JPS6042348A - (3-oxo-1-alkenyl)-cis-bicyclo(3.3.0)octene derivative - Google Patents

Abstract

NEW MATERIAL:The (3-oxo-1-alkenyl)-cis-bicyclo[3,3,0]octene derivative of formula I (R<1> is C5-10 straight, branched or cyclic alkyl or alkenyl; R<2> is H or OH-protecting group; R<3> is H or alkyl). EXAMPLE:3-(4-Methoxycarbonylbutyl)-6-exo-(3-oxo-trans-1-octenyl)-7-end o-tetrahydropyranyloxybicyclo[3,3,0]oct-2-ene. USE:Intermediate for the production of 9(0)-methano-DELTA6(9ALPHA)PGI1 having strong activity to inhibit the coagulation of blood platelet. PREPARATION:The compound of formula I can be produced fromthe compound of formula II through 7 steps via the compounds of formula III, formula IV, formula V, formula VI, formula VII and formula VIII, oxidizing the compound, and reacting with the compound of formula IX or the compound of formula X.

Description

Detailed Description of the Invention ♂t0 (wherein R1 is a straight chain, branched or cyclic alkyl group or alkenyl group having 5 to 10 carbon atoms, ♂ is a hydrogen atom or a hydroxyl group, and R5 is a hydrogen atom or an alkyl group).

(6-oxo-
1-Alkenyl)-cis-bicyclo[5-5゜0]octene derivative reduces the ketone, deprotects the hydroxyl group, and hydrolyzes the ester.11C ioha9(0)
-Mefi/ -△6(9" -POII Kj4< can be done (see reference side below).9(0)-Methano-△
6(9'''2-PGII has a strong anti-platelet aggregation effect; for example, when human platelets are used, its effect is comparable to that of the chemically unstable PGI2, and it is used in the treatment of various cardiovascular diseases. It is a compound used as a prophylactic drug (see test side below).

Previously, 9 (0) -Meta/ -△6("'PGII
The method for producing M is (a) using PGE1 as a raw material.
A method of manufacturing through 4 steps [Proceedings of the 106th Annual Meeting of the Pharmaceutical Society of Japan, p. 156 (1983)] and (1 mouthful of 1,6-
Method for manufacturing from cyclooctadiene through 19 steps [
Proceedings of the 106th Annual Meeting of the Pharmaceutical Society of Japan, p. 157 (1983), is known, but method (a) requires expensive raw materials, and method (b) produces the target product as a racemate. The disadvantage of both (a) and (b) was that the total yield was extremely low.

The present inventors have discovered that 9(0)-methano-△6"2-P can be produced from inexpensive raw materials in good yield and in an optically active form with stereospecific specificity.
As a result of extensive research in order to produce GII, the inventors discovered that the compound of the present invention can be used as an important intermediate to achieve the objective, and completed the present invention.

(6-oxo-
1-Alkenyl)-cis-bicyclo(C310)octene derivatives are available in addition to the naturally occurring ω-chain of the Brostag 2 engine skeleton, for example, in the literature [Ca5als-8tenzel, J.

et al., Prostaglandins, Ll.
eukotrienes Med, 1983.10 (
2), 197-212), it can be said to be an extremely useful intermediate in that it can also lead to grosstag 2 resin derivatives having non-natural ω-chains.

(6-oxo-
The 1-alkenyl)-7subicyclo(3,3,0)octene derivative can be produced according to the following reaction formula.

Similarly, in the present invention, the hydroxyl protecting group is a tetrahydropyranyl group, a methoxymethyl group, a 4-methoxytetrahydropyranyl group, a 1-ethoxyether group, a 1-methyl-1-methkinether group, a t-butyldimethylsilyl group. Examples include t-butyldimethylsilyl group, benzoyl group, acetyl group, etc.

1st process ↓ I(,’0 2nd process ↓ πδ 26 Go 6 still Pi. .

(In the formula, R1, Ki and R3 are the same as above, ": is a hydroxyl protecting group, and R5 is a tunyl group or an alkyl group.) [First step] This step is obtained by subjecting the cyclopentylidene derivative represented by the general formula (If) to a water utilization reaction.
A hydroxymethylcyclopentane derivative represented by [l] is produced.

The cyclopentylidene derivative represented by the general formula (If) reduces a Corey-2 ctone derivative to 2 ctol,
It is a compound that can be easily obtained by subjecting it to the Witteitz reaction, oxidizing the hydroxyl group, and then performing a methylene reaction (see the reference side below).

The water utilization reaction in this step is carried out by hydroboration and oxidation. For hydroboration, for example, 9-BBN (9-borabicyclo[6°6.1]nonane)
Hydroboration reagents such as , Texylbokun, etc. can be used. The amount of hydroboration reagent used is usually 1 to 1.
Use 5 equivalents.

When carrying out the reaction, it is desirable to carry out the reaction in a solvent.
For example, ether solvents such as tetrahydrofuran, diglyme, and diethyl ether can be used.

The reaction proceeds smoothly at -25°C to room temperature.

Additionally, the process involves hydroboration followed by oxidation without isolation of the product. For example, an oxidizing agent such as hydrogen peroxide can be used for the oxidation at °C. When performing oxidation using hydrogen peroxide, it is preferable to use it in a basic state, such as sodium hydroxide. The amount of oxidizing agent used is 5 to 15 equivalents.

The reaction proceeds smoothly at room temperature to 60°C.

Similarly, in this step, the compound produced by hydroboration using, for example, 9-BBN is presumed to have the following structure.

[Second Step] In this step, the hydroxymethylcyclobencune derivative represented by the general formula (2) obtained in the first step is oxidized to produce a β-hydroxyaldehyde derivative represented by the general formula. It is something.

For the oxidation, for example, dimethyl sulfoxide oxalyl chloride, a pyridine complex of dimethyl sulfoxide 7-sulfur trioxide, etc. can be used. The amount of the oxidizing agent to be used is usually 1 to 5 equivalents.

When carrying out the reaction, it is desirable to carry out the reaction in a solvent.
For example, halogenated hydrocarbons such as methylene chloride can be used.

Although the reaction varies depending on the type of oxidizing agent, it proceeds smoothly at 0° C. to room temperature.

In order to obtain the oxidation product of this step, a tertiary amine such as triethylamine or diisopropyletheramine is added to the reaction mixture and the mixture is treated at 0° C. to room temperature.

After the completion of this step, the product can be subjected to the next reaction in the sixth step without being isolated.

[Sixth step] This step is performed by dehydrating the β-hydroxyaldehyde represented by the general formula (rV) obtained in the second step to obtain bicycloC3, represented by the general formula (V), 3
, 0] for producing octenyl aldehyde derivatives.

Dehydration is carried out in the presence of an acidic catalyst. As acidic catalysts, acid-ammonium salts can be used. Acid-ammonium salt catalysts can be formed from acids and amines.

Examples of acids that can be used include trifluoroacetic acid, toluenesulfonic acid, camphorsulfonic acid, and acetic acid. Examples of amines that can be used include dibenzylamine, diethylamine, dimethylamine, diisopropylamine, piperidine, pyrrolidine, and piperazine. These acids and amines can be appropriately selected and used in combination, but a catalyst that is a combination of trifluoroacetic acid and dibenzylamine is preferable because it can obtain the desired product in good yield.

The amount of catalyst to be used may be about 0.2 equivalent, but it is preferable to use about 1 equivalent in order to cause the reaction to proceed rapidly.

In carrying out the reaction, it is desirable to use a solvent, and aromatic hydrocarbons such as benzene, toluene, and xylene can be used.

The reaction temperature can be selected from room temperature to 100°C, but in order to carry out the reaction smoothly, it is preferably carried out within the range of 50°C to 70°C.

[Fourth Step] In this step, the above 8i'! Bicyclo(13, o
) Octenylaldehyde derivatives and 6-carpoxyp, ＼
The alkenylbicyclo I:3.3°0]octene derivative represented by the general formula (Vl) is produced by reacting the compound with mi/ropylphosphonium fluoride.

This step needs to be carried out in the presence of a base.

As a base, t-butquine potassium, butyllithium,
Although the sodium salt of dimethyl sulfoxide and the like can be used, it is preferable to use t-butoxypotassium in order to carry out the reaction efficiently.

The amount of base to be used is usually 1 to 1.2 times the amount of carboxypropylphosphonium bromide used as the raw material.

In carrying out the reaction, ether solvents such as tetonohydrofuran, dimethoxyethane, diethyl ether, etc. can be suitably used, but there are no limitations as long as the solvent does not participate in the reaction.

The reaction proceeds smoothly by selecting a reaction temperature in the range of 0°C to 50°C.

The compound obtained in this step is usually produced as a free carboxylic acid, but for the reaction in the next step, it can be converted into a simple ester using conditions such as diazomethane or halogenated alkyl-diazabicycloundecene-a-heptandhryl. I have a child to let go of. Conversion to dimethyl can be carried out by a method easily available to those skilled in the art.

[Fifth Step] This step involves catalytically reducing the alkenylbicyclo(6,6io)octene derivative of the general formula (VI) obtained in the fourth step to selectively reduce only one of the olefins. Expression (Bishikuro [ro, 6
．． 0] This is for producing octene derivatives.

Examples of catalysts that can be used include palladium catalysts such as palladium-carbon and palladium black, Wilkinson catalysts, platinum, and nickel.

It is sufficient to use a so-called catalytic amount of the catalyst.

In carrying out this step, hydrogen may be reacted at normal pressure or under increased pressure.

It is desirable to use a solvent to carry out the reaction, and for example, alcohol solvents such as methanol and ethanol, and ester solvents such as ethyl acetate can be used.

The reaction proceeds smoothly by selecting a reaction temperature in the range of 5° C. to room temperature.

[Sixth Step] This step is performed to obtain the bicyclo compound represented by the general formula (2) obtained in the fifth step. O) A hydroxymethylbicycloC5,6,0)octene derivative represented by the general formula (2) is produced by selectively deprotecting the octene derivative.

For deprotection, tetra-n-butylammonium fluoride can be used as a deprotecting agent when R4 is a silyl group, and potassium carbonate can be used as a deprotecting agent when R4 is a benzoyl group, acetyl group, etc.

When carrying out the reaction, it is desirable to carry out the reaction in a solvent.
When using tetra-n-butylammonium fluoride as a deprotecting agent, ether solvents such as tetrahydrofuran, dimethoxyethane, and ethyl ether can be suitably used, and when using potassium carbonate as a dereefing agent, methanol and ethanol can be suitably used. Alcohol solvents such as the following can be suitably used.

The reaction proceeds smoothly at 5°C to room temperature.

[Seventh step] This step is based on the general formula (I'll
) coated with hydroxymethylbicyclo[,5,3,
0] The octene derivative is oxidized, and then the obtained product is converted into a compound represented by the general formula (2) or the general formula (
The (6-oxo-1-alkenyl)-cis-bicyclo(3,3,0)octene derivative represented by the general formula (I) is produced by reacting with the compound represented by the illusion.

The oxidation in this step needs to be carried out in the presence of an oxidizing agent. As the oxidizing agent, Collins' reagent, dimethyl sulfoxide-sulfur trioxide pyridine complex, pyridinium chlorochromate, dimethyl sulfoxide-oxalyl chloride, etc. can be used. The amount of oxidizing agent used is 7 to 10 equivalents in the case of Collins reagent, and 1 to 10 equivalents for other oxidizing agents.
Use 5 equivalents.

When carrying out the reaction, it is desirable to carry out the reaction in a solvent.
For example, halogenated hydrocarbons such as methylene chloride and chloroform are preferred.

The reaction proceeds smoothly at a temperature ranging from 0°C to room temperature.

In this step, the product obtained by subsequent oxidation is reacted without isolation with a compound represented by the above general formula or a compound represented by the above general formula 〇〇. Examples of the compound represented by the general formula (2-oxo-6,6 -dimethylhebutyl)phosphonate, dimethyl (2-oxy-4゜8-dimethyl-7-nonenyl)phosphonate, dimethyl (2-oxo-4,4,8-)rimether-
7-neu-nyl) phosphonate, dimethyl (2-oxo-2-7 clopentylethe/l/) phosphonate, etc. can be used, and the compound represented by the general formula (1) is tributylphosphine. -2-oxohebutyritene, tributylphosphine/-2-oxo-6-
Methylhebutylidene, tributylphosphine-2-oxo-6, dimethylhebutylidene, tributylphosphine-2-oxo-4,8-dimethyl-7-),
Tributylphosphine-2-oxo-4,4,8-trimethyl-71nodene, tributylphosphine-2-oxo-2-zochlorobenteletheridene, etc. can be used. When a compound represented by the general formula (a) is selected as a raw material, it is preferable to carry out the reaction in the presence of a base in order to obtain the desired product in a good yield, such as sodium hydride, butyl lithium, potassium t-butoxy, etc. can be used.

When carrying out the reaction, it is desirable to carry out the reaction in a solvent.
For example, ether solvents such as tetrahydrofuran, orthoxyethane and diethyl ether, and aromatic fa solvents such as Hensen, toluene and xylene can be used.

The reaction temperature ranges from -25°C to 50°C when using the compound represented by the general formula (2), and from 50°C to 50°C when using the compound represented by the general formula (3).
The range is 150'O.

Oka believes that the compound obtained by the oxidation in this step is a compound represented by the -direction (wherein a2 is a hydroxyl protecting group and R5 is a hydrogen atom or an alkyl group). be able to.

The present invention will be further explained in detail with reference to Reference Examples and Examples below.

Reference Example 1 (S r ;; = t-y'Hv) Knob 14/under argon atmosphere containing 2-oxa-6-oxo-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydro Bicinyloxyvinchloin (3,3,
(2.22g; 6mmo I) was dissolved in Toluev (IDm) and cooled to -75'O. Diisobutylaluminum hydride (25g/100Wf!
A hexane solution (5,1 m/m, 9 mmol) was added, and the mixture was stirred at -75°C for 70 minutes. Methanol was added until no hydrogen generation was observed at -75°C, and the temperature was raised to room temperature. After diluting with ethyl acetate (130 ml),
Washed with saturated saline (20 InI!×4 times).

After drying with anhydrous magnesium sulfate, the solvent was distilled off [1
-2-oxa-6-hydrroxy6-exo-t-buterdimethelsilyloxymethel-7-endotetrahydrobilanyloxybicycloC3,3,0)octane]
(2,53g, 100%) was obtained.

IR(neat) 23430.2950.2860.
8 Ro5c+++” Core set δ (CDCl2) 5.70-5.30 (m, 1H), 4.85-4.
55 (m, '2H), 4.40-3.25 (m, 50)
, 0.90 (s, 9H) Mass m/z i%) 2, 215 (5), 159
(17), 85 (100), 75 (, B), 73 (15
) [α]20 = −2so (c=1.98, MeO
H)D Reference Example 2 Potassium t-butoxy (3.16 g
, 28.2 rimole) was dissolved in THF (50 ml).

(10.07 g)
.

28.2 mmol) was added at room temperature. After stirring for 5 minutes, [1-2-oxa-6-vitrokidi-6-exo-opterdimetersilyloxymethylendotet 2hydrobinyloxybizok o (5,5,0
) octane) (140g, 9.1mmol)'1)
IF solution (50-) was added and stirred at room temperature for 20 minutes.

After adding a saturated aqueous ammonium chloride solution, the alcohol was distilled off under reduced pressure. The remaining aqueous layer was extracted with ether and washed with saturated brine. After drying over anhydrous magnesium sulfate, the ether was distilled off and the resulting residue was purified by silica gel column chromatography (ether 20-hexane = 2:5) to obtain [d-2α-allyl-6β-t-butyldimethyl Silyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol) (3.18g).

94 chi) was obtained.

IR (neat): 3500, 2950, 2870, 1
640°835cm' NMR, (CDC13) 5.80 (m, IH), 5.00 (m, 2H), 4.6
5 (bs, IH), 4.50-6.00 (m, 6H).

0.90 (s, 9H) Mass m/z zhong): 285 (1), 229 (1
), 211 (ro).

159 (26), 85 (100), 75 (21
), 73 (13) [α brother 0 = +21° (Q = 2.4
4, MeOH) Reference Example 6 [d-2α-allyl-6β-1-buterdimethylsilyloxymeth-4α-tetrahydropyranyloxy-1
α-Cyclopentane 9) (3.16 g.

8.5 mmol) was dissolved in methylene chloride (40+++A), and sodium acetate (280~, 2.6 mmol
) and Serai) (3.56 g) were added. Pyridinium chlorochromate ('3.
68 g, 17.1 mmol) was added, and the mixture was stirred at 0°C for 18 hours. Diluted with ether and subjected to Florisil column chromatography (ether:n-hexane-1:3-6
:1) to obtain [l-2α-allyl-6/-t-pteredimetersilyloxymethel-4α-tetrahydropyranyloxy-1-cyclopentanone (2.82 g,
90chi) was obtained.

IR (neat): 2950, 2880, 1748, 1
642°840cm-' NMRδ (CDCl2) 5.70 (m, , IH), 5. C]+(d, J=17H
z, IH).

5.00 (d, J=11Hz, 1H), 4.65 (b
sjH).

4.30 (m, IH), 5.30-4.00 (m, 4H
).

0.90 (s, 9H) Mass m/z (%): 209 (17), 1
59(17), 85(IDo), 75(35), 73
(23), 41(17) [α), = −55(c=2
．． 19, MeOH) Reference Example 4 \L/ Under argon atmosphere, C4-2α-allyl-6β-t-butyldimethylsilyloxymethyl-4α-tetonhydropinyloxy-1-cyclopentanone) (2,79
g, 7.57 mmol) in methylene chloride (26 mA)
Zinc-tetanium chloride bromide 7 reagent (Zn-TiCl4-CH2Br2/Tl
(11′, 46 mIV) was added. After confirming the disappearance of the raw materials by TLC, the reaction solution was poured into a mixed solution of saturated sodium bicarbonate solution (500 mJ) and ether (500 m7). After separating the ether layer, the aqueous layer was further extracted with ether. The ether layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (ether di-n-hexane = 1:10) to obtain [1-2-α-allyl-6
β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentylidene]
(2.48 g, 90%) was obtained.

IR (neat) 22950, 2870.1660゜16.40, 8 ro 5 crn floor δ (CDCl2) 5.60 (m, 11 (), 4.75~5.20
(m, 4H).

4.63 (bs, 1H), 5.50-4.30
(m, 5H).

0.90 (s, 9H) Mass m/Z (%): 159 (18), 133 (
11).

85 (100), 75 (19), 75 (15) [α)D
= 46 (c, = 2.84, Meα () Reference Example 5 Under an argon atmosphere, 9-bonbicycloC6,5゜1]nonane (dimer, 2.472 g, 20 jmmol) was
) suspended in IF (28N). [1-2-α-allyl-6β-t-butyldimethylsilyloxymethyl-4α
-tetoxyhydrobilanyloxo-1-cyclopentylidene) (2,476g, 6.75mmol) t7)
TI(F solution (45 ml) was lowered to a water-cooled bottom, and 5 to 1[]
The mixture was stirred at 0 for 7 hours and 60 minutes. 6N hydroxide sulfur rum aqueous solution (13.5 ml, 81 mmol) and 60% hydrogen peroxide solution (11, Eyff, 101.3 mmol)
was added and stirred at 60'C for 1 hour and 60 minutes. After TI(F) was distilled off under reduced pressure, it was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine. After drying over anhydrous sulfuric acid, the solvent was distilled off. Gel column chromatography (ether:
methanol-40:1) and purified with [d1(V-
Hydroxymethyl-2α-(6-hydroxypropyl)
-6β-t-butyldimethylsilyloxymethyl-4α
-tetoxyhydropyranyloxone clobencune) (2,
65g, 97%) wo? 4) fc.

IfL (neat): Ro 400, 2940, 2860
．． 855cm chaos δ(CDCl2) 4.65(t's, 1f(), 4.10(im,
1H), 5.15-3.95 (m, 8H)
, 0.90 (s, 9H)Mass m/z (
%, ): 159 (19), 149 (18).

133 (19), 121 (13), 105 (15), 9
5 (10), 91 (10), 85 (100), 79 (1
1).

75 (34), 7ro (18), 67 (17), 57 (2
4).

55(16), 43(17), 41(21) Reference Example 6 HP0 Oxalyl chloride (1
,88m1! , 20.0 mmol) was dissolved in 55 m/methylene chloride. Dimethyl sulfoxide (3,39m
, 47.7 mmol) in methylene chloride solution (15 mA
') was added. After stirring at −60”C for 20 minutes, Cd-1
α-Hydroxymethyl-2α-(3-hydroxypropyl)-6β-t-bunaldimethylzolyloxymether-
4α-tetrahydropyranyloxycyclopenkune) (
A solution of 1.48 g, 3.67 mmol) in methylene chloride (30 ml) was added. After stirring at -60°C for 20 minutes, triethylamine (15,36rILl) was added.

110#1 mmol) was added, and the temperature was raised to room temperature. Water was added and extracted with methylene chloride. The organic layer was washed with brine and dried over anhydrous magnesium sulfate.

The solvent was distilled off to obtain [2-hydroxy-6-formyl-
6-Nixo-tert-dimethylsilyloxymether-
7-Endo-tetra-hydropinyloxybicyclo[
3,5',O')octane) (1,19g.

8196) was obtained. From the spectral data, the compound was an equilibrium mixture between β-hydroxyaldehyde and 2 ctol.

IR (KBr): Ro450, 2950, 2870, 2
750.

1750-. 835crn Shimaki δ (CDCl2) 9.75 (trace), 4,65 (m, IH),
5j O ~ 4.50 (m, 6H), 0.90 (s, 9H
)Mass m/z (%): 515 (trac
ep-85).

Wabiφ (1s), 5s (1oo), 7s (17), 7s
・(12), 57(12), 47(11) Reference Example 7 [2-Hydroxy-6%:/lumi-6-nyxo-buterdimethylsilyloxomethyl-7-endotet 2ρhydropinyloxybicyclo r, 5.3.0
) ,,j-cutane) (1.19g, 2.97mmo
l) was dissolved in benzene ('4.5+++4'). Dibenzylammonium difluoroacetate (1.14 g, 3.66 mmol) was added under an argon atmosphere, and the mixture was stirred at 50 to 70°C for 16 hours. After cooling, water (5
0) was added and extracted with ether. The ether layer was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, and water. After drying over anhydrous magnesium sulfate, the solvent was distilled off.

The residue was purified by silica gel column chromatography (ether:n-hexane=1:1) to give (/-3-
Formyl-6-nixo-t-daterdimethelzolyloxymethyl-7-endo-tetrahydropyranyloxyl
Bicyclo[5,6,0)oct-2-ene) (1,0
3g, 82%) was obtained.

11t(ne;lt) :2950,2870,168
0,1620. ．． 835G1; 1 δ (CDCl2) 9.78 (s, IH), 6.71 (d, J=2Hz).

4.60 (bs, 1H), 5.0 [3-4.20 (m
, 6H).

0.90 (s, 9)i) Mass m/Z (%) 2295(1), 159(
33), 85 (100), 75 (26), 75 (19)
, 67(12).

57 (14), 45 (14), 43 (22,) ca]L
0 = −77° (c, = 2.77, MeOH) Reference Example 8 Ttir (J under argon atmosphere, carboxypropyl/l/), phenylphosphonium bromide)” (5,58 g,
13 mmol) was suspended in '1'HF (60TnI).
50 ml of 1-LP bath solution was added and stirred at room temperature for 10 minutes.To this was added [1-3-formyl-6-
Nixo t-butyldimeternyloxymether-7-
endo-nato2hydropyranyloxybicycloC3,3
, O)-oct-2-xn) (9901119,2,6
6 mmol) of THF solution (20 M) was added dropwise at room temperature.
Stirred for 0 minutes. Add saturated ammonium chloride aqueous solution,
The π stop was distilled off under reduced pressure. The remaining aqueous layer was adjusted to pH 5-4 with a 10-line hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off.

Ether was added to the residue, and insoluble materials were removed by filtration. An ethereal solution of diazomethane was added to the broth. 13-(4-carboquine-1-
After confirming that the spot of 7"tenyl)-6-nyxo-t-pterdimethylsilyloxymethel-7-endo-tetrahydropyranyloxybicyclo[6°5.0]oct-2-ene] has disappeared, add a small amount of formic acid. Add immediately saturated baking soda water.

Washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified using silica gel column Chromadog 2F (ether: n-hexane: 1:2).
) and purified by [:A-5-(4-methoxycarbonyl-1-butenyl)-6-nyxo-t-butenedimetersilyloxymeth-7-endotetrahydrobilanyloxopicyclo[6, 6,0]oct-2-ene)(
1,09g.

90chi) was obtained. (Z)- and 4)-isomer ratio is 2:1
Met.

IR (neat): 2950, 2870, 1745°8
40m' Core set δ(CDCl2) 6.24(d, J=16.H2, 1/3H, tran
s).

5.98 (d, J=11Hz, 2/3H, cis).

5.57 (BS, 1H), 5.30 (m, IH), 4
．． 60 (bs, IH), 120-4.25 (m, 8H)
.

2.95 (IH), 0.90 (s, 9H) Mass m
/z(%l:464(trace,M+),ro26(
20), 2ro 1 (28), 159 (29), 157 (1
6), 117 (11), 85 (100), 75 (25)
.

73(20), 67(12), 57(14), 43(1
3).

41 (13) [α), = -50 (c = i, filter 6, IVleOH) □ Reference example 9 C1-3-(4-methoxycarbonyl-1-butenyl)
, -6-nyxo-t-butyldimethyl/lyloxymethyl-7-endo-tetrahydropyranyloxybicyclo(:3.3.0)oct-2-ene] (547 mg, 1
．． 18 mmol) was dissolved in methanol (10 ml). 10% palladium/carbon (C1501 nt) was added, and the mixture was stirred for 1 hour at room temperature under a hydrogen atmosphere for 10 minutes. The catalyst was distributed from house to house, and the solvent of liquid F was distilled off. The residue was purified by silica gel column chromatography (ether: n-hexane-1=5
) and purified by [l-3-C4-methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo(3,3,0':l octo -2-ene) (509
~, 93%)'f: Obtained.

IR(neat); 2950, 28B0.1745.
840 on-'.

NM) 1.6 (CDC13”) 5.25 (d, J=IHz, IH), 4.60
(bs, IH), 3.65 (s, 3H).

2.90 (me If(), 0.90 (S,
9H).

Mass, m/z (%); 325 (8)-2
33(12)-159(2B), 85(100), 7
5(17), 73(13).

[α]2O-=-t,z°(C=1.68.MeO
H) - Reference Example 10 HPO [1-3-<4-methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3,3,
03 Oct-2-ene:) (585Qt 1.25mm
o l ) was dissolved in THF (5 ml). te)ra n
-Butylammonium fluoride (IMTl-IF bath solution 2.5 ml, 2.5 mmol) was added and stirred at room temperature for 3 hours. Saturated brine was added, and THF was distilled off under reduced pressure. 1 ml of residual water was extracted with ether, dried over anhydrous magnesium sulfate, and then the solvent was distilled off.

The product 13aWi was purified by silica gel column chromatography to obtain (1,-3-(4-methoxycarbonylbutyl)-6-nyxohydroxymethyl-7-endotetrahydropyranyloxybicyclo[3,3,0)octo-2 -ene) (425 mf, 95.2%) was obtained.

IR(neatton; 3480.2950.28
80. 1740 on ”・NM几δ(C1)C7!3) 5.25 (d, J=IHz, IH), 4.60(
m, 1)f), 3.66 (s, 3H), ;3
．． 00(m, If()・Mass, m/z (%); 352 (trac
e, M”L 268 (3), 85 (100)+
67 (11).

57 (10), 41 (11).

[α)20 ==-19° (c=2.09. Meol
-1) Example 1 Under an argon atmosphere, Collins test (Cr03・2Py1
660q+ 2.56mmol) and Serai l-(66
M) was suspended in methylene chloride (10 composition). ([-3-
(4-Methoxycarbonylbutyl)-6-nyxohydroxymethyl-7-endotetrahydropyranyloxypicyclo[3,3,O:]]octo2-:r-,:
y) (5(I+f+ 0.142 mmol)) in a methylene chloride bath solution (2.5 tnA) was added and stirred for 30 minutes under OC.

1-32 g of sodium hydrogen sulfate hydrate was added and the mixture was further stirred with OC for 10 minutes. Reaction 11k was filtered using anhydrous magnesium sulfate as a filter aid and washed with methylene chloride. The solvent was distilled off to give [3-(4-methoxycarbonylbutyl-6-exo-formyl-7-endo-tetrahydrobilanyloxybicyclo[3,3,
0: ]] Octo 2-en] 48m? , 96%).

On the other hand, sodium hydride (60% oily, 11■).

0.28 mmol) 'It1 Washed with pentane under an argon atmosphere and suspended in 3 ml of DME (dimethoxyethane). Dimethyl(2-oxoheptyl)phosphonate) (64mp, 0.29mmol) in DME solution (3
a) was added and stirred at room temperature for 25 minutes. [3-(4-methoxycarbonylbutyl)-6-nikin-formyl-7
-endotetrahydropyranyloxypicyclo[3,
A DME bath solution (3 ntl; ) of 3,03 oct-2-ene: ) (48 mg) was added, and after stirring at room temperature for 1 hour, saturated ammonium chloride aqueous solution -tL was added. Under reduced pressure, DME
After distilling off, the residue was extracted with ether, and the ether layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the residue obtained was purified by silica gel column chromatography (ether: n-hexane-2=5) to give [3-(4-methoxycarbonylbutyl)] -6-
Nixo(3-oxo-trans-1-octenyl)-
7-nindotetrahydropyranyloxybicyclo[3
,3,0]oct-2-ene] (35μ, 57%).

IR(neat); 2950, 2880, 1742
,1698°1672.1628crn'- NMI also δ (CDC13) 6.80 (+n, IH), 6.17 (dxd, J=
16.4Hz, IH), 5.30 (d, J=it-
1z, 1[l), 4.65. 4.55 (each bs.

total 1) J) + 3.68 (s, 3l-1)
, 3.00 (m, IH)・Mass m/z (%); 362 (10), 31
8 (13), 85 (100), 67 (16), 57
(18).

55 (13), 43 (20), 41 (20).

Examples 2-5 IIPO In a similar manner to Example 1, (3-oxo-1
The results of synthesizing the -alkenyl)-cis-bicyclo(3,3,0)octene derivative are shown in Ju-1, and its spectral data are shown in Table-2.

Table 2 Reference Example 11 (3-(4-methoxycarbonylbutyl)-6-nyxo(3-oxo-trans-1-octenyl)-7-nindotetrahydropyranyloxypicyclo[3,3,
0) Oct-2-ene] (32mf + 0.072mm
ol) was dissolved in methanol (5 Inl. -20C
Cool and add excess sodium borohydride. −
After stirring for 20 minutes at 20C, excess acetone was added. After returning to room temperature, add saturated ammonium chloride aqueous solution,
Methanol and acetone were distilled off under reduced pressure. The remaining aqueous layer was extracted with ether, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give (3-(4-methoxycarbonylbutyl)-6-nyxo(3-hydroxy-trans-1
-octenyl)-7-nindotetrahydropyranyloxybicyclo[:3.3.0]oct-2-ene] (
32 to 100 cracks) were obtained.

IR(neat); 3470, 3230.2950,
2880°1742 sub-1°NMRδ (CDC73) 5.57 (m, 2H), 5.28 (d, J
=IHz, IH), 4.63 (bs, IH).

3.65 (s, 3H), 2.95 (m, IH
).

Ma S S-m/z (%); 430 (ly M
+H20) t 302 (15), 85 (100),
67 (13).

57 (16), 55 (11), 43 (17)
.

41(18).

Reference Examples 12 to 15 The results and spectral data of various 3-oxo-1-alkenylcis-bicyclo[3,3,0:]octene derivatives reduced by the same method as Reference Example 11 are shown in Table 3. .

-3(Reference Example 16 01-1 + (:3-(4-methoxycarbonylbutyl)-6-nik/-(3-hydroxy-trans-1-octenyl)-
7-Nindotetrahydrobylanyloxybicyclo(3
,3,0)oct-2-ene] (32ml 0.072
mmol) acetic acid: water: THF (0,51111)
(3:l to 1.volume ratio) Dissolve in the mixed liquid, 45-50U
The mixture was stirred for 5 hours. After diluting with ether, 91% with saturated deuterated water
It was peaceful. The ether layer was washed with saturated brine and dried over anhydrous sulfurized magnesium.

The residue obtained by distilling off the solvent was purified by silica gel column chromatography (ether di-n-hexane = 5:1 to ether: methanol - 40:1), and the more polar fraction [3-(4 -Methoxycarbonylbutyl")-6-niki7-(3α-hydroxy-trans-1-octenyl)-7-nindohydrogysibicyclo(3,3,0)oct-2-xn] (13
1n? , 48%) and as a less polar fraction [3-(4-methoxycarbonylbutyl)-6-nixo(3β-hydroxy-trans-1-octenyl)].
-7-nindohydroxybicycloC3,3,0]oct-2-ene) (7 mg, 26 doses) was obtained. The spectral data of the α-epimer is shown below. The spectrum of the β-epimer is similar.

IR(neat); 3400, 2970.2930,
2870°1742cnr' - NMI(, δ(CDCJI!a) 5.60 (m+28)+5.33 (bs, I
H) +4.12 (m, IH), 3.69 (s
, 3H).

3.00 (m, IH).

Mass m/z (%); 346 (25, M+-
H2O), 328 (18), 315 (9), 302
(71).

275 (15), -247 (11), 232 (32)
, 199 (17L 193 (19).

180 (30), 179 (27)・-11 (-1 Reference Examples 17-20 H 10 H Various [3-(4-methoxycarbonylbutyl)-6-nikin-(3- Hydroxy-trans-1-alkenyl)-7-nindotetrahydropyranyloxybicyclo[3,3,03-A-clay2
Table 4 shows the results and spectral data of the de-'l'i (P-formation) of the 15-position hydroxyl group using silica gel column chromatography. The more polar isomer was designated as α-ebibu, and the less polar isomer was designated as β-epimer.

366 Needle example 21 0H [3-(4-methoxycarbonylbutyl)-6-nikin-(3α-hydroxy-trans-1-octenyl)-
7-Nindohydroxybicyclo(3,3,0)]]oct-2-ene] (10 ml, 0.021 mmol) was dissolved in methanol (0.3 ml) in gH. A 10% aqueous sodium hydroxide solution (0, zmlt) was added in OC. After stirring for 9 hours in OC, the mixture was neutralized with a 10% aqueous hydrochloric acid solution under cooling. After distilling off methanol under reduced pressure, the mixture was adjusted to pH 3 to 4. Extracted with ethyl acetate. Anhydrous IkL, (neat); 3350
,2910,2850,1700°14'50.125
0crn"-NM几δ(CDc43) 5.60 (m, 2)i), 5.33 (bS,
IH).

□, = s ox → 4. IL (m, LH).

3, go (m, 111) + 3.00 (!n,
IH) + Sterilization - Imperial Order Beka Ichibutsu) 〒44・Year-1; O, QO (Jin, :r=6HL 3t-1).

Ma s s (CI r NHs ) m'/z;
368 (M++ N H4) -Melting point; 73-79C [α)25 = +16° (C = -0,25,MeOH)
.

Similarly, 15β-epimer is also hydrolyzed, and 9(0)-
The 15β isomer of methano-2g (9(:t)-PGI 1 was obtained. Spectral data (I & NMR, M
a s s ) agrees with the data of Δ6(9α)-PGI engineering.

Reference Example 22 ~ λS H In the same manner as in Reference Example 21, each t[3-(4-methoxycarbonylbutyl)-6-nikin-(3α-hydroxy-trans-1-alkenyl)-7-nindohydroxybicyclo( 3,3,0)oct-2-ene] to each 1[9(0)-meta/-A6(9a)-P
'GI, @4 bodies)? :Tokuk. The results and hiss vector data are shown in Table 5.

Similarly, 15β-epimer is also hydrolyzed, and 9(0)-
The 15β isomer of the methano-Δ6(9α)-PGI, derivative was obtained. Spectral data (IR, NMR.

M a s s ) is in agreement with the data for Δ6(9α) 4a-r- and derivatives, respectively.

Among the compounds synthesized by the methods described above, for example, 9(0)-
Methano-Δ6(9α)-PGI has the following biological activities. When rabbit blood was used, adenosine diphosphate (ADP)-induced inflammation was demonstrated.

Regarding the effects on blood pressure, when using rats, it showed the same strength as PGI 2, and showed a blood pressure lowering effect at a dose of 0.1 μg/Wyy. 6 The influence on the power number is also PGI2
The strength is almost the same as that of 1, and in experiments using rats, 1
A dose of 7 to μ&gt; showed an increase in frequency of 6. It also showed anti-ulcer activity at a concentration as low as 10-'M in experiments using rabbit stomachs, which is comparable in strength to PGE2. Cytotoxicity is very weak, Ic. =5μg/
It's in ml.

patent applicant

Claims (1)

[Claims] (6-oxy-1-alkenyl)-cis-
BicycloC3,5,0)octene derivative (wherein R1 is a linear, branched or cyclic alkyl group or alkenyl group having 5 to 10 carbon atoms, R2 is a hydrogen atom or a hydroxyl group δ
R3 is a hydrogen atom or an alkyl group. ).