JPH0796506B2 - Bicyclo [3.3.0 octanes and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a novel bicyclo [3.3.0] octane and a method for producing the same. More in detail Prostaglandin I ₂
Relates to bicyclo [3.3.0] octanes, which are novel synthetic intermediates of isocarbacycline in which the oxygen atoms at the 6- and 9-positions are substituted with a methine group (-CH =), and a method for producing the same.

<Prior Art> Prostacyclin is a local hormone that is produced mainly in the inner wall of blood vessels of arteries in the living body, and is an important factor that regulates the cell function of the living body due to its powerful physiological activities such as platelet aggregation inhibitory activity and vasodilatory activity. There is an attempt 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 cannot be said to be a preferable compound because of its chemical instability as a drug. 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 methine group, that is, 9 (0) -methanoprostacyclin (carbacycline) is known as a prostacyclin that sufficiently satisfies chemical stability. [Prostacyclin, IRVaneand
See S. Bergstrom. Eds. Raven Press, NY p31-41] Expected as a drug. However, the biological activity of 9 (0) -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, which is one of the double bond isomers of carbacyclin, namely 9 (0) -methano-
It was discovered that ^{Δ6 (9α) -prostaglandin} I ₁ 's showed the most inhibitory action on platelet aggregation among these homologues,
Expected to be applied as a medicine [Ikegami et al., Tetrahedron Lett., 24, 3
493 (1983), JP-A-59-137445.

Regarding the production of such 9 (0) -methano-Δ ^{6 (9α) -prostaglandin} I ₁ (isocarbacycline), the following are known.

(1) Ikegami et al., Tetrahed
ron Letters), 24, 3493 ( 1983) and Chemistry
Chemistry Letters, 1984 , 1069: (2) Ikegami et al., Tetrahed
ron Letters), 24, 3493 ( 1983): (3) Ikegami et al., Journal of the Chemical Society, Chemical Communication (J.Che
m.Soc., Chemical Communications), 1984 , 1602: (4) Shibasaki et al., Tetrahed
ron Letters), 25, 5087 (1984): (5) Shibasaki et al., Tetrahed
ron Letters), 25 , 1067 (1984): (6) Kojima et al., Chemical and Pharmaceutical Bulletin (Chem.Pharm.Bull), 32 , 2866 (19
84): (7) Kojima et al. JP 60-28943 A: (8) Kurozumi et al., Tetrahed Letters
ron Letters), 27 , 6353 (1986): (9) Kurosumi et al., JP-A-63-77839, 7th IUPAC Co
nferenceon Organic Synthesis, Nancy.Jul. 4th-7th (1
988) Abstr. 4-A10: (10) Noyori et al .; Proceedings of the 53rd Autumn Meeting of the Chemical Society of Japan p4
99 (1986): (11) Hari et al., Proc. Of the 106th Annual Meeting of the Pharmaceutical Society of Japan p379
(1986): (12) Okamura et al. Proceedings of the 106th Annual Meeting of the Pharmaceutical Society of Japan p380
(1986): (13) Shibasaki et al., Tetrahedron Letters (Tetrahed
ron Letters), 25 , 5087 (1984): Are known.

Of these methods, method (1) and method (5) use PGE ₂ as a starting material, lead to a key intermediate through several steps, and then obtain the target isocarbacycline through several steps, which is industrial. It is hard to say that this is a simple manufacturing method.

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 is
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.

In the method (4), the starting material can be easily obtained from the optically active (R) -4-hydroxy-2-cyclopentenone by the method of the present inventors (JP-A-57-155116). This is also a method that can be used to industrially induce the key intermediate from the starting material without any problem. However, the process from the key intermediate to the final isocarbacyclines is long, and it cannot be a practical or industrial production method due to difficulties such as the use of organic mercury compounds and the incorporation of difficult-to-separate by-products. There is a drawback. The key intermediates of the methods (8) and (9) are the method of the present inventors (JP-A-62-61937) and the method of Shibasaki et al. [Tetrahedron Leders (Tetrahed).
ron Letters), 25 , 5087 (1984)] (R) -4-
Although it is a method obtained from hydroxy-2-cyclopentenone without any industrial problems, it is difficult to directly introduce a butane moiety in the process from the key intermediate to the isocarbacyclines, and the intermediate orthoester. It has the drawback that it has to be converted into isocarbacyclines via the body and the disulfone form. Further, the method (10) has a drawback that the stability and reproducibility of the process from the key intermediate to the isocarbacyclines are poor. The method (11) has a drawback that carbacyclin is by-produced during the production of the product isocarbacycline. Further, the method (12) can produce isocarbacycline from the starting material in the shortest number of steps, but the yield is low, and it cannot be said to be an industrially satisfactory method. Method ³⁵ is not a method that is industrially satisfactory because of low yield in the steps from the key intermediate to the isocarbacyclines.

<Disclosure of the Invention> The inventors of the present invention have reached the present invention as a result of intensive studies to find an efficient method for producing isocarbacyclines by paying attention to the above points.

