JPS6061564A - 6-nitroprostaglandin f, its preparation and use - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is H, 1-10C alkyl, substituted or unsubstituted phenyl, one equivalent of cation; R<2>, R<3> are H, tri-1-7C-hydrocarbon-silyl; R<4> is H, methyl; R<5> is unsubstituted alkyl of 5-8 carbon atoms or alkyl of 1-5 carbon atoms substituted with, e.g., substituent phenyl or phenoxy; n is 1-4]. EXAMPLE:11,15-Bis(t-butyldimethylsilyl)-6-nitroprostaglandin F1 and F1 methyl ester. USE:Medicine, diagnostic reagent and synthetic intermediate of, e.g., 6-oxoprostaglandin F. PREPARATION:6-Nitroprostaglandin E of formula II is reduced with a reducing reagent such as sodium borohydride, when needed, deprotected, hydrolyzed or subjected to salt formation reaction to give the compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to 6-nitroprostaglandin F, a method for producing the same, and uses thereof. More specifically, the present invention can be used as a synthetic intermediate for a compound useful as a diagnostic agent, and has pharmacological effects such as inhibiting platelet aggregation and vasodilation, and is also useful as a pharmaceutical. Prostaglandin F, a method for producing the same, and related thereto.

BACKGROUND OF THE INVENTION Natural prostaglandins are known as local hormones with high biological and pharmacological activity, and many studies have been conducted on their derivatives. Among the natural prostaglandins, prostaglandin Karasu α has uterine muscle contraction action, gastrointestinal smooth muscle contraction action, etc.
Applied to clinical practice (Pharmaceutical affairs.

VOJ, 25. ! +io, 8.1983). As a derivative of stablandin F, α, for example, 15-
Methylbrox rx Staclani/Zin F, a (Contr
acep order On+15.129.1976), and are expected to be applied to pharmaceuticals.

In addition, 6-oxoprostaglandin F and α are known as metabolites of brosc → and toiculin (Bio
chern, 13icphys, ActA, 57
4, 182.

1979). 6-Omi, shisoprostaglandin F1α
Although it is an inactive product, its application as a diagnostic agent for measuring blood and urine concentrations of pstacycline is being considered (Brlt.

J, of Urology+ 54, 26, 198
2).

Purpose of the Invention The present inventors conducted extensive research aimed at introducing a functional group into the 6-position of prostaclandin F, and as a result, synthesized 6-nitropro7 and tadalandin F, in which a nitro group was introduced at the 6-position. The present invention was achieved based on the discovery that such a compound is useful as a synthetic intermediate for 6-oxoprostaglandin F and also as a pharmaceutical.

Therefore, the present invention provides a novel compound 6-2) p-prostaglandin F, and a method for producing the same.

Structure and Effects of the Invention The present invention provides 6-2) q prostaglandin F, which is represented by [■] H.

In the above formula CI), R1 is a hydrogen atom, CI to CIO
It represents an alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted alicyclic group, a substituted or unsubstituted phenyl (C, to C,)fluor group, or a -equivalent cation.

Examples of the C3-CIO furkyl group include methyl,
Ethyl, n-propyl + 180-propyl.

n7'-)yl, 5ee-butyl, tert-butylln-pentyl, n-hexyl, n-hebutyl.

Linear or branched ones such as n-octyl, n-nonyl, n-decyl and the like can be mentioned.

As a substituent for a phenyl group that is directly substituted or non-required, for example, a hapgen atom! Hydroxy group, C, -C, 7cipoxy group, C0 to C4 which may be substituted with halogen atom
C1 which may be substituted with an alkyl group or a halogen atom
A ~c4 alkoxy group, a nitrile group, a carboxyl group, a (C, ~C0) alkoxycarbonyl group, etc. are preferred.

Examples of the halogen atom include fluorine, chlorine, and bromine, and particularly fluorine is preferably chlorine. Examples of the C2-C77 siloxy group include acetoxy.

Propionyloxy, n-butyryloxy.

iso-7'tyryloxy, n-vanlyloxy.

Mention may be made of 1so-hanlyloxy, caproyloxy, enantyloxy or benzoyloxy.

/% +81 C3-c4 alkyl groups which may be substituted include methyl, ethynu, n-propyl, 1
Preferred examples include 80-propyl, n-butyl, chloromethyl, dichloromethyl, and trifluoromethyl.

Examples of the C8-C4 alkoxy group which may be substituted with halogen include methoxy, ethoxy, n-pupoxy+180-propoxytll-butoxy! Preferred examples include chloromethoxy, dichloromethoxy, and trifluoropmethoxy. (C, -C,
) Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, and the like.

The substituted phenyl group can have 1 to 3, preferably 1 substituent as described above.

Substituted or unsubstituted alicyclic groups include saturated or unsaturated C3-C1, preferably C6-C6, particularly preferably C6 groups, substituted with the same substituents as mentioned above or unsubstituted; Examples include cyclopentyl, cyclohexyl, cyclohexenylfucycloheptylfucyclooctyl, and the like.

Examples of the substituted or unsubstituted phenyl (C, ~c,) alkyl group include benzyl, α-7enethyl, and β-7enethyl, in which the phenyl group is substituted with the same substituent as above or unsubstituted. It will be done.

One equivalent cation is, for example, NH,+.

Tetramethylammonium, monomethylammonium,
Ammonium cations such as dimethylammonium, trimethylammonium, benzyl ammonium, phenethyl ammonium, morpholinicum cation, monoethanol ammonium, piperidinium cation: Na+
Alkali metal cations such as , ni+; 1/2Ca, ”+
l 1/2Mg” + 1/2Zn”10, 1/3A/
Examples include divalent or trivalent metal cations such as '+.

R' is preferably a hydrogen atom, a c1-CIo furkyl group, or a -equivalent cation.

W and R3 are the same or different, hydrogen atoms, )
! I (C,-C,) is a group that forms an acetal bond with the oxygen atom of a hydrocarbon-silyl group or hydroxyl group.

)v(Ct-ct) Hydrocarbon silyl groups include, for example, trimethylsilyl and triethylsilyl.

t-methyldimethylsilyl group (C1-C4)
Preferred examples include furkylsilyl, diphenyl(C1-C4)alkylsilyl groups such as t-7'' tyldiphenylsilyl groups, and tribenzylsilyl groups.

An example of a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group is methoxymethyl.

l-ethoxyethyl, 2-methoxy-2-propyl, 2
-ethoxy-2-propyl t(2-methoxyethoxy)
Methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxobicic Elf [s, 1.
o) Hex-4-yl group may be mentioned.

Among these, 2-tetrahydropyranyl.

2-tetrahydrofuranyl, 1-ethoxyethyl, 2-
Methoxy-2-propyl, (2-methoxyethoxy)methyl is 6,6-dimethyl-3-oxa-2-oxo-
Particularly preferred is the bicyclo[3,1,0)hex-4-yl group.

Among these, W or W is a hydrogen atom.

Tri(C1-C4)alkylsilyl group, diphenyl(C
I-Ca) Furkylsilyl group, 2-tetrahuman r1 pyranyl group, 2-tetrahydrofuranyl group.

1-ethoxyethyl group, 2-ethoxy-2-butyl group, (2-methoxyethoxy)methyl group, or 6,6-dimethyl-3-oxa-2-oxo-bicyclo[3,1,
0]hex-4-yl group is preferred.

In the above formula (1) IC, R4 represents a hydrogen atom or a methyl group.

In the above formula [I], RS is an unsubstituted C5-C8 alkyl group: an optionally substituted phenyl group, phenoxy a, CI'=Cs phenoxy group or C3-C6
A substituted C, -C, alkyl group substituted with a cycloalkyl group; or a substituted or unsubstituted alicyclic group. C
The alkyl group of 5 to C1 may be linear or branched, such as n-pentyl, n-hexyl, 2-methyl-1-hexyl, 2-methyl-2-hexyl, n- Examples include hebutyl, n-octyl, and preferably pentyl+n-hexyl, 2-methyl-1-hexyl, 2-methyl-2-hexyl, and the like.

The ffl-substituted cI-C, alkyl group may be linear or branched, such as methyl, ethyl,
n-propyl + 1110-propyl.

Examples include n-butyl, dew-methyl, t-butyl+1-pentyl, and the like. These substituted alkyl groups include feni/L, group: fe/oxy; methoxy, ethoxy, n
-Propoxy.

C, -C, alkoxy groups such as 1so-poxy, n-butoxy, 180-butoxy, t-butoxy, n-pentoxy, n-hexoxy; C1 to C, cycloI such as cyclopentyl and cyclohexyl: + Substituted with furkyl group. These substituents may be further substituted with a specific substituent as a substituent for the substituted phenyl group of KRl.

Examples of the substituted C1-C, alkyl group include fr-C+-C, which is substituted with a phenoxy group or a phenyl group, which is optionally substituted with a fluorine atom, chlorine atom, methyl, ethyl or trifluoromethyl group. Furkyl group, or butoxymethyl, ethoxyethyl, propoxyethyl, butoxymethyl, methoxypropyl, 2
Preferred are -ethoxy-1,1-dimethylethyl and propoxydimethylmethyl, or cyclohexylmethyl, cyclohexylethyl, cyclohexyldimethylmethyl, 2-cyclohexyl-1,1-dimethylethyl, and the like.

As the substituted or unsubstituted alicyclic group, the same ones listed for R1 can be mentioned.

R1 is n-pentyl or n-hexino.

2-methyl-1-hexyl, 2-methyl-2-hexylcyclopentyl or cyclohexyl groups are preferred.

In the above formula (I), n represents an integer of 1 to 4, and particularly preferably 2 or 4 to S.

Preferred specific examples of the 6-nito-p prostaglandin F of the present invention include the following.

(100) 6-nitroprostaglandin F1α (1
02) t s-Methyl-6-nitroprostaglandin F, α (104) t 6-Methyl-6-nitroprostaglandin α (106) l 7-Methyl-6-nitroprostaglandin F , α (10 g) t s-Methyl-6-nitroprostaglandin F, α /v++) l + o-Fukyl-6-nitope p-staglandin 7 Fla (112) 20-ethyl-6-nitope p-staglandin F'Ia (114) 17-ethyl-6-nitoprostaglandin (1115) 15, 16-dimethyl-6-nitroprostaglandin 4α (118"l 17, 20-dimethyl-6-nitroprostaglandin) Zin F, α (120) 17-Methyl-20-ethyl-6-nitroprostaglandin F, α (122) I s-Cycloben-ω-pentanol-6-nitopp Sucgrandin F, α (124) +
5-cyclohexyl-ω-pentanol-6-2)
P prostaglandin F, α (126) te-cyclobenthyl ω-tetratrue 6-nito p prostaglandin F1α (128) 16-cyclohexyl-ω-
Tetra True 6-nito p prostaglandin F, α(1
30) 18-oxa-6-ditoprostaglandin 5α (132) 16-phenyl-ω-tetratrue 6-nitroprostaglandin F1α (134) 16- (m-fluorophenoxy)-ω
-Tetra true 6-nitroprostaglandin glaze (136) 2,3-dinol-6-nitroprostaglandin glaze (taa) t s-methyl-2,3-dinol-6-nitroprostaglandin F1g (140) 17120-:) Methyl-2,3-dinol-6-di)+17 prostaglandin 1et (142)
Methyl ester of (100) (144) (102)
Methyl ester of (146) Methyl ester of (104) (148) Methyl ester of (106) (1so)
Ethyl ester of (tos) (152) (1to)
Purpyl ester of (154) Sodium salt of (112) (156) Sodium salt of (114) (lss)
Sodium salt of (116) (160) Sodium salt of (118) (162) 11, 15- of (142)
11 of bis(t-butyldimethylsilyl)ether (164) (144), 11 of 15-bis(t-butyldimethylsilyl)ether (166) (146). ．． 15-bis(t-butyldimethylsilyl)ether (168) 11,15-bis(t-butyldimethylsilyl)ether of (148) The 6-nitroprostaglandins E of the present invention are represented by the following formula (Tl): It is produced by reducing the expressed 6-nito-μ prostaglandin E and subjecting it to deprotection, hydrolysis, or salt-forming reaction as necessary.

Examples of the reducing agent used in the reduction reaction include sodium borohydride, lithium borohydride, potassium borohydride, ram 1 lithium hydride trialkyl (C+~C,) boron, potassium triflukyl hydride (C1~C, ) Boron hydride compounds such as boron; diimbutylaluminum biterand, diisobutylaluminum-2.6-
Preferred examples include aluminum compounds such as di-t-butyl-4-methylphenoxyto, diisobutylaluminum-2,6-di-t-7'thyl-4-methylphenoxyto, and the like.

Solvents used in the reduction reaction include alcohols such as methanol, ethanol, and propatool; ethers such as diethyl ether, dioxane, and tetrahydrofuran;
1: Preferable examples include the one with a full body structure and the like.

The above-mentioned reducing agent used in the reduction reaction is preferably 0.5 to 50 times mole, particularly preferably 0.6 to 1 mole, relative to 6-nitroprostaglandin E represented by formula (II).
Use 0 times the molar amount. The amount of solvent used only needs to be sufficient to allow the reaction to proceed quickly, and is usually used to
1 to 10 for 6-nito p prostaglandin Eel) K
00 times capacity, preferably 5 to 100 times capacity is used. The reaction temperature varies depending on the raw materials, reagents, and solvents used, but it is carried out in the range of 0°C to 150°C, preferably in the range of 30°C to 100°C. The reaction time varies depending on the conditions, but is preferably about 0.1 to 48 hours, more preferably 0.1 to 24 hours. The reaction progresses in a thin layer p
It can be tracked by methods such as madography, and can be considered to have ended when the raw material disappears. After the reaction, the 6-2) Prustabrangin F represented by the formula CI) is separated and purified by treating the reaction solution in a conventional manner.

That is, it is separated and purified by a method using combination K, such as extraction, washing, drying, 8-condensation, and pomadography.

The target product produced by the above reduction reaction can then be subjected to membrane removal, hydrolysis, or salt production reaction, if necessary.

Removal of the protective group (R" and/or R") for the hydroxyl group can be carried out using, for example, acetic acid + pyrinnium p- Using salt or cation exchange resin as a catalyst, for example, water, tetrahydrofuran, ethyl needle, etc.
This reaction is suitably carried out using dioxene, acetone, acetonitrile, etc. as a reaction solvent. The reaction is usually -78℃
It is carried out for about 10 minutes to 3 days at a temperature range of ~+30°C. Also, there are protecting groups)! J (C, ~C,) hydrocarbon-
In the case of a silyl group, for example, the above-mentioned in the presence of acetic acid, tetrabutylammonium fluoride, cesium fluoride, etc., preferably one of the latter two (more preferably in the presence of a basic compound such as triethylamine). The reaction is carried out in a reaction solvent as described above (preferably a reaction solvent other than water) at a similar temperature and for a similar period of time.

The removal of the protecting group (R') of the carboxyl group, that is, the hydrolysis reaction, is carried out using an enzyme such as lipase in water or a solvent containing water at a temperature range of -10' to 160°C for 10 minutes to 10 minutes.
It will be held for about 24 hours.

According to the present invention, the compound having a carboxyl group produced by the hydrolysis reaction as in 81 above is then subjected to a salt-forming reaction, if necessary, to give the corresponding carboxylate.

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

In this way, 6-2) p-Prustabrangin F of the present invention is obtained.

The 6-nidoty7'q stavlandin E of the formula (IT), which is the raw material compound for the above reduction reaction, is represented by the following formula CII
I) 4-f-substituted-2-cyclopentenones represented by the following formula [■] and an organic lithium compound represented by the following formula [V]Cl/
Q......The organic copper compound obtained from the rust compound represented by (V) is subjected to a conjugate addition reaction, and then the nitroolefins represented by the following formula are reacted, and as necessary, They are produced by subjecting them to deprotection, hydrolysis, or salt-forming reactions, depending on the situation.

As can be understood from the definition, R" in the 4-substituted-2-cyclobentenones of formula [11] is the one obtained by removing the hydrogen atom from the definition of R1, and the specific examples of R" are those mentioned above. It is similar to

The synthesis of 4-1i-substituted-2-cyclobentenones is described in the literature Te
traltedron+ Vo/ 32, 171s
(1976) is used as a reference.

R" in the organolithium compound of formula rlV) is R"
Similarly, the definition of R' also excludes the hydrogen atom. Q in the copper compound of formula [v] is chlorine, fluorine,
Halogen atoms such as bromine: C, ~C, alkoxy groups such as methoxy, ethoxy, p-boxy groups: phenoxy groups;
Phenylthio group dimethylamino, diethylamino! Represents a di(C,-C,)alkylamino group such as dibu-μvir7mino group; or a cyano group.

To obtain an organocopper compound from an organolithium compound of formula (IV) and a copper compound of formula (V), refer to the literature Tetrahedr.
on Lott, +21, 1247 (1980)
is used as a reference.

In the nitroolefins of formula (VI), R'' is.

The hydrogen atom and -equivalent cation are removed from the definition of R1, and such compounds are described in the literature Journal of
the American Chemical 5oc
It can be obtained by the method described in ietyt 9g +4679 (1976).

#4-ffi-substituted-2-cyclobenzonones are reacted with the organocopper compound in stoichiometrically equimolar amounts, but usually 0 to 1 mole of 4-substituted-2-cyclobentenones. ．．
This is carried out using an organic copper compound in an amount of 5 to 2.0 times by mole, particularly preferably 1.5 times by mole.

The reaction temperature was -120°C to 0°C, I! ! fK is preferably within a temperature range of about 0°C to -30°C. Although the reaction time varies depending on the reaction temperature, it is usually sufficient to react at -78°C to -20°C for about 1 hour.

The reaction is carried out in the presence of an organic medium. An inert aprotic organic medium is used that is liquid at the reaction temperature and does not react with the reaction reagents.

Such aprotic inert organic media include, for example,
Saturated hydrocarbons such as pentane, hexane, heptane;
benzene, toluene.

Aromatic hydrocarbons such as xylene; diethyl ether,
Tetrahydrofuran, dioxane.

needle thread smelting such as dimethoxyethane, ethylene glycol dimethyl ether; others hexamethylphosphoric tri7mide (HMP), N,N-dimethylacetamide (DMF) + hi+N-dimethylacetamide (DMAC), dimethyl sulfoxide, 4-a
84-13i converted-2-
An alkenyl group, which is the i group of the organocopper compound, is added to the 3-position of the cyclobentenone, and an anion is added to the 2-position.
It is assumed that a so-called conjugate (, , 1 + 2 root) is formed.
By reacting the nitroonfins represented by the above formula (Vl), the desired 6-nitrobut p-staglandins E can be obtained. In the reaction of nitroolefins, the above formula [vl] may be diluted with a cocoon-weight aprotic organic medium in a reaction system in which an organocopper compound is conjugately added to a 4-substituted-2-cyclobentenone. This is carried out by adding nitroolefins represented by:

The nitroolefins are diru- olefins produced by conjugate addition.
The reaction is carried out in stoichiometrically equimolar amounts, but usually 0.5 to 2.0 times the mole of the 64-substituted-2-cyclopentenone used initially, particularly preferably, / is 0,8
~1.2 molar volumes are used.

Snow! , Horan, pζ-methylpyrrolidone-like rock 0
Examples include non-7", polar solvents, etc., and it is also possible to use a mixed solvent of 2 seconds or more of solvents.
-1: For the aprotic inert organic medium and 17, the inert medium used for producing the organocopper compound can also be used as it is. That is, in this case, the reaction may be carried out by adding the 4-substituted-2-cyclobentenones into the reaction system in which the organocopper compound was produced.

The amount of organic medium to be used is sufficient as long as the reaction proceeds smoothly, and usually 1 to 100 times the volume of the raw materials, preferably 2 to 30 times the volume is used.

The reaction is preferably carried out under an atmosphere of nitrogen or argon gas. In addition, trivalent phosphorus compounds such as trialkylphosphines (eg, triethylphosphine) are used in the reaction.

The reaction is preferably carried out in the presence of trifurkyl phosphite (eg, trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, tri-n-butyl phosphite, etc.).

The reaction temperature is -120°C to 0°C, preferably -0°C to -
A temperature range of about 30°C is adopted. The reaction time varies depending on the reaction temperature, but it is usually sufficient to react for about 1 hour at -78°C to -40°C, and it is efficient to monitor and determine the end point of the reaction using thin layer chromatography, etc. .

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.

The product thus obtained is deprotected and hydrolyzed as necessary in the same manner as described above.

It can be subjected to a salt-forming reaction, and the desired 6-nitroprostaglandin E can be obtained.

6-nitroprostaglandin E of formula CI) of the present invention is converted to 6-oxoprostaglandin F, prostaglandin F, etc. by the method shown below.

(A) Conversion of 6-nito-p prostaglandin F to 6-oxtuburostagland F by the following formula (1) Reacting prostaglandin F with (a) an acidic compound, (b) trivalent titanium 6-oxoprostase represented by Grangin F type is obtained. 6-oxoprostaglandin F is expected to be applied as a diagnostic agent (BrIL-J-Of Ur
ology+ 54126 +1982), and may also be applied as a pharmaceutical.

2) The reaction of converting a q group to an oxo group is generally known as the Nef reaction (J, U, Nef + An
n, +280.263 (1894) This reaction is known and many research examples have been reported to date. For this reason, many conversion reagents are known, but they can be roughly divided into three types: (a) those that react with acidic compounds, (b) those that react with trivalent titanium compounds, and (e) those that react with oxidizing agents. They are classified and each will be explained below.

(a) When reacting with an acidic compound: This is the most common Nef reaction method, in which a nitro compound is
First, it is reacted with a basic compound in water or an alcohol-based or ether-based solvent to form an acinide salt, and then reacted with hydrochloric acid or sulfuric acid to form the corresponding oxy compound. For example, W, E, No1 and + Chem, Re
v, +55.

13t (19s s ) +N, Kornblum et al., J. Am.

Chem, Soc, +LJ,, +1742 (1'965
), Y.

Mazur et al. + J, Am, Chem, Soc, +
Reports such as 99, 386 t (1977) are useful. Although this is a basic method, it can be hampered by the reaction under strongly alkaline and acidic conditions.

Examples of the basic compound used in the above reaction include sodium hydroxide, potassium hydroxide, sodium methylate, and sodium ethylate. The basic compound is used in an amount of 0.5 to 5.0 times, preferably 0.8 to 1.5 times, the amount of 6-nitrobrostaglandin F@ used.

Among the solvents used in the above reaction, examples of alcoholic solvents include methanol, ethanol, and isopropyl alcohol, and examples of etheric solvents include diethyl ether and tetrahydrofuran.

Examples include dimethoxyethane and dioxane.

The reaction conditions for contacting the 6-nitroprostaglandin F class basic compound with the above-mentioned solvent to form the 7-sinitro salt vary depending on the basic compound used, but when using sodium methylate, the reaction is carried out at 0°C within 30 minutes. It is enough to let them.

When the thus obtained fC7C7 cylindrip-intermediate is reacted with an acidic compound, the desired nitro group-oxy group conversion reaction is achieved.

As such an acidic compound, 1.0 to 5.0 times the mole of hydrochloric acid (preferably o, s to 6 m constant, preferably 1 to 4 N hydrochloric acid) to the basic compound used.
Alternatively, sulfuric acid (preferably 1-12N, particularly preferably 3-6N 1) is added to the reaction solution containing the 7-sinitro salt intermediate to react.

The reaction temperature varies somewhat depending on the type and concentration of acid used and the type of water-soluble organic medium, but usually -
The temperature is preferably 20°C to 80°C, preferably 0°C to 60°C, particularly preferably 20°C to 50°C. The reaction time varies depending on the reaction temperature and reaction conditions. The end point of the reaction is determined by tracking the reaction using an analytical means such as Togelafy, and when the reaction temperature is 40° C., the reaction ends within 0.5 to 5 hours.

佽) When reacting with a trivalent titanium compound; low-valent metal compounds such as trivalent titanium compounds, divalent vanadium compounds, and divalent chromium compounds are known, but trivalent titanium compounds is preferably used as %. Usually, titanium trichloride aqueous solution is used as a reducing agent, but the reaction solution is strongly acidic (p
Sixth, add a buffer salt such as ammonium acetate to the reaction system to lower the pH of the reaction solution from 4 to 7.
When L<, it may be necessary to reduce side reactions to around 6 to suppress side reactions. Even in this case, acidification is caused by a base such as sodium methylate before the reduction reaction)
By using F as a salt, the reaction proceeds more smoothly. Furthermore, since the present invention uses an aqueous solution of titanium trichloride, a relatively water-soluble organic medium such as an ether solvent such as diethyl ether, tetrahydrofuran, dimethoxyethane, or dioxane, or methanol or ethanol is used.

This is carried out in the presence of a furfur solvent such as isopropyl alcohol. For detailed experimental conditions, see J.E.
J'icMu r ry et al.

J, Org, Chem, + a s, 4 s 6
7 (s 97a).

J, E, McMurry + Aceounta Chsm
, Res, + 7 t281 (1974), etc. serve as a reference.

The reaction is carried out by first converting 6-nitrol'p-staglandin F into an acinitro salt intermediate in the same manner as described in (a), and then carrying out the reaction according to the method of J.E. McMurry et al. described above. That is, titanium trichloride and ammonium acetate are made into an aqueous solution (pH around 6) at a molar ratio of 1=6, and this aqueous solution is mixed with a reaction solution containing the 7-sinito p salt intermediate.

The amount of titanium chloride is between 1 and 20 for the acinitron salt intermediate.
twice the mole, preferably 2 to 15 times the mole, particularly preferably 3 times the mole
It is carried out using ~10 times the molar amount. 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, Examples include alcohol solvents such as isopropyl alcohol.

The reaction temperature is usually 0°C to 40°C, preferably 20°C to 30°C, and the reaction time varies depending on reaction conditions such as reaction temperature, reactant fir, PR, etc. Analytical means such as thin layer p-mography are used. The end point of the reaction is determined from K by following the reaction, and the reaction ends in 1 to 5 hours at room temperature.

(c) When reacting with an oxidizing agent; 2) Treating the p compound with a basic substance to form an acyni) p salt, and reacting it with various oxidizing agents to induce the nido compound into the corresponding oxo compound. It has the advantage of being able to be converted under relatively mild conditions using a method of . References for the base and oxidizing agent to be used as well as the reaction conditions include, for example, sodium methylate 7 (J, E, McMurry et al. + J, Org-Chem, 39, 259 (1974).
))l Sodium hydroxide-heavyt oxygen (J, R, m
11 tarns et al.

J,Org,Chem,, 43, 1271 (1
978) ).

Potassium carbonate-hydrogen peroxide (G, A, 01ah et al.

5ynthes+s, 667 (1980) ) +
#t-butoxide t-butylhide p-peroxide (P, A. Bartlett et al.

Tetrahedron Letters, 331
(1977) ) + sodium hydroxide, sodium t-
Butoxide or silica gel-potassium permanganate (
F, T, Williams + Jr, et al + J, Org.

Chem, + 27 H3699 (1962) +N
, Korr+blumCommun, , 635 (198
2) l) lyzti/l, 7mine or sodium hydride-ceric nitrate (G, A, 01ah et al. + 5y
nthesis+44 (1980) + R, C, Co
, olson et al.
etters, 23.3521 (1982)).

These reactions were actually performed using 6-dito-μ prostaglandin F.
When applied to the above, the conditions adopted will differ depending on the type of oxidizing agent used, but in any case, the method is carried out according to the above-mentioned cited document. That is, first, a method is adopted in which the exemplified base is reacted with 6-nitroprostaglandin F to form an acinitronic salt intermediate, which is then reacted with a post-brewing agent.

For example, when using hydrogen peroxide as an oxidizing agent,
After 6-nitroprostaglandin F is reacted with a base such as potassium carbonate in advance to form an acini)+- salt, a hydrogen peroxide solution ( Preferably, the reaction is carried out using 10 to 30% hydrogen peroxide solution.

In order to make the reaction proceed smoothly, it is preferable to further add a relatively water-soluble organic medium to the reaction system. Examples of such organic medium include ether solvents such as gel ether, tetrahydrofuran, dimethoxyethane, and dioxane.
Examples include alcoholic solvents such as methanol, ethanol, and isopropylfurfur.

The reaction temperature varies somewhat depending on the type and concentration of the water-soluble organic medium used, but it is usually carried out in the range of -20°C to 80°C, preferably 0°C to 60°C, particularly preferably 20°C to 50°C. The reaction time varies depending on the reaction temperature and reaction conditions, and the end point of the reaction is determined by tracking the reaction using analytical means such as thin layer chromatography; however, when the reaction temperature is 40°C, the reaction ends within 0.5 to 8 hours. do.

In addition, when t-butyl hydroperoxide is used as an oxidizing agent, t-butyl hydroperoxide is used in an amount equal to or more than the same mole, preferably 2 to 20 times the mole relative to the 6-2) +-prostaglandin F used. is added to the reaction solution containing the above-mentioned acinitro salt intermediate and allowed to react. The presence of a catalyst is essential for the completion of this reaction, and such catalysts include vanadium (Th') oxy-7cetyl-7cetonate, molpudenbentacarponyl, etc., and the amount used is t-butyl hydroper o for oxide,
i to 20 molds, preferably 1 to 1o molds
Used within the range of

The reaction temperature varies depending on the amount of t-butyl hydroperoxide used, the type of catalyst, the amount used, etc., but is usually -20°C.
~100'' C1 Preferably, the reaction is carried out in the range of θ°C to 80°C.The reaction time varies depending on the reaction temperature and reaction conditions, and the reaction end point is determined by K. However, the reaction temperature is 40℃
In the case of 0.5 hours to 24 hours, it ends.

Examples of oxidizing agents other than those exemplified here include molybdenum bent oxide pyridine-hexamethylphosphor 7
Examples include mido complex, potassium permanganate, cerium (TV) ammonium nitrate, and the like.

After the reaction, the resulting product is separated from the reaction solution and purified by conventional means. For example, extraction, washing, chromatography or a combination K of these may be used.

In this way, 6-nito p-butrostaglandin F is converted to 6-oxoprostaglandin F.
-Oxoprostaglandin F can be further subjected to a decapitation reaction, a hydrolysis reaction, or a salt production reaction in the same manner as described above, if necessary.

Preferred specific examples of 6-oxoprostaglandin F obtained by the above-mentioned method include the following.

(200)″6-oxoprostaglandin F, α(9
n*) 1ts-Beef Roux 6-oxyprostaglandin F, α (204) 16-Methyl-6-oxoprostaglandin F, α (206) ly-Methyl-6-oxoprostaglandin F1α (208) 1g-Methyl-6-oxoprostaglandin F1α (210) 17.20-Dimethyl-6-oxoprostaglandin F1α (212) 16,16.20-)dimethyl-6-oxyprostaglandin F,α (214 ) 17-Methyl-20-ethyl-6-oxoprostaglandin F1α (216) t s-cyclopentyl-ω-pentanol-6-oxoprostaglandin F, α (218) 15-cyclohexyl-ω-pentanol-6-oxoprostaglandin Brandin glaze (220) 15-(2,2-dimethyl)cyclopeftyl-ω-pentanol-6-oxyprostaglandin Atsushi α (222) 16-Cyclobenthyl-ω-tetratrue 6-Oxylabrustablandin F, σ (224) 18-Oxa-6-Ochirabrustabrandin 3α (226) 16-Phenyl-ω-Tetratrue 6-Ochirabrustabrandin F, α (228) 16-Phenoxy-ω-TetraTrue 6-
Oxoprostaglandin F, α03) Conversion of 6-nitroprostaglandin F to prostaglandin F represented by the following formula (I) Prostaglandin F represented by the following formula [■]H is obtained by reacting with tributyltin hydride in the presence of and subjecting it to deprotection, hydrolysis, or salt-forming reaction as necessary.

The amount of tributyltin hydride used in this method is 0.5 to 50 equivalents, preferably 0.5 to 50 equivalents, relative to 6-nitroprostaglandin F represented by the above formula (1).
．． It is used in a range of 8 to 30 equivalents, more preferably 1.0 to ]O equivalent.

In this method, a suitable radical generator is used as a reaction aid to initiate the reaction.

A radical generator which is usually used as a reaction aid for a radical reduction reaction such as tributyltin hydride is preferably used.

Examples of such radical generators include α,α'-7zobisimptilonitrile, bis-t-butyl peroxide, potassium dalaphite, sodium amalgam, and light irradiation. The amount of radical generator used is 0.05 per tributyltin/hydride.
It is effective to use it in a range of 20% by weight, preferably 0.1 to 5M.

The reaction is usually carried out under an inert atmosphere such as nitrogen or argon. In the method of the present invention, tributyltin hydride itself may be used as a solvent, or a solvent commonly used in the reduction reaction of tributyltin hydride may be used. Such solvents include benzene, toluene,
Aromatic hydrocarbons such as xylene; aliphatic hydrocarbons such as hexane and heptane; ethers such as ether and tetrahydrofuran are preferably used. When using a solvent, 0.0% for tributyltin hydride.
It is sufficient to use 5 to 50 times the volume.

The reaction temperature varies depending on the reaction aid used and the reaction conditions, but it is usually carried out in the range of 0 to 150°C, preferably 80 to 120°C. The reaction time varies depending on the reaction conditions such as the amount of the reaction aid, tributyltin hydride, and the reaction temperature.The reaction end point can be determined by tracking the reaction using thin-layer p-mography, but if the reaction temperature is 100℃. It will be completed in 0.5 to 12 hours.

After completion of the reaction, the prostaglandin F represented by the above formula [■] can be isolated by subjecting the reaction mixture to extraction, washing, drying, phosphorhybridization, etc. by a conventional method, It can also be isolated by directly subjecting the reaction mixture obtained by distilling off the solvent under reduced pressure to p-madography.

The thus obtained prostaglandin F can be further subjected to a deprotection reaction, a hydrolysis reaction, or a salt-forming reaction in the same manner as described above, if necessary.

Specific examples of the booster taglandin F type thus obtained include the following.

(300) Prostaglandin F, α (302) 15-methyl prostaglandin F, α (
304) 16-methyl prostaglandin hα (30
6) 17-methyl prostaglandin island α (308)
1g-Methyl prostaglandin F, alpha (310)
17120-dimethylprostaglandin F, α (312) 17-Methyl-20-methyl prostaglandin F, α (314) t s-cyclobenthyl ω-pentanol prostaglandin F, α (316) 15- Cyclohexyl-ω-pentatul prostaglandin F1α (318) 15-(2,2-dimethyl)cyclopentyl-ω-pentatul prostaglandin hα (32F) 18-oxa prostaglandin F,a(
322) 16-phenyl-ω-tetranorprostaglandin Fla (324) 16-phenoxy-ω-tetranorprostaglandin F, a Above KHI! As described above, the present invention provides novel 6-nitroprustabrandin F and a method for producing the same, and such compounds are useful as pharmaceuticals or diagnostic agents. It is also useful as a synthetic intermediate for prostaglandin F and prostaglandin F1aAl.

The present invention will be explained in more detail below with reference to Examples.

Reference example 1 ■-dl -3-t-butyldimethylsilyloxy-1
-Iodo-1-octene (478#.

1.3 nvnol) in an ether solution (lod) of 2
．． 2M t-butyllithium in pentane solution (1.2m
t, 2.6 mmol) was added at -78°C and stirred for 2 hours. Add cuprous iodide (248 Da) to this solution.

1.3 mmol) t) butylphosphine (57
8N + 2.9 mmol) in ether solution (31
1/) was added thereto, and the mixture was stirred at -78°C for 1 hour. Add d/-4-t-butyldimethylsilyloxy-2-silyloxy to this solution.
c: r bentenone (2t 2 tIIgt t, o m
A solution of mol) in ether (6 mt) was added thereto, and the mixture was stirred at -78°C for 15 minutes and at -40°C for 1 hour. After cooling to -78°C, methyl 6-di)tnia-6-hebutenoate (187
~, 1.0 nol) Add ether (51) solution 15
The mixture was stirred for 1 hour at -40°C and for 30 minutes at -20°C. Ether was added, and the mixture was washed with an ammoniacal aqueous ammonium chloride solution, then an aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated to obtain a crude product of 1.7411. This material was subjected to silica gel column chromatography (hexane:ethyl acetate = 10:l) and d/-
11,15-bis(t-butyldimethylsilyl)-6-
Nitroprostaglandin E, a mixture of methyl esters and their 15-epimers (232q, 0.362
mmol+36%) was obtained.

NMR (CD(1,, δ(pm)); o, o6(t2Hts), 0.84-0.86(21H
)11.1~2.6(22H+m)+3.61(3H+
8) +3.8~4.3 (2H1m), 4.5~
5.2 (IHIm) 15.35”-5,55(2
Htm).

IRC liquid film, 3'); 1740, 1555, 1460, 1440°+360.
1255,1160,1100゜1005.970,8
75,860,840°8+0.775°Mass (20eV; mle, %);626
(1+ M Me ) + 610 (4r M OM
e) +584 (29, M-tBLI), 570 (3
8).

553(23), 49B(17), 493(20).

464(22), 438(26)142B28).

405 (20) + 330 (40) + 299 (36) + 2
77 (200) + 245 (20) + 215 (20), 175 (25), 75 (94).

Reference Example 2 Ester: (g)-3(s)-L by exactly the same method as Reference Example J
-Butyldimethylsilyloxy-1-iodo-1-octene (1,2111, 3,3 mmol; rα Ling 30,6
°) and 4@-t-butyldimethylsilyloxy-2-cyclobentenone (636W + 3.0 mrno 11), I'S-bis(-butyldimethylsilyl)-6-nitro7'p Staclandin E1 methyl ester (656 mg.

1.023 mmol + 34%). The NMR, IR, and Mass of this product matched those of the compound obtained in Reference Example 1.

Ca Culm 22.3° (Me OH + CO, 71) Example 1 Methanol (200 ml) was cooled to 0°C and sodium borohydride (7601Q.

20 mmol) and stirred for 3 minutes. 1 among them
1. 15-bis(t--j methyldimethylsilyl)-6
-nito-p prostaclandin E, methyl ester (61
7 m9 + 0.963 mmol) of methanol (5
0ml) solution was added and kept at 0°C for 40 minutes. After adding a saturated aqueous ammonium chloride solution, methanol was distilled off under reduced pressure, extracted with ethyl acetate (xoomjxa), the separated organic layer was washed with brine, dried over 1 gnesium sulfate, and concentrated under reduced pressure to give 11.15- Bis(t-butyldimethylsilyl)-6-nitroprostaglandin F1α and F,β methyl ester)+-(s s smg, 0.
914 mmol + 95%) was obtained.

NMR (CDCd, δ (solution)); 0.06 (12H + Fl) 10.85 (21H) + 1,
+ ~2.4(23H+m)+3.6o(3H+s)+
3.8~4.2 (3H+m) +~4-7 (
IH+t))+5.2 s ~5.45 (2H+m
).

IR (liquid film νσ)・3500.2950.2860.1735.1545
.

+460.1435, 1360.1250, 1060°1000.965.835.770°Mass (20eV; mle +%); 586 (M-
57, 33), 572 (34) + 555 (35), 49
4 (47) + 463 (47).

454 (52) + 440 (56) + 423 (42) + 4
07 (40), 362 (32), 333 (34).

315 (100), 215 (60), 201 (43)+
189 (44) + 187 (91) + 175 (54) + 1
, 71. (41), 99 (s3), 7
s (s s ).

Example 2 +1,15-bis(t-butyldimethylsilyl)-6-
A solution of nitroprostaclandin F1α and Flβ methyl ester (528 μ, 0.Fl 2 mmol) in methanol (10 l1 rt) with 2.8% sodium
Methanol solution of methylate (t, 6m#.

0.82 mmol) and stirred at room temperature for 5 minutes.

This solution was mixed with ammonium acetate (7,79,0,1 mmo
The mixture was added to a mixed solution of the aqueous solution (1011 Ll) of 1) and an aqueous 25-titanium trichloride solution (10.2 ml, 16.4 mmol) and stirred at room temperature for 18 hours. Neutralize by adding sodium bicarbonate aqueous solution, and add ethyl acetate (xooazx
After extraction in step 3), the extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 497 ml of crude product. This product was subjected to silica gel column chromatography (hexane: ethyl acetate = 6 = 1 to 1:2) to obtain 11, Is-bis(
t=nibutyldimethylsilyl-6-oxyp p staclandin F, α methyl ester (2s 7tq, 0.
42 mmol + a 1; tl, ts-bis(t-butyldimethylsilyl) prostaglandin, consistent with the standard derived from methyl ester) and 11,15-bis(
t-butyldimethylsilyloxy)-6-oxybutyl p-staglandin F, β-methyl ester (1381A9.0
．． 23 mmal t 33%) was obtained.

11.15-bis(t-butyldimethylsilyl)-6-
Oxygen p-staglandin F, α-methyl ester: NMR (CD(1,, tl (KG); 0.04(1
2H+8) 10.86 (21H).

1.0~2.8 (23H+m) + 3.60 (
3I(+s) 13.65~4.25 (3H+m
) +5.2 s ~5.4 s (2Hl m LI
R (liquid film, α-1): 3460+2950t2870s174011720+
1460.1360, 1250, 1060.100G.

970.835,775°Mass (20eV+ m/e+%>+594 (M-
Hto, 10) + 555 (M-tBu, 34)
.

538(41), 463(27), 423(31).

405 (46) + 391 (58) + 379
(40) +331 (33)+267(9-7)+2
15 (75) + 175 (72), 143 (100) 11
11 (56).

75 (42) + 73 (47).

11.15-bis(t-butyldimethylsilyl)-6-
Oxoprostaglandin F, β methyl ester: NMR (CDC7+, δ(PF)); 0.06 (12
)1ts)+0.87(21H)+1.0~2.8(2
2H1m) 13.61 (3H9s+) 13.7s ~
4.3 s (4Htm) +5.2~5.4 (2H
+m).

IRC liquid film, cm-'); 350012950128701174011710+
1460.1360,1250,1060.1000゜970.835,775''-' Mass (20eV; m/e +%); 594 (M
Hl()+2), 5ss(3) 153B(4), 50
6(23), 48B(31).

413(27), 395(35), 267(16).

241 (15) + 215 (32) + 201 (12).

175(29), 143(45), 115(11).

111(25), 75(100).

Example 3 6-oxoprostaglandin F, α methyl ester: 11115-bis(t-butyldimethylsilyl)-6-
Okitsuorostaglandin F, α-methyl ester (12
4q, 0.203 mmol) was dissolved in 10 mt of acetonitrile, 0.2% mt of pyridine and 0.5 mt of hydrofluoric acid-pyridine were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was neutralized by adding an aqueous sodium bicarbonate solution, and the resulting aqueous layer was extracted with ethyl acetate (50dX4). The separated organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 85m ! 5J of crude product was obtained. This product was purified by preparative thin layer chromatography (ethyl acetate: acetone = 4:1), and 6-oxybu-p stadalandin F, α-methyl ester (65'I9゜0.169
mmall 83%) was obtained.

NMR (CDC/, δ (furnace)); 0.87 (3H+t) tl, O ~ 1.8 (16H+m)
+2.1~2.7 (6H, m)+ 3.2~4.3 (6H1m)+3.61 (3H*s)+
5.2-5.6 (2H+m).

IR (liquid film + am') z 3400.2950,2870,1710°1430.
1240, 1190, 1175° 1040.965.

Mass (20eV; rn/e +%): 366
(M-H, O+ 13 ), 348 (M-zH, O+1
8)+335(8)+330(5)+323(+4)+
319 (12) + 279 (23) + 265 (33), 2
23(67), 208(39).

196 (72), +95 (54), +64 (34L14
3 (96) + 121 (43) + 111 (
83) +99 (100), 95 (58), 71 (27
).

In the same manner, 6-oxybrostaglandin F, β-methyl ester was obtained from I+, 15-bis(t-butyldimethylsilyl)-6-oxybrostaglandin F, β-methyl ester.

NMR (CDCI!, δ(pP)); 0.67 (3)
r+t), 1.1-2.7 (22n1m) 13.0-4
．． z(6J(,m), 3.62(3H+8)+5.3~
5.55 (2H, m).

IR (CHC/s, crn-1) p 3300', 2930, 2870, 1710° 1440
．． 1260, 1170, 1040°960'.

M'ass (20eV + ml e +%); 36
e (M-H:O+z)+348 (M-2H2018)
+330(3)+L90(16)+157(14)+1
43 (100) + 136 (44) + 129 (13) + t
t7(x3)+xxs(z),zx(so).

109(13), 99(28).

Example 4 6-oxysolostacrandin Fla methyl ester (
261n9! Dissolve 68 amol) in 1ml (f)/ml and add 5N sodium hydroxide (0.14ml).

0.6 s mmol) was added thereto, and the mixture was stirred at 40°C for 3 hours.

The mixture was acidified by adding a saturated aqueous ammonium chloride solution and then diluted hydrochloric acid, and extracted with ethyl acetate ('50 ml x 5). The obtained organic layer was washed with brine and dried (Mg5
Oj post-determination yielded 25 μm of crude product. This product was separated by silica gel column chromatography (ethyl acetate: 7 setone: IHiL"9:10:1), and 6-ocituprostaclandin F (1(21"&+57#m0)
1+84%). This product completely matched the standard product synthesized separately.

Rf O, 28 (pp form: methanol: acetic acid = 9
0:5:5; yellow color developed by anisaldehyde) Reference Example 3 A reaction was carried out using exactly the same method as in Reference Example 1. However, methyl 4-nitro-4-hentenoate is used instead of methyl 6-nitro-6-heptenoate, and 11.
15-bis(t-butyldimethylsilyl)-6-2)
q -2,3-Dinorprostaglandin E1 methyl ester in yield 434″?′ + 3000-NMR (CDC/,, δ(F)); o, o6(t 2H+5) 10.86 (21n1m )1
1.1~2.6 (1sHtm)+3.61 (3H+
8)+a,e ~4.3 (2H+m)+4.5
〜5.1 (IH+m)+5.3 s 〜s, s 5(
2HTm).

IRC liquid film + Cm') x 1740.1555,1460,1360°1255.
1160, 1100, 1005°970. 875.
860,840. 810. 775°Mass (2
0eV); 598 (MMe!2) 1582 (M OM
e + 2 ) +556 (M-tBu, 31).

Examples 5 to 8 The same procedure as in Example 1 was carried out using 11.15-bis(1-butyldimethylsilyl)-6-nitro-2,3-dinorp-staclandin E obtained in Reference Example 3 and methyl ester as the starting material. By reduction reaction, 11.15-bis(t-butyldimethylsilyl)-6-dil-rho 2.3-dinorbrostaclandin F1α and F,β methyl ester (a rate 5tst Example 5), Example 2 11.15-bis(t-butyldimethylsilyl) was obtained by conversion reaction and separation similar to
-6-oxo-2,3-dinorprostaglandin F,
α methyl ester (yield SZS + Back Example 6), Example 3
The same deprotection reaction as in Example 4 gave 6-oxo-2,3-dinorp-staclandin F, α-methyl ester (yield: 87 cm, Example 7), and the same hydrolysis reaction as in Example 4 gave 6-
Oxo-2,3-dinorbu p-staglandin Flα (yield 79%, Example 8) was obtained. The spectra are shown in Table 1.

Table 1 Example 9 11.15-bis(t-7' methyldimethylsilyl)-6
- Nitrobrostaglandin F, alpha methyl ester (3
22 Da, o, s mmol) of toluene (811 Lt
) solution to trimethyltin 1 hydride (1,451/
, s, o mmol) and a, a'-7 zobisisobutyronitrile (164''I + 1.0 mmol) were gradually added dropwise to a solution of t, renin (s td ) under heating under reflux under a phonetic atmosphere. After reacting for 30 minutes, the mixture was allowed to cool, the toluene was concentrated under reduced pressure, and the product was separated by silica gel column chromatography (solvent: hexane: ethyl acetate = 6:1), and the product was denidated. 11.15 -bis(t-butyldimethylsilyl)-prostaglandin F
, α methyl ester (117m+1i'+0.196m
rn01+39'j) was obtained. This product is a sample obtained separately, thin layer chromatography (3 solvent system), and NMR.
, I.R.

and Mass were in complete agreement.

NMR (CDCJ, δ (ferment)): n l'l G (19M-a)-n Q? /
911J 1-1.1~3.0 (25Hsm)
+ 3.66 (3I (+8) +4, o5 (3Htm
) t5.48 (2H+m).

IR (neat + am), + 3630.1730.971m.

Mass (20eV+m/e)y 541 (M+-tBu>.

Claims (1)

[Claims] 1. 6-nitroprostaglandin F represented by the following formula [I) H. l R' is a hydrogen atom, C1-C,. a furkyl group or -
6 of claim 1, which is an equivalent cation.
-Nitroprostaglandin F. 3, 1' is n-pentyl group, n-hexyl group, 2-methyl-1-hexyl group, 2-methyl-2-hexyl group,
6-nitroprostaglandin F according to claim 1 or 2, which is a cyclopentyl group or a cyclohexyl group. 48R2 and R8 are the same or different hydrogen atoms, tri(
C8-C,) alkylsilyl group, diphenyl (C3-C
4) Furkylsilyl group, 2-tetrahydropyranyl group,
2-tetrahydrocolanyl group, l-ethoxyethyl group,
2-ethoxy-2-propyl group, (2-methoxyethoxy)methyl group, or 6,6-cymethyl-3-oxa-2
6-2)p prostaglandins according to any one of claims 1 to 3, which are -oxybicycloC3,1,0)hex-4-yl groups. 5. Subjecting 6-nitoP prostaclandin E represented by the following formula LIT to a reduction reaction, and deprotecting as necessary. 1. A method for producing 6-nitroprostaglandin F represented by the following formula H, which comprises subjecting it to hydrolysis or salt-forming reaction. G. A method for producing 6-nitroprostaglandins F according to claim 5, wherein the reduction is carried out with a borohydride compound or an aluminum compound. 7. Reduction is carried out using alcohols, ethers or aromatic hydrocarbons as a solvent 4? A method for producing 6-nitroprostaglandin F according to claim 1 or 2. & 4-substituted-2-cyclobentenones represented by the following formula [m) 210, and an organolithium compound represented by the following formula CIV) and the following formula EV) C1,
IQ ・・・・・・・・・・・・ Copper compound represented by [V) is subjected to a conjugate addition reaction with an organocopper compound obtained from 6-2) P prostaglandin F represented by the following formula (Il) is obtained by subjecting it to film removal, hydrolysis or salt production reaction as necessary, and then subjecting it to reduction reaction to obtain A method for producing 6-nitroprostaglandins F represented by the following formula [I] H 6-2) R prostaglandin F represented by (
a) Reacting with an acidic compound; (B) Reacting with a trivalent titanium compound or reacting with a valley falsification agent, and then subjecting it to a film-retaining reaction, hydrolysis reaction, or salt-forming reaction as necessary. A method for producing 6-oxoprostaglandin F represented by the following formula [■]. 10 Reacting 6-nitroprostaglandin F represented by the following formula (I) H with tributyltin hydride in the presence of a radical generator, and subjecting it to deprotection, hydrolysis, and salt-forming reactions as necessary. A method for producing prostaglandin F represented by the following formula [■] H , characterized by: