JPH0432812B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula (In the formula, R ¹ is a straight chain, branched or cyclic alkyl group or alkenyl group having 5 to 10 carbon atoms, R ²
and R ³ is a hydrogen atom or a hydroxyl group protecting group,
R ⁴ is a hydroxyl group, an acetyloxy group or a butenyl group. ) related to bicyclo[3.3.0]octene derivatives.

The bicyclo[3.3.0]octene derivative of the present invention represented by the above general formula () undergoes a hydration reaction, then a deprotection reaction of the hydroxyl group, and is further oxidized.
(0)-Methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ and its analogs (see Reference Examples below). 9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ has a strong platelet aggregation inhibiting effect, and for example, when human platelets are used, its effect is comparable to that of the chemically unstable PGI ₂ . , is a compound used as a therapeutic or preventive drug for various cardiovascular diseases (see test examples below).

Conventionally, methods for producing 9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ include (a) a method in which PGE ₂ is used as a raw material through 14 steps [Proceedings of the 103rd Annual Meeting of the Pharmaceutical Society of Japan] 156
(1983)], (b) Method for producing from 1,3-cyclooctadiene through 19 steps [Pharmaceutical Society of Japan No. 103
Annual Meeting Proceedings, p. 157 (1983)] and (c) Process for producing furfural through 12 steps (Pharmaceutical Society of Japan,
104th Annual Meeting (Sendai) Proceedings p282) is known.
In method (a), the raw materials are expensive; in method (b), the target product is produced as a racemate; in both (a) and (b), the total yield is very low; and in method (c), The disadvantage of the method was that the final product was very difficult to purify.

The present inventors have discovered that 9(0)-methano-
As a result of intensive research to produce Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ and its analogues, we discovered that the compound of the present invention could serve as an important intermediate to achieve the objective, and completed the present invention. did.

The bicyclo[3.3.0]octene derivative of the present invention represented by the general formula () can be produced according to the following reaction formula.

In addition, the protecting group for hydroxyl group in the present invention is a ^{tetrahydropyranyl} group, a methoxymethyl group,
4-methoxytetrahydropyranyl group, 1-ethoxyethyl group, 1-methyl-1-methoxyethyl group, t-butyldimethylsilyl group, diphenyl-
Examples include t-butylsilyl group, benzoyl group, acetyl group, triethylsilyl group, etc., and R ³ includes t-butyldimethylsilyl group, benzoyl group, acetyl group, tetrahydropyranyl group, methoxymethyl group, 4-methoxy Examples include a tetrahydropyranyl group, a 1-ethoxyethyl group, a 1-methyl-1-methoxyethyl group, a diphenyl-t-butylsilyl group, and a triethylsilyl group.

The present invention can be produced according to the following reaction formula.

[First step] This step reduces the bicyclo[3.3.0]octenyl aldehyde derivative represented by the general formula () to produce bicyclo[3.3.0]octenyl methyl alcohol represented by the general formula (-a). It is used to produce derivatives.

Among the bicyclo[3.3.0]octenylaldehyde derivatives represented by the above general formula (), which are the raw materials for this step, compounds in which R ¹ is linear or branched are used in the Proceedings of the 104th Annual Meeting of the Pharmaceutical Society of Japan (Sendai) Compounds in which R ¹ is cyclic can also be produced according to the same method (see Reference Examples below).

This step needs to be carried out in the presence of a reducing agent. As the reducing agent, diisobutylaluminum hydride, sodium borohydride, lithium aluminum hydride, etc. can be used. The amount of the reducing agent to be used is equivalent to or slightly in excess of the bicyclo[3.3.0]octenyl aldehyde derivative represented by the general formula ().

It is desirable to carry out this step in a solvent, such as alcohol solvents such as methanol and ethanol, ether solvents such as diethyl ether and tetrahydrofuran, aromatic solvents such as benzene and toluene, methylene chloride, and chloroform. Examples include halogenated solvents such as halogenated solvents, which can be appropriately selected and used depending on the reducing agent used. The reaction proceeds at -100 to 50°C.

[Second process]

In this step, the bicyclo[3.3.0]octenylmethyl acetate derivative represented by the general formula (-b) is obtained by acetylating the bicyclo[3.3.0]octenylmethyl alcohol derivative obtained in the first step. It is manufactured.

For acetylation, acetic anhydride, which is normally used in this type of reaction, is used.

In carrying out this step, pyridine, 4-dimethylaminopyridine, etc. can be used as a catalyst.

This step is preferably carried out in a solvent, and aromatic solvents such as benzene and toluene, ether solvents such as diethyl ether and tetrahydrofuran, and halogen solvents such as methylene chloride can be used.

The reaction can be carried out at -25°C to 100°C.

[Third step]

This step consists of the general formula (-
The pentenylbicyclo[3.3.0]octene derivative represented by the general formula (-c) is produced by reacting the bicyclo[3.3.0]octenyl methyl acetate derivative represented by b) with lithium dialkyl cuprate. . Lithium dialkyl cuprate is made by copper iodide and 3-butenyllithium (for the manufacturing method, see RFCunico, Y.-K.Han, J.Organomet.
Chem., 174 , 247 (1979)].

In carrying out this step, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, etc. can be suitably used.

The reaction can be carried out at -100°C to 50°C.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1 (Si=t-butyldimethylsilyl group) {3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyl Diisobutylaluminum hydride (1.25 mmol, 0.71 ml, 1.76 M Hexane solution) was added at -78°C and stirred for 90 minutes. Methanol was added dropwise to the reaction solution until no hydrogen was generated, and then diluted with ether. Further, saturated brine was added and stirring was continued until the organic layer became transparent. After separating the ether layer, the ether extraction was repeated, and the ether layers were combined and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain {3-hydroxymethyl-6(S)-
[3'(S)-t-butyldimethylsilyloxy-
1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (373 mg, 88
%) was obtained as an almost colorless oil.

IR (neat): 3350cm ^-1 . NMRδ (CDCl ₃ ) 5.47 (m, 3H), 4.13 (m, 3H), 3.73
(m, 1H), 2.97 (m, 1H). Massm/z: 451 (M ⁺ -57). Example 2 (THP=tetrahydropyranyl group) {3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-
(1S,5S)-cis-bicyclo[3.3.0]octo-2
-ene} (370 mg, 0.83 mmol) was subjected to the same reaction procedure as in Example 1 to prepare {3-hydroxymethyl-6
(S)-[3'(S)-tetrahydropyranyloxy-
1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (316 mg, 85%)
was obtained as an almost colorless oil.

IR (neat): 3345cm ^-1 . NMRδ (CDCl ₃ ) 5.45 (m, 3H), 4.55 (m, 2H), 4.10
(m, 3H), 3.50-4.00 (m, 5H), 2.98
(m, 1H). Massm/z: 364 (M ⁺ -84). Example 3 {3-hydroxymethyl-6(S)-[3'(S)-
t-Butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]
acetic anhydride (0.29 mmol, 27 μ) in a solution of oct-2-ene (97 mg, 0.19 mmol) in pyridine (1.5 ml).
and a catalytic amount of 4-dimethylaminopyridine were added at room temperature, and the mixture was stirred for 30 minutes. A saturated aqueous copper sulfate solution was added to the reaction mixture, and the mixture was extracted with ether. The ether layer was washed with water and then dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to give {3-acetoxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]- 7
(R)-t-butyldimethylsilyloxy-(1S,
5S)-cis-bicyclo[3.3.0]oct-2-ene} (104 mg, 100%) was obtained as a colorless oil.

IR (neat): 1755cm ^-1 . NMRδ (CDCl ₃ ) 5.47 (m, 3H), 4.55 (s, 2H), 4.01
(m, 1H), 3.68 (m, 1H), 2.93 (m,
1H), 2.05(s, 3H). Massm/z: 493 (M ⁺ -57). Example 4 {3-hydroxymethyl-6(S)-[3'(S)-
From tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (85 mg, 0.19 mmol) By the same reaction procedure as in Example 3, {3-acetoxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-
Tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (93 mg,
100%) was obtained as an almost colorless oil.

IR (neat): 1750cm=1. NMRδ (CDCl ₃ ) 5.45 (m, 3H), 4.55 (m, 4H), 4.05
(m, 1H), 3.40-4.00 (m, 5H), 2.91
(m, 1H), 2.05 (s, 3H). Massm/z: 406 (M ⁺ -84). Example 5 Cuprous iodide (163 mg, 0.85 mmol) in THF
Freshly prepared 3-butenyllithium (1.70 mmol, 1.31 ml, 1.30 M hexane solution) was added to the suspension (1.5 ml) at -30°C, and the mixture was stirred for 30 minutes. After cooling the reaction solution to -78°C, {3-acetoxymethyl-6
(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-
Butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (213mg,
A solution of 0.39 mmol) in THF (1 ml) was added, and the mixture was stirred for 1 hour under the same conditions. After further stirring at room temperature for 0.5 hour,
The reaction was stopped with a saturated aqueous ammonium chloride solution. After extraction with ether, the ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography to obtain {3-(4'-pentenyl)-6
(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-
Butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (154 mg,
73%) was obtained as an almost colorless oil. This substance contains about 10% of {2-(3'-butenyl)-3-methylidene-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-(1S ，
5S)-cis-bicyclo[3.3.0]octane}.

IR (neat): 1645cm ^-1 . NMRδ (CDCl ₃ ) 5.40-6.05 (1H, m), 5.35 (2H, m),
5.20 (about 1H, bs), 4.90 (2H, m), 4.00
(1H, m), 3.60 (1H, m), 2.90 (about 1H, m), Massm/z: 489 (M ⁺ -57). Example 6 {3-acetoxymethyl-6(S)-[3'(S)-
From tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (191 mg, 0.39 mmol) Example 5
By exactly the same reaction procedure, {3-(4'-pentenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-
Tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (133 mg,
70%) was obtained as an almost colorless oil. This substance contains about 10% of {2-(3'-butenyl)-3-methylidene-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-(1S, 5S )
-cis-bicyclo[3.3.0]octane}.

IR (neat): 1645cm ^-1 . NMRδ (CDCl ₃ ) 5.40-6.05 (1H, m), 5.35 (2H, m),
5.20 (about 1H, bs), 4.90 (2H, m), 4.55
(2H, m), 4.00 (1H, m), 3.40-3.70
(5H, m), 2.90 (approx. 1H, m), Massm/z: 402 (M ⁺ -84). Reference example 1 {3-(4'-pentenyl)-6(S)-[3'(S)
−
t-Butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]
Oct-2-ene} (175 mg, 0.32 mmol) (purity approx.
9-BBN in THF (1.2 ml) solution of
(0.42 mmol, 0.83 ml, 0.5 MTHF solution) was added at 0°C and stirred under the same conditions for 5 hours. After further stirring at room temperature for 0.5 hour, 6N NaOH aqueous solution (0.21 ml) and 30% hydrogen peroxide solution (0.18 ml) were added to the reaction solution. After stirring at 60°C for 1 hour, the reaction solution was diluted with water and extracted with ether. The ether layer was washed with saturated aqueous sodium thiosulfate and saturated brine, and then dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to give {3-(5'-hydroxypentyl)-6(S)-
[3'(S)-t-butyldimethylsilyloxy-
1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (145 mg, 81
%) as an almost colorless oil.

IR (neat): 3350cm ^-1 . NMRδ (CDCl ₃ ) 5.47 (m, 2H), 5.24 (m, 1H), 4.05
(m, 1H), 3.64 (m, 3H), 2.91 (m,
1H). Massm/z: 507 (M ⁺ -57). Reference example 2 {3-(4'-pentenyl)-6(S)-[3'(S)
−
Tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (156 mg, 0.32 mmol) ( purity approximately 90%)
From {3-
(5'-hydroxypentyl)-6(S)-[3'(S)
−
Tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (121 mg, 75%) Obtained as an almost colorless oil.

IR (neat): 3400cm ^-1 . NMRδ (CDCl ₃ ) 5.45 (m, 2H), 5.24 (m, 1H), 4.60
(m, 2H), 4.05 (m, 1H), 3.40~3.70
(m, 7H), 2.91 (m, 1H). Massm/z: 420 (M ⁺ -84). Reference example 3 {3-(5'-hydroxypentyl)-6(S)-
[3'(S)-t-butyldimethylsilyloxy-
1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (22 mg,
A tetra-n-butylammonium fluoride solution (0.3 mmol, 0.3 ml, 1 MTHF solution) was added to the solution (0.039 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with saturated brine and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was separated and purified using silica gel column chromatography (ethyl acetate-acetone, 95:5) to obtain {3-(5'-hydroxypentyl)
-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S, 5S)
-cis-bicyclo[3.3.0]oct-2-ene}
(13 mg, 100%) was obtained as an almost colorless viscous liquid.

IR (neat): 3350cm ^-1 . NMRδ (CDCl ₃ ) 5.52 (m, 2H), 5.28 (bs, 1H), 4.07
(m, 1H), 3.65 (m, 3H), 2.97 (m,
1H). Massm/z: 318 (M ⁺ -18). Reference example 4 {3-(5'-hydroxypentyl)-6(S)-
[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (20mg, 0.040mmol)
in a mixed solvent of acetic acid-water-THF (3:1:1) (1
ml) and heated at 60°C for 3 hours. After evaporating the solvent, a small amount of saturated sodium bicarbonate water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography, and {3-
(5'-hydroxypentyl)-6(S)-[3'(S)
−
Hydroxy-1'-trans-octenyl]-7
(R)-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (13 mg, 100%) was obtained as an almost colorless viscous liquid. Various spectral data were completely consistent with those obtained in Reference Example 3.

Reference example 5 {3-(5'-hydroxypentyl)-6(S)-
[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (12 mg,
0.036 mmol) in acetone-H ₂ O (1:4, 1.5 ml)
Using Pt obtained by reducing PtO ₂ as a catalyst, the mixture was stirred at 60° C. for 24 hours in the presence of sodium bicarbonate (3.2 mg, 0.038 mmol) in an oxygen stream. Filter the catalyst, 10%
After neutralization with an aqueous HCl solution, acetone was distilled off.
After making the mixture weakly acidic again with a 10% aqueous HCl solution, the mixture was thoroughly extracted with ethyl acetate. Dry the extract over anhydrous sodium sulfate and distill off the solvent.
(+)-9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ (8 mg, 61
%) was obtained as an almost colorless viscous oil.

IR (neat): 3350, 1700, 1450, ^{1250cm -1} . NMRδ (CDCl ₃ ) 5.60 (m, 2H), 5.31 (bs, 1H), 4.11
(m, 1H), 3.80 (m, 1H), 3.00 (m,
1H), 0.90 (t, J=6Hz, 3H). Mass (CI, NH ₃ ) m/z: 368 (M ⁺ +NH ₄ ). [α] ²⁰ _D = +16° (c = 0.25, MeOH) Reference example 6 {2(R)-allyl-3(R)-[3'(S)-t-
butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentanone} (354 mg, 0.72 mmol) in methylene chloride (7 ml)
Add zinc-titanium chloride-methylene bromide reagent (Zn- _TiCl4 - _{CH2Br2 /} THF, 3.74
ml, approximately 1.3 equivalents) was added. After stirring for 30 minutes under the same conditions, the raw materials disappeared, so the reaction solution was poured into a two-layer system of ether-saturated aqueous sodium bicarbonate solution to stop the reaction. Then, the ether layer was separated and further extracted with ether. The combined ether layers were washed with saturated ammonium chloride water and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain {2(R)-allyl-3(R)-
[3'(S)-t-butyldimethylsilyloxy-
3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene) (326 mg, 88%) was obtained as a nearly colorless oil.

IR (neat): 3078, 2930, 2850, 1648, 1460, 1360, 1247cm ^-1 . NMRδ (CDCl ₃ ) 5.70 (m, 1H), 5.40 (m, 2H), 4.70~
5.05 (m, 4H), 4.02 (m, 1H), 3.76
(1H, m), 2.00-2.60 (m, 6H), 1.38
(m, 9H), 0.88 (s, 18H), 0.02 (s,
12H). Massm/z: 433 (M ⁺ -57), 419, 391. Reference example 7 {2(R)-allyl-3(R)-[3'(S)-t-
Butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene} (698 mg, 1.42 mmol) and 9-borabicyclo[3.3.0 ] Nonane (9-BBN)-THF solution (7.10 mmol, 14.2 ml) was added at room temperature and stirred for 3 hours. Next, 6N-NaOH aqueous solution (6.9
ml) and a 30% aqueous H ₂ O ₂ solution (5.8 ml) were slowly added dropwise at room temperature, and the mixture was stirred at 60°C for 2 hours. The reaction solution was extracted with ether, and the ether layer was washed with an aqueous sodium thiosulfate solution and water. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain {1(S)
-Hydroxymethyl-2(S)-(3'-hydroxypropyl)-3(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4 (R)-t-butyldimethylsilyloxycyclopentane} (442mg, 59%)
was obtained as a colorless oil.

IR (neat): 3345, 2920, 2850, 1456, 1360, 1246cm ^-1 . NMRδ (CDCl ₃ ) 5.35 (m, 2H), 3.95 (m, 2H), 3.59
(m, 4H), 2.16 (m, 4H), 1.10~1.80
(m, 16H), 0.87 (s, 18H), 0.04 (s,
12H). Massm/z: 469 (M ⁺ -57), 451, 394, 377. Reference example 8 Under exactly the same conditions as Reference Examples 6 and 7, {2(R)
-Allyl-3(R)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)-tetrahydropyranyloxy-1-cyclopentanone}( 432mg,
{1(S)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3) with a yield of 74% from
(S)-[3'(S)-tetrahydropyranyloxy-
275 mg of 3'-cyclopentyl-1'-trans-propenyl-4(R)-tetrahydropyranyloxycyclopentane was obtained as an almost colorless oil.

IR (neat): 3350, 2930, 2850, 1450, 1365, 1200cm ^-1 . NMRδ (CDCl ₃ ): 5.34 (m, 2H), 4.50 (m, 2H), 4.00
(m, 2H), 3.60 (m, 8H). Massm/z: 466 (M ⁺ ), 448. Reference example 9 DMSO (0.83 ml,
11.7 mmol) in methylene chloride (4 ml) at -78
The mixture was added over 5 minutes at ℃ and stirred for 15 minutes under the same conditions. To this {1(S)-hydroxymethyl-2(S)
-(3'-Hydroxypropyl)-3(S)-[3'(S
)
-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-4(R)
-t-butyldimethylsilyloxycyclopentane} (473 mg, 0.900 mmol) in methylene chloride (3
ml) solution was added dropwise and stirred for an additional 15 minutes at -78°C. Under the same conditions, triethylamine (2.50ml,
18.0 mmol) was added, the cooling bath was removed, and the mixture was stirred for 15 minutes. Methylene chloride was distilled off under reduced pressure, and benzene (8 ml) and dibenzylamine trifluoroacetate (220 mg, 0.900 mmol) were added to the resulting residue, followed by stirring at 70°C for 4 hours. The reaction solution was diluted with ether, washed with an inexpensive aqueous ammonium solution, a saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent,
The residue was purified by silica gel column chromatography to give {3-formyl-6(S)-[3'(S)-t
−
Butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-
Butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (385mg,
85%) was obtained as an almost colorless oil.

IR (neat): 2950, 2850, 1675, 1450, 1360, 1250cm ^-1 . NMRδ (CDCl ₃ ) 9.82 (s, 1H), 6.72 (bs, 1H), 5.45
(m, 2H), 4.05 (m, 1H), 3.76 (m,
1H), 3.23 (m, 1H), 1.10~2.80 (m,
15H), 0.87, 0.90 (2s, 18H), 0.03(s,
12H). Massm/z: 447 (M ⁺ −57), 433, 357, 337, 315, 301, 200, 71. Reference example 10 In the same manner as in Reference Example 9, {1(S)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3
(S)-[3'(S)-tetrahydropyranyloxy-
Yield 68% from 3'-cyclopentyl-1'-trans-propenyl-4(R)-tetrahydropyranyloxycyclopentane (275 mg, 0.74 mmol)
{3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-
Trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (223 mg) was obtained as an almost colorless oil.

IR (neat): 2950, 2850, 1680cm ^-1 . NMRδ (CDCl ₃ ) 9.81 (s, 1H), 6.74 (bs, 1H), 5.45
(m, 2H), 4.48 (m, 2H), 3.20~4.10
(m, 7H). Massm/z: 444 (M ⁺ ), 359. Example 7 By the same reaction procedure as in Example 1, {3-
Formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S, 5S )-cis-bicyclo[3.3.0]oct-2-ene} (418mg, 0.83mmol)
from {3-hydroxymethyl-6(S)-[3'(S)
-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)
-t-butyldimethylsilyloxy- (1S, 5S)
-cis-bicyclo[3.3.0]oct-2-ene}
(372 mg, 86%) was obtained as an almost colorless oil.

IR (neat): 3350cm ^-1 . NMRδ (CDCl ₃ ) 5.45 (m, 3H), 4.13 (m, 3H), 3.70
(m, 1H), 2.98 (m, 1H). Massm/z: 449 (M ⁺ -57). Example 8 By the same reaction procedure as in Example 1, {3-
Formyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis- Bicyclo[3.3.0]oct-2-ene} (368mg, 0.83mmol) to {3
-hydroxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-
1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (306 mg, 83%)
was obtained as an almost colorless oil.

IR (neat): 3345cm ^-1 . NMRδ (CDCl ₃ ) 5.45 (m, 3H), 4.55 (m, 2H), 4.10
(m, 3H), 3.50-4.00 (m, 5H), 2.98
(m, 1H). Massm/z: 362 (M ⁺ -84). Example 9 By the same reaction procedure as in Example 3, {3-
Hydroxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-
1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (96 mg,
0.19mmol) from {3-acetoxymethyl-6
(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis -bicyclo[3.3.0]oct-2-ene} (103 mg, 100%) was obtained as a colorless oil.

IR (neat): 1755cm ^-1 . NMRδ (CDCl ₃ ) 5.47 (m, 3H), 4.54 (s, 2H), 4.00
(m, 1H), 3.68 (m, 1H), 2.92 (m,
1H), 2.05(s, 3H). Massm/z: 492 (M ⁺ -57). Example 10 By the same reaction procedure as in Example 3, {3-
Hydroxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-
trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (84mg, 0.19mmol)
from {3-acetoxymethyl-6(S)-[3'(S)
-Tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-
Bicyclo[3.3.0]oct-2-ene} (91 mg,
100%) was obtained as an almost colorless oil.

IR (neat): 1750cm ^-1 . NMRδ (CDCl ₃ ) 5.45 (m, 3H), 4.55 (m, 4H), 4.05
(m, 1H), 3.40-4.00 (m, 5H), 2.91
(m, 1H), 2.05 (s, 3H). Massm/z: 404 (M ⁺ -84). Example 11 By the same reaction procedure as in Example 5, {3-
Acetoxymethyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-
1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (211 mg,
0.39mmol) to {3-(4′-pentenyl)-6
(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis -bicyclo[3.3.0]oct-2-ene} (149 mg, 70%) was obtained as an almost colorless oil. This substance also contained about 10% of substances generated by γ-attack.

IR (neat): 1645cm ^-1 . NMRδ (CDCl ₃ ) 5.40-6.05 (1H, m), 5.35 (2H, m),
5.20 (about 1H, bs), 4.90 (2H, m), 4.00
(1H, m), 3.60 (1H, m), 2.90 (about 1H,
m). Massm/z: 487 (M ⁺ -57). Example 12 By the same reaction procedure as in Example 5, {3-
Acetoxymethyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-
trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (190mg, 0.39mmol)
from {3-(4'-pentenyl)-6(S)-[3'(S
)
-Tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-
Bicyclo[3.3.0]oct-2-ene} (131mg,
70%) was obtained as an almost colorless oil. This substance also contained about 10% of substances generated by γ-attack.

IR (neat): 1645cm ^-1 . NMRδ (CDCl ₃ ) 5.40-6.05 (1H, m), 5.35 (2H, m),
5.20 (about 1H, bs), 4.90 (2H, m), 4.55
(2H, m), 4.00 (1H, m), 3.40~3.70
(5H, m), 2.90 (approx. 1H, m). Massm/z: 400 (M ⁺ -84). Reference example 11 By the same reaction operation as in Reference Example 1, {3-
(4'-pentenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-
1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (173 mg,
0.32 mmol) (approx. 90% purity) to {3-(5'-hydroxypentyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-
1'-trans-propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (140 mg, 80
%) was obtained as an almost colorless oil.

IR (neat): 3350cm ^-1 . NMRδ (CDCl ₃ ) 5.47 (m, 2H), 5.24 (m, 1H), 4.05
(m, 1H), 3.64 (m, 3H), 2.91 (m,
1H). Massm/z: 505 (M ⁺ -57). Reference example 12 By the same reaction operation as in Reference Example 2, {3-
(4'-pentenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-
trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (154mg, 0.32mmol)
(purity about 90%) to {3-(5'-hydroxypentyl)-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7( R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octo-
2-ene} (115 mg, 72%) was obtained as an almost colorless oil.

IR (neat): 3400cm ^-1 . NMRδ (CDCl ₃ ) 5.45 (m, 2H), 5.24 (m, 1H), 4.60
(m, 2H), 4.05 (m, 1H), 3.40~3.70
(m, 7H), 2.91 (m, 1H). Massm/z: 418 (M ⁺ -84). Reference example 13 By the same reaction operation as in Reference Example 3, {3-
(5'-hydroxypentyl)-6(S)-[3'(S)
−
t-Butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-
t-Butyldimethylsilyloxy-(1S,5S)-
cis-bicyclo[3.3.0]oct-2-ene} (21
mg, 0.039 mmol) to {3-(5'-hydroxypentyl)-6(S)-[3'(S)-hydroxy-3'-
Cyclopentyl-1'-trans-propenyl]-7
(R)-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (12 mg, 100%) was obtained as an almost colorless viscous liquid.

IR (neat): 3350cm ^-1 . NMRδ (CDCl ₃ ) 5.52 (m, 2H), 5.28 (bs, 1H), 4.07
(m, 1H), 3.65 (m, 3H), 2.97 (m,
1H). Massm/z: 316 (M ⁺ -14). Reference example 14 By the same reaction operation as in Reference Example 4, {3-
(5'-hydroxypentyl)-6(S)-[3'(S)
−
Tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (19 mg ，
0.040 mmol) from {3-(5'-hydroxypentyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)
-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (12 mg, 100%) was obtained as an almost colorless viscous liquid. Various spectral data were completely consistent with those obtained in Reference Example 13.

Reference example 15 By the same reaction operation as in Reference Example 5, {3-
(5'-hydroxypentyl)-6(S)-[3'(S)
−
Hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)
-cis-bicyclo[3.3.0]oct-2-ene}
(11 mg, 0.036 mmol) to {3-(4'-carboxybutyl)-6(S)-[3'(S)-hydroxy-3'-
Cyclopentyl-1'-trans-propenyl]-7
(R)-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (7 mg, 60%) was obtained as a colorless white solid.

Melting point: 115-116°C (recrystallized from ethyl acetate-n-hexane) IR (KBr): 3430, 2960, 1700, 1655 ^{cm -1} . NMRδ (CDCl ₃ ) 5.62 (2H, m), 5.32 (1H, bs), 3.90
(2H, m), 3.00 (1H, m). Mass (CI, NH ₃ ) m/z: 366 (M ⁺ +NH ₄ ). Test Example 1 (+)-9(0)-Methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ has the biological activity described below. When rabbit blood was used, platelet aggregation induced by adenosine diphosphate (ADP) was inhibited with a strength 1/10 of PGI ₂ , and when human blood was used, PGI 1/2 of ₂
It showed the strength. Regarding the effect on blood pressure, when using rats, it showed the same strength as PGI ₂ ,
It showed a blood pressure lowering effect at a dose of 0.1 μg/Kg. The effect on cardiac index was almost the same as that of PGI ₂ , and an experiment using rats showed an increase in cardiac index at a dose of 1 μg/Kg. It also showed antiulcer activity at a low concentration of 10 ^-6 M in experiments using rabbit stomachs, which is comparable in strength to PGE ₂ . Cytotoxicity is very weak, IC ₅₀ = 5μg/ml
It is.

Test example 2 (+)-3-(4'-carboxybutyl)-6(S)
-[3'-(S)-hydroxy,3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene has the following biological activities.
rabbit stomach epithelial cells
Using the method of Murota et al. [K. Matsuoka,
YMitsui, and S.Murota, J.Pharm.Dyn . ,5,
911 (1982)], 0.5×10 ^-6 M
It showed remarkable anti-ulcer effects at low concentrations. This activity is superior to, if not inferior to, PGE _2, a typical prostaglandin with anti-ulcer activity.
While PGE ₂ induces severe diarrhea, the above carbacycline analogs do not have a diarrhea-inducing effect.

Claims (1)

[Claims] 1. General formula A bicyclo[ ^3.3.0 ]octene ^derivative represented by
R ³ is a hydrogen atom or a hydroxyl group protecting group, and R ⁴ is a hydroxyl group, an acetyloxy group or a butenyl group. )