JPS5810383B2 - 16-alkyl-20-alkoxyprostadiene - Google Patents

Description

Detailed Description of the Invention The present invention is based on the formula (where A is >c=o +R1, R4 is a lower alkyl group; R2 and R3 are a hydrogen atom or a hydroxyl protecting group, and R
5 means a hydrogen atom.

However, at least one of R2 and R3 represents a hydroxyl protecting group.

Same below. The present invention relates to a method for producing a 16-alkyl-20-alkoxy prostadienoic acid derivative, which is characterized by removing a protecting group from a hydroxyl-protected prostadienoic acid derivative shown in ().

In the hydroxyl-protected prostadienoic acid derivative represented by the above formula (I), there are no particular limitations on the protecting groups for the hydroxyl groups of R2 and R3, as long as they do not cause any change in other parts of the compound upon removal. , preferably one that can be removed under mild conditions.

Such protecting groups include, for example, tetrahydropyran-
Heterocyclic groups such as 2-yl group, tetrahydrothiopyran-2-yl group; trimethylsilyl group; acetyl group, propionyl group, benzoyl group, P-phenylbenzoyl group,
Examples include acyl groups such as trifluoroacetyl groups; hydrocarbon groups such as methyl, ethyl, and trityl groups; and carbonate residues such as benzyloxycarbonyl and ethoxycarbonyl groups.

In addition, R1 and R4 in formula (I) and formula (■)
Examples of the lower alkyl group include methyl group, ethyl group, propyl group, isopropyl group, and butyl group.

Additionally, a dashed bond to the cyclopentane ring in these formulas indicates an alpha (α) configuration, i.e., the bond is below the plane of the cyclopentane ring, and a thick solid bond indicates a beta (β) configuration. This indicates that the bond is above the plane of the cyclopentane ring.

Note that the bond indicated by a wavy line in the side chain means either an α bond or a β bond.

When carrying out the method of the present invention to remove a hydroxyl protecting group, it is preferable to select appropriate conditions depending on the nature of the protecting group.

When the protecting group for the hydroxyl group is a heterocyclic group such as a tetrahydropyran-2-yl group or a trityl group, the compound (I
) may be treated with acid.

Suitable acids for use in the vessel are, for example, organic acids such as formic acid, acetic acid, propionic acid, and oxalic acid; and mineral acids such as hydrochloric acid and sulfuric acid.

As the reaction solvent, for example, water, methanol, ethanol, tetrahydrofuran, dioxane or a mixed solvent thereof is used.

There is no particular limitation on the reaction temperature, but the reaction is usually carried out at room temperature to elevated temperature.

When the protecting group for a hydroxyl group is an acyl group such as an acetyl group, a propionyl group, a hensoyl group, a P-phenylbenzoyl group, or a trifluoroacetyl group, an acid or a base can be used as appropriate, but it is convenient to carry out the reaction in the presence of a base. It is.

Preferred acids or bases include mineral acids such as hydrochloric acid and sulfuric acid; basic substances such as caustic soda, soda carbonate, and potassium carbonate.

As the reaction solvent, for example, water, methanol, ethanol, tetrahydrofuran, dioxane or a mixture thereof can be used.

When the hydroxyl protecting group is, for example, a trimethylsilyl group, this is carried out by contacting it with water.

This water may contain acids or bases. Furthermore, instead of water, a water-containing organic solvent such as water-containing tetrahydrofuran, dioxane, methanol, ethanol, etc. can also be used.

When the protecting group is a methyl group, ethyl group, etc., it is treated with boron trihalide, aluminum chloride, etc. in a halogenated hydrocarbon such as methylene chloride or chloroform.

Additionally, when removing carbonate residues such as benzyloxycarbonyl groups, hydrogen bromide/acetic acid is commonly used.

Isolation and purification of the target compound after the reaction is completed by conventional methods.

For example, the target compound (I
Separation and purification of I) is preferred.

Among the target compounds of the present invention, those having free carboxyl groups can be converted into nontoxic salts.

Acceptable salts include, for example, alkali metal or alkaline earth metal salts such as sodium potassium, calcium and ammonium salts, tetramethylammonium salts,
These include organic amine salts such as dimethylamine salt, piperidine salt, and monoethanolamine salt.

The object compound (n) of the present invention and its salts thus obtained are novel compounds that have not been described in any literature, and have pharmacological effects similar to those observed in prostaglandin F2α and prostaglandin E2. There is selectivity in

Note that the raw material compound (I) used in the present invention is a new compound, and an example of a method for producing it from a known compound is shown in the following reference example.

Furthermore, dimethyl (7) used in Reference Example 1-(a)
-Medoxy 3-methyl-2-oxo)hebutylphosphonate, and dimethyl (
7-Nitoxy 3-methyl-2-oxo)peptylphosphonate is a new product, and the present inventors prepared this compound by the method shown in the reaction formulas in Tables I and II.

Reference example 1 (a) Anhydrous dimethoxyethane 60Tr in nitrogen stream
After adding 6851r1g of 50% oily sodium hydride to Ll, a solution of 3.81ml of dimethyl(7-medoxy-3-methyl-2-oxo)butylphosphonate dissolved in 40ml of anhydrous dimethoxyethane was added dropwise, and the mixture was heated at room temperature for 2 hours. Stir.

Next, 5.0 g of 4β-formyl-2-oxo-5α-p-phenylbenzoyloxy-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta(b) furan
A solution prepared by dissolving this in 150 ml of anhydrous dimethoxyethane was added dropwise, and the mixture was further stirred at room temperature for 1 hour and 30 minutes.

After the reaction is completed, dry ice powder is added to the reaction solution to neutralize it, 200 ml of water is added and the mixture is saturated with sodium chloride, followed by extraction four times with 501 nl of methylene chloride each.

The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oily 4β-[4-methyl-3-oxo-8-methoxy-1-transoctenyl-2-oxo-5α-p. -phenylbenzoyloxy-3aα・
9.22 of a crude product of 4α, 5β, 6aα to hexahydro-2H-cyclopenta[b]furan is obtained.

(b) To 250 ml of anhydrous ether were added 3.78 S'y of sodium borohydride and 5.57'y of zinc chloride, and after stirring at room temperature for 1 hour and 30 minutes, crude 4β-[4-methyl-3-oxo-8-methoxy -1-transoctenylcy2-oxo-5α-p-phenylbenzoyloxy3aα・4α°5β・6aα-hexahydro-2H-
A solution prepared by dissolving 9.22 of cyclopenta(b)furan in 10 Qml of anhydrous tetrahydrofuran was added dropwise, and the mixture was further stirred at room temperature for 2 hours.

After the reaction was completed, dry ice powder was added to the reaction solution to neutralize it, 150 TL of water was added, and then 50 mL of ether was added for 3
Extract twice, combine the extracts, wash with water, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure to obtain crude product 7.71.

This was subjected to silica gel column chromatography, and n
4β-(3(S)-Hydroxy-4-methyl-8- Methoxy-1-transoctenylcy2-oxo-5α-p-phenylbenzoyl, tki'/-3a
4β-(3(R
)-Hydroxy-4-methyl-8-methoxy-1-transoctenylcy2-oxo-5α-p-phenylbenzoyloxy-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta(b) Furan 1.31 get.

(e) 4β-(3(S)-hydroxy-
4-methyl-8-methoxy-1-transoctenyl)
-2-,oxo-5α-p-phenylbenzoyloxy 3aα・4α・5β・6aα-hexahydro-2H-cyclopenta(b) 2.01 parts of furan and 15 parts of anhydrous methanol
0TLl, 300r/1g of potassium carbonate was added thereto, the mixture was stirred at room temperature for 3 hours and then at 40°C for 1 hour, and then acetic acid was added to neutralize the mixture, and methanol was distilled off under reduced pressure.

100 ml of water was added to the resulting residue containing crystals, and then sodium chloride was added to saturate the mixture, followed by 5 ml each of ethyl acetate.
The extracts were combined three times with 0rILl, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the crude target product.

This was subjected to silica gel column chromatography, developed using a methylene chloride-ethyl acetate mixture as an eluent, and 4β-C3(S)-hydroxy-4-methyl-8-
Methoxy-1-transoctenyl-5α-hydroxy-2-octenyl-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta(b) Furan 1.2879
Get 1.

(d) 4β-(3(S)-hydroxy-4-methyl-8
-Methoxy-1-transoctenylcou 5α-hydroxy-2-oxo-3aα・4α-5β・6aα-hexahydro-2H-cyclopenta[b]furan 1.287
9P was dissolved in 50 ml of anhydrous methylene chloride, 1.025 ml of 2,3-dihydropyran, f? Woka; c-1 further K p
- Add 12 rrlf/toluenesulfonic acid 1 aqueous phase, stir at room temperature for 30 minutes, and then add 30 ml of methylene chloride.

Next, the methylene chloride layer was separated, washed with a cooled aqueous sodium hydrogen oxide solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude 4β-[4-methyl-8-methoxy-3(S)-( Tetrahuman; copylan-2-yloxy)-1-) lance-octenylter-2-oxo-5α-
(tetrahydropyran-2-yloxy)-3aα・4
α·5β·6aα-hexahydro-2H-cyclopenta[b) Furan 1.9576P is obtained.

(e) The above crude 4β-[4-methyl-8
-methoxy-3(S)-(tetrahydropyran-2-yloxy)-1-)-ysuoctenyl]-2-oxo-5α-(tetrahydropyran-2-yloxy)-3
aα・4α・5β・6aα Hexahydro-2H-cyclopenta[b]furan 1.95761 to anhydrous toluene 80
A toluene solution 13 containing 1.27S' of diisobutylaluminum hydride was dissolved in TLl, purged with nitrogen gas, and cooled to -60°C with dry ice/acetone.
ml dropwise and stirred at the same temperature for 30 minutes.

Next, 15+yyj! of ethyl acetate was added to the reaction solution at the same temperature. After sequentially adding 7 ml of methanol and 5 mA of water, 70 ml of water was added at room temperature to precipitate a white precipitate.

After removing this precipitate, an organic layer and an aqueous layer are separated.

The aqueous layer was extracted three times with 50 TrL of benzene each, and the extract and organic layer were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure below room temperature to 4β-[4-methyl -8-methoxy-3(S)-(
Tetrahydropyran-2-yloxy)-1-) lance octenyl ter-2-hydroxy-5α-(tetrahydropyran-2-yloxy) -3aα・4α・5β・6
aα-hexahydro-2H-cyclopentac b, 17
7 n 2.0463s” & get.

(f) 50% oily sodium hydride 93 in a nitrogen stream
Add 25 ml of anhydrous dimethyl sulfoxide to 5rII9 and heat to 70-75°C, and heat for about 1 hour until the generation of hydrogen gas stops.
Stir the time.

Then, after returning to room temperature, 4-carboxybutyltriphenylphosphonium bromide 4.5f? Add 4 more
β-[4-Methyl-8-methoxy-3(S)-(tetrahydropyran-2-yloxy)-1-)7suoctenyl]-2-hydroxy-5α-(tetrahydropyran-2-yloxy)-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta[b]furan 2.04
A solution of 631 dissolved in 15 ml of anhydrous dimethyl sulfoxide was added and stirred at room temperature for 1 hour.

After reaction 1 is completed, dry ice powder is added to the reaction solution to neutralize it, and then a solution obtained by adding dry ice to a mixed solution of 150 ml of ethyl acetate and 70 ml of ether to saturate it is added.

At this time, wash with dry ice-saturated ethyl acetate and cold water.

The organic layer was separated, and the aqueous layer was extracted three times with 30 ml each of ethyl acetate. The extract and organic layer were combined, washed with ice water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude 9α-hydroxy-16. -Methyl 11α・15(S)-bis(tetrahydropyran-2-yloxy)-20-methoxy-
3.4 g of 5-cis-13-trans-prostadienoic acid
get.

The ice crystals were subjected to silica gel column chromatography and developed using a mixture of ethyl acetate and n-hexane as the eluent to obtain 1.4998 g of an oily substance showing [α)''7+1.32 (C=1.14 chloroform). .

(g) 9α-hydroxy-16-methyl 11α・15 (
S)-bis(tetrahydropyran-2-yloxy)-
Dissolve 20-methoxy-5-cis-13-transprostadienoic acid 153.8rn9 in 5 ml of ether and
Cool to ~-5°C.

Next, 2.0 grams of chromic anhydride, 9.0 grams of manganese sulfate hydrate.
Add water to 65P and concentrated sulfuric acid 2.13ml to make a total volume of 50ml
Add solution 5Q+n7 cooled to 0 to -5°C and stir at the same temperature for 3 hours.

After the reaction is complete, add 10ml of water to the reaction solution and add 30ml each of ether.
The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 16-methyl-
9-oxo11α・15(S)-bis(tetrahydropyran-2-yloxy)-20-methoxy-5-cis-
143.51 ng of 13-trans prostadienoic acid are obtained.

Reference example 2 (a) 4β-[3(R)-hydroxy-] in nitrogen stream
4-Methyl-8-methoxy-1-transoctenyl-2-oxo-5α-p-phenylbenzyloxy-
3aα・4α・5β・6aα-hexahydro-2H-cyclopenta[b]furan 1.31 to anhydrous methanol 12
Add 196 w1f of potassium carbonate dissolved in 0 ml and stir at room temperature for 3 hours, then at 40°C for 1 hour, neutralize by adding acetic acid, and methanol is distilled off under reduced pressure.

Add 100 rnl of water to the resulting residue containing crystals, then add sodium chloride to saturate it, then extract three times with 50 ml each of ethyl acetate, and combine the extracts and saturated chloride.)
After washing with an aqueous Jumium solution, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude target product.

This was subjected to silica gel column chromatography and developed using a methylene chloride-ethyl acetate mixture as an eluent.
-methoxy-1-)7suoctenyl]-5α-hydroxy7-2-ox”) -3aα・4α・5β・6aα
-hexahydro-2H-cyclopenta[b]furan 0.
Obtain 6947g.

(b) 4β-(3(R)-hydroxy-4-methyl-8
-methoxy-1-to7suoctenyl]-5α-hydroxy-2-oxo-3aα・4α・5α・6aα-hexahydro-2H-cyclopenta[b]furan 0.694
7"Si' was dissolved in 30 rul of anhydrous methylene chloride, and 2
・Processing and further processing of 3-dihydropyran 0.5611 K p
- Add 6.3 drops of toluenesulfonic acid monohydrate and let it stand at room temperature.
After stirring for 0 minutes, add 20 rul of methylene chloride.

Next, the methylene chloride layer was separated, washed with a cooled aqueous sodium hydrogen oxide solution and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude 4β-[4-methyl-8-methoxy-3(R )-(tetrahydropyran-2-yloxy)-1-) lance-octenyl]-2-oxo-5α-
(tetrahydropyran-2-yloxy)-3aα・4
1.0693 g of α·5β·6a α-hexahydro-2H-cyclopentaCb) furan are obtained.

(e) 4β-[4-Methyl-8-methoxy-3(R)-(tetrahydropyran-2-yloxy)] in a nitrogen stream
-1-) lance-octenyl]-2-oxo-5α-(tetrahydropyran-2-yloxy) -3aα・4α
・5β・6aα-hexahydro-2H-cyclopenta [
b] Dissolve 1.0693y of furan in 50ml of anhydrous toluene, cool to -60°C after purging with nitrogen gas, dropwise add 7.1rnl of a toluene solution containing diisobutylaluminum hydride 6951n9, and stir at the same temperature for 30 minutes.

Next, 15 ml of ethyl acetate, 71 ml of methanol and 5 ml of water were added to the reaction solution at the same temperature, and then 5 ml of water was added at room temperature.
When 0 Tnl is added, a white precipitate is deposited.

After removing the precipitate, an organic layer and an aqueous layer are separated.

The aqueous layer was extracted three times with 50ml of benzene each, and the organic layer of the extracts was combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure below room temperature.
β-[4-Methyl-8-methoxy-3(R)-(tetrahydropyran-2-yloxy)-1-)lanthoctenyl-2-hydroxy-5α-(tetrahydropyran-2-yloxy)-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta[b]furan 0.97
Get 911.

(d) Hydrogenation of 50% oil in a nitrogen stream) Add 15 ml of anhydrous dimethyl sulfoxide to 468 rng of IJum, heat to 70-75°C, and stir for about 1 hour until hydrogen gas stops being generated.

Then, after returning to room temperature, 4-carboxybutyltriphenylphosphonium bromide 2.25? and further 4β-[4-methyl-8-methoxy-3(R)-(tetrahydropyran-2-yloxy)-1-transoctenyl]-2-hydroxy-5α-(tetrahydropyran-2-yloxy) -3aα・4α・5β・6aα
-Hexahtrow 2H-cyclopenta[Ib) furan 0
．． 9791? 10wLl of anhydrous dimethyl sulfoxide
Add the solution dissolved in and stir at room temperature for 1 hour.

After the reaction is completed, dry ice powder is added to the reaction solution to neutralize it, and then dry ice is added to a mixed solution of 150 ml of ethyl acetate and 70 ml of ether to make it saturated.

At this time, wash with ethyl acetate saturated with dry ice and cold water.

The organic layer was separated, and the aqueous layer was further extracted three times with 30 ml each of ethyl acetate. The extract and organic layer were combined, washed with ice water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude 9α-hydroxy-16-methyl. -11α・15(R)-bis(
Tetrahydropyran-2-yloxy)-20-methoxy-5-cis-13-trans-prostadienoic acid2.
205' is obtained.

The crystals were subjected to silica gel column chromatography and developed using a mixture of ethyl acetate and n-hexane as an eluent to obtain the desired product 0.8031f.

(e) 9α-hydroxy-16-methyl-11α・15
(R)-bis(tetrahydropyran-2-yloxy)
140.6rr1 g of -20-methoxy-5-cis-13-transprostadienoic acid is dissolved in 5 ml of ether and cooled to 0 to -5°C.

Then chromic anhydride2. Og, manganese sulfate hydrate9.
Add water to 65P and concentrated sulfuric acid 2.13m7 to make a total volume of 50m
1, add 5 ml of the solution cooled to 0 to -5°C, and stir at the same temperature for 3 hours.

After the reaction is complete, add IQml of water to the reaction solution and add 30 ml each of ether.
The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 16-methyl-9-
12.5rr1 g of oxo-11α.15 (R) -bis(tetrahydropyran-2-yloxy)-20-methoxy-5-cis-13-transprostadienoic acid is obtained.

Example 1 16-Methyl-9-oxo-11α.15(S)-bis(tetrahydropyran-2-yloxy)-20-methoxy-5-cis-13-transprostadienoic acid 14
3.5■ was dissolved in 7 ml of acetic acid-water-tetrahydrone run mixture (volume ratio 19:11:3) and stirred at 40°C±2°C for 3 hours.

After completion of the reaction, the solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and developed using a mixture of ethyl acetate and n-hexane as an eluent to obtain 11α·15(S)- 67.8 drops of dihydroxy-20-methoxy-16-methyl-9-oxo-5-cis-13-)transprostadienoic acid are obtained.

Example 2 16-Methyl-9-oxo-11α·15(R)-bis(tetrahydropyran-2-yloxy)-20-methoxy-5-cis-13-transprostadienoic acid 12
0.51rIg was added to an acetic acid-aqueous tetrahydrofuran mixture (
Dissolve in 7ml (volume ratio 19:11:3) and heat at 40℃±2℃
Stir for 3 hours.

Thereafter, the treatment was carried out in the same manner as in Example 3, and 11α·15(R)-dihydroxy-20-methoxy-16-methyl-9-oxo-5-cis-13-transprostadienoic acid 59.
Obtain 7r11g.

Reference Example 3 (a) After suspending 555 mg of 50% oily sodium hydride in 40 rrL of dry dimethoxyethane, dimethyl (7-medoxy 3 (R
)-Methyl-2-oxo)hebutylphosphonate 3.0
A solution of 74f dissolved in 20 ml of dry dimethoxyethane is added and stirred for about 1 hour until no hydrogen generation is observed.

Then 4β-formyl-2-oxo-5α-p-phenylbenzoyloxy-3aα・4α・5β・6aα-hexahydro-2H-cyclopentaCb, lfuran 4.1
A solution of 1 dissolved in 70 rrL of dry tetrahydrofuran was added and stirred at room temperature for 1 hour and 30 minutes.

After the reaction is completed, dry ice powder, 250 rfLl of methylene chloride, and 200 rul of water are mixed into the reaction solution, and then the aqueous layer and the organic layer are separated.

The aqueous layer was extracted four times with 4 Qml of methylene chloride each, and the extracts were combined, washed with water, and then dried.

Next, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and developed using a mixture of ethyl acetate and n-hexane (volume ratio 1:1) as an eluent to obtain colorless oily 4β. -[8-methoxy-4(R)-
Methyl-3-oxo-1-transoctenylcou-2-
Oxo-5α-P-phenylbenzoyloxy-3aα
4.692 g of 4α·5β·6aα-hexahydro-2H-cyclopenta(”b)furan are obtained.

(b) After adding 2.71 g of sodium borohydride and 4.91 g of anhydrous zinc chloride to 260 ml of dry ether and stirring at room temperature, 4β-[8-methoxy-4(R)-methyl obtained in (a) above was added. -3-oxo-1-transoctenyl-2-oxo-5α-P-phenylbenzoyloxy-3aα・4α・5β・6aα-hexahydro-
A solution of 4.69 S' of 2H-cyclopenta[b]furan dissolved in 75 ml of dry dimethoxyethane is added and stirred at room temperature for 2 hours.

After the reaction was completed, 50rrLl of ice water was gradually added to the reaction solution.
Next, 200 TrLl of water was added and the mixture was shaken, and then the aqueous layer and organic layer were separated.

The aqueous layer was extracted five times with 50 rIL of ether each, and the extracts were combined, washed with water, and then dried.

Next, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, using a mixture of ether-n-hexane (volume ratio 3:1) as an eluent to show the development of 4β-[3(S). -hydroxy-8-methoxy-4
(R)-Methyl-1-transoctenyl)-2-,oxo-5α-P-phenylbenzoyloxy-3aα・
2.2191 of 4α.5β.6aα-hexahydro-2H-cyclopenta[b]furan is obtained.

3(R)-hydroxy form of crystal showing form) 0.78
1.175S', a mixture of 3y and quartz and the 3(R)-hydroxy form of quartz, is obtained.

4β-[”3(S)-hydroxy-8-methoxy-4(R)-methyl-1-transoctenyl-2-oxo-5α-P-phenylbenzoyloxy-3aα・4α・5β・6aα-hexahydro-
2H-cyclopenta(b,l) Furan 2.21S' and anhydrous potassium carbonate 315"V were mixed with dry methanol 120mA.
! Stir at room temperature for 5 hours.

Next, acetic acid was added to the reaction solution to neutralize it, and the solvent was distilled off under reduced pressure. To the resulting residue, 250 ml of ether and 50 ml of water were added.
Add rIll and shake to separate the organic and aqueous layers.

Wash the organic layer with water and add 40ml of ether to the aqueous layer! Extract twice.

The organic layer and extract were combined, washed with water, dried, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and first developed using chloroform as an eluent to extract methyl P-phenylbenzoate. except.

Then methanol-chloroform mixture (volume ratio 1:4)
The oily 4β-[3(S)
-Hydroxy-8-methoxy-4(R)-methyl-1-
7suoctenyl]-5α-hydroxy-2-oxo-3aα・4α・5β・6aα-hexahydro-2H-
629rr1 g of cyclopenta[b]furan is obtained.

(d) 4β-(”3(S)-hydroxy-8-methoxy-4(R)-methyl-1-transoctenyl-5α-hydroxy-2-oxo-3a obtained in (C) above)
α・4α・5β・6aα-hexahydro-2H-cyclopenta[b]furan 629rn9 is dried in methylene chloride 2
1 g of 2,3-dihydropyran 510 W and 15 rr I9 of P-)luenesulfonic acid monohydrate were added to the solution, and the mixture was stirred at room temperature for 15 minutes.

Next, the reaction solution was washed twice with a cooled aqueous sodium hydrogen oxide solution, washed with water, dried, and then the solvent was distilled off under reduced pressure. 1) as an eluent to obtain an oily 4β-[8-methoxy-4(R)-
Methyl-3(S)-(tetrahydropyran-2-yloxy)-1-)lansoctenyl]-2-oxo-5α
-(tetrahydropyran-2-yloxy) -3aα
・4α・5β・6aα-hexahydro-2H-cyclopenta [53727864 mg was obtained.

m) (e) Ten cocoons 4β-[8-methoxy- obtained in d)
4(R)-methyl-3(S)-(tetrahydropyran-
2-yloxy')-1 transoctenyl]-2-oxo-5α-(tetrahydropyran-2-yloxy)
-3aα・4α・5β・6aα-hexahydro-2H
- Cyclopenta
Add 2.1 ml of toluene solution containing Ig and stir for 30 minutes.

Next, 5 ml of ethyl acetate Q was added to the reaction solution at the same temperature! and 2 ml of water were sequentially added, and then 50 Tll of benzene and 10 ml of water were added.
QmA! Add and stir.

After removing the white precipitate, an organic layer and an aqueous layer are separated.

The aqueous layer was extracted five times with 30 rnl of benzene each time, the extract and the organic layer were combined, washed with water and dried, and then the solvent was distilled off under reduced pressure to obtain a colorless oily 4β-[8-methoxy-4(R)-methyl- 3(S
)-(tetrahydropyran-2-yloxy)-1-)
Lance-octenyl-2-hydroxy-5α-(tetrahydropyran-2-yloxy)-3aα・4α・5β
・6aα-hexahydro-2H-cyclopenta[”b)
Furan 4o4rIIg is obtained.

(f) 50% oily sodium hydride in a nitrogen stream 19
Add 7 rul of dry dimethyl sulfoxide to 5 r/1 g, heat to 60°C, and stir for about 1 hour until hydrogen gas stops being generated.

Then, after returning the temperature to room temperature, 930 rrIg of 4-carboxybutyltriphenylphosphonium bromide was added, and to the resulting bright red solution was added the 4β-[8-
Methoxy-4(R)-methyl-3(S)-(tetrahydropyran-2-yloxy)-1-) lance octenyl-2-hydroxy-5α-(tetrahydropyran-2
-yloxy)-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta[b]furan 404rn9
A solution prepared by dissolving the above in 5 ml of dry dimethyl sulfoxide was added, and the mixture was stirred at room temperature for 2 hours.

After the reaction is completed, the reaction solution is dispersed in 150 WL of a mixture of ethyl acetate and ether saturated with dry ice (volume ratio 2:1), 70 RR of ice water is added, and the mixture is shaken, and then the organic layer and the aqueous layer are separated.

The aqueous layer was extracted four times with 50 wL each of ethyl acetate, the extract and organic layer were combined, washed with water and dried, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography with ethyl acetate-n- Developed using a hexane mixture (volume ratio 1:2) as an eluent to obtain oily 9α-hydroxy-20.
-Methoxy-16(R)-methyl-11α・15(S)
-bis(tetrahydropyran-2-yloxy)-5(
cis), 13(trans)prostadienoic acid 3601n
Get 9.

(g) 9α-hydroxy-20- obtained in (f) above
Methoxy-16(R)-methyl-11α・15(S)-
360 ml of bis(tetrahydropyran-2-yloxy)-5(cis),13(trans)prostadienoic acid was dissolved in 25 rnl of ether and pre-cooled to 0 to -5°C. Jones reagent [chromic anhydride 2.0 ml] ? , 11 ml of a solution prepared by adding water to 9.65 P of manganese sulfate hydrate and 2.13 rIL of concentrated sulfuric acid to make a total volume of 50 ml), and stirred at the same temperature for 1 hour and 30 minutes.

After the reaction is complete, add 50 liters of ether and saturated sulfuric acid to the reaction solution.

Add 40 ml of aqueous solution and shake to separate an aqueous layer and an organic layer.

The aqueous layer was extracted four times with 40 rrL of ether each, and the extract and organic layer were combined, washed with water, dried, and the solvent was distilled off under reduced pressure to obtain the crude 20
-methoxy-16(R)-methyl-9-oxo-11α
・ .

15(S)-bis(tetrahydropyran-2-yloxy-)-5(cis),13(trans)prostadienoic acid 327rn9 is obtained.

Reference example 4 (a) 50% oily sodium hydride in nitrogen stream
・5281rI9 dried dimethoxyethane 45rrLl
A solution of 2.93 S' of butylphosphonate dissolved in 20 rnl of dry dimethoxyethane was added dropwise to dimethyl (7-medoxy 3(S)-methyl-2-oxo) showing suspension, and the mixture was stirred at room temperature for 1 hour and 30 minutes.

Then 4β-formyl-2-oxo-5α-p-phenylbenzoyloxy-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta[b]furan 4.04
A solution of fI dissolved in 80 rrLl of dry tetrahydrone was added dropwise, and the mixture was stirred at room temperature for 1 hour and 30 minutes.

After the reaction is completed, dry ice powder is added to the reaction solution to neutralize it, 15 Qml of water is added, the mixture is saturated with sodium chloride, and the mixture is extracted four times with 50 WLl each of methylene chloride.

The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was subjected to silica gel column chromatography using an ether-n-hexane mixture (volume ratio 3:1) as the eluent. Expand 4β-[8-
Methoxy-4(S)-methyl-3-oxo-1-transoctenyl]-2-oxo-5α-p-phenylbenzoyloxy-3aα・4α・5β・6aα-hexahydro-2H-cyclopentaC, b) Furan Obtain 3.3 g.

(b) After suspending 1.65 f of sodium borohydride and 2.98 P of anhydrous zinc chloride in 200 Ill of dry ether and stirring at room temperature for 1 hour and 30 minutes, the 4β-[8-methoxy-4( S)-Methyl-3-oxo-1-transoctenyl-2-Jki7-5α-
p-phenylbenzyloxy-3aα・4α・5β・
6aα-hexahydro-2H-cyclopenta[b] A solution of 3.31 ml of furan dissolved in 5 Qml of dry tetrahydrone was added dropwise, and the mixture was stirred at room temperature for 2 hours.

After the reaction is complete, add dry ice powder to the reaction solution to neutralize it, add 1507711 of water, and then add 50w11 of ether for 3
Extract times.

The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain an oily substance 2.81.

This oil was subjected to silica gel column chromatography and developed using an ether-n-hexane mixture (volume ratio 4:1) as an eluent. S)-Methyl-1-transoctenyl)-2-, t-\-so5α-p-phenylbenzoyloxy-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta[b]furan 1.26 g obtain.

(e) 4β-[3(S)-hydroxy-8-methoxy-4(S)-methyl-1-transoctenyl-2-oxo-5α-p-phenylbenzoyloxy- obtained in (b) above 3aα・4α・5β・6aα-hexahydro-2H-cyclopenta(b) Furan 1.21S' was dissolved in 40 vol of dry methanol, 169 ~ of anhydrous potassium carbonate was added, and the mixture was stirred at room temperature for 3 hours.

Next, 11 g of glacial acetic acid was added to the reaction solution to neutralize it, and methanol was distilled off under reduced pressure. The resulting residue was mixed with 30 m of water.
Add 1.

Add more sodium chloride to saturate, then add 3 ether each
Extract 3 times at 0 m7.

The extracts were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting oil was subjected to silica gel column chromatography using a chloroform-ethyl acetate mixture (volume ratio 1:4) as the eluent. and expand to give 4β-(3(S)-hydroxy-8-methoxy-4(S')-methyl-1-transoctenyl-5α-hydroxy-2-oxo-3aα・4α・5β・
651.7111 g of 6aα-hexahydro-2H-cyclopenta[b]furan are obtained.

(d) 4β-[3(S)-hydroxy-8-methoxy-4(S)-methyl-1-transoctenyl-5α-hydroxy-2-oxo-3 obtained in (c) above
aα・4α・5β・6aαα-hexahydro-2H-cyclopenta[b]Furan 650WI9 was dissolved in 13 ml of dry methylene chloride, and 2,3-dihydropyran 699 m?
and 4 mg of p-toluenesulfonic acid monohydrate were added and stirred at room temperature for 30 minutes.

After the reaction is completed, 50 ml of chloroform and 20 ml of a refrigerated aqueous sodium hydrogen oxide solution are added to the reaction solution and shaken.

The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and a mixture of ether and n-hexane (volume ratio 1:2) was added. The oily 4β-[8-methoxy-4(S)-methyl-3(S)
)-(tetrahydropyran-2-yloxy)-1-4
lance-octenyl]-2-oxo-5α-(tetrahydropyran-2-yloxy)-3aα・4α・5β・6
aα-hexahydro-2H-cyclopenta [53727
Obtain 86911 g.

(e) 4β-[8-methoxy-4(S)-methyl-3(S)-tetrahydropyran-2-yloxy)-1-tra7suoctenyl]-2- obtained at the upper surface Φ in a nitrogen stream
Oxo-5α-(tetrahydropyran-2-yloxy) -3aα・4α・5β・6aα-hexahydro-2
Dissolve 55rnfj of H-cyclopenta[b]sulfuran in 40wLl of dry toluene, cool to -60°C with dry ice/acetone after purging with nitrogen gas, and dropwise add 3.36mA' of toluene solution containing 328.3rn9 diisobutylaluminum hydride. Stir for 30 minutes.

Next, 0.3 ml of ethyl acetate and 3 rnl of methanol/L/Q were sequentially added to the reaction solution at the same temperature, and then the mixture was returned to room temperature and 50 wL of water was added to precipitate a white precipitate.

The precipitate is removed by P and the organic layer and aqueous layer are separated.

The aqueous layer was extracted twice with 50 ml each of benzene, and the extract and organic layer were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure below room temperature.
β-[8-methoxy-4(S)-methyl-3(S)-(
Tetrahydropyran-2-yloxy)-1-transoctenyl-2-hydroxy-5α-(tetrahydropyran-2-yloxy)-3aα・4α・5β・6a
α-hexahydro-2H-cyclopenta(b)furan 4
Obtain 92.2 FV.

(f) 50% oily sodium hydride in a nitrogen stream 211.
7rnl of dry dimethyl sulfoxide was added to 51n9, heated to 60-65°C, and stirred for about 1 hour until the generation of hydrogen gas ceased.

Then, after returning the temperature to room temperature, 1.01 fI of 4-carboxybutyltriphenylphosphonium bromide was added to the resulting bright red solution, and the 4β-[8-methoxy-4(S)-methyl- 3(S)-(Tetrahydropyran-2-yloxy)-1-transoctenyl-2-hydroxy-5α-(tetrahydropyran-2-yloxy)-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta(b , l franc 442.9m9
A solution prepared by dissolving the above in 5 ml of dry dimethyl sulfoxide was added, and the mixture was stirred at room temperature for 1 hour.

After the reaction is completed, dry ice powder is added to the reaction solution to neutralize it, and then a solution saturated by adding dry ice to a mixed solution of 6011 L of ether and 30 ml of water is added.

Next, the organic layer and the aqueous layer were separated, and the aqueous layer was treated with ethyl acetate (3 ml each).
The extract and organic layer were combined, washed with ice water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The resulting residue was subjected to silica gel column chromatography using a mixture of ethyl acetate and n-hexane (volume ratio 1:1).
was developed using 9α-hydroxy-20 as an eluent.
-methoxy-16(S)-methyl-11α・15(S)
-bis(tetrahydropyran-2-yloxy)-5(
cis), 13(') lance) frostadienoic acid 262r
Get rIgwo.

(g) 9α-hydroxy-2 obtained in (f) above
0-Methoxy-16(S)-methyl-11α・15(S
)-bis(tetrahydropyran-2-yloxy)-5
(cis), 13 (trans) prostadienoic acid 262r
/19 in 7.7 rnl of ether and cooled to 0-5°C.

Next, chromic anhydride 20'? , manganese sulfate hydrate9.
Add water to 655' and 2.13ml of concentrated sulfuric acid to make a total volume of 50
m1 and 7.711 from the solution cooled to 0-5℃
Add sample No. 11 to the above solution and stir at the same temperature for 3 hours.

After the reaction is complete, add 10 rnl of water to the reaction solution and add 3 ml each of ether.
The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 20-methoxy-
16(S)-methyl-9-oxo-11α・15(S)
-bis(tetrahydropyran-2-yloxy)-5(
cis), 13 (trans) prostadienoic acid 260rr
Obtain 1g.

Example 3 20-Methoxy-16(R)-methyl-9-oxo-11α·15-bis(tetrahydropyran-2-yloxy)-5(cis)13()lance) obtained in Reference Example 3
Prostadienoic acid 327rn9 was added to 7Ffil of acetic acid-water-tetrahydrofuran mixture (volume ratio 19:11:3) and stirred at 40°C for 2 hours.

After completion of the reaction, the solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and developed using ethyl acetate as an eluent to obtain colorless oily 1.
1α・15(S)-dihydroxy-20-methoxy-1
6(R)-Methyl-9-oxo-5(cis),13(trans)prostadienoic acid 179rrI9 is obtained.

Example 4 20-methoxy-16(S)-methyl-9-oxo-11α·15(S)-bis(tetrahydropyran-2-yloxy)-5(cis),13() obtained in Reference Example 4
260 WIg of prostadienoic acid was added to 4 ml of acetic acid-aqueous tetrahydrone lan mixture (volume ratio 19:11:3).
1 and stir at 40°C for 3 hours.

After the completion of the reaction, the solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and developed using ethyl acetate as an eluent to obtain 11α・15(S
)-dihydroxy-20-methoxy-16(S)-methyl-9-oxo-5(cis),13(trans)prostadienoic acid (119.21r1 g) is obtained.

Reference example 5 (a) 50ml of anhydrous dimethoxyethane in a nitrogen stream
After adding 480rn9 of 50% oily sodium hydride to dimethyl(7-nitoxy3-methyl-2-oxo)heptylphosphonate) 2.8f? A solution prepared by dissolving .

Next, 4β-formyl-2-oxo-5α-p-phenylbenzoyloxy-3aα・4α・5β・6aα-hexahythrow-2H-cyclopenta[b]furan 3.5
1 A solution dissolved in 70+ytJ of anhydrous tetrahydrofuran was added dropwise to the mixture, and the mixture was further stirred at room temperature for 1 hour and 30 minutes.

After the reaction is completed, dry ice powder is added to the reaction solution to neutralize it, 150 ml of water is added, the mixture is saturated with sodium chloride, and extracted four times with 50 rIL of methylene chloride each.

The extracts are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained crude product was subjected to silica gel column chromatography and developed using a mixture of n-hexane and ethyl acetate as an eluent to obtain 4β-[8-ethoxy-4-methyl-
3-oxo-1-transoctenyl-2-oxo-
5α-p-phenylbenzoyl oxy7-3aα・4α・
5β・6aα-hexahydro-2H-cyclopenta(b
) 2.52 of furan was obtained.

(b) 1.17 P of sodium borohydride and 2.11 P of zinc chloride were added to 120 w11 of anhydrous ether, and after stirring at room temperature for 1 hour and 30 minutes, 4β-[8-ethoxy-
4-Methyl-3-oxo-1-transoctenyl-2-oxo-5α-p-phenylbenzoyloxy-
3aα・4α・5β・6aα-hexahydro-2H-cyclopenta(b) 2.5y of furan to 36m/? of anhydrous tetrahydrofuran? Add dropwise the solution dissolved in
Stir the time.

After the reaction was completed, dry ice powder was added to the reaction solution to neutralize it, 50rrLl of water was added, and then extracted three times with 50ml each of ether.The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. to obtain the crude product.

This was subjected to silica gel column chromatography, and n
- Using a hexane-ether mixture as the eluent, the 4β-[8-ethoxy-3(S)-hydroxy-4-methyl-1-transoctenyl)-2-, oxo-5α-p- Phenylbenzoyloxy-3aα・4
4β-[8-ethoxy-
3(R)-Hydroxy-4-methyl-1-transoctenyl-2-oxo-5α-p-phenylbenzoyloxy-3aα・4α・5β・6aα-hexahydro-
0.89S' of 2H-cyclopenta(b)furan is obtained.

(c) 4β-[8-ethoxy-3(S) in nitrogen stream
-hydroxy-4-methyl-1-transoctenyl)
-2-oxo-5α-p-phenylbenzyloxy-
3aα・4α・5β・6aα-hexahydro-2H-cyclopenta[b]furan 1.23F in anhydrous methanol 6
gm1, add 170~ of potassium carbonate, stir at room temperature for 3 hours, neutralize by adding acetic acid, and remove methanol under reduced pressure.

Add 50rrL of saturated sodium chloride aqueous solution to the obtained residue.
1 and extracted three times with 50 ml each of ether.

After combining the extracts and washing with saturated aqueous sodium chloride solution,
Dry over anhydrous magnesium sulfate and concentrate under reduced pressure.

The obtained crude product was subjected to silica gel column chromatography, first using chloroform and then ethyl acetate (eluent: 0.93 chloroform).

4β-[8-Ethoxy-3(S)-hydroxy-4-methyl-1-transoctenyl-5α-hydroxy-
635rr1 g of 2-oxo-3aα.4α.5β.6aα-hexahydro-2H-cyclopenta[b]furan is obtained.

(d) 4β-[8-ethoxy-3(S)-hydroxy-
4-Methyl-1-transoctenylcou 5α-hydroxy-2-oxo-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta[b]furan 600rr
I9 was dissolved in 20 ml of anhydrous methylene chloride, 460 rn9 of 2,3-dihydropyran was added, and 2.5 H% of p-41J enesulfonic acid monohydrate was added, stirred at room temperature for 30 minutes, and cooled with sodium hydrogen oxide. Add 10 ml of aqueous solution.

Next, the methylene chloride layer is separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained crude product was subjected to silica gel column chromatography, and an ether-n-hexane mixture (c=0.76,
4β-[8-ethoxy-4-methyl-3(S)-(tetrahydropyran-2-yloxy)-1-transoctenyl-2-oxo-5α-(
Tetrahydropyran-2-yloxy)-3aα・4α
・5β・6aα-hexahydro-2H-cyclopenta(
b) Furan 782~ is obtained.

(e) 4β-[8-ethoxy-4-methyl-3(S)-(tetrahydropyran-2-yloxy)-1-)7suoctenyl]-2-oxo-5α-(
Tetrahydropyran-2-yloxy) -3aα・4
α・5βΦ6aα-hexahydro-2H-cyclopenta(b,) 7277750m was dissolved in 30ml of anhydrous toluene, and after purging with nitrogen gas, it was cooled to -60°C or less with dry ice/acetone to contain 0.65P of diisobutylaluminum hydride. Add 6.6 ml of toluene solution dropwise and stir at the same temperature for 30 minutes.

Next, 5 ml of ethyl acetate, 2.5 ml of methanol, and 1 ml of water were sequentially added to the reaction solution at the same temperature, and then 5 ml of water was added at room temperature.
Add 0rIll and shake well to precipitate a white precipitate.

This precipitate is removed and separated into an organic layer and an aqueous layer.

The aqueous layer was extracted three times with 50ml each of benzene, the extract was combined with the organic layer, washed with water, and anhydrous sulfuric acid 41.0ml (c=0.
4β-[8-ethoxy-4-
Methyl-3(S)-(tetrahydropyran-2-yloxy)-1-) 77suoctenyl]-2-hydro-]
]]]1-/-5α-tetrahydropyran-yloxy)-3aα・4α・5β・6aα-hexahydro-2H
- cyclopenta(b, l furan 640 ~ is obtained.

(G) Add 10 ml of anhydrous dimethyl sulfoxide to 300 drops of 50% oily sodium hydride in a nitrogen stream and add 65 to 70 g.
Heat to ℃ and stir for about 1 hour until hydrogen gas stops being generated.

Then, after returning to room temperature, 1.38S' of 4-carboxybutyltriphenylphosphonium bromide was added, and further 4β-[8-ethoxy-4-methyl-3(S)-(tetrahydropyran-2-yloxy) -1-transoctenylcou2-hydroxy-5α-(tetrahydropyran-2-yloxy)-3aα・4α・5β・6aα-
Hexahydro-2H-cyclopenta[b]furan 62O
A solution of FF1& dissolved in 51 rL of anhydrous dimethyl sulfoxide is added and stirred at room temperature for 1 hour.

After the reaction was completed, dry ice powder was added to the reaction solution to neutralize it, and then 100 TILl of ethyl acetate and 5011 TIL of ether were added to the reaction solution.
Add dry ice to the 1A' mixture and add to the saturated solution.

At this time, the reactor is flushed with dry ice-saturated ethyl acetate and cold water.

The organic layer was separated and the aqueous layer was diluted with 30 rrLl of ethyl acetate.
Extract twice, and combine the extract and organic layer, wash with ice water, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure.

The obtained crude product was subjected to silica gel column chromatography, and an ethyl acetate-n-hexane mixture was used as an eluent of 1.0
chloroform).

20-ethoxy-9α-hydroxy-16-methyl-1
400 mg of 1α.15(S)-bis(tetrahydropyran-2-yloxy)-5-cis-13-transprostadienoic acid is obtained.

(g) 20-ethoxy-9α-hydroxy-16-methyl-11α・15(S)-bis(tetrahydropyran-
380 WIg of 2-yloxy)-5-cis-13-4 lanceprostadionic acid are dissolved in 11.6 ml of ether and cooled to 0 to -5°C.

Next, chromic anhydride 2.0g, manganese sulfate hydrate9.
Add water to 65 g and 2.13 ml of concentrated sulfuric acid to make a total volume of 50 r.
11.61 L of solution cooled to 0 to -5°C without ILl
1 and stir at the same temperature for 3 hours.

After the reaction is complete, add 20ml of water to the reaction solution and add 50ml each of ether.
The extracts were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 20-ethoxy-1
6-Methyl-9-oxo-11α・15(S)-bis(
Tetrahydropyran-2-yloxy)-5-cis-1
3-trans prostadienoic acid 350rn9 is obtained.

Reference example 6 (a) 4β-[8-ethoxy-3(R) in nitrogen stream
-Hydroxy-4-methyl-1-transoctenyl-2-oxo-5α-p-phenylbenzoyloxy-
3aα・4α・5β・6aα-hexahydro-2H-cyclopenta(b) Furan 860■
Dissolve in WLl, add 118rIIg of potassium carbonate, and stir at room temperature for 3 hours.

Next, acetic acid was added to neutralize the mixture, and methanol was distilled off under reduced pressure.

The resulting residue containing crystals is as follows: 23.2 (c=0.8
4β-[8-ethoxy-3(R
)-Hydroxy-4-If-1-transoctenyl-5α-hydroxy-2-oxo-3aα・4α・5
β・6aα-hexahydro-2H-cyclopenta(b
, l 777380m9 is obtained.

(b) 4β-[8-ethoxy-3(R)-hydroxy-
4-Methyl-1-transoctenyl]-5α-hydroquine-2-oxo-3aα・4α・5β・6aα-hexahydro-2H-cyclopenta(,b)furan 350
2.3-
Dihydropyran 270rn9 was added, and then 1.5mg of p-toluenesulfonic acid monohydrate was added, and after stirring at room temperature for 30 minutes, 7rnl of dilute aqueous sodium bicarbonate solution was added.

Next, the methylene chloride layer was separated, and the following reference example 5 = 1.3
4β-(8-ff-)xy-4-
Methyl-3(R)-(tetrahydropyran-2-yloxy)-1-)9nsoctenyl]-2-oxo-5α
-(tetrahydropyran-2-yloxy) -3aα
・4α・5β・6aα-hexahydro-2H-cyclopenta(b) Furan 396 is obtained.

(e) 4β-[8-ethoxy-4-methyl-3(R)-(tetrahydropyran-2-yloxy)-1-)lansoctenyl]-2-oxo-5α-(
Tetrahydropyran-2-yloxy) -3aα・4
α・5β・6aα-hexahydro-2H-cyclopenta(b,l Furano 3851r1 After gas substitution, cool to -60℃ or below, dropwise add 3.4ml of toluene solution containing 330rr1 g of diisobutylaluminum hydride, Stir for a minute.

Next, 4rnl of ethyl acetate and 2rnl of methanol were added to the reaction solution.
1 and 1 rul of water are added sequentially.

4β-[8-ethoxy-4-methyl-3(R)-(tetrahydropyran-2-yloxy)-1-) lance octenyl-2-hydroxy showing the following 15,6 (c=1.0 chloroform) -5α-(tetrahydropyran-2-yloxy)-3aα・4α・5β・6aα-
Hexahydro-2H-cyclopenta[b]furan 330
Obtain rII9.

(d) 50% oily hydrogenation in nitrogen stream) I
Jum 150 ~ anhydrous dimethyl sulfoxide 5wt1
was added, heated to 65-70°C, and stirred for about 1 hour until the generation of hydrogen gas stopped.

Then, the temperature was returned to room temperature, 4-carboxybutyltriphenylphosphonium bromide 6901119 was added, and 4β-[8-ethoxy-4-methyl-3(R)-tetrahydropyran-2-yloxy)-1-)ransuoc Tenylku 2-hydroxy-5α-(tetrahydropyran-2-yloxy)=3aα・4α・5β・6aα-hexahydro-2H-cyclopenta[b]furan 310r
A solution of r1g dissolved in anhydrous dimethyl sulfoxide 3rILl is added and stirred at room temperature for 1 hour.

After completion of reaction 4 2,0 (c=0.8 chloroform)
20-ethoxy-9α-hydroxy-16-methyl-11α・15(R)-bis(tetrahydropyran-
2-yloxy)-5-cis-13-trans-prostadienoic acid 179 is obtained.

(e) 20-ethoxy-9α-hydroxy-16-methyl-11α・15(R)-bis(tetrahydropyran-
160 m9 of 2-yloxy)-5-cis-13-)lansprostadienoic acid were dissolved in 4,6 rul of ether,
Cool to 0-5°C.

Next, chromic anhydride 2.01, manganese sulfate hydrate 9.
Add water to 65S' and 2.13rrLl of concentrated sulfuric acid and the total amount is 50mA! Add 4 to 6 drops of the solution cooled to 0 to -5°C and stir at the same temperature for 3 hours.

After the reaction is completed, the same procedure as in Reference Example 1-(g) is carried out to obtain 20-ethoxy-16-methyl-9-oxo-11α.
15(R)-bis(tetrahydropyran-2-yloxy)-5-cis-13-trans-prostadienoic acid 1
Obtain 40 mg.

Example 5 20-ethoxy-16-methyl-9-oxo-11α・
15(S)-bis(tetrahydropyran-2-yloxy)-5-cis-13-transprostadienoic acid 35
0rrIg was dissolved in 10 ml of acetic acid-aqueous tetrahydrofuran mixture (volume ratio 19:11:3) and incubated at 40°C ± 2°C.
Stir the time.

After completion of the reaction, the solvent was distilled off from the reaction solution under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and developed using ethyl acetate as an eluent. S)-dihydro-xy-16-methyl-9-oxo-5-cis-1 3-4 lansprostadienoic acid 177 is obtained.

Example 6 20-ethoxy-16-methyl-9-oxo-11α・
15(R)-bis(tetrahydropyran-2-yloxy)-5-cis-13-transprostadienoic acid 14
0g in acetic acid-water-tetrahydrofuran mixture (volume ratio 19
:11:3) Dissolve in 5+aA' and stir at 40°±2°C for 1 hour.

Colorless oily 2 showing the following (c=0.93 chloroform)
0-Ethoxy-11α・15(R)-dihydroxy-1
6-Methyl-9-oxo-5-cis-13-transprostadienoic acid 78rn9 is obtained.

Claims (1)

[Scope of Claims] (In the formula, A represents >C=0; R1 and R4 represent a lower alkyl group; R2 and R3 represent a hydrogen atom or a hydroxyl protecting group; and R
5 means a hydrogen atom. However, at least - in R2 and R3 means a hydroxyl-protecting group. A method for producing a novel 16-alkyl-20-alkoxy prostadienoic acid derivative, which comprises removing a protecting group from a hydroxyl-protected prostadienoic acid derivative.