JPH046696B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to secoprostaglandins and methods for producing the same. More specifically, the present invention relates to so-called 11,12-secoprostaglandins, which have no carbon atom at the 11th position, which are prostaglandins that have been attracting attention as pharmaceuticals in recent years, and methods for producing the same.

Traditionally, prostaglandins have important physiological roles in living organisms, including antiplatelet, antiulcer, antiallergic, blood pressure regulating, proinflammatory, immunomodulating, and bone metabolism regulating effects. (For example, "prostaglandins" by Katori, Yamamoto, and Sato et al.
(1978) Kodansha Scientific Publishing).

Therefore, attempts have been made to use these prostaglandins as medicines to treat various diseases in mammals.
Natural prostaglandins such as F ₂ α and prostaglandin E ₂ are used as labor stimulants. However, natural prostaglandins are rapidly metabolized and inactivated in vivo, so they cannot necessarily be considered suitable medicines. Furthermore, its biological effects are wide-ranging as mentioned above, and it has drawbacks such as lack of specificity as a drug.

Furthermore, these secoprostaglandins can be produced by complex chemical and biochemical methods, but these methods also have the disadvantage of high production costs and, as a result, difficulty in obtaining them. For this reason, prostaglandins with high selectivity for physiological activity and easily available are being investigated (for example, SMRberts et al. .S.Pharmacol
Activity of Prostanoids, Pergumon Press
Ltd. (1979)). Among these traditionally known prostaglandins are
Derivatives are known in which an appropriate substituent is introduced into the C ₂₀ prostanoic acid skeleton, or a carbon atom constituting the prostanoic acid skeleton is replaced with a heteroatom. In addition, there are a few known unique prostaglandins, such as secoprostaglandins in which the prostanoic acid skeleton carbon atoms are omitted (for example, EJCragol Jr et al.
Journal. of. Medicinal. Chemistry (J.Med.Chem.), 20, 35 (1977)). These secoprostaglandins are type 1 PGs and type 2 PGs.
No PGs are known. Furthermore, there is no known method for producing type 2 secoprostaglandins. Therefore, the present inventors focused on this point, and as a result of intensive research, they arrived at the present invention.

That is, the present invention provides the following formula [I] [In the formula, A represents an oxygen atom, B represents a double bond (-CH=CH-), Y represents an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 5 or 6 carbon atoms, and R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable cation, and Z
is a hydrogen atom or t-butyldimethylsilyl. ] These are secoprostaglandins shown by.

A more specific explanation of the compound represented by the above formula [I] provided by the present invention is as follows. In the formula, R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable cation. Examples of the alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, t-butyl, and cyclohexyl groups, of which methyl and ethyl groups are preferred. Pharmaceutically acceptable cations include metal cations selected from alkali metals such as sodium, potassium, lithium, etc., alkaline earth metals such as calcium, magnesium, etc., and other metals such as aluminum, and ammonium cations. can be given. Among them, sodium ion is preferred as supported by the production method described below. Z is a hydrogen atom or t-butyldimethylsilyl, but may also be tetrahydropyranyl or trimethylsilyl. Y is carbon number 1
~10 alkyl group or a cycloalkyl group having 5 or 6 carbon atoms. Specific examples include alkyl groups such as methyl, propyl, butyl, hexyl, nonyl, and decyl, alkenyl groups such as 2-propenyl, 2-putenyl, 2-pentenyl, and 2-octenyl, and cycloalkyl groups such as cyclopentyl and cyclohexyl. It will be done. Other reference examples that can be used as Y include phenyl, o-, m-,
p-, trifluoromethylphenyl, o-, m
-, p-, aryl group such as fluorophenyl, tolyl, or arylmethyl group, phenoxymethyl, p-fluorophenoxymethyl, o-, m
-, p-, aryloxymethyl such as trifluoromethylphenoxymethyl, and the like.

Therefore, specific examples of preferred compounds represented by [] above are as follows.
In addition, the compounds (4) to (6) and their derivatives are shown as reference examples.

