JPH0451534B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on 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, and R ² and R ³ are a hydrogen atom or a hydroxyl group protecting group.) Regarding bicyclo[3.3.0]octenylaldehyde derivatives. The bicyclo[3.3.0]octenyl aldehyde derivative represented by the above general formula () of the present invention is a 3-
9( 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 . , a compound used as a therapeutic or preventive drug for various cardiovascular diseases. Conventionally, methods for producing 9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ include (a) a method in which PGI 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)
The disadvantage of both was that the overall yield was very low. The present inventors have discovered that 9(0)-methano-
As a result of repeated research into the production of 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 thus the present invention was developed. completed. 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, the protecting group for hydroxyl group in the present invention is a ^{tetrahydropyranyl} group, a methoxymethyl group,
4-methoxytetrahydropyranyl group, 1-ethoxymethyl group, 1-methyl-1-methoxyethyl group, t-butyldimethylsilyl group, diphenyl-
Examples include t-butylsilyl group, benzoyl group, acetyl group, etc., and as ^R3 , t-butyldimethylsilyl group, benzoyl group, acetyl group,
Tetrahydropyranyl group, methoxymethy 1 group, 4
Examples include -methoxytetrahydropyranyl group, 1-ethoxymethyl group, 1-methyl-1-methoxyethyl group, and diphenyl-t-butylsilyl group. (In the formula, R ¹ is a linear, branched or cyclic alkyl group or alkenyl group having 1 to 10 carbon atoms, and R ² and R ³ are a hydrogen atom or a protecting group for a hydroxyl group.) [First Step] This step is to produce an allylcyclopentylidene derivative represented by the general formula () by methyleneating the allylcyclopentanone derivative represented by the general formula (). The allylcyclopentanone derivative represented by the above general formula (), which is the raw material for this step, has the general formula (In the formula, R ² represents a hydroxyl group protecting group.) Cyclopentenones represented by the general formula (In the formula, R ¹ is the same as defined above, R ³ is a hydroxyl protecting group, and X is a group

[Second step]

In this step, the hydroxymethylcyclopentane derivative represented by the general formula () is produced by subjecting the allylcyclopentylidene derivative represented by the general formula () obtained in the first step to a hydration reaction. 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), dithiamylborane, thexylborane, etc. can be used. The amount of hydroboration reagent used is usually 1~
Use 3 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, for example, an oxidizing agent such as hydrogen peroxide can be used. When performing oxidation using hydrogen peroxide, it is preferable to use it in a basic state, such as sodium hydroxide. The amount of oxidizing agent used is 5 to 15 equivalents. The reaction proceeds smoothly at room temperature to 80°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. [Third Step] This step oxidizes and dehydrates the hydroxymethylcyclopentane derivative represented by the general formula () obtained in the second step to obtain bicyclo[3.3.0 ] This method produces octenyl aldehyde derivatives. In the oxidation, for example, dimethyl sulfoxide-oxalyl 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. 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. In order to obtain the oxidation product of this step, a tertiary amine such as triethylamine or diisopropylethylamine is added to the reaction mixture and the reaction mixture is treated at -70°C to room temperature. Subsequently, this step involves dehydration. Dehydration is carried out in the presence of an acidic catalyst. As acidic catalysts, acid-ammonium salts can be used. Acid-ammonium salt catalysts can be formed from acids and amines. Examples of acids that can be used include trifluoroacetic acid, toluenesulfonic acid, camphorsulfonic acid, and acetic acid. In addition, amines that can be used include dibenzylamine, diethylamine,
Examples include 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 used may be around 0.2 equivalent, but
It is preferable to use about 1 equivalent in order to cause the reaction to proceed rapidly. In carrying out the reaction, it is desirable to use a solvent, and aromatic hydrocarbons such as benzene, toluene, and xylene can be used. The reaction temperature can be selected from room temperature to 100℃,
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. The bicyclo[3.3.0]octenylaldehyde derivative represented by the general formula () obtained in this step can be led to a free compound by subjecting it to a deprotection reaction, and if desired, the free compound can be Reprotection with other protecting groups is also possible. The bicyclo[3.3.0]octenyl aldehyde derivative of the present invention has an asymmetric carbon atom in the molecule, but in the present invention, the asymmetric carbon atom may have an R configuration, an S configuration, or any of these. This includes a mixture of proportions of . Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples. Reference example 1 (Si=t-butyldimethylsilyl group) {2(R)-allyl-3(R)-[3'(S)-t-
Butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentanone} (707 mg,
A zinc-titanium chloride-methylene bromide reagent (Zn- _TiCI4 - _CH2Br2 / _THF , 7.48ml, about 1.3 equivalents) was added to a solution of 1.44mmol) in methylene chloride (7ml) at room temperature. 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-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene} (652 mg, 88%)
was obtained as an almost colorless oil. IR (neat): 3080, 2930, 2850, 1650, 1460,
1360, 1250cm ^-1 ． NMRδ (CDCl ₃ ) 5.70 (m, 1H), 5.41 (m,
2H), 4.75-5.10 (m, 4H), 4.02 (m,
1H), 3.70 (1H, m), 2.00~2.70 (m,
6H), 1.40 (m, 8H), 0.88 (s,
21H), 0.02(s, 12H). Mass m/z: 435 (M ⁺ -57), 421, 393, 323,
303, 289, 229, 147, 75, 73. Reference example 2 {2(R)-allyl-3(R)-[3'(S)-t-
Butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxy-1-cyclopentylidene} (700mg,
1.42 mmol) in THF solution (7.10 mmol, 14.2 ml) of 9-borabicyclo[3.3.1]nonane (9-BBN)
was added at room temperature and stirred for 3 hours. Next to the reaction system
A 6N-NaOH aqueous solution (6.9 ml) and a 30% H ₂ O ₂ aqueous 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-
1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxycyclopentane} (502
mg, 67%) as a colorless oil. IR (neat): 3350, 2930, 2850, 1460, 1360,
1250cm ^-1 ． NMRδ (CDCl ₃ ) 5.38 (m, 2H), 3.96 (m,
2H), 3.59 (m, 4H), 2.83 (m, 1H),
2.16 (m, 3H), 1.10~1.80 (m,
15H), 0.87(s, 21H), 0.04(s,
12H). Mass m/z: 471 (M ⁺ -57), 453, 396, 379,
339, 325, 321, 247, 229, 75, 73. Reference example 3 (THP=tetrahydropyranyl group) Under exactly the same conditions as Reference Examples 1 and 2, {2(R)
-Allyl-3(R)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-4
{1(S)-hydroxymethyl-2(S)-(3'-hydroxypropyl)-3( S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]
-4(R)-tetrahydropyranyloxycyclopentane} (374 mg) was obtained as an almost colorless oil. IR (neat): 3350, 2930, 2850, 1450, 1365,
1200cm ^-1 ． NMRδ (CDCl ₃ ) 5.35 (m, 2H), 4.50 (m,
2H), 4.00 (m, 2H), 3.60 (m, 8H). Mass m/z: 468 (M ⁺ ), 450. Example 1 DMSO (0.83 ml,
A methylene chloride solution (4 ml) of 11.7 mmol) was added over 5 minutes at -78°C, and the mixture was stirred under the same conditions for 15 minutes. To this {1(S)-hydroxymethyl-2(S)
-(3'-Hydroxypropyl)-3(S)-[3'(S
)
-t-butyldimethylsilyloxy-1'-trans-octenyl]-4(R)-t-butyldimethylsilyloxycyclopentane} (475 mg,
A solution of 0.900 mmol) in methylene chloride (3 ml) was added dropwise, and the mixture was further stirred at -78°C for 15 minutes. Add triethylamine (2.50ml, 18.0mmol) under the same conditions,
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, and the mixture was stirred at 70°C for 4 hours. The reaction solution was diluted with ether, washed with an aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to give {3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]- 7
(R)-t-butyldimethylsilyloxy-(1S,
5S)-cis-bicyclo[3.3.0]oct-2-ene} (441 mg, 97%) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1680, 1460, 1360,
1250cm ^-1 ． NMRδ (CDCl ₃ ) 9.82 (s, 1H), 6.73 (bs,
1H), 5.48 (m, 2H), 4.08 (m, 1H),
3.76 (m, 1H), 3.24 (m, 1H), 1.10
~2.80 (m, 14H), 0.87, 0.90 (2s,
21H), 0.03(s, 12H). Mass m/z: 449 (M ⁺ −57), 435, 359, 339,
317, 303, 202, 73. Example 2 {3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)- Cis-bicyclo[3.3.0]oct-2-ene} (18.9 mg, 0.0374 mmol) in acetic acid
The mixture was mixed with 0.2 ml of a mixed solvent of H ₂ O-tetrahydrofuran (3:1:1) and stirred at 45°C for 3 hours. After evaporating the solvent under reduced pressure, saturated aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporating the solvent was purified by silica gel column chromatography to obtain {3-formyl-6(S)-[3'(S)-hydroxy-1'-trans-oftenyl]-7(R) -Hydroxy-(1S,
5S)-cis-bicyclo[3.3.0]oct-2-ene} (8.3 mg, 80%) was obtained as an almost colorless oil. IR (neat): 3400, 2950, 2850, ^{1680cm -1} . NMRδ (CDCl ₃ ) 9.82 (s, 1H), 6.73 (bs,
1H), 5.45 (m, 2H), 4.10 (m, 1H),
3.80 (m, 1H), 3.24 (m, 1H). Mass m/z: 278 (M ⁺ ), 260 (M ⁺ −H ₂ O). Example 3 {3-formyl-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octo- 2-ene} (27.8 mg, 0.1 mmol) was dissolved in anhydrous methylene chloride (1 ml), dihydropyran (84 mg, 1 mmol) followed by a catalytic amount of para-toluenesulfonic anhydride were added thereto, and the mixture was stirred at room temperature for 5 minutes. After stopping the reaction with saturated aqueous sodium bicarbonate solution, the mixture was extracted with ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography to obtain {3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7 (R)-tetrahydropyranyloxy-
(1S,5S)-cis-bicyclo[3.3.0]octo-2
-ene} (42.4 mg, 95%) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1680cm ^-1 . NMRδ (CDCl ₃ ) 9.82 (s, 1H), 6.75 (bs,
1H), 5.44 (m, 2H), 4.50 (m, 2H),
3.20-4.10 (m, 7H). Mass m/z: 446 (M ⁺ ), 361. Example 4 In the same manner as in Example 1, {1(S)-hydroxymethyl-2(S)-(3′-hydroxypropyl)-3
(S)-[3'(S)-tetrahydropyranyloxy-
1'-trans-octenyl]-4(R)-tetrahydropyranyloxycyclopentane} (374 mg,
{3-formyl-6
(S)-[3'(S)-tetrahydropyranyloxy-
1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (232 mg) was obtained as an almost colorless oil. Various spectral data are consistent with those obtained in Example 3. Reference example 4 3-Carboxypropyltriphenylphosphonium bromide (321 mg, 0.748 mmol) in THF
(3.0 ml), t-butoxypotassium (167 mg, 1.49 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. {3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7 was added to the resulting red-orange ylide solution.
