JPS59231066A - Preparation of 6-oxoprostaglandin e1 compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a drug having blood platelet coagulation inhibiting activity, hypotensive activity, gastric ulcer suppressing activity, etc., easily, from an easily available raw material, by converting the nitro group of a 6-nitroprostaglandin E1 compound to oxo group. CONSTITUTION:The nitor group of a 6-nitroprostaglandin E1 compound of formula I (R1 is H, 1-12C alkyl, 3-10C cycloalkyl, etc.; R2 and R3 are H, tri(1-7C) hydrocarbon-silyl, etc.; R4 is H, methyl, ethyl, etc.; R5 is alkyl, 3-10C cycloalkyl, etc.), its 15-epimer,their antipode or their mixture, is converted to oxo group with a trivalent titanium compound (e.g. titanium trichloride). If necessary, the product is deprotected and/or hydrolyzed to obtain the objective compound of formula II (R11 is H, 1-12C alkyl, etc.; R21 and R31 are H, tri(1-7C)hydrocarbonsilyl, etc.).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel method for producing 6-oxoprostaglandin E, which is useful as a pharmaceutical. For more details 6
- Conversion of the nitro group at position 6 of p-staglandin E, etc. into an oxo group, followed by optional deprotection and/or
Or 6-oxoprostaglandin E, which is more useful as a pharmaceutical product than K after being subjected to a hydrolysis reaction.

This invention relates to a method for manufacturing a class of products. .

Conventional method 6 - Oxoprostaglandin sushi has a strong platelet aggregation inhibiting effect similar to that of prostacyclin and a blood pressure lowering effect based on smooth muscle relaxing effect, and is known as an in vivo active substitute by-product of prostacyclin. Te~・ru (C,P
.

Quilley et al., European Journal, Op.
) 7-Macology, Vol. 57, pp. 273-276, 197
9; P, Y, K, Wong et al., European Journal, No. 1, Pharmacology, vol. 60, pp. 245-248, 1979).

Prostacyclin has an active half-life of about a few minutes at physiological pH, and there is a problem with its stability as a pharmaceutical, but the above-mentioned 6-oxoprostaglandin sushi is more stable than prostacyclinin ( C, P, Quil
(Refer to the above-cited literature) Therefore, the application of 6-oxoprostaglandin E and its analogues to pharmaceuticals is expected.

Conventionally, such compounds are produced in several steps using prostaglandin F, α, and their analogs as starting materials via prostacyclin (Q! reference). However, this production method requires many steps to obtain the target compound.

Purpose of the Invention The present inventors have conducted intensive research to find an advantageous chemical synthesis method for 6-oxoprostaglandin E, and as a result, have discovered optically active 4-hydroxy-2-cyclopente 7') - Converting the nido-group of 6-nitrope "1 staglandin EIM to an oxo group, which is obtained in a high yield through a stepwise reaction, and then optionally subjecting it to deprotection and/or hydrolysis and/or salt-forming reaction." 6-oxoprostaglandin E, etc. can be easily converted into i(I) by
This is what led to the present invention.

Therefore, an object of the present invention is to provide a simple and industrially advantageous method for producing 6-oxoprostaglandin E using readily available raw material compounds.

Structure and Effects of the Invention The production method of the present invention provides 6-dito-1 cobrosta which is a compound represented by the following formula CI) A compound represented by the following formula [1], which is characterized by converting the nido IJ group of grandin L class into an oxo group, and then subjecting it to deprotection and/or hydrolysis and/or salt formation reaction depending on the case, This is a method for producing 6-okirafu 1j futaglandin E, which is the 15-shrimp body, its enantiomer, or a mixture thereof in any proportion.

As described above, the manufacturing method of the present invention uses a compound of the above formula CI) which has a 21-stem at the 6th position according to the prostaglandin nomenclature, and converts this nitro group into an oxo group. 6- represented by the above formula [IT] with the conversion reaction as the key reaction.
It manufactures Oxoprosta "Grandin E".

For reference, the position number representation of prostaglandin in the form of brostanic acid is shown in the following formula Cm).

In the above formula CI), R is a hydrogen atom, a straight C or branched alkyl group having 1 to 12 carbon atoms, 1 cycloalkyl group having 3 to 10 carbon atoms, 1 aralkyl group having 7 to 12 strands, and is a substituted or unsubstituted phenyl group.

As the straight chain or branched chain furkyl group having 1 to 12 carbon atoms, for example, methyl, ethylfuprovil, phthyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl groups and isomeric forms thereof are preferable. Although it can be mentioned as ~・, it is preferable for methyl group crab%.

As a cycloalkyl group having 3 to 10 carbon atoms, for example, c is cyclofurohyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl, cyclobutyl, and for a cyclodecyl group, 2,3-diethyl/ 1, cyclopropyl, 2,2-dimethylcyclobenzene.

Preferable examples include 4-tert-butylcyclohexyl group and the like.

Examples of the 7-ralkyl group having 7 to 12 carbon atoms (for example, benzyl, l-phenethyl, 2-7enethyl, 3-phenylproyl, 4-phenylbutyl, etc. are preferable) can be mentioned. .

As an R-substituted or unsubstituted pheni/L group, examples include 'tf
, , phenyl group, 0-riIjlovenyl.

m-chlorophenyl, p-chlorophenino 1no↑p-fluorophenyl, 2.4-dichlorophenyl, (0
1m + or p-) tolylu p-enalphenyl,
Preferred examples include p-t-butylphenyl, 2,5-dimethylphenyl, and 4-chlorop-2-methylphenyl.

As R7, a hydrogen atom and a methyl group are particularly preferred.

R2 and R1 are the same or different, hydrogen atom, t! I (C, -C,) hydrocarbonated silyl group, or water @
It is a group that forms a cetal bond with the oxygen group of the group. As the tri(C+-C7) hydrocarbon silyl group,
For example, trimethylsilyl, ] ethylsilyl, t
Examples include -butyldimethylsilyl t-dityldiphenylsilyl group, and t-butyldimethylsilyl group is particularly preferred. Examples of the group that forms an acetal bond with the oxygen atom of the hydroxyl group include Eva, methoxymezal, and 1-ethoxyethyl.

2-methoxy-2-propyl, 2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl-6,6-dimethyl-3-oxa-2 −
Oxo-bicyclo [a, 1. , o] to]kis-4-yl, and 2-tetrahydropyranyl group is particularly preferred.

These silyl groups and groups forming a 7-cetal bond are to be understood as holding groups for a hydroxyl group. These retained groups can be easily removed under mildly acidic to neutral conditions to yield the final product, free hydroxyl groups, which are useful as pharmaceuticals. As R2, R, a hydrogen atom is particularly preferred.

R4 is a hydrogen atom, a methyl group, an ethyl group, a vinyl group, or an ethynyl group;

A methino group is preferable, and a hydrogen atom is particularly preferable. R5 is a straight or branched alkyl group having 4 to 12 carbon atoms which may contain an oxygen atom, or a cycloalkyl group having 3 to 10 carbon atoms. + FA
It is a linear or branched alkyl group having 1 to 6 carbon atoms.

Examples of the straight chain or branched alkyl group which may contain an oxygen atom having 4 to 12 carbon atoms include butyl, pentyl, hexyl, heptyl, octyl, 2-methylhexyl, (S)-2-methylhexyl. , (6) -2-Methylhexyl, 2-methyl-2-hegycyl, 2-hexyl, 1.1-dimethylpentyl, 2-ethoxyethyl group, preferably pentyl, hexyl, (R)-mol is (S)-2-methylhexyl.

Examples include 2-hexyl group.

Schiff's 7 alkyl group having 3 to 10 carbon atoms is kZ, for example, cyclopropyl, cyclobutyl.

Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononylfucyclodecyl group as well as 2,3-diethylcyclopentyl, 2,2-dimethylcyclopentyl.

Preferred examples include alkyl-substituted cycloalkyl groups such as 4-t-butylcyclohexyl.

Examples of the linear or branched chain furkyl group substituted with a cycloalkyl group having 7 to 12 carbon atoms include cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 3-cyclobentyl 7'' +=+vil, cyclohexylmethyl, 1- Examples include cyclohexylethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl, cyclooctylmethyl, 3-cyclopropylpropyl, and 4-cyclopropylbutyl groups.

Examples of the linear or branched alkyl group having 1 to 6 carbon atoms substituted with a substituted or unsubstituted phenyl group or phenoxy group include benzyl, 1-phenethyl, 2-phenethylpurpyl, 4-phenylbutyl, 1- Examples include phenylpentyl, phenoxymethyl, (3-chlorophenoxy)methyl, (4-chlorophenoxy)methyl+(3-trifluoro, methylphenoxy)methyl group, and the like.

Among these R3, particularly pentyl, hexyl, heptyl, (S)-2-methylhexyl.

(Q-2-methylhexyl, 2-methyl-2=hexyl, 2-hexyl, 1,1-dimethylpentyl, cyclopentyl, 3-)'lopylpentyl, cyclohexyl, cyclohexylmethyl, 2-ethoxyethyl, benzyl.

2-phenethyl and phenoxymethyl groups are preferred.

In the above formula [II), R and l are a hydrogen atom, a straight or branched alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, a 7-ralkyl group having 7 to 12 carbon atoms, a substituted or It is an unsubstituted phenyl group or a pharmaceutically acceptable cation. Among these, the same group as K in common with R1 in formula CI) is preferably the same group, and examples of pharmaceutically acceptable cations include lithium,
metal cations such as sodium, potassium) magnesium, calcium, and trimethylamine, dimethylamine, ethylamine, triisopropylamine.

Dicyclohexylamine, α-7enethylamine, ethylenediamine, piperidine, morpoline, pyridine,
Examples include amine cations such as ethano, -lamine, and jetanolamine, and quaternary ammonium cations such as tetramethylammonium and benzyltrimethylammonium. 3, R81 is particularly preferably a hydrogen atom, a methyl group, or a sodium ion. It is mentioned as a thing.

Rt+ + R□ are the same or different hydrogen atoms.

(c, -Cy) A hydrocarbon silyl group or a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group, and the same as those listed in R,, R, K of formula (I) Those are listed as preferred.

The 6-nitroprostaglandin E group represented by the above formula (I) used in the method of the present invention was separately proposed by the present inventors, and was prepared by adding an organic steel sodium compound to the 4-substituted-2-cyclopente group. It can be easily obtained by a method of conjugate addition and then reaction with nitroolefins. The manufacturing process is illustrated as follows.

In addition, the prostaglandin derivative represented by the above formula CI) l[II] has the 6th position in the boostaglandin nomenclature
Since the 8th, 11th, 12th, and 15th positions are asymmetric carbons, various stereoisomers exist, and the method of the present invention converts the natural stereoisomers of these isomers into [I].

Although illustrated and illustrated as [II), the production method of the present invention includes all these stereoisomers and mixtures thereof in arbitrary proportions as it can be carried out without any problems.

A specific example of the compound represented by the above formula [I] is given as a 6-2ham conductor corresponding to a specific example of the 6-othenbrostaglandin E of the above formula (IT). .

The production method of the present invention involves converting the nitro group of 6-nitros p-staglandin El represented by the above formula CI) into an oxyne group, and then optionally subjecting it to deprotection and/or hydrolysis and/or salt formation reaction. achieved.

The reaction that converts a nitro group to an oxo group generally has a neck (
Nef) as a reaction since ancient times (J, U.

NefyAnn, +280, 263 (1894)) is a well-known reaction, and numerous research cases have been reported to date. Therefore, many conversion reagents are known, but they can be broadly classified into three types: (1) (method using acid, (21) reductive conversion method, and (21) oxidative conversion method. explain.

(Method using 11 acids; This is the most common Nef reaction method, in which a nitro compound is first reacted with a base such as sodium hydroxide or sodium alcoholate in water or an alcohol-based or ether-based solvent. After converting it into an acinitron salt, it is reacted with hydrochloric acid or sulfuric acid to form the corresponding oxy compound. For example, W, E, Nn1and+Chem, R
ev,, 55, l 37 (195s).

N, Kornblum et al. + J, Am, Chem.
, Soc, w 87.

1742 (1965) +Y, Mazur et al. +J, Am
, Chem.

Reports such as 5OQ-+ 99.3861 (1977) are helpful. Although this is a basic method, it can be hampered by the reaction under strongly alkaline and acidic conditions.

(Method of converting into 21N elements; low valence metal compounds, such as trivalent titanium compounds,
Divalent vanadium compound.

Although divalent chromium compounds are known, trivalent titanium compounds are particularly preferably used. Usually, a titanium trichloride aqueous solution is used as a reducing agent, but since the reaction solution is strongly acidic (pH 1 or less), a mild titanium trichloride solution such as ammonium acetate is used as a reducing agent. Add r salt to the reaction system to adjust the pH of the reaction solution.
There are cases where it is necessary to suppress side reactions by controlling the value to be between 4 and 7, preferably around 6. Even in this case, the reaction proceeds smoothly by converting it into a 7-sinitro salt with a base such as sodium methylate before subjecting it to the reduction reaction. Moreover, since the present invention uses a titanium trichloride aqueous solution, a relatively water-soluble organic medium, such as diethyl ether! This is carried out in the presence of an ether solvent such as tetrahydrofuran, dimethoxyethane, dioxane, or an alcohol solvent such as methanol or ethanol.

J and E for detailed experimental conditions.

McMurry et al. + J-Org, Chem.
+ 3814367 (1973) + J, E, McM
urry+Accounts, Che+n.

Re8. +7.281 (1974) et al. are a reference.

(3) Oxidative conversion method: The nitro compound is treated with a basic substance to form an acinitro salt, and the nitro compound is reacted with various oxidizing agents to convert the nitro compound into the corresponding oxo compound. Although it has the advantage of being able to be converted using relatively mild conditions, it has the disadvantage that it is difficult to control if the molecule contains a functional group that reacts with the oxidizing agent used. References for the base and oxidizing agent used, as well as the reaction conditions, include, for example, sodium methylate-ozone (1, E.

McMurry et al. + J, Org, Chem-+
39 + 259 (1974)) + sodium hydroxide singlet oxygen (J, R, Wi II i ams
et al., J, Org, Chem, +43.1271 (19
78)) + potassium carbonate-hydrogen peroxide (G , A ,
Of a l+et al+5ynthesis+662(1
98(1)), phosphorus t-butoxide t-butyl hydroperoxide (P, A, Bartlett et al. + Tetrahedron Letters+331
(+977)), potassium hydroxide, sodium t-butoxide or silica gel-peroxide? 7 Potassium ganate (F,
T', Wi] l iams, Jr.

et al+ J, Org, Chern,, 27.36119
(1962).

N., Kornblum et al., T.J., Org.
Che'rn, + 47 + 4534 (1982) +
J, H, C1ark et al + J, Chem, Soc, +
Chem, Commun, +635 (+982) + triethylamine or sodium hydride, - ceric ammonium nitrate (G, A, Olgb et al.

5 synthesis+ 44 (t 9 s o )
+ R, C, Cookson et al.

Tetrahedron Letters, 23
, 3521 (1982)).

In the method of the present invention, 6-oxoprostaglandin E represented by the above formula (1) has a β-hydro dicyclopene f/7 skeleton and a partially busy allyl alcohol skeleton in the side chain. has the property that undesirable side reactions are likely to proceed under strongly basic conditions, strongly acidic conditions, and strongly oxidizing conditions.For this reason, the conditions for the above-mentioned dil.O group-oxo group conversion reaction This does not mean that it will be applied as is!

The present inventors believe that the above nitro group-oxo group conversion reaction involves converting the nitro compound into the corresponding acinide monosalt intermediate in the presence of a base, and then reacting with an acid, an oxidizing agent, or an oxidizing agent to form the corresponding oxo group. As a result of intensive research on the conditions for the 21-ro group-okyne group conversion reaction, keeping in mind the reaction mechanism of forming a compound, we found that 6-nitroprostaglandin E, represented by the above formula CI), was converted into a weakly basic compound. By reacting with an aqueous trivalent titanium compound solution to which a buffer salt has been added in the presence of the compound, it is possible to convert it into 6-oxoprostaglandin E represented by the above formula [1]. be.

The reaction conditions will be described below.

The weakly basic compound used here is preferably one that has weak reactivity with the cyclobentenone skeleton and has the ability to selectively (2) extract hydrogen on the carbon to which the latch is bonded. Examples of the compound include triphenylphosphine and triglyphosphine.

Tetraztylammonium fluoride, potassium fluoride, potassium carbonate, tetramethylquanidine, diimprohylamine, morpholine, pyrrolidine, piperidine,
Examples include triethylamine, and triphenyl-sphine is particularly preferred.

As the trivalent titanium compound, a commercially available titanium trichloride aqueous solution can be used as is. However, the reaction was carried out only with an aqueous titanium trichloride solution.1! The pH of the reaction system becomes less than 1, making it strongly acidic, which is undesirable. Therefore, the pH is usually adjusted to around neutrality (PH4 to 7).
, preferably around 6) The above reaction is carried out with the addition of a buffer salt to control K.

Such buffer salts include, for example, sodium formate, ammonium acetate, sodium acetate! Examples include potassium acetate, sodium conophosphate, sodium succinate, sodium tartrate, sodium phthalate, sodium phosphate, disodium phosphate, potassium phosphate, dipotassium phosphate, and ammonium acetate is particularly preferred. ℃・.

The above-mentioned weak base compound is used in an amount of 0.5 to 20 times, preferably 1 to 10 times, by mole relative to the normally used 6-nitrogerostaglandi 7E.
It is used in a range of 20 to 20 times the mole, preferably 2 to 15 times the mole, particularly preferably 3 to 10 times the mole. The amount of buffer salt used varies depending on the amount of resin and titanium trichloride used.
This is determined while observing changes in pH, but for example, when using ammonium acetate, if 6 times the molar amount of titanium trichloride is used, the pH of the reaction solution will be around 6.1.

In order for the reaction to proceed smoothly, it is recommended to further add a relatively water-soluble organic medium to the reaction system, such as ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, and dioxane, or methanol, ethanol, Isopropyl alcohol,
Examples include alcohol-based solvents such as.

The reaction temperature is usually 0°C to 40°C, preferably 20°C to 30°C.
The reaction time varies depending on the reaction conditions such as the reaction temperature, the red color of the reactant, and the tone.The reaction end point is determined by tracking the reaction using analytical means such as thin layer chromatography. It will be completed in 1 to 48 hours.

After the reaction, the resulting product is separated from the reaction solution and purified by conventional means. For example, extraction.

This is carried out by washing, chromatography or a combination thereof.

(Site 6-2l q prostaglandin E.

is converted into 6-oxoprostaglandin El, but the hydroxyl group (11th and/or 15th position) and/or 1
If the compound retains the carboxyl group at this position, it is then subjected to deprotection and/or hydrolysis and/or salt-forming reaction by a conventional method.

For example, when the protecting group is a group that forms a 7-cetal bond with the oxygen atom of the hydroxyl group, removal of the protecting group of the hydroxyl group can be carried out using, for example, acetic acid m + p-toluenesulfonic acid, Catalyst with pyridinium salt or cation exchange resin, etc.”
For example, water, tetrahydrofuran, ethyl ether, dioxane, methanol, and ethanol.

This reaction is suitably carried out using acetone, acetonyl, etc. as a reaction solvent. The reaction is usually -78℃~+100℃
The treatment is carried out at a temperature range of 10 minutes to 3 days. Also,
When the protecting group is a (Ct~C,) hydrocarbon silyl group, the above-mentioned Removal of the protecting group on the carboxyl group can be carried out in the same reaction solvent at a similar temperature using, in the case of esters, an enzyme such as lipase or esterase.
The reaction is carried out in the reaction solvent as described above at a temperature range of -10°C to +100°C for about 10 minutes to 24 hours.

According to the present invention, the carboxyl group-containing compound produced by the protective group removal reaction as described above is then, if necessary, further subjected to a salt production reaction to give a carbo/acid salt.

The salt-forming reaction is known per se and involves neutralizing the carboxylic acid with approximately the same amount of a basic compound, such as sodium hydroxide, potassium hydroxide, sodium carbonate or ammonia, trimethylamine, monoethanolamine, morpholine, in a conventional manner. This is done by causing a reaction.

Specific examples of the 6-oxoprostaglandin El represented by the formula [rl] thus obtained are listed below. The prostaglandin note is PGE.
, is abbreviated as .

01) 6-oxo-PGE.

02) 15-methyl-6-oxo→'i” G E
.

03) 16-Methyl-6-oxo-PGE.

04) 17-Methyl-6-oxo-PGE.

05) 18-Methyl-6-oxo-PGE.

06) 19-Methyl-6-oxo-PGE.

07) 20-Methyl-6-oxo-PGE.

08) 20-ethyl-6-ox7-PGE.

09) 20-propyl-6-oxo-PGg.

10) 16-ethyl-6-oxo-PGE.

1]) 17-ethyl-6-oxo-PGE.

+2) 15.16-dimethyl-6-okine-PGE
.

13) 16.17-dimethyl-6-okine-PGE
.

14) 16.20-dimethine-6-oxo-PG
E.

15) 17.20-di)-f-ru6-oky-P
G.E.

1s) 16.16.20-methyl-6-ox-7-PGE.

17) 17-methyl-20-ethyl-6-oxo-
P.G.E.

18) 17.20-diethyl-6-oxo-PGE
119) 15-cyclopentyl-ω-pentanol-6-oxo-PGE.

2o) 15-cyclohexyl-ω-pentanol6
-”Kiso 1'GE.

21) 15-(2,3-diethyl)cyclopropyl-ω-pentanol-6-okine-PGE.

22) 15-(2,2-dimethyl)cyclobenzene-ω-pentanol-6-oxo-PGE.

23) 15-(4-j-butyl)cyclohexyl-
〇-pentanol-6-oxo PGE.

24) 16-cyclobenzene ω-tetratrue 6
-Oxo-P G E + 25) 16-cyclopentyl-ω-trinor-6-
Okin PGE.

26) IT-Schiff 1 Bench Lou ω-Tri/Lou 6-
Oxo-PGE.

27) 1s-Cyclobenyl ω-dinol-6-oxo-PGE.

28) 16-Cyclobexidyl-ω-tetratrue 6
-Okin-Pi.

29) 16-cyclohexyl-ω-trinor-6-
Oxo-PGE.

30) 17-cyclohexyl-ω-trinor-6-
Oxo-PGE.

31) 18-cyclohexyl-〇-dino-6-oxo PGE.

32) 16-cyclooctyl-ω-tetratrue6
-Oxo-PGFJ.

33) 18-Cyclopropyl-ω-dinol-6-okine-PGE.

34) 19-cyclopropyl-ω-true 6-oxo-PGE.

35) 18-oxo-6-oxo-PGE.

36) 16-phenyl-ω-tetratrue 6-okine-PGE.

37) 17-phenyl-ω-trinor-6-oxo-
P.G.E.

38) 16-phenoxy-ω-tetratrue-6-oxo-PGE.

39) Methyl esters of the compounds of 01) to 38) 4o) Ethyl esters of the compounds of of) to 38) 4
X) Monolithium salts of compounds of Ot) to 38) 42
) Of) ~ 41) Hydroxyl groups (11-position and 15-position)
position) is a t-butyldimethylsilyl group and/or a 2-
Ethers preserved with a tetrahydropyranyl group 43) 15-shrimp derivatives of the compounds of 01) to 42) 44) Enantiomers of the compounds of Of) to 42) 45)
Examples include, but are not limited to, enantiomers of the compound 43).

6-oxoprostaglandin E represented by the above formula (IF) produced by the above method, R□,
6-oxoprostaglandin E, which is a compound represented by the following formula in which R1 is a hydrogen atom, its stereoisomer, or a mixture of any ratio thereof, has platelet aggregation inhibiting action, blood pressure lowering action, and gastric ulcer suppressing action. It is a useful compound known to have physiologically active effects specific to prostaglandins, such as antianginal, vasodilatory, and antihypertensive.

It is a compound that is expected to be used as a drug that controls vascular activity such as anti-myocardial infarction, anti-thrombosis, anti-arteriosclerosis, and suppresses metastasis of malignant tumors, as well as a drug for treating hypertension and gastric ulcers.

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

Example 1 dl-11,Is-bis(t-butyldimethylsilyl)
-Mixture of 6-nitroprostaglandin E, methyl ester and its 15-shrimp form (] 44'? +
0.22 mmol! ) in tetrahydrofuran solution (
siiK triphenylphosphine (173j9+0.6
After stirring at room temperature for 15 minutes, add 25% titanium trichloride aqueous solution (1.64 ml, approx. 2.64 mm
ol! ) and ammo-+7 acetate (1,221+t
5. An aqueous solution prepared by dissolving samal) in 2M water and methanol (Sat) were added, and the mixture was stirred at room temperature for 5 hours.

A saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to obtain a crude product of 32411y. This material was subjected to thin layer pomagography for preparation (hexane = ethyl acetate = 3:1) and dl
11 +15-bis(t-butyldimethylsilyl)-6
- Mixture of oxituprostagra/gin E, methyl ester and its 15-shrimp form (4ZTn9+0.068
amal + 32%).

NMR (CDC15! δ (PPI)) ;o
, o3(12H+s")+0.56(21H'),s,
+~1.7(12HL2.15~2.70(IOH)+
3-60 (3H18)+3, 85-4, 20
(2H+m) + 5, 35~5, 6o(2H, m
).

IR (liquid film, α).

2960+2940.28fiO, 1745+1720
11460.1435, 1405, 1360, 1250
゜1155.1100,1000,965,935. ．．
865°835.805,775. (i40, 1MS
(20eV; rrv'e + %); 553
(0,5)+478(3)+422(4)+421(1
2) +407(4), 403(4), 389(3), 3
71(3), 321(8).

297(3) 1289(2), 2fi9(3), 215
(4), 203 (3) + 143 (4) + 132 (4)
t 111 (4) + 76 (9) + 75 (100)
.

Example 2 A mixture of dl-11,15-bis(t-butyldimethylsilyl)-6-nitroprostaglandin E, methyl ester and its 15-shrimp form (
Tributylphosphine (74 da + 0.37 mmoi) was added to a tetrahydrofuran solution (5at) of a 9 w, 61 nmol) and stirred at room temperature for 15 minutes, followed by a 25% titanium trichloride aqueous solution (0.41 ml, approx. 0.66 mmol) and ammonium acetate (3os
@, 3.96. Amal) was dissolved in 2 mAK of water and stirred for another 5 hours at room temperature. Example 1
A crude product of 122 µm was obtained by post-treatment in the same manner as above, and preparative thin layer p-mography (hexane: ethyl acetate = 3
: 1) The corresponding 6-okine body (8Wp,
13 μmoi, 2]%) was obtained. The spectra of this product completely matched those obtained in Example 1.

Example 3 dl-11,1s-bis(t-7
Dimethoxyethane solution (511/) of a mixture (401R9+ 62 amal) of K-tetramethylguanidine (107
After adding 1R9,0,93mmo/') and stirring at room temperature for 5 minutes, 25511; titanium trichloride aqueous solution (o, 41m,
o, e s amal ) and ammonium acetate (3 o
An aqueous solution of 9.3.96 mmol of 5II dissolved in 2-proof water was added, and the mixture was further stirred at room temperature for 5 hours. Example 1
A crude product of 60~ was obtained by post-treatment in the same manner as above, and preparative thin layer p-mography (hexane: ethyl acetate = 3:
1) Corresponding 6-O-Imaso with K (614/,
9.8 Am0I + 16%) was obtained. The spectra of this product completely matched those obtained in Example 1.

Example 4 dl-1t, ts-bis(t-7
'Tyldimethylsilyl)-S-di)-prostaglandin E, methyl ester and its 15-shrimp form mixture (72 mg, 0.11 mmojff) was added to a methanol solution (3 m/) with 25% titanium trichloride aqueous solution (o ,a
An aqueous solution of 2+d, about 1.32 mmo'l) and ammonium acetate (6 s oq, 7.92 mmoJ) dissolved in water 2- was added, and the mixture was stirred at room temperature for 20 hours. Example 1
The same post-treatment and chromatographic separation as above were carried out to obtain the corresponding 6-okine body (r3 mg, o, o2+mmoA, 19%). The spectra of this product completely matched those obtained in Example 1.

Example 5 11,15-bis(t-butyldimethylsilyl)-6-troglostaglandin EH methyl ester Cl92m9+0.30 mmol;
(a')+5 22.3° (C0,71°CH30H
) 3 in isobrobilalf-/l/ (10+u),
s mmol) was added and stirred at room temperature for 15 minutes.

A 25% titanium trichloride aqueous solution (O, S Zm
/, 1.32 mmol) and ammonium acetate (6
, IL7.9 mmall) dissolved in 1MK of water was added, and the mixture was stirred at room temperature for 5 hours. The same post-treatment as in Example 1 was carried out, and the resulting crude product was subjected to preparative thin layer chromatography (hexane:acetic acid). ethyl-3=1) and 11
．． 15-bis(t-butyldimethylsilyl)-6-ocitabu1 costaglandin E1 methyl ester (61,
0.10 mmol, 34%). The NMR, IR, MS, and TLC of this product were completely consistent with those of the d1 form in which q<+ was omitted in Example 1.

The above 11,15-bis(t-butyldimethylsilyl)-
6-Ogisonorostagrandiso E, male ester (6
1m9. o, to mmol) to 10 ml of acetonitrino. and 0.25 ml of pyridine and o.
5 mt of pyridine and 0.5 ml of hydrogen fluoride-pyridine were added and reacted for 3 hours at room temperature. The reaction solution was neutralized by adding a saturated aqueous solution containing hydrogen carbonate and rionic acid, and then extracted with ethyl acetate. The organic layer obtained was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product of 55. The product was obtained.

This was separated into a thin layer for preparation (-\xane: ethyl acetate), and 6-oxuprosucglandine E, methyl ester (28 mg
, 0.074 mmo/, 74%).

NMR (CDC'/, δ(Sir)); 0.87(3
H)+1.1~1.7(12H+m)l :lO~3
．． 0(12H+m)+3.63(3H+SL 3.7
~4.3(2H+m)+5.45~5.65(2)
(+m).

IR (liquid film Iα) 3400.2950, 2870, 17, 10, 1720
゜1435.1410,1370,1250,1200
゜1160.1075.1'020.970,7300
[α)” −4i° (CO, 62+ CH30H).

mp 41-42℃ (hexane-ether recrystallization)
.

Example 6 II, +5-bis(t-notyldimethylsilicate) 17 (S), 20-dimethyl-6-oxyp-staglandin El methyl ester (30 smg, 0.46 mmO) was prepared in the same manner as in Example 1. / ;Ca3
The formula -15,7°(CO,681CH30H')) is 5
- Torahitry 7 Rough (10ml) K Soluff
l: L, l-liphenylphosphine (482ry,
1.84 mm0/) was added and stirred at room temperature for 30 minutes.

Add to this solution a 25% titanium trichloride aqueous solution (1,64at
, 2.64 mmol) and ammonium acetate (1,
After adding an aqueous solution of 22 g, 15.8 mmo/) dissolved in 2 at of water and stirring at room temperature for 12 hours, the same post-treatment as in Example 1 was carried out, and the obtained crude product was transferred to a preparative thin layer p.
Madography (hexane:ethyl acetate-4:I)
11.15-bis(t-butyldimethylsilyl) 17(S), 20-dinobule-6-ochinprostaglandin E, methyl ester (90~) with FC.

0.14 mmol, 31%) was obtained from it 6HMR (
CDC/,, δ(c)); 0.04 (12H2s) + 0.86 (24HL 1.
1~1.7(13H+m)+2.1~2.7(IOIJ
, m), 3.63 (3H+s), 3.8-4.3 (
211°m), 5.35~s, 6o (2H, m).

IR (liquid film + m-1); 2970.2950,2870.1?20,1460°1435.1405,1370. +360.1250°1155.1100,1000,970,935.88
01B35,805,770.7300 M S (20e V s m / e +%); [α
)” -35,5° (C], 02, CH
30I-1>.

DMS (20eV: m/e +%); 581 (8,
M-t-C4H9), 506(4), 449(30).

431 (10) + 417 (8), 407 (18), 33
9 (10) + 321 (9), 297 (8), 143 (1
2).

111(II), 75(100).

II, 15-bis(t-butyldinotylsilyl)
17 (S), 20-dimethyl-6-oxoprostaglandin E1 methyl ester (c+omp.

Dissolve 0.14 mmol in m/ml of ace]nitrile (]+) using the same method as in Example 5, and add 0.14 mmol of pyridine
, 25 ml), followed by hydrogen fluoride-pyridine (o,
smz) and reacted at room temperature for 3 hours. The reaction mixture was neutralized by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine. After drying with 1 sulfuric acid and concentrated under reduced pressure to 80I
A crude product of I+2 was obtained. This product was separated by preparative thin layer chromatography (hexane:ethyl acetate-1=4), and 17(S), 20-dimethyl-6-oxoprostaglandin E1 methyl ester (4sTn9.o
, t2mmall + 86%).

NMR (CDC4,a (PFI)); 0.86 (
6H) + 1, 0~1, 7(13H+m), 2
．． 1 to 2.7 (10H+m) +3.3 (IHID, 0
), 3.60 (311-, +8), 3.8
~+, 3 (3H.

2HK decrease in D, O), 5.4~s, 1i (2■l
, m).

IR (liquid film, a).

3420.2950. :2')20,28701174
0°1720.1460.1440. +415.138
0゜1290.1250.12+10 +1160+1
08011010.970°NI S (20e V y m / e +%); [
6 tails -44,9° (CO,44, CH30T().

MS (20eV; m/e+%); 392 (+2.M-H, 0), 374 (22) + 293
(28)+261(15), 243(17), 233(
18).

23137), 215 (25), 1st (1s) + 17
9 (22), 143 (100) + 133 (23).

127 (40), 111 (74), 57 (34).

Examples 7 to 15 The following compounds were synthesized in the same manner as Examples 1, 5, and 6.

17■, 20-Dinotyl-6-oxoprostaglandin E-thyl ester (Example 7) 15-cyclobenthyl-ω-pentanol-6-oxoprostaglandin E1
Methyl ester (Example 8) 15-Cyclohexyl-ω-pentanol-6-oxoprostaglandin E1 methyl ester (Example 9) +6-Cyclobexyl-ω-tetratuno1. -6-Oquinbrostagranodine E, methyl ester (Example 10
) 18-oxo-6-oxoprostaglandin E, methyl ester (Example 11) 16-Methyl-6-oxoprostaglandin E, methyl ester (Example) 2) 16.16-dimethyl-
6-oxoprostaglandin E, methyl ester (l
Hfir Example 13) 1' 5-Methyl-6-ochine prostaglandin Sushi methyl ester (Example z) 17.17-Dimethyl-6-ochine prostaglandin El methyl ester (Example 15) Spectra are displayed together.

Claims (1)

[Claims] 1. 6-nitrogp staglandin E, which is a compound represented by the following formula [■], its 15-form, its enantiomer, or a mixture thereof in any proportion; , the following formula [former 8, the definitions of Ra and Rs are A method for producing 6-oxoprostaglandin E1, which is the same compound as above, its 15-form, its enantiomer, or a mixture thereof in any proportion. 2. A method for producing 6-oxoprostaglandin E according to claim 1, which comprises converting a nitro group into an oxo group using a trivalent titanium compound. 1. A method for producing 6-oxoprostaglandin E according to claim 2, which is carried out by adding a buffer salt to the reaction W form. 4. A method for producing 6-oxoprostaglandin E1 according to claim 2 or 3, which is carried out in the presence of a weakly basic compound. 5. Process for producing 6-oxoprostaglandin E according to claim 4, wherein the weakly basic compound is triphenylphosphine. 3.6. Claim, wherein the trivalent titanium compound is titanium trichloride. A method for producing 6-oxoprostaglandin E1 according to any one of the range #2 to #5. 7. A method for producing 6-oxoprostaglandin E according to any one of claims 1 to 6, which is carried out in a water-containing medium. 8. The organic medium is an ether type. or the method for producing 6=oxoprostaglandin E according to claim 7, which is an alcohol-based solvent. 9. The 6-oxo compound according to any one of claims 1 to 8, wherein R1 and/or RlI in the above formula [i] and/or the above formula [II] are a hydrogen atom or a methyl group. A method for producing prostaglandin E. IO in the above formula CI) and/or in the above formula (11), R,, R3 and/or R□, R□ are hydrogen atoms. 2-tetrahydropyranyl, 1-ethoxyethyl, t-
Claim 1, which is a butyldimethylsilyl group.
, jJ-The method for producing 6-oxoprostaglandin E1 according to any one of Item 9. 11. Production of 6-oxoprostaglandin diseases according to any one of claims 1 to 10, wherein R4 in the above formula CI) and the above formula (II) is a hydrogen atom or a methyl group. Law. 1z In the above formula [I] and the above formula [11], R5 is pentyl, hepatyl, heptyl + (S) -2
-Methylhexyl, @-2-methylhegycyl, 2-methyl-2-hexyl, 2-hexyl 1. Dodimethylpentyl, cyclopentyl, 3-propylcyclopentyl, cyclohexyl, cyclohexylmethyl, 2-ethoxyethyl. The method for producing 6-oxinbrostaglandin El according to any one of claims 1 to 11, which is a benzyl, 2-phenethyl or phenoxymethyl group. 13.6-oxinbrostaglandin 14, 6- 13. The method for producing 6-oxoprostaglandin E according to any one of claims 1 to 12, wherein the oxoprostaglandin avian is 6=oxoprostaglandin E, methyl ester. 15.6-Oxoprostaglandin E, class 17(S
), 20-dimethyl-6-oxoprostaglandin E, and its methyl ester. . 166-oxoprostaglandin E1 is 17(b)
, 20-dimethyl-6-oxoprostaglandin Sushi and its methyl ester, 6-oxoprostaglandin E according to any one of claims FffJ items 1 to 12. manufacturing method of types. 17,6-oxoprostaglandin E, and the like are 15-cyclohexyl-ω-pentanol-6-oxoprostaglandin E1 and its methyl ester, any one of claims 1 to 12 The method for producing 6-oxoprostaglandin E1 described above. 18, 6-oxoprostaglandin E, class 16■
-Methyl-6-oxoprostaglandin E and its methyl ester Claims 1 to 12
A method for producing 6-oxoprostaglandin E according to any one of the above items. 19.6-oxoprostaglandin E, M is 16-7
Enoxy ω-tetratrue 6-ocitub 1J staglandin E, and the 6-6 according to any one of claims 1 to 12'fJ4, which is a methyl ester thereof.
A method for producing oxoprostaglandin E. 206-oxoprostaglandin E1 is 15- (
3-7” p-bil) cyclobento-ω-pentanol-6-oxoprostaglandin E. and its methyl ester I!i!
A method for producing 6-oxoprostaglandin E according to any one of Items 1 to 12 of Item 1. 216-Oxoprostaglandin E, etc. have the above formula [I
] and the 6-oxoprostaglandin hill according to any one of claims 1 to 20, which is a stereoisomer having an absolute structure represented by the above formula [11]. ′