JPH0219839B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for selectively removing acetal-type protecting groups. More specifically, the present invention provides a method for selectively removing only acetal-type protecting groups by treating a compound having one or more acetal-type protecting groups and silyl ether-type protecting groups in the molecule with an alkyl aluminum halide. Regarding. Acetal-type protecting groups can be deprotected under mild to acidic conditions, and are frequently used as protecting groups for hydroxyl groups and the like in the synthesis of prostaglandins and antibiotics. On the other hand, in recent years, silyl ether-type protecting groups have also been widely used as protecting groups for hydroxyl groups, etc. in the synthesis of prostaglandins and antibiotics, similar to acetal-type protecting groups, because silyl ethers are easy to generate and deprotection is simple. It has come to be. The silyl ether type protecting group also has the same function as the acetal type protecting group in that it can be removed under weakly acidic to acidic conditions. However, of course, if both groups are present, the objective of selective deprotection will not be achieved under acidic conditions. However, silyl ether type protecting groups such as t-butyldimethylsilyl group can be selectively deprotected with fluorine ion while leaving acetal type protecting groups such as tetrahydropyranyl group, and can be used as a protecting group for hydroxyl groups etc. It is becoming increasingly useful. If this reverse reactivity, that is, selective deprotection of the tetrahydropyranyl group while leaving the t-butyldimethylsilyl group, becomes possible, the range of combinations of two protecting groups in synthetic chemistry will be dramatically expanded. is expected. Furthermore, it is known that a drawback of silyl ether type protecting groups such as t-butyldimethylsilyl group is that rearrangement occurs when alkoxide anions, etc. are present in the vicinity [Y. Torisawa.
M.Shibasaki and S.Ikegami, Tetrahedron
Letters, 1865 (1979)]. In other words, prostaglandin synthesis, especially its anticancer effect, is attracting attention.
In the synthesis of PGD ₂ and PGI ₂ derivatives, it has been desirable to protect the 11-position hydroxyl group with a silyl ether type protecting group such as t-butyldimethylsilyl group. Conversion of the silyl group occurred, resulting in a significant drop in synthesis efficiency. On the contrary, if the 11-position hydroxyl group is protected with an acetal group-protecting group such as a tetrahydropyranyl group, the above-mentioned α-chain introduction reaction proceeds quantitatively (see Reference Examples below). For this reason, selective deprotection of the acetal type protecting group in the presence of silyl ether is highly desired. Against this background, the present inventors have conducted intensive research to develop a reaction that can selectively regenerate hydroxyl groups, etc. only from acetal in the presence of silyl ether, and as a result, the present invention has achieved that objective. The present invention was completed after discovering what could be achieved.

Examples of the acetal-type protecting group of the present invention include tetrahydropyranyl group, 1-ethoxyethyl group, methoxymethyl group, methylthiomethyl group, benzyloxymethyl group, t-butoxymethyl group,
2-methoxyethoxymethyl group, 2,2,2-trichloroethoxymethyl group, bis(2-chloroethoxy)methyl group, 2-(trimethylsilyl)ethoxymethyl group, 3-bromotetrahydropyranyl group, tetrahydrothiopyranyl group , 4-methoxy-tetrahydropyranyl group, tetrahydrofuranyl group, 1-methyl-1-methoxyethyl group, etc., and examples of the silyl ether type protecting group include t-
Butyldimethylsilyl group, triethylsilyl group,
tribenzylsilyl group, (triphenylmethyl)
Examples include dimethylsilyl group, t-butyl-diphenylsilyl group, methyldiisopropylsilyl group, methyldi-t-butylsilyl group, and triphenylsilyl group. In particular, examples of compounds having these protecting groups include the following compounds.

R ³ R ² R ¹ Si-O- (CH ₂ ) ₁₀ -O-CR ⁴ R ⁵ -X-
^R6 , (In the formula, R ¹ , R ² and R ³ are an alkyl group or an aryl group, R ⁴ and R ⁵ are a hydrogen atom or an alkyl group, R ⁶ is an alkyl group, and R ⁴ or R ⁵ and R ⁶ are (They can also be combined to form a polymethylene chain. Aluminum chloride, diethylaluminum chloride, diisobutylaluminum chloride, methylaluminum dichloride,
Dimethylaluminum bromide, diethylaluminum bromide, etc. can be used. The amount of alkyl aluminum halide used is 1 to 5 equivalents based on the raw material.

The present invention is preferably carried out in a solvent, and halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as toluene and benzene can be suitably used as the solvent.

The reaction temperature is not particularly limited, but the reaction will normally proceed smoothly by selecting a temperature in the range of -25°C to room temperature.

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

Example 1 1-tetrahydropyranyloxy-10-t-butyldimethylsilyloxydecane (24.6 mg,
0.066 mmol) was dissolved in anhydrous methylene chloride (0.5 ml). Dimethylaluminum chloride (1.57 M in hexane) (0.08 ml, 0.126 mmol) was added at −25° C. under an argon atmosphere and the reaction temperature was raised to room temperature. After 15 minutes, disappearance of the raw materials was confirmed by HLC, and then the mixture was cooled to -25°C again. A saturated aqueous potassium hydrogen carbonate solution (1 ml) was added, ether (3 ml) was quickly added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with ether, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, it was purified by silica gel column chromatography (hexane/ether = 2/1) to obtain 1-t-butyldimethylsilyloxy-10-decanol (18.1 mg,
95%).

NMRδ (ppm); 3.40-3.70 (4H), 1.10-1.65
(17H), 0.90 (9H, s), 0.05 (6H, s). IR (neat); 3400, 2980, 2900, 1470, 1260,
1102, 840, 780cm ^-1 . Example 2 1-tetrahydropyranyloxy-10-t-butyldimethylsilyloxydecane (25.7 mg,
0.069 mmol) was dissolved in anhydrous methylene chloride (0.5 ml). Methylaluminum dichloride (1.16M hexane solution) at −25°C under argon atmosphere.
(0.12 ml, 0.14 mmol) was added and stirred for 30 minutes.
After confirming the disappearance of the raw materials by TLC, a saturated aqueous potassium hydrogen carbonate solution (1 ml) was added, and then ether (3 ml) was quickly added, followed by stirring at room temperature for 30 minutes. The reaction solution was extracted with ether, and the organic layer was washed with saturated brine. After drying with anhydrous magnesium sulfate, it was purified by silica gel column chromatography (hexane/ether = 2/1) to obtain 1-t-butyldimethylsilyloxy-10-decanol (17.9
mg, 90%).

NMRδ (ppm); 3.40-3.70 (4H), 1.10-1.65
(17H), 0.90 (9H, s), 0.05 (6H, s). IR (neat); 3400, 2980, 2900, 1470, 1260,
1102, 840, 780cm ^-1 . Example 3 1-(1-ethoxy)-ethoxy-10-t-butyldimethylsilyloxydecane (49.6 mg,
0.14 mmol) was dissolved in anhydrous methylene chloride (1 ml), and dimethylaluminum chloride (1.57 M hexane solution) (0.18 ml,
0.28 mmol) was added. After stirring at -25°C for 1 hour, saturated aqueous potassium hydrogen carbonate solution (3 ml) and ether (3 ml) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with ether, purified by silica gel column chromatography (hexane/ether = 1/1), and 1-t-butyldimethylsilyloxy-10-
Obtained decanol (25 mg, 60%).