That is, in the present invention, first, the following formula [Ia] [Wherein, R ³ represents a chlorine atom, a bromine atom or an iodine atom; R ⁴ and R ⁵ are the same or different, a hydrogen atom, a tri (C ₁ -C ₇ ) hydrocarbon silyl group, or R ⁴ , R ⁵ represents a group which forms an acetal bond or an ester bond together with the oxygen atom to which it is bonded; R ⁶ represents a hydrogen atom, a methyl group or a vinyl group; R ⁷ represents a linear or branched C _{3 to} C ₈ alkyl group; phenyl group; C _{3 to} C ₁₀ cycloalkyl group; or C _{1 to} C ₆ alkoxy group, phenyl group, phenoxy group or C _{3 to} C ₁₀ cycloalkyl group-substituted straight chain or Branched chain C _{1 to} C ₅
Represents an alkyl group; n represents 0 or 1.

A bicyclo [3.3.0] octane which is a compound represented by the formula, its enantiomer or any mixture thereof, and a process for producing the same are provided.

In the above formula [Ia], R ⁴ and R ⁵ are the same or different, and a hydrogen atom, a tri (C ₁ -C ₇ ) hydrocarbon silyl group, or R ⁴ and R ⁵ are the oxygen to which they are bonded. It represents a group that forms an acetal bond or an ester bond together with an atom (oxygen atom derived from a 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; Preferred examples include a diphenyl (C ₁ -C ₄ ) alkylsilyl group such as t-butyldiphenylsilyl group; a di (C ₁ -C ₄ ) alkylphenyl group such as dimethylphenyl group; or a tribenzylsilyl group. be able to. Of these, a tri (C ₁ -C ₄ ) alkylsilyl group, a diphenyl (C ₁ -C ₄ ) alkylsilyl group and a phenyldi (C ₁ -C ₄ ) alkylsilyl group are preferable, and a t-butyldimethylsilyl group,
A trimethylsilyl group is particularly preferred.

Examples of the group that forms an acetal bond with an oxygen atom derived from a hydroxyl group include, for example, methoxymethyl group, 1-ethoxyethyl group, 2-methoxy-2-propyl group, 2-ethoxy-2-propyl group, (2- (Methoxyethoxy) methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, or 6,6-dimethyl-3-oxa-2-oxobicyclo [3.3.0] hex-4-yl group Can be mentioned. 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy) methyl group, 6,6-dimethyl-3-oxa-2-
The oxobicyclo [3.3.0] hex-4-yl group is particularly preferred. Of these, a 2-tetrahydropyranyl group is particularly preferable.

Examples of the group that forms an ester bond with the oxygen atom derived from the hydroxyl group to which R ⁴ or R ⁵ is bonded include a formyl group,
(C ₁ -C ₅ ) alkanoyl groups such as acetyl group, propionyl group, butanoyl group, pentanoyl group; benzoyl group,
A substituted or unsubstituted benzoyl group such as a toluyl group may be mentioned. An acetyl group and a benzoyl group are particularly preferable.

In the above formula [Ia], R ⁶ represents a hydrogen atom, a methyl group, or a vinyl group.

In the above formula [Ia], R ⁷ is a linear or branched chain.
C ₃ -C ₁₀ alkyl group; a phenyl group: C ₃ -C ₁₀ cycloalkyl group; or C ₁ -C ₆ alkoxy group, a phenyl group, a straight-chain substituted with a phenoxy group or a C ₃ -C ₁₀ cycloalkyl group Moku represents a branched chain C ₁ -C ₅ alkyl group.

As the straight chain or branched chain C ₃ -C ₈ alkyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2 -Methylpentyl group, 2-methylhexyl group,
The 2,2-dimethylhexyl group is preferred.

The case where the phenyl group of R ⁷ and the C ₃ -C ₁₀ cycloalkyl group have a substituent is also shown as a reference example. Examples of the substituent include a halogen atom, a protected hydroxyl group (eg, silyloxy group, C _{1 to} C ₆ alkoxy group, etc.), C ₁
To C ₄ alkyl groups and the like. Examples of the C ₃ -C ₁₀ cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group,
Examples thereof include a cycloheptyl group, a cyclooctyl group, and a cyclodecyl group. Of these, a cyclopentyl group and a cyclohexyl group are preferable.

In a linear or branched C _{1 to} C ₅ alkyl group substituted with a C _{1 to} C ₆ alkoxy group, a phenyl group, a phenoxy group or a C _{3 to} C ₁₀ cycloalkyl group, as a C _{1 to} C ₆ alkoxy group Examples thereof include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group, a t-butoxy group and a hexyloxy group. In addition,
The case where the phenyl group, the phenoxy group, or the C _{3 to} C ₁₀ cycloalkyl group further has a substituent is also shown as a reference example. Examples of such substituents and C ₃ -C ₁₀ cycloalkyl groups are the same as those exemplified above.
Examples of the straight chain or molecular chain C _{1 to} C ₅ alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group and the like. You can Examples of R ⁷ include butyl group, pentyl group, hexyl group, heptyl group, 2
-Hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2-methylpentyl group, 2-methylhexyl group, cyclopentyl group, cyclohexyl group, phenyl group, phenoxy group, cyclopentylbutyl group, cyclohexylmethyl group, etc. Can be mentioned as a preferable example.
In addition, the substituent may be bonded to any position thereof.

In the above formula [Ia], n represents 0 or 1. n
When = 0, the following formula [I-a-1] [Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined above. ] The natural configuration of the ω chain represented by the formula [Ia-
2] [Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as defined above. ] One of the non-natural configurations of the ω chain represented by or a mixture thereof in any ratio. Among them, the natural configuration at the 15-position represented by the above formula [Ia-1] is preferable. Also in the case of n = 1, (R) -arrangement at 16th position, (S)
-Comprising configurations and mixtures thereof in any proportion.

The bicyclo [3.3.0] octanes represented by the above formula [Ia] are particularly useful stereoisomers because the configurations at 2-position, 6-position and 7-position are natural prostacyclin type. The invention also includes stereoisomers due to different steric configurations at each position or a mixture thereof in any ratio.

Preferred specific examples of the novel bicyclo [3.3.0] octanes represented by the above formula [Ia] provided by the present invention include the compounds shown below.

(1) (1S, 5R, 6R, 7R) -2-Chloro-3-methylene-6-{(E, 3'S) -3'-hydroxy-1'-octenyl} -7-hydroxybicyclo [3.3. 0] octane (2) (1S, 5R, 6R, 7R) -2-chloro-3-methylene-6-{(E, 3'S) -3'-hydroxy-5'-methyl-1'-nonenyl} -7-Hydroxybicyclo [3.3.
0] octane (3) Compound having 5'-position of (S) -configuration of compound of (2) (4) Compound of 5'-position of (R) -configuration of compound of (2) (5) (1S, 5R, 6R, 7R) -2-Bromo-3-methylene-6-{(E, 3'S) -3'-hydroxy-4'-methyl-1'-octenyl} -7-hydroxybicyclo [ 3.
3.0] Octane (6) (1S, 5R, 6R, 7R) -2-Iodo-3-methylene-6-{(E, 3'R) -3'-hydroxy-4 ', 4'-
Dimethyl-1′-octenyl} -7-hydroxybicyclo [3.3.0] octane (7) (1S, 5R, 6R, 7R) -2-Bromo-3-methylene-6-{(E, 3 ′S)- 3'-Hydroxy-1'-decenyl} -7-hydroxybicyclo [3.3.0] octane (8) (1S, 5R, 6R, 7R) -2-chloro-3-methylene-6-{(E, 3 ' S) -3'-Hydroxy-3'-cyclopentyl-1'-propenyl} -7-hydroxybicyclo [3.3.0] octane (9) (1S, 5R, 6R, 7R) -2-chloro-3-methylene- 6-{(E, 3'S) -3'-hydroxy-3'-cyclohexyl-1'-propenyl} -7-hydroxybicyclo [3.3.0] octane (10) (1S, 5R, 6R, 7R)- 2-bromo-3-methylene-
6-{(E, 3'R) -3'-hydroxy-3'-phenyl-1'-propenyl} -7-hydroxybicyclo [3.
3.0] Octane (11) (1S, 5R, 6R, 7R) -2-Bromo-3-methylene-
6-{(E, 3'S) -3'-hydroxy-3'-phenoxy-1'-propenyl} -7-hydroxybicyclo [3.3.0] octane (12) (1S, 5R, 6R, 7R)- 2-bromo-3-methylene-
6-{(E, 3'S) -3'-hydroxy-3 '-(3 "
-Butylcyclopentyl) -1'-propenyl} -7-
Hydroxybicyclo [3.3.0] octane (13) (1S, 5R, 6R, 7R) -2-iodo-3-methylene-
6-{(E) -4'-hydroxy-1'-octenyl}
-7-Hydroxybicyclo [3.3.0] octane (14) (1S, 5R, 6R, 7R) -2-chloro-3-methylene-
6-{(E) -4'-hydroxy-4'-methyl-1 '
-Octenyl} -7-hydroxybicyclo [3.3.0] octane (15) (1S, 5R, 6R, 7R) -2-chloro-3-methylene-
6-{(E) -4'-hydroxy-4'-vinyl-1 '
-Octenyl} -7-hydroxybicyclo [3.3.0] octane (16) (1S, 5R, 6R, 7R) -2-Bromo-3-methylene-
6-{(E) -4'-hydroxy-4'-methyl-4 '
-Cyclopentyl-1'-butenyl} -7-hydroxybicyclo [3.3.0] octane (17) (1S, 5R, 6R, 7R) -2-iodo-3-methylene-
6-{(E) -4'-hydroxy-4 ', 6'-dimethyl-1'-nonenyl} -7-hydroxybicyclo [3.3.
0] octane (18) (13) to (17) compounds with 4'-position (S)
-Configuration compounds (19) (13) to (17) have 4'-configuration (R)
-Configuration compound (39) 7,3'-bis (t-butyldimethylsilyl) ether of the compound of (1) to (12) (40) 7,3'-bis of the compound of (1) to (12) (2-Tetrahydropyranyl) ether (41) 7,3'-Diacetate of the compound of (1) to (12) (42) 7,3'-Dibenzoate of the compound of (1) to (12) (43 ) 7-t-Butylsilyl ether of compound of (13) to (19) 4'-trimethylsilyl ether (44) 7,4'-bis (2-tetrahydropyranyl) ether of compound of (13) to (19) (45) 7,4'-Diacetate of compounds (13) to (19) (46) 7,4'-Dibenzoate of compounds (13) to (19) (47) (1) to (19) , And the stereoisomers of the asymmetric carbon on the substituents at the 1-, 5-, 6-, 7- and 6-positions of the compounds of (39) to (46) are not limited to these. Not shall.

The above formula [Ia] or the following formula [Ib] [In the formula, R ¹ represents a chlorine atom or an iodine atom. R ⁴ ,
R ⁵ , R ⁶ , R ⁷ and n are the same as defined above. ] Bicyclo [3.3.0] octanes represented by the formula [I
I] Bicyclo [3.3.0] octanes represented by or the following formula [III] [Wherein R ⁴¹ , R ⁵¹ , R ⁶ , R ⁷ and n are the same as defined above. ] The compound is obtained by halogenating a hydroxybicyclo [3.3.0] octane represented by the formula [1] and, if necessary, subjecting it to a deprotection reaction.

The halogenation method may be any method as long as it converts an allyl alcohol into an allyl halide, and for example, a hydroxybicyclooctane represented by the above formula [II] or [III] may be substituted. It can be obtained by reacting with a phenylsulfonyl halide or an optionally substituted alkylsulfonyl halide in the presence of a base and, if necessary, a deprotection reaction. Examples of phenylsulfonyl halide that may be substituted or alkylsulfonyl halide that may be substituted include, for example, p-toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-toluene bromide. Examples thereof include sulfonyl and methanesulfonyl bromide. The amount of these sulfonyl chlorides used is 0.5 to 30 equivalents, preferably 1 to 5 equivalents, relative to the starting bicyclo [3.3.0] octanes. Examples of the base used include nitrogen-containing aromatic rings such as pyridine, 4-dimethylaminopyridine, 2,6-lutidine, quinoline, and imidazole, n-butyllithium, sec-butyllithium, t-butyllithium, and methyl. Organolithium such as lithium and phenyllithium,
Grineer's reagents such as methylmagnesium chloride and phenylmagnesium bromide are preferably used, among which pyridine, 4-dimethylaminopyridine and n-butyllithium are preferably used. The amount of these bases used is 0.5 to 50 equivalents, preferably 1 to 5 equivalents, based on the starting bicyclo [3.3.0] octanes. In addition, pyridine, 2,6
-A liquid base such as lutidine can also be used as a solvent for the reaction. The reaction temperature of this reaction is -100 to 100.
C., preferably -80 to 50.degree. Reaction time is 0.
It is 1 to 30 hours, preferably 0.5 to 5 hours. The reaction solvent is methylene chloride, chloroform, carbon tetrachloride,
Organic chlorine solvents such as 1,2-dichloroethane, ether solvents such as ethyl ether, tetrahydrofuran and dimethoxyethane, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like are preferably used, but especially methylene chloride, tetrahydrofuran and the like. Is preferred. As mentioned above, a base such as pyridine or 2,6-lutidine can also be used as a solvent. In this reaction, as a reaction intermediate, the following formula [I-3-1] Via the sulfonyl oxide bicyclo [3.3.0] octane represented by the formula [Ia] or the bicyclo represented by the above formula [Ib] of these sulfonyloxybicyclo [3.3.0] octanes. [3.3.0] Conversion to octanes proceeds in the reaction system. The above formula [I
-3-1] represented by sulfonyloxybicyclo [3.
3.0] Octanes are isolated by the method described above or
Bicyclo [3.3.0] octanes represented by the above formula [Ia] or the above formula [Ib] can also be obtained by halogenating with lithium halide, sodium halide or the like.

The bicyclo [3.3.0] octanes represented by the above formula [Ia] or the above formula [Ib] are bicyclo [3.3.0] octanes represented by the above formula [II] or the above formula [III]. Therefore, it can also be obtained by performing the following halogenation method. For example, phosphorus trichloride, phosphorus tribromide,
Phosphorus trihalides such as phosphorus triiodide, phosphine dihalides such as triphenylphosphine dichloride, triphenylphosphine dibromide, triphenylphosphine geodide, phosphonic acid triphenyl-methyl chloride, phosphonic acid triphenyl-bromide Ethyl, phosphophenylphosphonate-triphenylphosphonates such as methyl iodide-alkyl halides, triphenylphosphine-
Carbon tetrachloride, triphenylphosphine-carbon tetrabromide, triphenylphosphine-carbon tetraiodide and other triphenylphosphine-tetrahalogenated carbons, etc. (New Experimental Chemistry Course, Vol. 14, Synthesis and Reaction of Organic Compounds Ip361 ~ P369, p4
25-p430, edited by The Chemical Society of Japan, Maruzen 1977, etc.) is not limited to this.

Bicyclo [3.3.0] octanes represented by the above formula [Ia] and bicyclo [3.3.
When [0] octanes are obtained as a mixture, they can be isolated by an ordinary separation means such as silica gel column chromatography, high performance liquid chromatography, silica gel thin layer chromatography, and recrystallization.

The product thus obtained can optionally be subjected to a deprotection reaction. When the protecting group is a group that forms an acetal bond with an oxygen atom derived from a hydroxyl group, for example, acetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, or a cation exchange resin is used as a catalyst,
For example, water, methanol, ethanol or tetrahydrofuran in the coexistence of water, methanol, ethanol, etc.,
It is preferably carried out by using ethyl ether, dioxane, acetone, acetonitrile or the like as a reaction solvent. The reaction temperature is usually -78 ° C to + 50 ° C for about 10 minutes to 3 days. When the protecting group is a tri (C ₁ -C ₇ ) hydrocarbon group, for example, acetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, or another acid is used as a catalyst in the above reaction solvent at the same temperature. Or using a fluorine-based reagent such as tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid, hydrogen fluoride-pyridine, etc., using tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile, etc. as a reaction solvent. It is preferably carried out at the same temperature for a similar time. When the protecting group is a group which forms an ester bond with the oxygen atom of the hydroxyl group, for example, an aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or a water-alcohol mixed solvent, or sodium methoxide, It can be carried out by hydrolysis in a methanol or ethanol solution containing potassium methoxide or sodium ethoxide.

The hydroxybicyclo [3.3.0] octanes represented by the above formula [II], which is a raw material in the production method of the present invention, can be obtained, for example, by the method separately filed by us (JP-A-62-61937). (See Japanese Patent Laid-Open No. 62-258330, etc.). The hydroxybicyclo [3.3.0] octane represented by the above formula [III], which is a raw material in the production method of the present invention, can be produced, for example, in the same manner as in the method of Shibasaki et al. Or in accordance with the method. [Tetrahedron Letters, 25 , 5087 (1984). (See JP-A-60-202838, etc.).

The thus-obtained bicyclo [3.3.0] octanes represented by the above formula [Ia] are also useful compounds as useful intermediates for synthesizing isocarbacycline, which is promising as a drug. That is, using the bicyclo [3.3.0] octane represented by the above formula [Ia] as a starting material, the following formula [V] The isocarbacycline represented by can be manufactured. According to this method, the following formula [I-4] Isocarbacyclines represented by the above formula [V] can be similarly produced from the bicyclo [3.3.0] octanes represented by Examples of the optionally substituted alkylsulfonyloxy group represented by R ¹⁵ or R ³⁵ of the bicyclo [3.3.0] octane represented by the above formula [I-4] include the following. Examples of the substituent of the phenylphonyloxy group which may be substituted include a C _{1 to} C ₄ alkyl group such as a methyl group, an ethyl group, an isopropyl group and a t-butyl group, or a halogen atom. , A bromine atom is preferred. Examples of the alkyl group which may be substituted include the above C _{1 to} C ₄ alkyl groups, and examples of the substituent include a halogen atom. Of these, preferred are p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, p-bromobenzenesulfonyloxy group and the like. The bicyclo [3.3.0] octanes represented by the above formula [I-4] can be obtained by, for example, the method separately filed by the present inventors (Japanese Patent Laid-Open No. 62-61937) or the method of Shibasaki et al. [Tetrahedron Leders]. (Tetrahedron
Letters), 25 , 5087 (1984)] and the like.

In addition, the following formula [I-3-a] [In the formula, R ¹³ represents a chlorine atom, a bromine atom, an iodine atom, an optionally substituted phenylsulfonyloxy group or an optionally substituted alkylsulfonyloxy group. R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are the same as defined above. ] Bicyclo [3.3.0] octanes represented by or the following formula [I-3-b] [In the formula, R ³³ represents a chlorine atom, a bromine atom, an iodine atom, an optionally substituted phenylsulfonyloxy group or an optionally substituted alkylsulfonyloxy group. R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are the same as defined above. ] Bicyclo [3.3.0] octanes represented by the formula [I
V] [In the formula, R ⁸ represents a C _{1 to} C ₁₀ alkyl group, and X represents a halogen atom. ] The isocarbacyclines represented by the above formula [V] can be produced by reacting with an organozinc compound represented by the formula [1] and optionally by deprotection reaction.

In the present production method, it is preferable to carry out the reaction in the presence of a copper reagent represented by the following formula [VI] CuY ... [VI] [wherein Y is the same as the above definition] and represented by the above formula [VI]. The copper reagent may be mixed with the organozinc compound represented by the above formula [IV] in advance, or may be directly added to the reaction system. The above-mentioned formula [I-3-a] or the above-mentioned formula [I-3-b] which is a raw material of this production method
The bicyclo [3.3.0] octanes represented by are preferably those represented by the above formula [I-3-a]. In the above formula [I-3-a] or the above formula [I-3-b]
R ¹³ or R ³³ is preferably a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyloxy group, a methanesulfonyloxy group or an orifluoromethanesulfonyloxy group. Preferred groups for R ⁴ , R ⁵ , R ⁶ , R ⁷ , and n are the same as those described above. As a raw material for this reaction, a mixture of compounds of the above formula [I-3-a] or the above formula [I-3-b] may be used. The above formula [IV]
In the organozinc reagent represented by, X represents a halogen atom, and an iodine atom is particularly preferable. R ⁸ represents a C ₁ -C ₁₀ alkyl group, which is a methyl group, an ethyl group, an isopyryl group,
A butyl group, a t-butyl group, a hexyl group, a decyl group and the like are preferable, and a methyl group is particularly preferable. Examples of Y of the copper reagent represented by the above formula [VI] include a cyano group and a halogen atom, and a cyano group is preferable. The amount of the organozinc reagent represented by the above formula [IV] is the above formula [I-3-
a] or the bicyclo [3.3.0] octane represented by the above formula [I-3-b], in an amount of 0.8 to 100 times mol, relative to 1 mol.
It is preferably 1.0 to 50 times mol. The amount of the copper reagent represented by the above formula [VI] used is 0 to 20 times, preferably 1 to 20 moles per 1 mol of the organozinc reagent represented by the above formula [IV].
It is 0.1 to 2 times the molar amount. The reaction temperature at this time is -80 ° C to 100
C, preferably -30 to 70 ° C. Reaction time is 0.5-3
It is 0 hours, preferably 1 to 5 hours. Examples of the reaction solvent include ether solvents such as ethyl ether, tetrahydrofuran, dioxane and dimethoxyethane, hydrocarbon solvents such as benzene, toluene and hexane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide and the like. Selected from organic polar solvents, etc., tetrahydrofuran,
Diethyl ether, dimethylacetamide and the like are preferable.

The organozinc compound represented by the above formula [IV] used in the reaction can be prepared, for example, by the method shown by Knochel et al. [P.Knochel et al., J. Org. Chem., 53 , 23
90 (1988), etc.]. That is, in metal zinc, in the presence of the solvent, such as alkyl halides such as 1,2-dibromoethane,
Next, after activating the zinc by adding an activator such as trimethylchlorosilane, the following formula [VII] It can be easily prepared by reacting a halogenated butanoate represented by the formula [wherein R ⁸ X is the same as defined above]. As the activator at this time, 1,2-dibromoethane and trimethylchlorosilane are particularly preferable, and each is used in an amount of 0 to 1 equivalent, preferably 0.01 to 0.1 equivalent of zinc. The amount of the halogenated butanoates represented by the above formula [VII] used is 0.8 to 10 equivalents, preferably 1 to 1.5 equivalents of zinc. The solvent for the reaction is the same as the above-mentioned solvent, but tetrahydrofuran is particularly preferable. The reaction temperature and time are 20 to 100 ° C. when activating zinc, and adding an alkyl halide such as dibromoethane,
0.5 to 30 minutes, preferably 50 to 70 ° C, 0.5 to 5 minutes, and 0 to 50 ° C, 10 at the time of the next addition of trimethylchlorosilane.
Minutes to 1 hour, preferably 10 to 30 minutes. The reaction temperature in the reaction between the activated zinc and the halogenated butanols represented by the above formula [VII] is 0 to 80 ° C, preferably 20 to 40 ° C, and the reaction time is 1 to 50 hours. It is preferably 8 to 15 hours. In addition, the organozinc compound represented by the above formula [IV] used in this reaction is a copper compound according to the method of Ochiai et al. [See H. Ochiai et al., J. Org. Chem., 52 , 4418 (1987)]. It can also be prepared using activated zinc. The organozinc compound represented by the above-mentioned [IV] thus prepared can be directly used in the next reaction without isolation.

The final reaction liquid containing the isocarbacyclines represented by the above formula [V] obtained by the above reaction 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 or the like, if desired.

Further, the product obtained here can be subjected to a deprotection reaction if necessary. Of the protecting groups, the deprotection reaction of R ⁴² and R ⁵² is carried out in the same manner as the deprotection reaction of the compound represented by the above formula [Ia] or the above formula [Ib]. Further, the removal of the protective group of the 1-position carboxylic acid ester is carried out by the above formula [Ia] or the above formula [Ia]
-B] can be achieved by the ester bond hydrolysis method in the deprotection reaction of the compound.

The bicyclo [3.3.0] represented by the above formula [Ia] or the above formula [Ib] obtained by halogenating the hydroxybicyclooctanes represented by the above formula [II] or the above formula [III]. ] The reaction liquid containing octanes,
The isocarbacyclines represented by the above formula [V] can also be produced by reacting with the organozinc compound represented by the above formula [IV] as it is, and by deprotecting if necessary.

Thus, the above formula [I-3-a] or the above formula [I-3
The isocarbacyclines represented by the above formula [V] are obtained by using the bicyclo [3.3.0] octanes represented by -b] as a starting material.

Hereinafter, the present invention will be described in more detail with reference to Examples.

In the formula, -OZ ₁ represents a t-butyldimethylsilyloxy group, and -OZ ₂ represents a trimethylsilyloxy group.

[Example 1] (1S, 5S, 6R, 7R) -2-Hydroxy-3-methylene-6
-{(E) -3'S) -3'-t-butyldimethylsilyloxy-1'-octenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] octane (Compound (i)) 131 mg ( (0.25 mmol) was dissolved in 1 ml of methylene chloride, cooled with ice, and 122 mg (1.0 mm of 4-dimethylaminopyridine).
ol) was added. 190m of p-toluenesulfonyl chloride there
g (1.0 mmol), and after stirring at room temperature for 3 hours, add water,
Extracted twice with hexane. The combined organic layers were washed successively with saturated aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. When the obtained crude product was purified by silica gel column chromatography, 92 mg (yield 70%) of (1S, 5R, 6R, 7R) -2 was eluted in a 5% ethyl acetate-hexane eluate.
-Chloro-3-methylene-6-{(E, 3'S) -3'-
t-butyldimethylsilyloxy-1′-octenyl}
-7-t-Butyldimethylsilyloxybicyclo [3.3.
0] octane (compound- (ii)) was obtained.

[Example 2] (1S, 5S, 6R, 7R) -2-Hydroxy-3-methylene-6
-{(E) -3'S5'S) -3'-t-butyldimethylsilyloxy-5'-methyl-1'-nonenyl} -7-
By reacting 200 mg (0.37 mmol) of t-butyldimethylsilyloxybicyclo [3.3.0] octane (compound (iii)) in the same manner as in [Example 1], (1S, 5R, 6R, 7R)
-2-Chloro-3-methylene-6-{(E, 3'S5'S)
-3'-t-butyldimethylsilyloxy-5'-methyl-1'-nonenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] octane (Compound (iv)) 133
mg (yield 65%) was obtained.

[Example 3] (1S, 5S, 6R, 7R) -2-Hydroxy-3-methylene-6
-{(E) -4'-methyl-4'-trimethylsilyloxy-1'-octenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] octane (Compound (v)) 168 mg (0.35 mmol) By reacting in the same manner as in [Example 1], (1S, 5R, 6R, 7R) -2-chloro-
3-Methylene-6-{(E) -4'-methyl-4'-trimethylsilyloxy-1'-octenyl} -7'-t
-Butyldimethylsilyloxybicyclo [3.3.0] octane (compound (iv)) 131 mg (yield 75%) was obtained.

[Example 4] (1S, 5S, 6R, 7R) -2-Hydroxy-3-methylene-6
-{(E, 4'S) -4'-methyl-4'-trimethylsilyloxy-1'-octenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] octane (compound (v) -2) By reacting 100 mg (0.19 mmol) in the same manner as in [Example 1], (1S, 5R, 6R, 7R)
-2-Chloro-3-methylene-6-{(E, 4'S)-
4'-methyl-4'-trimethylsilyloxy-1'-
Octenyl} -7′-t-butyldimethylsilyloxybicyclo [3.3.0] octane (Compound (iv) -2) 75 mg
(Yield 73%) was obtained.

[Example 5] (1S, 5S, 6R, 7R) -2-Hydroxy-3-methylene-6
-{(E, 3'S) -3'-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-propenyl} -7
-T-Butyldimethylsilyloxybicyclo [3.3.0]
By reacting 120 mg (0.24 mmol) of octane (compound (vii)) in the same manner as in [Example 1], (1S, 5R, 6R, 7
R) -2-Chloro-3-methylene-6-{(E, 3'S)-
3'-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-propenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] octane (compound (v
ii)) 89 mg (71% yield) was obtained.

[Reference Example 1] (1S, 5S, 6R, 7R) -3-Hydroxymethyl-6-{(E,
3'S) -3'-t-butyldimethylsilyloxy-
1'-octenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] -2-octene (compound (i
x)) 201 mg (0.40 mmol) was dissolved in 1.5 ml of methylene chloride, and then ice-cooled, and 195 mg (1.6 mm) of 4-dimethylaminopyridine.
ol), then p-toluenesulfonyl chloride 229mg (1.2mm
ol) was added. After stirring at room temperature for 3.5 hours, water was added and the mixture was extracted twice with hexane. The combined organic layers were washed successively with saturated aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The obtained crude product was purified by silica gel column chromatography to obtain 129 mg (62%) of (1S, 5S, 6R, 7R) -3-chloromethyl-6- {E, 3 in the 30% benzene-hexane eluate. ′ S) -3′-t-butyldimethylsilyloxy-1′-octenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] -2-octene (compound (x)) was obtained.

[Reference Example 2] The following compounds were obtained from the following starting materials in the same manner as in [Reference Example 1].

[Reference Example 3] 2 ml of tetrahydrofuran was added to 850 mg (13 mmol) of zinc powder, and 45 μ (0.52 mmol) of dibromoethane was added thereto, followed by stirring at 65 ° C. for 1 minute. After stirring at room temperature for 20 minutes, trimethylchlorosilane (50 μ, 0.39 mmol) was added, and the mixture was further stirred at room temperature for 20 minutes. Methyl 4-iodobutanoate 2.85 g (1
2.5 mmol) dissolved in 5 ml of tetrahydrofuran and added, 40
The mixture was stirred at ° C for 15 hours. After cooling the solution to -10 ° C, 990 mg of copper cyanide (11 mmol) and 950 mg of lithium chloride (22 mm
ol) was dissolved in 10 ml of tetrahydrofuran, and the whole solution was added, followed by stirring under ice cooling for 10 minutes. The solution was cooled to -25 ° C,
This was the alkylating reagent solution.

(1S, 5R, 6R, 7R) -2-Chloro-3-methylene-6-
{(E, 3'S) -3'-t-butyldimethylsilyloxy-1'-octenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] -2-octane (Compound (i
i)) Tetrahydrofuran solution of 42 mg (0.08 mmol) (1 m
l) was cooled to -25 ° C, 4 ml of the above alkylating reagent solution was added, and the mixture was stirred under ice cooling for 2 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with ether. The combined organic layers were saturated aqueous potassium hydrogen sulfate solution, then saturated aqueous sodium hydrogen carbonate,
The extract was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated. The obtained crude product was purified by silica gel column chromatography to obtain 44 mg (94% yield) of isocarbacycline methyl ester 11,15-bis-t-butyldimethylsilyl ether (in a 1% ethyl acetate-hexane eluate). Compound (xi)) was obtained.

[Reference Example 4] In the same manner as in [Reference Example 3], the following product was obtained from the following starting materials.

[Reference Example 5] (1S, 5S, 6R, 7R) -2-Hydroxy-3-methylene-6
-{E, 3'S) -3'-t-butyldimethylsilyloxy-1'-octenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] octane (compound (i)) 2
A solution of 52 mg (0.50 mmol) in tetrahydrofuran (2 ml) was cooled to −78 ° C., .38 ml of a hexane solution of n-butyllithium (1.55M, 0.59 mmol) was added, and the mixture was stirred for 15 minutes, and then p-toluene chloride under ice cooling. Add 112 mg (0.59 mmol) of sulfonyl and add 1
The mixture was stirred at 0 to 20 ° C for 3 hours. When monitored by TLC, it was found that the p-toluenesulfonic acid ester of (compound (i)) and the chloro compound [(compound (ii) of Example 1] were produced in the reaction solution. After cooling to −25 ° C., 4 ml of an alkyl reagent solution prepared in the same manner as in [Reference Example 3] was added, and the mixture was stirred for 2 hours under ice cooling.A saturated ammonium chloride aqueous solution was added, and the mixture was extracted twice with ether.
The combined organic layer was washed with a saturated aqueous solution of potassium hydrogen sulfate,
Then, it was washed with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate, and the solvent was evaporated. The crude product obtained was purified by silica gel column chromatography to yield 1%.
230 mg (yield 78%) of isocarbacycline methyl ester 11,15-bis-t- was eluted with ethyl acetate-hexane.
Butyldimethylsilyl ether (compound (xi)) was obtained.

(Refer to [Example 1] for physical data) [Reference Example 6] The following product was obtained from the following starting materials in the same manner as in [Reference Example 5].

[Reference Example 7] (1S, 5S, 6R, 7R) -3-Chloromethyl-6-{(E, 3 '
S) -3'-t-butyldimethylsilyloxy-1'-
Octenyl} -7-t-butyldimethylsilyloxybicyclo [3.3.0] octene (compound (x)) 76 mg (0.14 m
mol) was added with 4 ml of the alkyl reagent solution prepared in [Reference Example 3] at -25 ° C, and the mixture was stirred under ice cooling for 3 hours. The crude product obtained by post-treatment in the same manner as in [Reference Example 3] was produced by silica gel chromatography to obtain 91 mg of an oily substance in the eluate of 1% -ethyl acetate-hexane. If this is further purified by high performance liquid clast (column, YMC-PACK SJ
-043, mobile phase hexane) 8 mg (yield 10%) of isocarbacycline methyl ester 11,15-bis-t-butyldimethylsilyl ether (compound (xi)) was obtained.

(See [Example 8] for physical data)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07D 309/12 C07F 7/18 F

Claims (11)

[Claims] 1. The following formula [I-a]: Bicyclo [3.3.0] octanes, which are compounds represented by, their enantiomers, or any mixture thereof. 2. The bicyclo [3.3.0] octanes according to claim 1, wherein R ³ is a chlorine atom. 3. R ⁴ and R ⁵ are t-butyldimethylsilyl groups,
The bicyclo [3.3.0] according to claim 1 or 2, which is a trimethylsilyl group or a 2-tetrahydropyranyl group.
Octanes. 4. The bicyclo [3.3.0] octanes according to claim 1, wherein R ⁶ is a hydrogen atom. 5. The bicyclo [3.3.0] octanes according to claim 1, wherein R ⁶ is a methyl group. 6. R ⁷ is a butyl group, a pentyl group, a hexyl group,
Heptyl group, 2-hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2-methylpentyl group, 2-methylhexyl group, cyclopentyl group, cyclohexyl group, phenyl group, phenoxy group, cyclopentylbutyl group, Or a bicyclo [3.3.0] octane according to any one of claims 1 to 5, which is a cyclohexylmethyl group. 7. The bicyclo [3.3.0] octanes according to any one of claims 1 to 6, wherein n is 0. 8. The bicyclo [3.3.0] octanes according to claim 1, wherein n is 1. 9. The following formula [II] The bicyclo [3.3.0] octanes represented by the formula [1.a] are halogenated and, if necessary, subjected to a deprotection reaction.
Octane production method. 10. A reaction of hydroxybicyclo [3.3.0] octane represented by the formula [II] with an optionally substituted phenylsulfonyl halide or an optionally substituted alkylsulfonyl halide in the presence of a base. 10. The method for producing bicyclo [3.3.0] octanes according to claim 9, which is characterized by subjecting it to a deprotection reaction if necessary. 11. The following formula [I-1] according to claim 10, wherein the optionally substituted phenylsulfonyl halide or the optionally substituted alkylsulfonyl halide is p-toluenesulfonyl chloride. [Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , and n are the same as defined in claim 1. ] The manufacturing method of the bicyclo [3.3.0] octane represented by these.