JPH0476983B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, R ¹ is a hydrogen atom, a tetrahydropyranyl group or a 4-methoxytetrahydropyranyl group, and R ² is a hydrogen atom or a t-butyldimethylsilyl group.)
This invention relates to octenyl aldehyde derivatives and methods for producing the same. The bicyclo[3.3.0]octenylaldehyde derivative of the present invention represented by the general formula () can be obtained by subjecting it to the reaction process described later (3-oxo-
1-alkenyl)-cis-bicyclo[3.3.0]octene derivatives. (3-oxo-
The 1-alkenyl)-cis-bicyclo[3.3.0]octene derivative reduces the ketone, deprotects the hydroxyl group, and hydrolyzes the ester.
9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ (see Reference Example below). 9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ −
PGI ₁ has a strong platelet aggregation inhibitory effect, and for example, when human platelets are used, its effect is comparable to that of the chemically unstable PGI ₂ , and it is used as a therapeutic or preventive drug for various cardiovascular diseases. This is the compound used (see test example 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)] and (b) A method for producing it from 1,3-cyclooctadiene through 19 steps [Pharmaceutical Society of Japan No.
Proceedings of the 103rd Annual Meeting, p. 157 (1983)] is known, but method (a) requires expensive raw materials, method (b) produces the target product as a racemate, and method (a) (b) Both had a drawback that the total yield was very low. The present inventors have discovered that 9(0)-methano-
As a result of intensive research to produce Δ ⁶⁽⁹ 〓 ⁾ −PGI ₁ ,
The present invention was completed by discovering that the compound of the present invention and the method for producing the same can be an important intermediate and method for achieving the object. The bicyclo[3.3.0]octenyl aldehyde derivative represented by the general formula () of the present invention can be used in addition to the natural ω-chain of the prostaglandin skeleton, for example, in the literature [Casals-Stenzel, J. et al.
Prostaglandins, Leukotrienes Med.1983, 10
(2), 197-212], it can be said to be an extremely useful intermediate in that it can lead to prostaglandin derivatives having non-natural ω-chains with higher activity. The bicyclo[3.3.0]octenylaldehyde derivative of the present invention represented by the general formula () can be produced according to the following reaction formula. In addition, as a protecting group for a hydroxyl group in the present invention,
R ¹ is a tetrahydropyranyl group or a 4-methoxytetrahydropyranyl group, and R ² is t-
It is a butyldimethylsilyl group. (In the formula, R ¹ and R ² are the same as above.) [First step] In this step, the cyclopentylidene derivative represented by the general formula () is subjected to a hydration reaction to obtain a compound represented by the general formula (). The following hydroxymethylcyclopentane derivatives are produced. The cyclopentylidene derivative represented by the above general formula () is a compound that can be easily obtained by reducing a Corey lactone derivative to lactol, subjecting it to the Witteitsch reaction, oxidizing the hydroxyl group, and then carrying out a methylenation reaction (see reference examples below). ). The hydration reaction in this step is carried out by hydroboration and oxidation. In the hydroboration, for example, a hydroboration reagent such as 9-BBN (9-borabicyclo[3.3.1]nonane), thexylborane, and dithiamylborane can be used. The amount of hydroboration reagent used is usually 1~
Use 1.5 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 -25°C to room temperature. Additionally, the process involves hydroboration followed by oxidation without isolation of the product. For oxidation, an oxidizing agent such as alkaline hydrogen peroxide, amine oxide, oxygen, peracid, etc. can be used. The amount of oxidizing agent used is 5 to 15 equivalents. The reaction proceeds smoothly at room temperature to 60°C. In this step, for example, the compound produced by hydroboration using 9-BBN is It is presumed that it has a structure like this. [Second step] This step oxidizes the hydroxymethylcyclopentane derivative represented by the general formula () obtained in the first step to produce a β-hydroxyaldehyde derivative represented by the general formula (). It is. In the oxidation, for example, dimethyl sulfoxide-oxalyl chloride, dimethyl sulfoxide-sulfur trioxide pyridine chains, etc. can be used. The amount of the oxidizing agent to be used is usually 1 to 5 equivalents. The reaction is preferably carried out in a solvent, and for example, halogenated hydrocarbons such as methylene chloride can be used. The reaction varies depending on the type of oxidizing agent, but at -70℃
~Proceeds smoothly at room temperature. The oxidation product of this step is obtained by adding a tertiary amine such as triethylamine or diisopropylethylamine to the reaction mixture and treating at -70°C to room temperature. Under these conditions in which dialdehyde is produced, intramolecular aldol condensation occurs rapidly, and the β-hydroxyaldehyde represented by the above general formula () is obtained. It can also be subjected to a three-step reaction. [Third Step] In this step, in the presence of an acidic catalyst, the β-hydroxyaldehyde represented by the general formula () obtained in the second step is dehydrated to obtain a bicyclo[ 3.3.0] For producing octenyl aldehyde derivatives. Dehydration must be 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 containing a combination of trifluoroacetic acid and dibenzylamine is particularly preferred since the desired product can be obtained in good yield. The amount of catalyst to be used may be about 0.2 equivalents, but in order for the reaction to proceed quickly, 1 equivalent amount is sufficient.
It is preferable to use an equivalent amount. 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℃,
In order to carry out the reaction smoothly, it is preferable to carry out the reaction at a temperature in the range of 50°C to 70°C. An ω-chain can be introduced into the bicyclo[3.3.0]octenyl aldehyde derivative obtained as described above by subjecting it to steps A to D as described below. (In the formula, R ¹ and R ² are the same as above, R ³ is a hydrogen atom or an alkyl group, and R ⁴ is a straight chain, branched chain, or cyclic alkyl group or alkenyl group having 5 to 10 carbon atoms. , R ⁵ is a phenyl group or an alkyl group.) [Step A] This step is performed in the presence of a base to convert bicyclo[3.3.0]octenyl represented by the general formula () obtained in the third step to An alkenylbicyclo[3.3.0]octene derivative represented by the above general formula () is produced by reacting an aldehyde derivative with 3-carboxypropylphosphonium bromide. This step needs to be carried out in the presence of a base. Potassium t-butoxy, butyl lithium, sodium salt of dimethyl sulfoxide, etc. can be used as the base, but potassium t-butoxy is preferably used in order to carry out the reaction efficiently. The amount of base to be used is usually 1% per 3-carboxypropylphosphonium bromide as the raw material.
~1.2 equivalents are used. To carry out the reaction, use tetrahydrofuran,
Ether solvents such as dimethoxyethane and diethyl ether 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 is isolated as an ester using the conditions of diazomethane or alkyl halide-diazabicycloundecene-acetonitrile. be able to. Conversion into an ester can be carried out using methods that can be easily performed by those skilled in the art. [Step B] This step consists of alkenylbicyclo[3.3.0] represented by the general formula () obtained in the step A.
The method involves catalytically reducing an octene derivative to produce a bicyclo[3.3.0]octene derivative represented by the general formula () in which only one of the olefins is selectively reduced. Examples of catalysts that can be used include palladium catalysts such as palladium-carbon and palladium black, Wilkinson's catalyst, 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,
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 temperature in the range of -25°C to room temperature. [Step C] This step selectively deprotects R ² of the bicyclo[3.3.0]octene derivative represented by the general formula () obtained in the B step, and
Hydroxymethylbicyclo[3.3.0]
This is to produce octene derivatives. For deprotection, tetra-n-butylammonium fluoride can be used as a deprotecting agent when R ² is a silyl group, and potassium carbonate can be used when R 2 is a benzoyl group, acetyl group, etc. The reaction is preferably carried out in a solvent, and when using tetra-n-butylammonium fluoride as a deprotecting agent, ether solvents such as tetrahydrofuran, dimethoxyethane, and ethyl ether can be suitably used. methanol when using potassium carbonate as a deprotecting agent,
Alcohol solvents such as ethanol can be suitably used. The reaction proceeds smoothly at -25°C to room temperature. [Step D] In this step, the hydroxymethylbicyclo[3.3.0]octene derivative represented by the general formula () obtained in the step C is oxidized, and then the obtained product is converted into the hydroxymethylbicyclo[3.3.0]octene derivative represented by the general formula (). The (3-oxo-1-alkenyl)-cis-bicyclo[3.3.0]octene derivative represented by the general formula (XI) can be produced by reacting with a compound represented by It is manufactured. The oxidation in this step must 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 the oxidizing agent used is 7 to 10 equivalents in the case of Collins reagent, and 1 to 5 equivalents for other oxidizing agents. The reaction is preferably carried out in a solvent, and halogenated hydrocarbons such as methylene chloride and chloroform are preferred. The reaction proceeds smoothly in the range of -70°C to room temperature. In this step, the product obtained by subsequent oxidation is reacted with the compound represented by the general formula () or the compound represented by the general formula () without isolation. Examples of the compound represented by the general formula () include dimethyl (2-
oxoheptyl) phosphonate, dimethyl (2
-oxo-3-methylheptyl) phosphonate, dimethyl (2-oxo-3,3-dimethylheptyl) phosphonate, dimethyl (2-oxo-4,8-dimethyl-7-nonenyl) phosphonate, dimethyl (2-oxo-4 , 4,8-trimethyl-7-nonenyl) phosphonate, dimethyl (2-oxo-2-cyclopentylethyl) phosphonate, etc., and examples of the compound represented by the general formula () include tributylphosphine-2 -Oxoheptylidene, tributylphosphine-2-oxo-3-methylheptylidene, tributylphosphine-2-oxo-
3,3-dimethylheptylidene, tributylphosphine-2-oxo-4,8-dimethyl-7-nonenylidene, tributylphosphine-2-oxo-4,4,8-trimethyl-7-nonenylidene,
Tributylphosphine-2-oxo-2-cyclopentylethylidene and the like can be used.
