JPH0257549B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 7-hydroxyprostacyclin derivatives. More specifically, the present invention uses a 7-hydroxyprostaglandin _F2α derivative as a raw material, reacts it with a mercury compound, and then treats it with a borohydride compound. The present invention relates to a method for efficiently producing 7-hydroxyprostacyclin derivatives, which are also important as intermediates for the synthesis of pharmaceuticals.

Prostacyclin is a compound that is attracting attention due to its useful physiological activities, such as platelet aggregation inhibitory activity, antihypertensive activity, antiulcer activity, and antiasthma activity. , one of the difficulties is that they have various physiological activities. Furthermore, the enol ether bond contained in prostacyclin's skeleton is extremely susceptible to hydrolysis by water, and this is also a cause of difficulty in developing prostacyclin as a medicinal product.

The present inventors focused on this point and found that 7-hydroxyprostacyclin derivatives with a hydroxyl group introduced at the 7-position exhibit extremely high resistance to hydrolysis [Sakauchi et al., Tetrahedron Letters] (Tetrahedron Letters), 22, 1417
~1420 (1981)].

Furthermore, by reacting the 7-hydroxyprostacyclin derivative with a fluorinating reagent such as diethylacinosulfate trifluoride, a fluorine atom can be introduced at the 5- or 7-position, and the resulting 5- or The 7-fluoroprostacyclin derivative was found to be extremely stable and highly active, and a separate application has already been filed (see the figure below).

7-Hydroxyprostacyclin derivatives, which are themselves useful as stable prostacyclin derivatives and are also useful as raw materials that can lead to other stabilized prostacyclin derivatives such as fluorinated prostacyclin derivatives, can be obtained by the following reaction. It is produced from prostacyclin by the route shown by the formula (Japanese Patent Application Laid-Open No. 57-95980).

This production method involves a large number of steps and requires multiple steps to obtain prostacyclin used as a raw material compound, making it difficult to obtain. Therefore, the above production method cannot be used as a method for producing 7-hydroxyprostacyclin derivatives. This is not industrially satisfactory.

Therefore, the present inventor conducted intensive research on a method for efficiently producing 7- _{hydroxyprostacyclin} derivatives using easily available raw material compounds. It was discovered that the desired 7-hydroxyprostacyclin derivative can be more easily produced than the 7-hydroxyprostaglandin F ₂ α derivative by reacting the compound with a mercury compound and then treating the compound with a borohydride compound. This invention has been achieved.

In other words, the following formula [] [In the formula, G is -CO ₂ R ⁵ , R ⁵ is a hydrogen atom,
_C1 - _C10 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted alicyclic group, substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group or tri( _C1 - _C7) ) is a hydrocarbon-silyl group; R ¹ is a hydrogen atom or a methyl group; R ² is an unsubstituted C ₅ - C ₈ alkyl group, a substituted or unsubstituted alicyclic group, or a substituted or unsubstituted alicyclic group; Good phenyl group, phenoxy group C ₁ - C ₆ alkyl group or
A substituted _C1 - _C5 alkyl group substituted with a _C5 - _C6 cycloalkyl group; ^R3 and ^R4 are the same or different, hydrogen atom, _C2 - _C7 acyl group, tri(C ₁ to _C7 ) hydrocarbon-silyl group or 1-alkoxyalkyl group. The bonds (substituents) at the 8th and 9th positions on the cyclopentane ring are cis. ] 7-hydroxyprostaglandin represented by
reacting the F ₂ α derivative with a mercuric carboxylic acid salt, mercury halide or mercury oxide in an inert organic medium;
The following formula [], which is then treated with a borohydride compound [In the formula, G, R ¹ , R ² , R ³ and R ⁴ are the same as defined above. ] This is a method for producing a 7-hydroxyprostacyclin derivative represented by the following.

The 7-hydroxyprostaglandin F ₂ α derivative represented by the above formula [], which is the raw material compound in the production method of the present invention, has four carbon atoms (8, 9, 11, 12 positions) and 7-position of the cyclopentane ring. 15th place 2
Two carbons are asymmetric carbons, but among these, the bonds (substituents) at the 8th and 9th positions on the cyclopentane
includes all diastereoisodies and epimers other than those in trans relationship with each other.
Since the chemical reaction in the production method of the present invention can be fully predicted to proceed without conformational change,
The conformation of the resulting 7-hydroxyprostacyclin derivative represented by the formula [] is exactly the same as that of the compound of the formula [], that is, the derivative of 7-hydroxyprostaglandin F ₂ α. Become.

G represents -CO ₂ R ⁵ , where R ⁵ is a hydrogen atom,
_C1 - _C10 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted alicyclic group, substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group or tri( _C1 - _C7) ) is a hydrocarbon-silyl group.

Examples of C ₁ to _{C 10} alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n
-Butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and other linear or branched ones can be mentioned.

Substituents for substituted or unsubstituted phenyl groups include, for example, halogen atoms, hydroxy groups, C ₂
~ _C7 acyloxy group, _C1 to _C4 alkyl group optionally substituted with a halogen atom, _C1 to _C4 alkoxy group optionally substituted with a halogen atom,
A nitrile group, a carboxyl group, a ( _C1 - _C5 ) alkoxycarbonyl group, etc. are preferred. The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine. Examples of the C ₂ to C ₇ acyloxy group include acetoxy, propionyloxy, n
-butyryloxy, iso-butyryloxy, n-
Mention may be made of valeryloxy, iso-valeryloxy, caproyloxy, enantyloxy or benzoyloxy.

Examples of C ₁ to C ₄ alkyl groups optionally substituted with halogen include methyl, ethyl, n-propyl, iso-propyl, n-butyl, chloromethyl,
Preferred examples include dichloromethyl and trifluoromethyl. Preferred examples of the _C1 - _C4 alkoxy group which may be substituted with halogen include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, chloromethoxy, dichloromethoxy, trifluoromethoxy, etc. be able to.
Examples of the ( _C1 - _C6 ) alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl,
Examples include butoxycarbonyl and hexyloxycarbonyl.

The substituted phenyl group has 1 to 3 substituents as described above.
, preferably one.

Substituted or unsubstituted alicyclic groups include saturated or unsaturated _C5 -C8, preferably _C5 - _C8 , substituted with the same substituents as above or unsubstituted.
Mention may be made of C ₆ , particularly preferably C ₅ groups, such as cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl and the like.

Examples of the substituted or unsubstituted phenyl ( _C1-2 ) alkyl group include benzyl, α-phenethyl, and β _- phenethyl, in which the phenyl group is substituted with the same substituent as mentioned above or unsubstituted.

As a tri(C ₁ - C ₇ ) hydrocarbon silyl group,
For example, trimethylsilyl, triethylsilyl, t
- Tri(C ₁ to _{C 4} ) such as butyldimethylsilyl group
Diphenyl(C ₁ -C ₄ )alkylsilyl, such as alkylsilyl, t-butyldiphenylsilyl group,
tribenzylsilyl group or dimethyl-(2,4,
Preferred examples include 6-tri-t-butylphenoxy)silyl group.

G is preferably -CO ₂ R ⁵ in which R ⁵ is a C ₁ -C ₁₀ alkyl group, especially a methyl group.

R ¹ is a hydrogen atom or a methyl group. Preferred examples of the protected ethynyl group include trimethylsilylethynyl and t-butyldimethylsilylethynyl groups. Among these, a hydrogen atom or a methyl group is preferred.

R ² is an unsubstituted C ₅ - C ₈ alkyl group; an optionally substituted phenyl group, phenoxy group, C ₁ -
A substituted C1 _{- C5 alkyl group substituted with a C6 alkoxy} group or a _C5 - _C6 cycloalkyl group; or a substituted or unsubstituted alicyclic group. _C5 ～
The C ₈ unsubstituted alkyl group may be linear or branched, such as n-pentyl, n-hexyl, 2-methyl-1-hexyl, 2-methyl-2-hexyl, n-heptyl,
n-octyl etc., preferably n-pentyl, n-
Examples include hexyl, 2-methyl-1-hexyl, 2-methyl-2-hexyl, and the like. replacement
The _C1 - _C5 alkyl group may be linear or branched, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl,
Examples include sec-butyl, t-butyl, n-pentyl and the like. These substituted alkyl groups are
Phenyl group; Phenoxy group; _C1 to _C6 alkoxy groups such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, n-pentoxy, n-hexoxy; cyclopentyl, cyclohexyl etc.
Substituted with _C5 - _C6 cycloalkyl groups. These substituents may be further substituted with the substituents listed as substituents for the substituted phenyl group of R ⁵ .

Examples of the substituted C1-C5 alkyl group include _C1 - _C5 alkyl groups substituted with a phenoxy group or a phenyl group, which may be substituted with a fluorine atom, a chlorine atom, methyl, ethyl or _{trifluoromethyl} group. C ₂ alkyl group, or propoxymethyl,
Ethoxyethyl, propoxyethyl, ptoxymethyl, methoxypropyl, 2-ethoxy-1,1
-dimethylethyl, proboxydimethylmethyl,
Alternatively, cyclohexylmethyl, cyclohexylethyl, cyclohexyldimethylmethyl, 2-cyclohexyl-1,1-dimethylethyl, etc. are preferable.

As the substituted or unsubstituted alicyclic group, the same ones listed for R ⁵ can be mentioned.

R ² is n-pentyl, 2-methyl-1
-Hexyl, cyclopentyl or cyclohexyl group is preferred.

R ³ and R ⁴ are the same or different, a hydrogen atom,
It is a group that forms an acetal bond with the oxygen atom of a _C2 - _C7 acyl group, a tri( _C1 - _C7 ) hydrocarbon-silyl group, or a hydroxyl group, that is, a 1-alkoxyalkyl group.

Examples of C ₂ to C ₇ acyl groups include acetyl,
propionyl, n-butyryl, iso-butyryl,
Examples include n-valeryl, iso-valeryl, caproyl, enantyl, benzoyl and the like.

Among these, _C2 - _C6 aliphatic acyl groups such as acetyl, n- or iso-butyryl, caproyl,
Or benzoyl is preferred.

As a tri(C ₁ - C ₇ ) hydrocarbon-silyl group,
The same things as those listed in R ⁵ can be mentioned.

Examples of groups that form an acetal bond with the oxygen atom of a hydroxyl group include methoxymethyl, 1-ethoxyethyl, 2-methoxy-2-propyl, 2
-Ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl,
Mention may be made of the 4-(4-methoxy-tetrahydropyranyl) group or the 6,6-dimethyl-3-oxa-2-oxo-bicyclo[3.1.0]hex-4-yl group. Among these, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-methoxy-2-propyl,
Particularly preferred are the (2-methoxyethoxy)methyl, 4-(4-methoxytetrahydropyranyl) group or the 6,6-dimethyl-3-oxa-2-oxo-bicyclo[3.1.0]hex-4-yl group.

These silyl groups, acyl groups, and groups forming acetal bonds are hydroxyl group-protecting groups.

It should be understood that

Among these, R ³ and R ⁴ include t-butyldimethylsilyl group, 2-tetrahydropyranyl group,
Acetyl group and 1-methyl-1-hexyl group are preferred.

7-hydroxyprostaglandin F ₂ α represented by the above formula [] used as a raw material compound
The derivative can be easily produced by a method separately filed by the present inventors (see the figure below).

[In the formula, R ¹¹ is the same as R ¹ , R ³¹ is a group with a hydrogen atom removed from R ³ , R ⁴¹ is a group with a hydrogen atom removed from R ⁴ , G ¹ is -CO ₂ R ⁵¹ , and R ⁵¹ is a group obtained by removing a hydrogen atom from ^R5 . ] The 7-hydroxyprostaglandin F ₂ α derivative represented by the above formula [] is dissolved in an inert organic medium,
By reacting with a mercury compound and then treating with a borohydride compound, the desired 7-hydroxyprostacyclin derivative [] can be obtained. The inert organic medium used at this time is:
Aprotic organic media such as ethyl ether,
Ether-based organic media such as isopropyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and halogenated hydrocarbon-based organic media such as chloroform, methylene chloride, and carbon tetrachloride are preferably used. As the mercury compound, carboxylic acid mercury salts, mercury halides, and mercury oxides are preferably used. Examples of carboxylic acid mercury salts include mercury acetate, mercury trifluoroacetate, etc.
Examples of mercury halides include mercury chloride, mercury bromide, and mercury iodide. Among these, mercury acetate, mercury trifluoroacetate, and mercury chloride are particularly preferred. The mercury compound is used in an amount of 0.9 to 5 times, preferably 1.0 to 3 times, the amount of the 7-hydroxyprostaglandin F ₂ α derivative serving as the raw material substrate. The reaction temperature is -50°C to 100°C, preferably -30°C to 50°C. The reaction time usually ranges from 5 minutes to 2 hours. The reaction is carried out by adding to a solution or mixture of the mercury compound in an inert organic medium a source substrate or a solution of the source substrate dissolved in the same or different inert organic medium used to dissolve the mercury compound, or vice versa. It starts depending on how you add it. It is thought that an intermediate represented by the following formula [A] is probably produced by this first-stage reaction.

[In the formula, G, R ¹ to ^{R 4} are the same as defined above, and X represents a mercury counter anion. ] 7-Hydroxyprostaglandin of formula []
The F ₂ α derivative is reacted with a mercury compound in an inert organic medium and then treated with a borohydride compound.
It is thought that the HgX residue of the compound of formula [A] is reductively eliminated by such treatment.

The mercury compound used here has the following formula [] M(R ₈ H) ₄ -mBHm ... [] [In the formula, M is an alkali metal atom and R ₈ is C _1
-C6 alkyl group, _C1 - _C6 alkoxy group or cyano group, and m is an integer of 1-4. ] A borohydride compound represented by these is preferred. Here, M is preferably an alkali metal atom such as sodium, potassium, or lithium, and _R8 is, for example, methyl, ethyl, n-
_C1 - _C6 alkyl groups such as propyl, n-butyl, sec-butyl, n-pentyl group (amyl group); C1 _{- C6} alkoxy groups such as methoxy, ethoxy, propoxy, butoxy groups are preferred. Can be mentioned. Examples of such borohydride compounds include sodium borohydride, lithium borohydride, lithium triethylborohydride, sodium triethylborohydride, and tri-sec hydride.
―Sodium butylboronate, hydrogenated tri-sec―
Lithium butyl boron, potassium tri-sec-butyl boron hydride, potassium trisamyl boron hydride, sodium trimethoxy boron hydride,
Examples include lithium trimethoxyborohydride, sodium triethoxyborohydride, lithium triethoxyborohydride, sodium tripropoxyborohydride, sodium cyanoborohydride, and the like. Among these, sodium borohydride, sodium trimethoxyborohydride, and sodium triethoxyborohydride are particularly preferred.

The amount of such borohydride compound to be used is determined by the formula []
The molar amount is usually 1 to 50 times that of the 7-hydroxyprostaglandin F ₂ α derivative.

The treatment with the borohydride compound, ie the reductive mercury (HgX) elimination reaction, is carried out in the same inert organic medium, preferably a protic medium, used in the first stage reaction with the mercury compound. Examples of the protic medium include methyl alcohol, ethyl alcohol, isopropyl alcohol, water, and mixtures thereof.

When treating with a borohydride compound, the following method is employed.

That is, the inert organic medium used in the first step may be removed using a method such as distillation under reduced pressure, and then the protic medium may be added, or the protic medium may be added without performing the removal operation. Good too. At this time, preferably 1/3 to 10 times (volume) of the protic medium is used as compared to the inert organic medium used in the first step. When using water as the protic medium, for example, alkaline water prepared using sodium hydroxide or the like may be used.
The reaction time is usually 30 minutes to 24 hours.

The crude reaction product thus obtained may be post-treated according to a commonly used method. For example, by adding a sparingly soluble organic solvent to water such as hexane, pentane, petroleum ether, or ethyl ether, or by directly concentrating the reaction mixture under reduced pressure and performing the same procedure, the resulting organic mixture is washed with brine and then sulfuric anhydride is added. After drying with a desiccant such as magnesium, anhydrous sodium sulfate, or anhydrous potassium carbonate, the organic medium is removed under reduced pressure to obtain a crude product. The crude product can be purified, if desired, by a purification means such as column chromatography, thin layer chromatography, liquid chromatography, or the like. In this way, the 7-hydroxyprostacyclin derivative represented by the above formula [] can be easily and efficiently produced.

Specific examples of the 7-hydroxyprostacyclin derivatives produced according to the present invention include the following.

(1) 7-hydroxyprostacyclin (2) 15-cyclopentyl-7-hydroxyprostacycline (3) 15-cyclohexyl-7-hydroxyprostacycline (4) 17-methyl-7-hydroxyprostacyclin (5) 15-methyl -7-Hydroxyprostacyclin (6) Methyl ester of (1) to (5) (7) Ethyl ester of (1) to (5) (8) 11,15-bis-t-butyldimethylsilyl of (6) Ether (9) The 11th position of (6) is protected with a methoxyisopropyl group, the 15th position is protected with a t-butyldimethylsilyl group (10) The 11th position of (6) is a t-butyldiphenylsilyl group,
Compound (11) in which the 15th position is protected with a t-butyldimethylsilyl group (11) Compound in which the 11th position of (6) is protected with a 4-(4-methoxytetrahydropyranyl) group and the 15th position is protected with a t-butyldimethylsilyl group (12) The 11th position of (6) is dimethyl (2,4,6-tri-t
-butylphenyloxy)silyl group, 15th position is t
- Compound protected with butyldimethylsilyl group.

The present invention is useful as a stabilized prostacyclin derivative, and is also useful as a manufacturing raw material that can lead to other stabilized prostacyclin derivatives, such as 7-fluoroprostacyclin derivatives and 5-fluoroprostacyclin derivatives.
-Hydroxyprostacyclin derivatives, easily obtained 7-hydroxyprostaglandins
This provides a method for producing F ₂ α derivatives more simply and efficiently, and its significance is immeasurable in producing useful pharmaceuticals.

The present invention will be explained below with reference to Examples, but is not limited thereto.

Example 1 (7S, 8R, 9S, 11R, 15S) - 200 mg of 11,15-bis-t-butyldimethylsilyl ether of 5,6-dehydro-7-hydroxyprostaglandin F ₂ α methyl ester was added to 40 mg of tetrahydrofuran.
ml of mercury trifluoroacetate () in tetrahydrofuran under ice-cooling under an argon atmosphere.
ml solution. After removing the ice bath and allowing the reaction to proceed at room temperature for 10 minutes, 4 ml of methanol and 62 mg of sodium borohydride were added again under ice cooling. When the addition was completed, the ice melt was removed and the mixture was stirred for 1 hour. The mixture was passed through Celite. Add 150 ml of ether, wash 3 times with saturated brine, dry distillate over anhydrous potassium carbonate-anhydrous magnesium sulfate, and transfer the resulting oil to a Florisil column (n-hexane-ethyl acetate-1% triethylamine 97/
3) Purify (7S, 8R, 9S, 11R, 15S) -7
-116 mg of 11,15-bis-t-butyldimethylsilyl ether of hydroxyprostacyclin methyl ester was obtained.

The spectral data of this product were as follows.

'H-nmr (CDCl ₃ ) δ; 5.48 (2H, m), 4.75 (1H, m) 4.46 (1H, t, J = 7Hz), 4.27 (1H.s), 4.07 (1H, m), 3.83 ( 1H, m), 3.66 (3H, s). C-13nmr (ppm); 174.4, 158.7, 135.9, 128.6, 99.2, 82.7, 77.9, 77.5, 72.8, 53.5, 51.4, 41.6, 38.5, 33.6, 31.8, 25.9, 25.8, 25.1, 25.0, 24.7, 22 .6，18.2 , 18.0, 14.0, -4.7, -4.6, -4.5, -4.2. Mass (trimethylsilyl ether) 70eV m/e; 682 (M ⁺ ), 625, 551, 535, Example 2 (7R, 8R, 9S, 11R, 15S) - 95 mg of 11,15-bis-t-butyldimethylsilyl ether of 5,6-dehydro-7-hydroxyprostaglandin F ₂ α-methyl ester was added to 2 mL of tetrahydrofuran.
ml and treated in the same manner as in Example 1 using a solution of 73 mg of mercury trifluoroacetate in 1.5 ml of tetrahydrofuran.The obtained crude product was subjected to florisil column chromatography (n-hexane-
Ethyl acetate - Purify with 1% triethylamine 100/1 and target (7R, 8R, 9S, 11R, 15S)
54 mg of 11,15-bis-t-butyldimethylsilyl ether of -7-hydroxyprostacyclin methyl ester was obtained. The spectral data of this product were as follows.

H-nmr (CDCl ₃ ) δ; 5.38 (2H, m), 4.73 (1H, m), 4.50 (1H, d, J = 9Hz), 4.39 (1H, t, = 7Hz), C-13nmr (ppm) ; 174.3, 158.9, 134.9, 129.6, 97.4, 85.2, 78.9, 73.2, 71.9, 51.4, 50.2, 49.9, 41.9, 38.3, 33.7, 31.8, 25.9, 25.2, 25.0, 24.7, 22.6, 18.3, 14. 0, ―4.2, -4.6, -5.0 Mass (70eV) (trimethylsilyl ether) m/e; 682 (M ⁺ ), 625, 551, 535, Example 3 (7S, 8R, 9S, 11R, 15S)-5,6-dehydro-7-hydroxyprostaglandin F ₂ α in which the hydroxyl groups at the 11th and 15th positions are protected with a methoxyisopropyl group and a t-butyldimethylsilyl group, respectively. Add 1 ml of tetrahydrofuran solution containing 45 mg of methyl ester to 1 ml of tetrahydrofuran solution containing 24 mg of mercury chloride ().
ml mixture at room temperature and reacted at room temperature for 15 minutes, the crude product obtained by treatment in the same manner as in Example 1 was subjected to florisil column chromatography (n-hexane-ethyl acetate-1% triethylamine). to obtain 28 mg of 7-hydroxyprostacyclin methyl ester in which the hydroxyl groups at the 11th and 15th positions were protected with a methoxyisopropyl group and a t-butyldimethylsilyl group, respectively.

The spectral data of this product were as follows.

nmr (CDCl ₃ ) δ; 5.57 (2H, m), 4.80 (1H, m), 4.53 (1H, t, J=7Hz), 4.30 (1H, s), 4.20-3.80 (2H, m), 3.68 ( 3H, s), 3.20 (3H, s), Mass spectrum (20eV) (trimethylsilyl ether); 640 (M ⁺ ), 608, 568, 551, Example 4 (7RS, 8R, 9S, 11R, 15S)-5,6-dehydro-15-cyclopentyl-7-hydroxy-
11,15-bis-t- of 16,17,18,19,20-pentanol-prostaglandin F ₂ α methyl ester
Using 100 mg of butyldimethylsilyl ether, the reaction was carried out in the same manner as in Example 1, followed by post-treatment to obtain the desired (7RS, 8R, 9S, 11R, 15S)-15-cyclopentyl-7-hydroxyprostacyclin methyl ester. , 55 mg of 15-bis-t-butyldimethylsilyl ether was obtained.

The spectral data of this product were as follows.

'H-nmr (CDCl ₃ C) δ; 5.50 (2H, m) 4.77 (1H, m), 4.50 (1H, t, J = 7Hz), 4.27 (1H, s), 4.02 (1H, m), 3.90 (1H, m), 3.65 (3H, s). Mass (20eV) m/e; 608 (M ⁺ ), 551. Example 5 (7RS, 8R, 9S, 11R, 15S)-5,6-dehydro-15-cyclohexyl-7-hydroxy-
Using 85 mg of 11,15-bis-t-butyl dimethyl ether of 16,17,18,19,20-pentanol prostaglandin F ₂ α methyl ester, reaction was carried out in the same manner as in Example 1 to obtain the desired product (7RS ,8R,9S,
11R,15S)-11,15 of 15-cyclohexyl-7-hydroxyprostacyclin methyl ester
-Bis-t-butyldimethylsilyl ether 40
I got mg.

The spectral data of this product were as follows.

'H-nmr (CDCl ₃ ) δ; 5.48 (2H, m), 4.78 (1H, m), 4.45 (1H, t, J=7Hz), 4.25 (1H, s), 4.0 (1H, m), 3.9 (1H, m), 3.68 (3H, s), Mass (20eV) m/e; 622 (M ⁺ ), Example 6 (7RS, 8R, 9S, 11R, 15S)-15-t-butyldimethylsilyl ether-11-t-butyl of -5,6-dehydro-7-hydroxy-17,20-dimethyl prostaglandin F ₂ α methyl ester 60 mg of diphenylsilyl ether was reacted in the same manner as in Example 1 to obtain the desired products (7RS, 8R, 9S, 11R,
30 mg of 15-t-butyldimethylsilyl ether-11-t-butyldiphenylsilyl ether of 15S)-7-hydroxy-17,20-dimethyl prostacyclin methyl ester was obtained.

The spectral data of this product were as follows.

'H-nmr (CDCl ₃ ) δ; 5.55 (2H, m), 4.9-3.8 (5H, m), 3.70 (3H, s), Mass (20eV) m/e; 762 (M ⁺ ) Example 7 (7RS, 8R, 9S, 11R, 15S)-5,6-dehydro-7-hydroxyprostaglandin F ₂ α methyl ester of 15-t-butyldimethylsilyl ether 11-[4-(4-methoxytetrahydropyranyl) )] Using 50 mg of ether, react in the same manner as in Example 1 to obtain the desired products (7RS, 8R, 9S,
30 mg of 15-t-butyldimethylsilyl ether 11-[4-(4-methoxytetrahydropyranyl)] ether of 11R,15S)-7-hydroxyprostacycline methyl ester was obtained.

The spectral data of this product were as follows.

'H-nmr (CDCl ₃ ) δ; 5.5 (2H, m), 4.9 ~ 3.8 (5H), 3.70 (4, t, J = 5Hz), 3.68 (3H, s), 3.25 (3H, s) Mass ( 20eV) me; 553 (M ⁺ _- 57) Example 8 (7RS, 8R, 9S, 11R, 15S)-5,6-dehydro-7-hydroxyprostaglandin F ₂ α methyl ester of 15-t-butyldimethylsilyl ether 11-(2-tetrahydropyranyl) ether 100 mg was reacted in the same manner as in Example 1 using
Purpose (7RS, 8R, 9S, 11R, 15S) -7-
Hydroxyprostacyclin methyl ester
15-t-butyldimethylsilyl ether 11-(2
-Tetrahydropyranyl) ether (58 mg) was obtained.

The spectral data of this product were as follows.

'H-nmr (CDCl ₃ ) δ; 5.55 (2H, m), 5.0-3.7 (6H), 3.65 (5H, s and m). Mass (20eV) m/e; 523 (M ⁺ -57). Example 9 (7RS, 8R, 9S, 11R, 15S)-5,6-dehydro-7-hydroxyprostaglandin F ₂ α methyl ester of 15-t-butyldimethylsilyl ether 11-dimethyl (2,4,6-tri- The desired 15-t-butyl of (7RS, 8R, 9S, 11R, 15S)-7-hydroxyprostacyclin methyl ester was obtained by reacting 120 mg of t-butylphenyloxy)silyl ether in the same manner as in Example 1. Dimethylsilyl ether 11-dimethyl (2,
62 mg of 4,6-tri-t-butylphenyloxy)silyl ether compound was obtained.

The spectral data of this product were as follows.

'H-nmr (CDCl ₃ ) δ; 7.33 (3H, s), 5.65 (2H, m), 5.0-3.7 (5H), 3.66 (3H, s). Mass (20eV) m/e; 757 (M-57). Example 10 Dry 85 mg of 11,15-diacetate of methyl ester of (7R)-5,6-dehydro-15-cyclopentyl-7-hydroxy-16,17,18,19,20-pentanor prostaglandin F ₂ α It was dissolved in 2 ml of tetrahydrofuran and cooled to -30°. A solution of 115 mg of mercury () trifluoroacetate in 1 ml of dry telorahydrofuran was added, and after stirring for 5 minutes,
34 mg of sodium boron hydride and 1 ml of methanol
was added and stirred at the same temperature for 1 hour. 30 ml of ethyl ether was added, and the organic layer was washed with saturated brine and dried over anhydrous potassium carbonate-anhydrous magnesium sulfate. After that, a small amount of triethylamine was added, evaporated under reduced pressure, and purified by silica gel chromatography (hexane-ethyl acetate = 7:3, containing 0.1%).
triethylamine).

63 mg of (7R)-η-hydroxyprostacyclin (7R)-15-cyclopentyl-7-hydroxy-16,17,18,19,20-11,15 of pentanorprostacycline methyl ester
-Diacetate compound was obtained.

The spectral data of this product were as follows.

IR (coating): 3770, 1735cm ^-1 NMR (CDCl ₃ ) δ: 1.98, 2.02 (6H, 2s), 3.67
(3H, s) 4.1-5.2 (5H, m), 5.50-5.75 (2H,
m) Example 11 Example from 200 mg of 11,15-diacetate of (7S)-5,6-dehydro-15-cyclopentyl-7-hydroxy-16,17,18,19,20-pentanor prostaglandin _F5α methyl ester Similarly to 10, (7S)-15-cyclopentyl-7-
121 mg of 11,15-diacetate of hydroxy-16,17,18,19,20-pentanorprostacycline methyl ester was obtained.

The spectral data of this product were as follows.

IR (coating): 3470, 1740cm ^-1 NMR (CDCl ₃ C) δ: 1.98, 2.00 (6H, 2S), 3.65
(3H, S) 4.28 (1H, S), 4.50 (1H, t, J=
7Hz) 4.60-5.30 (3H, m), 5.40-5.65 (2H,
m)) Example 12 (7R)-5,6-dehydro-7-hydroxyprostaglandin F ₂ α methyl ester 11,15
-220 mg of mercury trifluoroacetate was added to a solution of 220 mg of diacetate in 5 ml of dry tetrahydrofuran under ice cooling, and after 10 minutes, 5 ml of methanol and 90 mg of sodium hydride were added, followed by stirring at room temperature for 1 hour. Add 100 ml of ethyl ether, wash with saturated saline, dry over anhydrous potassium carbonate-anhydrous magnesium sulfate, and evaporate under reduced pressure to fluorisil column chromatography (cyclohexane-ethyl acetate = 9:1, containing 0.3% triethylamine). 120 mg of 11,15-diacetate of (7R)-7-hydroxyprostacyclin methyl ester was obtained.

The spectral data of this product were as follows.

IR (coating): 3460, 1735 cm ^-1 NMR (CDCl ₃ ) δ: 2.00 (6H, S), 3.65 (3H,
S), 4.22-5.35 (5H, m), 5.45-5.75 (2H,
m), Example 13 (7S)-5,6-dehydro-7-hydroxyprostaglandin F ₂ α methyl ester 11,15
-200 mg of the diacetate was reacted in the same manner as in Example 12 to obtain 120 mg of the 11,15-diacetate of (7S)-7-hydroxyprostacyclin methyl ester. The spectral data of this product were as follows.

IR (coating): 3470, 1740cm ^-1 NMR (COCl ₃ ) δ: 1.98, 2.00 (6H, 2S), 3.66
(3H, S) 4.25 (1H, S), 4.52 (1H, t, J=7Hz) 4.60-5.30 (3H, m), 5.35-5.60 (2H, m)

Claims (1)

[Claims] 1. The following formula [] [In the formula, G is -CO ₂ R ⁵ , R ⁵ is a hydrogen atom,
_C1 - _C10 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted alicyclic group, substituted or unsubstituted phenyl ( _C1 - _C2 ) alkyl group or tri( _C1 - _C7) ) hydrocarbon-silyl group; R ¹ is a hydrogen atom or a methyl group; R ² is an unsubstituted C ₅ - C ₈ alkyl group, a substituted or unsubstituted alicyclic group, or a substituted or unsubstituted alicyclic group; A phenyl group, a phenoxy group, a substituted _C1 - _C5 alkyl group substituted with a _{C1 -} C6 alkyl group or a _{C5-C6 cycloalkyl} group; ^R3 and ^R4 are the same or different Hydrogen atom, _C2 - _C7 acyl group,
It is a tri(C ₁ -C ₇ ) hydrocarbon-silyl group or a 1-alkoxyalkyl group. The bonds (substituents) at the 8th and 9th positions on the cyclopentane ring are cis. ] 7-hydroxyprostaglandin represented by
reacting the F ₂ α derivative with a mercuric carboxylic acid salt, mercury halide or mercury oxide in an inert organic medium;
The following formula [], which is then treated with a borohydride compound [In the formula, G, R ¹ , R ² , R ³ and R ⁴ are the same as defined above. ] A method for producing a 7-hydroxyprostacyclin derivative represented by: 2. 7 of Claim 1, wherein the carboxylic acid mercury salt is mercury acetate or mercury trifluoroacetate.
-Process for producing hydroxyprostacyclin derivatives. 3. The method for producing a 7-hydroxyprostacyclin derivative according to claim 1, wherein the mercury halide is mercury chloride. 4 The boron hydride compound has the following formula [] M (R ₈ ) ₄ -mBHm ... [] [In the formula, M is an alkali metal atom, and R ₈ is C _1
-C6 alkyl group, _C1 - _C6 alkoxy group or cyano group, and m is an integer of 1-4. 7-7 according to any one of claims 1 to 3, which is a borohydride compound represented by
Method for producing hydroxyprostacyclin derivatives. 5. The method for producing a 7-hydroxyprostacyclin derivative according to claim 4, wherein the borohydride compound is sodium borohydride, sodium trimethoxyborohydride, or sodium triethoxyborohydride. 6. The method for producing a 7-hydroxyprostacyclin derivative according to any one of claims 1 to 5, wherein in the above formula [], G is a methoxycarbonyl group. 7 In the above formula [], R ² is an n-pentyl group,
Claim 1 which is a 2-methyl-1-hexyl group, a cyclohexyl group or a cyclopentyl group
6. A method for producing a 7-hydroxyprostacyclin derivative according to any one of Items 6 to 6. 8 In the above formula [], R ³ and R ⁴ are the same or different, t-butyldimethylsilyl group, 2-tetrahydropyranyl group, acetyl group, 1-methoxy-1-methylethyl group, 4-(4-methoxytetrahydropyranyl group) ) group or dimethyl (2,4,6
-tri-t-butylphenyloxy)silyl group according to any one of claims 1 to 7.
A method for producing a 7-hydroxyprostacyclin derivative as described in Section 1.