JPS6377853A - Isocarbacyclines and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is H, 1-4C alkyl, etc.; R<2> and R<3> are H, tri(1-7C)hydrocarbon-silyl, etc.,; R<4> is H, methyl or vinyl; R<5> is (O- containing) 3-9C alkyl, alkenyl, (substituted) phenyl, etc.; n is 0 or 1; Ar is (substituted) phenyl], its enantiomer or their mixture at arbitrary ratio. EXAMPLE:4, 4-Bis( phenylsulfonyl )isocarbacycline-11, 15-bis( t-butyl-dimethylsilyl )ether methyl ester. USE:A drug expected to have platelet coagulation inhibiting action, vasodilating action, hypotensive action, etc., and its intermediate. PREPARATION:The compound of formula I can be produced by treating a compound of formula II (R<11> is 1-4C alkyl, etc.) with a base and site-specifically reacting with a compound of formula III [R<21> and R<31> are tri(1-7C)hydrocarbon- silyl, etc.].

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(O)- in which the oxygen atom at position 6.9 of prostaglandin 1 is substituted with a methylene group (-HC-)
Methanol-ΔGC5d)-prostaglandin 11 (
isocarbacycline), and itself relates to novel isocarbacycline derivatives and methods for producing the same.

<Prior art> Prostaglandin is a local hormone produced mainly in the inner wall of arteries in living organisms, and its powerful physiological activities include platelet aggregation inhibiting activity.

Prostacyclin is an important factor that regulates cell functions in living organisms through vasodilatory activity, etc., and attempts are being made to directly provide this substance as a pharmaceutical product [Clinical Pharmacology of Prostacyclin (Cl 1nical P)]
hermacology of prostacycl
in), Raven Press, N, Y
,.

1981].

However, since natural prostacyclin has an enol ether bond in its molecule that is highly susceptible to hydrolysis, it is easily deactivated under neutral or acidic conditions, and is not a desirable compound as a pharmaceutical because of 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 atom at the 6.9-position of prostacyclin is substituted with a methylene group, i.e., 9(O)-methanoprostacyclin (carbacycline), are known as prostacyclins that have sufficient chemical stability. [Prostacyclin]
n), J.R., Vane and S.

BeraStrom, Eds, Raven Pr.
ess, N, Y.

It is expected to be a co-pharmaceutical, see pp. 31-41. However, the biological activity of this 6.9 (O)-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(O)-methano-
It was discovered that ΔG(9cA)-prostaglandin 1 exhibits the strongest platelet aggregation inhibitory effect among its congeners, and its application as a pharmaceutical is expected [Ikegami et al. Tetrahedron Letters] (Tetra
hedron Lett, ).

24, 3493 (1983), JP-A-59-1374
Publication No. 45].

Conventionally, the following methods are known for producing 9(O)-methano-ΔG (9oO-prostaglandin 11 (isocarbacycline)).

(1) Ikegami et al., Tetrahedron Letters (Tet
rahedron LetterS), 24.3
493 (1983) and Chemistry Letters
c hemistry Letters), 1984
．． 1069: (2) Ikegami et al., Tetrahedron Letters,
24.3497 (1983): (3) Ikegami et al., Journal of the Chemical Society. Chemical Communication (J, Chem, So
c., Chemical Communication
s), 1984.1602: (4) Murasaki et al., Tetrahedron Letters
Letters), 25°5087 (1984)
: Key intermediate (5) Shibasaki et al., Tetrahedron Letters (Tetra
hedron headters).

25, 1067 (1984): Key intermediate isopotent luvacycline (6) Kojima et al., Chemical and Pharmaceutical Bulletin (Chem, Pharm, Bull),
32.2866 (1984): (7) Kojima et al. JP-A-60-28943: (Ul)-isocarbacycline Among these seven methods, method (1) and method (5) use PGE2 as the starting material. This method is difficult to describe as an industrial production method, as the key intermediate is obtained through several steps, and the target product, isocarbacycline, is obtained through several more steps.

In addition, both method (a) and method (3) require a multi-step process from expensive Corey lactone to obtain the corresponding starting materials and key intermediates, and the total yield is not high and is not necessarily suitable for industrial use. It has the disadvantage that it is not an advantageous method.However, method (6) and method (the force is
This is an undesirable manufacturing method for pharmaceutical production as it can only be obtained in the body.

Finally, in method (4), the starting material is not only easily obtained from optically active (R)-4-hydroxy-2-cyclobentenone by the method of the present inventors (Japanese Patent Application Laid-Open No.
No. 7-155116), it is a method that can be produced industrially without any problems by deriving the key intermediate from the starting material. 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.

<Purpose of the Invention> The present inventors focused on the above-mentioned points, and as a result of intensive research to discover 9(O)-methanol ΔG (900-prostaglandin 11 class (isocarbacyclines)) and its production method, This has led to the present invention.

<Configuration and Effects of the Invention> That is, the present invention provides novel isocarbacyclines which are compounds represented by the following formula [I], their enantiomers, or mixtures thereof in arbitrary proportions, and methods for producing the same.

In the above formula [I], R1 represents a hydrogen atom or a C1 to C4 alkyl group or alkenyl group. Cl in R1
Examples of the alkyl group of -04 include methyl group, ethyl group, propyl group, and butyl group, and examples of the alkenyl group include 2-propene group.

Examples include 3-butene group, among which methyl group and 2-propene group are preferred.

In the above formula [I], R2 and R3 are the same or different and represent a group that forms an acetal bond with a hydrogen atom, a tri(C+-Cy) hydrocarbon silyl group, or an oxygen atom of a hydroxyl group.

Examples of tri(C+ to C7) hydrocarbon silyl groups include tri(CI-04) alkylsilyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group 1°C-butyldimethylsilyl group: [-butyldiphenyl Diphenyl (CI"C4) alkylsilyl group such as silyl group, dimethylphenyl group, di<Cl
-04) Alkylphenyl group; or tribenzylsilyl group are preferred.

Among these, tri(C+ to C4) alkylsilyl group,
Diphenyl(C+-C4)alkylsilyl group and phenyldi(C+-C,s)alkylsilyl group are preferred, and t-butyldimethylsilyl group and trimethylsilyl group are particularly preferred.

Further, as a group that forms an acetal bond with the oxygen atom of water Ml, for example, a 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-cymethyl-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.

6.6-dimethyl-3-oxa-2-oxobicic
[3,1,0]hex-4-yl group is particularly preferred.

Among them, 2-tetrahydropyranyl 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 [I], R4 represents a hydrogen atom, a methyl group, or vinyl U.

In the above formula [I], R5 is a linear or branched 03-C9 alkyl group, alkenyl group or alkynyl group which may contain an oxygen atom; substituted or unsubstituted phenyl group; substituted or unsubstituted phenoxy group; substituted or unsubstituted C3-CIO cycloalkyl group; or C1-C6 alkoxy group, optionally substituted phenyl group.

Represents a straight or branched C1-C5 alkyl group substituted with an optionally substituted phenoxy group or an optionally substituted C3-CIG cycloalkyl group.

Straight chain or branched chain that may contain M atoms 03~
The C9 alkyl group, alkenyl group or alkynyl group is 2-methoxyethyl group.

2-ethoxyethyl 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 u, 2
．． 2-dimethylhexyl group, 4-hexyn-1-yl group, 4-hexyn-2-yl group.

Examples include 3-pentyn-1-yl group, 4-heptyn-2-yl group, and 5-hebuten-2,6-dimethyl-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-heptyn-2-yl group
yl group.

5-hebuten-2,6-dimethyl-1-yl group is preferred.

Substituted phenyl group, substituted phenoxy group, and C3-CIG
Substituents for the substituted cycloalkyl group include, for example, a halogen atom, a protected water l! 1 group (for example, silyloxy group, C+ to C6 alkoxy group, etc.).

Examples include 01-C4 alkyl groups. 03~C10
Examples of the cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group, and a cyclohebutyl group.

Examples include a cyclooctyl group and a cyclodecyl group. Among these is the cyclopentyl group.

Cyclohexyl group is preferred.

Straight chain or branched chain C1-C6 substituted with a C1-C6 alkoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted 03-CIo cycloalkyl group In the C5 alkyl group, examples of the 01-C6 alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group, a t-butoxy group, and a hexyloxy group. Examples of the substituents of the (optionally substituted) engineering diyl group, the optionally substituted phenoxy group, or the optionally substituted C3-C+o cycloalkyl group and the C3-C+a cycloalkyl group include the above-mentioned examples. The same thing can be mentioned. The straight chain or branched chain C1-C5 alkyl group is, for example, a methylpentyl group.

Propyl group, isopropyl group, butyl group, isobutyl i
, 5ec-butyl group, t-butyl group, pentyl group, etc. Such R5 includes butyl group, pendel group, hexyl group, heptyl group, 2-hexyl group,
2-methyl-2-hexyl group, 2-methylbutyl group, 2
-Methylpentyl group, cyclopentyl group, cyclohexyl group, phenyl group, phenoxy group, cyclooctylmethyl group.

Preferred examples include cyclohexylmethyl group. Note that the substituent may be bonded to any position thereof.

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

Ar represents a substituted or unsubstituted phenyl group, and examples of the substituent include those mentioned above, preferably phenyl group, p-tolyl group, etc.

In addition, in the compound represented by the above formula [I], the bicyclo[3,3,0]octane ring itself and its cyclo[3
,3,0] The carbon to which the substituent is bonded on the octane ring; stereoisomers exist due to the asymmetric environment of the carbon substituted by the hydroxyl group on the ω mirror, but in the present invention, It includes any stereoisomer, and may be a mixture of these stereoisomers in any proportion. Among these, compounds having the steric structure represented by the formula are most preferred.

3 represented by the above formula [I] provided in the present invention
, 6,7-trisubstituted bicyclo[3,3,0] -2-octenes include the compounds shown below.

(11(1, 5, 6S, 7R)-3-(4-carbomethoxy-2,2-bisphenylsulfonylbutyl)-
6-[(dan-13shadow)-3-hydroxy-1-octenyl]-7-hydroxybicyclo[3,3,OF-2-
Octene (2) (1 shadow, 5 shadow, 6 shadow, 7R) -3-(4-carbomethoxy-2,2-hisphenylsulfonylbutyl)-
6-[(E,33)-3-hydroxy-1-nonenyl 1
-7-Hydroxybicyclo[3,3,0] -2-octene (3) (1 shadow, 5 shadow, 6 shadow, 7R) -3-(4-carbomethoxy-2,2-hisphenylsulfonylbutyl)-
6-[(dan, 3->-3-hydroxy-4-methyl-
1=octenyl]-7-hydroxybicyclo[3,3,
0] -2-octene (4) (1S, 58.68,
7R)-3-(4-13lupomethoxy-2,2-biphenylsulfonylbutyl)-6-[(E, 3 shadow)-3-
hydroxy-4,4-dimethyl-1-octenyl]-7
-Hydroxybicyclo[3,3,0] -2-octene(51(13,58,6S,7R)-3-(4-carbomethoxy-2,2-biphenylsulfonylbutyl)-
6-[(dan,3S)-3-hydroxy-5-methyl-1
-Octenylco-7-hydrocytopenic [3,3,0
] -2-octene (6) (Is, 53.6S, 7
R)-3-(4-1)lupomethoxy2,2-biphenylsulfonylbutyl)-6-[(dan-13 shadow)-3-
Hydroxy-5-methyl-1-nonenyl]-7-hydroxybicyclo[3,3,0]-2-octencibomethoxy-2,2-bisphenylsulfonylbutyl)-6-
[(E,3S)-3-hydroxy-3-cycloben-1-propenyl]-7-hydroxybicyclo[3,
3,0] -2-octene (lO) (IS, 5S, 6S, 7R) -3-(4-
Carbomethoxy-2,2-biphenylsulfonylbutyl)-6-[(dan,3kage)-3-hydroxy-3-cyclohexyl-1-propenyl]-7-hydroxybicyclo[3,3,0] - 2-octene (Ill (18,5S,6S,7R)-3-(4-
Carbomethoxy-2,2-biphenylsulfonylbutyl)-6-[(E,3S)-3-hydroxy-3-cyclohexyl-1-butenyl]-7-hydroxybicyclo[3,3,0] -2 -Octene (121<IS, 5S, 6S, 7R) -3-(4-IJ
rubomethoxy-2,2-biphenylsulfonylbutyl')-6-[(dan,3shadow)-3-hydroxy-5-phenoxy-1-pentenyl]-7-hydroxybicyclo[
3,3,01-2-octene (131 (18,5S, 6
S,7R)-3-(4-carbomethoxy-2,2-biphenylsulfonylbutyl)-6-[(dan,3S)-3
-human Oxy5-ethoxy1-pentenyl]-7-
Hydroxybicyclo[3,3,0]-2-octene (
141 (1 shadow, 5 shadow, 6 shadow, 7e)-3-(4-carbomethoxy-2,2-biphenylsulfonylbutyl')
-6-[(dan,4tech)-4-hydroxy-4-methyl-
1-octenyl]-7-hydroxybicyclo[3,3,
0] -2-octene solid (1 shadow, 5 shadow, 6 shadow, 7R)
-3-<4-carbomethoxy-2,2-biphenylsulfonylbutyl)-6-[(E,4R)-4-hydroxy-4-methyl-1-octenyl]-7-hydroxybicyclo[3,3 , OF -2-octene (16) (1
Shadow, 5 shadow, 68.7 length)-3-(4-carbomethoxy-
2,2-biphenylsulfonylbutyl)-6-[(dan-)-4-hydroxy-4-vinyl-1-octenyl]
-7-hydroxybicyclo[3,3,OF -2-octene U'r (1S, 58.6S, 7R) -3-(4
-carbomethoxy-2,2-biphenylsulfonylbutyl)-6-[(dan-〉-3-hydroxy-1=hepten-7-yn-1-yl-7-hydroxybisylbutyl)
3,3,0] -2-octene f181 (1S, 5
S, 6S, 7R)-3-(4-tribomethoxy-2,2
-bisphenylsulfonylbutyl)-6-[(E)-3
-Hydroxy-1-octen-6-yn-1-yl]-
7-Hydroxybicyclo[3,3,0]-2-octene 09) (1) ~ (Foundation)'s 3-(4-carbomethoxy-1-p-trisulfonylbutyl) form (1) ~ Hao's methyl Ester compound G! In compounds n(1) to (21) in which the methyl ester of (11 to 09) is an allyl ester, the water vi group at the 7th position and the hydroxyl group on the substituent at the 6th position are protected with a [-butyldimethylsilyl group] Compound.

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.

(!41　(Enantiomer of the compound of 11-no.

(2a (1) The 1st, 5th, 6th, and 7th positions of the compound of
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 novel isocarbacyclines represented by the above formula [II] are prepared by treating a compound represented by the following formula [II] with a base, and then treating the compound represented by the following formula [I] with a base.
3,6.7-trisubstituted bicyclo[3,3,0]-2-octenes, which are the compound represented by I[], its enantiomer 9, or a mixture thereof in any proportion, in the presence of a palladium compound. It is obtained by reacting in a position-specific manner and carrying out a deprotection reaction and a hydrolysis reaction as necessary.

Similarly, the novel isocarbacycline represented by the above formula [II] is represented by the following formula [II] [wherein R11 and Ar are the same as defined above]. ] is treated with a base, and then 3-methylene-2,6,7-trisubstituted bicyclo[ It can be obtained by reacting 3,3,0 co-octanes in a position-specific manner in the presence of a palladium compound, and further performing a deprotection reaction and a hydrolysis reaction as necessary.

In the sarylsulfonyl compound represented by the above formula [II], which is a raw material for this reaction, RII is C+ ''-C
represents an alkyl group or alkenyl group of a. As such a group, the same alkyl group or alkenyl group as exemplified as R1 in the above formula [II can be mentioned as a preferable group, but a methyl group is particularly preferable.

In the above formula [II], Ar represents a substituted or unsubstituted phenyl group. Such groups include A of the above formula [II
Although the same groups as exemplified as r can be mentioned, phenyl group and p-tolyl group are particularly preferred.

In the allyl acetate represented by the above formula [1[[] or [IV], which is the other raw material for this reaction, R
1 and R31 are the same or different, and are tri(C+~
C7) Represents a hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of water 14. Tori (
As the group forming an acetal bond with the oxygen atom of the C+ to Cy) hydrocarbon silyl group or water R group, the same groups as exemplified for R2 or R3 in the formula [II above can be mentioned as preferred.

In the above formula [■] or [IV], R4 is a hydrogen atom,
Represents a methyl group or a vinyl group, R5 is a linear or branched C3-C9 alkyl group that may contain an oxygen atom; a substituted or unsubstituted phenyl group; a substituted or unsubstituted phenyl group; a substituted or Unsubstituted phenoxy group: substituted or unsubstituted 03-Coo cycloalkyl group; or C1 to C8 alkoxy group, optionally substituted phenyl group, optionally substituted 03-C+a
Straight chain or branched 1 substituted with cycloalkyl group
1C+ to C5 alkyl group, all of which are represented by the above formula [
Preferred examples include those similar to those exemplified for R5 in [I].

W[II[] or [rV] represents 0 or 1.

The 3,6,7-trisubstituted-bicyclo[3,3,0]-2-octenes represented by the formula [nl] are described, for example, in Shibasaki et al.; Tetrahedron Letters.
, 25.5087 (1984), and the manufacturing process is briefly introduced as shown in the following process diagram.

That is, This is the manufacturing process.

3-methylene-2,6,7 represented by formula [IV]
-Trisubstituted hisicyl O[3,3,0]-octanes are produced by two methods separately proposed by the present inventors.

In other words, the above cited document <Tetrahedron Letters,
A synthetic route ( Route A) or cyclization reaction of an acetylene derivative obtained using optically active 4-hydroxy-2-cyclobentenone as a starting material (Route B)
obtained by. The reaction route is briefly shown below.

<Route A> [TV] Route B> 1) Methylenated alkali Acetate represented by the above formula [111] or [TV] is introduced into a 4,4-bisarylsulfonylisocarbacycline represented by the above formula [II]. (The reaction is carried out by treating the bisarylsulfonyl compound represented by the above formula [II] with a base in the presence of palladium.
] or [rV].

The bisarylsulfonyl compound represented by the above formula [II] is used in an amount of 0.5 to 30 equivalents, preferably 1 to 5 equivalents, relative to the acetate represented by the above formula [111] or [IV]. The base used in the reaction with the bisarylsulfonyl compound is an organic alkali metal or an alkali metal hydride, such as lobethyllithium, 5ec-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 base used is determined by the above formula [I
0.5 to 30 equivalents M1 is used, preferably 1 to 10 equivalents, with respect to the bisarylsulfonyl compound represented by [I], but in principle, 1 equivalent ω is used.

The reaction temperature of such salt-forming reaction is -100°C to 100°C,
Preferably the temperature is -78°C to 2°C, and the reaction time is 5 minutes to 50 hours, preferably 10 minutes to 2 hours. The reaction is carried out in an organic solvent, and the solvents used include ether, ether solvents such as tetrahydro-7-9 dioxane, hydrocarbon solvents such as n-hexane and benzene, and others such as DMF and DMSO, but preferably Use ether and tetrahydrofuran.

The alkali metal salt of the sarylsulfonyl compound thus obtained is reacted with furyl acetate represented by the above formula [II[] or [IV]] in the presence of palladium.

The reaction is carried out directly using the above formula [III or [■
] can be added to proceed. This reaction is carried out in the presence of palladium, and the palladium compound used is, for example,
It is possible to use the various palladium complexes mentioned, preferably tetrakis(triphenylphosphine)palladium(O).

Bis[bis(1,2-diphenylphosphino)-ethane]palladium (O) and bis[bis(1,3-diphenylphosphine)-propane]palladium (O) are used, but the present invention is not limited thereto.

The amount used is o, ooi to 1 equivalent, preferably 0.01 to 0.2 equivalent M, relative to the acetate compound represented by the above formula [II1] or [IV]. The reaction temperature at this time is -30°C to 200°C, preferably 0°C to 100°C, and the reaction time is 10 minutes to 100 hours, preferably 1 hour to 24 hours. The reaction is carried out in a paid solvent, but the same solvent used in the previous salt-forming reaction can be used.

The reaction solution thus treated may be post-treated according to a commonly used method. For example, an organic mixture obtained by adding a poorly soluble paid 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 solvent is removed under reduced pressure to obtain a crude product. The crude product 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 required, whereby the reaction proceeds in a position-specific manner and finally a novel isocarbacycline represented by the above formula [II] is obtained.

When the protecting group of the hydroxyl group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, the removal of the protecting group of the hydroxyl group is carried out using a catalyst such as acetic acid a, a pyridinium salt of p-toluenesulfonic acid, or a cation exchange resin. For example, the reaction is preferably carried out using water, tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile, or the like as a reaction solvent.

The reaction is usually carried out at a temperature range of -78°C to +30°C for 10 minutes to 30 minutes.
It is held for about a day. Also, Bq is tri (C+~C7)
In the case of hydrocarbon silyl groups, for example acetic acid.

It is carried out in the presence of butylammonium fluoride, cesium fluoride, aqueous hydrogen fluoride, pyridine-hydrogen fluoride in the reaction solvent as described above at similar temperatures and for similar times.

Hydrolysis of esters can be carried out in a conventional manner using lithium hydroxide, sodium hydroxide,
Potassium hydroxide and -40℃~100℃, preferably O℃
The reaction is carried out at a temperature range of -50°C for 10 minutes - 24 hours.

Thus, the above formula [I
A compound represented by I is prepared. 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 themselves have ilcarbacycline-like activity, such as platelet aggregation inhibiting action, vasodilatory action,
It is expected to have antihypertensive and cell protective effects.

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 the examples, -OZ is 108i" BIJ -Me
2 (t-butyldimethylsilyloxy group).

<Example> Example 1 Methyl-4,4-bis(phenylsulfonyl)but/nee t-400av (1,05 mmol>2IdT
NaH (60% in oil) was added to the HF solution under a nitrogen stream.
)441IIg (1.1 mmol) was added at 0°C and stirred for 1 hour. Here, 450 mg (O, 82 mmol) of 2dTl-I expressed by the above formula (1)
Add F solution, then bis[bis(1,2-diphenylphosphino)-ethane]palladium(O) 80tr
pi (O, 09 mmol) was added, heated to 60°C, and stirred for 5 hours. After repulsion, 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), 4,4-bis(phenylsulfonyl)isocarbacycline-11,15-bis(t-butyldimethylsilyl)ether methyl ester (2) was subjected to 493I
ng (70%) was obtained.

IR(c!M-', neat): 2950.
2860.1740.1580°1460, 1440.
1330.1310.1255.114ONMR(δp
DIII, CDCf3): 0.9 (s + m
, 21H).

1.2-2.4 (II, 14H)
.

2.6-3.1 (1,7H).

3.7 (s, 3H), 3.75 (n+
, 11-1).

4.05 (m, IH), 5.4 (m
, 2H).

5.55 (m, 1 H), 7.1-8.
0<m, 10)-1) Example 2 +31 (2) Methyl-4,4
-bis(phenylsulfonyl)butanoate 59q (
1,05 mmol) of 0.8 dTHF solution under nitrogen flow (NaHiO% in oil) 6.2 rItg (
O, 15 mmol) was added at 0°C and stirred for 1 hour.

Here, the acetate body 68■(
Add a 0.8d T HF solution of O, 12 mmol),
Then bis[bis(1,2-diphenylphosphino)
Ethane] Palladium (O) 6,3tn9 (O,0
07 mmol) was added thereto, and the mixture was stirred at air temperature for 3 hours and at 60°C for 4 hours.

After the reaction, the reaction was combined with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The resulting 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 4.
641ftg (59%) of 4-bis(phenylsulfonyl)isocarbacycline-11,15-bis([-butyldimethylsilyl)ether methyl ester (2) 1 recovered 23m3 (34%) of acetate was obtained. The spectrum is shown in Example It matched perfectly with 1.

Example 3 Disilyl compound (z87η (O, 10 mmol) was made into a solution of 2- in dry tetrahydrofuran (2-), and 470 u!l ( The mixture was stirred at room temperature for 10 hours. Water was added and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Silica gel column chromatography (ethyl acetate, 2% methanol) to remove the desilylated form (
4) Obtained 51 my (79%).

NMR(δI)I)m, CD(J3
): 0.9(m, 3
1).

1.2-2.4 (m, 14).

2.6-3.1 (m, 7H).

3.65 (s, 3l-1).

3.65-4.05 (m, 21-ri).

5.4 (m, 2H), 5.55 (
l, 1 t-1).

7.1 to 8.0 (10, IOH) Example 4 Na H8.8 mW (60% in o
il.

Methyl-4,4-bis(phenylsulfonyl)butanoate 84Irtg (0.22 mn+ol) treated with
Acetate 116q (O, 2 mmol) represented by the above formula (5) is added to a 1dTHF solution of O, 22 mmol).
of tetrakistriphenylphosphine palladium (O) 13/ng (O,01
1 mmol) was added thereto, 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 ether, methyl ester form (6)
1%) obtained.

NMR (δDI)m, CDCf3): 0, 9
(s + m, 21H).

1, 0-2.4 (m, 181-1).

2, 6 ~ 3.1<m, 7H).

3, 65 (S, 3H).

3, 7 ~ 4.1 (m, 2H).

5, 3 to 5.6 (+n, 3H).

7, 1-8.0 <m, 10H) Example 5 (7) f8) Nitrogen stream TNa
H 6.8 mg (60% in oil.

65 mg of methyl-4,4-bis(phenylsulfonyl)butanoate (
0.17 mmol) of 1teTHF solution, acetate 78# (0.15
mmol) in 1dTHE, then bis[bis(1,
2-diphenylphosphino)ethane]palladium(O
) 7.2rrpy (0.008111101>) was added and stirred at 80°C for 10 hours.

On the way, 7.2 tons of the above palladium (O) was added at 5 hours.
rry<0.008ml) was added. After the reaction, the reaction was terminated with a saturated aqueous solution of Ammonium monoxide and extracted with ethyl acetate. After washing the oral layer with water and saturated saline,
It was 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 a grade of 92 cm (13%).

NMR (δl)pill CDCf3): 0, 9
(s + m, 12H).

1, 1-2.4 (m, 14t-1).

1, 1<3, 3H), 2.6-3.1(Il
l, 7H).

3,65 (s, 3)1), 3.8(m
, 1H).

5, 3 ~ 5.6 (m, 3H).

7, 1 to 8.0 (m, 101-1) Example 6 (9)) NaH 9rrtg (0.23 mmo) in nitrogen atmosphere
Methyl-4.4 treated with l, 60% 1nOi1)
-Bis(phenylsulfonyl)butanoate 84my
(0.22 mmol) of 1dTHF solution,
Acetate body 110rrtg represented by the above formula (9)
(0.2 mmol) of 1 m IDMF solution was added, and then 9 μ (0.01 mmol) of bis[bis(1,2-diphenylphosphino)ethane]palladium(O) was added, and the mixture was stirred at 60° C. for 5 hours.

After repulsion, the reaction was terminated with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. After washing the R layer with water and saturated saline, anhydrous lii! Dry over magnesium chloride and concentrate under reduced pressure. The crude product was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 20: 1 - + 10
: 1), and the resultant (10) 1 13mg (
65%).

NMR (δI)l)m CDCf3): 0, 9<s
, 18H), 1.0 to 2.4 (m, 1
5H).

2, 6 to 3.0 (m, 7H).

3, 70 (S, 3H).

3, 6 ~ 4.1 (III, 2)-1>.

5, 3 ~ 5.6 (m, 3 1-1>.

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] [In the formula, R^1 represents a hydrogen atom or an alkyl group or alkenyl group of C_1 to C_4: R^2 and R^3 are the same or different and represent a hydrogen atom, 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 is a hydrogen atom, a methyl group , or represents a vinyl group: R^5 is a straight chain or branched chain C_3 to C_9 alkyl group, alkenyl group or alkynyl group which may contain an oxygen atom; substituted or unsubstituted phenyl group; substituted or unsubstituted Phenoxy group; substituted or unsubstituted C
_3~C_1_0 cycloalkyl group; or C_1~C
_6 alkoxy group, optionally substituted phenyl group,
represents a straight chain or branched chain C_1 to C_5 alkyl group substituted with an optionally substituted phenoxy group or an optionally substituted C_3 to C_1_0 cycloalkyl group: n represents 0 or 1; Ar is Represents a substituted or unsubstituted phenyl group. ] A novel isocarbacycline which is a compound represented by these, its enantiomer, or a mixture thereof in any proportion. 2. The novel isocarbacyclines according to claim 1, wherein R^1 is a methyl group. 3. The novel isocarbacyclines according to claim 1, wherein R^1 is a hydrogen atom. 4. The novel isocarbacyclines according to claim 1, wherein R^1 is a vinyl group. 5. R^2 and R^3 are the same or different, hydrogen atom,
trimethylsilyl group, dimethyl-t-butylsilyl group,
The novel isocarbacyclines according to any one of claims 1 to 4, which are a tetrahydropyranyl group or a methoxymethyl group. 6. The novel isocarbacyclines according to any one of claims 1 to 5, wherein R^4 is a hydrogen atom. 7, R^5 is a butyl group, pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2-methylpentyl group, cyclopentyl group, cyclohexyl group, phenyl 7. The novel isocarbacyclines according to any one of claims 1 to 6, which is a phenoxy group, a cyclopentylmethyl group, or a cyclohexylmethyl group. 8. The novel isocarbacyclines according to any one of claims 1 to 7, wherein n=0. 9. The novel isocarbacyclines according to any one of claims 1 to 8, wherein Ar is a phenyl group or a p-tolyl group. 10. The following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [II] [In the formula, R^1^1 represents an alkyl group or alkenyl group of C_1 to C_4, and Ar is the same as the above definition. be. ] The compound represented by the following formula [I
II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [III] [In the formula, R^2^1 and R^3^1 are the same or different and represent a tri(C_1-C_7) hydrocarbon silyl group or a hydroxyl group. It represents a group that forms an acetal bond with an oxygen atom, and R^4, R^5 and n are the same as defined above. ] 3,6,7-trisubstituted bicyclo[
3.3.0]-2-octenes are reacted position-specifically in the presence of a palladium compound, and if necessary, a deprotection reaction and a hydrolysis reaction are performed [I] ▲ Formula, There are chemical formulas, tables, etc. ▼... [I] [In the formula, R^1, R^2, R^3, R^4, R^5, A
r and n are the same as defined above. ] A method for producing a novel isocarbacycline, which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion. 11. The novel method for producing isocarbacyclines according to page 10 of the claims, wherein R^1^1 in the above formula [II] is a methyl group. 12. A novel method for producing isocarbacyclines according to page 10 or page 11 of the claims, wherein the base is an organic alkali metal or an alkali metal hydride. 13. The method for producing isocarbacycline according to any one of claims 10 to 12, wherein the palladium compound is organic palladium (O). 14. The following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [II] [In the formula, R^1^1 and Ar are the same as the above definitions. ] A compound represented by the following formula [I
V] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [IV] [In the formula, R^2^1, R^3^1, R^4, R^5 and n are the same as in the above definition] 3-methylene-2,6,7-trisubstituted bicyclo[3.3.0]-octanes, which are compounds, their enantiomers, or mixtures thereof in arbitrary proportions, are reacted regiospecifically in the presence of a palladium compound. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼... [I] [In the formula, R^1, R^ 2, R^3, R^4, R^5, A
r and n are the same as defined above. ] A method for producing a novel isocarbacycline, which is a compound represented by the following, its enantiomer, or a mixture thereof in any proportion. 15. The novel method for producing isocarbacyclines according to claim 14, wherein R^1^1 in the above formula [II] is a methyl group. 16. A novel method for producing isocarbacyclines according to claim 14 or page 15, wherein the base is an organic alkali metal or an alkali metal hydride. 17. The method for producing isocarbacycline according to any one of claims 14 to 16, wherein the palladium compound is organic palladium (O).