When a compound represented by the above general formula () 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. can be used. The reaction is preferably carried out in a solvent, and for example, ether solvents such as tetrahydrofuran, dimethoxyethane and diethyl ether, aromatic solvents such as benzene, toluene and xylene, etc. can be used. The reaction temperature is in the range of -25°C to 50°C when using the compound represented by the general formula (),
Further, when using a compound represented by the above general formula (), the temperature is in the range of 20°C to 150°C. The compound obtained by oxidation in this step has the general formula (In the formula, R ¹ is a protecting group for a hydroxyl group, and R ³ is a hydrogen atom or an alkyl group.) The present invention will be further explained in detail with reference to Reference Examples and Examples below. Reference example 1 Under argon atmosphere [2-oxa-3-oxo-
6-Exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane] (2.22g, 6mmol)
was dissolved in toluene (10ml) and cooled to -75°C.
Diisobutylaluminum hydride (25g/100ml
Add 5.1 ml of hexane solution, 9 mmol) and heat at -75℃ for 70 min.
Stir for a minute. Methanol was added at −75° C. until no hydrogen generation was observed, and the temperature was raised to room temperature. After diluting with ethyl acetate (130 ml), the mixture was washed with saturated saline (20 ml x 4 times). After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain [l-2-oxa-3-hydroxy-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0] Octane] (2.33 g, 100%) was obtained. IR (neat): 3430, 2950, 2860, 835 cm ^-1 . NMR δ (CDCl ₃ ) 5.70 ~ 5.30 (m, 1H), 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). [α] ²⁰ _D = -28° (c = 1.98, MeOH). Reference example 2 Potassium t-butoxy (3.16 g, 28.2 mmol) was dissolved in THF (50 ml) under an argon atmosphere. Methyltriphenylphosphonium bromide (10.07 g, 28.2 mmol), which had been thoroughly dried in advance at 100° C. under reduced pressure, was added at room temperature. After stirring for 5 minutes, [l-2-oxa-3-hydroxy-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane] (3.40 g,
9.1 mmol) in THF solution (30 ml) and stirred at room temperature.
Stir for 20 minutes. After adding a saturated aqueous ammonium chloride solution, THF 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 subjected to silica gel column chromatography (ether: n-hexane = 2:3).
[d-2α-allyl-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol]
(3.18g, 94%) was obtained. IR (neat): 3500, 2950, 2870, 1640, 835 cm ^-1 . NMR δ (CDCl ₃ ) 5.80 (m, 1H), 5.00 (m, 2H), 4.65 (bs,
1H), 4.30-3.00 (m, 6H), 0.90 (s, 9H). Mass m/z (%): 285(1), 229(1), 211(3), 159
(26), 85 (100), 75 (21), 73 (13). [α] ²⁰ _D = +21° (c = 2.44, MeOH). Reference example 3 [d-2α-allyl-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol] (3.16 g,
8.5 mmol) was dissolved in methylene chloride (40 ml), and sodium acetate (280 mg, 2.6 mmol) and Celite (3.36 g) were added. Pyridinium chlorochromate (3.68 g,
17.1 mmol) was added thereto, and the mixture was stirred at 0°C for 18 hours. Dilute with ether and perform Florisil column chromatography (ether: n-hexane = 1:3~
3:1) [l-2α-allyl-3β-t
-Butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentanone (2.82 g, 90%) was obtained. IR (neat): 2950, 2880, 1748, 1642, ^{840cm -1} . NMR δ (CDCl ₃ ) 5.70 (m, 1H), 5.03 (d, J = 17Hz, 1H),
5.00 (d, J=11Hz, 1H), 4.65 (bs, 1H),
4.30 (m, 1H), 3.30~4.00 (m, 4H), 0.90
(s, 9H). Mass m/z (%): 209(17), 159(17), 159(17), 85
(100), 75 (35), 73 (23), 41 (17). [α] ²⁰ _D = -55° (c = 2.19, MeOH). Reference example 4 Under an argon atmosphere, [l-2α-allyl-3β-t
-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentanone] (2.79 g, 7.57 mmol) in methylene chloride (26
ml) and the zinc-titanium chloride-methylene bromide reagent (Zn- _TiCl4 - _{CH2Br2 /}
THF, 46 ml) 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 ml) and ether (500 ml). 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 = 1:10),
[l-2α-allyl-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentylidene] (2.48g, 90%)
I got it. IR (neat): 2950, 2870, 1660, 1640, 835 cm ^-1 . NMR δ (CDCl ₃ ) 5.60 (m, 1H), 4.75-5.20 (m, 4H), 4.63
(bs, 1H), 3.30-4.30 (m, 5H), 0.90 (s,
9H). Mass m/z (%): 159(18), 133(11), 85(100), 75
(19), 73(13). [α] ²⁰ _D = -43° (c = 2.84, MeOH). Reference example 5 9-borabicyclo [3.3.1] under argon atmosphere
Nonane (dimer, 2.472g, 20.3mmol) in THF
(28ml). [l-2α-allyl-3β-t
-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentylidene] (2.476 g, 6.75 mmol) in THF solution (45
ml) was added dropwise under ice-cooling, and the mixture was stirred at 5 to 10°C for 7 hours and 30 minutes. 6N sodium hydroxide aqueous solution (13.5ml,
81 mmol) and 30% hydrogen peroxide solution (11.5 ml,
101.3 mmol) was added and stirred at 60°C for 1 hour and 30 minutes.
After THF was distilled off under reduced pressure, the residue was extracted with ethyl acetate.
The organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine. After drying with anhydrous magnesium sulfate,
The solvent was distilled off. The residue was subjected to silica gel column chromatography (ether: methanol = 40:
1), [d-1α-hydroxymethyl-2α-(3-hydroxypropyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxycyclopentane] (2.65 g,
97%). IR (neat): 3400, 2940, 2860, 835 cm ^-1 . NMR δ (CDCl ₃ ) 4.65 (bs, 1H), 4.10 (m.1H), 3.15-3.95 (m,
8H), 0.90(s, 9H). Mass m/z (%): 159(19), 149(18), 133(19), 121
(13), 105(15), 93(10), 91(10), 85(100), 79(11),
75
(34), 73(18), 67(17), 57(24), 55(16), 43(17),
41
(twenty one). [α] ²⁰ _D = 2° (c = 1.65, MeOH). Example 1 Oxalyl chloride (1.88 ml, 21.6 mmol) was dissolved in 55 ml of methylene chloride at −60° C. under an argon atmosphere. Dimethyl sulfoxide (3.39ml,
47.7 mmol) in methylene chloride (15 ml) was added. After stirring at -60℃ for 20 minutes, [d-1α-hydroxymethyl-2α-(3-hydroxypropyl)-3β
-t-butyldimethylsilyloxymethyl-4α
-tetrahydropyranyloxycyclopentane]
(1.48 g, 3.67 mmol) in methylene chloride solution (30
ml) was added. After stirring at −60° C. for 20 minutes, triethylamine (15.36 ml, 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 give [2-hydroxy-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane] (1.19 g, 81% ) was obtained. From the spectral data, the compound was an equilibrium mixture between β-hydroxyaldehyde and lactol. IR (kBr): 3450, 2950, 2870, 2750, 1730, 835
cm ^-1 . NMR δ (CDCl ₃ ) 9.75 (trace), 4.65 (m, 1H), 3.10~4.50 (m,
6H), 0.90(s, 9H). Mass m/z (%): 313 (trace, M ⁺ -85), 159
(15), 85 (100), 75 (17), 73 (12), 57 (12), 47 (11). Example 2-1 [2-Hydroxy-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-
Endo-tetrahydropyranyloxybicyclo[3.3.0]octane] (1.19 g, 2.97 mmol) was dissolved in benzene (4.5 ml). Under an argon atmosphere,
Dibenzylammonium trifluoroacetate (1.14 g, 3.66 mmol) was added and stirred at 50-70°C for 16 hours. After cooling, water (50 ml) 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),
[l-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (1.03 g, 82%) was obtained. IR (neat): 2950, 2870, 1680, 1620, ^{835cm -1} . NMR δ (CDCl ₃ ) 9.78 (s, 1H), 6.71 (d, J = 2Hz), 4.60
(bs, 1H), 3.00~4.20 (m, 6H), 0.90 (s,
9H). Mass m/z (%): 295(1), 159(33), 85(100),
75(26), 73(19), 67(12), 57(14), 45(14), 43(22)
．． [α] ²⁰ _D = -77° (c = 2.77, MeOH). Example 2-2 Under an argon atmosphere, “l-3-formyl-6-
Exo-t-butyldimethylsilyloxymethyl-7-endotetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (1.09g,
A 1M solution of tetrabutylammonium fluoride in THF (3.1
ml, 3.1 mmol) was added under ice cooling and stirred at room temperature for 4 hours. The reaction solution was poured into a cold saturated aqueous ammonium chloride solution and extracted with ether. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1).
-formyl-6-exo-hydroxymethyl-7
-Endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (0.66 g, 87%) was obtained. IR (neat): 3300, 2900, 2830, 1670, 1605 cm ^-1 . NMR δ (CDCl ₃ ): 9.78 (s, 1H), 6.77 (d,
1H, J=12Hz), 4.55-4.75 (m, 1H), 3.1
~4.1 (m, 7H), 2.4~2.8 (m, 4H), 1.2~
1.8 (m, 8H). Mass m/z (%): 183(1), 182(1), 165(2), 85
(100), 67(3), 57(3). [α] ²⁰ _D = -133° (c = 1.58, MeOH). Example 3 Oxalyl chloride (1.88
ml, 21.6 mmol) was dissolved in methylene chloride (55 ml), and a solution of DMSO in methylene chloride (DMSO 3.39 ml, 47.7 mmol/15 ml CH ₂ Cl ₂ ) was added at -60°C.
Added in minutes. After stirring at -60℃ for 20 minutes, d-1α-
A methylene chloride solution (30 ml) of hydroxymethyl-2α-(3-hydroxypropyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxycyclopentane (1.48 g, 3.67 mmol) was added dropwise over 5 minutes. . Further at -60℃
After stirring for 20 minutes, triethylamine (15.36 ml,
110.1 mmol) was added, and the temperature was raised to room temperature. Add dibenzylammonium trifluoroacetate (1.14g, 3.66mmol) to this reaction solution.
was added, and methylene chloride was distilled off. Benzene (45 ml) was added to this residue to dissolve it, and the mixture was stirred at 50-70°C for 16 hours under an argon atmosphere. Water (50 ml) was added to the reaction solution, and the mixture was extracted with ether. The ether layer is a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution,
After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography (ether: n-hexane =
l-3-formyl-6
-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxy-
Bicyclo[3.3.0]oct-2-ene (1.03g, 74
%) was obtained. Reference example 6 Under an argon atmosphere, 3-carboxypropyltriphenylphosphonium bromide (5.58 g,
13 mmol) was suspended in THF (60 ml). A THF solution (50 ml) of t-butoxypotassium (3.01 g, 26 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. There, a THF solution of [l-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (990 mg, 2.6 mmol) (20 ml) was added dropwise and stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added, and THF was distilled off under reduced pressure. The remaining water layer was adjusted to pH5~ with 10% hydrochloric acid aqueous solution.
4 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 filtrate. By thin layer chromatography [3
-(4-carboxy-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-
After confirming that the spots of endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] had disappeared, a small amount of formic acid was added, and the mixture was immediately washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was subjected to silica gel column chromatography (ether:
n-hexane = 1:2), [l-3
-(4-methoxycarbonyl-1-butenyl)-6
-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (1.09 g, 90
%) was obtained. The (Z)- and (E)-isomer ratio was 2:1. IR (neat): 2950, 2870, 1745, 840cm ^-1 . NMR δ (CDCl ₃ ) 6.24 (d, J = 16Hz, 1/3H, trans), 5.98
(d, J=11Hz, 2/3H, cis), 5.57 (bs,
1H), 5.30 (m, 1H), 4.60 (bs, 1H), 3.20~
4.25 (m, 8H), 2.95 (1H), 0.90 (s, 9H). Mass m/z (%): 464 (trace, M ⁺ ), 323 (20),
231 (28), 159 (29), 157 (16), 117 (11), 85 (100)
，
75(25), 73(20), 67(12), 57(14), 43(13), 41(13). [α] ²⁰ _D = -50° (c = 1.36, MeOH). Reference example 7 [l-3-(4-methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene]
(547 mg, 1.18 mmol) was dissolved in methanol (10 ml). Add 10% palladium/carbon (150mg),
The mixture was stirred at room temperature for 1 hour and 10 minutes under a hydrogen atmosphere. The catalyst was separated and the solvent of the liquid was distilled off. The residue was subjected to silica gel column chromatography (ether: n
-hexane=1:5), [l-3-
(4-methoxycarbonylbutyl)-6-exo-
t-Butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (509 mg, 93%) was obtained. IR (neat): 2950, 2880, 1745, 840cm ^-1 . NMR δ (CDCl ₃ ) 5.25 (d, J = 1Hz, 1H), 4.60 (bs, 1H),
3.65 (s, 3H), 2.90 (m, 1H), 0.90 (s,
9H). Mass m/z (%): 325(8), 233(12), 159(28), 85
(100), 75(17), 73(13). [α] ²⁰ _D = -12° (c = 1.68, MeOH). Reference example 8 [l-3-(4-methoxycarbonylbutyl)-
6-Exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (585mg,
1.26 mmol) was dissolved in THF (5 ml). Tetra-n-butylammonium fluoride (1M
A THF solution (2.5 ml, 2.5 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. Saturated brine was added, and THF was distilled off under reduced pressure. The remaining aqueous layer was extracted with ether, dried over anhydrous magnesium sulfate, and then the solvent was distilled off.
The residue was purified by silica gel column chromatography to obtain [l-3-(4-methoxycarbonylbutyl)-6-exo-hydroxymethyl-7-
Endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (425 mg, 95.2%) was obtained. IR (neat): 3480, 2950, 2880, 1740cm ^-1 . NMR δ (CDCl ₃ ) 5.25 (d, J = 1Hz, 1H), 4.60 (m, 1H),
3.66 (s, 3H), 3.00 (m, 1H). Mass m/z (%): 352 (trace, M ⁺ ), 268(3), 85
(100), 67(11), 57(10), 41(11). [α] ²⁰ _D = -19° (c = 2.09, MeOH) Reference example 9 Under an argon atmosphere, Collins reagent (CrO ₃
2Py, 660mg, 2.56mmol) and Celite (660mg)
was suspended in methylene chloride (10ml). [l-3-
(4-methoxycarbonylbutyl)-6-exo-
A methylene chloride solution (2.5 ml) of hydroxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (50 mg, 0.142 mmol) was added, and the mixture was stirred at 0°C for 30 minutes. Add 1.32g of sodium hydrogen sulfate hydrate and further heat to 0°C.
The mixture was stirred for 10 minutes. The reaction solution was filtered using anhydrous magnesium sulfate as a filtering agent and washed with methylene chloride. The liquids were combined, the solvent was distilled off, and [3-(4-
methoxycarbonylbutyl)-6-exo-formyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (48 mg,
%) was obtained. On the other hand, sodium hydride (60% oily, 11mg,
0.28 mmol) was washed with pentane under an argon atmosphere and suspended in 3 ml of DME (dimethoxyethane). A DME solution (3 ml) of dimethyl (2-oxoheptyl) phosphonate (64 mg, 0.29 mmol) was added, and the mixture was stirred at room temperature for 25 minutes. [3-(4-methoxycarbonylbutyl)-6-exo-formyl-7
A DME solution (3 ml) of -endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (48 mg) was added, and after stirring at room temperature for 1 hour, a saturated aqueous ammonium chloride solution was added. After distilling off DME under reduced pressure, 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 = 2:5) to obtain [3-(4-methoxycarbonylbutyl)]. -6-exo-(3-oxo-trans-1-octenyl)-7-endo-
Tetrahydropyranyloxybicyclo [3.3.0]
Oct-2-ene] (35 mg, 57%) was obtained. IR (neat): 2950, 2880, 1742, 1698, 1672,
1628cm ^-1 . NMR δ (CDCl ₃ ) 6.80 (m, 1H), 6.17 (d×d, J=16, 4Hz,
1H), 5.30 (d, J = 1Hz, 1H), 4.65, 4.55
(each bs, total 1H), 3.68 (s, 3H), 3.00 (m,
1H). Mass m/z (%): 362(10), 318(13), 85(100), 67
(16), 57(18), 55(13), 43(20), 41(20). Reference examples 10-13 Various dimethyl (2-
Table 1 shows the results of synthesizing (3-oxo-1-alkenyl)-cis-bicyclo[3.3.0]octene derivatives by reaction with oxoalkyl)phosphonates.
The spectral data is shown in Table 2.

【table】

【table】

[Table] Reference example 14 [3-(4-methoxycarbonylbutyl)-6-
Exo-(3-oxo-trans-1-octenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (32mg,
0.072 mmol) was dissolved in methanol (5 ml).
Cool to −20° C. and add excess sodium borohydride. After stirring for 20 minutes at −20° C., excess acetone was added. After returning the temperature to room temperature, a saturated aqueous ammonium chloride solution was added, and 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-exo-(3-hydroxy-trans-1-
octenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene]
(32 mg, 100%) was obtained. IR (neat): 3470, 3230, 2950, 2880, 1742 cm ^-1 . NMR δ (CDCl ₃ ) 5.57 (m, 2H), 5.28 (d, J = 1Hz, 1H),
4.63 (bs, 1H), 3.65 (s, 3H), 2.95 (m,
1H). Mass m/z (%): 430 (1, M ⁺ −H ₂ O), 302 (15),
85(100), 67(13), 57(16), 55(11), 43(17), 41(18)
．． Reference examples 15-18 Various 3-oxo-1-
Table 3 shows the results and spectrum data of the reduction of alkenyl-cis-bicyclo[3.3.0]octene derivatives.

【table】

[Table] Reference example 19 [3-(4-methoxycarbonylbutyl)-6-
exo-(3-hydroxy-trans-1-octenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (32
mg, 0.072 mmol) in acetic acid:water:THF (0.5ml)
(3:1:1, volume ratio) Dissolve in the mixed liquid, 45-50
Stirred at ℃ for 5 hours. After diluting with ether, the mixture was neutralized with saturated sodium bicarbonate solution. The ether layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (ether: n-hexane = 5:1
~ether:methanol=40:1) and as a more polar fraction [3-
(4-methoxycarbonylbutyl)-6-exo-
(3α-hydroxy-trans-1-octenyl)
-7-endo-hydroxybicyclo[3.3.0]oct-2-ene] (13 mg, 48%) and as a less polar fraction [3-(4-methoxycarbonylbutyl)-6-exo-(3β-hydroxy -trans-1-octenyl)-7-endo-
Hydroxybicyclo[3.3.0]oct-2-ene]
(7 mg, 26%) 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, 1742 cm ^-1 . NMR δ (CDCl ₃ ) 5.60 (m, 2H), 5.33 (bs, 1H), 4.12 (m,
1H), 3.69 (s, 3H), 3.00 (m, 1H). Mass m/z (%): 346 (25, M ⁺ −H ₂ O), 328 (18),
315(9), 302(71), 275(15), 247(11), 232(32),
199(17), 193(19), 180(30), 179(27). Reference examples 20-23 Various [3-(4-methoxycarbonylbutyl)-6-exo-(3-hydroxy-trans-1-alkenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]] were prepared in the same manner as in Reference Example 19. Oct-2-ene] was removed from THP, and then 15-
Isomers based on positional hydroxyl groups were separated. The results and spectral data are shown in Table 4. In both cases, the highly polar isomer was designated as the α-epimer, and the less polar isomer was designated as the β-epimer.

[Table] *All spectra are of α-epimer. The spectrum of the β-epimer is similar.
Reference example 24 [3-(4-methoxycarbonylbutyl)-6-
Exo-(3α-hydroxy-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]oct-2-ene] (10mg, 0.027mmol)
was dissolved in methanol (0.3ml). 10% at 0℃
Aqueous sodium hydroxide solution (0.2 ml) was added. 0
After stirring at °C for 9 hours, the mixture was neutralized with a 10% aqueous hydrochloric acid solution while cooling. After distilling off methanol under reduced pressure, PH3-4
and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain [9(0)-methanol Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ ] (10 mg, 100%). IR (neat): 3350, 2910, 2850, 1700, 1450,
1250cm ^-1 . NMR δ (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 ). Melting point: 73-79°C [α] ²⁰ _D = +16° (c = 0.25, MeOH). Similarly, the 15β-epimer is also hydrolyzed, and 9
The 15β isomer of (0)-methanolΔ ⁶⁽⁹ 〓 ⁾ -PGI ₁ was obtained.
The spectral data (IR, NMR, Mass) are consistent with the Δ ⁶⁽⁹ 〓 ⁾ −PGI ₁ data. Reference examples 25-28 Various [3-(4-methoxycarbonylbutyl)-6-exo-(3α-
hydroxy-trans-1-alkenyl)-7-
endo-hydroxybicyclo[3.3.0]octo-
[2-ene] was hydrolyzed to obtain various [9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ derivatives]. The results and spectral data are shown in Table-5. Similarly, the 15β-epimer body is also hydrolyzed, and 9
The 15β isomer of the (0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ derivative was obtained. Spectral data (IR, NMR, Mass)
are in agreement with the data for the Δ ⁶⁽⁹ 〓 ⁾ −PGI ₁ derivative, respectively.

【table】

[Table] Reference example 29 [2
-Oxa-3-oxo-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane] (1.11 g, 3.88 mmol) [1α -Hydroxymethyl-2α-(3-hydroxypropyl)-3β-(1-methyl-1-methoxyethyloxymethyl)-4α-tetrahydropyranyloxycyclopentane] (1.13 g, 81%) was obtained. IR (neat): 3400, 2940, 2860, 831 cm ^-1 . NMR δ (CDCl ₃ ) 4.61 (bs, 1H), 3.40-4.20 (m, 9H), 3.20
(s, 3H), 1.34 (s, 6H). Mass m/z: 360, 342, 328, 257. Example 4 [1α-
From hydroxymethyl-2α-(3-hydroxypropyl)-3β-(1-methyl-1-methoxyethyloxymethyl)-4α-tetrahydropyranyloxycyclopentane (1.13 g, 3.14 mmol) [3
-Formyl-6-exo-(1-methyl-1-methoxyethyoxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (690 mg, 65%) as a colorless oil. obtained as. IR (neat): 1680, 1620cm ^-1 . NMR δ (CDCl ₃ ) 9.77 (s, 1H), 6.72 (d, J = 2Hz), 4.60
(bs, 1H), 3.00~4.20 (m, 6H), 3.20 (s,
3H), 1.34(s, 6H). Mass m/z: 338, 306, 253. Reference example 30 [3-formyl-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octo-
[3-(4-
Carboxy-1-butenyl)-6-exo-(1-
Methyl-1-methoxyethyloxymethyl)-7
-Endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (965 mg, 91%) was obtained. The (Z)- and (E)-isomer ratio was 2:1. IR (neat): 3400, 1710, 840cm ^-1 . NMR δ (CDCl ₃ ) 6.23 (d, J = 16Hz, 1/3H, trans), 5.95
(d, J=11Hz, 2/3H, cis), 5.55 (bs,
1H), 5.30 (m, 1H), 4.60 (bs, 1H), 3.30~
4.20 (m, 5H), 3.20 (s, 3H), 2.95 (m,
1H), 1.34 (s, 6H). Mass m/z: 408 (M ⁺ ), 377, 364, 323. Further, by the reaction operation exactly the same as in Reference Example 6, [3
-(4-carboxy-1-butenyl)-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] l
-3-(4-methoxycarbonyl-1-butenyl)
-6-Exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] was quantitatively obtained as a colorless oil. IR (neat): 2950, 1742cm ^-1 . NMR δ (CDCl ₃ ) 6.22 (d, J = 16Hz, 1/3H, trans), 5.95
(d, J=11Hz, 2/3H, cis), 5.58 (bs,
1H), 5.30 (m, 1H), 4.62 (m, 1H), 3.67
(s, 3H), 3.25-4.10 (m, 5H), 3.20 (s,
3H), 3.00 (m, 1H), 1.34 (s, 6H). Mass m/z: 390, 350, 338, 332, 306, 248,
230, 204, 191, 143, 131, 117, 91, 86,
85, 79, 73, 67. [α] ²⁰ _D = -43.5° (c = 0.718, MeOH). Reference example 31 [l-3
-(4-methoxycarbonyl-1-butenyl)-6
-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene]
(498 mg, 1.18 mmol) from [3-(4-methoxycarbonylbutyl)-6-exo-(1-methyl-1
-methoxyethyloxymethyl)-7-endo-
Tetrahydropyranyloxybicyclo [3.3.0]
Oct-2-ene] (425 mg, 85%) was obtained. IR (neat): 2950, 2880, 1742, 840cm ^-1 . NMR δ (CDCl ₃ ) 5.23 (d, J = 1Hz, 1H), 4.60 (bs, 1H),
3.65 (s, 3H). 3.40-4.10 (m, 5H), 3.20 (s, 3H), 2.90
(m, 1H), 1.34 (s, 6H). Mass m/e: 424 (M ⁺ ), 393, 392, 339. Reference example 32 [3-(4-methoxycarbonylbutyl)-6-
exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (42
mg, 1 mmol) was dissolved in THF (11 ml), and while cooling with ice, 0.5NHCl (5.5 ml) was added and stirred under the same conditions for 10 minutes. Add acetic acid ethyl ester (109ml),
The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was subjected to silica gel column chromatography (ether:
Purified with n-hexane = 1:2) [l-3-
(4-methoxycarbonylbutyl)-6-exo-
Hydroxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene] (334 mg, 95%) was obtained as a colorless oil. The various spectral data completely matched the spectral data of the substance obtained in Reference Example 8. Test example: For example, 9 of the compounds synthesized by the above method
(0)-Methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ has the biological activity described below. When using rabbit blood, it inhibited platelet aggregation induced by adenosine diphosphate (ADP) with a strength 1/10 that of PGI ₂ , and
When human blood was used, it showed half the strength of PGI ₂ . Regarding the effect on blood pressure, when used in rats, it showed a similar strength as PGI ₂ , and showed a blood pressure lowering effect at a dose of 0.1 μg/Kg. The effect on heart rate was also similar to that of PGI ₂ , and in experiments using rats, a dose of 1 μg/Kg showed an increase in heart rate. It also showed anti-ulcer activity at a low concentration of 10 ^-6 M in experiments using rabbit stomachs, which is comparable to PGE ₂ . Cytotoxicity is very weak, IC ₅₀ =5 μg/ml.

Claims (1)

[Claims] 1. General formula Bicyclo[3.3.0 ^] octenylaldehyde ^derivative represented by ). 2 In the presence of an acidic catalyst, the general formula The general formula consists of dehydrating a β-hydroxyaldehyde represented by A method for producing a bicyclo[3.3.0]octenylaldehyde derivative represented by (wherein R ¹ is a hydrogen atom,
It is a tetrahydropyranyl group or a 4-methoxytetrahydropyranyl group, and R ² is a hydrogen atom or t
-butyldimethylsilyl group. ). 3 General formula The general formula consists of oxidizing a hydroxymethylcyclopentane derivative represented by and then dehydrating the resulting reaction mixture in the presence of an acidic catalyst. A method for producing a bicyclo[3.3.0]octenylaldehyde derivative represented by (wherein R ¹ is a hydrogen atom,
It is a tetrahydropyranyl group or a 4-methoxytetrahydropyranyl group, and R ² is a hydrogen atom or t
-butyldimethylsilyl group. ).