NMRδ (ppm); 3.40-3.70 (4H), 1.10-1.65
(17H), 0.90 (9H, s), 0.05 (6H, s). IR (neat); 3400, 2980, 2900, 1470, 1260,
1102, 840, 780cm ^-1 . Example 4 [2-oxa-3-oxo-6-exo-t-
Butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo [3.3.0]
Octane] (54 mg, 0.15 mmol) was dissolved in anhydrous methylene chloride (1 ml). -25℃ under argon atmosphere
After adding dimethylaluminum chloride (1M hexane solution) (0.3 ml, 0.3 mmol) at room temperature,
Stir for hours. The mixture was cooled again to -25°C, 25% aqueous potassium hydroxide solution (3 ml) and ether (3 ml) were added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off to give [2-oxa-3-oxo-6-exo-t-butyldimethylsilyloxymethyl-7-
endo-hydroxybicyclo[3.3.0]octane]
(40mg, 96%) was obtained.

NMRδ (ppm); 4.90 (1H, m), 4.15 (1H,
ABq), 3.65 (2H, dd), 0.90 (9H, s),
0.05 (6H, s). IR (neat); 3460, 2950, 2780, 1770cm ^-1 . Example 5 2-(6-methoxycarbonyl-2-Z-hexenyl)-3-exo-t-butyldimethylsilyloxymethyl-4-endo-tetrahydropyranyloxy-1-cyclopentylidene (17.5 mg,
0.037 mmol) was dissolved in anhydrous methylene chloride (0.6 ml). Dimethylaluminum chloride (1M hexane solution) (0.19
ml, 0.19 mmol) and stirred at -25°C for 1.5 hours. A 25% aqueous potassium hydroxide solution (1.9 ml) and ether (3 ml) were added, and the reaction solution was extracted with ethyl acetate. The organic layer is a saturated aqueous sodium bicarbonate solution,
It was washed successively with saturated saline. After drying over anhydrous magnesium sulfate, it was purified by silica gel column chromatography (hexane/ether = 1/1).
-(6-Methoxycarbonyl-2-Z-hexenyl)-3-exo-t-butyldimethylsilyloxymethyl-4-endo-hydroxy-1-cyclopentylidene (12.7 mg, 89%) was obtained.

NMRδ (ppm); 5.40 (2H), 4.80-4.95 (2H),
3.30~4.20 (4H), 3.65 (3H, s), 0.90
(9H, s), 0.10 (6H, s). IR (neat); 3450, 2950, 2780, 1745, 1730
(sh.) cm ^-1 . Massm/z (%); 325 (23), 233 (32), 201
(40), 183 (22), 159 (27), 75 (100). Mili−MS; 325.1832 (M ⁺ −57), M ⁺ −57=
C ₁₇ H ₂₉ C ₄ Si=325.1833. Example 6 4-(2-tetrahydropyranyloxyethyl)
-Azetidin-2-one (17.6mg, 0.056mmol)
was dissolved in anhydrous methylene chloride (0.5ml).
Dimethylaluminum chloride (1.57M solution in hexane) (0.089
ml, 0.14 mmol) and the reaction temperature was raised to room temperature. After 30 minutes, after confirming the disappearance of the raw material by TLC,
Cooled again to -25°C. Saturated aqueous potassium hydrogen carbonate solution (1 ml) was added, ether (5 ml) was quickly added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying with anhydrous magnesium sulfate, silica gel column chromatography (methylene chloride/
acetone = 4/1) to give 4-(2-hydroxy-ethyl)-azetidin-2-one (13
mg, 100%) as a sticky oil.

NMRδ (ppm); 0.26 (s, 6H), 0.98 (s, 9H),
1.80-2.28 (m, 2H), 2.69 (dd, J=15.3
Hz, 1H), 3.20 (dd, J=15.5Hz, 1H),
3.74 (t, J=7Hz, 2H), 3.60~4.35 (m,
2H). IR (neat); 3410, 1718 cm ^-1 .

