, but sodium hydride is preferably used. The amount of the base used is 0.5 to 30 equivalents, preferably 1 equivalent to the bisarylsulfonyl compound represented by the above formula [].
~10 equivalents are used, but in principle 1 equivalent is used. The reaction temperature of such salt-forming reaction is −100°C to 100°C.
℃, preferably -78℃ to 2℃, 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, and the solvents used include ether solvents such as ether, tetrahydrofuran, and dioxane, hydrocarbon solvents such as n-hexane and benzene, and other solvents such as DMF and DMSO.
Ether and tetrahydrofuran are preferably used. The alkali metal salt of the bisarylsulfonyl compound thus obtained is reacted with allyl acetate represented by the above formula [] or [] in the presence of palladium. The reaction can proceed without isolating the alkali metal salt of the bisarylsulfonyl compound by adding the compound of the above formula [] or [] as it is. This reaction is carried out in the presence of palladium, and the palladium compound used can be, for example, various palladium complexes described in Shin Jikken Kagaku Koza ( 12 , 230-243), and is preferably tetrakis(triphenylphosphine)palladium. (O), bis[bis(1,2-diphenylphosphine)-ethane]palladium (O), and bis[bis(1,3-diphenylphosphine)-propane]palladium (O). It is not limited. The amount used is 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalent, relative to the acetate compound represented by the above formula [] or []. The reaction temperature at this time is -30°C to 200°C, preferably 0°C to
The reaction time is 10 minutes to 100 hours, preferably 1 hour to 24 hours. The reaction is carried out in an organic solvent, but the same solvent used in the previous salt-forming reaction can be used. The reaction solution thus obtained may be post-treated according to a commonly used method. For example, an organic mixture obtained by adding a sparingly soluble organic solvent to water such as hexane, pentane, ethyl ether, or ethyl acetate is washed with brine as necessary, and then treated with a drying agent such as anhydrous magnesium sulfate or anhydrous sodium sulfate. After drying, the organic solvent is removed under reduced pressure to obtain a crude composition. The crude composition can be purified by purification means such as column chromatography, thin layer chromatography, liquid chromatography, etc., if desired. Next, the obtained product is subjected to deprotection reaction and hydrolysis as necessary, whereby the reaction proceeds in a position-specific manner and finally a novel isocarbacycline represented by the above formula [] is obtained. When the protecting group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, the protective group of the hydroxyl group can be removed using a catalyst such as acetic acid, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin. , tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile, etc. as the reaction solvent.
The reaction usually takes place in the temperature range of -78°C to +30°C for 10 minutes to 3
It is held for about a day. In addition, the protecting group is tri(C ₁
~ _C7 ) In the case of a hydrocarbon silyl group, for example, acetic acid, tetrabutylammonium fluoride, cesium fluoride, hydrogen fluoride water, pyridine-
It is carried out in the presence of aqueous hydrogen fluoride, in a reaction solvent as described above, at a similar temperature and for a similar period of time. Hydrolysis of esters is carried out by the usual method, i.e. lithium hydroxide, sodium hydroxide, potassium hydroxide in water or a water-containing solvent at -40°C to 100°C;
The reaction is preferably carried out at a temperature range of 0°C to 50°C for 10 minutes to 24 hours. In this way, a compound represented by the above formula [] having an isocarbacycline skeleton is produced. In the production method of the present invention, (1) Starting materials that are industrially easily available are used. (2) The skeleton synthesis according to the method of the present invention proceeds in a position-specific manner and has a high yield. It has the following advantages. Furthermore, the novel isocarbacyclines obtained by the present invention are expected to have isocarbacycline-like activities such as platelet aggregation inhibiting action, vasodilatory action, antihypertensive action, and cytoprotective action. It is also a useful compound as an intermediate for the synthesis of isocarbacycline, which is considered a promising drug. EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto. In addition, -OZ- in the examples -OSi ^t Bu・Me ₂ (t
-butyldimethylsilyloxy group). <Example> Example 1 Methyl-4,4-bis(phenylsulfonyl)
44 mg (1.1 mmol) of NaH (60% in oil) in a 2 ml THF solution of 400 mg (1.05 mmol) butanoate under a nitrogen stream
was added at 0°C and stirred for 1 hour. Here, the above formula (1)
A 2 ml THF solution of 450 mg (0.82 mmol) of the acetate represented by is added, and bis[bis(1,2
-diphenylphosphino)-ethane] palladium (O) 80 mg (0.09 mmol) was added, 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. The crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 20:1 → 10:1), 4.
493 mg (70%) of 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 ~ 2.4 (m, 14H), 2.6 ~ 3.1 (m, 7H), 3.7 (s, 3H) , 3.75 (m, 1H), 4.05 (m, 1H), 5.4 (m, 2H), 5.55 (m, 1H), 7.1~8.0 (m, 10H) Example 2 Methyl-4,4-bis(phenylsulfonyl)
Butanoate 59 mg (1.05 mmol) in 0.8 ml THF solution with 6.2 mg (0.15 mmol) NaH (60% in oil) under nitrogen stream
was added at 0°C and stirred for 1 hour. Here, the above formula (3)
0.8 of 68 mg (0.12 mmol) of acetate expressed as
Add mlTHF solution and then add bis[bis(1,2
-diphenylphosphino)ethane] 6.3 mg (0.007 mmol) of palladium (O) was added, and the mixture was heated at room temperature for 3 hours.
The mixture was stirred at 60°C 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 composition was subjected to silica gel column chromatography (hexane: ethyl acetate = 20:1 → 10:1),
64 mg (59
%), 23 mg (34%) of recovered acetate was obtained. The spectrum completely matched that of Example 1. Example 3 87 mg (0.10 mmol) of the disilyl compound (2) was dissolved in 2 ml of dry tetrahydrofuran (2 ml), 470 μ (0.47 mmol) of tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at room temperature for 10 hours. Water was added, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The product was subjected to silica gel column chromatography (ethyl acetate, 2% methanol) to obtain 51 mg (79%) of the desilylated product (4). NMR (δppm, _CDcl3 ); 0.9 (m, 3H), 1.2-2.4
(m, 14H), 2.6-3.1 (m, 7H), 3.65 (s,
3H), 3.65-4.05 (m, 2H), 5.4 (m, 2H),
5.55 (m, 1H), 7.1~8.0 (m, 10H) Example 4 NaH8.8mg (60% in oil, 0.22mmol) under nitrogen stream
1 ml of 84 mg (0.22 mmol) of methyl-4,4-bis(phenylsulfonyl)butanoate treated with
Acetate 116 represented by the above formula (5) in THF solution
mg (0.2 mmol) in 1 ml THF 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, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (hexane:ethyl acetate = 20:1 → 10:1), and 17(S), 20-
Dimethyl-4,4-bis(phenylsulfonyl)
128 mg (71%) of isocarbacycline disilylether, methyl ester (6) was obtained. NMR (δppm, _CDcl3 ): 0.9 (s+m.12H), 1.0~
2.4 (m, 18H), 2.6-3.1 (m, 7H), 3.65 (s,
3H), 3.7-4.1 (m, 2H) 5.3-5.6 (m, 3H),
7.1~8.0 (m, 10H) Example 5 NaH6.8mg (60% in oil, 0.17mmol) under nitrogen stream
1 ml of 65 mg (0.17 mmol) of methyl-4,4-bis(phenylsulfonyl)butanoate treated with
To the THF solution, 78 mg (0.15 mmol) of acetate represented by the above formula (7) was added to 1 ml of THF solution, and then bis[bis(1,2-diphenylphosphino)
7.2 mg (0.008 mmol) of palladium (O) was added thereto, and the mixture was stirred at 80°C for 10 hours. During the 5th hour, 7.2 mg (0.008 mmol) of the above palladium (O) was added.
added. 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), and the resultant (8)
Obtained 92 mg (73%). NMR ( _δppmCDcl3 ); 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~
5.6 (m, 3H), 7.1~8.0 (m, 10H) Example 6 NaH9mg (0.23mmol, 60% in oil) in nitrogen atmosphere
1 ml of 84 mg (0.22 mmol) of methyl-4,4-bis(phenylsulfonyl)butanoate treated with
To the THF solution, add 1 ml DMF solution of 110 mg (0.2 mmol) of the acetate represented by the above formula (9),
Next, 9 mg (0.01 mm
ol) and 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 grade material (10). NMR ( _δppmCDcl3 ); 0.9 (s, 18H), 1.0-2.4
(m, 15H), 2.6~3.0 (m, 7H), 3.70 (s,
3H), 3.6-4.1 (m, 2H), 5.3-5.6 (m,
3H), 7.1~8.0 (m, 10H)

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ represents a hydrogen atom or a C ₁ to _{C 4} alkyl group or alkenyl group; R ² and R ³ are the same or different, and are a hydrogen atom, a tri(C ₁ to _{C 7} ) hydrocarbon silyl group, or represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group: R ⁴ represents a hydrogen atom, methyl group, or vinyl group: R ⁵ represents a straight or branched chain C ₃ to C that may contain an oxygen atom ₉ Alkyl group, alkenyl group or alkynyl group; phenyl group optionally substituted with a halogen atom, C ₁ - C ₆ alkoxy group or C ₁ - C ₄ alkyl group; halogen atom, C ₁
- a phenoxy group optionally substituted with a _C6 alkoxy group or a _C1 - _C4 alkyl group; a phenoxy group optionally substituted with a halogen atom, a _C1 - _C6 alkoxy group, or a _C1 - _C4 alkyl group; optional _C3 - _C10 cycloalkyl group; or substituted with () _C1 - _C6 alkoxy group, ()halogen atom, _C1 - _C6 alkoxy group or _C1 - _C4 alkyl group; phenyl group, () halogen atom, C ₁ - C ₆ alkoxy group, or phenoxy group optionally substituted with a C ₁ - _{C 4} alkyl group, or () halogen atom, C ₁ - _{C 6} alkoxy group or represents a straight chain or branched C1 _{- C5} alkyl group substituted with a _C3 - _C10 cycloalkyl group optionally substituted with a _C1 - _C4 alkyl group: n is 0 or 1 represents: Ar represents a phenyl group which may be substituted with a _C1 to _C4 alkyl group. ] An isocarbacycline which is a compound represented by these, its enantiomer, or a mixture thereof in any proportion. 2 The following formula [] [In the formula, R ¹¹ represents a C ₁ to C ₄ alkyl group or an alkenyl group, and Ar represents a phenyl group which may be substituted with a C ₁ to _{C 4} alkyl group. ] The compound represented by is treated with a base, and then the following formula [] [In the formula, R ²¹ and R ³¹ are the same or different,
Represents a tri(C ₁ - C ₇ ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group: R ⁴ represents a hydrogen atom, methyl group or vinyl group: R ⁵ does not contain an oxygen atom Straight-chain or branched _C3 - _C9 alkyl, alkenyl or alkynyl group which may be substituted with a halogen atom, a _C1 - _C6 alkoxy group or a _C1 - _C4 alkyl group Phenyl group; halogen atom, C ₁ ~
Phenoxy group optionally substituted with a C ₆ alkoxy group or a C ₁ to C ₄ alkoxy group; a phenoxy group optionally substituted with a halogen atom, a C ₁ to _{C 6} alkoxy group, or a C ₁ to _{C 4} alkyl group Good _C3 - _C10 cycloalkyl group; or () _C1 - _C6 alkoxy group,
() Halogen atom, C ₁ to C ₆ alkoxy group, or
A phenyl group optionally substituted with a C ₁ to C ₄ alkyl group, () a halogen atom, a C ₁ to _{C 6} alkoxy group, or a phenoxy group optionally substituted with a C ₁ to C ₄ alkyl group, or () Straight chain or branched chain substituted with a halogen atom, a C ₃ - _{C 10} cycloalkyl group which may be substituted with a C ₁ - _{C 6} alkoxy group, or a C ₁ - C ₄ alkyl group
represents a _C1 - _C5 alkyl group; n represents 0 or 1; ] 3,6,7-trisubstituted bicyclo[3.3.0]-2-octenes, which are the compound represented by the formula, its enantiomer, or a mixture thereof in any proportion, are reacted in a position-specific manner in the presence of a palladium compound. The following formula [] is characterized by carrying out a deprotection reaction and a hydrolysis reaction as necessary. In the formula, R ¹ represents a hydrogen atom or a C ₁ to _{C 4} alkyl group or alkenyl group; R ² and R ³ are the same or different and represent a hydrogen atom, a tri(C ₁ to C ₇ ) hydrocarbon silyl group, or Represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group: R ⁴ , R ⁵ , Ar, and n are the same as defined above. ] A method for producing an isocarbacycline, which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion. 3 The following formula [] [In the formula, R ¹¹ represents a C ₁ to C ₄ alkyl group or an alkenyl group, and Ar represents a phenyl group which may be substituted with a C ₁ to _{C 4} alkyl group. ] The compound represented by is treated with a base, and then the following formula [] [In the formula, R ²¹ and R ³¹ are the same or different,
Represents a tri(C ₁ - _{C 7} ) hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group: R ⁴ represents a hydrogen atom, methyl group or vinyl group: R ⁵ contains an oxygen atom a straight-chain or branched _C3 - _C9 alkyl group, alkenyl group or alkynyl group which may be substituted with a halogen atom, a _C1 - _C6 alkoxy group or a _C1 - _C4 alkyl group; Group; halogen atom, C ₁
- a phenoxy group optionally substituted with a _C6 alkoxy group or a _C1 - _C4 alkyl group; a phenoxy group optionally substituted with a halogen atom, a _C1 - _C6 alkoxy group, or a _C1 - _C4 alkyl group; a _C3 - _C10 cycloalkyl group; or () a _C1 - _C6 alkoxy group;
() Halogen atom, C ₁ to C ₆ alkoxy group, or
A phenyl group optionally substituted with a C ₁ to C ₄ alkyl group, () a halogen atom, a C ₁ to _{C 6} alkoxy group, or a phenoxy group optionally substituted with a C ₁ to _{C 4} alkyl group, or () Straight chain or branched chain substituted with a halogen atom, a C ₁ to C ₆ alkoxy group, or a C ₃ to _{C 10} cycloalkyl group which may be substituted with a C ₁ to C ₄ alkyl group
represents a _C1 - _C5 alkyl group; n represents 0 or 1; ] 3-methylene- which is a compound represented by, its enantiomer, or a mixture thereof in any proportion
The following formula is characterized in that 2,6,7-trisubstituted bidiclo[3.3.0]-octanes are reacted positionally in the presence of a palladium compound, and further a deprotection reaction and a hydrolysis reaction are performed as necessary. [] [In the formula, R ¹ represents a hydrogen atom or a C ₁ to _{C 4} alkyl group or alkenyl group; R ² and R ³ are the same or different, and are a hydrogen atom, a tri(C ₁ to _{C 7} ) hydrocarbon silyl group, Or it represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group: R ⁴ , R ⁵ , Ar, and n are the same as defined above. ] A method for producing an isocarbacycline, which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion.