JPS5851957B2 - Phosphonic acid ester derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel phosphonic acid ester derivatives having the general formula and their alkali metal salts.

In the above formula, R1 represents a hydrogen atom or a lower alkyl group, R2 and R3 represent a lower alkyl group, and R4 represents a lower alkyl group or a phenyl group.

In the general formula (I), R1, R2 and R3
Examples of the lower alkyl group of R4 include alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, and isopropyl, and examples of the lower alkyl group of R4 include methyl, ethyl, n-propyl, and isopropyl. ,
n-butyl, isobutyl, 5ee-butyl, tert-
Examples include alkyl groups having 1 to 4 carbon atoms such as butyl, and examples of alkali metal ions forming alkali metal salts include metal ions such as sodium, potassium, and lithium.

The compound having the general formula (I) is a compound useful as a bronchodilator. show,
A represents an ethylene group or a cis-vinylene group.

) is an important synthetic intermediate for glosstaglandin derivatives.

The compound having the general formula (I) of the present invention has the general formula (In the formula, R4 has the same meaning as described above.

) in the presence of a base, a methyl phosphonate having the general formula (wherein R1, R2 and R3 have the same meanings as above, and R6 is methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, 5ee-butyl, j
Indicates a lower alkyl group such as ert-butyl.

) with a carboxylic acid ester.

The base used in this reaction is not particularly limited as long as it is a base used in normal ester condensation reactions, but examples include methyllithium, n-butyllithium, 5ec-butyllithium, phenyllithium, and diisopropyllithium amide. Organolithium compounds are preferred.

The reaction is carried out in the presence of an inert solvent, preferably an ether such as ethyl ether, tetrahydrofuran or dimethoxyethane, and the reaction is carried out in the presence of an inert gas such as argon or nitrogen. It is preferable to let

The reaction temperature is preferably a low temperature of -78° to 0°C, and the reaction time is usually 1 to 5 hours, although it varies depending on the reaction temperature.

After completion of the reaction, the target compound (I) of the present invention can be obtained by treating the reaction mixture according to a conventional method.

For example, after adding acetic acid and water to the reaction mixture, extraction is performed with an organic solvent such as ethyl ether, and the organic solvent layer is washed with water.
It can be obtained by drying and distilling off the solvent.

If necessary, the obtained target compound can be prepared using conventional methods such as vacuum distillation, column! It can be further purified by chromatography or the like.

As mentioned above, the compound (I) of the present invention is an important synthetic intermediate compound of the prostaglandin derivative (n) which exhibits a bronchodilator effect, and the method for producing it will be explained below.

For example, a compound having the above general formula (II) in which substituent A is a cis-vinylene group can be synthesized by the following steps.

In the above formula, A' represents a cis-vinylene group, R7 and R8 represent a hydroxyl group-protecting group, and R1, R2, R3 and R5 have the same meanings as described above.

[Journal of the American Chemical Society (J, Am, Chem, Soc,
) Vol. 91, p. 5675 (1969)] Each step carried out using a known compound represented by the general formula (V) as a starting material will be described.

The first step is a step of producing a compound having the general formula (VI), in which the compound having the general formula (V) is converted into an alkali metal salt of the compound of the present invention having the general formula (I) (wherein R1, R2, R3, and R4 have the same meanings as described above, and Mkichi represents an alkali metal ion such as sodium, potassium, or lithium.

) is achieved by reacting with

The solvent used in the reaction is not particularly limited, and may be any solvent commonly used in Witzig reactions.

The second step is a step of producing a compound having the general formula (■), and is achieved by reducing the compound having the general formula (VI).

The reaction is carried out using a reducing agent in the presence or absence of a solvent.

The reducing agent used is not particularly limited as long as it converts a carbonyl group into a hydroxyl group without reducing double bonds, such as sodium borohydride, potassium borohydride, lithium borohydride, Metal hydride compounds such as zinc boron, tri-tert-butoxylithium aluminum hydride, trimethoxylithium aluminum hydride, sodium cyanoborohydride, and lithium-9b to boraperhydrophenalenoidide are preferably used.

The third step is a step of producing a compound having the general formula (■), in which a reaction for converting the hydroxyl-protecting group R7 of the compound having the general formula (■) and a reaction for protecting the hydroxyl group are carried out according to a conventional method. This is achieved by

The fourth step is a step of producing a compound having the general formula (IX), and is achieved by reducing the compound having the general formula (■).

The reaction is carried out in the presence of a reducing agent.

Examples of reducing agents used include diisobutylaluminum hydride, sodium borohydride, potassium borohydride, lithium borohydride, trije
Metal hydride compounds such as rt~butoxylithium aluminum and trimethoxylithium aluminum hydride are preferably used.

In particular, diisobutylaluminum hydride is preferably used because the reaction progresses at relatively low temperatures and side reactions are less likely to occur.

The fifth step is a step of producing a compound having the general formula (X), in which the compound having the general formula (IX) is manufactured by the general formula (wherein R9 is an aryl group such as phenyl or an alkyl group such as n-butyl). Indicates a hydrocarbon group such as

M2 represents an alkali metal such as sodium or potassium.

), which is then converted to the free acid by treatment with an acid in a conventional manner, and then, if necessary, the carboxyl group of the resulting compound is esterified.

A compound having the general formula (IX) is converted into a compound having the general formula (XI).
) is usually carried out in the Wittzig reaction step in which the compound 1 having the general formula (IX) is reacted in the presence of a solvent.
About 1 mole of the compound having the general formula (XI)
This is carried out using Witschg's reagent in an amount of between 20 and 20 moles, preferably in excess.

The product obtained by the above Wittzig reaction is a salt, which is easily converted into the free acid by treatment with an organic acid such as acetic acid, propionic acid, oxalic acid; or a mineral acid such as hydrochloric acid or hydrobromic acid. It can be converted to .

Next, an optional reaction of esterifying the carboxyl group of the compound thus obtained is accomplished by contacting the free acid with an esterifying agent according to a conventional method.

The sixth step is a step of producing a compound having the general formula (n), and is achieved by oxidizing the compound having the general formula (X) and then removing the hydroxyl protecting group by a conventional method.

In this oxidation reaction, chromic acids, particularly chromic anhydride-pyridine complex salt (Colins reagent), and chromic anhydride-concentrated sulfuric acid-water (Jone B reagent) are usually used as particularly suitable oxidizing agents.

Among the compounds having the general formula (II) thus obtained, those in which R5 is a hydrogen atom can be converted into a salt by a conventional method.

Furthermore, when the target compound obtained in this way is obtained as a mixture of various geometric isomers and optical isomers, these can be separated and resolved in an appropriate synthetic step.

A pharmacological test regarding the bronchodilator effect of the prostaglandin derivative having the general formula (II) obtained here will be described below.

Test method A specimen was administered intravenously to a guinea pig weighing 400 to 6,000 kg, which was anesthetized with bentoparbital sodium, and then 2 μf of histamine solution was added to the guinea pig. /kg to 3
μ? /kg intravenously administered using the Konzett-R65sler method.
e Pathology and Pharmakol
195, p. 71, 1940] was used to determine the rate of suppression of increase in airway resistance.

The value was calculated. Test results: Table 1 illustrates the results of the bronchodilatory effects of the tested prostaglandin derivatives in guinea pigs.

Compound A: 9-oxo-11α・15α-dihydroxy-17β-methyl-20-isopropylidenepros)-
5(cis)・13(J lance)-dienoic acid compound B: 9-oxo-11α・15α-dihydroxy-20-isopropylideneprost 5(cis)・13(
trans)-dienoic acid Therefore, the compound having the general formula (n) is useful as a medicine for use in cases where bronchodilation is required.

The dosage form for that purpose is usually administered by an aerosol spray.

The amount used varies depending on symptoms, age, body weight, etc., but is usually 20 μm to 150 μm per day for adults.

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

Example 1 Dimethyl 2-oxo-4,8-dimethyl-7-ranenylphosphonate Dimethyl methylphosphonate) 10.2f of tetrahydrofuran solution (80rnl) was heated at 60°C in an argon stream.
15.1% n-butyllithium-hexane solution 417
Add 3,7-dimethyl-6-octenoic acid methyl ester 7 to the dimethyl methylphosphonate carbanion synthesized by adding 711 dropwise under stirring while keeping the temperature below -50°C.
．． A tetrahydrofuran solution of 227y (3077I0) was added dropwise, and the mixture was further stirred at -50 to -60°C for 3 hours and 10 minutes, and then the cooling bath was removed and stirring was continued at room temperature until the internal temperature reached 0°C.

After the reaction is completed, acetic acid and water are sequentially added to the reaction mixture, and the mixture is extracted with ether.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent is distilled off from the extract.

When the obtained residue is distilled under reduced pressure, it has a boiling point of 124-127
℃10. Oily target compound with 1 Hg 4.851
' is obtained.

Infrared absorption spectrum (liquid film) νmaXcr/L-1 near 15 Nuclear magnetic resonance spectrum CCCI, ) δppm: 0.9
0 (3H, doublet, J=6Hz) 1.57 (3H1-double) 1.64 (3H1-double) 2.89 (2H1 doublet, J-23H2) 3.66 (
6H, doublet, J=11Hz) 4.96 (IH1 triplet, J=7H7) Example 2 Dimethyl 2-oxo-8-methyl-7 Nylphosphonate nonedimethyl Methylphosphonate and 7-methyl-6
The reaction was carried out in the same manner as in Example 1 using -octenoic acid methyl ester to obtain the target compound having a boiling point of 123-126°C, 10 mmHg.

Infrared absorption spectrum (liquid film) νmaxCrrL.

715 Nuclear magnetic resonance spectrum (CC14) δppm: 1.60
(3H, double line) 1.68 (3H1 double line) 3.08 (2H, double line, J=23Hz) 3.78 (
6H, doublet, J=11Hz) 5.13 (LH1 triplet, J-7Hz) Reference example 1 3-oxo-6-syn (3-oxo-5.9 dimethyldec-1.8-genyl) - 7-y Phthiacetoxy-
2-Oxabicyclo[3.3.0]-octane 52.9% oily sodium hydride (321 cm) was washed with dry petroleum ether to remove oil, and then suspended in 20 ru of dimethoxyethane in an argon stream. Dimethyl 2-oxo-4.8- obtained in Example 1 was cooled with water and stirred.
Dimethyl-7-ranenylphosphonate 2.035fI
After dropping a dimethoxyethane solution (20rn) and stirring for an additional 3 hours, add 10ml of dimethoxyethane.

Add this solution to 3-oxo-6-syn-formyl-antiacetoxy 2-oxabicyclo-[3.3.
0]-octane 1.35P dimethoxyethane solution (3
0 ml) was added dropwise, and the mixture was further stirred for 2 hours.

After the reaction is completed, acetic acid and then ether are added to the reaction mixture, and the organic solvent layer is washed with water, dried over anhydrous sodium sulfate, and then the solvent is distilled off.

The obtained residue was purified by column chromatography using silica gel, and the target compound 1.6 was obtained as an oil.
9P is obtained.

Infrared absorption spectrum (liquid film) maxcrrL'17
70.1740.1695.1670°630 Nuclear magnetic resonance spectrum (CDC13) δppm: 0.
90 (Double line on 3H, J=6Hz) 1.61 (3H, -double line) 1.65 (3H1-double line) 2.03 (3H1-double line) Reference example 2 3-oxo-6-tun ( 3α-hydroxy-5,9-dimethyldeca-1,8-genyl)-7antiacetoxy2-oxabicyclo[3,3,0]-octane and 3-oxo-6-syn(3β-hydroxy-5, 9-dimethyldecato8-genyl)-7-antiacetoxy2
-Oxabicyclo[3.3.0]-octane 3-oxo-6-syn(3-oxo-5.9dimethyldec-1.8-genyl)-7-antiacetoxy-2-
To a solution of 270 μl of oxabicyclo[3.3.O]-octane dissolved in 4 ml of dimethoxyethane, 0.5 μl was added under water cooling.
5M-zinc borohydride-dimethoxyethane solution 0.8
ml and stir for an additional hour.

After the reaction is complete, excess reagent is decomposed with dilute acetic acid, water is added, and the mixture is extracted with ethyl acetate.

After washing the extract with water and drying with anhydrous sodium sulfate, the solvent is distilled off from the extract and the resulting residue is subjected to preparative thin layer chromatography and purified using ether as a developing solvent. 89 m9 of the 3α-isomer of the desired compound are obtained from the fraction, and 80 μ of the 3β-isomer of the desired compound are obtained from the more polar portion.

3α-isomer: Infrared absorption spectrum (liquid film) νmaxCrIL.

3500.1780 Nuclear magnetic resonance spectrum (CDC13) δppm: 0.9
1 (3H, double line, J=6Hz) 1.58 (3H1-
multiplet) 1.65 (3H, - multiplet) 5.51 (2L multiplet) 3β-isomer: Infrared absorption spectrum (liquid film) 'maxcr/L'35
00.1780 Nuclear magnetic resonance spectrum (CDC13) δppm: 0.
90 (3H1 doublet, J=6Hz) 1.57 (3H1- doublet) 1.64 (3H, - doublet) 5.51 (2H, multiplet) Reference example 3 3-oxo-6-syn ( 3α-hydroxy-5,9-dimethyldeca-1,8-genyl) -7-antihydroxy-2-oxabicyclo[3,3,0]-octane 3-oxo-6-syn (3α-hydroxy-5, 9-dimethyldeca-1,8-genyl)-7-antiacetoxy-2-oxabicyclo[3,3,0]-octane 12
After dissolving the solution in 2 ml of anhydrous methanol, 65 ml of anhydrous potassium carbonate was added and stirred for 20 minutes.

After the reaction is complete, acetic acid and then water are added, followed by extraction with ethyl acetate.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent is distilled off from the extract to obtain the target compound 931n9 in the form of an oil.

Infrared absorption spectrum (liquid film) νmaxcrrL”77
0 Nuclear magnetic resonance spectrum (CDC13) δppm: 019
1 (3H1 doublet, J=6Hz) 1.58 (3H, - doublet) 1.68 (3H1 doublet) 5.54 (2H1 multiplet) Reference example 4 3-oxo-6-syn[3α -(2-tetrahydropyranyloxy)-5,9-dimethyldec-1,8-genyl]-7-anti-(2-tetrahydropyranyloxy)-2-oxabicyclo[3,3,0]-octane 3-Oxo-6-syn(3α-hydroxy-5,9-dimethyldec-1,8-genyl)-77-thihydroxy-2-oxabicyclo[3,3,0)-octane 150
(2) is reacted with dihydropyran in the presence of a catalytic amount of picric acid in a conventional manner and treated to obtain 301m9 of the crude target compound.

Infrared absorption spectrum (liquid film) νmaX""'1
770.1030 Nuclear magnetic resonance spectrum (CDC13) δppm: 0.
91 (3H, doublet, J=6Hz) Reference example 5 3-hydroxy-6-syn[3α-(2-tetrahydropyranyloxy)-5,9-dimethyldec-1,8-genyl]-7- Anti-(2-tetrahydropyranyloxy)-2-oxabicyclo[3.3.O]-octane 3-oxo-6-syn[3α-(2-tetrahydropyranyloxy)-5.9-dimethyldec- 1,8-genyl]-7-anti-(2-tetrahydropyranyloxy)-2-oxabicyclo[3,3,0]-octane 19
After cooling a solution of 0.0 cm dissolved in 5 ml of toluene to -60°C, a toluene solution (1 m7) of diisobutylaluminum hydride 190 η was added dropwise while stirring, and the mixture was further stirred for 30 minutes.

After the reaction is completed, 1 ml of methanol and water are added, and the mixture is extracted with ethyl acetate.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent was distilled off from the extract to obtain 170 ml of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) νmaxcfrL.

3420.1030 Nuclear magnetic resonance spectrum (CDC13) δppm: 0.9
1 (3H1 doublet, J-6Hz) Reference Example 6 9α-hydroxy-11α·15α-di(2-tetrahydropyranyloxy)-17-methyl-20-inpropylidenepros)-5 (cis).

Stir a dimethyl sulfoxide solution of 13(trans)-dienoic acid 2M-sodium methylsulfinyl chloride in a dimethyl sulfoxide solution of 27711 in a stream of argon at below 20 °C. When added dropwise, a red ylide solution is obtained.

Add 3-hydroxy-6-syn[3α-(2-tetrahydropyranyloxy)-5,9-dimethyldeca-] to this solution.
1,8-genyl]-7-anti-(2-tetrahydropyranyloxy)-2-oxabicyclo[3,3,O]
- 5 TL of dimethyl sulfoxide solution of 220 μl of octane
1 and stirred at room temperature for 20 hours.

After the reaction is complete, dimethyl sulfoxide is distilled off under reduced pressure.
An aqueous sodium hydrogen carbonate solution is added to the resulting residue, and the mixture is washed with ethyl acetate to remove neutral substances.

Next, the aqueous layer was acidified with oxalic acid to a pH of around 3 and added with hexane.
After extraction with an ether mixed solvent (1:1), the extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off from the extract to obtain the target compound 198 in the form of an oil.

Infrared absorption spectrum (liquid film) νmaXCrIL.

3400.1708 Nuclear magnetic resonance spectrum (CCI4) δppm: 0.9
1 (3H1 doublet, 6Hz) 5.01 (IH1 triplet, 6Hz) Reference example 7 9α-hydroxy-11α・15α-di(2-tetrahydropyranyloxy)-17-methyl 20-isopropylideneprost-5 (cis)13()lance)-dienoic acid methyl ester 9α-hydroxy-11α・15α
-di(2tetrahydropyranyloxy)-17-methyl 20-isopropylideneprost-5(cis).

13 ()7 ounce) --) 730 ■ of enoic acid to 5 ether
An ethereal solution of diazomethane is added to the solution in Tll until the reaction mixture assumes a pale yellow color.

After the reaction is completed, the solvent is distilled off under reduced pressure to obtain the desired oily compound 728.

Infrared absorption spectrum (liquid film) νmaxCrrL”34
00.1730 Nuclear magnetic resonance spectrum (CC14) δppm: 0.91
(3H, doublet, J=6Hz) 5.01 (IH, triplet, J=6Hz) Reference example 8 3-oxo-6-syn(3-oxo-9-methyldecato-8-genyl)-7 -Anti(pphenylbenzoyloxy)-2-oxacis-bicyclo[3.3.O]-
After washing 346 μl of oily sodium hydride with 52.9% octane with dry petroleum ether to remove oil, it was suspended in 20 rrLl of dimethoxyethane, and dimethyl 2-oxo 8 obtained in Example 2 was cooled with water in an argon stream. A solution (20 ml) of 2.075 P of -methyl-7-ranenylphosphonate in dimethoxyethane is added dropwise, and after further stirring for 3 hours, 10 ml of dimethoxyethane is added.

Add 1.22 g of 3-oxo-6-syn-formyl-anti(p-phenylbenzoyloxy)-2-oxa-cisbicyclo-[3.3.0]-octane to this solution under water cooling.
A dimethoxyethane solution of P (301rLl) was added dropwise,
Stir for an additional 2 hours.

After the reaction is completed, the reaction mixture is treated in the same manner as in Reference Example 1, and the resulting product is purified by column chromatography using silica gel to obtain the target compound 1.37S' in the form of an oil.

Infrared absorption spectrum (liquid film) νmaxcr/L.

1783.1723 1680 16351280.1
185.11201755 Nuclear magnetic resonance spectrum (CDC13) δppm: 5.0
~5.5 (3H1 multiplet) 6.28 (IH, doublet) 6.8 (LH1 quartet) 7.3 ~ 8.2 (9H1 multiplet) Reference example 9 3-oxo-6-syn (3α-hydroxy-9methyldeca-1,8-genyl) -7-7th(p-phenylbenzoyloxy) -2-oxa-cis-bicyclo(
3-3.O]-octane and 3-oxo-6-syn(
3β-hydroxy-9-methyldecato-8-genyl)
-7-Anti(p-phenylbenzoyloxy)2-oxa-cis-bicyclo[3.3.O]octane 3-oxo-6-syn(3-oxo-9-methyldecato-8-genyl)-7- Anti(p-phenylbenzoyloxy)-2-oxa-cis-bicyclo[3.3.O
]-To a solution of 290 μl of octane dissolved in 5 rrL of dimethoxyethane, 1 ml of a 0.55 M zinc borohydride dimethoxyethane solution was added under water cooling, and the mixture was further stirred for 1 hour.

After the reaction is completed, the same treatment as in Reference Example 2 is carried out, and the obtained product is purified by preparative thin layer chromatography using ether as a developing solvent. The isomer 95■ is obtained, and the more polar part gives the 3β-isomer 77m9.

3α-isomer infrared absorption spectrum (liquid film) maxCIrL-1:
3500.1780.1720.1615, 1280.
1185.1120.975.750 Nuclear magnetic resonance spectrum (CDC13) δppm: 4.13 (LH1 multiplet) 4.9-5.4 (3H, multiplet) 5.64 (2H1 multiplet) 7.3-8 .2 (9H, multiplet) 3β-isomer infrared absorption spectrum (liquid film) maXcrrL-1:
3500.1780, 1720, 1615.1280.
1185.1120. 975.750 Nuclear magnetic resonance spectrum (CDC13) δppm: 4, 13 (I H1
4.9-5.4 (3H1 multiplet) 5.64 (2H1 multiplet) 7.3-8.2 (9H1 multiplet) Reference example 10 3-oxo-6-syn (3α-hydroxy- 9-methyldecato-8-genyl)-7-antihydroxy-2-
Oxacis-bicyclo[3.3.O]-octane 3-oxo-6-syn(3α-hydroxy-9-methyldecato-8-genyl)-7-anti(p-phenylbenzoyloxy)-2-oxacis -Bicyclo [3・3
After dissolving 140 μm of 0]-octane in 3 mA of anhydrous methanol, 75 μm of anhydrous potassium carbonate was added and stirred for 35 minutes.

After the reaction was completed, the same post-treatment as in Reference Example 3 was carried out to obtain 99 cm of the target compound in the form of an oil.

Infrared absorption spectrum (liquid film) νmaxCrrL.

3400.1760.1175.1080°70 Nuclear magnetic resonance spectrum (CDCl s ) δppm: 1
．． 60 < 6H, doublet) 3.8-4.2 (2H1 multiplet) 4.8-5.3 (2H, multiplet) 5.55 (2H1 multiplet) Reference example 11 3-oxo-6- Syn[3α-(2-tetrahydropyranyloxy)-9-methyldec-18-genyl]-7
-Anti(2-tetrahydropyranyloxy)-2-oxa-cis-bicyclo[3.3.0]-octane 3-oxo-6-syn(3α-hydroxy-9methyldecato-8-genyl)-7- Antihydroxy-2-oxa-cis-bicyclo[3.3.O]-octane 3.0
1.85 P of dihydropyran was added to a solution of 81 dissolved in 15 m of benzene at room temperature, then a catalytic amount of picric acid was added under water cooling, and the mixture was left to stand for 3 hours.

After the reaction was completed, 200 Ttl of ether was added to the reaction solution, and 1
Wash once with 0% sodium bicarbonate, then with water until neutral, and dry over anhydrous sodium sulfate.

The solvent is distilled off and the residue is purified by silica gel column chromatography to obtain the desired oily compound 4,3.

Infrared absorption spectrum (liquid film) νmaxCrIL.

1775.1130,1070,1015,70 Nuclear magnetic resonance spectrum (CDCl2) δppm: 4.7
(2K, multiplet) 4.8-5.2 (2H1 multiplet) 5.0 (2H1 multiplet) Reference example 12 3-hydroxy-6-syn [3α-(2-tetrahydropyranyloxy)-9- Methyl decato 8-genyl]
-7~anti(2-tetrahydropyranyloxy)-2
-oxa-cisbicyclo[3.3.0]-octane 3-oxo-6-syn[3α-(2-tetrahydropyranyloxy)-9-methyldecato-8-genyl]-7
-anti(2-tetrahydropyranyloxy)-2-oxa-cis-bicyclo[3.3.0]-octane 4.3
When treated in the same manner as in Reference Example 5, the target compound 4.12 is obtained as an oil.

Infrared absorption spectrum (liquid film) maxcrIL-1:
3400.1130.1070.1015, 70 Nuclear magnetic resonance spectrum (CDC13) δppm: 4.7
(2H1 multiplet) 5.15 (IH1 triplet) 5.6 (2H1 multiplet) Reference example 13 9α-hydroxy-11α・15α-di(2tetrahydropyranyloxy)-20-isoprobiliteneprost-5( cis)・13(trans)-dienoic acid 3-hydroxy-6-syn[3α-(2-tetrahydropyranyloxy)-9-methyldecato-8-genyl]
-7-anti(2-tetrahydropyranyloxy)-2
-Ox-cis-bicyclo[3.3.O]-octane 4
．． When 11 is used and treated in the same manner as in Reference Example 6, the target compound 3.62 is obtained as an oil.

Infrared absorption spectrum (liquid film) νmaxCrrL'34
50.3200.2750.1715.1160.11
05.1020 Nuclear magnetic resonance spectrum (CDC13) δppm: 4.7
3 (2H1 multiplet) 5.17 (LH1 triplet) 5.5 (4H1 multiplet) Reference example 14 9-oxo-11α・15α-dihydroxy 17-methyl-20-isopropylideneprost-5(cis)・1
3(trans)-dienoic acid ■ 9α obtained in Reference Example 6
-hydroxy 11α・15α-di(2-tetrahydropyranyloxy)-17-methyl-20-isopropyritine floss)-5(cis)・13(trans)dienoic acid 7
50■ with 2omi of acetone! After dissolving in the solution, 1 ml of Jones reagent was added at around -13°C, and the mixture was further stirred for 20 minutes.

After the reaction is complete, excess reagent is decomposed with isopropyl alcohol, water is added, and the mixture is extracted with ethyl acetate.

After washing the extract with water and drying with anhydrous sodium sulfate, the solvent was distilled off from the extract, and an oily 9-oxo-11α・15
α-di(2-tetrahydropyranyloxy)-17-methyl-20-isopropyritine frost 5 (cis 1)
・631■ of 13()lance)-dienoic acid are obtained.

Infrared absorption spectrum (liquid film) max CrIL'17
45.1710 Nuclear magnetic resonance spectrum (CCI,) δppm: 0.9
1 (3H1 doublet, J=6Hz) 9-oxo-11α・15α-di(2-tetrahydrohyranyloxy)-17-methyl-20-isopropylideneprost-5(cis)・13(trans)-diene Acid 625μ is acetic acid-water tetrahydrofuran (15ml 111
After dissolving in a mixed solvent of 5rIl (115ml), 35°C
Stir for 4 hours.

After the reaction is completed, water is added to the reaction mixture and extracted with ethyl acetate.

After washing the extract with water and drying over anhydrous sodium sulfate, the solvent was distilled off from the extract to obtain a residue of 610 cm.

When this is purified by column chromatography using silica gel, an oily 9-oxo-11α・15α
-Dihydroxy-17-methyl-20=isopropylideneprost-5(cis)13(trans)-dienoic acid 203 ml is obtained.

Specific optical rotation [α) D-44,3° (C-1, tetrahydrofuran) Infrared absorption spectrum (liquid film) νmaXcIrL.

3380.1740,1710 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
0.91 (3H1 multiplet, J=6Hz) 1.59 (3H) 1.65 (3H) 4.11 (2H1 multiplet) 5.38 (2H1 multiplet) 5.65 (2H, multiplet) Reference example 15 9-oxo-11α・15α-dihydroxy 17-methyl-20-isopropylideneprost-5(cis)・1
3(trans)-dienoic acid methyl ester ■ 9α-hydroxy 11α・15 obtained in Reference Example 7
α-di(2-tetrahydropyranyloxy)-17-methyl-20-improvilitenprost-5(cis).
When 13(trans)dienoic acid methyl ester 751■ is reacted and treated in the same manner as in Reference Example 14 (■), oily 9-oxo-11α·15α-di(2-tetrahydropyranyloxy)-17-methyl 20 -Impropylideneprost-5(cis).13()lance) -dienoic acid methyl ester 630 ml is obtained.

Infrared absorption spectrum (liquid film) νmaxcfrL'17
45 Nuclear magnetic resonance spectrum (CCI4) δppm: 0.9
0 (heavy line on 3H, J=6Hz) 3.67 (heavy line on 3H, -double line) 9-oxo-11α・15α-di(2-tetrahydropyranyloxy)-17-methyl-20-inpropylideneprost- When 5(cis)・13(trans)-dienoic acid methyl ester 610■ was reacted and treated in the same manner as in Reference Example 14 (■), oily 9-oxo-11α・1
190 μl of 5α-dihydroxy-17-methyl-20-impropylideneprost-5(cis)13()lance)-dienoic acid methyl ester are obtained.

Infrared absorption spectrum (liquid film) νmaxCrIL.

3400.1736 Nuclear magnetic resonance spectrum (CD3CO■3) δppm: 0
．． 90 (3H1 doublet, 6Hz) 1.58 (3H1 doublet) 1.60 (3H1 doublet) 3.67 (3H1 doublet) 5.38 (2H1 multiplet) 5.65 (2H1 multiplet) Reference example 16 9-oxo-11α・15α-dihydroxy 20-inpropylideneprost-5 (cis)・13 (trans)
-dienoic acid■ 9-α-hydroxy 11α・obtained in Reference Example 13
15α-di(2-tetrahydropyranyloxy) -2
0-Inpropylideneprost-5(cis).13(trans)-dienoic acid 12.9S' was dissolved in acetone 3001r.
Jones reagent 257 was dissolved in Ll and cooled to -20°C.
Drop 711.

After the completion of the dropwise addition, the mixture was stirred at -20°C for 1 hour.

After the reaction is completed, the reaction mixture is poured into ice water 21 and extracted with ether.

The extract is dried over anhydrous sodium sulfate and the solvent is distilled off to obtain an oily substance 10.31.

When this is purified by column chromatography using 10 oz of silica gel, oily 9-oxo-11α・15
α-di(2tetrahydropyranyloxy)-20-inpropylideneprost-5(cis)・13()lance)
-dienoic acid 8.41P is obtained.

Infrared absorption spectrum (liquid film) νmaxcrrL.

1745.1710.1135.1020, 70 Nuclear magnetic resonance spectrum (CDC13) δppm: 4.7
(2H1 multiplet) 5.0-5.8 (5H1 multiplet) 9-oxo-11α・15α-di(2-tetrahydropyranyloxy)-20-(sopropyriteneprostol 5
8.4 IP of -(cis).13(trans)-dienoic acid was dissolved in 100 r/Ll of acetic acid, 100 ml of water, and 30 rr/Ll of tetrahydrofuran, heated at 40°C for 1.5 hours, and further 100 ml of water was added. Warm to 40°C for 5 hours.

After the reaction was completed, the reaction mixture was diluted with 5007rL of saturated saline solution, and a mixed solvent of ethyl acetate and benzene (i:i) was added.
Extract with

After washing with saturated brine, the solvent is distilled off to obtain 6,9i oil.

This was subjected to column chromatography using 100S' silica gel to obtain the desired product with a diameter of 2°810.

When recrystallized from ethyl acetate-hexane, the melting point is 64.
9-oxo-11α・15 as a crystal with −66°C
α-dihydroxy-20-isopropylideneprost-
5(cis).13(trans)-dienoic acid 2.1y is obtained.

Specific optical rotation [α) D-57.5° (C=1, tetrahydrofuran) Infrared absorption spectrum (Nujol) ”maXCrr
L”3380,173011705.1160,70 Nuclear magnetic resonance spectrum (CD3COCD3) δppm:
4.08 (2H1 multiplet) 5.17 (IH, triplet) 5.42 (2H1 multiplet) 5.68 (2H1 multiplet) Mass spectrum m/e: 392 Sodium salt 408 m9 (1,04 mmol) of the above carboxylic acid ) to 30
After dissolving in 10 ml of aqueous methanol, 30% of sodium bicarbonate 10 Qmp (i, 19 mmol)
Add 10 TL of methanol solution containing 1% water and stir at room temperature.
Stir for an hour.

After the reaction is complete, the solvent is distilled off at low temperature, resulting in 9-oxo-1
1α.15α-dihydroxy-20-isopropylidenepros)-5(cis).13(trans)-dienoic acid sodium salt 500i is obtained as a waxy powder.

Claims (1)

[Claims] 1 General formula (wherein R1 represents a hydrogen atom or a lower alkyl group,
R2 and R3 represent a lower alkyl group, and R4 represents a lower alkyl group or a phenyl group. ) and its alkali metal salts.