Reference example 1 [2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-hydroxy-1-cyclopentylidene] (657 mg, 1.72 mmol) was dissolved in anhydrous dimethylformamide (1.7 ml). Imidazole (40 mg, 5.90 mmol) and t-butyldimethylchlorosilane (596 mg, 3.96 mmol) were added, the reaction vessel was purged with argon, and the mixture was stirred at room temperature for 15 minutes. Add saturated ammonium chloride aqueous solution and add ether (25 ml x
4). Wash the extract with saturated saline,
It was dried with anhydrous magnesium sulfate. The solvent was distilled off and purified by silica gel column chromatography (hexane/ether = 10/1).
(6-methoxycarbonyl-2-Z-hexenyl)
-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxy-1-
Cyclopentylidene (855 mg, 100%) was obtained.

NMRδ (ppm); 5.45 (2H), 4.85 (2H), 4.00
(1H), 3.65 (3H, s), 0.90 (18H), 0.10
(12H). IR (neat); 1745, 1660 cm ^-1 . Massm/z (%); 439 (M ⁺ − ^t Bu) (19), 233
(39), 201 (39), 189 (15), 183 (18), 173
(10), 159 (22), 147 (83), 73 (100). Mili−MS; 439.27041 (M ⁺ − ^t Bu). M ⁺ − ^t Bu=
C ₃₃ H ₄₄ O ₄ Si ₂ = 439.2698. [α] ²⁰ _D = -38° (c = 1.36, MeOH). Reference example 2 9-borabicyclo [3.3.0] under argon atmosphere
Nonane (dimer, 1.65g, 13.6mmol) was dissolved in THF (24
ml) and cooled at 0°C to [l-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxy-1-cyclopentyl]. THF solution (10ml) of Liden] (2.70g, 5.4mmol)
added. After stirring at 0°C for 2 hours, 3N aqueous sodium hydroxide solution (5 ml) and 30% hydrogen peroxide solution (5 ml) were added. The reaction solution was heated to 60°C and stirred for 1.5 hours. After distilling off most of the THF, cool with water, add ether (30 ml), and add 10% hydrochloric acid to pH ~
I gave it a 5. Extract with ethyl acetate, wash the extract with saturated aqueous sodium thiosulfate solution and saturated brine,
It was dried with anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (hexane/ether = 3/1 → 1/1).
[d-1α-hydroxymethyl-2α-
(6-methoxycarbonyl-2-Z-hexenyl)
-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxycyclopentane] (1.97 g, 71% was obtained.

NMRδ (ppm); 5.40 (2H), 4.15 (1H), 3.65
(3H, s) 3.20-3.80 (5H), 0.90 (18H),
0.10 (6H, s), 0.05 (6H, s). IR (neat); 3450, 1742 cm ^-1 .

Massm/z (%); 514 (M ⁺ , 1.4), 233 (42),
221 (22), 219 (11), 201 (34), 189 (20), 73
(100). Mili−MS; 514.3515 (M ⁺ ), C ₂₇ H ₅₄ O ₅ Si ₂ =
514.3506. [α] ²⁰ _D = +4° (c = 1.36, MeOH). Reference example 3 Under an argon atmosphere, [d-1α-hydroxymethyl-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxycyclopentane] (1.77 g, 3.44 mmol) in anhydrous methylene chloride (70 ml), and Collins
Reagent (8.8g, 34mmol) was added. After stirring for 30 minutes at 0°C, 17.6 g of sodium hydrogen sulfate monohydrate
was added and diluted with methylene chloride. The reaction solution was brought to room temperature, and ether was added until the entire reaction solution became cloudy.
After adding anhydrous magnesium sulfate and stirring for 5 minutes, the mixture was filtered through a Florisil column. By distilling off the solvent of the filtrate, pure [d-1α
-formyl-2α-(6-methoxycarbonyl-2
-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxycyclopentane] (1.60 g, 91%) was obtained.

NMRδ (ppm); 9.85 (1H, d), 5.35 (2H),
4.20 (1H), 3.65 (3H, s), 3.40~3.60
(2H), 2.80 (1H), 0.90 (18H), 0.10 (6H,
s), 0.05 (6H, s). IR (neat); 1750, 1730 (sh.) cm ^-1 . Massm/z (%); 497 (M ⁺ -15) (1.5), 456
(16.5), 455 (M ⁺ −57) (46), 363 (12),
323 (12), 249 (17), 231 (21), 217 (22),
199 (43), 189 (27), 181 (12), 171 (30), 73
(100). [α] ²⁰ _D = +1° (c = 1.00, MeOH). Reference example 4 [d-1α-formyl-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxycyclopentane] (1.65g,
3.22 mmol) was dissolved in anhydrous toluene (33 ml),
The tube was sealed under an argon atmosphere. After heating at 180℃ for 18 hours and distilling off toluene, silica gel column chromatography (hexane/ether = 3/1 →
1/1). [2-hydroxy-3-(4
-methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-
7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]octane] (1.44 g, 87%) was obtained as a nearly colorless oil. From the spectral data, it was a mixture of 2,3-exo, exo 2,3-endo, and endo.

NMRδ (ppm); 5.20-6.00 (2H), 4.30 (0.4H),
3.10~4.0 (3.6H), 3.65 (3H, s), 0.90
(18H), 0.05~0.10 (12H). IR (neat); 3430, 1740, 1720 (sh.) cm ^-1 . Massm/z (%); 455 (18), 437 (13), 323
(38), 249 (19), 231 (70), 218 (13), 217
(68), 205 (16), 199 (59), 189 (47), 181
(14), 171 (43), 157 (45), 155 (14), 147
(87), 73(100). Reference example 5 [2-Hydroxy-3-(4-methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-
Butyldimethylsilyloxybicyclo [3.3.0]
Octane] (2,3-exo, exo, 2,3-
A mixture of endo and endo (12 mg, 0.023 mmol) was dissolved in methanol (0.3 ml), 10% palladium on carbon (3.0 mg) was added, and the mixture was catalytically reduced with hydrogen gas. The reaction was followed by TLC on AgNO ₃ -silica gel, and the disappearance of the starting material was observed in 2 hours. The reaction solution was diluted with ether, and palladium on carbon was filtered off using Celite. The solvent was distilled off and [2-hydroxy-3
-(4-methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-
Endo-t-butyldimethylsilyloxybicyclo[3.3.0]octane] (12 mg, 100%) was obtained as a nearly colorless oil.

NMRδ (ppm); 4.30 (0.4H), 3.0~4.1 (3.6H),
3.65 (3H, s), 0.90 (18H), 0.10 (6H),
0.05 (6H). IR (neat); 3450, 1742, 1725 (sh.) cm ^-1 . Massm/z (%); 457 (38), 325 (40), 233
(90), 219 (100), 201 (69), 173 (81). Reference example 6 [2-Hydroxy-3-(4-methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]octane]
(12 mg) was dissolved in pyridine (0.5 ml), and methanesulfonyl chloride (11 μ) was dissolved in pyridine (0.5 ml) under an argon atmosphere.
was added and stirred at room temperature. Methanesulfonyl chloride (10μ
) was added. After confirming that the raw materials had disappeared, a saturated aqueous ammonium chloride solution was added and extracted with ether, and the organic layer was washed three times with a saturated aqueous copper sulfate solution. It was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was dissolved in toluene (0.2 ml), diazabicycloundecene (20μ) was added, and the mixture was dissolved under an argon atmosphere.
The mixture was stirred at 100°C for 2 days. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ether. The ether layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane/ether = 10/1) to obtain [l-3-(4-methoxycarbonylbutyl)-6-exo-t-butyldimethyl]. Silyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene]
(5.6 mg, 48%) was obtained.

NMRδ (ppm); 5.30 (1H), 3.85 (1H), 3.65
(3H, s), 3.60 (2H), 2.90 (1H), 0.90
(9H, s), 0.85 (9H, s), 0.05 (12H). IR (neat): 1745cm ^-1 . Massm/z (%); 439 (M ⁺ -57) (25), 243
(11), 233 (64), 207 (53), 201 (42), 189
(11), 183 (21), 175 (19), 173 (14), 159
(14), 157 (14), 149 (17), 148 (12), 147
(67), 73(100). Mili−MS; 439.2697(M ⁺ − ^t Bu), M ⁺ − ^t Bu=
C ₂₃ H ₄₃ O ₄ Si ₂ =439.2697. Reference example 7 (l-3-[4-methoxycarbonylbutyl)-
6-Exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene] (4.8
Pyridinium p _- toluenesulfonate (1 mg,
0.004 mmol) and stirred at 25°C for 16 hours. After diluting the reaction solution with ether, 1% HCl aqueous solution, saturated
Washed with NaHCO ₃ water and saturated saline, respectively.
After drying over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography. [3-(4-methoxycarbonylbutyl)-
6-Exo-hydroxymethyl-t-butyldimethylsilyloxybicyclo[3.3.0]octo-2
-Ene] was obtained as an almost colorless oily substance (yield: 60%).

IR (neat); 3480, 1740cm ^-1 . NMRδ (ppm); 5.30 (1H), 3.85 (1H), 3.65
(3H, s), 3.60 (2H), 2.90 (1H). Reference example 8 [3-(4-methoxycarbonylbutyl)-6-
Exo-hydroxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene] (118 mg, 0.31 mmol) in DMSO
(3.5 ml) and triethylamine (0.26 ml), and a DMSO solution (2.5 ml) of SO ₃ ·py (148 mg, 0.93 mmol) was added under stirring at room temperature. After stirring for 1 hour and 20 minutes under the same conditions, the mixture was poured into ice water and extracted with ether. The ether layer was washed with water and saturated brine, and then dried over magnesium sulfate. When the solvent is distilled off, approximately
110 mg of aldehyde compound was obtained and subjected to the next reaction without purification. Sodium hydride (oil-based 60
%, 17 mg, 0.43 mmol) was washed with pentane under an argon atmosphere and suspended in 3 ml of THF. A THF solution (0.5 ml) of dimethyl (2-oxoheptyl) phosphonate (103 mg, 0.47 mmol) was added to this, and the mixture was stirred at room temperature for 30 minutes. A THF solution (1.5 ml) of aldohyde was added to this anion solution, and after stirring for 40 minutes under the same conditions, the reaction was stopped with 0.11 ml of acetic acid. The reaction solution was diluted with ether, washed with saturated NaHCO ₃ water, and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography [3-(4-methoxycarbonylbutyl)-6-exo-(3-oxo-trans-1
-octenyl)-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-
[Ene] (107 mg, 73%) was obtained as an almost colorless oil.

IR (neat); 1742, 1698, 1672, 1628 cm ^-1 . NMR δ (ppm); 6.80 (dd, 1H), 6.17 (dd,
1H), 5.30 (d, J = 1Hz, 1H) 4.00 (m,
1H), 3.68 (s, 3H), 3.00 (m, 1H). Reference example 9 [3-(4-methoxycarbonylbutyl)-6-
exo-(3-oxo-trans-1-octenyl)-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene] (93
mg, 0.20 mmol) was dissolved in 65% aqueous acetic acid (1.7 ml) and tetrahydrofuran (0.17 ml) and stirred at 50°C for 1 hour. The reaction solution was poured into saturated NaHCO ₃ water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain [3-(4-methoxycarbonylbutyl)-6-exo-(3-oxo-trans-1-octenyl)-7-endo-hydroxy] 72 mg of bicyclo[3.3.0]oct-2-ene] as a nearly colorless oil (yield: 99
%)Obtained.

IR (neat); 3470, 2950, 1740, 1699, 1675,
1625cm ^-1 . NMRδ (ppm); 6.65 (dd, J=16), 8Hz,
1H), 6.16 (d, J=16Hz, 1H), 5.30
(broad s, 1H), 3.90 (qd, J=8,2
Hz, 1H), 3.68 (s, 3H), 3.00 (m, 1H),
1.80~2.80 (m, 12H), 1.10~2.80 (m,
10H), 0.90 (t, J=6Hz, 3H). [α] ²⁰ _D = +105° (c = 1.488, MeOH). Reference example 10 [3-(4-methoxycarbonylbutyl)-6-
Exo-(3-oxo-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]
Oct-2-ene] (36 mg, 0.1 mmol) was dissolved in anhydrous toluene (1 ml). Prior to this, a toluene solution of diisobutylaluminum hydride (1.76M 0.57ml, 1mmol) was mixed with 2,6-di-t-butyl-4-methylphenol (331mg, 1.5mmol).
The mixture was added to a toluene solution (2.6 ml) under ice-cooling, and stirred for 1 hour under the same conditions. A toluene solution of the above reaction starting material was added to this at -78°C. The reaction solution was brought to −10° C. over 2.5 hours, and further stirred at the same temperature for 3 hours. The reaction was stopped with 0.34 ml of water and incubated at room temperature for 1
Stir for hours. After filtering off insoluble matter, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain [3-(4-methoxycarbonylbutyl)-6-exo-(3α-hydroxy-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0] Oct-2-ene] (20.6 mg, 57
%) and [3-(4-methoxycarbonylbutyl)-6-exo-(3β-hydroxy-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]oct-2-ene] (8.3 mg ,twenty three
%) were obtained in each case as an oil. The spectral data of the α-epimer is shown below. The spectrum of the β-epimer is similar.

IR (neat); 3400, 2970, 2930, 2870, 1742cm
^-1 . NMRδ (ppm); 5.60 (m, 2H), 5.33 (bs, 1H),
4.12 (m, 1H), 3.80 (m, 1H), 3.69 (s,
3H), 3.00 (m, 1H). Massm/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 example 11 [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 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 over anhydrous magnesium sulfate, the solvent was distilled off to obtain [9(0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ ) (10 mg, 100%).

IR (neat); 3350, 2910, 2850, 1700, 1450,
1250cm ^-1 . NMRδ (ppm); 5.60 (m, 2H), 5.31 (bs, 1H),
4.11 (m, 1H), 3.80 (m, 1H), 3.00 (m,
1H), 0.90 (tJ=6Hz, 3H). Mass (CI, NH ₃ ) m/z; 368 (M ⁺ +NH ₄ ). Melting point: 733-79°C [α] ²⁵ _D = +16° (c = 0.25, MeOH). Similarly, the 15β-epimer is also hydrolyzed, and 9
The 15β isomer of (0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ was obtained.
Spectrum data (IR, NMR, Mass) is 9
It was consistent with the data for (0)-methano-Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ .

Test example 9(0)-methanol synthesized by the above method
Δ ⁶⁽⁹ 〓 ⁾ -PGI ₁ has the biological activity described below.
When rabbit blood was used, platelet aggregation induced by adenosine diphosphate (ADP) was inhibited by PGI _2.
When human blood was used, the inhibition was 1/10 as strong as that 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 is almost the same as the strength of PGI ₂ , and in experiments using rats,
An increase in heart rate was observed at a dose of 1 μg/Kg.
In experiments using rabbit stomachs, anti-ulcer properties were also shown.
It is active at concentrations as low as 10 ^-6 M, which is similar to PGE ₂
It is about the same strength. Cytotoxicity is very weak,
IC ₅₀ =5 μg/ml.

Claims (1)

[Claims] 1. It consists of treating a compound having one or more acetal-type protecting groups and silyl ether-type protecting groups in the molecule with an alkyl aluminum halide,
Selective removal method of acetal type protecting group.