JPS62201838A - 3-formyl-cis-bicyclo(4.3.0)non-2-ene derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> and R<2> are OH-protecting group or H). EXAMPLE:3-Formyl-7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydro pyranyl oxybicyclo[4.3.0]non-2-ene. USE:Intermediate for stable prostacycline analog. PREPARATION:A compound of formula II is subjected to Witting reaction to obtain an alpha,beta-unsaturated ester derivative of formula III, which is oxidized after the reduction of its double bond. The obtained cyclopentanone derivative is methylenized to an exomethylene compound. The compound is hydroborated and oxidized to a hydroxymethylcyclopentane derivative of formula IV, which is reduced to obtain a diol compound. The compound is subjected to aldol condensation accompanied by dehydration to obtain the objective compound of formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to 3 represented by the following general formula (1): -formyl-cis-bicyclo(
4,3LO) non-2-ene derivatives. 3-formyl-cis-bicyclo(4,
3,0) Non-2-ene derivatives can be useful intermediates for prostacyclin analogs.

[Prior art]

Prostacyclin (hereinafter referred to as 'F'PG2) is known as a natural physiologically active substance and has the structure shown by the following formula, and its chemical name is (5Z, 11B)-(9α, 11α).

158)-6,9-epoxy-11,15-dihydroxyprosta-5,13-dienoic acid.

PGI 2 exists in the arterial wall and has a strong platelet aggregation inhibiting effect and a peripheral artery smoothing effect [Natural
v-(Nature), 263,663(197
6)).

PGI, which exhibits such an effect, is useful for the prevention and treatment of cerebral thrombosis, myocardial infarction, and acute angina pectoris induced by increased thrombotic tendency, and is expected to be developed.

Furthermore, prostaglandins including PGI2 are known to protect the gastric mucosa and increase gastric mucosal blood flow [2
83 Inflammation Seminar “Prostaglandin” Proceedings, page 50 (sponsored by the Japanese Society of Inflammation)], PGIs that exhibit such effects
2 is expected to be applicable to the prevention and treatment of gastrointestinal ulcers, typified by gastric ulcers.

However, PGI2 is a very unstable substance, which poses an obstacle to its practical application as a pharmaceutical.

In order to solve this problem, research has been carried out on stable analogues in which the oxygen atom between carbon atoms at the 6.9-position of PGI2 is replaced with a carbon atom. 0P-41483 (JP-A-54-13054
3) The carbacycline compound represented by the general formula (1) [JP-A-54-130543] and the 90-methano-Δ-PG11 shown by the chemical formula α [JP-A-56-32436] are both Chemically stable PGI
2 related compounds. Also, the 5-position double bond of 910)-methanoprostacyclin (carbacycline) is
9ρ)-methanol--J”a)-PGI transferred to α) position
, (isocarbacycline, chemical formula (V)) is also chemically stable enough and has been reported as a PGI2 analog compound with strong physiological activity (Japanese Patent Application Laid-Open No. 59-1374
45).

(OP-41483A=Cyclontyl) δHOH As a key intermediate for synthesizing such a chemically stable PGI2 analog compound, a compound represented by the following general formula (■ or ■) is used.

R'6 < R3 and R4 represent a hydrogen atom or a hydroxyl group protecting group 0) a(OR'5 (tm and R6 represent a hydrogen atom or a hydroxyl group protecting group) [While the invention is being solved As a result of extensive research aimed at providing prostacyclins that are stable with almost no decomposition at room temperature and have excellent pharmacological properties, the present inventors found that the prostacyclins represented by the general formula (11) The present invention was completed by discovering that 3-formyl-cis-bicyclo(4,3,0) non-2-ene rib conductor can be an important intermediate for synthesizing excellent stable prostacyclin analogs.

[Means for solving problems]

The present invention provides 3-formyl- represented by the general formula (1) above.
It is a cis-bicyclo(4,3,0) non-2-ene derivative.