(1) 9-oxo-14-hydroxynonadeca-5-
Cis-12-trans-dienoic acid (2) 14-cyclohexyl-14-hydroxy-9-
Oxotetradeca-5-cis-12-trans-
Dienoic acid (3) 9-oxo-14-hydroxynonadeca-5,
16-cis-12-trans-trienoic acid (4) 9-oxo-14-hydroxy-15-(m-trifluoromethyl)phenoxypentadeca-5
-cis-12-trans-dienoic acid (5) 9-oxo-14-hydroxy-15-p-fluorophenoxypentadeca-5-cis-12-trans-dienoic acid (6) 9-oxo-14- Hydroxy-15-m-chlorophenoxypentadeca-5-cis-12-trans-dienoic acid (7) The 14-hydroxyl group of (1) to (6) is a t-butyldimethylsilyl group or a tetrahydropyranyl group. Compounds protected by .

(8) Preferred examples include methyl ester, ethyl ester, t-butyl ester, sodium salt, and ammonium salt of the acids (1) to (6).

The secoprostaglandins of the present invention represented by the above formula [I] are represented by the following formula [] [In the formula, Z' represents a protecting group, and Y is the same as defined in the above formula. ] Ketones represented by the following formula [] [In the formula, X is a halogen atom, R' is a carbon number of 1 to
6 represents an alkyl group, and B is the same as defined above. ] Alkylated with a halide represented by
Then, if necessary, it is produced by deprotection, hydrolysis and/or reaction with a base.

In the above formula [], Z' is a protecting group, and the same ones as mentioned above can be mentioned, Y can be mentioned as the same ones as mentioned above, and Y is as mentioned above.

Further, in the above formula [], X is a halogen atom such as a bromine atom or a chlorine atom, B represents a double bond or a triple bond, and R' is an alkyl group having 1 to 6 carbon atoms, as described above. Examples include alkyl groups.

The above alkylation is usually accomplished by using a base to enolize and activate the ketones represented by [] above by a method known per se, and then reacting with a halide. As the base used here, lithium diethylamide, lithium diisopropylamide, lithium isopropylcyclohexylamide, potassium hydride, sodium hydride, etc. are usually preferably used. As the medium, ethers such as ether, tetrahydrofuran, and dioxane are preferably used.

After the ketones represented by the above formula [] are reacted with the above formula base, the reactivity of the resulting enolate is changed by adding trialkyl boron such as triethyl boron or triethanolamine borate, and then a halide is reacted. In order to carry out this reaction, which is also mentioned as a preferred reaction mode, dimethyl sulfoxide may be added in addition to the above medium. The alkylation reaction using boron compounds was carried out by Rathke et al.
Although this method was proposed as a method for suppressing polyalkylation, it can be fully applied to the alkylation reaction of the present invention (MWRathke, A. Lindert Syn.
Commun.), 8, 9, (1978)). The reaction temperature for the alkylation reaction is selected to be in the range of -78° to 40°C, preferably in the range of -20° to 20°C. The amount of the halide of formula [] to be used may be stoichiometric with respect to the ketone of formula [] as a raw material. The progress of the reaction is followed by the method of thin layer chromatography. The reaction time varies depending on the type of halide selected and the reaction temperature, but it is usually completed within 10 minutes to 3 hours. The reaction product can be purified by conventional means such as extraction, washing, chromatography, or a combination thereof.

In this way, in the secoprostaglandins represented by the above formula [I] of the present invention, A is an oxo group (=0), Z is a protecting group, and R has 1 to 1 carbon atoms.
Secoprostaglandins, which are the alkyl group of 6, are produced.

The secoprostaglandins thus obtained can be prepared by methods known per se (for example, E. J. Corey et al., Journal of American Chemical Society (J. Amer.
Chem.Soc), 94.6190 (1972)), secoprostaglandins in which Z is a hydrogen atom in the above formula [I] can be obtained.

Furthermore, secoprostaglandins in which R in the above formula [I] is a hydrogen atom are produced by hydrolyzing secoprostaglandins obtained by the method described above. Hydrolysis is achieved by reacting secoprostaglandins in an alkaline aqueous solution, such as an aqueous solution of lithium hydroxide, sodium hydroxide, or potassium hydroxide. In order to make the reaction proceed smoothly, ethers such as tetrahydrofuran and dioxane, and alcohols such as methyl alcohol and ethyl alcohol may be added. By neutralizing the reaction solution with an acid such as hydrochloric acid, sulfuric acid, or oxalic acid, and extracting the liberated carboxylic acid by a conventional method, secoprostaglandins in which R is a hydrogen atom in the above formula [I] are produced. You can.

The above-mentioned deprotection and hydrolysis reactions can be carried out in any order, and various secoprostaglandins can be obtained by doing so.

Furthermore, in the above formula [I], secoprostaglandins in which R is a pharmaceutically acceptable cation can be obtained by reacting the product (carboxylic acid) obtained after the above hydrolysis reaction with a base. As the base, lithium hydroxide, sodium hydroxide, potassium hydroxide aqueous solution, aqueous ammonia, etc. are preferably used. In the reaction, a product can be obtained by stoichiometrically mixing a carboxylic acid and a base, and removing the medium by distillation under reduced pressure or, if the medium is water, by freeze-drying.

In addition, the ketones represented by the above formula [] used as raw materials in the production method of the present invention are, for example, methyl vinyl ketone and the following formula [] [In the formula, L represents phenylthio or 1-pentynyl, n represents 1 or 2, and z' and y are the same as defined above. ] It can be obtained by reacting an organocopper lithium compound represented by: The thus obtained ketones represented by the above formula [] are isolated and purified,
By subjecting to the above-mentioned reaction, the above formula [I]
Secoprostaglandins represented by are obtained.

Therefore, the present invention also provides the following manufacturing method.

That is, methyl vinyl ketone has the above formula []
The organocopper lithium compound represented by the above formula [] is reacted, then the halide represented by the above formula [] is reacted, and then, if necessary, the compound is deprotected, hydrolyzed, and/or reacted with a base. This is a method for producing secoprostaglandins represented by I].

The organocopper lithium compound represented by the above formula [] used here is, for example, disclosed in Japanese Patent Application Laid-open No. 52-83524.
It can be prepared by the method described in the above publication.

That is, an anhydrous diethyl ether solution of copper pentylide obtained from 1-pentyne was obtained, and the formula [In the formula, Z' and Y are the same as defined above. ] It is obtained by dropping an organic lithium compound prepared from an iodo compound represented by the following formula and n-butyllithium.

Another method is to add an ether solution of phenylthiocopper and hexamethylphosphorus triamide to an ether solution of an organolithium compound prepared from the above-mentioned iodo compound and butyllithium. Ketones represented by the above formula [] are obtained by adding methyl vinyl ketone to the ether solution of the organocopper lithium compound thus obtained and stirring at a low temperature. After the reaction, it can be treated with water or a strong electrolyte aqueous solution such as an ammoniacal ammonium chloride solution, and isolated and purified by a conventional method.

Thus, in the secoprostaglandins of the present invention represented by the above formula [I], A is an oxo group (=0), Z is a protecting group, and R is an alkyl group having 1 to 6 carbon atoms. Various secoprostaglandins are produced by using such compounds and carrying out deprotection, hydrolysis, and reaction with a base in the same manner as described above.

The thus obtained secoprostaglandins represented by formula [I] are novel compounds and are expected to be used as pharmaceuticals. The compound of the present invention is easy to synthesize, can be produced at low production cost, and is expected to have an activity similar to that of conventional secoprostaglandins. It has the characteristic that it can also be considered a derivative of saturated fatty acids. The combination of these advantages is expected to provide effective oral and parenteral pharmaceuticals for the treatment and prevention of a variety of human and animal diseases. That is, the present invention has potential applications in the cardiovascular, renal, gastrointestinal and reproductive systems, and in the control of lipid metabolism, inflammation, blood coagulation, platelets, skin diseases and certain cancers, and the regulation of immune function. Provides extremely useful compounds.

The present invention will be explained below with reference to examples, but the following examples are given for the purpose of illustrating the present invention, and the present invention is not limited thereto.

Example 1 256μ of n-butyllithium was added to a solution of 40mg of diisopropylamine in tetrahydrofuran at -78°C and reacted for 30 minutes, followed by 7(S)-t-butyldimethylsiloxide deca-5-trans-ene-2-
Add 1 ml of tetrahydrofuran solution containing 120 mg of
After reacting at -78°C for 15 minutes, the mixture was stirred at room temperature for 2 hours. After adding 0.39 ml of triethylboron (1M tetrahydrofuran solution) and stirring at room temperature for 10 minutes, methyl 7-iodo-5-cis-heptenoate was added.
1133.5 mg was added and reacted for 2 hours. ether 30
ml, washed with saturated NH ₄ Cl, then saturated NaCl, dried over MgSO ₄ and evaporated under reduced pressure.
85:15) twice, and the target methyl 9-oxo-14(S)-t-butyldimethylsiloxynonadeca-5-cis-12-trans-dienoate was extracted from the portion corresponding to Rf0.48. Obtained 40 mg. The physical properties of this product were as follows.

NMR (CDCl ₃ ) δ; 3.63 (3H, s), 3.63−4.15 (1H, m), 5.35
(4H, m) MS (20 eV) m/s; 437 (M ⁺ -15), 395 Example 2 0.45 ml of N-butyllithium (1.4 M solution) and 65 mg of diisopropylamine in 2 ml of tetrahydrofuran at -78°C. Lithium diisopropylamide solution obtained by conditioning for 10 minutes at -78℃
Butyldimethylsiloxide deca-5-trans-
150 mg of en-2-one was added dropwise, then at -78°C.
Stirred for 10 minutes and at -20°C for 5 minutes. To this, 7-
180 mg of methyl iodo-5-cis-heptenoate was added, and the mixture was allowed to react while gradually lowering the temperature from -20°C to room temperature over about 1 hour. The reaction solution was treated in a conventional manner to obtain 268 mg of a crude product. this thing
Developed twice with TLC (silica gel; cyclohexane: ethyl acetate = 85:15), and from the part corresponding to Rf0.48, the desired 9-oxo-14-t-butyldimethylsiloxynonadeca-5-cis-12 40 mg of methyl -trans-dienoate was obtained. The physical properties of this product were almost the same as those obtained in Example 1.

Example 3 67 mg of the ketone obtained in Example 1, 1.5 ml of acetic acid, 0.7 ml of tetrahydrofuran, and 0.7 ml of H ₂ O were stirred at room temperature overnight and treated in a conventional manner to obtain 50 mg of 9-oxo-14.
Methyl -(S)-hydroxynonadeca-5-cis-12-trans-dienoate was obtained.

NMR (CCl ₄ ) δ; 3.60 (3H, s), 3.8−4.1 (1H, m), 5.2−5.6
(4H, m) IE (coating); 3400, 1740, 1720 cm ^-1 Example 4 After reacting 50 mg of the keto alcohol obtained in Example 3 with 1 ml of methanol and 0.5 ml of 1N NaOH at room temperature for 5 hours, ether Add hexane (10 ml - 10 ml), add 0.7 ml of 1NHCl, separate the organic layer, wash with saturated brine (2 times 3 ml), and add MgSO ₄
After drying and distilling it off under reduced pressure, it was purified by TLC (cyclohexane-ethyl acetate-acetic acid 40:60:20).
43 mg of 9-oxo-14(S)-hydroxynonadeca-5-cis-12-trans-dienoic acid was obtained.

NMR ( _CDCl3 ) δ; 3.8-4.2 (1H, m), 5.2-5.7 (4H, m), 6.7
(2H, m) Reference example 1 3(R)-t-butylmethylsiloxy-1-iodo-1-trans-octene (1.84 g,
t-butylithium (1.9M pentane solution, 5.3ml,
10 mmol) was added thereto and stirred at -78°C for 2 hours. It contains phenylthiocopper (1) (863 mg, 5.0 mmol) and hexamethylsulfolastramide (1.63 g, 1.82
ml, 10 mmol) in ether solution (5 ml) -
It was added at 78°C and stirred for 1 hour. Add freshly distilled methyl vinyl ketone (420 mg, 0.49 ml,
6.0 mmol) in ether solution (3 ml) was added to -40°C.
The reaction was carried out for 1 hour. Add saturated ammonium chloride aqueous solution, extract with ether, and dry (MgSO ₄ )
After that, the crude product obtained by concentration was subjected to silica gel chromatography (hexane:ether solution = 9:1).
7(R)-t-butyldimethylsiloxide deca-5-trans-en-2-one (644 ml,
2.06 mmol, 41.3%) was obtained.

NMR (CCl ₄ , 60MHz, ppm); 0.086 (6H, s), 0.84 (12H, bs), 1.27 (8H,
m) 2.06 (3H, s), 2.2~2.5 (4H, m), 3.95
(1H, m), 5.3-5.5 (2H, m).

1R (neat, cm ^-1 ); 1720, 1460, 1360, 1260, 1080, 975, 840,
780 Example 5 Potassium hydride (23% content, 522 mg, 3.0 mmol)
was suspended in 30 ml of dry pentane and washed with mineral oil. 7(R)-t-butyldimethylsiloxide deca-5-trans-en-2-one (644 mg, 2.06 mmol) in tetrahydrofuran (3
ml) solution and stirred at room temperature for 20 minutes. Then triethylborane (1M solution in tetrahydrofuran)
4.0ml, 4.0mmol) and stirred at room temperature for 10 minutes.
A 2 ml tetrahydrofuran solution of methyl 7-bromo-5-cis-heptenoate (546 mg, 2.47 mmol) was added thereto, and the mixture was reacted at room temperature for 2 hours. Brine was added to the reaction solution, extracted with ethyl acetate, dried (MgSO ₄ ), and concentrated to obtain 1.02 g of a crude product. This product was subjected to preparative thin layer chromatography (hexane: ether solution = 3:1) to separate the product, Rf0.04 (hexane: ether solution = 4:1)
The desired product 14(R)-
Methyl t-butyldimethylsiloxy-9-oxononadeca-5-cis-12-trans-dienoate (163 mg, 0.361 mmol, 17.5%) was obtained.

NMR (CCl ₄ ) δ; 0.02 (6H, s), 0.82 (12H, bs), 1.23−
(10H, m), 1.8~2.35 (12H, m), 3.53 (3H,
s), 3.90 (1H, m), 5.2-5.4 (4H, m).

1E (painted); 1740, 1720, 1440, 1360, 1250, 1205,
1170, 1080, 970, 840, 780 cm ^-1 Example 6 14(S)-t-butyldimethylsiloxy-9-oxononadeca-5-cis-12 obtained in Example 5
-Methyl trans-dienoate (163 mg,
0.361 mmol) in the same manner as in Example 3, acetic acid (3 ml),
It was dissolved in THF (1 ml) and water (1 ml) and stirred at room temperature for 20 hours. Toluene was added and concentrated under reduced pressure, and 192 mg of the obtained crude product was subjected to preparative thin layer chromatography (hexane: ethyl acetate = 2:1) to isolate 14(R)-hydroxy-9-oxononadeca-
Methyl 5-cis-12-trans-dienoate (66
mg, 0.195 mmol, 54.0%).

NMR (CDCl ₃ ) δ; 0.86 (3H, m), 1.3 (10H, m), 1.8-2.5
(12H, m), 4.00 (1H, m), 5.2~5.6 (4H,
m), 6.03 (2H, bs).

IE (painted); 3460, 1735, 1710, 1435, 1360, 1245,
1215, 1160, 970 cm ^-1 Example 7 14(S)-hydroxy-9- obtained in Example 6
Methyl oxononadeca-5-cis-12-trans-dienoate (66 mg, 0.195 mmol) was dissolved in methanol (3 ml) in the same manner as in Example 4, 1.0N caustic soda (1 ml, 1 mmol) was added, and the reaction was allowed to rise to room temperature for 3 hours. Ta. After distilling off methanol, neutralize with aqueous oxalic acid solution, extract with ethyl acetate, dry (MgSO ₄ ),
Concentrated to give 14(R)-hydroxy-9-oxononadeca-5-cis-12-trans-dienoic acid (62 mg,
0.191 mmol, 98.1%) was obtained.

NMR (CDCl ₃ ) δ; 0.86 (3H, m), 1.3 (10H, m), 1.8-2.5
(12H, m), 4.00 (1H, m), 5.2~5.6 (4H,
m), 6.03 (2H, bs).

Reference Example 2 In the same manner as Reference Example 1, 3(R)-t-butyldimethylsiloxy-3-cyclohexyl-1-iodo-1-trans-propene ([α] _D ¹⁸ =19.5°627
mg, 1.65 mmol) to 157 mg (0.48 mmol, 29.4%)
7(S)-t-butyldimethylsiloxy-7-cyclohexylhept-5-trans-ene-2-
Got it on.

NMR ( _CDCl3 , 60MHz, ppm); 0.08 (6H, s), 0.85 (9H, s), 0.9-1.9
(11H, m) 2.08 (3H, s), 2.15~2.50 (4H,
m), 3.67 (1H, m), 5.3-5.5 (2H, m).

1R (neat, cm ^-1 ); 1720, 1640, 1450, 1360, 1250, 1090,
1050, 835, 775.

Example 8 In the same manner as in Example 1, n-butyllithium (1.56M, 0.32ml, 0.5mmol) and diisopropylamine (61mg, 0.6mmol) were dissolved in THF (3ml).
7(S)-t-butyldimethylsiloxy-7-cyclohexylhept-5- was added to the lithium diisopropylamide solution obtained by reacting at 78°C for 30 minutes.
Trans-en-2-one (157mg, 0.48mmol)
A THF (3 ml) solution of was added dropwise at -78°C, stirred for 15 minutes, and then stirred at room temperature for 1 hour.

To this reaction solution, methyl 7-iodo-5-cis-heptenoate (162 mg, 0.6 mmol) was added to THF (1 ml).
The solution was added and stirred at room temperature for 1 hour.

The same post-treatment as in Example 1 was carried out to obtain 307 mg of crude product, which had an RF of 0.35 (hexane: ethyl acetate = 9:1) for preparative thin layer chromatography (hexane: ethyl acetate = 85:15). ), the desired methyl 14(R)t-butyldimethylsiloxy-14-cyclohexyl-9-oxonotetradeca-5-cis-12-trans-dienoate (93 mg, 0.20 mmol, 41.8 %) was obtained.

NMR (CCl ₄ ) δ; 0.02 (6H, s), 0.83 (9H, s), 0.9-1.9
(13H, m), 1.9-2.4 (12H, m), 3.51 (3H,
s), 3.69 (1H, m), 5.2-5.7 (4H, m).

IE (painted); 1740, 1720, 1440, 1360, 1250, 1095, 965,
840, 780 cm ^-1 Reference Example 3 In the same manner as Reference Example 1, 3(R)-t-butyldimethylsiloxy-3-cyclohexyl-1-iodo-1-trans-propene ([α] _D ¹⁸ = +26.7° ，
627mg, 1.65mmol) to 162mg (0.5mmol, 30.3
%) of 7(S)-t-butyldimethylsiloxy-7
-cyclohexylhept-5-trans-ene-
2-on was obtained.

NMR ( _CDCl3 , 60MHz, ppm); 0.08 (6H, s), 0.85 (9H, s), 0.9-1.9
(11H, m) 2.08 (3H, s), 2.15~2.55 (4H,
m), 3.67 (1H, m), 5.3-5.5 (2H, m).

1R (neat, cm ^-1 ); 1720, 1640, 1450, 1360, 1255, 1095,
1050, 835, 775 cm ^-1 .

Example 9 In the same manner as in Example 1, n-butyllithium (1.56M, 0.32ml, 0.5mmol) and diisopropylamine (50mg, 0.5mmol) were mixed in THF (3ml).
7(R)-t-butyldimethylsiloxy-7-cyclohexylhept-5- was added to the lithium diisopropylamide solution obtained by reacting at 78°C for 30 minutes.
Trans-en-2-one (162mg, 0.5mmol)
A THF (1.5 ml) solution of was added dropwise at -78°C, stirred for 15 minutes, and then stirred at room temperature for 1 hour. Add methyl 7-iodo-5-cis-heptenoate (162 mg,
Add a solution of 0.6 mmol) in THF (1 ml) and stir at room temperature.
Stir for hours. Perform the same post-processing as in Example 1.
321 mg of crude product was obtained, and the desired product was obtained from the fraction corresponding to Rf0.35 (hexane: ethyl acetate = 9:1) for preparative thin layer chromatography (hexane: ethyl acetate = 4:1). Methyl 14(R)t-butyldimethylsiloxy-14-cyclohexyl-9-oxonotetradeca-5-cis-12-trans-dienoate (22 mg, 0.047 mmol, 9.5%) was obtained.

NMR (CCl ₄ ) δ; 0.01 (6H, s), 0.84 (9H, s), 0.9-1.9
(13H, m), 1.9-2.4 (12H, m), 3.56 (3H,
s), 3.69 (1H, m), 5.2-5.5 (4H, m).

IE (painted); 1740, 1720, 1440, 1255, 1100, 970, 840,
780cm ^-1 Example 10 Methyl 14(R)t-butyldimethylsiloxy-14-cyclohexyl-9-oxonotetradeca-5-cis-12-trans-dienoate obtained in Example 9 (22 mg, 0.047 mmol ) in the same manner as in Example 3, acetic acid (1 ml), THF (0.33 ml), water (0.33 ml)
It was dissolved in water and left at room temperature for 4 days. 15 mg of the concentrate was subjected to preparative thin layer chromatography (hexane:ethyl acetate = 2:1) to isolate 14(R)-hydroxy-14-cyclohexyl-9-oxotetradeca-5-cis-12-trans-diene. Methyl acid (13 mg, 0.037 mmol, 79.0%) was obtained.

NMR (CCl ₄ ) δ; 0.85-1.9 (13H, m), 1.9-2.6 (12H, m),
3.56 (3H, s), 3.63 (1H, m), 5.2-5.55
(4H, m).

IR (CCl ₄ solution); 3430, 1740, 1720, 1455, 1440, 1255,
1175, 1010, 980 cm ^-1 MS (20 eV) m/s; 350 (M ⁺ ), 332 (M-H ₂ O).

Example 11 14(R)-hydroxy-14- obtained in Example 10
Methyl cyclohexyl-9-oxotetradeca-5-cis-12-trans-dienoate (13 mg,
0.037 mmol) in the same manner as in Example 4 and Example 7.
It was dissolved in THF (2 ml), water (2 ml), and 2.0N caustic soda aqueous solution (0.1 ml, 0.2 mmol) and reacted at room temperature for 20 hours. After concentration, neutralize with oxalic acid aqueous solution,
The liberated acid was extracted with ethyl acetate, dried and concentrated to give almost pure 14(R)-hydroxy-14-cyclohexyl-9-oxotetradeca-5-cis-12-.
Trans-dienoic acid (10mg, 0.030mmol, 80.5
%) was obtained.

NMR ( _CDCl3 ) δ; 0.8-2.0 (13H, m), 2.1-2.5 (12H, m),
3.8 (1H, m), 4.8 (2H, bs), 5.2~5.6 (4H,
m).

Claims (1)

[Claims] 1. The following formula [] [In the formula, A represents an oxygen atom, B represents a double bond (-CH=CH-), Y represents an alkyl group having 1 to 10 carbon atoms or a cycloalkyl group having 5 or 6 carbon atoms, and R is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable cation, and Z
is a hydrogen atom or t-butyldimethylsilyl. ] Secoprostaglandins shown by. 2. The secoprostaglandins according to claim 1, wherein in the above formula [], R is a hydrogen atom. 3. The secoprostaglandins according to claim 1, wherein in the above formula [I], R is a methyl group. 4. The secoprostaglandins according to claim 1, wherein in the above formula [I], R is an alkali metal cation. 5 Claims 1 to 4, wherein in the above formula [I], Y is an alkyl group having 1 to 10 carbon atoms.
Secoprostaglandins according to any one of paragraphs. 6 Any one of claims 1 to 4, wherein in the above formula [I], Y is a pentyl group
Secoprostaglandins as described in Section. 7. The secoprostaglandins according to any one of claims 1 to 4, wherein in the formula [I], Y is a cyclohexyl group. 8. The secoprostaglandins according to any one of claims 1 to 7, wherein in the above formula [I], Z is a hydrogen atom.