(R)-t-butyldimethylsilyloxy-(1S,
A solution of 5S)-cis-bicyclo[3.3.0]oct-2-ene} (189 mg, 0.374 mmol) in THF (1.5 ml) was added and stirred for 30 minutes. The reaction solution was diluted with ether, and after confirming acidity (PH≈4) with a 10% aqueous HCl solution, the ether layer was separated. After further extraction with ether, the ether layers were combined, washed with saturated NaCl water, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was dissolved in a small amount of ether and converted into methyl ester with an ether solution of diazomethane. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-
[3'(S)-t-butyldimethylsilyloxy-
1'-trans-octenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (194 mg, 88
%) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1750, 1460, 1360,
1250cm ^-1 ． NMRδ( _CDCl3 )6.27(d, J=16Hz, 2/5H,
trans), 6.02 (d, J=11Hz, 3/
5H, cis), 5.51 (m, 4H), 4.07 (m,
1H), 3.70 (m, 1H), 3.69 (s, 3H),
2.97 (m, 1H), 1.10~2.70 (m,
16H), 0.87, 0.90 (2s, 21H), 0.03
(s, 12H). Mass m/z: 590 (M ⁺ ), 534, 533, 519,
458, 427, 401, 301, 75, 73. [α] ²⁰ _D = -37° (c = 0.614, CHCl ₃ ). Reference example 5 {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethylsilyloxy-1'-trans-octenyl]-7(R)
-t-butyldimethylsilyloxy- (1S, 5S)
-cis-bicyclo[3.3.0]oct-2-ene}
(31 mg, 0.05 mmol) in THF (0.5 ml) was added a tetrabutylammonium fluoride THF solution (0.16 ml, 1M solution) and stirred at room temperature for 15 hours. After stopping the reaction with saturated ammonium chloride water, THF was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-1' -trans-octenyl]-7(R)-hydroxy-(1S,
5S)-cis-bicyclo[3.3.0]oct-2-ene} (15 mg) was obtained as a colorless caramel (79%). IR (neat): 3400, 2950, 1742cm ^-1 . NMRδ( _CDCl3 )6.30(d, J=16Hz, 1/3H,
trans), 6.02 (d, J=11Hz, 2/
3H, cis), 5.60 (m, 3H), 5.40 (m,
1H), 4.10 (m.1), 3.80 (m, 1H),
3.70 (s, 3H), 3.02 (m, 1H). [α] ²⁰ _D = -35° (c = 0.466, MeOH). Mass m/z (%): 362 (7, M ⁺ ), 344 (44),
326 (19), 300 (37), 220 (54) 168 (41),
178 (55), 43 (100). Reference example 6 3-Carboxypropyltriphenylphosphonium bromide (32.1mg, 0.0748mmol) in THF
(0.3 ml), t-butoxypotassium (16.7 mg, 0.149 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. {3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R) was added to the resulting red-orange ylide solution.
-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (16.7
mg, 0.0374 mmol) in THF (0.15 ml),
Stir for 30 minutes. Dilute the reaction solution with ether and add 10
After confirming acidity (PH≒4) with a %HCl aqueous solution, the ether layer was separated. After further extraction with ether, the ether layers were combined, washed with saturated NaCl water, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was dissolved in a small amount of ether and converted into methyl ester with an ether solution of cyazomethane. After distilling off the solvent, the residue was separated and purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-tetrahydropyranyloxy] -1'-trans-octenyl]-7(R)-tetrahydropyranyloxy-
(1S,5S)-cis-bicyclo[3.3.0]octo-2
-ene} (15.9 mg, 80%) was obtained as an almost colorless oil. IR (neat): 2948, 2850, 1745cm ^-1 . NMRδ( _CDCl3 )6.27(d, J=16Hz, 2/5H,
trans), 6.02 (d, J=11Hz, 3/
5H, cis), 5.51 (m, 4H), 4.55 (m,
2H), 3.70-4.10 (m, 2H), 3.69 (s,
3H), 3.50-3.70 (m, 4H), 3.00 (m,
1H). Mass m/z: 530 (M ⁺ ), 499. Reference example 7 {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-1'-trans-octenyl]-7(R)-tetrahydropyranyloxy −(1S,5S)−cis−
Bicyclo[3.3.0]oct-2-ene} (15.9mg,
0.03 mmol) in acetic acid-H ₂ O-THF (3:1:1)
(0.5 ml) and stirred at 45°C for 3 hours. After evaporating the solvent under reduced pressure, saturated aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-
[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (8.7 mg, 80
%) was obtained as a colorless caramel. The spectral data are consistent with those obtained in Reference Example 5. Reference example 8 {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,
RhCl(Ph ₃ P) ₃ (5 mg) was added to a solution of 5S)-cis-bicyclo[3.3.0]oct-2-ene} (15 mg, 0.041 mmol) in benzene (0.5 ml), and the mixture was heated under a hydrogen stream (normal pressure). ) and stirred at room temperature for 1 hour and at 45°C for 1.5 hours.
After removing the catalyst using a short silica gel column, the resulting residue was purified again using silica gel column chromatography to obtain 9 mg of a colorless oil. This was dissolved in methanol (0.2ml). 10% at 0℃
Aqueous sodium hydroxide solution (0.1 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 give {3-(4'-
carboxybutyl)-6(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octo-2 -ene} (9 mg) was obtained as a colorless solid. IR (neat): 3350, 2910, 2850, 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 ). Melting point: 73-79°C [α] ²⁰ _D = +60° (c = 0.25, MeOH). Reference example 9 {3-(4'-methoxycarbonylbutyl)-6
(S)-[3'(S)-hydroxy-1'-trans-octenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (10
mg, 0.027 mmol) was dissolved in methanol (0.3 ml). 10% aqueous sodium hydroxide solution (0.2
ml) was added. After stirring at 0°C for 9 hours, under cooling,
% aqueous hydrochloric acid solution. After distilling off methanol under reduced pressure, the pH was adjusted to 3 to 4 and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give [9(O)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ ] (10 mg,
100%). Spectral data is reference example 8
It matches what we got. Reference example 10 {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 an almost 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). Mass m/z: 433 (M ⁺ −57) 419, 391. Reference example 11 {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[3.3.1 ] A THF solution (7.10 mmol, 14.2 ml) of nonane (9-BBN) was added at room temperature, and the mixture was 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, the residue was purified by silica gel column chromatography, and {1(S)-
Hydroxymethyl-2(S)-(3'-hydroxypropyl)-3(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclobentyl-1'-trans-bropenyl]-4( R)-t-butyldimethylsilyloxycyclopentane} (442 mg, 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). Mass m/z: 469 (M ⁺ -57) 451, 394, 377. Reference example 12 Under exactly the same conditions as Reference Examples 10 and 11, {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-
3'-cyclopentyl-1'-trans-propenyl]-4(R)-tetrahydropyranyloxycyclopentane} (275 mg) 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). Mass m/z: 466 (M ⁺ ), 448. Example 5 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 to the resulting residue were added benzene (8 ml) and trifluoroacetate of dibenzylamine (220 mg, 0.900 mmol), and the mixture was stirred at 70°C for 4 hours. The reaction solution was diluted with ether, washed with an aqueous ammonium chloride 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). Mass m/z: 447 (M ⁺ -57), 433, 357, 337,
315, 301, 200, 71. Example 6 {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} (18.9 mg,
0.0374 mmol) was mixed with a mixed solvent (0.2 ml) of acetic acid-H ₂ O-tetrahydrofuran (3:1:1) and stirred at 45°C for 3 hours. After evaporating the solvent under reduced pressure, saturated aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography to obtain {3-formyl-6(S)-[3'(S)
−
Hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)
-cis-bicyclo[3.3.0]oct-2-ene}
(8.7 mg, 84%) was obtained as an almost colorless oil. IR (neat): 3400, 2950, 2850, ^{1684cm -1} . NMRδ( _CDCl3 ). 81 (s, 1H), 6.74 (bs, 1H),
5.45 (m, 2H), 4.10 (m, 1H), 3.80
(m, 1H), 3.23 (m, 1H). Mass m/z: 276 (M ⁺ ), 258 (M ⁺ −H ₂ O). Example 7 {3-formyl-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-
Bicyclo[3.3.0]oct-2-ene} (27.6mg,
0.1 mmol) was dissolved in anhydrous methylene chloride (1 ml), dihydropyran (84 mg, 1 mmol) followed by a catalytic amount of anhydrous para-toluenesulfonic acid was added thereto, and the mixture was stirred at room temperature for 5 minutes. After stopping the reaction with saturated aqueous sodium bicarbonate solution, the mixture was extracted with ether. The organic layer was washed with saturated brine, and the resulting residue was purified by silica gel column chromatography to obtain {3-formyl-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl] -1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-
(1S,5S)-cis-bicyclo[3.3.0]octo-2
-ene} (39.5 mg, 89%) 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). Mass m/z: 444 (M ⁺ ), 359. Example 8 In the same manner as in Example 4, {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. Various spectral data are consistent with those obtained in Example 7. Reference example 13 3-Carboxypropyltriphenylphosphonium bromide (321 mg, 0.748 mmol) in THF
(3.0 ml), t-butoxypotassium (167 mg, 1.49 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. {3-formyl-6(S)-[3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R) was added to the obtained red-orange ylide solution. -t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]
Oct-2-ene} (189 mg, 0.374 mmol)
A THF (1.5 ml) solution was added and stirred for 30 minutes. The reaction solution was diluted with ether, and after confirming acidity (PH≈4) with a 10% aqueous HCl solution, the ether layer was separated.
After further extraction with ether, the ether layers were combined, washed with saturated NaCl water, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was dissolved in a small amount of ether, and methyl ester was obtained with an ether solution of cyazomethane. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography to obtain {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-t-butyldimethyl Silyloxy-3'-cyclopentyl-1'-trans-
propenyl]-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]
Oct-2-ene} (175 mg, 80%) was obtained as an almost colorless oil. IR (neat): 2950, 2850, 1745, 1460, 1358,
1240cm ^-1 ． NMRδ( _CDCl3 )6.25(d, J=16Hz, 2/5H,
trans), 6.01 (d, J=11Hz, 3/
5H, cis), 5.50 (m, 4H), 4.07 (m,
1H), 3.69 (m, 1H), 3.68 (s, 3H),
2.98 (m, 1H), 1.10~2.70 (m,
17H), 0.87, 0.90 (2s, 18H), 0.03
(s, 12H). Mass m/z: 588 (M ⁺ ), 532, 531, 517. [α] ²⁰ _D = -37° (c = 1.618, CHCl ₃ ). Reference example 14 {3-(4'-methoxycarbonyl-1'-butenyl)-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} (81 mg, 0.14 mmol) in THF
(1.5 ml) A tetrabutylammonium fluoride THF solution (0.42 ml, 1M solution) was added to the solution, and the mixture was stirred at room temperature for 16 hours. After stopping the reaction with saturated ammonium chloride water, THF was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-3'-Cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-
Bicyclo[3.3.0]oct-2-ene} (49mg,
100%) was obtained as a colorless caramel. IR (neat): 3400, 1740, 1430, 1160, 1090,
965cm ^-1 ． NMRδ( _CDCl3 )6.22(d, J=16Hz, 1/3H,
trans), 5.95 (d, J=11Hz, 2/
3H, cis), 5.13-5.74 (m, 4H, Olefinik proton), 3.66 (s,
3H), 3.50-4.00 (m, 2H), 3.02
(m, 1H). Mass m/z: 360 (M ⁺ ), 342 (M ⁺ −H ₂ O), 324
(M ⁺ −2H ₂ O), 298, 273. [α] ²⁰ _D = −30° (c = 1.16, MeOH). Reference example 15 3-Carboxypropyltriphenylphosphonium bromide (32.1mg, 0.0748mmol) in THF
(0.3 ml), t-butoxypotassium (16.7 mg, 0.149 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. {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} (16.6mg, 0.0374mmol) in THF
(0.15ml) solution was added and stirred for 30 minutes. The reaction solution was diluted with ether and acidified (PH
After confirming ≒4), the ether layer was separated. After further extraction with ether, the ether layers were combined, washed with saturated NaCl water, and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was dissolved in a small amount of ether and converted into methyl ester with an ether solution of cyazomethane. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-tetrahydropyranyloxy] -3'-cyclopentyl-1'-trans-propenyl]-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octo-
2-ene} (16.2 mg, 82%) was obtained as an almost colorless oil. IR (neat): 2948, 2850, 1745cm ^-1 . NMRδ( _CDCl3 ) 6.27(d, J=16Hz,
2/5H, trans), 6.02 (d, J=
11Hz, 3/5H, cis), 5.50 (m,
4H), 4.55 (m, 2H), 3.70~4.10 (m,
2H), 3.69 (s, 3H), 3.50~3.70 (m,
4H), 3.00 (m, 1H). Mass m/z: 528 (M ⁺ ), 497. Reference example 16 {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-1'-trans-propenyl]-7(R) -tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octo-
2-ene} (15.8 mg, 0.03 mmol) in acetic acid-H ₂ O-
Mix with THF (3:1:1) (0.5ml), 45℃
The mixture was stirred for 3 hours. After evaporating the solvent under reduced pressure, saturated aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography to give {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-3 '-cyclopentyl-1'-trans-propenyl]-7(R)
-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (9.2 mg, 85%) was obtained as a colorless caramel. The spectral data are consistent with those obtained in Reference Example 14. Reference example 17 {3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)
-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (15mg, 0.041mmol)
RhCl(Ph ₃ P) ₃ (5 ml) in benzene (0.5 ml) solution
mg) at room temperature for 1 hour under a hydrogen stream (atmospheric pressure).
The mixture was stirred at 45°C for 1.5 hours. After removing the catalyst using a short silica gel column, the resulting residue was purified again using silica gel column chromatography to obtain 8 mg of colorless viscous oil. This was mixed with methanol (0.2
ml). A 10% aqueous sodium hydroxide solution (0.1 ml) was added at 0°C. After stirring at 0°C for 9 hours,
The mixture was neutralized with a 10% aqueous hydrochloric acid solution under cooling. After distilling off methanol under reduced pressure, the pH was adjusted to 3 to 4 and extracted with ethyl acetate. After drying with anhydrous magnesium sulfate,
The solvent was distilled off and {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} (8 mg) was obtained as a colorless solid. IR (KBr): 3430 (OH), 2960, 1700, 1655cm ^-1 . NMRδ (CDCl ₃ ) 5.60 (2H, m), 5.32 (1H,
bs), 3.90 (2H, m), 3.00 (1H, m),
1.00~2.70 (25H, m). Mass (CI, NH ₃ ) m/z: 366 (M ⁺ +NH ₄ ). Reference example 18 {3-(4'-methoxycarbonylbutyl)-6
(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octo-2 -ene} (10 mg, 0.027 mmol) was dissolved in methanol (0.3 ml). A 10% aqueous sodium hydroxide solution (0.2 ml) was added at 0°C. After stirring at 0° C. for 9 hours, the mixture was neutralized with a 10% aqueous hydrochloric acid solution while cooling.
After distilling off methanol under reduced pressure, adjust the pH to 3 to 4,
Extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give {3-(4'-carbutyl)-6(S)-[3'(S)-hydroxy-3'-cyclopentyl-1'-trans-propenyl]- 7(R)
-Hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (10 mg, 100%) was obtained as a colorless solid. When this was recrystallized from ethyl acetate-hexane, a colorless powder with a melting point of 115-116°C was obtained. The spectral data are consistent with those obtained in Reference Example 17. Test example {(+)-3-(4-carboxybutyl)-6(S)
-[3(S)-hydroxy-3-cyclopentyl-
Regarding 1-trans-propenyl]-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene, Murota et al. Method [K.Matsuoka, Y.Mitsui, and S.
Murota, J.Pharm. Dyn . , 5, 911 (1982)] showed a significant anti-ulcer effect at a concentration as low as 0.5 x 10 ^-6 M. This is about the same strength of activity as PGE ₂ , a typical prostaglandin that has anti-ulcer effects. Furthermore, while PGE ₂ induces severe diarrhea, the above carbacycline analogs did not show any diarrhea-inducing effect.

Claims (1)

[Claims] 1. General formula Bicyclo[ ^3.3.0 ]octenyl ^aldehyde derivative represented ^by It is a protecting group for atoms or hydroxyl groups.)