In the present invention, the protecting group for the hydroxyl group of W in the general formula (I) includes a trimethylsilyl group, a triethylsilyl group, a tribenzylsilyl group, a t-butyldimethylsilyl group, a diphenyl-1-butylsilyl group, a p-methoxybenzyl group, Illustrative examples include l-methyl-1-methoxyethyl group, benzyl group, etc. As the protecting group for the hydroxyl group of B2, tetrahydropyranyl group, 1-ethoxyethyl group, methoxymethyl group, diphenyl-1-butylsilyl group s
Examples include p-methoxybenzyl group, benzyl group, etc. The 3-formyl-cis-bicyclo(4,10) non-2-ene derivative represented by the general formula (1) is converted into a conjugated diene by Wittig reaction. After the conversion, the protecting group W is selectively deprotected and 5-chiine is introduced, leading to a novel stable prostacyclin analog with high physiological activity (see Reference Examples below).

3-formyl- represented by the general formula (1) of the present invention
The cis-bicyclo(4,3,0)non-2-ene derivative can be produced according to the following reaction formula.

R2δ R2σ R2δ C[) [First step] This step is performed by subjecting the Raffle form represented by the general formula (2) to a Wittig reaction, thereby converting the general formula (conversion)
This method produces an α,β-unsaturated ester derivative represented by the following formula. The lactol compound represented by the general formula above can be easily obtained by reduction of Corey lactone (see Reference Examples below).

The Wittig reaction in this step is carried out using a stable ylide such as carbomethoxymethylenetriphenylphosphorane or carboethoxymethylenetriphenylphosphorane in an aromatic hydrocarbon such as toluene or benzene. The amount of stable ylide used is usually 1 to 2 equivalents, and the reaction is carried out at 50°C to 13°C.
Proceeds smoothly at 0°C.

[Second Step] In this step, the α,β-unsaturated ester derivative represented by the general formula (2) obtained in the first step is reduced to obtain a hydroxy-ester derivative represented by the general formula (2). It is manufactured. This reduction reaction was carried out using 5% pd-C, 10 chips.
d-C, can be carried out under 1 atmosphere of hydrogen in the presence of the Wilkinson complex. Ethanol, methanol, benzene, acetic acid ethyl ester, etc. can be used as the solvent, and the reduction reaction easily proceeds at 0°C to 50°C in the presence of these solvents.

[Third Step] This step is for producing a cyclopentanone derivative represented by the general formula αI) by oxidizing the hydroxy-ester compound represented by the general formula (I) obtained in the second step. It is. This oxidation reaction easily proceeds by using Collins reagent or pyridinium chlorochromate in a halogenated hydrocarbon solvent such as methylene chloride. An 8wern oxidation reaction can also be used as a reaction that is simpler in terms of experimental operations. The Swern oxidation reaction can be carried out using 2-3 equivalents of oxalyl chloride, 4-5 equivalents of DM80, 10-15 equivalents of triethylamine in methylene chloride. Incidentally, the reaction temperature can be selected from a range of 8° C. to room temperature.

[Fourth step] In this step, the cyclopentanone derivative represented by the general formula α■) obtained in the third step is methyleneated to produce an exo-methylene derivative represented by the general formula αW. It is something to do. This methylenation reaction uses a reagent prepared from zinc-methylene bamide-titanium tetrachloride in tetrahydrofuran.

The methylenation reaction is carried out in a halogenated hydrocarbon solvent such as methylene chloride, and the reaction temperature is 0°C to 5°C.
A range of 0°C can be selected.

[Fifth Step] In this step, a hydroxymethylcyclopentane derivative represented by the general formula αl is produced by subjecting the exo-methylene derivative represented by the general formula αV obtained in the fourth step to a water utilization reaction. It is. The water utilization reaction in this step is carried out by hydroboration and oxidation. For hydroboration, for example, 9-BBN
(9-borabicyclo(3+,3,1)nonane)
, thexylborane, and the like can be used. The amount of hydroboration reagent used is usually IN1.
Use 5 equivalents. The reaction is preferably carried out in a solvent, and for example, ether solvents such as tetrahydrofuran, diglyme, and diethyl ether can be used. The reaction proceeds smoothly at 5°C to room temperature. Furthermore, in this step, for zero oxidation, in which oxidation is performed without isolating the product following hydroboration, an oxidizing agent such as hydrogen peroxide can be used, for example.

When performing oxidation using hydrogen peroxide, it is preferable to use it in a basic state, such as sodium hydroxide. The amount of the oxidizing agent used is 5 to 15 equivalents, and the reaction proceeds smoothly at room temperature to 60°C.

[Sixth Step] This step is to reduce the hydroxymethylcyclopentane derivative represented by the general formula αV obtained in the fifth step to produce a diol compound represented by the general formula αV. . The reduction reaction can be carried out using a reducing agent such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran or ether. The reaction temperature can be selected from a range of 0°C to 40°C.

[Seventh Step] This step is performed by converting the general formula (XIV
) The 6-membered enal represented by the general formula (1) is produced by oxidizing the diol represented by the formula (1) and then subjecting it to aldol condensation accompanied by dehydration.

,(,Ae-)”Cli, e.g. difucare L=X t
vf, 4'7 dooxalyl chloride, dimethyl sulfoxide-sulfur trioxide pyridine complex, etc. can be used. The amount of the oxidizing agent to be used is usually 1 to 5 equivalents.

It is preferable to carry out the reaction in a solvent, but the reaction proceeds smoothly at 70°C to room temperature, although it varies depending on the type of oxidizing agent.

The oxidation product in this step is obtained by adding a tertiary amine such as triethylamine or diisopropylethylamine to the reaction mixture and treating the mixture at 0°C to room temperature.

After the oxidation reaction was completed, the product was subjected to the next dehydration reaction without being isolated.

The dehydration reaction is carried out by heating the product obtained in the oxidation reaction in the presence of an acidic catalyst. As the acidic catalyst, an acid-ammonium salt can be used. Acid-ammonium salt catalyst can be formed from an acid and an amine. Examples of acids that can be used include trifluoroacetic acid, toluenesulfonic acid, camphorsulfonic acid, and acetic acid. Also, examples of amines that can be used include dibenzylamine and diethylamine. , dimethylamine, diisopropylamine, and (lysine, pyrrolidine,
Examples include piperazine and the like.

These acids and amines can be appropriately selected and used in combination, and in particular, the amount of trifluoroacetic acid catalyst used may be about 0.2 equivalent, but in order to make the reaction proceed quickly, it is recommended to use about 1 equivalent. is preferred.

When 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'O, but in order to carry out the reaction smoothly, it is preferably carried out within the range of 50°C to 70'O.

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

Reference Example 1 Under an argon atmosphere, [2-oxa-3-oxo-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydrobilanyloxybicyclo(3,3,
0) Octane) (Log.

27 mmol) was dissolved in toluene (80 ml), -7
Cooled to 8°C. Diisobutylaluminum hydride (1
M toluene solution 40.5ml, 40.5mmo
1) was added and stirred at -78°C for 60 minutes.

Methanol was added at −78° C. until no hydrogen generation was observed, and the temperature was raised to room temperature. Add v1 Japanese saline solution, extract with ethyl acetate, dry with anhydrous magnesium sulfate,
The solvent was distilled off to give [2-oxa-3-hydroxy-6-nixo[-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo(3,3,0
) Octane] (10.1 g, 100%) was obtained.

IR(naat): 3430, 2950°2860
．． 835cm-'.

NMR (CDCIs) δ: 5.70-5.30
(m.

IH), 4.85-4.55 (m, 2H).

4.40-3.25 (m, 5H), 0.90 (s,
9H).

Mass m/z (%): 213 (5).

159 (17), 85 (100), 75 (19)
, 73 (13).

Reference example 2 xy-6-nyxo-t-butyJT>J methylsilyloxymethyl-7-nindotetrahydropyranyloxybicyclo(3,3,0)octane] (10.1g, 27m
mo I) was dissolved in toluene (100 ml).

(Carbomethoxymethylene) trif, near L/phosphorane (11.7 g, 35 mmol) was added at 60°C.
Stirred for 2 hours. After cooling, the solvent was distilled off and the resulting residue was subjected to silica gel column chromatography (ether: n
-hexane-1:2) and [2α-(3-methoxycarbonyl-2-propenyl)-3β-t-7
'Tyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol] (10
, 9g, 94%) was obtained.

IR (neat): 353G, 2960°2875.1
? 30,1660°840cm-'.

NMR (CDCI δ: 7.06 (m, IH
).

5.95 (d, J=15Hz, LH).

4.66 (bs, IH), 3.70 (s, 3H)
.

0.90 (s, 9H), 0.05 (s, 6H).

Ma ss m/z (%): 211 (1)
.

159 (37), 85 (100), 75 (26),
73 (18), 43 (9).

Reference example 3 H H [2α-(3-methoxycarbonyl-2-propenyl)
-3β-t-butyldimethylsilyloxymethyl-4α
-tetrahydropyranyloxy-1α-cyclopentanol) (7.0 g, 16.4 mmol) was dissolved in methanol (50 ml).

10% palladium/carbon (700 μ) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The catalyst was filtered off, and the solvent of the filtrate was distilled off to give 2α-(3-methoxycarbonylpropyl)-3β-t-butyldimethylsilyloxymethyl-4
α-tetrahydropyranyloxy-1α-cyclopentanol) (6.5 g, 93%) was obtained.

IR(neat):3520,2940°2B50,1
738,830cs-'.

NMR (CDC13) δ: 4.67 (b
s, IH).

3.66 (s, 3H), 0.90 (s
, 9H).

0.05 (s, 6H).

Mass m/z (%) 157 (10
).

211 (1), 165 (29), 15
9 (62), 119 (11), 85 (
100).

75 (28), 73 (22), 43
(12).

Reference Example 4. Dimethyl sulfoxide (6,5
ml, 90.6 mmol) of methylene chloride solution (30
rnl) was added. After stirring at -78℃ for 30 minutes, [2α
-(3-methoxycarbonylpropyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol) (6
, 5 g, 15.1 mO methylene chloride solution (5
0 m, l) was added. After stirring at -78°C for 30 minutes, triethylamine (31.3ml, 226.5mmo 1)
was added and the temperature was raised to room temperature. Water was added, extracted with methylene chloride, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (ether 20-
Hexane-1=2) was purified from [2α-(3-methoxycarbonylpropyl)-3β-1-butyldimethylsilylsoxymethyl-4α-tetrahydropyranyloxy-
1-Cyclopentanone) (6.2 g, 95%) was obtained.

IR (neat): 2900, 2810°1 730,
820cm-'.

NMR (CDCis) δ: 4.63 (bs
, IH).

3.66 (s, 3H), 0.90 (s
, 9H).

0.05 (s, 6H).

Massm/z (%’): 209 (2).

159 (28), 85 (100), 7
5 (29), 73 (29), 43 (3
).

41(22).

Reference Example 5 Under an argon atmosphere, [2α-(3-methoxycarbonylpropyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyl] 1
-Cyclopentanone] (10g + 23mmol)
was dissolved in methylene chloride (100 ml), and zinc-
Titanium chloride-methylene bromide reagent (Z n-T
iCl a CH! Brff1/THF)
The reaction solution added at step C until the raw materials disappeared was poured into a mixed solution of saturated aqueous sodium bicarbonate (500 ml) and ether (500 ml). Celite was added to this mixture and the mixture was filtered through Celite. 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: n-hexane-1=6) [2α-(3
-methoxycarbonylpropyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentanone) (7.6g, 7
6%).

IR(neat):2900. 2800°173
0. 1645. 1240. 820cm-'.

NMR (CDCts) δ: 4.83 (d,
2H).

4.63 (bs, IH), 3.80 (s,
3H).

0.90 (a, 9H), 0.05 (s, 6H)
.

Mass m/z (%): 193 (1
8).

159 (41), 85 (100), 75 (37
), 73 (31), 43 (15).

Reference Example 6 Under an argon atmosphere, [2α-(3-methoxycarbonylpropyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentylidene] (7.5 g).

17.6 mmol) was dissolved in THF (70 ml). At 0°C, a THF solution of dithiamylborane (0,
9M, 43ml, 38.7mmol) was added dropwise. 0℃
After stirring for 1 hour, 6N aqueous sodium hydroxide solution (
25.5 ml (1,153 mmol 1) and 30% oxidized hydrogen water (22 ml 1.194 mmol) were added. After stirring at room temperature for 1 hour, the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off [1α
-Hydroxymethyl-2α-(3-methoxycarbonylpropyl)-3β-[-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxycyclopentane] (7.8 g, 100%) was obtained.

IR (neat): 3450, 2930°2850.8
35 countries - 1°NMR (CDCIs) δ: 4.66 (bs
, IH).

3.66 (s, 3H), 0.90 Cm
, 9H).

0.05 (s, 6H).

Massm/z (%) 185 (15).

255 (9), 193 (30), 15
9 (54), 85 (100), 57 (10
0), 43 (52).

Reference Example 7 HO＼ Under an argon atmosphere, lithium aluminum hydride (3.34 g, 88 mmo 1) was dissolved in THF (70 ml).
suspended in. Under water cooling, [1α-hydroxymethyl-2α
-(3-methoxycarbonylpropyl)-3α-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxycyclopentane) (7.8g, 17
．． A THF solution (100 ml) of 6 mmol 1) was added dropwise. After stirring for 30 minutes under water cooling, sodium sulfate・l
O permanent was added, and the mixture was filtered through Celite. The solvent was distilled off to leave a residue.

The distillate was purified by silica gel column chromatography (ether) [1α-hydroxymethyl-2α-(4
-hydroxybutyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxycyclopentane] (6.8 g, 93%) was obtained.

IR (neat): 3420.2935°2850.1
730,830 cm-'.

NMR (CDClx) δ: 4.63 (bs,
IH).

4.10 (m, IH), 0.90 (s, 9H)
.

0.05 (s, 6H).

Massm/z (%): 3at (M”-85°3)
, 275 (4), 183 (8).

159 (35), 85 (100), 4
1 (31).

Example 1 Under an argon atmosphere, oxalyl chloride (9 ml, 10
5.6 mmol) was dissolved in methylene chloride (TOm + ). Dimethyl sulfoxide (16,2
m1.228.8mmo I> methylene chloride (40m
l) was added. After stirring at -78°C for 30 minutes, [1α-hydroxymethyl-2α-(4-hydroxybutyl)-3
β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxycyclobentane) (6.8g
.

16.4 mmol) of methane chloride solution (40 ml
> was added. After stirring for 30 minutes at -78°C, triethylamine (73ml 1.528mmol>) was added and the temperature was raised to room temperature. Methylene chloride was distilled off. Benzene (150ml) and dibenzylammonium difluoroacetate were added under an argon atmosphere. (51g+16
．． 4 mmol 1) was added and stirred at 60°C for 5 hours. After cooling, water was added and the mixture was 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:+) [3
-formyl-7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxybicyclo(4,3,0)non-2-ene) (3 g, 46
%) was obtained.

rR (neat): 2950.2870°1680.1
630,835C@-'.

NMR (CDCIs) δ: 943 (s, LH).

6.70 (BS, IH), 4.63 (BS.

IH), 0.90 (s, 9H), 0.05
(5,6H).

Massm/z (%): 309 (M'-85゜tr
ace), 159 (33), 85 (too), 75
(26), 73 (10).

57(14).

Reference Example 8 Enylphosphor size = Omi Promide (1.1 g, 2.5 m-m
ol) to THF (10ml)! Q: It's cloudy. A T)[F solution (10 ml) of 1-butoxypotassium (560 μm, 5 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. There, c3-formyl-7-niki/-[-butyldimethylsilyloxymethyl-8-endotetrahydrobilanyloxybicyclo[4°3.0]non-2-ene) (200
(2) A THF solution (5 ml) of 0.5 m-mol I) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. v1 aqueous ammonium chloride solution was added, and the reaction solution was adjusted to pH 5 with a 10% aqueous hydrochloric acid solution.
-4 and extracted with ethyl acetate. After drying the Ir layer over anhydrous magnesium sulfate, the solvent was distilled off. Ether was added to the residue, and an ethereal solution of diazomethane was added at 0°C. By thin layer chromatography (3-
(4-carboxy-1-butenyl)-7-exo-t-
Butyldimethylsilyloxymethyl-ranyloxybicyclo(4.3.0)non-2-ene]
After confirming the disappearance of the spores 7), oligosaccharide was added and immediately washed with saturated sodium bicarbonate solution and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ether: n-hexane-14) to give (3-(4-methoxycarbonyl-2-butenyl)- 7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxybicyclo(4.3.0)non-2-ene)(
210■, 88%). The isomer ratio of (Z)- and (E)- was 2:1.

IR (neat) = 2950.2860.

1740, 1430.1255.

1200, 1030.835cs-'.

NMR (CDCIs) δ: 6.12 (d.J
Simple 16, 5Hz, 1/3H, trans).

5, 96 (d.J-12Hz.2/31(.

c i s), 5.63 (b s. I H
), 5.30 (m, IH), 4.65 (bs,
IH).

3, 70 (s. 3H), 0.90 (s. 9H).

Mass m/z (%): 479 (M”+1.

trace), 337 (12), 245 (14), 2
13 (9), 159 (34).

85 (100), 57 (17).

Reference Example 9 Under an argon atmosphere, (3-(4-methoxycarbonyl-1-butenyl)-7-exo-t-butyldimethylsilyloxymethyl-8-endo-tetrahydropyranyloxybicyclo(4.3.0)nona -2-ene) (1
6 0g. 0.33mmo 1) in THF (0.5m
l). Tetra-n-butylammonium fluoride (IMT) IFtl solution, 0, 68ml, 0.68
mmol> was added, and the mixture was stirred at room temperature all day and night. After adding saturated brine, the mixture was extracted with ether, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ether: n-hexane-l:
1) lul! Shiku3-(4-methoxycarbonyl-1-butenyl)-7-exo-hydroxymethyl-8
-Endo-tetrahydropyranyloxybicyclo (4.
3.0) non-2-ene) (108■.

90%).

IR (n@at): 349G. 2950.

2880, 1740.1435, 1200.

1 0 2 0, 8 6 53-'.

NMR (CDC Is) δ: 6.30 (d, J■
16.5Hz. 1/3H. trans).

5, 83 (d, J-1 2Hz.2/3H.

c i s), 5.60 (bs, IH), 5.30 (
m, IH), 4.68 (m, IH).

3,70 (s.3H).

Massm/z (%): 364 (M” trace), 280 (15), 199 (
5), 117 (11), 85 (100
).

2B (29).

Reference Example 10 Under an argon atmosphere, (3-(4-methoxycarbonyl-
1-butenyl)-7-exo-hydroxymethyl-8-
endo-tetrahydropyranyloxybicyclo(4,3
,01 non-2-ene] (108 g, 0.3 mmo I
) was dissolved in dimethyl sulfoxide (2 ml). A dimethyl sulfoxide solution (2 ml) of triethylamine (0.25 ml, 1.8 mmol 1) and JLt7y-trioxide/pyridine complex (286+ 1-FJ mmol) was dissolved in dimethyl sulfoxide (2 ml). and stirred at room temperature for 1 hour and 10 minutes. Added ice water and extracted with ethyl acetate.
Washed with water and saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give (3-(4-methoxycarbonyl-1-butenyl)-7-exo-formyl-8-endo-tetrahydropyranyloxybicyclo(4,3,0
) nona-2-ene) <106 ■.

100%) was obtained. On the other hand, sodium hydride (oil 60
%, 18w, 0.45 mmol 1) was washed with pentane under an argon atmosphere and suspended in THF (5 rril). Dimethyl (2-oxoheptyl)phosphonate (133w, 0.6mmo +) in THF solution (5ml
) and stirred at room temperature for 40 minutes.

(3-(4-methoxycarbonyl-1-butenyl)-7
-exo-formyl-8-endo-tetrahydropyranyloxybicyclo(4,3,0)non-2-ene) (1
Add a THF solution (5 ml) of
Stirred for 0 minutes. l! After adding aqueous ammonium chloride solution, extraction was performed with ether, and the ether layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography (ether:n-hexane=1:3) to give 3-(4-methoxycarbonyl-1-butenyl). -7-
Nixo(3-oxo-trans-1-octenyl)-
8-endo-tetrahydropyranyloxybicyclo(4
, 3,0) non-2-ene] (112μ, 84%) was obtained.

IR(neat):2940.28B0°1740.1
700,1675°1625.1430,1200°1030C11-'.

N1vLR(CDCl2)δ: 6.81 (m, I
H).

6.22 (dd, J-16, 5, 3Hz.

LH), 6.08 (d, J-1,5Hz.

1/3 Htrans), 5.82 (d.

J=12Hz, 2/3Hcis).

5.56 (BS, LH), 5.30 (m.

IH), 4.62 (m, IH), 3.70 (s, 3
H), 0.88 (L, 3H).

Massrn/z (%): 376 (8).

332 (12), 85 (100), 57 (18
), 55 (13), 41 (2).

Reference Example 11 Under an argon atmosphere, (3-(4-methoxycarbonyl-
1-Butenyl-7-nyxo(3-oxa-trans-
1-octenyl)-8-endo-tetrahydropyranyloxybicyclo(4,3°O]non-2-ene) (
110+a+t, 0.24m-m o I) was dissolved in methanol (2ffl+).

Cool to −25° C. and add excess sodium borohydride. After stirring at -25°C for 30 minutes, a small amount of acetone and a saturated ammonium chloride aqueous solution were added, and after drying with a sieve, the solvent was distilled off and (3-(4-methoxycarbonyl-1-butenyl)-7-nyxo(3- hydroxy-trans-1-
octenyl)-8-endo-tetrahydropyranyloxybicyclo(4,3,0)non-2-ene) (112■
.

100%) was obtained.

IR(neat) =3450.2900°2850
．． 1738, 1430°120.0. 1020clI-'.

NMR (CD C1s) δ: 6.11 (d, J
= m16.5Hz, 1/3H, trans).

5.82 (d, J-12Hz, 2/3H.

c I s), 5.58 (m, 3H)
, 5.25 (m, LH), 4.68 (
bs, IH).

3.70 (s, 3H), 0.88 (t
, 3H).

Massm/zc%): 442 (M”-H
zO, trace), 358 (10).

314 (11), 234 (31), 1
50 (21), 85 (100), 41
(24).

Reference Example 12)-7-nyxo(3-hydroxy-trans-1-
octenyl)-8-endo-tetrahydropyranyloxybicyclo(4,3,0)non-2-ene (112■,
0.24 mmol) in vinegar M:water:THF (2ml)
(3: l: 1. volume ratio) Dissolve in mixed solution and heat at 50°C.
The mixture was stirred for 4 hours and 30 minutes.

After cooling, the mixture was diluted with ethyl acetate and neutralized with saturated aqueous sodium bicarbonate.

The ethyl acetate layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (ether 20-hexane-5=1), and a more viscous fraction (3-(4-nodoquinecarbonyl-1 -butenyl)-7-nyxo(3α-hydroxy-trans-1
-(3-(4-methoxycarbonyl-1-butenyl)-7-nyxo(3β
-Hydroxy-trans-1-octenyl)-8-endo-hydroxybicyclo(4,3,0)non-2-ene] (26μ, 26%) were obtained, respectively. The spectral data of the α-epimer is shown below, and the spectrum of the β-epimer is similar.

IR(neat)! 3400,2950°28B0,1
745.1440°740CJI-'.

NMR (CDCI3) δ: 6.06 (d, J Army 16Hz, l/3H, trans).

5.81 (d, J-12Hz, 2/3H.

c i s), 5.53 (m, 3H), 5.25 (
m, LH), 3.10 (s, 3H).

0.86 (t, 3H).

Massm/z (%) 158 (M'''-Hzo, 19)
, 314 (11), 244° (28), 227 (9
), 117 (45) 91 (59), 43 (
100).

Under an argon atmosphere, (3-(4-methoxycarbonyl-
1-butenyl)-7-nixo(3α-hydroxy-trans-1-octenyl)-8-endo-hydroxybicyclo(4,3,0)non-2-ene 3 (30w,
0.08 mmol 1) was dissolved in methanol (0.7 ml). At 0°C, 10% aqueous sodium hydroxide solution (0,
7 ml) was added and stirred day and night. After neutralizing with IN hydrochloric acid aqueous solution at 0°C, methanol was distilled off, and the remaining aqueous layer was adjusted to pl (4) with IN hydrochloric acid aqueous solution. After extraction with ethyl acetate and washing with saturated brine, anhydrous magnesium sulfate was added. After drying with
-octenyl)-8-endohydrogysibicyclo[4
,3,0]non-2-ene) (28 mg, 97%).

IR (neat): 3375.2950°2B70,1
720, 1440° 1120, 965cm-'.

NMR (CDCl j) δ: 6.10 (d, J-1
6Hz, 1/3H, trans).

5.85 (d, J=12Hz, 2/3H.

e i s) , 5.63 (m,, 3I()
, 5.40-5.13 (m, 3H), 0.90
(t, 3H).

Massm/z (%): 344 (M'-Hto, 1
2), 300 (20), 230 (12), 220 (
15), 150 (48), 91 (56), 43 (100).

Similarly, the 15β-epimer was also hydrolyzed, (3-(4
-carboxy-1-butenyl)-7-nyxo(3β-
Hydroxy-trans-1-octenyl)-8-endo-hydroxybicyclo(4,3,0)non-2-ene]
I got it. Spectral data (IR, NMR, Mas
s) is [3-(4-carboxy-1-butenyl)-
7-Nixo(3α-hydroxy-trans-1-octenyl)-8-endo-hydroxybicyclo[4°3.
0]non-2-ene].

Test Example 3-(4-carboxy-1-butenyl)-7-nixo(3α-hydroxy-trans-1-octenyl)-8-endo-hydroxybicyclo(4,3,0)nona synthesized by the above method -2-ene and 3-(4-carboxy-1-butenyl)-7-nyxo(3β-hydroxy-trans-1-octenyl)-8-endo-hydroxybicyclo(4,3,0)non-2-ene As shown in Table 1, ADP or collagen was used as the platelet aggregating agent.

Claims (1)

[Claims] 1) 3 represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R^1 and R^2 are hydroxyl protecting groups or hydrogen atoms.) -Formyl-cis-bicyclo[4,3,0]non-2-ene derivative.