JPH0791224B2 - Method for producing isocarbacyclines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to 2,6,7-trisubstituted-3-methylenebicyclo [3.3.
Isocarbacycline [9 (0) ^{-methano Δ6 (9α) -prostaglandin} starting from [0] ^octanes
I ₁ ] type manufacturing method. More specifically, the oxygen atom at the 6,9α-position of the prostaglandin I ₂ starting from 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octanes is a methine group (-CH =). The present invention relates to a regioselective method for producing isocarbacyclines substituted with.

<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 it is important to regulate the cell function of the living body by its strong physiological activities such as platelet aggregation inhibitory activity and vasodilatory activity. It is a factor, and attempts are being made to directly use this as a drug.
[Clinical Pharmacology of Prostacyclin,
Raven Press, NY, 1981].

However, since natural prostacyclin has an enol ether bond in the molecule which is very easily hydrolyzed, it is easily hydrolyzed and inactivated under neutral or acidic conditions, and it is a preferable compound because of its scientific instability as a drug. Not really. Therefore, a chemically stable synthetic prostacyclin derivative having physiological activity similar to that of natural prostacyclin has been earnestly searched.

Among them, a derivative obtained by substituting the oxygen atom at the 6,9α-position of prostacyclin with a methylene group, that is, 9 (0) -methanoprostacyclin (carbacycline) is known as a prostacyclin that sufficiently satisfies chemical stability. Or, [Prostacyclin, IRV
aneand, S. Bergstrom. Eds. Raven Press, NY p31-41]] Application as a drug is expected. However, the biological activity of 9 (0) -methanoprostacyclin is weaker than that of natural prostacyclin, and moreover, its action selectivity cannot be said to be specific, and it cannot be said to be necessarily a preferable compound.

In recent years, isocarbacycline, which is one of the double bond isomers of carbacyclin, namely 9 (0) -methano-
^{△ 6 (9α)} - prostaglandin I ₁ such that, the homolog is found to exhibit the strongest inhibiting platelet aggregation action among, application as good chemicals have come to be expected [Ikegami et al, tetra Hedron Letters (Tetrahedron Le
tt.), 24 , 3493 (1983), JP-A-59-137445].

Conventionally, the following has been known for the production of such 9 (0) methano-Δ ^{6 (9α) -prostaglandin} I ₁ ^{(isocarbacycline).} It is as follows.

(1) Ikegami et al., Tetrahed Letters
ron Letters), 24, 3493 ( 1983) and Chemistry
Letters (Chemistry Letters), 1984, 1069: (2) Ikegami et al., Tetrahed Letters
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 Letters
ron Letters), 25 , 5087 (1984): (5) Shibasaki et al., Tetrahed Letters
ron Letters), 25 , 1067 (1984): (6) Kojima et al., Chemical and Pharmaceutical Bulletin (Chem.Pharm.Bull.), 32 , 2866 (1
984): (7) Kojima et al., JP 60-28943 A: (8) Kurozumi et al., Tetrahed Letters
ron Letters), 27 , 6353 (1986): (9) Kurosumi et al., JP 63-77839 A, 7th IUPAC C
onference on Organic Synthesis, Nancy, Jul. 4th-7th
(1988) Abstr. 4-A10: (10) Proceedings of the 53rd Autumn Meeting of the Chemical Society of Japan, p. P499
(1986); (11) Hari et al., Proc. Of the 106th Annual Meeting of the Pharmaceutical Society of Japan p379 (1
986): (12) Okamura et al. Proceedings of the 106th Annual Meeting of the Pharmaceutical Society of Japan p380 (1
986): (13) Shibasaki et al., Tetrahedro Letters
n 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 method is out of the question as a manufacturing method intended only for dl form and intended for commercialization.

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 due to difficulties such as the use of organic mercury compounds and the incorporation of difficult-to-separate by-products, it cannot be a practical or industrial production method. There are difficulties. In methods (8) and (9), the key intermediate is the method of the present inventors (JP-A-62-61937) and the method of Shibasaki et al. [Tetrahedron Letters (Tetrahed).
ron Letters), 25, 5087 (1984)] (R) -4-
Although it is a method that can be obtained from hydroxy-2-cyclopentenone without any industrial problems, it is difficult to directly introduce the butanoic acid moiety in the process from the key intermediate to the isocarbacyclines, and the ortho It has a drawback that it has to be converted into isocarbacyclines via an ester form or a disulfone form. In addition, 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. The method (13) cannot be said to be industrially satisfactory because of low yield in the steps from the key intermediate to the isocarbacyclines.

Recently, the present inventors have introduced a butanoic acid moiety directly by reacting 3-alkoxycarbonylpropyl zinc halides with an allyl halide or an allyl tosylate intermediate in the presence of a cuprous salt by a method proposed separately. Then
We found that the isocarbacycline skeleton was constructed at once. The reaction formula is as follows.

However, if the drawbacks of this method are emphasized, it is not possible to secure the stability that the allyl halide or allyl tosylate intermediate as the starting material withstands the industrial production method, and chloride is produced in the usual tosylate preparation process. The resulting chloride is a stereoisomer of allyl alcohol, which is a starting material, and is mixed with an allyl rearranged product, and the desired product is obtained under the same reaction conditions from the product via the allyl rearrangement. There is no point. Therefore, the regiospecificity of the products in the total reaction tends to deteriorate. This process is illustrated by the flow of the main product of the reaction as shown in the following figure.

<Disclosure of the Invention> The inventors of the present invention have reached the present invention as a result of diligent research to find out a regioselective production method of isocarbacyclines by paying attention to the above points.

That is, the present invention provides the following formula (1) 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octanes represented by the following formula (2) An organozinc compound represented by the following formula (3) Cu-X ² (3) Represented by the following formula (4), wherein the reaction is carried out in the presence of a cuprous salt and, if necessary, a deprotection reaction is carried out. A method for producing an isocarbacycline represented by:

2,6,7-trisubstituted-used as a raw material in the present invention
Some of the 3-methylenebicyclo [3.3.0] octanes are known compounds, and according to the method separately proposed by the present inventors, the following synthetic route (produced by Scheme I) Further, Y is _{^{(R 3 O) 2 P (}} = S) O- in which 2,6,7-trisubstituted-3-methylene-bicyclo [3.3.0] octanes is Y is (R
³ O) ₂ P (= O) O- (Japanese Patent Application Laid-Open No. 62-6193)
It can be manufactured in accordance with (Gazette No. 7) (Scheme
I), Y in the _{^{(R 3 O) 2 P (}} = O) S- in which 1,6,7- trisubstituted-3-methylene-bicyclo [3.3.0] octanes are the following synthetic pathway (Scheme II) It is possible to manufacture.
The Scheme II reaction is a novel reaction, and the obtained compound is also a novel derivative.

In the above formula (1), Y is a substituent (R ³ O) ₂ P (= B)
A- or R ⁴ OC (= O) O- represent. Substituent (R ³ O) ₂
P (= B) in A-, R ³ represents a C ₁ -C ₆ hydrocarbon group, A
And B both represent an oxygen atom, or either A or B represents an oxygen atom, and the other represents a sulfur atom. Further, in the substituent R ⁴ OC (═O) O—, R ⁴ represents a C _{1 to} C ₆ hydrocarbon group. R ¹ represents a hydrogen atom, a methyl group, or a vinyl group, R ² is a linear or branched C _{3 to} C ₈ alkyl group,
An alkenyl group, an alkynyl group, or a C _{3 to} C ₁₀ cycloalkyl group, Z ¹⁰ and Z ²⁰ are the same or different, and a tri (C _{1 to} C ₇ ) hydrocarbon silyl group, or an oxygen to which it is bonded It represents a group that forms an acetal bond or an ester bond together with an atom, and n represents 0 or 1.

Examples of the C _{1 to} C ₆ hydrocarbon group of R ³ in (R ³ O) ₂ P (= B) A- among the substituents represented by Y include a methyl group, an ethyl group, a propyl group and a phenyl group. And the substituent Y
Preferred examples of include a diethoxyphosphoryloxy group, a dipropoxyphosphoryloxy group, a diphenoxyphosphoryloxy group, a dimethoxythiophosphoryloxy group, a diethoxythiophosphoryloxy group, a dimethoxyphosphorylthio group, and a diethoxyphosphorylthio group. You can

In R ⁴ OC (═O) O— in the substituent represented by Y
Examples of the C _{1 to} C ₆ hydrocarbon group of R ⁴ include a methyl group, an ethyl group, a propyl group, an allyl group, a butyl group, a hexyl group, a phenyl group, and the like. A group corresponding to ⁴ can be mentioned.

The linear or branched C ₃ -C ₈ alkyl group for R ² is n
-Propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, 1-methylpentyl group, 1-methylhexyl group, 1,1-dimethylpentyl group, 2 -Methylpentyl group, 2-methylhexyl group, 5-methylhexyl group, 2,5-dimethylhexyl group and the like, and preferably n-butyl group, n-pentyl group, n-hexyl group, (R) -Or (S)-
Alternatively, (RS) -1-methylpentyl group, (R)-or (S)-or (RS) -2-methylhexyl group and the like can be mentioned.

The straight-chain or branched C ₃ -C ₈ alkenyl element for R ² is 2-butenyl group, 2-pentenyl group, 3-pentenyl group, 2-hexenyl group, 4-hexenyl group, 2-methyl-4-hexenyl group. Group, 6-methyl-5-heptenyl group and the like.

The linear or branched C ₃ -C ₈ alkynyl group for R ² is 2-butynyl group, 2-pentynyl group, 3-pentynyl group, 2-hexynyl group, 4-hexynyl group, 2-octynyl group, 1- Methyl-3-pentynyl group, 1-methyl-
Examples thereof include 3-hexynyl group and 2-methyl-4-hexynyl group.

Examples of the C _{3 to} C ₁₀ cycloalkyl group of R ² include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group, and the like, but a cyclopentyl group and a cyclohexyl group are preferable. Is mentioned.

As the tri (C ₁ -C ₇ ) hydrocarbon silyl group of Z ¹⁰ and Z ²⁰ ,
For example, a trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, t- butyl tri (C ₁ ~C ₄₎ alkylsilyl group such as a dimethylsilyl group, diphenyl (C ₁ -C such as t-butyldiphenylsilyl group ₄ ) Preferred examples include an alkylsilyl group, a di (C ₁ -C ₄ ) alkylphenylsilyl group such as a dimethylphenylsilyl group, and a tribenzylsilyl group. (Tri C ₁ -C ₄ ) alkylsilyl, diphenyl (C ₁
To C ₄ ) alkylsilyl group is preferable, and t-butyldimethylsilyl group is particularly preferable.

Further, as the group forming an acetal bond with the oxygen atom to which it is bonded, for example, a methoxymethyl group, a 1-ethoxyethyl group, a 2-methoxy-2-propyl group, a 2-ethoxy-2-propyl group ( 2-methoxyethoxy) methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, or 2-tetrahydrofuranyl group can be mentioned. A 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, a 1-ethoxyethyl group, a 2-ethoxy-2-propyl group and a (2-methoxyethoxy) methyl group are preferable, and a 2-tetrahydropyranyl group is particularly preferable.

The group forming an ester bond with the oxygen atom to which it is bonded is, for example, a formyl group, an acetyl group, a propionyl group, a butanoyl group, a pentanoyl group or the like (C ₁ -C ₅ ) acyl group or a benzoyl group. , A toluyl group, and the like. An acetyl group and a benzoyl group are particularly preferable.

In the above formula (1), the carbon atom to which R ¹ , R ² , and OZ ²⁰ are bonded is an asymmetric carbon, but in the method of the present invention, either the R isomer or the S isomer or a mixture thereof in any ratio is used. Can also be included.

In the above formula (1), n represents 0 or 1. When n is 0, the above formula (1) is represented by the following formula (1-0), 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octanes represented by the following formula, where n is 1, the above formula (1) is represented by the following formula (1-1), 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octanes represented by

2,6,7-Trisubstituted-3-methylenebicyclo [3.3.0] represented by the above formula (1) (including (1-0) and (1-1))
The configuration of the bicyclo ring of octanes and the configuration of the 6,7-position are particularly useful stereoisomers because they have the same configuration as the natural prostacyclin skeleton, but in the production method of the present invention, It also includes possible stereoisomers due to different stereoisomerism at positions or a mixture thereof in any ratio. Further, in the production method of the present invention, since the compatible isomer at the position where Y at the 2-position is bonded gives the same product, any stereoisomer can be equally used as a starting material.

The 2,6,7-trisubstituted-3-methylenebicyclo [3.3] represented by the above formula (1) used as a starting material in the method of the present invention.
Before enumerating the preferred representative examples of [3.0] octanes, the derivatives in which Y and Z ¹⁰ and Z ²⁰ , which are the basic compounds thereof, are hydrogen atoms are as follows: (001) (1S, 5R, 6R, 7R) -3-methylene-6-[(E,
3S) -3-Hydroxy-1-octenyl] -7-hydroxybicyclo [3.3.0] octane (002) (1S, 5R, 6R, 7R) -3-methylene-6-[(E,
3S) -3-Hydroxy-1-nonenyl] -7-hydroxybicyclo [3.3.0] octane (003) (1S, 5R, 6R, 7R) -3-methylene-6-[(E,
3S, 5S) -3-Hydroxy-5-methyl-1-nonenyl] -7-hydroxybicyclo [3.3.0] octane (004) (1S, 5R, 6R, 7R) -3-methylene-6-[(E ,
3S, 5R) -3-Hydroxy-5-methyl-1-nonenyl] -7-hydroxybicyclo [3.3.0] octane (005) (1S, 5R, 6R, 7R) -3-methylene-6-[(1
E, 3S) -3-Hydroxy-9-methyl-1,8-decanedienyl] -7-hydroxybicyclo [3.3.0] octane (006) (1S, 5R, 6R, 7R) -3-methylene-6- [ (E,
3S) -3-Hydroxy-4-methyloct-1-ene-
6-ynyl] -7-hydroxybicyclo [3.3.0] octane (007) (1S, 5R, 6R, 7R) -3-methylene-6-[(E,
3S) -3-Hydroxy-3-cyclopentyl-1-propenyl] -7-hydroxybicyclo [3.3.0] octane (008) (1S, 5R, 6R, 7R) -3-methylene-6-[(E,
3S) -3-Hydroxy-3-cyclohexyl-1-propenyl] -7-hydroxybicyclo [3.3.0] octane (009) (1S, 5R, 6R, 7R) -3-methylene-6-[(E,
3S) -3-Hydroxy-3-methyl-1-octenyl]
-7-Hydroxybicyclo [3.3.0] octane (010) (1S, 5R, 6R, 7R) -3-methylene-6-[(E,
3S) -3-Hydroxy-3-vinyl-1-octenyl]
-7-Hydroxybicyclo [3.3.0] octane (011) (1S, 5R, 6R, 7R) -3-methylene-6-
[(E) -4-Hydroxy-1-octenyl] -7-hydroxybicyclo [3.3.0] octane (012) (1S, 5R, 6R, 7R) -3-methylene-6-[(E,
4S) -4-Hydroxy-1-octenyl] -7-hydroxybicyclo [3.3.0] octane (013) (1S, 5R, 6R, 7R) -3-methylene-6-
[(E) -4-Hydroxy-4-methyl-1-octenyl] -7-hydroxybicyclo [3.3.0] octane (014) (1S, 5R, 6R, 7R) -3-methylene-6-[(E ,
4S) -Hydroxy-4-methyl-1-octenyl] -7
-Hydroxybicyclo [3.3.0] octane (015) (1S, 5R, 6R, 7R) -3-methylene-6-
[(E) -4-Hydroxy-4-methyl-1-nonenyl] -7-hydroxybicyclo [3.3.0] octane (016) (1S, 5R, 6R, 7R) -3-methylene-6-
Examples of the basic compound include [(E) -4-hydroxy-4-vinyl-1-octenyl] -7-hydroxybicyclo [3.3.0] octane. In the method of the present invention, since the free hydroxyl group is supplied to the reaction in a protected form, the t-butyldimethylsilyl group is taken as an example of a representative protecting group, and the substituent Y at the 2-position of the bicyclo [3.3.0] octane ring is While not exemplifying the above, a specific example of the 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octane represented by the above formula (1), which is the starting material of the method of the present invention, is exemplified as follows: 101) Bis (t-butyldimethylsilyl) ethers of compounds (001) to (016) substituted with a diethoxyphosphoryloxy group at the 2-position (102) Dipropoxyphosphoryloxy group substituted at the 2-position (001) To bis (t-butyldimethylsilyl) ethers of compounds (103) (103) Bis (t-butyldimethylsilyl) ethers of compounds (001) to (016) substituted with a diphenoxyphosphoryloxy group at the 2-position Kind (104) Bis (t-butyldimethylsilyl) ethers of the compounds (001) to (016) substituted with a dimethoxythiophosphoryloxy group at the position (105) (001) to ((2) substituted with a diethoxythiophosphoryloxy group at the 2-position. Bis (t-butyldimethylsilyl) ethers of the compound of (016) (106) Bis (t-butyldimethylsilyl) ethers of the compounds of (001) to (016) in which a dimethoxyphosphorylthio group is substituted at the 2-position (107) ) Bis (t-butyldimethylsilyl) ethers of the compounds (001) to (016) substituted with a diethoxyphosphorylthio group at the 2-position (108) (001) to () substituted with a methoxycarbonyloxy group at the 2-position Bis (t-butyldimethylsilyl) ethers of the compound of (016) (109) Bis (t-butyl) of the compounds of (001) to (016) substituted with an ethoxycarbonyloxy group at the 2-position. (Dimethylsilyl) ethers (110) Bis (t-butyldimethylsilyl) ethers of compounds (001) to (016) substituted with a propyloxycarbonyloxy group at the 2-position (111) Allyloxycarbonyloxy at the 2-position Bis (t-butyldimethylsilyl) ethers of compounds (001) to (016) substituted with a group (112) Bis (001) of compounds (001) to (016) substituted with a butyloxycarbonyloxy group at the 2-position. t-Butyldimethylsilyl) ethers (113) Bis (t-butyldimethylsilyl) ethers of compounds (001) to (016) substituted with a hexyloxycarbonyloxy group at the 2-position (114) Phenoxycarbonyl at the 2-position Bis (t-butyldimethylsilyl) ethers of compounds (001) to (016) substituted with an oxy group (115) Bis (t) of compounds (101) to (114) -Butyldimethylsilyl) ether is a bis (t-butyldiphenylsilyl) ether (116) The bis (t-butyldimethylsilyl) ether of the compounds of (101) to (114) is bis (2-tetrahydropyrani). (117) Compounds in which bis (t-butyldimethylsilyl) ether of compounds of (101) to (114) is changed to bis (2-ethoxyethoxy) ether (118) (101) Examples of the compound group in which the bis (t-butyldimethylsilyl) ether of the compound (1) to (114) is a bis (acetoxy) ether can be mentioned, but the invention is not limited thereto.

In the production method of the present invention, the 2,6,7-trisubstituted-3-methylenebicyclo [3.3.
[0] Octanes are reacted with an organozinc compound represented by the above formula (2) in the presence of a cuprous salt represented by the above formula (3) in an organic medium to obtain the target compound represented by the above formula. The production of isocarbacyclines represented by (4) can be achieved.

The organozinc compound represented by the above formula (2) corresponds to 4
-From halogenated butanoic acid esters and metallic zinc, P.
Method of P. Knochel et al. (J.Org.Chem., 1989, 53,
2390). That is, metallic zinc is activated with 1,2-dibromoethane and then trimethylchlorosilane in an organic medium such as tetrahydrofuran, and then the corresponding halides are added in an approximately equal amount relationship to metallic zinc to give 25- A solution of the target organozinc compound is prepared by reacting at 30 ° C. for several hours to several days. In the above formula (2), R ⁵ represents a C _{1 to} C ₁₀ hydrocarbon group, and X ¹ represents a halogen atom. As the C _{1 to} C ₁₀ hydrocarbon group for R ⁵ , a methyl group, an ethyl group, a propyl group,
Examples thereof include a butyl group, a t-butyl group, a hexyl group, an octyl group, a decyl group, an allyl group, a cyclohexyl group and a phenyl group, but a methyl group and an ethyl group are preferable, and a halogen atom of X ¹ is iodine. Examples thereof include an atom, a bromine atom and a chlorine atom, and an iodine atom is particularly preferable in view of the reactivity of the corresponding halide.

In the production method of the present invention, the cuprous salt represented by the above formula (3) is brought into contact with the above-mentioned organozinc compound solution in an organic medium to first carry out as an organocopper zinc complex. This preparation method is also performed according to the method of P. Knochel et al. That is, using tetrahydrofuran or the like as an organic medium and using cuprous salts in an amount approximately equivalent to the organozinc compound, -30 ° C to 40 ° C, preferably -15 ° C to
An organic copper-zinc complex is obtained by reacting in the temperature range of 5 ° C for several minutes to several tens of minutes. In this case, coexistence of a salt or a lithium salt such as lithium promotes the complexing effect and often gives a good result. The amount of this lithium salt used is 1 to 5 times the molar amount of the cuprous salts, and especially 2
˜3 times the molar amount is preferred. Further, in the cuprous salts represented by the above formula (3), X ² represents a cyano group or a halogen atom, and examples of the halogen atom include a chlorine atom, a bromine atom and an iodine atom, and any of them is preferably used.

The production method of the present invention is completed by adding 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octanes represented by the above formula (1) to the organocopper zinc complex thus prepared. To be done. As the organic medium used in the present production method, diethyl ether, tetrahydrofuran, dioxane, ether-based medium such as 1,2-dimethoxyethane are preferably mentioned, but tetrahydrofuran is particularly preferable, and tetrahydrofuran is basically used, but hexane is preferable. It does not matter if a hydrocarbon-based medium such as benzene or benzene is mixed as a mixed medium. In addition, as will be described later, 2,6,7-trisubstituted-in the system represented by the above formula (1)
It is also possible to continue to use the solvent system mixed in when the 3-methylenebicyclo [3.3.0] octanes were prepared. The amount of the organic medium used is not particularly limited as long as the desired reaction proceeds smoothly, but is usually mm
It is carried out in the range of 1 to 1000 ml in terms of reaction scale represented by ol, preferably 10 to 100 ml. 2,6,7-Substituted-3-methylenebicyclo [3.
3.0] The organocopper-zinc complex reacts stoichiometrically equimolar with octanes, but it does not matter if the organocopper-zinc complex becomes excessive, and it is usually 1 to 30 mol times, preferably 1 to 15 mol times. It is carried out in a molar range.

The reaction temperature is in the range of -30 ° C to 50 ° C, preferably -10 ° C to 30 ° C. The reaction time varies depending on the cuprous salts and starting materials used, or the reaction temperature, and is usually
It is carried out while tracing the disappearance of the starting materials by using an analytical means such as thin layer chromatography, but the reaction is completed at 0 ° C to 20 ° C for several hours to several tens of hours.

Isolation of the isocarbacyclines represented by the above formula (4), which is the desired product after the termination of the reaction, can be carried out by a usual post-treatment method such as extraction, washing, drying, chromatography after concentration, distillation and the like. Are separated and purified by.

Further, in the production method of the present invention, the corresponding alcohol derivative (compound of the above formula (1) in which Y is a hydroxyl group) is used as a starting material, and the 2,6,7-trisubstituted-3-type represented by the above formula (1) is used.
The reaction is carried out by adding the organocopper zinc complex solution to the reaction system in which methylenebicyclo [3.3.0] octanes are prepared, and thereby obtaining the desired isocarbacycline derivative represented by the above formula (4). Is also possible.

The product obtained up to this point in the production method of the present invention has the following formula (4 '): Is an isocarbacycline having two protected hydroxyl groups. The method of the present invention may optionally include a deprotection reaction step leading to a free hydroxyl group in the final form as a pharmaceutical.

The deprotection reaction is known per se, and when the protecting group is a group which forms an acetal bond with the oxygen atom to which it is bound, for example, acetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate. It is preferably carried out by using a cation exchange resin or the like as a catalyst and using tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile or the like in the coexistence of water, methanol, ethanol or water, methanol, ethanol or the like as a reaction solvent. It Reaction temperature is usually -78 ℃ ~ +50
It is carried out in the temperature range of ° 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 the like is used as a catalyst at the same temperature in the above-mentioned reaction solvent, or tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid,
It is preferably carried out by using a fluorine-based reagent such as hydrogen fluoride-pyridine and using tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile or the like as a reaction solvent at the same temperature as above for a similar period of time.
In the case of a group which forms an ester bond with the oxygen atom to which each protecting group is bound, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, an aqueous solution of calcium hydroxide or a water-alcohol mixed solvent, or sodium methoxide is used. It can be carried out by hydrolysis in a methanol or ethanol solution containing potassium methoxide or sodium ethoxide.

Thus, according to the present invention, the following formula (4) An isocarbacycline represented by can be produced.

Specific examples of the isocarbacyclines represented by the formula (4) include compounds corresponding to the compounds exemplified by the 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octanes of the formula (2). It can be given as it is.

As described above in detail with respect to the production method of the present invention, 2,6,7-trisubstituted-3-methylenebicyclo [3.3.
[0] Octanes are reacted with an organozinc compound of formula (2) in the presence of a cuprous salt of formula (3) and, if necessary, a deprotection reaction is carried out. , Has the following features. That is, (1) 2,6,7-trisubstituted-3 of the formula (1) which is a starting material
-Methylenebicyclo [3.3.0] octane is more stable than the corresponding tosylate and halide.

(2) Retaining highly regioselectivity from any of the 2-position stereoisomers of the starting material, and providing the target product of the formula (4) in high yield.

(3) The same reaction proceeds not only with the cuprous cyanide salt but also with the cuprous halide salt.

(4) As a feature of the organozinc compound and organocopper zinc complex, it is inactive to the ester functional group, and therefore, the reaction can be carried out without protecting the ester group.

Therefore, the production method of the present invention has high selectivity,
It provides an efficient and industrially excellent production method in terms of high yield and short process.

The embodiments of the present invention include the following.

1. The following formula (1) 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octanes represented by the following formula (2) An organozinc compound represented by the following formula (3) Cu-X ² (3) The following formula (4) is characterized in that the reaction is carried out in the presence of a cuprous salt represented by A method for producing an isocarbacycline represented by:

2. Y is a substituent _{^{(R 3 O) 2 P (}} = B) preparation of isocarbacyclin such claim 1 wherein the A-.

3. Y is a substituent _{^{(R 3 O) 2 P (}} = B) A- a, A and B are the preparation of isocarbacyclin such claim 1, wherein both oxygen atoms.

4. The method for producing isocarbacyclines according to Item 1, wherein Y is a substituent R ⁴ OC (═O) O—.

5. R ² is a linear or branched C ₃ -C ₈ alkyl group or
Any one of items 1 to 4 which is a C _{3 to} C ₁₀ cycloalkyl group 1.
A method for producing isocarbacyclines according to the item 1.

6. The method for producing isocarbacyclines according to any one of items 1 to 5, wherein n is 0.

7. The method for producing isocarbacyclines according to any one of items 1 to 5, wherein n is 1.

8. The method for producing isocarbacyclines according to any one of items 1 to 7, wherein the reaction is performed in the presence of a lithium salt.

Hereinafter, the present invention will be described in more detail with reference to examples.
In the formulas of Examples, OZ ₁ is t-butyldimethylsilyloxy group, OZ ₂ is trimethylsilyloxy group, and OZ ₃ is t-.
Butyldiphenylsilyloxy group, OZ ₄ is abbreviated and represents a 2-tetrahydropyranyloxy group and OZ ₅ acetoxy group.

Example 1 Zinc (785 mg, 12 mmol) was placed in a 25 ml reactor, and after replacement with nitrogen gas, dry tetrahydrofuran (10 ml) was added. Then, 60 μ of 1,2-dibromoethane was added thereto, heated at 65 ° C. for 1 minute, and then stirred at room temperature for 30 minutes. In addition, 80
μ Trimethylchlorosilane was added, and the mixture was stirred at room temperature for 30 minutes. Then, methyl 4-iodobutanoate (2.28 g, 10
mmol) in dry tetrahydrofuran (20 ml) was added,
The mixture was heated and stirred at 40 ° C for 20 hours. In a 100 ml reactor, a solution of cuprous chloride (990 mg, 10 mmol) and lithium chloride (850 mg, 20 mmol) in dry tetrahydrofuran (20 ml) was prepared, and the above-mentioned reaction solution was added thereto at 0 ° C. Stir for 30 minutes. (1S, 5R, 6R, 7R) -2-diethoxyphosphoryloxy-3-methylene-6-[(E, 3S) -3 was added to this reaction solution.
-T-butyldimethylsilyloxy-1-octenyl]
-7-t-Butyldimethylsilyloxybicyclo [3/3 /
A solution of [0] octane 1 (515 mg, 0.80 mmol) in dry tetrahydrofuran (20 ml) was added at 0 ° C, and the mixture was stirred at room temperature for 20 hours. Saturated ammonium chloride solution was added to the reaction solution to terminate the reaction, which was extracted with ethyl acetate (2 x 150 ml), the separated organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. The product (1.044 g) was obtained. This product was subjected to silica gel column chromatography (silica gel 100
g; eluate, hexane: ethyl acetate = 19: 1) for purification, and then the desired isocarbacycline methyl ester 1
1,15-bis (t-butyldimethylsilyl) ether A '
(440 mg, 0.74 mmol, 93%) was obtained.

NMR (CDCl ₃ , ppm) δ; 0.05 (12H, s), 0.8-1.0 (21H, s × 2 and m), 1.0-2.5 (22H, m), 2.7-3.0 (1H, m), 3.64 (3H , s), 3.6-3.8 (1H, m), 4.0-4.3 (1H, m), 5.25 (1H, bs), 5.4-5.55 (2H, m). IR (liquid film) cm ^-1 ; 1740,1255,1110,1002,968,835,772. In order to obtain stereoselectivity in the above reaction, the reaction product was introduced into the above compounds A and B and subjected to HPLC analysis. 62 mg of the above-mentioned product was collected and
l) dissolved in. 1.0M tetrabutylammonium fluoride in tetrahydrofuran (2ml, 2m
mo) was added and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was poured into ethyl acetate (200 ml) and washed with a saturated aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution in that order, and the obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated. To give 64 mg of crude product. This was subjected to HPLC analysis to confirm and quantify Compounds A and B by comparing the retention time and UV absorption of the standard. HPLC conditions were quantification at UV wavelength of 210 nm using NUCLEOSIL 50-5 column (Gaskuro Kogyo KK, 4.6 × 250 mm) and eluent hexane containing 3% ethanol (flow rate 0.8 ml / min). Target compound A : By-product B = 99.
It was 7: 0.3.

Examples 2-9 Examples 2 to 9 were carried out in exactly the same manner as in Example 1. Reaction substrate (2,6,7-trisubstituted represented by the formula (1)-
Table 1 shows 3-methylenebicyclo [3.3.0] octanes), reaction scale, cuprous salt, reaction conditions, yield, and production ratio of compounds A and B. The reaction substrate α
-1 , β- 1 , 1 , α- 2 , and β- 2 are as follows.

Example 10 Zinc (392mg, 6mmol) in dry tetrahydrofuran (5mmo
l) Add 30μ of 1,2-dibromoethane to the solution and add 1 at 65 ℃.
After heating for 1 minute, the mixture was stirred at room temperature for 30 minutes. After that, 40 μL of trimethylchlorosilane was added, and the mixture was stirred at room temperature for 30 minutes, and then methyl 4-iodobutanoate (1.14 g, 5 mmo
l) in dry tetrahydrofuran (5 ml) and add 40 ° C
The mixture was heated and stirred for 18 hours. In another reactor, cuprous chloride (495m
A solution of g, 5 mmol) and lithium chloride (425 mg, 10 mmol) in dry tetrahydrofuran (10 ml) was prepared, and 0 was added to the above reaction solution.
Then, the mixture was added at 0 ° C., and sales were expanded at 0 ° C. for 30 minutes to prepare a copper-zinc complex solution.

On the other hand, (1S, 5R, 6R, 7R) -2-hydroxy-3-methylene-6-[(E, 3S) -3-t-butyldimethylsilyloxy-1-octenyl] -7-t-butyldimethylsilyl Oxybicyclo [3.3.0] octane (904mg, 1.78mmo
l) in dry tetrahydrofuran (20 ml) was cooled to -78 ° C and 1.5 M n-butyllithium in hexane (1.
3 ml, 1.95 mmol) was added, and the mixture was stirred at −78 ° C. for 10 minutes, diethyl chlorophosphate (432 mg, 2.5 mmol) was added, and the mixture was added at 0 ° C.
For 1 hour and room temperature for 30 minutes. The copper-zinc complex solution prepared above was added to this solution at 0 ° C., and then at 2 ° C.
Stir for hours and then at room temperature for 18 hours. After confirming the completion of the reaction, post-treatment was carried out in the same manner as in Example 1 to obtain 1.55 g of a crude product, which was similarly column-separated and subjected to isocarbacycline methyl ester 11,15-bis (t-butyldimethylsilyl).
Ether A '(882 mg, 1.49 mmol, 84%) was obtained.

A 142 mg portion of this was sampled, and tetrabutylammonium fluoride solution (1.0
M, 2 ml, 2 mmol) was added to carry out desilylation reaction (room temperature, 20 hours), and 110 mg of desilylated crude product was obtained by the same post-treatment. HPLC analysis of this yielded compounds A and B
The production ratio of was calculated to be 99.5: 0.5.

Examples 11-14 In the same manner as in Example 1, 0.2 mmol of each of the reaction substrates 3 , 4 , 5 , 6 (see the figure below) was used, and the reaction was carried out under the condition of copper-zinc complex (2.5 mmol) using CuCl (2.5 mmol). I did. The reaction conditions and the reaction results are shown in Table 2.

Examples 15-30 In the same manner as in Example 1, using reaction substrates 7 to 22 (0.2 mmol), a zinc compound (2 mmol) prepared from 4-iodobutanoic acid ester (2 mmol) was treated with CuCl (2 mmol) and LiCl (4 m).
mol) in the presence of the reaction. Post-treatment and column separation after completion of the reaction gave the corresponding products 7A 'to 19A ' in the indicated yields. From the NMR spectrum of this product, it was confirmed that most of the products were the target regioisomers, and the reaction proceeded highly regioselectively. Table 3 shows reaction substrates, products, and reaction yields.
The product spectra are summarized in Table 4 below.

Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location // A61K 31/557 AEL C07F 9/117 9155-4H

Claims (1)

[Claims] 1. The following formula (1) 2,6,7-trisubstituted-3-methylenebicyclo [3.3.0] octanes represented by the following formula (2) An organozinc compound represented by the following formula (3) Cu-X ² (3) The following formula (4) is characterized in that the reaction is carried out in the presence of a cuprous salt represented by A method for producing an isocarbacycline represented by: